Pharmacotherapy: a pathophysiologic approach [6. ed] 9780071416139, 0-07-141613-7, 0-07-146392-5, 0-07-146393-3, 0-07-146394-1, 0-07-146390-9

Table of contents :
Content: SECTION 1:BASIC CONCEPTS - L. Michael Posey, Section Editor 1. Pharmacoeconomics: Principles, Methods and Appplications by Lisa A. Sanchez2. Health Outcomes and Quality of Life by Stephen Joel Coons3. Evidence-Based Medicine by Elaine Chiquette and L. Michael Posey4. Documentation of Pharmacy Services by George MacKinnon III and Neil J. MacKinnon5. Clinical Pharmacokinetics and Pharmacodynamics by Larry A. Bauer6. Pharmacogenetics by Y.W. Francis Lam and Larisa M. Cavallari7. Pediatrics by Milap C. Nahata and Carol Taketomo8. Geriatrics by Catherine Lindblad, Shelly L. Gray, David R.P. Guay, Emily R. Hajjar, Teresa C. McCarthy, and Joseph T. Hanlon9. Pharmacoepidemiology by Andy Stergachis and Thomas K. Hazlet10. Clinical Toxicology by Peter A. ChykaSECTION 2: CARDIOVASCULAR DISORDERS - Robert L. Talbert, Section Editor11. Cardiovascular Testing by Robert L. Talbert12. Cardiopulmonary Resuscitation by Jeffery F. Barletta13 Hypertension by Joseph J. Saseen and Barry L. Carter14. Heart Failure by Robert B. Parker, J. Herbert Patterson, and Julie A. Johnson15. Ischemic Heart Disease by by Robert L. Talbert16. Acute Coronary Syndromes by Sarah A. Spinler, and Simon de Denus17. Arrhythmias by Jerry L. Bauman and Marieke Dekkar Schoen18. Diastolic Heart Failure and the Cardiomyopathies by Jean M. Nappi and Michael R. Zile 19. Venous Thromboembolism by Stuart T. Haines, Mario Zeolla and Dan M. Witt20. Stroke by Susan Fagan and Daniel C. Hess21. Hyperlipidemia by Robert L. Talbert22. Peripheral Arterial Disease by Barbara J. Hoeben and Robert L. Talbert23. Use of Vasopressors and Inotropes in Shock by Maria I. Rudis and Joseph F. Dasta24. Hypovolemic Shock by Brian L. ErstadSECTION 3: RESPIRATORY DISORDERS - Robert L. Talbert, Section Editor25. Pulmonary Function Testing by Jay I. Peters and Stephanie M. Levine26. Asthma by H. William Kelly and Christine A. Sorkness27. Chronic Obstructive Lung Disease by Sharya V. Bourdet28. Acute Respiratory Distress Syndrome by Peter Gal and J. Lawrence Ransome29. Drug-Induced Pulmonary Diseases by Hengameh H. Raissy, Michelle Harkins, and Patricia l. Marshik30. Cystic Fibrosis by Gary Milavetz and Jeffery J. SmithSECTION 4: GASTROINTESTINAL DISORDERS - Joseph T. DiPiro, Section Editor31. Evaluation of the Gastrointestinal Tract by Marie A. Chisholm and Mark W. Jackson32. Gastroesophageal Reflux Disease by Dianne B. Williams and Robert R. Schade33. Peptic Ulcer Disease by Rosemary R. Berardi and Lynda S. Welage34. Inflammatory Bowel Disease by Joseph T. DiPiro and Robert R. Schade35. Nausea and Vomiting by Cecily V. DiPiro and A. Thomas Taylor36. Diarrhea, Constipation and Irritable Bowel Syndrome by William J. Spruill and William E. Wade37. Portal Hypertension and Cirrhosis by Edward G. Timm and James J. Stragand38. Drug-Induced Liver Disease by William R. Kirchain and Mark A. Gil39. Pancreatitis by Rosemary R. Berardi and Patricia A. Montgomery40. Viral Hepatitis by Manjunath P. Pai, Renee-Claude Mercier, and Marsha A. RaebelSECTION 5: RENAL DISORDERS - Gary R. Matzke, Section Editor41. Quantification of Renal Function by Thomas C. Dowling42. Acute Renal Failure by Bruce A. Mueller43. Chronic Kidney Disease: Progression Modifying by Melanie S. Joy, Abhijit Kshirsagar, and James Paparello44. Chronic Kidney Disease: Therapeutic Approach for the Management of Complications by Joanna Hudson and Kunal Chaudhary45. Hemodialysis and Peritoneal Dialysis by Edward Foote and Rowland Elwell46. Drug-Induced Renal Disease by Thomas D. Nolin, Jonathan Himmelfarb, and Gary R. Matzke 47. Glomerulonephritis by Alan H. Lau48. Drug Therapy Individualization with Renal Insufficiency by Gary R. Matzke and Reginald F. Frye49. Disorders of Sodium, Water, Calcium, and Phosphorus Homeostasis by Melanie S. Joy and Gerald A. Hladik50. Disorders of Potassium and Magnesium Homeostasis by Donald F. Brophy and Todd W.B. Gehr 51. Acid-Base Disorders by Paul M. PalevskySECTION 6: NEUROLOGIC DISORDERS - Barbara G. Wells, Section Editor52. Evaluation of Neurologic Illness by Susan C. Fagan and Fenwick T. Nichols53. Multiple Sclerosis by Jacquelyn L. Bainbridge, John R. Corboy and Barry E. Gidal54. Epilepsy by Barry E. Gidal and William R. Garnett55. Status Epilepticus by Stephanie J. Phelps, Collin A. Hovinga and Bradley A. Boucher56. Acute Management of the Brain Injury Patient by Bradley A. Boucher, Stephanie J. Phelps, and Shelly D. Timmons57. Parkinson's Disease by Merlin V. Nelson, Richard C. Berchou and Peter A. LeWitt58. Pain Management by Terry L Baumann59. Headache Disorders Deborah S. King and Katherine C. HerndonSECTION 7: PSYCHIATRIC DISORDERS - Barbara G. Wells, Section Editor60. Evaluation of Psychiatric Illness by Patricia A. Marken, Mark E. Schneiderhan and Stuart Munro61. Childhood Disorders by Julie A. Dopheide, Karen A. Theesen and Michael Malkin62. Eating Disorders by Patricia A. Marken and Roger W. Sommi63. Alzheimer's Disease by Jenniofer D. Faulkner, Jody Bartlett and Paul Hicks64. Substance-related Disorders: Overview and Depressants, Stimulants, & Hallucinogens by Paul L. Doering65. Substance-related Disorders: Alcohol, Nicotine, & Caffeine by Paul L. Doering66. Schizophrenia by M. Lynn Crimson and Peter F. Buckley67. Depressive Disorders by Judith Kando, Barbara G. Wells and Peggy E. Hayes68. Bipolar Disorder by Martha P. Fankhauser and Marlene P. Freeman69. Anxiety Disorders: Generalized Anxiety Disorder, Panic, and Social Anxiety Disorders by Cynthis K. Kirkwood70. Anxiety Disorders: Obsessive-Compulsive Disorder and Post-traumatic Stress Disorder by Cynthia K. Kirkwood, Eugene H. Makela, Barbara G. Wells, and Peggy E. Hayes71. Sleep Disorders by Cherry W. Jackson, and Judy L. CurtisSECTION 8: ENDOCRINOLOGIC DISORDERS - Robert L. Talbert, Section Editor72. Diabetes Mellitus by Curtis L. Triplitt, Charles A. Reasner and William L. Isley73. Thyroid Disorders by Robert L. Talbert74. Adrenal Gland Disorders by John G. Gums and John M. Tovar75. Pituitary Gland Disorders by Amy M. Heck, Jack A. Yanovski and Karim Anton CalisSECTION 9: GYNECOLOGIC AND OBSTETRIC DISORDERS - Barbara G. Wells, Section Editor76. Pregnancy and Lactation: Therapeutic Considerations by Denise L. Walbrandt Pigarelli, Connie K. Kraus and Beth E. Potter77. Contraception by Lori M. Dickerson and Kathryn K. Bucci78. Menstruation-Related Disorders by Martha P. Fankhauser and Marlene P. Freeman79. Endometriosis by Deborah A. Sturpe and Alkesh D. Patel80. Hormone Replacement Therapy in Women by Sophia N. Kalantaridou, Susan R. Davis and Karim Anton Calis SECTION 10: UROLOGIC DISORDERS - L. Michael Posey, Section Editor81. Erectile Dysfunction by Mary Lee82. Management of Benign Prostatic Hyperplasia by Mary Lee83. Urinary Incontinence by Eric S. Rovner, Jean Wyman, Thomas Lackner and David R.P. GuaySECTION 11: IMMUNOLOGIC DISORDERS - Gary C. Yee, Section Editor84. Function and Evaluation of the Immune System by Phillip D. Hall and Mary S. Hayney85. Systemic Lupus Erythematosus and Other Collagen-Vascular Diseases by Jeffrey C. Delafuente and Kimberly A. Cappuzzo86. Allergic and Pseudoallergic Drug Reactions by Joseph T. DiPirop and Dennis Ownby87. Solid Organ Transplantation by Heather J. Johnson and Kristine S. SchonderSECTION 12: BONE AND JOINT DISORDERS - L. Michael Posey, Section Editor88. Osteoporosis and Osteomalacia by Mary Beth O'Connell and Terry L. Seaton89. Rheumatoid Arthritis by Arthur A. Schuna90. Osteoarthritis by Mary Elizabeth Elliott and Mary E. Elliott91. Gout and Hyperuricemia by David W. Hawkins and Daniel RahnSECTION 13: DISORDERS OF THE EYES, EARS, NOSE, AND THROAT - L. Michael Posey, Section Editor92. Glaucoma by Timothy S. Lesar, Richard G. Fiscella ande Deepak Edward93. Allergic Rhinitis by J. Russell May and Philip H. SmithSECTION 14: DERMATOLOGIC DISORDERS - L. Michael Posey, Section Editor94.Dermatologic Drug Reactions and Self-Treatable Skin Disorders and Skin Cancer by Nina H. Cheigh 95. Acne Vulgaris by Dennis West, Lee E. West, Marcia Letizia Musumeci and Giuseppe Micali96. Psoriasis by Dennis P. West, Lee E. West, Laura Scuderi and Giuseppe Micale97. Atopic Dermatitis by Nina H. CheighSECTION 15: HEMATOLOGIC DISORDERS - Gary C. Yee, Section Editor98. Hematopoiesis by William P. Petros and Solveig Ericson99. Anemias by Beata Ineck, Barbara J. Mason and E. Gregory Thompson100. Coagulation Disorders by Betsy M. Bickert and Janet L. Kwiatkowski101. Sickle Cell Disease by C.Y. Jennifer Chan and Reginald Moore102. Drug-Induced Hematologic Disorders by Thomas E. JohnsSECTION 16: INFECTIOUS DISEASES - Joseph T. DiPiro, Section Editor103. Laboratory Tests to Direct Antimicrobial Pharmacotherapy by Michael J. Rybak and Jeffrey R. Aeschlimann104. Antimicrobial Regimen Selection by David S. Burgess and Betty J. Abate105. Central Nervous System Infections by Elizabeth D. Hermsen and John C. Rotschafer106. Lower Respiratory Tract Infections by Mark L. Glover and Michael D. Read107. Upper Respiratory Tract Infections by Yasmin Khaliq, Sarah Forgie and George Zhanel108. Skin and Soft Tissue Infections by Susan L. Pendland, Douglas N. Fish and Larry H. Danziger109. Infective Endocarditis by Michael A. Crouch and Angie Ververka110. Tuberculosis by Charles A. Peloquin111. Gastrointestinal Infections and Enterotoxigenic Poisonings by Steven J. Martin and Rose Jung112. Intra-abdominal Infections by Joseph T. DiPiro and Thomas R. Howdieshell113. Parasitic Diseases by JV Anandan114. Urinary Tract Infections and Prostatitis by Elizabeth A. Coyle and Randall A. Prince115. Sexually Transmitted Diseases by Leroy C. Knodel116. Bone and Joint Infections by Edward P. Armstrong and Leslie L Barton117. Sepsis and Septic Shock by S. Lena Kang-Birken and Joseph T. DiPiro118. Superficial Fungal Infections by Thomas E.R. Brown and Thomas W.F. Chin119. Invasive Fungal Infections by Peggy L. Carver120. Infections in Immunocompromised Patients by Douglas N. Fish121. Antimicrobial Prophylaxis in Surgery Salmaan Kanji and John W. Devlin122. Vaccines, Toxoids, and Other Immunobiologics by Mary S. Hayney123. Human Immundeficiency Virus Infection by Countney V. Fletcher and Thomas N. KakudaSECTION 17: ONCOLOGIC DISORDERS - Gary C. Yee, Section Editor124. Cancer Treatment and Chemotherapy by Carol McManus Balmer and Amy Wells Valley125. Breast Cancer by Celeste Lindley126. Lung Cancer by Rebecca S. Finley and Jeannine S. McCune127. Colorectal Cancer by Lisa E. Davis128. Prostate Cancer by Jill M. Kolesar129. Malignant Lymphomas by Val R. Adams and Gary C. Yee130. Ovarian Cancer by William C. Zamboni, Laura J. Jung and Margaret E. Tonda131. Acute Leukemias by Helen L. Leather and Betsy Birkert132. Chronic Leukemias by Timothy R. McGuire and Steven Z. Pavletic133. Melanoma by Rowenta N. Schwartz134. Hematopoietic Stem Cell Transplantation by Janelle B. Perkins and Gary C. YeeSECTION 18: NUTRITIONAL DISORDERS - Gary C. Matzke, Section Editor135. Assessment of Nutrition Status and Requirements by Katherine Hammond Chessman and Vanessa J. Kumpf136. Prevalence and Significance of Malnutrition by Gordon Sacks and Pamela D. Reiter137. Parenteral Nutrition by Todd W. Mattox and Pamela D. Reiter138. Enteral Nutrition by Vanessa J. Kumpf and Katherine Hammond Chessman139. Nutrition in Major Organ Failure by Renee M. DeHart and Sunshine J. Yocum140. Obesity by John V. St. Peter and Mehmood A. Khan

Citation preview

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Sixth Edition

PHARMACOTHERAPY A Pathophysiologic Approach

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Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The editors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the editors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

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Sixth Edition

PHARMACOTHERAPY A Pathophysiologic Approach

Editors Joseph T. DiPiro, PharmD, FCCP Professor and Executive Dean, South Carolina College of Pharmacy, University of South Carolina, Columbia, and Medical University of South Carolina, Charleston Robert L. Talbert, PharmD, FCCP, BCPS Professor, College of Pharmacy, University of Texas at Austin; Professor, Departments of Medicine and Pharmacology, University of Texas Health Science Center at San Antonio, Texas Gary C. Yee, PharmD, FCCP Professor and Chair, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska Gary R. Matzke, PharmD, FCP, FCCP Professor, Department of Pharmacy and Therapeutics, School of Pharmacy, Renal-Electrolyte Division, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania Barbara G. Wells, PharmD, FASHP, FCCP, BCPP Dean and Professor, School of Pharmacy, The University of Mississippi, University, Mississippi L. Michael Posey, BS Pharm President, PENS Pharmacy Editorial and News Services, Athens, Georgia

MCGRAW-HILL Medical Publishing Division New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto

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Pharmacotherapy: A Pathophysiologic Approach, Sixth Edition C 2005, 2002 by The McGraw-Hill Companies, Inc. All rights Copyright
reserved. Printed in the United States of America. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. C 1999, 1997, 1993 by Appleton & Lange. Previous editions copyright


1 2 3 4 5 6 7 8 9 0 DOWDOW 0 9 8 7 6 5 Set ISBN 0-07-141613-7 Book p/n 0-07-146392-5 E-book download access card p/n 0-07-146393-3 and sticker p/n 0-07-146394-1 E-book ISBN 0-07-146390-9 This book is sold with codes for access to an Online Learning Center and an e-book version of the text. This book is not returnable unless the shrink-wrap and the scratch-off coating on the codes are intact. Please tell the authors and publisher what you think of this book by sending your comments to [email protected]. Please put the author and title of the book in subject line. This book was set in Times Roman by TechBooks, Inc. The editors were Michael Brown, Andrew Hall, Karen G. Edmonson, and Peter J. Boyle. The production supervisor was Richard Ruzycka. The text designer was Joan O’Connor. The cover designer was Elizabeth Pisacreta. Barbara Littlewood prepared the index. RR Donnelley was printer and binder. This book is printed on acid-free paper. C 1999 by Obi-Tabot Tabe. The images used on the Cover images copyright
cover and spine are taken from a 9 × 4-1/2 oil painting by Obi-Tabot Tabe, PharmD, a painter, graphic designer, scientific illustrator, and pharmacist. Dr. Tabe, originally from Cameroon, is a graduate of the University of Pittsburgh, School of Pharmacy. The painting incorporates the artist’s impressions of concepts introduced in the pharmacy curriculum. The painting can be seen in the student lounge of Salk Hall at the university.

Cataloging-in-publication data is on file for this title at the Library of Congress.

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Dedication To those pharmacists who had the courage and perseverance to pioneer the development of the clinical practice of pharmacy.

To the contemporary pharmaceutical care practitioners who continue to expand their impact on patient outcomes and thereby serve as role models for their colleagues and students while clinging tenaciously to the highest standards of practice.

To our mentors, whose vision provided educational and training programs that encouraged our professional growth and challenged us to be innovators in our patient care, research, and educational endeavors.

To our faculty colleagues for their efforts and support for our mission to provide a comprehensive and challenging educational foundation for the clinical pharmacists of the future.

And finally to our families for the time that they have sacrificed so that this sixth edition would become a reality.

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CONTENTS

.....................................................................................................................................................................................................................................

Foreword . . . . . . . . . . . . . . . . . . . . . xv

9.

Pharmacoepidemiology . . . . . . . . . . 115 Andy Stergachis Thomas K. Hazlet

10.

Clinical Toxicology . . . . . . . . . . . . 125 Peter A. Chyka

Foreword to the First Edition . . . . . . . . . . . xvii Preface . . . . . . . . . . . . . . . . . . . . . . xix Contributors . . . . . . . . . . . . . . . . . . . xxi Guiding Principles of Pharmacotherapy . . . . . xxxiii

SECTION 2. CARDIOVASCULAR DISORDERS . . . . . . . . . . . 149 Robert L. Talbert, Section Editor

SECTION 1: BASIC CONCEPTS . . . . . . . . . 1 L. Michael Posey, Section Editor

1.

2.

3.

4.

5.

6.

7.

8.

11.

Cardiovascular Testing . . . . . . . . . . . 149 Robert L. Talbert

12.

Cardiopulmonary Resuscitation. . . . . . . 171 Jeffrey F. Barletta

Health Outcomes and Quality of Life . . . . 17 Stephen Joel Coons

13.

Evidence-Based Medicine . . . . . . . . . . 27 Elaine Chiquette L. Michael Posey

Hypertension . . . . . . . . . . . . . . . 185 Joseph J. Saseen Barry L. Carter

14.

Documentation of Pharmacy Services . . . . . . . . . . . . . . . . . . 39 George E. MacKinnon, III Neil J. MacKinnon

Heart Failure. . . . . . . . . . . . . . . . 219 Robert B. Parker J. Herbert Patterson Julie A. Johnson

15.

Ischemic Heart Disease . . . . . . . . . . 261 Robert L. Talbert

16.

Acute Coronary Syndromes . . . . . . . . 291 Sarah A. Spinler Simon de Denus

17.

Arrhythmias . . . . . . . . . . . . . . . . 321 Jerry L. Bauman Marieke Dekker Schoen

18.

Diastolic Heart Failure and the Cardiomyopathies . . . . . . . . . . . 357 Jean M. Nappi Michael R. Zile

19.

Venous Thromboembolism . . . . . . . . . 373 Stuart T. Haines Mario Zeolla Daniel M. Witt

Pharmacoeconomics: Principles, Methods, and Applications . . . . . . . . . . . . . . . 1 Lisa A. Sanchez

Clinical Pharmacokinetics and Pharmacodynamics . . . . . . . . . . . 51 Larry A. Bauer Pharmacogenetics . . . . . . . . . . . . . . 75 Larisa H. Cavallari Y. W. Francis Lam Pediatrics . . . . . . . . . . . . . . . . . . 91 Milap C. Nahata Carol Taketomo Geriatrics . . . . . . . . . . . . . . . . . 103 Catherine I. Lindblad Shelly L. Gray David R. P. Guay Emily R. Hajjar Teresa C. McCarthy Joseph T. Hanlon

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20.

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CONTENTS

Stroke . . . . . . . . . . . . . . . . . . . 415 Susan C. Fagan David C. Hess

21.

Hyperlipidemia . . . . . . . . . . . . . . 429 Robert L. Talbert

22.

Peripheral Arterial Disease . . . . . . . . . 453 Barbara J. Hoeben Robert L. Talbert

23.

24.

Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock . . . . . . . . . 461 Maria I. Rudis Joseph F. Dasta Hypovolemic Shock . . . . . . . . . . . . 479 Brian L. Erstad

SECTION 4. GASTROINTESTINAL DISORDERS . . . . . . . . . . . 605 Joseph T. DiPiro, Section Editor

31.

Evaluation of the Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . 605 Marie A. Chisholm Mark W. Jackson

32.

Gastroesophageal Reflux Disease . . . . . . 613 Dianne B. Williams Robert R. Schade

33.

Peptic Ulcer Disease . . . . . . . . . . . . 629 Rosemary R. Berardi Lynda S. Welage

34.

Inflammatory Bowel Disease . . . . . . . . 649 Joseph T. DiPiro Robert R. Schade

35.

Nausea and Vomiting. . . . . . . . . . . . 665 Cecily V. DiPiro A. Thomas Taylor

36.

Diarrhea, Constipation, and Irritable Bowel Syndrome. . . . . . . . . . . . . . 677 William J. Spruill William E. Wade

37.

Portal Hypertension and Cirrhosis . . . . . 693 Edward G. Timm James J. Stragand

38.

Drug-Induced Liver Disease . . . . . . . . 713 William R. Kirchain Mark A. Gil

39.

Pancreatitis . . . . . . . . . . . . . . . . 721 Rosemary R. Berardi Patricia A. Montgomery

40.

Viral Hepatitis . . . . . . . . . . . . . . . 737 Manjunath P. Pai Renee-Claude Mercier Marsha A. Raebel

SECTION 3. RESPIRATORY DISORDERS . . . . . . . . . . . 495 Robert L. Talbert, Section Editor

25.

26.

Introduction to Pulmonary Function Testing . . . . . . . . . . . . . . . . . . 495 Jay I. Peters Stephanie M. Levine Asthma . . . . . . . . . . . . . . . . . . 503 H. William Kelly Christine A. Sorkness

27.

Chronic Obstructive Pulmonary Disease . . 537 Sharya V. Bourdet Dennis M. Williams

28.

Acute Respiratory Distress Syndrome. . . . 557 Peter Gal J. Laurence Ransom

29.

Drug-Induced Pulmonary Diseases . . . . . 577 Hengameh H. Raissy Michelle Harkins Patricia L. Marshik

30.

Cystic Fibrosis . . . . . . . . . . . . . . . 591 Gary Milavetz Jeffrey J. Smith

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SECTION 5. RENAL DISORDERS . . . . . . . 761

51.

Gary R. Matzke, Section Editor

41.

Quantification of Renal Function . . . . . . 761 Thomas C. Dowling Thomas J. Comstock

ix

Acid-Base Disorders . . . . . . . . . . . . 983 Gary R. Matzke Paul M. Palevsky

SECTION 6. NEUROLOGIC DISORDERS . . 1003 Barbara G. Wells, Section Editor

42.

Acute Renal Failure . . . . . . . . . . . . 781 Bruce A. Mueller

43.

Chronic Kidney Disease: ProgressionModifying Therapies . . . . . . . . . . . . 799 Melanie S. Joy Abhijit Kshirsagar James Paparello

44.

45.

46.

Chronic Kidney Disease: Therapeutic Approach for the Management of Complications . . . . . . . . . . . . . . . 821 Joanna Q. Hudson Kunal Chaudhary Hemodialysis and Peritoneal Dialysis . . . . 851 Rowland J. Elwell Edward F. Foote Drug-Induced Kidney Disease . . . . . . . 871 Thomas D. Nolin Jonathan Himmelfarb Gary R. Matzke

47.

Glomerulonephritis . . . . . . . . . . . . 891 Alan H. Lau

48.

Drug Therapy Individualization for Patients with Renal Insufficiency . . . . . . . . . . 919 Reginald F. Frye Gary R. Matzke

49.

50.

Disorders of Sodium, Water, Calcium, and Phosphorus Homeostasis . . . . . . . . . . 937 Melanie S. Joy Gerald A. Hladik Disorders of Potassium and Magnesium Homeostasis . . . . . . . . . . . . . . . . 967 Donald F. Brophy Todd W. B. Gehr

52.

Evaluation of Neurologic Illness. . . . . . 1003 Susan C. Fagan Fenwick T. Nichols

53.

Multiple Sclerosis . . . . . . . . . . . . 1007 Jacquelyn L. Bainbridge John R. Corboy

54.

Epilepsy . . . . . . . . . . . . . . . . . 1023 Barry E. Gidal William R. Garnett

55.

Status Epilepticus . . . . . . . . . . . . . 1049 Stephanie J. Phelps Collin A. Hovinga Bradley A. Boucher

56.

Acute Management of the Brain Injury Patient . . . . . . . . . . . . . . . . . . 1061 Bradley A. Boucher Stephanie J. Phelps Shelly D. Timmons

57.

Parkinson’s Disease . . . . . . . . . . . . 1075 Merlin V. Nelson Richard C. Berchou Peter A. LeWitt

58.

Pain Management. . . . . . . . . . . . . 1089 Terry J. Baumann

59.

Headache Disorders. . . . . . . . . . . . 1105 Deborah S. King Katherine C. Herndon

SECTION 7. PSYCHIATRIC DISORDERS . . 1123 Barbara G. Wells, Section Editor

60.

Evaluation of Psychiatric Illness . . . . . . 1123 Patricia A. Marken Mark E. Schneiderhan Stuart Munro

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CONTENTS

61.

Childhood Disorders . . . . . . . . . . . 1133 Julie A. Dopheide Karen A. Theesen Michael Malkin

62.

Eating Disorders . . . . . . . . . . . . . 1147 Patricia A. Marken Roger W. Sommi

63.

Alzheimer’s Disease . . . . . . . . . . . 1157 Jennifer D. Faulkner Jody Bartlett Paul Hicks

64.

Substance-Related Disorders: Overview and Depressants, Stimulants, and Hallucinogens . . . . . . . . . . . . . . 1175 Paul L. Doering

65.

Substance-Related Disorders: Alcohol, Nicotine, and Caffeine . . . . . . . . . . 1193 Paul L. Doering

66.

Schizophrenia . . . . . . . . . . . . . . 1209 M. Lynn Crismon Peter F. Buckley

SECTION 8. ENDOCRINOLOGIC DISORDERS . . . . . . . . . . . 1333 Robert L. Talbert, Section Editor

72.

Diabetes Mellitus . . . . . . . . . . . . . 1333 Curtis L. Triplitt Charles A. Reasner William L. Isley

73.

Thyroid Disorders . . . . . . . . . . . . 1369 Robert L. Talbert

74.

Adrenal Gland Disorders . . . . . . . . . 1391 John G. Gums John M. Tovar

75.

Pituitary Gland Disorders . . . . . . . . . 1407 Amy M. Heck Jack A. Yanovski Karim Anton Calis

SECTION 9. GYNECOLOGIC AND OBSTETRIC DISORDERS . . . 1425 Barbara G. Wells, Section Editor

67.

68.

69.

70.

71.

Depressive Disorders . . . . . . . . . . . 1235 Judith C. Kando Barbara G. Wells Peggy E. Hayes Bipolar Disorder . . . . . . . . . . . . . 1257 Martha P. Fankhauser Marlene P. Freeman Anxiety Disorders I: Generalized Anxiety, Panic, and Social Anxiety Disorders . . . . 1285 Cynthia K. Kirkwood Sarah T. Melton Anxiety Disorders II: Posttraumatic Stress Disorder and Obsessive-Compulsive Disorder . . . . . . . . . . . . . . . . . 1307 Cynthia K. Kirkwood Eugene H. Makela Barbara G. Wells Sleep Disorders . . . . . . . . . . . . . . 1321 Cherry W. Jackson Judy L. Curtis

76.

Pregnancy and Lactation: Therapeutic Considerations . . . . . . . . . . . . . . 1425 Denise L. Walbrandt Pigarelli Connie K. Kraus Beth E. Potter

77.

Contraception . . . . . . . . . . . . . . 1443 Lori M. Dickerson Kathryn K. Bucci

78.

Menstruation-Related Disorders . . . . . . 1465 Martha P. Fankhauser Marlene P. Freeman

79.

Endometriosis . . . . . . . . . . . . . . 1485 Deborah A. Sturpe Alkesh D. Patel

80.

Hormone Therapy in Women . . . . . . . 1493 Sophia N. Kalantaridou Susan R. Davis Karim Anton Calis

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SECTION 10. UROLOGIC DISORDERS . . . 1515

89.

Rheumatoid Arthritis . . . . . . . . . . . 1671 Arthur A. Schuna

90.

Osteoarthritis . . . . . . . . . . . . . . . 1685 Karen E. Hansen Mary Elizabeth Elliott

91.

Gout and Hyperuricemia . . . . . . . . . 1705 David W. Hawkins Daniel W. Rahn

L. Michael Posey, Section Editor

81.

Erectile Dysfunction . . . . . . . . . . . 1515 Mary Lee

82.

Management of Benign Prostatic Hyperplasia . . . . . . . . . . . . . . . 1535 Mary Lee

83.

Urinary Incontinence . . . . . . . . . . . 1547 Eric S. Rovner Jean Wyman Thomas Lackner David Guay

SECTION 13. DISORDERS OF THE EYES, EARS, NOSE, AND THROAT . . . . . . . . . 1713 L. Michael Posey, Section Editor

92.

Glaucoma . . . . . . . . . . . . . . . . 1713 Timothy S. Lesar Richard G. Fiscella Deepak Edward

93.

Allergic Rhinitis . . . . . . . . . . . . . 1729 J. Russell May Philip H. Smith

SECTION 11. IMMUNOLOGIC DISORDERS . . . . . . . . . . 1565 Gary C. Yee, Section Editor

84.

Function and Evaluation of the Immune System . . . . . . . . . . . . . . . . . . 1565 Philip D. Hall Mary S. Hayney

85.

Systemic Lupus Erythematosus and Other Collagen-Vascular Diseases . . . . . . . . 1581 Jeffrey C. Delafuente Kimberly A. Cappuzzo

86.

87.

Allergic and Pseudoallergic Drug Reactions. . . . . . . . . . . . . . . . . 1599 Joseph T. DiPiro Dennis R. Ownby

SECTION 14. DERMATOLOGIC DISORDERS . . . . . . . . . . 1741 L. Michael Posey, Section Editor

94.

Dermatologic Drug Reactions, Self-Treatable Skin Disorders, and Skin Cancer . . . . . . . . . . . . . . . . . . 1741 Nina H. Cheigh

95.

Acne Vulgaris . . . . . . . . . . . . . . 1755 Dennis P. West Lee E. West Maria Letizia Musumeci Giuseppe Micali

96.

Psoriasis . . . . . . . . . . . . . . . . . 1769 Dennis P. West Lee E. West Laura Scuderi Giuseppe Micali

97.

Atopic Dermatitis . . . . . . . . . . . . . 1785 Nina H. Cheigh

Solid-Organ Transplantation . . . . . . . 1613 Heather J. Johnson Kristine S. Schonder

SECTION 12. BONE AND JOINT DISORDERS . . . . . . . . . . 1645 L. Michael Posey, Section Editor

88.

Osteoporosis and Osteomalacia . . . . . . 1645 Mary Beth O’Connell Terry L. Seaton

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SECTION 15. HEMATOLOGIC DISORDERS . . . . . . . . . . 1793

108.

Skin and Soft Tissue Infections . . . . . . 1977 Susan L. Pendland Douglas N. Fish Larry H. Danziger

109.

Infective Endocarditis . . . . . . . . . . . 1997 Michael A. Crouch Angie Veverka

110.

Tuberculosis . . . . . . . . . . . . . . . 2015 Charles A. Peloquin

111.

Gastrointestinal Infections and Enterotoxigenic Poisonings . . . . . . . . 2035 Steven Martin Rose Jung

Gary C. Yee, Section Editor

98.

99.

Hematopoiesis . . . . . . . . . . . . . . 1793 William P. Petros Solveig Ericson Anemias . . . . . . . . . . . . . . . . . 1805 Beata Ineck Barbara J. Mason E. Gregory Thompson

100.

Coagulation Disorders . . . . . . . . . . 1833 Betsy Bickert Janet L. Kwiatkowski

101.

Sickle Cell Disease . . . . . . . . . . . . 1855 C. Y. Jennifer Chan Reginald Moore

112.

Intraabdominal Infections . . . . . . . . . 2055 Joseph T. DiPiro Thomas R. Howdieshell

102.

Drug-Induced Hematologic Disorders . . . 1875 S. Jay Weaver Thomas E. Johns

113.

Parasitic Diseases . . . . . . . . . . . . . 2067 JV Anandan

114.

Urinary Tract Infections and Prostatitis . . 2081 Elizabeth A. Coyle Randall A. Prince

115.

Sexually Transmitted Diseases . . . . . . 2097 Leroy C. Knodel

116.

Antimicrobial Regimen Selection . . . . . 1909 David S. Burgess Betty J. Abate

Bone and Joint Infections . . . . . . . . . 2119 Edward P. Armstrong Leslie L. Barton

117.

Central Nervous System Infections . . . . 1923 Elizabeth D. Hermsen John C. Rotschafer

Sepsis and Septic Shock . . . . . . . . . 2131 S. Lena Kang-Birken Joseph T. DiPiro

118.

Superficial Fungal Infections . . . . . . . 2145 Thomas E. R. Brown Thomas W. F. Chin

Lower Respiratory Tract Infections . . . . 1943 Mark L. Glover Michael D. Reed

119.

Invasive Fungal Infections. . . . . . . . . 2161 Peggy L. Carver

120.

Infections in Immunocompromised Patients. . . . . . . . . . . . . . . . . . 2191 Douglas N. Fish S. Diane Goodwin

SECTION 16. INFECTIOUS DISEASES . . . 1891 Joseph T. DiPiro, Section Editor

103.

104.

105.

106.

107.

Laboratory Tests to Direct Antimicrobial Pharmacotherapy . . . . . . . . . . . . . 1891 Michael J. Rybak Jeffrey R. Aeschlimann

Upper Respiratory Tract Infections . . . . 1963 Yasmin Khaliq Sarah Forgie George Zhanel

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121.

Antimicrobial Prophylaxis in Surgery . . . 2217 Salmaan Kanji John W. Devlin

132.

Chronic Leukemias . . . . . . . . . . . . 2513 Timothy R. McGuire Steven Z. Pavletic

122.

Vaccines, Toxoids, and Other Immunobiologics . . . . . . . . . . . . . 2231 Mary S. Hayney

133.

Melanoma . . . . . . . . . . . . . . . . 2525 Rowena N. Schwartz

134.

Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . 2541 Janelle B. Perkins Gary C. Yee

123.

Human Immunodeficiency Virus Infection . . . . . . . . . . . . . . . . . 2255 Courtney V. Fletcher Thomas N. Kakuda

SECTION 17. ONCOLOGIC DISORDERS . . 2279 Gary C. Yee, Section Editor

SECTION 18. NUTRITIONAL DISORDERS . . . . . . . . . . 2559 Gary R. Matzke, Section Editor

124.

Cancer Treatment and Chemotherapy . . . 2279 Carol McManus Balmer Amy Wells Valley Andrea Iannucci

135.

Assessment of Nutrition Status and Nutrition Requirements . . . . . . . . . . 2559 Katherine Hammond Chessman Vanessa J. Kumpf

125.

Breast Cancer . . . . . . . . . . . . . . 2329 Celeste Lindley Laura Boehnke Michaud

136.

Prevalence and Significance of Malnutrition . . . . . . . . . . . . . . . 2579 Gordon Sacks Pamela D. Reiter

126.

Lung Cancer . . . . . . . . . . . . . . . 2365 Rebecca S. Finley Jeannine S. McCune

137.

Parenteral Nutrition . . . . . . . . . . . . 2591 Todd W. Mattox Pamela D. Reiter

127.

Colorectal Cancer. . . . . . . . . . . . . 2383 Patrick J. Medina Lisa E. Davis

138.

Enteral Nutrition . . . . . . . . . . . . . 2615 Vanessa J. Kumpf Katherine Hammond Chessman

128.

Prostate Cancer . . . . . . . . . . . . . . 2421 Jill M. Kolesar

139.

129.

Lymphomas . . . . . . . . . . . . . . . 2439 Val R. Adams Gary C. Yee

Nutritional Considerations in Major Organ Failure . . . . . . . . . . . 2635 Renee M. DeHart Sunshine J. Yocum

140.

Ovarian Cancer . . . . . . . . . . . . . . 2467 William C. Zamboni Laura L. Jung Margaret E. Tonda

Obesity. . . . . . . . . . . . . . . . . . 2659 John V. St. Peter Mehmood A. Khan

Glossary . . . . . . . . . . . . . . . . . . . . 2677

130.

131.

Acute Leukemias . . . . . . . . . . . . . 2485 Helen L. Leather Betsy Bickert

Index . . . . . . . . . . . . . . . . . . . . . . 2695 Color plates appear between pages 1740 and 1741.

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FOREWORD

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Drug therapy often represents the best treatment for human diseases and illnesses, and the spectrum of effective medications continues to improve at a remarkable pace. This is likely to continue over the coming years, as our understanding of disease pathogenesis and molecular pharmacology rapidly expands, fueling the discovery of new classes of medication. This, coupled with impressive advances in technology and our understanding of the human genome, promises to usher in a new wave of targeted therapies and individualized medicine that may further improve the efficacy and reduce the toxicity of medications. However, most of the highly effective medications currently available for clinical use emerged from classical pharmacology and chemistry, on a foundation of incomplete knowledge of disease mechanisms. This may contribute in part to the propensity of many medications to produce adverse drug effects or to exhibit limited efficacy in a subset of patients with a given diagnosis. These imperfect medications will remain the mainstay of therapeutics for years to come. The limited efficacy and potential toxicity of many of today’s medications, coupled with the rapidly expanding portfolio of medications for disease treatment and prevention, creates enormous complexity in selecting optimal medications for individual patients. Thus, the expertise of clinically educated and trained pharmacists is increasingly important if we are to ensure patients receive the most effective medications in the doses and combinations that are optimal for them and their illnesses. The sixth edition of Pharmacotherapy: A Pathophysiologic Approach contains a wealth of information that will be an invaluable resource to students and practitioners who work to expand their knowledge of pharmacotherapy and translate it into better drug therapy for individual patients. In a perfect world, every patient would benefit from the collective talents of a health care team that is fully able to integrate knowledge of disease pathogenesis and pharmacotherapy, thereby optimizing drug therapy for each individual. Such a team is incomplete without a clinical pharmacist. How many clinical pharmacists does it take in this day and age? Can one justify 25 pharmacists for a 58-bed hospital? That’s the reality at St. Jude Children’s Research Hospital, where I have worked for the last 25 years. And this wasn’t even seriously challenged when the “health care consultants” rolled into town 10 years ago. Why not? The reasons are multiple, yet simple in the end: Pharmacists are integrally involved in the pharmacotherapy of every patient. The medical staff would not have it any other way, and the patients deserve no less. That’s as it should be everywhere, in hospitals and clinics and community pharmacies. Moreover, pharmacists have become integral to the process of defining the future state of pharmacotherapy, by bringing unique expertise to the research enterprise. That must continue as well. The pharmacists of the present and future must integrate pharmacology, pathophysiology, therapeutics, and, increasingly, genetics into complex treatment decisions. Pharmacotherapy: A Pathophysiologic Approach is an important tool to this end. By providing pharmacy students and practicing pharmacists (plus physicians and nurses) with a comprehensive and definitive source of information about diseases and their drug treatment, it is a conduit to the clinical use of pharmacotherapeutic principles by pharmacists, which is the sine qua non of pharmacy practice in the twenty-first century. Health care in the United States and other developed countries has made great progress in recent decades, yet there are many opportu-

nities to improve the way these advances are deployed, especially drug therapy. Studies have shown that even when there are clear guidelines for appropriate use of medications for specific diseases, too many patients receive suboptimal drug therapy for too long. This is caused in part by far more drug therapy choices than most clinicians can master and also by aggressive marketing—to physicians, pharmacists, and directly to consumers—which can inappropriately shape prescribing habits. Who is to intervene in the name of rational therapeutics? The well-armed pharmacist, for one! Reality is even more alarming when one also considers adverse drug effects. A 2000 Institute of Medicine (IOM) report documented that adverse drug effects are common in the United States, representing the sixth leading cause of death according to published metaanalyses. This is staggering news. Yet even if overstated by 100% it is an enormous concern for patients. Pharmacists must intervene and make definitive strides to reduce the adverse effects of medications, and they must be armed with pharmacotherapeutic knowledge and given time in their clinical practice to do so. This textbook serves as a source of such knowledge for those who are devoted to this end, whether they are matriculating toward their pharmacy degree or striving to advance their contributions in a busy clinical practice. A 2001 IOM report documented a substantial gap in health care between those who receive the best and those who receive the average in health care in the United States. Recent studies have also documented that when patients exceed their cap in prescription drug coverage, they often discontinue medications or take fewer doses of prescribed therapy, even when adverse consequences can result if chronic diseases are left untreated. The cost-consequences of inadequate prescription drug coverage may well exceed the cost-savings of capping or limiting prescription drug benefits. How might pharmacists change this equation for the better? Perhaps one approach would be to avoid the use of unnecessarily expensive medications when less expensive medications are equally effective. Another would be to help minimize the adverse economic and health care impact of adverse drug effects. The pages of this text are filled with information that could simultaneously translate into greater efficacy, lower toxicity, and more cost-effective use of medications. Pharmacists who translate this knowledge to everyday treatment decisions can play a vital role in showing not only that the best drug therapy can be safe and cost-effective, but that it does not always require the newest medication on the market. This will require a wealth of knowledge and determination by pharmacists, if they are to offset the power of marketing prescription drugs to prescribers and directly to the public. Pharmacotherapy: A Pathophysiologic Approach is a comprehensive scholarly effort by leading practitioners and educators who have created a definitive and unbiased resource that is based on a wealth of clinical experience and academic expertise. It offers a solid foundation for the education of future clinicians and for the practice of pharmacotherapy today, loaded with ammunition to fight the forces of irrational prescribing. William E. Evans, PharmD Professor of Pharmacy and Pediatrics University of Tennessee Colleges of Pharmacy and Medicine Director and CEO St. Jude Children’s Research Hospital Memphis, Tennessee xv

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FOREWORD TO THE FIRST EDITION

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Evidence of the maturity of a profession is not unlike that characterizing the maturity of an individual; a child’s utterances and behavior typically reveal an unrealized potential for attainment, eventually, of those attributes characteristic of an appropriately confident, independently competent, socially responsible, sensitive, and productive member of society. Within a period of perhaps 15 or 20 years, we have witnessed a profound maturation within the profession of pharmacy. The utterances of the profession, as projected in its literature, have evolved from mostly self-centered and self-serving issues of trade protection to a composite of expressed professional interests that prominently include responsible explorations of scientific/technological questions and ethical issues that promote the best interests of the clientele served by the profession. With the publication of Pharmacotherapy: A Pathophysiologic Approach, pharmacy’s utterances bespeak a matured practitioner who is able to call upon unique knowledge and skills so as to function as an appropriately confident, independently competent pharmacotherapeutics expert. In 1987, the Board of Pharmaceutical Specialties (BPS), in denying the petition filed by the American College of Clinical Pharmacy (ACCP) to recognize “clinical pharmacy” as a specialty, conceded nonetheless that the petitioning party had documented in its petition a specialist who does in fact exist within the practice of pharmacy and whose expertise clearly can be extricated from the performance characteristics of those in general practice. A refiled petition from ACCP requests recognition of “pharmacotherapy” as a Specialty Area of Pharmacy Practice. While the BPS had issued no decision when this book went to press, it is difficult to comprehend the basis for a rejection of the second petition. Within this book one will find the scientific foundation for the essential knowledge required of one who may aspire to specialty practice as a pharmacotherapist. As is the case with any such publication, its usefulness to the practitioner or the future practitioner is limited to providing such a foundation. To be socially and professionally responsible in practice, the pharmacotherapist’s foundation must be continually supplemented and complemented by the flow of information appearing in the primary literature. Of course this is not unique to the general or specialty practice of pharmacy; it is essential to the fulfillment of obligations to clients in any occupation operating under the code of professional ethics. Because of the growing complexity of pharmacotherapeutic agents, their dosing regimens, and techniques for delivery, pharmacy is obligated to produce, recognize, and remunerate specialty practitioners who can fulfill the profession’s responsibilities to society for service expertise where the competence required in a particular case exceeds that of the general practitioner. It simply is a component of our covenant with society and is as important as any other facet of that relationship existing between a profession and those it serves. The recognition by BPS of pharmacotherapy as an area of specialty practice in pharmacy will serve as an important statement by the profession that we have matured sufficiently to be competent and

willing to take unprecedented responsibilities in the collaborative, pharmacotherapeutic management of patient-specific problems. It commits pharmacy to an intention that will not be uniformly or rapidly accepted within the established health care community. Nonetheless, this formal action places us on the road to an avowed goal, and acceptance will be gained as the pharmacotherapists proliferate and establish their importance in the provision of optimal, cost-effective drug therapy. Suspecting that other professions in other times must have faced similar quests for recognition of their unique knowledge and skills I once searched the literature for an example that might parallel pharmacy’s modern-day aspirations. Writing in the Philadelphia Medical Journal, May 27, 1899, D. H. Galloway, MD, reflected on the need for specialty training and practice in a field of medicine lacking such expertise at that time. In an article entitled “The Anesthetizer as a Speciality,” Galloway commented: The anesthetizer will have to make his own place in medicine: the profession will not make a place for him, and not until he has demonstrated the value of his services will it concede him the position which the importance of his duties entitles him to occupy. He will be obliged to define his own rights, duties and privileges, and he must not expect that his own estimate of the importance of his position will be conceded without opposition. There are many surgeons who are unwilling to share either the credit or the emoluments of their work with anyone, and their opposition will be overcome only when they are shown that the importance of their work will not be lessened, but enhanced, by the increased safety and dispatch with which operations may be done. . . . It has been my experience that, given the opportunity for one-onone, collaborative practice with physicians and other health professionals, pharmacy practitioners who have been educated and trained to perform at the level of pharmacotherapeutics specialists almost invariably have convinced the former that “the importance of their work will not be lessened, but enhanced, by the increased safety and dispatch with which” individualized problems of drug therapy could be managed in collaboration with clinical pharmacy practitioners. It is fortuitous—the coinciding of the release of Pharmacotherapy: A Pathophysiologic Approach with ACCP’s petitioning of BPS for recognition of the pharmacotherapy specialist. The utterances of a maturing profession as revealed in the contents of this book, and the intraprofessional recognition and acceptance of a higher level of responsibility in the safe, effective, and economical use of drugs and drug products, bode well for the future of the profession and for the improvement of patient care with drugs. Charles A. Walton, PhD San Antonio, Texas

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PREFACE

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Pharmacists and other health care professionals who evaluate, design, and recommend pharmacotherapy for the management of their patients face many new and exciting challenges in these early years of the twenty-first century. As we complete our work on the sixth edition of Pharmacotherapy: A Pathophysiologic Approach, we recognize just how much our tasks as editors have become equally complicated, trying to balance the need to provide accurate, thorough, and unbiased information about the treatment of diseases against the hard publishing realities of deadlines, word counts, and book length. We thus strive to keep foremost in our minds the precepts that first led us to embark on this endeavor: r r r r

r

Advance the quality of patient care through optimal medication management based on sound pharmacotherapeutic principles. Stimulate the student to achieve higher levels of learning. Motivate young practitioners to enhance the breadth, depth, and quality of care they can provide to each of their patients. Challenge established pharmacists and other primary-care providers to learn the new concepts and refine their understanding of the basic tenets of pathophysiology and therapeutics. Inform the pharmacy and medical communities about the standards of medication therapy management toward which we all should strive and which all patients will one day expect and, yes, demand.

While our emphasis in past editions has been on how to incorporate diseases that were previously untreatable with pharmacologic agents, new features in this sixth edition are focused more on the realities of teaching entry-level doctor of pharmacy students and meeting their postgraduate needs. We have incorporated a number of new pedagogical devices into chapters that will enable students and practitioners to more quickly grasp the important concepts and find related passages in the text. The addition of more features to disease-oriented chapters and the inclusion of more design elements give this edition a striking new look: r

r

r

r

r r

Key concepts are listed at the beginning of each chapter and are identified in the text with numbered icons so that the reader can jump to the material of interest. The most common signs and symptoms of diseases as manifested in typical patients are presented in highlighted Clinical Presentation tables in disease-specific chapters. Clinical controversies in treatment or patient management are highlighted in shaded boxes to assure that the reader is aware of these issues and how practitioners are responding to them. Each chapter has about 100 of the most important and current references relevant to each disease, with most published since 1997. For easy reference, abbreviations and acronyms and their meanings are presented at the end of each chapter. A glossary of the medical terms used throughout the text is tabulated and presented at the end of the book.

r

Finally, the diagnostic flow diagrams, desired outcomes of treatment, dosing guidelines, monitoring approaches, and treatment algorithms that were present in the fifth edition have been refined.

This edition includes two new chapters: Documentation of Pharmacy Services, which addresses the critical need for pharmacists to record their medication therapy management interventions, and SolidOrgan Transplantation, which combines material that was previously spread throughout several organ-specific chapters. Before writing for this edition began, each editor read chapters from other editors’ sections and made suggestions for enhancement. During editing, we reviewed each passage of text—and the references cited—for continued relevance and accuracy. We made deletions, asked authors to summarize concepts more succinctly or use tables to present details more concisely, included new medications as they entered the U.S. market or emerged in other countries, and updated references. This process continued as the book entered production, and even during the review of final proofs, we continued to make changes to ensure that this book is as current and complete as is possible. Standard formats have remained relatively unchanged since the first edition of Pharmacotherapy. When seeking information in the disease-oriented chapters, users will find these sections: Key Concepts, Epidemiology, Etiology, Pathophysiology, Clinical Presentation (including diagnostic considerations), Treatment (including desired outcomes, general approaches, nonpharmacologic therapy, pharmacologic therapy, and pharmacoeconomic considerations), and Evaluation of Therapeutic Outcomes. As the world increasingly relies on electronic means of communication, we are committed to keeping Pharmacotherapy and its companion works, Pharmacotherapy Casebook: A Patient-Focused Approach and Pharmacotherapy Handbook, integral components of clinicians’ toolboxes. With the launch of this edition the Web site with unique features designed to benefit students, practitioners, and faculty that was initiated with the fifth edition has been extensively expanded. One can now find learning objectives and self-assessment questions for each chapter on the site. In closing, we also stop once again to acknowledge the many hours that Pharmacotherapy’s 200 authors contributed to this labor of love. Without their devotion to the cause of improved pharmacotherapy and dedication in maintaining the accuracy, clarity, and relevance of their chapters, this text would unquestionably not be possible. In addition, we thank Michael Brown and his colleagues at McGraw-Hill—especially Jack Farrell, Marty Wonsiewicz, and Peter Boyle—for their consistent support of the Pharmacotherapy family of resources, insights into trends in publishing and higher education, and the necessary and critical attention to detail so necessary in a book such as this one. The Editors March 2005

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CONTRIBUTORS

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Betty J. Abate, PharmD, BCPS Coordinator of Drug Information Services, Hurley Medical Center, Department of Pharmacy, Farmington Hills, Michigan Chapter 104

Larry A. Bauer, PharmD, FCP, FCCP Professor, Departments of Pharmacy and Laboratory Medicine, University of Washington, Seattle, Washington Chapter 5

Val R. Adams, PharmD Associate Professor, University of Kentucky College of Pharmacy, Oncology Clinical Specialist, Markey Cancer Center, Lexington, Kentucky Chapter 129

Jerry L. Bauman, PharmD, BCPS, FCCP, FACC Professor, Departments of Pharmacy Practice and Medicine, University of Illinois, Chicago, Illinois Chapter 17

Jeffrey R. Aeschlimann, PharmD Assistant Professor, Division of Infectious Diseases, University of Connecticut School of Pharmacy, Adjunct Assistant Professor of Medicine, University of Connecticut School of Medicine, Farmington, Connecticut Chapter 103 JV Anandan, PharmD, BCPS Adjunct Associate Professor, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University; Pharmacy Specialist, Department of Pharmacy Services, Detroit, Henry Ford Hospital, Detroit, Michigan Chapter 113 Edward P. Armstrong, PharmD, BCPS, FASHP Professor, Department of Pharmacy Practice and Science, University of Arizona, College of Pharmacy, Tucson, Arizona Chapter 116 Jacquelyn L. Bainbridge, PharmD Associate Professor, Department of Clinical Pharmacy, School of Pharmacy; Department of Neurology, School of Medicine, University of Colorado Health Sciences Center, Denver, Colorado Chapter 53 Carol McManus Balmer, PharmD Associate Professor and Director, Postgraduate Professional Education, University of Colorado School of Pharmacy, Denver, Colorado Chapter 124

Terry J. Baumann, PharmD, BCPS Adjunct Assistant Professor, Ferris State University, Clinical Pharmacy Manager, Department of Pharmacy, Munson Medical Center, Traverse City, Michigan Chapter 58 Rosemary R. Berardi, PharmD, FASHP, FCCP Professor of Pharmacy, University of Michigan College of Pharmacy, Clinical Pharmacist, Gastroenterology and Liver Diseases, Department of Pharmacy, University of Michigan Health System, Ann Arbor, Michigan Chapters 33 and 39 Richard C. Berchou, PharmD Assistant Professor, Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, Michigan Chapter 57 Betsy Bickert, PharmD Pediatric Oncology/Stem Cell Transplant Clinical Pharmacist, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Chapters 100 and 131 Bradley A. Boucher, PharmD, FCCP, FCCM Professor of Clinical Pharmacy and Associate Professor of Neurosurgery, University of Tennessee Health Sciences Center, Clinical Pharmacist, Regional Medical Center at Memphis, Memphis, Tennessee Chapters 55 and 56

Jeffrey F. Barletta, PharmD Critical Care Specialist, Department of Pharmacy, Spectrum Health, Grand Rapids, Michigan Chapter 11

Sharya V. Bourdet, PharmD, BCPS Clinical Assistant Professor, University of North Carolina School of Pharmacy, Clinical Specialist, Medicine Intensive Care Unit, University of North Carolina Hospitals, Chapel Hill, North Carolina Chapter 27

Jody Don Bartlett, PharmD, BCPP Clinical Specialist in Psychiatry, Central Texas Veterans Health Care System, Waco VA Medical Center, Waco, Texas Chapter 63

Donald F. Brophy, PharmD, FCCP, BCPS Associate Professor of Pharmacy and Medicine, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia Chapter 50

Leslie L. Barton, MD Professor of Pediatrics, University of Arizona School of Medicine, Director, Pediatric Residency Program, University Medical Center, Tucson, Arizona Chapter 116

Thomas E. R. Brown, BScPhm, PharmD Clinical Coordinator–Women’s Health, and Assistant Professor, University of Toronto, Pharmacy, Sunnybrook and Women’s College Health Science Centre, Toronto, Ontario, Canada Chapter 118 xxi

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CONTRIBUTORS

Kathryn K. Bucci, PharmD, BCPS, FASHP Clinical Education Consultant, Pfizer, Inc., Southold, New York Chapter 77 Peter F. Buckley, MD Professor and Chairman, Department of Psychiatry, Medical College of Georgia, Augusta, Georgia Chapter 66 David S. Burgess, PharmD Clinical Associate Professor, College of Pharmacy, University of Texas at Austin, Department of Pharmacology and Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas Chapter 104 Karim Anton Calis, PharmD, MPH, BCPS, BCNSP, FASHP Clinical Professor, Department of Pharmacy Practice and Science, School of Pharmacy, University of Maryland, Baltimore Maryland, Clinical Specialist, Endocrinology and Women’s Health, Coordinator, Drug Information Service, Pharmacy Department, Clinical Research Center, National Institutes of Health, Bethesda, Maryland Chapters 75 and 80 Kimberly A. Cappuzzo, PharmD, MS Assistant Professor of Pharmacy, Virginia Commonwealth University School of Pharmacy, Clinical Pharmacist/Geriatric Pharmacotherapy Specialist, Virginia Commonwealth University (VCU) Medical Center, Richmond, Virginia Chapter 85

Nina Han Cheigh, PharmD Clinical Assistant Professor and Coordinator of Academic Programs, University of Illinois College of Pharmacy, Chicago, Illinois Chapters 94 and 97 Kathy Hammond Chessman, BS, PharmD, BCNSP, BCPS Associate Professor, Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, Medical University of South Carolina, Clinical Pharmacy Specialist, Pediatrics, Medical University of South Carolina Children’s Hospital, Charleston, South Carolina Chapters 135 and 138 Thomas W. F. Chin, BScPhm, PharmD Clinical Pharmacy Specialist, and Assistant Professor, St. Michael’s Hospital, and University of Toronto, Pharmacy and Innercity Health Programme Department, Toronto, ON, Canada Chapter 118 Elaine Chiquette, PharmD, BCPS Clinical Assistant Professor, University of Texas at Austin, College of Pharmacy, Medical Science Liaison, Amylin Pharmaceuticals, San Antonio, Texas Chapter 3 Marie A. Chisholm, PharmD Associate Professor of Pharmacy, University of Georgia College of Pharmacy, Clinical Associate Professor of Medicine, Medical College of Georgia, Augusta, Georgia Chapter 31

Barry L. Carter, PharmD, FCCP, BCPS Professor and Head, Division of Clinical and Administrative Pharmacy, University of Iowa College of Pharmacy, Iowa City, Iowa Chapter 13

Peter A. Chyka, FAACT, DABAT Professor, Department of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee Chapter 10

Peggy L. Carver, PharmD Associate Professor of Pharmacy, University of Michigan College of Pharmacy, Clinical Pharmacist, Infectious Diseases, University of Michigan Health System, Ann Arbor, Michigan Chapter 119

Thomas J. Comstock, PharmD Senior Manager, Global Medical Affairs, Nephrology Medical Communications, Amgen, Inc., Thousand Oaks, California Chapter 41

Larisa H. Cavallari, PharmD, BCPS Assistant Professor of Pharmacy Practice, University of Illinois at Chicago, Chicago, Illinois Chapter 6

Stephen Joel Coons, PhD Professor, University of Arizona College of Pharmacy, Tucson, Arizona Chapter 2

C. Y. Jennifer Chan, PharmD Clinical Associate Professor in Pharmacy, University of Texas in Austin, College of Pharmacy, Clinical Associate Professor of Pediatrics, University of Texas Health Science Center in San Antonio, Clinical Manager, Pediatrics, Methodist Children’s Hospital of South Texas, San Antonio, Texas Chapter 101 Kunal Chaudhary, MD, FACP Assistant Professor, Pennsylvania State University, Nephrologist, Lehigh Valley Hospital, Allentown, Pennsylvania Chapter 44

John R. Corboy, MD Associate Professor of Neurology, University of Colorado School of Medicine, Director, University of Colorado Multiple Sclerosis Center, Denver, Colorado Chapter 53 Elizabeth A. Coyle, PharmD Clinical Assistant Professor, University of Houston College of Pharmacy, Clinical Specialist, Infectious Diseases, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chapter 114

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CONTRIBUTORS

M. Lynn Crismon, PharmD, FCCP, BCPP Behrens Inc Centennial Professor of Pharmacy, Associate Dean for Clinical Programs, Director of Psychiatric Pharmacy Program, University of Texas at Austin College of Pharmacy, Clinical Pharmacologist, Office of the Medical Director, Texas Department of Mental Health and Mental Retardation, Austin, Texas Chapter 66 Michael A. Crouch, PharmD, BCPS Assistant Professor, School of Pharmacy, Department of Pharmacy Practice, Virginia Commonwealth University, Richmond, Virginia Chapter 109 Judy L. Curtis, PharmD, BCPP, FASHP Assistant Director, CNS Regional Medical Services, Janssen Medical Affairs, LLC, Owing Mills, Maryland Chapter 71 Larry H. Danziger, PharmD Professor, Department of Pharmacy Practice, Associate Vice Chancellor for Research, University of Illinois at Chicago, Chicago, Illinois Chapter 108 Joseph F. Dasta, MSc Professor, Division of Pharmacy Practice and Administration, Ohio State Unviersity College of Pharmacy, Ohio State University Medical Center, Columbus, Ohio Chapter 23 Lisa E. Davis, PharmD, FCCP, BCPS, BCOP Associate Professor of Clinical Pharmacy, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania Chapter 127 Susan R. Davis, PhD, MBBS, FRACP Director of Research, Jean Hailes Foundation, Clayton, Australia Chapter 80 Simon de Denus, Bpharm, MSc Invited Professor, Faculty of Pharmacy, University of Montreal, Fellow in Cardiovascular Research, Montreal Heart Institute, Montreal, Quebec, Canada Chapter 16 Renee M. DeHart, PharmD, BCPS Associate Professor, Pharmacy Practice, Samford University, McWhorter School of Pharmacy, Clinical Pharmacy Specialist, Medical Center East Family Practice Residency Program, Birmingham, Alabama Chapter 139 Jeffrey C. Delafuente, MS, FCCP, FASCP Professor, Director of Geriatric Programs, Interim Director Community Pharmacy Program, Virginia Commonwealth University, Richmond, Virginia Chapter 85

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John W. Devlin, PharmD, BCPS, FCCM Associate Professor, Northeast University School of Pharmacy, Boston, Massachusetts, Clinical Pharmacist, Medical ICU, Tufts-New England Medical Center, Boston, Massachusetts Chapter 121 Lori M. Dickerson, PharmD, FCCP, BCPS Associate Professor of Family Medicine, Assistant Residency Program Director, Department of Family Medicine, Medical University of South Carolina, Charleston, South Carolina Chapter 77 Cecily V. DiPiro, PharmD Clinical Assistant Professor, University of Georgia College of Pharmacy, Manager, Department of Pharmacy, MCG Health System, Augusta, Georgia Chapter 35 Joseph T. DiPiro, PharmD, FCCP Professor and Executive Dean, South Carolina College of Pharmacy, University of South Carolina, Columbia, and Medical University of South Carolina, Charleston Chapters 34, 86, 112, and 117 Paul L. Doering, MS Distinguished Service Professor of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville, Florida Chapters 64 and 65 Julie A. Dopheide, PharmD, BCPP Associate Professor of Clinical Pharmacy, Psychiatry, and Behavioral Sciences, Schools of Pharmacy and Medicine, University of Southern California, Psychiatric Pharmacist Specialist, Los Angeles and USC Medical Center, Los Angeles, California Chapter 61 Thomas C. Dowling, PharmD, PhD Assistant Professor, Director, Renal Clinical Pharmacology Laboratory, University of Maryland School of Pharmacy, Baltimore, Maryland Chapter 41 Deepak P. Edward, MD Associate Professor, Department of Ophthalmology, University of Illinois at Chicago Eye and Ear Infirmary, Chicago, Illinois Chapter 92 Mary Elizabeth Elliott, PharmD, PhD Associate Professor, School of Pharmacy, University of Wisconsin–Madison, Pharmacist, Veterans Affairs Medical Center, Madison, Wisconsin Chapter 90 Rowland J. Elwell, PharmD Assistant Professor of Pharmacy Practice, Albany College of Pharmacy, Albany, New York Chapter 45

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Solveig G. Ericson, MD, PhD Associate Professor of Medicine, West Virginia University School of Medicine, Director, Blood and Marrow Transplant/Hematologic Malignancy Program, WVU Hospitals, Inc, Mary Babb Randolph Cancer Center, Morgantown, West Virginia Chapter 98

Sarah Forgie, MD, FRCP(C) Assistant Professor, Pediatrics, Division of Infectious Diseases, University of Alberta, Consultant, Pediatric Infectious Diseases, Associate Director, Infection Control, Stollery Children’s Hospital, Department of Pediatrics, Faculty of Medicine and Dentistry, Edmonton, Alberta, Canada Chapter 107

Brian L. Erstad, PharmD, FCCM, FCCP, FASHP Professor, Department of Pharmacy Practice and Sciences, College of Pharmacy, University of Arizona, Tucson, Arizona Chapter 24

Marlene P. Freeman, MD Assistant Professor of Psychiatry and Obstetrics and Gynecology, University of Arizona College of Medicine, Director, Women’s Mental Health Program, Tucson, Arizona Chapters 68 and 78

Susan C. Fagan, PharmD, BCPS, FCCP Professor of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Adjunct Professor of Neurology, Medical College of Georgia, Augusta, Georgia Chapters 20 and 52

Reginald F. Frye, PharmD, PhD Associate Professor, Department of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville, Florida Chapter 48

Martha P. Fankhauser, MS Pharm, FASHP, BCPP Clinical Associate Professor, Department of Pharmacy Practice and Science, University of Arizona, College of Pharmacy, Tucson, Arizona Chapters 68 and 78 Jennifer D. Faulkner, PharmD, BCPP Clinical Practitioner Faculty, University of Texas, Clinical Pharmacy Specialist, Psychiatry, Central Texas Veterans Health Care System, Temple, Texas Chapter 63 Rebecca S. Finley, PharmD, MS, FASHP Vice President, Meniscus Educational Institute, West Conshohocken, Pennsylvania Chapter 126 Richard G. Fiscella, BS Pharm, MPH Clinical Professor, Department of Pharmacy Practice, Adjunct Assistant Professor, Department of Ophthalmology, University of Illinois at Chicago Chapter 92 Douglas N. Fish, PharmD, BCPS Associate Professor and Vice Chair, Department of Clinical Pharmacy, University of Colorado Health Sciences Center, Clinical Specialist in Infectious Diseases/Critical Care, University of Colorado Hospital, Denver, Colorado Chapters 108 and 120 Courtney V. Fletcher, PharmD Professor, Department of Pharmacy Practice, University of Colorado Health Sciences Center, School of Pharmacy, Denver, Colorado Chapter 123 Edward F. Foote, PharmD, FCCP, BCPS Chair and Associate Professor of Pharmacy, Wilkes University, Nesbitt School of Pharmacy, Wilkes-Barre, Pennsylvania Chapter 45

Peter Gal, PharmD, BCPS, FCCP, FASHP Clinical Professor, School of Pharmacy, University of North Carolina at Chapel Hill, Director, Neonatal Pharmacotherapy Laboratory and Fellowship Program, Department of Neonatal Medicine, Women’s Hospital of Greensboro, Greensboro, North Carolina Chapter 28 William R. Garnett, PharmD, FCCP Professor of Pharmacy and Neurology, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia Chapter 54 Todd W. B. Gehr, MD Professor of Internal Medicine, Chairman of Nephrology, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia Chapter 50 Barry E. Gidal, PharmD Professor, School of Pharmacy, University of Wisconsin, Madison, Wisconsin Chapter 54 Mark A. Gil, PharmD Professor of Clinical Pharmacy, University of Southern California, Clinical Pharmacy, Los Angeles, California Chapter 38 Mark L. Glover, PharmD Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, Nova Southeastern University, Palm Beach Gardens, Florida, Clinical Pharmacist/Faculty, Miami Children’s Hospital, Miami, Florida Chapter 106 S. Diane Goodwin, PharmD, FCCP Clinical Pharmacist, Durham Regional Hospital, Duke University Health System, Durham, North Carolina Chapter 120 Shelly L. Gray, PharmD, MS, BCPS Associate Professor and Director, Geriatric Pharmacy Program, University of Washington School of Pharmacy, Seattle, Washington Chapter 8

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David R. P. Guay, PharmD, CGP, FCP, FCCP, FASCP Professor, Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, Minnesota Chapters 8 and 83

Thomas K. Hazelet, PharmD, DrPH Associate Professor, Department of Pharmacy, University of Washington, Pharmaceutical Outcomes Research and Policy Program, Seattle, Washington Chapter 9

John G. Gums, PharmD Professor of Pharmacy and Medicine, Departments of Pharmacy Practice and Community Health and Family Medicine, Director of Clinical Research in Family Medicine, University of Florida, Family Practice Medical Group, Gainesville, Florida Chapter 74

Amy M. Heck Sheehan, PharmD Associate Professor of Pharmacy Practice, Purdue University School of Pharmacy, Drug Information Specialist, Clarian Health Partners, Indianapolis, Indiana Chapter 75

Stuart T. Haines, PharmD, BCPS, CDE, CACP, FASHP Professor and Vice Chair, University of Maryland School of Pharmacy, Clinical Specialist, Antithrombosis Service, University of Maryland Medical System, Baltimore, Maryland Chapter 19 Emily R. Hajjar, PharmD Assistant Professor of Clinical Pharmacy, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania Chapter 8 Philip D. Hall, PharmD, FCCP, BCPS, BCOP Associate Professor, Department of Pharmaceutical Sciences, Medical University of South Carolina, Clinical Specialist in Hematology/Oncology, Hollings Cancer Center and Medical University Hospital, Charleston, South Carolina Chapter 84 Joseph T. Hanlon, PharmD, MS, BCPS, FASCP, FASHP Visiting Professor, Geriatrics Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 8 Karen E. Hansen, MD Assistant Professor of Medicine, University of Wisconsin, Chief of Rheumatology at the VA Hospital, Madison, Wisconsin Chapter 90 Michelle Sue Harkins, MD Assistant Professor of Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico Chapter 29 David W. Hawkins, PharmD Professor and Senior Associate Dean, Mercer University Southern School of Pharmacy, Atlanta, Georgia Chapter 91 Peggy E. Hayes, MD President, Hayes CNS Services, LLC, San Diego, California Chapter 67 Mary S. Hayney, PharmD, BCPS Assistant Professor of Pharmacy, University of Wisconsin School of Pharmacy, Madison, Wisconsin Chapters 84 and 122

Elizabeth D. Hermsen, PharmD, MBA Infectious Diseases Research Fellow, University of Minnesota College of Pharmacy, Minneapolis, Minnesota Chapter 105 Katherine C. Herndon, PharmD, BCPS Clinical Education Consultant, Pfizer, Inc., Birmingham, Alabama Chapter 59 David C. Hess, MD Professor and Chairman, Department of Neurology, Medical College of Georgia, Augusta, Georgia Chapter 20 Paul B. Hicks, MD, PhD Professor, Department of Psychiatry and Behavioral Science, Texas A&M University System Health, Science Center College of Medicine, Deputy Director, Mental Health and Behavioral Medicine, Central Texas Veterans Health Care System, Waco, Texas Chapter 63 Jonathan Himmelfarb, MD Director, Division of Nephrology and Transplantation, Maine Medical Center, Portland, Maine Chapter 46 Gerald A. Hladik, MD Associate Professor of Medicine, Department of Medicine, Division of Nephrology, University of North Carolina School of Medicine, Chapel Hill, North Carolina Chapter 49 Barbara J. Hoeben, PharmD Clinical Pharmacy Flight Commander, 59th Wilford Hall Medical Center, Lackland AFB, Texas Chapter 22 Collin A. Hovinga, PharmD Assistant Professor of Neurosurgery, University of Miami School of Medicine, Neuropharmacologist, Miami Children’s Hospital Institute, Miami, Florida Chapter 55 Thomas R. Howdieshell, MD, FACS, FCCP Associate Professor of Surgery, Division Chief, Trauma/Burns/Surgical Critical Care, Department of Surgery, University of New Mexico Health Sciences Center, Albuquerque, New Mexico Chapter 112

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Joanna Q. Hudson, PharmD, BCPS Associate Professor of Clinical Pharmacy, Department of Pharmacy and Medicine, University of Tennessee, Memphis, Tennessee Chapter 44

Laura L. Jung, PharmD Medical Writer, Syntazz Communications, Inc, Mount Holly, North Carolina Chapter 130

Andrea Iannucci, PharmD, BCOP Assistant Clinical Professor, University of California, San Francisco School of Pharmacy, San Francisco, California, Oncology Clinical Specialist, University of California, Davis Medical Center, Sacramento, California Chapter 124

Rose Jung, PharmD, BCPS Assistant Professor, University of Colorado Health Sciences Center, School of Pharmacy, Department of Clinical Pharmacy, Clinical Specialist in Critical Care, University of Colorado Hospital, Denver, Colorado Chapter 111

Beata A. Ineck, PharmD, BCPS, CDE Assistant Professor, University of Nebraska Medical Center, Primary Care Clinical Pharmacist, VA Nebraska Western Iowa Health Care System–Omaha Division, Omaha, Nebraska Chapter 99

Thomas N. Kakuda, PharmD Associate Clinical Research Scientist, and Clinical Assistant Professor, Abbott Laboratories and University of Minnesota, Minneapolis, Minnesota Chapter 123

William L. Isley, MD Associate Professor of Medicine, Mayo College of Medicine, Senior Associate Consultant, Mayo Clinic, Rochester, Minnesota Chapter 72

Sophia N. Kalantaridou, MD, PhD Assistant Professor, Department of Obstetrics and Gynecology, University of Ioannina, School of Medicine, University Hospital, Ioannina, Greece Chapter 80

Cherry W. Jackson, BS, BS Pharm, PharmD, PCPP Professor and Assistant Dean, Admissions and Student Affairs, South University School of Pharmacy, Savannah, Georgia Chapter 71

Judith C. Kando, PharmD, BCPP Assistant Director, CNS Regional Medical Services, Janssen Medical Affairs Chapter 67

Mark W. Jackson, MD Gastroenterologist, Fort Sanders Regional Hospital and Baptist Hospital of East Tennessee, Knoxville, Tennessee Chapter 31

S. Lena Kang-Birken, PharmD Associate Professor, Department of Pharmacy, University of the Pacific, Santa Barbara, California Chapter 117

Thomas E. Johns, PharmD, BCPS Clinical Assistant Professor, College of Pharmacy, University of Florida, Manager, Clinical Practice Operations, Shands Hospital at the University of Florida, Gainesville, Florida Chapter 102

Salmaan Kanji, BSc Pharm, PharmD Associate Scientist, Ottawa Health Research Institute, Clinical Specialist-Critical Care, Ottawa Hospital, General Campus, Ottawa, Ontario, Canada Chapter 121

Heather J. Johnson, PharmD, BCPS Assistant Professor, University of Pittsburgh School of Pharmacy, Department of Pharmacy and Therapeutics, Clinical Pharmacy Director, Istituto Mediterraneo Per I Trapianti, University of Pittsburgh Medical Center/Italy Chapter 87

H. William Kelly, PharmD, BCPS Professor Emeritus of Pharmacy and Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, New Mexico Chapter 26

Julie A. Johnson, PharmD, BCPS, FCCP Professor and Chair of Pharmacy Practice, Professor of Pharmaceutics and Medicine (Cardiology), Director, Center for Pharmacogenomics, College of Pharmacy, Gainesville, Florida Chapter 14 Melanie S. Joy, PharmD, FCCP Associate Professor of Medicine, Assistant Professor of Pharmacy, Division of Nephrology and Hypertension, University of North Carolina Schools of Medicine and Pharmacy, Chapel Hill, North Carolina Chapters 43 and 49

Yasmin Khaliq, BSc(Pharm), PharmD Lecturer, Department of Medicine, University of Ottawa, Drug Information Pharmacist, Ottawa Hospital, Ottawa, Ontario, Canada Chapter 107 Mehmood A. Khan, MD, FACE Vice President Medical and Scientific Affairs, Takeda Pharmaceuticals North America, Inc, Lincolnshire, Illinois Chapter 140 Deborah S. King, PharmD Associate Professor, Pharmacy Practice and Medicine, Department of Pharmacy Practice and Medicine, University of Mississippi Medical Center, Jackson, Mississippi Chapter 59

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William R. Kirchain, PharmD, CDE Wilber and Mildred Robichaux Professor of Pharmacy, Chair, Division of Clinical and Administrative Sciences, Xavier University of Louisiana, College of Pharmacy, New Orleans, Louisiana Chapter 38

Helen L. Leather, B Pharm, BCPS Clinical Assistant Professor, University of Florida, College of Pharmacy, Clinical Pharmacy Specialist, BMT/Leukemia, Shands at the University of Florida, Gainesville, Florida Chapter 131

Cynthia K. Kirkwood, PharmD Associate Professor of Pharmacy, Vice Chair for Education, Virginia Commonwealth University, Richmond, Virginia Chapters 69 and 70

Mary W. Lee, PharmD, BCPS, FCCP Dean and Professor of Pharmacy Practice, Midwestern University, Chicago College of Pharmacy, Downers Grove, Illinois Chapters 81 and 82

Leroy C. Knodel, PharmD Director of Drug Information Service and Associate Professor, Department of Pharmacology, University of Texas Health Sciences Center at San Antonio, Clinical Associate Professor, College of Pharmacy, University of Texas at Austin, Austin, Texas Chapter 115

Timothy S. Lesar, PharmD Director of Pharmacy, Albany Medical Center, Department of Pharmacy, Albany, New York Chapter 92

Jill M. Kolesar, PharmD, BCPS Associate Professor, University of Wisconsin School of Pharmacy, Faculty Supervisor-Analytical Instrumentation Laboratory, Madison, Wisconsin Chapter 128 Connie K. Kraus, PharmD, BCPS Clinical Associate Professor of Pharmacy, University of Wisconsin School of Pharmacy, Madison, Wisconsin Chapter 76 Abhijit V. Kshirsagar, MD, MPH Assistant Professor of Medicine, University of North Carolina at Chapel Hill, Attending Physician UNC Hospitals, Chapel Hill, North Carolina Chapter 43 Vanessa J. Kumpf, PharmD, BCNSP Clinical Specialist, Nutrishare, Inc, Elk Grove, California Chapters 135 and 138 Janet L. Kwiatkowski, MD Assistant Professor of Pediatrics, University of Pennsylvania School of Medicine, Attending Hematologist, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Chapter 100 Thomas E. Lackner, PharmD Professor of Pharmacy and Clinical Pharmacist Specialist in Geriatrics, Institute for the Study of Geriatric Pharmacotherapy, Experimental and Clinical Pharmacotherapy, University of Minnesota, College of Pharmacy, Minneapolis, Minnesota Chapter 83 Y. W. Francis Lam, PharmD Associate Professor of Pharmacology and Medicine, Clinical Associate Professor of Pharmacy, Departments of Pharmacology and Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas Chapter 6 Alan H. Lau, PharmD, FCCP Professor, University of Illinois at Chicago College of Pharmacy, Chicago, Illinois Chapter 47

Stephanie M. Levine, MD Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of Texas Health Science Center, San Antonio, Texas Chapter 25 Peter A. LeWitt, MD Professor of Neurology, Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Clinical Neuroscience Center-A Parkinson Foundation Center of Excellence, Southfield, Michigan Chapter 57 Catherine I. Lindblad, PharmD Assistant Clinical Specialist and Assistant Professor, Department of Experimental and Clinical Pharmacology, Institute for the Study of Geriatric Pharmacotherapy, University of Minnesota College of Pharmacy, Clinical Pharmacist Specialist in Geriatrics, Minneapolis Veterans Affairs Medical Center, Minnneapolis, Minnesota Chapter 8 Celeste M. Lindley, PharmD, BCPS, BCOP Associate Professor, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina Chapter 125 George E. MacKinnon, III, RPh, MS, PhD, FASHP Adjunct Professor, Thunderbird, The Garvin School of International Management, Glendale, Arizona, Associate Medical Director, Center for Pharmaceutical Appraisal and Outcomes Research, Abbott Laboratories, Abbott Park, Illinois Chapter 4 Neil J. MacKinnon, RPh, MS, PhD Associate Professor and Merck Frosst Chair of Patient Health Management, Dalhousie University College of Pharmacy, Halifax, Canada Chapter 4 Eugene H. Makela, PharmD, BCPP Associate Professor, Department of Clinical Pharmacy, West Virginia University School of Pharmacy, Morgantown, West Virginia Chapter 70 Michael Malkin, MD Assistant Clinical Director, UCLA, Director, Juvenile Court Mental Health Services (Psychiatrist), Los Angeles County Department of Mental Health, Los Angeles, California Chapter 61

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Patricia A. Marken, BS Pharm, PharmD, FCCP, BCPP Chair and Professor of Pharmacy Practice, Professor of Psychiatry, School of Pharmacy and Medicine, University of Missouri–Kansas City, Kansas City, Missouri Chapters 60 and 62 Patricia L. Marshik, PharmD Associate Professor, University of New Mexico, Health Sciences Center, Albuquerque, New Mexico Chapter 29 Steven J. Martin, PharmD, BCPS, FCCM Associate Professor and Director, Infectious Diseases Research Laboratory, University of Toledo College of Pharmacy, Toledo, Ohio Chapter 111 Barbara J. Mason, PharmD Professor and Vice Chair, Department of Pharmacy Practice, Idaho State University College of Pharmacy, Primary Care Clinical Pharmacist, Boise Veterans Affairs Medical Center, Boise, Idaho Chapter 99 Todd W. Mattox, PharmD, BCNSP Clinical Assistant Professor, Department of Pharmacy Practice, University of Florida, Clinical Assistant Professor, Department of Pharmacy Practice, Nova Southeastern College of Pharmacy, Coordinator, Nutrition Support Team, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida Chapter 137 Gary R. Matzke, PharmD, FCP, FCCP Professor, Department of Pharmacy and Therapeutics, School of Pharmacy, Renal-Electrolyte Division, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania Chapters 46, 48, and 51 J. Russell May, PharmD, FASHP Clinical Professor, Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Pharmacist, Medical College of Georgia Health System, Augusta, Georgia Chapter 93 Teresa C. McCarthy, MD, MS Assistant Professor, Department of Family Medicine and Community Health, University of Minnesota Medical School, Minneapolis, Minnesota Chapter 8 Jeannine Sue McCune, BSPharm, PharmD Assistant Professor, University of Washington, Seattle, Washington Chapter 126

Sarah T. Melton, PharmD, BCPP Consultant Pharmacist, Melton Healthcare Consulting, LLC, Lebanon, Virginia Chapter 69 Renee-Claude Mercier, PharmD Associate Professor of Pharmacy and Medicine, College of Pharmacy, University of New Mexico–Health Sciences Center, Albuquerque, New Mexico Chapter 40 Giuseppe Micali, MD Professor of Dermatology, Department of Dermatology, University of Catania, Catania, Italy Chapters 95 and 96 Laura Boehnke Michaud, PharmD, BCOP Clinical Pharmacy Specialist–Breast Oncology, Division of Pharmacy, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chapter 125 Gary Milavetz, PharmD Associate Professor of Pharmacy and Assistant Head for Academic Affairs, Division of Clinical and Administrative Pharmacy, University of Iowa College of Pharmacy, Clinical Pharmacist, Pediatric Allergy and Pulmonary Division, University of Iowa Hospitals and Clinics, Iowa City, Iowa Chapter 30 Patricia A. Montgomery, PharmD Clinical Pharmacy Specialist, Mercy General Hospital, Sacramento, California Chapter 39 Reginald H. Moore, MD Assistant Professor, University of Texas Heath Science Center at San Antonio, Department of Pediatrics, Hematology, Oncology, & Immunization, Associate Director of Regional Sickle Cell Program Christus Santa Rosa Children’s Hospital, San Antonio, Texas Chapter 101 Bruce A. Mueller, PharmD, FCCP, BCPS Professor and Department Chair, Clinical Sciences Department, College of Pharmacy, University of Michigan, Ann Arbor, Associate Director, Department of Pharmacy Services University of Michigan Health Systems, Ann Arbor, Michigan Chapter 42

Timothy R. McGuire, PharmD, FCCP Associate Professor, College of Pharmacy, University of Nebraska, Omaha, Nebraska Chapter 132

Stuart Munro, MD Chair, Department of Psychiatry, University of Missouri–Kansas City, School of Medicine, Assistant Medical Director, Western Missouri Mental Health Center, Kansas City, Missouri Chapter 60

Patrick J. Medina, PharmD, BCOP Assistant Professor, University of Oklahoma College of Pharmacy, Oklahoma City, Oklahoma Chapter 127

Maria Letizia Musumeci, MD, PhD Dermatologist, Department of Dermatology, University of Catania, Catania, Italy Chapter 95

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Milap C. Nahata, MS, PharmD Professor of Pharmacy, Pediatrics and Internal Medicine, Division Chairman, Pharmacy Practice and Administration, Ohio State University College of Pharmacy, Associate Director, Department of Pharmacy, Ohio State University Medical Center, Columbus, Ohio Chapter 7 Jean M. Nappi, PharmD, FCCP, BCPS Professor of Pharmacy and Clinical Sciences, College of Pharmacy, Medical University of South Carolina Clinical Specialist, Cardiology, Medical University of South Carolina, Charleston, South Carolina Chapter 18 Merlin V. Nelson, PharmD, MD Neurologist, Department of Neurology, Affiliated Community Medical Center, Willmar, Minnesota Chapter 57 Fenwick T. Nichols, III, MD, FACP Professor of Neurology, Medical College of Georgia, Augusta, Georgia Chapter 52 Thomas D. Nolin, PharmD, PhD Clinical Pharmacologist, Division of Nephrology and Transplantation, Maine Medical Center, Portland, Maine Chapter 46 Mary Beth O’Connell, PharmD, BCPS, FCCP, FSHP Associate Professor, Department of Pharmacy Practice, Wayne State University, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan Chapter 88

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Alkesh D. Patel, MD Clinical Assistant Professor, University of Maryland, Baltimore School of Medicine, Baltimore, Maryland, Family Physician, University Care at Shipley’s Choice, Millersville, Maryland Chapter 79 J. Herbert Patterson, PharmD, FCCP, BCPS Associate Professor of Pharmacy and Research Associate Professor of Medicine, University of North Carolina at Chapel Hill, School of Pharmacy, Chapel Hill, North Carolina Chapter 14 Steven Z. Pavletic, MD Principal Investigator, National Cancer Institute, Head, Graft-versus-Host and Autoimmunity Unit, National Cancer Institute, Bethesda, Maryland Chapter 132 Charles A. Peloquin, PharmD Adjoint Professor of Pharmacy and Medicine, University of Colorado, Denver, Director, Infectious Disease Pharmacokinetics Laboratory, National Jewish Medical and Research Center, Denver, Colorado Chapter 110 Susan L. Pendland, MS, PharmD Associate Professor, Section of Infectious Diseases Pharmacotherapy, Department of Pharmacy Practice, University of Illinois at Chicago, College of Pharmacy, Chicago, Illinois Chapter 108 Janelle B. Perkins, PharmD, BCPS Assistant Professor, College of Medicine, University of Florida, Manager, BMT Clinical Research H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida Chapter 134

Dennis R. Ownby, MD Professor of Pediatrics and Internal Medicine, Head, Section of Allergy and Immunology, Medical College of Georgia, Augusta, Georgia Chapter 86

Jay I. Peters, MD Professor of Medicine, Division of Pulmonary Diseases and Critical Care Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas Chapter 25

Manjunath P. Pai, PharmD, BCPS Assistant Professor, University of New Mexico College of Pharmacy, Albuquerque, New Mexico Chapter 40

William P. Petros, PharmD Mylan Chair of Pharmacology, Associate Professor of Pharmacy and Medicine, West Virginia University Health Sciences Center, Associate Director for Anti-Cancer Drug Development, MRB/WVU Cancer Center, Morgantown, West Virginia Chapter 98

Paul M. Palevsky, MD Professor of Medicine, University of Pittsburgh School of Medicine, Chief, Renal Section, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania Chapter 51 James Paparello, MD Clinical Assistant Professor, Feinberg School of Medicine, Northwestern University, Evanston, Illinois Chapter 43 Robert B. Parker, PharmD, FCCP Associate Professor, Department of Pharmacy, University of Tennessee, College of Pharmacy, Memphis, Tennessee Chapter 14

Stephanie J. Phelps, PharmD, FCCP Professor, Departments of Pharmacy and Pediatrics, Vice-Chair, Professional Experiential Program, The University of Tennessee Health Science Center, Director, Pharmacokinetics Service, LeBonheur Children’s Medical Center, Memphis, Tennessee Chapters 55 and 56 Denise Walbrandt Pigarelli, PharmD Clinical Associate Professor of Pharmacy, School of Pharmacy, University of Wisconsin-Madison, Clinical Pharmacy Specialist, William S. Middleton Memorial VA Hospital, Madison, Wisconsin Chapter 76

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L. Michael Posey, BS Pharm President, PENS Pharmacy Editorial and News Services, Athens, Georgia Chapter 3 Beth E. Potter, MD Assistant Professor, Department of Family Medicine, University of Wisconsin–Madison, Madison, Wisconsin Chapter 76 Randall A. Prince, PharmD Professor, College of Pharmacy, University of Houston, Adjunct Professor of Medicine, University of Texas M. D. Anderson Cancer Center, Houston, Texas Chapter 114 Marsha A. Raebel, PharmD, BCPS, FCCP Pharmacotherapy Research Manager, Clinical Research Unit, Kaiser Permanente of Colorado, Adjoint Associate Professor, University of Colorado Health Sciences Center School of Pharmacy, Aurora, Colorado Chapter 40 Daniel W. Rahn, MD President, Medical College of Georgia, Professor of Medicine and Rheumatology, Medical College of Georgia Hospital and Clinics, Augusta, Georgia Chapter 91 Hengameh H. Raissy, PharmD Research Assistant Professor of Pediatrics, Department of Pediatrics, University of Mexico Health Sciences Center, Albuquerque, New Mexico Chapter 29 J. Laurence Ransom, MD, FAAP Clinical Associate Professor of Pediatrics, University of North Carolina at Chapel Hill, Medical Director, Neonatal Intensive Care Unit, Moses Cone Health System, Greensboro, North Carolina Chapter 28 Charles A. Reasner, II, MD, FACE, FACP Professor of Medicine, University of Texas Health Science Center at San Antonio, Medical Director, Texas Diabetes Institute, San Antonio, Texas Chapter 72 Michael D. Reed, PharmD, FCCP, FCP Professor of Pediatrics School of Medicine, Case Western Reserve University, Director, Pediatric Clinical Pharmacology and Toxicology, Rainbow Babies and Children’s Hospital, Pediatric Pharmacology Division, Cleveland, Ohio Chapter 106 Pamela D. Reiter, PharmD, BCPS Adjoint Assistant Professor, University of Colorado, School of Pharmacy, Clinical Pharmacy Specialist, Pediatric ICU and Trauma, Children’s Hospital, Denver, Colorado Chapters 136 and 137 John C. Rotschafer, PharmD Professor, Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota Chapter 105

Eric S. Rovner, MD Associate Professor of Urology, Department of Urology, Medical University of South Carolina, Charleston, South Carolina Chapter 83 Maria I. Rudis, PharmD, ABAT, BCPS Assistant Professor of Clinical Pharmacy and Clinical Emergency Medicine, School of Pharmacy and Keck School of Medicine, University of Southern California, Los Angeles, USC School of Pharmacy, Director, Emergency Medicine and Critical Care Pharmacy Residency Program, Los Angeles, California Chapter 23 Michael J. Rybak, PharmD Associate Dean for Research, Professor of Pharmacy and Medicine, Director, Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan Chapter 103 Gordon S. Sacks, PharmD, BCNSP, FCCP Clinical Associate Professor, University of Wisconsin Schools of Pharmacy and Medicine, Nutrition Support Team Coordinator, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Chapter 136 John V. St. Peter, PharmD, BCPS Associate Professor, Experimental and Clinical Pharmacology, Division of Endocrinology, University of Minnesota College of Pharmacy, Hennepin Center for Diabetes and Endocrinology, Hennepin County Medical Center, Minneapolis, Minnesota Chapter 140 Lisa A. Sanchez, PharmD President, PE Applications, Highlands Ranch, Colorado Chapter 1 Joseph J. Saseen, PharmD, FCCP, BCPS Associate Professor of Clinical Pharmacy and Family Medicine, University of Colorado Health Sciences Center, Denver, Colorado Chapter 13 Robert R. Schade, MD Professor, Department of Medicine, Chief, Section of Gastroenterology and Hepatology, Medical College of Georgia, Augusta, Georgia Chapters 32 and 34 Mark E. Schneiderhan, PharmD, BCPP Clinical Assistant Professor, Department of Pharmacy Practice, University of Illinois at Chicago, Pharmacotherapist, Department of Psychiatry, University of Illinois Medical Center, Chicago, Illinois Chapter 60 Marieke Dekker Schoen, PharmD, BCPS Clinical Associate Professor, Departments of Pharmacy Practice and Medicine, Section of Cardiology, University of Illinois, Chicago, Illinois Chapter 17

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Kristine S. Schonder, BS Pharm, PharmD Assistant Professor, University of Pittsburgh School of Pharmacy, Clinical Pharmacist, Thomas E. Starzl Transplantation Institute, Pittsburgh, Pennsylvania Chapter 87

Andy Stergachis, PhD, RPh Professor, Departments of Epidemiology and Pharmacy, Northwest Center for Public Health Practice, University of Washington, Seattle, Washington Chapter 9

Arthur A. Schuna, MS Clinical Professor, University of Wisconsin School of Pharmacy, Clinical Coordinator and Pharmacotherapist in Rheumatology, William S. Middleton VA Medical Center, Madison, Wisconsin Chapter 89

James J. Stragand, MD, PhD, FACG, FACP Attending Gastroenterologist, St. Charles Medical Center, Bend, Oregon Chapter 37

Rowenta N. Schwartz, PharmD, BCOP Associate Professor, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania Chapter 133

Deborah Ann Sturpe, PharmD, BCPS Assistant Professor, University of Maryland School of Pharmacy, Baltimore, Maryland Chapter 79

Laura Scuderi, MD Resident in Dermatology, Department of Dermatology, University of Catania, Catania, Italy Chapter 96

Carol Taketomo, PharmD Assistant Clinical Professor of Pharmacy Practice, University of Southern California School of Pharmacy, Pharmacy Manager, Children’s Hospital of Los Angeles, Los Angeles, California Chapter 7

Terry L. Seaton, PharmD Professor of Pharmacy Practice, St. Louis College of Pharmacy, Clinical Pharmacist Faculty, Mercy Family Medicine, St. Louis, Missouri Chapter 88

Robert L. Talbert, PharmD, FCCP, BCPS Professor, College of Pharmacy, University of Texas at Austin; Professor, Departments of Medicine and Pharmacology, University of Texas Health Science Center at San Antonio, Texas Chapters 11, 15, 21, 22, and 73

Jeffrey J. Smith, MD Associate Professor of Pediatrics (Clinical), University of Iowa College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa Chapter 30

A. Thomas Taylor, PharmD Assistant Dean and Associate Department Head, University of Georgia College of Pharmacy, Clinical Professor of Family Medicine, Department of Family Medicine, Medical College of Georgia School of Medicine, Augusta, Georgia Chapter 35

Philip H. Smith, MD Assistant Professor of Medicine, Medical College of Georgia, Augusta, Georgia, Children’s Medical Center of Georgia, VAH Augusta, Augusta, Georgia Chapter 93 Roger W. Sommi, Jr., BS Pharm, PharmD, FCCP, BCPP Professor of Pharmacy Practice and Psychiatry, University of Missouri Kansas City, Department of Pharmacy, Kansas City, MO Chapter 62 Christine A. Sorkness, PharmD Professor of Pharmacy and Medicine, University of Wisconsin–Madison, Madison, Wisconsin Chapter 26 Sarah A. Spinler, PharmD, FCCP Associate Professor of Clinical Pharmacy, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania Chapter 16 William J. Spruill, PharmD Associate Professor, Department of Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia, Athens, Georgia Chapter 36

Karen A. Theesen, PharmD, BCPP Senior Regional Medical Scientist II, Research and Development, GlaxoSmithKline, Minneapolis, Minnesota Chapter 61 E. Gregory Thompson, MD Affiliate Faculty, Department of Pharmacy Practice, Idaho State University, Meridian, Idaho, Clinical Instructor of Medicine, University of Washington, Seattle, Washington Chapter 99 Edward G. Timm, PharmD, MS Senior Clinical Pharmacy Specialist, Critical Care and Adjunct Assistant Professor, Albany Medical Center Hospital and Albany College of Pharmacy, Albany, New York Chapter 37 Shelly D. Timmons, MD, PhD Neurological Surgeon, Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee Chapter 56 Margaret E. Tonda, PharmD Director of Clinical Development, Alza Corp, Mountain View, California Chapter 130

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John Mark Tovar, PharmD Clinical Fellow in Pharmacy and Family Medicine, Departments of Pharmacy Practice and Community Health and Family Medicine, University of Florida, Gainesville, Florida Chapter 74

Dianne B. Williams, PharmD, BCPS Clinical Assistant Professor, University of Georgia College of Pharmacy, Durg Information Specialist MCG Health, Inc, Augusta, Georgia Chapter 32

Curtis L. Triplitt, PharmD, CDE, BCPS Instructor, Department of Medicine, Division of Diabetes, Clinical Assistant Professor of Pharmacy, University of Texas Health Science Center at San Antonio, Texas Chapter 72

Daniel M. Witt, PharmD Adjoint Assistant Professor, University of Colorado School of Pharmacy, Manager, Clinical Pharmacy Services, Kaiser Permanente of Colorado Pharmacy Administration, Aurora, Colorado Chapter 19

Amy Wells Valley, PharmD, BCOP Oncology Pharmacy Specialist and Senior Consultant, Pharmacy Healthcare Solutions, Grapevine, Texas, Clinical Assistant Professor, University of Texas College of Pharmacy, Austin, Texas Chapter 124

Jean F. Wyman, PhD, RN Professor and Cora Medil Siehl Chair in Nursing Research, University of Minnesota School of Nursing, Minneapolis, Minnesota Chapter 83

Angie Veverka, BS, PharmD Assistant Professor of Pharmacy, Wingate University School of Pharmacy, Wingate, North Carolina Chapter 109

Jack A. Yanovski, MD, PhD Head, Unit on Growth and Obesity, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland Chapter 75

William E. Wade, PharmD, FASHP, FCCP Professor of Pharmacy, College of Pharmacy, University of Georgia, Athens, Georgia Chapter 36 Sherman Jay Weaver, PharmD, MPH Manager, Health Information and Outcomes, ACS State HealthCare Solutions, Atlanta, Georgia Chapter 102 Lynda S. Welage, PharmD, FCCP Professor of Pharmacy and Associate Dean for Academic Affairs, University of Michigan College of Pharmacy, Clinical Pharmacist, Critical Care, Department of Pharmacy, University of Michigan Health System, Ann Arbor, Michigan Chapter 33 Barbara G. Wells, PharmD, FASHP, FCCP, BCPP Dean and Professor, School of Pharmacy, University of Mississippi, University, Mississippi Chapters 67 and 70 Dennis P. West, PhD Professor of Dermatology and Director, Dermatopharmacology Program, Department of Dermatology, Northwestern University, Chicago, Illinois Chapters 95 and 96

Gary C. Yee, PharmD Professor and Chair, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska Chapters 129 and 134 Sunshine J. Yocum, PharmD Assistant Professor of Pharmacy Practice, Samford University McWhorter School of Pharmacy, Birmingham, Alabama Chapter 139 William C. Zamboni, PharmD Assistant Professor, Pharmaceutical Sciences and Medicine, University of Pittsburgh Schools of Pharmacy and Medicine, Assistant Member of Molecular Therapeutics and Drug Development Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania Chapter 130 Mario Zeolla, PharmD Assistant Professor of Pharmacy Practice, Albany College of Pharmacy, Patient Care Pharmacist, Eckerd Patient Care Center, Albany, New York Chapter 19

Lee E. West, BS Consultant Pharmacist, Department of Dermatology, Northwestern University, Chicago, Illinois Chapters 95 and 96

George G. Zhanel, PharmD, PhD Professor, Department of Medical Microbiology, University of Manitoba, Coordinator-Antibiotic Resistance Program, Department of Medicine, Health Sciences Centre, Microbiology Health Sciences Centre, Winnipeg, Canada Chapter 107

Dennis M. Williams, PharmD, BCPS Associate Professor, Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina, Chapel Hill, Clinical Specialist, Pulmonary Disease, UNC Hospitals, Chapel Hill, North Carolina Chapter 27

Michael R. Zile, MD, FACC Charles Ezra Daniel Professor of Medicine, Medical University of South Carolina, Director of MICU, Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina Chapter 18

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GUIDING PRINCIPLES OF PHARMACOTHERAPY

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1. There should be a justifiable and documented indication for every medication that is used. 2. A medication should be used at the lowest dosage and for the shortest duration that is likely to achieve the desired outcome. 3. When a patient is adequately treated with a single drug, monotherapy is preferred. 4. Newly approved medications should be used only if there are clear advantages over older medications. 5. Whenever possible, the selection of a medication regimen should be based upon evidence obtained from controlled clinical trials. 6. The timing of drug administration should be considered as a possible influence on drug efficacy, adverse effects, and interactions with other drugs and food. 7. A medication regimen should be simplified as much as possible to enhance patient adherence. 8. A patient’s perception of illness or the risks and benefits of therapy may affect adherence and treatment outcomes. 9. Careful observation of a patient’s response to treatment is necessary to confirm efficacy, prevent, detect, or manage adverse effects, assess compliance, and determine the need for dosage adjustment or discontinuation of drug therapy.

10. A medication should not be given by injection when giving it by mouth would be just as effective and safe. 11. Before medications are used, lifestyle modifications should be made, when indicated, to obviate the need for drug therapy or to enhance pharmacotherapy outcomes. 12. Initiation of a drug regimen should be done with full recognition that a medication may cause a disease, sign, symptom, syndrome, or abnormal laboratory test. 13. When a variety of drugs are equally efficacious and equally safe, the drug that results in the lowest health care cost or is most convenient for the patient should be chosen. 14. When making a decision about drug therapy for individual patients, societal effects should be considered. 15. The possible reasons for failure of medication regimens include inappropriate drug selection, poor adherence, improper drug dose or interval, misdiagnosis, concurrent illness, interactions with foods or drugs, environmental factors, or genetic factors. Joseph T. DiPiro, PharmD, FCCP Barbara G. Wells, PharmD, FASHP, FCCP, BCPP David W. Hawkins, PharmD August 13, 2001

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PHARMACOTHERAPY A Pathophysiologic Approach

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1 PHARMACOECONOMICS: PRINCIPLES, METHODS, AND APPLICATIONS Lisa A. Sanchez

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Pharmacoeconomics identifies, measures, and compares

the costs and consequences of drug therapy to health care systems and society.

treatment options and are similar in the way they measure costs (dollar units). They differ, however, in their measurement of outcomes and expression of results.

2 The perspective of a pharmacoeconomic evaluation is

6 In today’s health care settings, pharmacoeconomic methods

paramount because the study results will be highly dependent on the perspective selected.

3 Health care costs can be categorized as direct medical, di-

rect nonmedical, indirect nonmedical, intangible, opportunity, and incremental costs.

can be applied for effective formulary management, individual patient treatment, medication policy determination, and resource allocation.

7 When evaluating published pharmacoeconomic studies,

4 Economic, humanistic, and clinical outcomes should be

considered and valued using pharmacoeconomic methods, to inform local decision making whenever possible.

the following factors should be considered: study objective, study perspective, pharmacoeconomic method, study design, choice of interventions, costs and consequences, discounting, study results, sensitivity analysis, study conclusions, and sponsorship.

5 To compare various health care choices, economic valua-

8 Use of economic models and performance of pharma-

Today’s cost-sensitive health care environment has created a competitive and challenging workplace for clinicians. Competition for diminishing resources has necessitated that the appraisal of health care goods and services extends beyond evaluations of safety and efficacy and considers the economic impact of these goods and services on the cost of health care. A challenge for health care professionals is to provide quality patient care with minimal resources. An interest in defining the value of medicine is a common thread that unites today’s health care practitioners. With serious concerns about rising medication costs and consistent pressure to decrease pharmacy expenditures and budgets, clinicians/prescribers, pharmacists, and other health care professionals must answer the question, “What is the value of the pharmaceutical goods and services I provide?” Pharmacoeconomics, or the discipline of placing a value on drug therapy,1 has evolved to answer this question. Challenged to provide high-quality patient care in the least expensive way, clinicians have developed strategies aimed at containing costs. However, most of these strategies focus solely on determining the least expensive alternative rather than the alternative that

represents the best value for the money. The “cheapest” alternative— with respect to drug acquisition cost—is not always the best value for patients, departments, institutions, and health care systems. Quality patient care must not be compromised while attempting to contain costs. The products and services delivered by today’s health professionals should demonstrate pharmacoeconomic value, that is, a balance of economic, humanistic, and clinical outcomes. Pharmacoeconomics can provide the systematic means for this quantification. This chapter discusses the principles and methods of pharmacoeconomics and how they can be applied to clinical pharmacy practice and thereby how they can assist in the valuation of pharmacotherapy and other modalities of treatment in clinical practice.

tion methods are used, including cost-minimization, costbenefit, cost-effectiveness, and cost-utility analyses. These methods all provide the means to compare competing

coeconomic analyses on a local level both can be useful and relevant sources of pharmacoeconomic data when rigorous methods are employed, as outlined in this chapter.

PRINCIPLES OF PHARMACOECONOMICS DEFINITIONS 1 Pharmacoeconomics has been defined as the description and analysis of the cost of drug therapy to health care systems and 1

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society.2 More specifically, pharmacoeconomic research is the process of identifying, measuring, and comparing the costs, risks, and benefits of programs, services, or therapies and determining which alternative produces the best health outcome for the resource invested.3 For most practitioners, this translates into weighing the cost of providing a pharmacy product or service against the consequences (outcomes) realized by using the product or service to determine which alternative yields the optimal outcome per dollar spent. This information can assist clinical decision makers in choosing the most costeffective treatment options.4 There is a distinct relationship between pharmacoeconomics, outcomes research, and pharmaceutical care. Pharmacoeconomics is not synonymous with outcomes research. Outcomes research is defined more broadly as studies that attempt to identify, measure, and evaluate the results of health care services in general.5 Outcomes research is discussed further in Chapter 2. Pharmacoeconomics is a division of outcomes research that can be used to quantify the value of pharmaceutical care products and services. Pharmaceutical care has been defined as the responsible provision of drug therapy for the purposes of achieving definite outcomes.6 By accepting this as the paradigm or vision for our profession, pharmacy is accepting responsibility for managing drug therapy so that positive outcomes are produced. Cost is defined as the value of the resources consumed by a program or drug therapy of interest. Consequence is defined as the effects, outputs, or outcomes of the program of drug therapy of interest. Consideration of both costs and consequences differentiates most pharmacoeconomic evaluation methods from traditional costcontainment strategies and drug-use evaluations.

PERSPECTIVES 2 Assessing costs and consequences—the value of a pharmaceu-

tical product or service—depends heavily on the perspective of the evaluation. Common perspectives include those of the patient, provider, payer, and society. A pharmacoeconomic evaluation can assess the value of a product or service from single or multiple perspectives. However, clarification of the perspective is critical because the results of a pharmacoeconomic evaluation depend heavily on the perspective taken. For example, if comparing the value of alteplase (tissue plasminogen activator, or tPA) with that of streptokinase from a patient or societal perspective, tPA may be the best-value alternative because a 1% reduction in mortality rates is observed in this large population. Yet, from a small community hospital’s perspective, streptokinase may represent a better value because it provides similar outcomes for less money. Once the perspective is clear, a full evaluation of the relevant costs and consequences can begin. Again, perspective is critical because the value placed on a treatment alternative will be dependent heavily on the point of view taken.

PATIENT PERSPECTIVE Patient perspective is paramount because patients are the ultimate consumers of health care services. Costs from the perspective of patients are essentially what patients pay for a product or service, that is, the portion not covered by insurance. Consequences, from a patient’s perspective, are the clinical effects, both positive and negative, of a program or treatment alternative. For example, various costs from a patient’s perspective might include insurance copayments and outof-pocket drug costs, as well as indirect costs, such as lost wages. This perspective should be considered when assessing the impact of

drug therapy on quality of life or if a patient will pay out-of-pocket expenses for a health care service.

PROVIDER PERSPECTIVE Costs from the provider’s perspective are the actual expense of providing a product or service, regardless of what the provider charges. Providers can be hospitals, managed-care organizations (MCOs), or private-practice physicians. From this perspective, direct costs such as drugs, hospitalization, laboratory tests, supplies, and salaries of health care professionals may be identified, measured, and compared. However, indirect costs may be of less importance to the provider. When making formulary management or drug-use policy decisions, the viewpoint of the health care organization should dominate. PHARMACOECONOMIC CONTROVERSY Surprisingly few providers are prepared to identify and measure their true economic costs. Charge data may be more readily available but usually are not reflective of the true costs of health care. Thus it can be challenging translating charges into costs. A cost-to-charge ratio may be useful in many instances. Additionally, a common proxy used for costs of medications is average wholesale price (AWP). However, realistically, there are no providers actually paying AWP for their drugs, and AWP therefore is not an accurate proxy for drug-cost data.

PAYER PERSPECTIVE Payers include insurance companies, employers, or the government. From this perspective, costs represent the charges for health care products and services allowed, or reimbursed, by the payer. The primary cost for a payer is of a direct nature. However, indirect costs, such as lost workdays and decreased productivity, also may contribute to the total cost of health care to the payer. When insurance companies and employers are contracting with MCOs or selecting health care benefits for their employees, then the payer’s perspective should be employed.

SOCIETAL PERSPECTIVE The perspective of society is the broadest of all perspectives because it is the only one that considers the benefit to society as a whole. Theoretically, all direct and indirect costs are included in an economic evaluation performed from a societal perspective. Costs from this perspective include patient morbidity and mortality and the overall costs of giving and receiving medical care. An evaluation from this perspective also would include all the important consequences an individual could experience. In countries with nationalized medicine, society is the predominant perspective. PHARMACOECONOMIC CONTROVERSY Controversy surrounds the issue of study perspective. Many researchers assert that society is the only relevant and the most appropriate perspective from which to conduct a pharmacoeconomic analysis. However, in the United States, these studies can be very resource-intensive in terms of time and money. Further, organizations may need to focus solely from their own perspectives to obtain the data necessary to inform timely decision making.

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TABLE 1–1. Example of Health Care Cost Categories Cost Category

Costs

Direct medical costs

Medications Supplies Laboratory tests Health care professionals’ time Hospitalization Transportation Food Family care Home aides Lost wages (morbidity) Income forgone due to premature death (mortality) Pain Suffering Inconvenience Grief Lost opportunity Revenue forgone

Direct nonmedical costs

Indirect costs

Intangible costs

Opportunity costs

COSTS 3 Once a perspective is chosen, the costs and consequences as-

sociated with a given product or service may be identified and measured using pharmacoeconomic methods. A comparison of two or more treatment alternatives should extend beyond a simple comparison of drug acquisition costs. Health care costs or economic outcomes can be grouped into several categories: direct medical, direct nonmedical, indirect nonmedical, and intangible costs.7 Other costs often discussed in pharmacoeconomic evaluations include opportunity and incremental costs. Inclusion of these various cost categories, when appropriate, provides a more accurate estimate of the total economic impact of a health care program or treatment alternatives on a specific population, organization, or patient. Table 1– 1 contains examples of these costs. Again, the costs that are identified, measured, and ultimately compared vary depending on the perspective.

DIRECT MEDICAL COSTS Direct medical costs are the costs incurred for medical products and services used to prevent, detect, and/or treat a disease.7 Direct medical costs are the fundamental transactions associated with medical care that contribute to the portion of gross national product spent on health care. Examples of these costs include drugs, medical supplies and equipment, laboratory and diagnostic tests, hospitalizations, and physician visits. Direct medical costs can be subdivided into fixed and variable costs. Fixed costs are essentially “overhead” costs (e.g., heat, rent, electricity) that are not readily influenced at the treatment level and thus remain relatively constant. For this reason, they are often not included in most pharmacoeconomic analyses. Variable costs, which change as a function of volume, include medications, fees for professional services, and supplies. As more services are used, more funding must be used to provide them. PHARMACOECONOMIC CONTROVERSY Should personnel costs be considered fixed or variable costs? In a hospital setting, one might consider whether switching

3

from a drug that requires a three-times-daily versus oncedaily administration truly saves time for health care personnel. Some argue that staffing is relatively constant and that such a change would not cause the hospital to reduce its overall personnel levels, whereas others maintain that such a change allows personnel to perform other activities that provide value. In times of downsizing, personnel often are viewed as variable costs by hospital administrators.

DIRECT NONMEDICAL COSTS Direct nonmedical costs are any costs for nonmedical services that are results of illness or disease but do not involve purchasing medical services.7 These costs are consumed to purchase services other than medical care and include resources spent by patients for transportation to and from health care facilities, extra trips to the emergency department, child or family care expenses, special diets, and various other out-of-pocket expenses.

INDIRECT NONMEDICAL COSTS Indirect nonmedical costs are the costs of reduced productivity (e.g., morbidity and mortality costs).7−9 Indirect costs are costs that result from morbidity and mortality and are an important source of resource consumption, especially from the perspective of the patient. Morbidity costs are costs incurred from missing work (i.e., lost productivity), whereas mortality costs represent the years lost as result of premature death. To estimate indirect costs, two techniques typically are used: (1) human capital (HC) and (2) willingness-to-pay (WTP) methods. The HC approach attempts to value morbidity and mortality (primarily wages and productivity) losses based on an individual’s earning capacity using standard labor wage rates.10 This approach raises an ethical dilemma because the value of a life is related directly to income. Using the WTP approach (contingent valuation), the indirect and intangible aspects of a disease can be valued. Patients are asked how much money they would be willing to spend to reduce the likelihood of illness.11 However, the values obtained through this method may be unreliable because of the substantial differences in valuations of life that result from the subjective nature of this approach.

INTANGIBLE COSTS Intangible costs are those of other nonfinancial outcomes of disease and medical care.7 Examples include pain, suffering, inconvenience, and grief, and these are difficult to measure quantitatively and impossible to measure in terms of economic or financial costs. In pharmacoeconomic analyses, frequently intangible costs are identified but not quantified formally.

OPPORTUNITY COSTS Opportunity costs represent the economic benefit forgone when using one therapy instead of the next best alternative therapy.12 Therefore, if a resource has been used to purchase a program or treatment alternative, then the opportunity to use it for another purpose is lost. In other words, opportunity cost is the value of the alternative that was forgone.

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INCREMENTAL COSTS Incremental costs represent the additional cost that a service or treatment alternative imposes over another compared with the additional effect, benefit, or outcome it provides.13 As medical interventions become increasingly intense, costs generally increase. However, the additional outcome gained per additional dollar spent generally decreases. At some point of increasing expenditures, there may be no additional benefits or even a reduction in outcome. Thus incremental costs are the extra costs required to purchase an additional unit of effect and provide another way to assess the pharmacoeconomic impact of a service or treatment option on a population.

CONSEQUENCES

PHARMACOECONOMIC CONTROVERSY The challenge with using intermediate consequences of medical interventions lies in finding appropriate interim outcome indicators that can reliably predict the long-term effects of a program or treatment alternative.

METHODS OF PHARMACOECONOMICS 5 The pharmacoeconomic methods of evaluation are listed in

Fig. 1–1. These methods or tools can be separated into two distinct categories: economic and humanistic evaluation techniques. These methods have been used in a variety of fields and are being applied increasingly to health care.16

4 Similar to costs, the outcomes or consequences of a disease and

its treatment are an equally important component of pharmacoeconomic analyses. The manner in which consequences are quantified is a key distinction among pharmacoeconomic methods because the assessment of costs is relatively standard. Like costs, the consequences (or outcomes) of medical care also can be categorized. One approach is to separate outcomes into three categories: economic, clinical, and humanistic. Economic outcomes are the direct, indirect, and intangible costs compared with the consequences of medical treatment alternatives.14 Clinical outcomes are the medical events that occur as a result of disease or treatment (e.g., safety and efficacy end points).14 Humanistic outcomes are the consequences of disease or treatment on patient functional status or quality of life along several dimensions (e.g., physical function, social function, general health and well-being, and life satisfaction).14 Assessing the economic, clinical, and humanistic outcomes (ECHO) associated with a treatment alternative provides a complete model for decision making.

POSITIVE VERSUS NEGATIVE CONSEQUENCES These consequences (outcomes) can be further categorized as positive or negative. An example of a positive outcome is a desired effect of a drug (efficacy or effectiveness measure), possibly manifested as cases cured, life-years gained, or improved health-related quality of life (HRQOL). Since all drugs have adverse effects, negative consequences also can occur with their use. A negative outcome is an undesired or adverse effect of a drug, possibly manifested as a treatment failure, an adverse drug reaction (ADR), a drug toxicity, or even death. Pharmacoeconomic evaluations should include assessments of both types of outcomes. Evaluating only positive outcomes may be misleading because of the potential detriment and expense associated with negative outcomes. Thus the balancing of positive and negative consequences is important in any pharmacoeconomic evaluation.

ECONOMIC EVALUATION METHODS The basic task of economic evaluation is to identify, measure, value, and compare the costs and consequences of the alternatives being considered. The two distinguishing characteristics of economic evaluation are as follows: (1) Is there a comparison of two or more alternatives? and (2) Are both costs and consequences of the alternatives examined?17 A full economic evaluation encompasses both characteristics, whereas a partial economic evaluation addresses only one. Pharmacoeconomic evaluations conducted in today’s health care settings may be either partial or full economic evaluations. Partial economic evaluations may include simple descriptive tabulations of outcomes or resources consumed and thus require a minimum of time and effort. If only the consequences or only the costs of a program, service, or treatment are described, the evaluation illustrates an outcome or cost description. A cost-outcome or costconsequence analysis (CCA) describes the costs and consequences of an alternative but does not provide a comparison with other treatment options.15 Another partial evaluation is a cost analysis that compares the costs of two or more alternatives without regard to outcome. Full economic evaluations include cost-minimization, costbenefit, cost-effectiveness, and cost-utility analyses. Each method is used to compare competing programs or treatment alternatives. The methods are all similar in the way they measure cost (in dollars) and different in their measurement of outcomes. Although a full economic evaluation generally provides higher-quality and more useful information, the time, resources, and effort employed are also great. Thus health care practitioners and clinicians also find it necessary to employ various partial economic evaluations. Application of economic evaluation methods to health care products and services, especially pharmaceuticals, may increase their acceptance by health care professionals and society.18 The methods used most commonly by health care practitioners are discussed in the next sections and summarized briefly in Table 1–2.

INTERMEDIATE AND FINAL CONSEQUENCES Consequences also can be discussed in terms of intermediate and final outcomes. Intermediate outcomes can serve as a proxy for more relevant final outcomes. For example, achieving a decrease in lowdensity lipoprotein cholesterol levels with a lipid-lowering agent is an intermediate consequence that may serve as a proxy for a more final outcome such as a decrease in myocardial infarction rate.15 Intermediate consequences are used commonly in clinical and pharmacoeconomic analyses as proxies predictive of final outcomes because their use reduces the cost and time required to conduct a trial.

FIGURE 1–1. Components of pharmacoeconomics.

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TABLE 1–2. Summary of Pharmacoeconomic Methodologies Method

Description

Application

Cost Unit

COI

Estimates the cost of a disease on a defined population

$$$

NA

CMA

Finds the least expensive cost alternative Measures benefit in monetary units and computes a net gain Compares alternatives with therapeutic effects measured in physical units; computes a C/E ratio Measures therapeutic consequences in utility units rather than physical units; computes a C/U ratio

Use to provide baseline to compare prevention/treatment options against Use when benefits are the same

$$$

Assume to be equivalent

Can compare programs with different objectives Can compare drugs/programs that differ in clinical outcomes and use the same unit of benefit

$$$

$$$

$$$

Natural units

$$$

QALYs

NA

QOL score

CBA CEA

CUA

QOL

Physical, social, and emotional aspects of patient’s well-being that are relevant and important to the patient

Use to compare drugs/programs that are life extending with serious side effects or those producing reductions in morbidity Examines drug effects in areas not covered by laboratory or physiologic measurements

Outcome Unit

Key: CBA, cost-benefit analysis; CEA, cost-effectiveness analysis; CMA, cost-minimization analysis; COI, cost-of-illness evaluation; CUA, cost-utility analysis; QOL, quality of life; QALY, quality-adjusted life-year.

COST-OF-ILLNESS EVALUATION A cost-of-illness (COI) evaluation identifies and estimates the overall cost of a particular disease for a defined population.8 This evaluation method is often referred to as burden of illness and involves measuring the direct and indirect costs attributable to a specific disease. The costs of various diseases, including peptic ulcer disease, mental disorders, and cancer, in the United States have been estimated. By successfully identifying the direct and indirect costs of an illness, one can determine the relative value of a treatment or prevention strategy. For example, by determining the cost of a particular disease to society, the cost of a prevention strategy could be subtracted from this to yield the benefit of implementing this strategy nationwide. COI evaluation is not used to compare competing treatment alternatives but to provide an estimation of the financial burden of a disease. Thus the value of prevention and treatment strategies can be measured against this illness cost. Various examples of COI studies are available in the literature, including the burden or cost of Alzheimer’s disease.19,20

COST-MINIMIZATION ANALYSIS Cost-minimization analysis (CMA) involves the determination of the least costly alternative when comparing two or more treatment alternatives. With CMA, the alternatives must have an assumed or demonstrated equivalency in safety and efficacy (i.e., the two alternatives must be equivalent therapeutically). Once this equivalency in outcome is confirmed, the costs can be identified, measured, and compared in monetary units (dollars). CMA is a relatively straightforward and simple method for comparing competing programs or treatment alternatives as long as the therapeutic equivalence of the alternatives being compared has been established. If no evidence exists to support this, then a more comprehensive method such as cost-effectiveness analysis should be employed. Remember, CMA shows only a “cost savings” of one program or treatment over another.21

Employing CMA is appropriate when comparing two or more therapeutically equivalent agents or alternate dosing regimens of the same agent.21 For example, if drugs A and B are antiulcer agents and have been documented as equivalent in efficacy and incidence of adverse drug reactions (ADRs), then the costs of using these drugs could be compared using CMA. These costs should extend beyond a comparison of drug acquisition costs and include costs of drug preparation (pharmacist and technician time), administration (nursing time), and storage. When appropriate, other costs to be valued may include the cost of physician visits, number of hospital days, and pharmacokinetic consultations. The least expensive agent, considering all these costs, should be preferred. This method has been used frequently, and its application could expand given the increasing number of “me too” products and generic competition in the pharmaceutical marketplace.22

COST-BENEFIT ANALYSIS Cost-benefit analysis (CBA) is a method that allows for the identification, measurement, and comparison of the benefits and costs of a program or treatment alternative. The benefits realized from a program or treatment alternative are compared with the costs of providing it. Both the costs and the benefits are measured and converted into equivalent dollars in the year in which they will occur.8,16 Future costs and benefits are discounted or reduced to their current value. These costs and benefits are expressed as a ratio (a benefit-tocost ratio), a net benefit, or a net cost. A clinical decision maker would choose the program or treatment alternative with the highest net benefit or the greatest benefit-to-cost (B/C) ratio.9 Guidelines for the interpretation of this ratio are indicated16,21,23 : r

If the B/C ratio is greater than 1, the program or treatment is of value. The benefits realized by the program or treatment alternative outweigh the cost of providing it.

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If the B/C ratio equals 1, the benefits equal the cost. The benefits realized by the program or treatment alternative are equivalent to the cost of providing it. If the B/C ratio is less than 1, the program or treatment is not economically beneficial. The cost of providing the program or treatment alternative outweighs the benefits realized by it.

CBA should be employed when comparing treatment alternatives in which the costs and benefits do not occur simultaneously. CBA also may be used when comparing programs with different objectives because all benefits are converted into dollars. CBA also can be used to evaluate a single program or compare multiple programs. However, valuing health benefits in monetary terms can be difficult and controversial. The expression of some health benefits as monetary units is neither appropriate nor widely accepted. Therefore, unless the benefits of a program or treatment alternative are expressed appropriately in dollars, CBA should not be employed.21 CBA may be an appropriate method to use in justifying and documenting the value of an existing health care service or the potential worth of a new one. For example, when a clinical pharmacy service is competing for institutional resources, CBA can provide data to document that the service yields a high return on investment compared with other institutional services competing for the same resources. However, the relative magnitude of the costs and benefits for the service must be considered when making this resource-allocation decision. If a service costs $100 to implement and results in a benefit to the hospital of $1000 and a service that costs $100,000 to implement results in a benefit of $1 million, both have a B/C ratio of 10.21 Thus caution should be exercised when using B/C ratios and CBA as a comparison tool. Numerous examples of CBAs have been published in the literature recently.24−27 However, of all pharmacoeconomic evaluation methods, CBA is probably used the least. Although this method has the advantage of valuing indirect costs monetarily (using the HC and WTP approaches) and intangible benefits (using the WTP approach), the valuation of outcomes such as productivity and quality of life is difficult to perform reliably and meaningfully.10,28 Because of difficulties in measuring indirect and intangible benefits, many CBAs measure and quantify direct costs and direct benefits only. Some researchers assert that these should not be considered “true” CBAs because they do not take into account the indirect costs and benefits.28

COST-EFFECTIVENESS ANALYSIS Cost-effectiveness analysis (CEA) is a way of summarizing the health benefits and resources used by competing health care programs so that policymakers can choose among them.17 CEA involves comparing programs or treatment alternatives with different safety and efficacy profiles. Cost is measured in dollars, and outcomes are measured in terms of obtaining a specific therapeutic outcome. These outcomes are often expressed in physical units, natural units, or nondollar units (lives saved, cases cured, life expectancy, or drop in blood pressure).8,13,29 The results of CEA are also expressed as a ratio—either as an average cost-effectiveness ratio (ACER) or as an incremental costeffectiveness ratio (ICER). An ACER represents the total cost of a program or treatment alternative divided by its clinical outcome to yield a ratio representing the dollar cost per specific clinical outcome gained, independent of comparators. The ACER can be summarized as follows7,13,21 : health care costs ($) ACER = clinical outcome (not in $)

This allows the costs and outcomes to be reduced to a single value to allow for comparison. Using this ratio, the clinician would choose the alternative with the least cost per outcome gained.9 The most cost-effective alternative is not always the least costly alternative for obtaining a specific therapeutic objective. In this regard, costeffectiveness need not be cost reduction but rather cost optimization.30 Often clinical effectiveness is gained at an increased cost. Is the increased benefit worth the increased cost? Incremental CEA may be used to determine the additional cost and effectiveness gained when one treatment alternative is compared with the next best treatment alternative.7 Thus, instead of comparing the ACERs of each treatment alternative, the additional cost that a treatment alternative imposes over another treatment is compared with the additional effect, benefit, or outcome it provides. The ICER can be summarized as follows: ICER =

costA ($) − costB ($) effectA (%) − effectB (%)

This formula yields the additional cost required to obtain the additional effect gained by switching from drug A to drug B. CEA is particularly useful in balancing cost with patient outcome, determining which treatment alternatives represent the best health outcome per dollar spent, and deciding when it is appropriate to measure outcome in terms of obtaining a specific therapeutic objective. In addition, CEA may provide valuable data to support drug policy, formulary management, and individual patient treatment decisions. Globally, CEA is being used to set public policies regarding the use of pharmaceutical products (national formularies) in countries such as Australia,31 New Zealand, and Canada.32 These countries, along with others, including Spain, the United Kingdom, Italy, and the United States, even have their own guidelines for conducting research. PHARMACOECONOMIC CONTROVERSY Which ratio is the right ratio to use in pharmacoeconomic analyses? Experts differ over which ratio, ACER or ICER, is the most appropriate and useful. ACER reflects the cost per benefit of a new strategy independent of other alternatives, whereas ICER reveals the cost per unit of benefit of switching from one treatment strategy (that already may be in place) to another.13

COST-UTILITY ANALYSIS Pharmacoeconomists sometimes want to include a measure of patient preference or quality of life when comparing competing treatment alternatives. Cost-utility analysis (CUA) is a method for comparing treatment alternatives that integrates patient preferences and HRQOL. CUA can compare cost, quality, and the quantity of patient-years. Cost is measured in dollars, and therapeutic outcome is measured in patient-weighted utilities rather than in physical units. Often the utility measurement used is a quality-adjusted life year (QALY) gained. QALY is a common measure of health status used in CUA, combining morbidity and mortality data.33 Results of CUA are also expressed in a ratio, a cost-utility ratio (C/U ratio). Most often this ratio is translated as the cost per QALY gained or some other health-state utility measurement.8,16 The preferred treatment alternative is that with the lowest cost per QALY (or other health-status utility). QALYs represent the number of full years at full health that are valued equivalently to the number of years as experienced. For example, a full year of health in a disease-free patient would equal 1.0 QALY, whereas a year spent with a specific disease might be valued significantly lower, perhaps as 0.5 QALY, depending on the disease.

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CUA is the most appropriate method to use when comparing programs and treatment alternatives that are life extending with serious side effects (e.g., cancer chemotherapy),34 those which produce reductions in morbidity rather than mortality (e.g., medical treatment of arthritis),30,35 and when HRQOL is the most important health outcome being examined. CUA is employed less frequently than other economic evaluation methods because of a lack of agreement on measuring utilities, difficulty comparing QALYs across patients and populations, and difficulty quantifying patient preferences. CUA is complex, and thus CUA may be limited in scope of application from a hospital or MCO perspective. Nevertheless, when comparing treatment alternatives where HRQOL is the most important health outcome being examined, CUA should be considered. PHARMACOECONOMIC CONTROVERSY Because QALYs and other utility measures are highly subjective, there is some disagreement among researchers regarding which scales should be preferred for measuring utility.

HUMANISTIC EVALUATION METHODS Pharmacoeconomic evaluations also may focus on humanistic concerns. Methods for evaluating the impact of disease and treatment of disease on a patient’s HRQOL, patient preferences, and patient satisfaction are all growing in popularity and application to pharmacotherapy decisions. These methods also can assist clinicians in quantifying the value of pharmaceuticals. HRQOL has been defined as the assessment of the functional effects of illness and its consequent therapy as perceived by the patient.36 These effects often are displayed as physical, emotional, and social effects on the patient.17 Measurement of HRQOL usually is achieved through the use of patient-completed questionnaires. Many questionnaires are available, and most are either disease-specific or generic measures of health status.37,38 Various overviews on HRQOL and its application to pharmacy have been published.15,38−41 For further discussion on health outcomes and HRQOL, refer to Chapter 2.

APPLICATIONS OF PHARMACOECONOMICS Health care practitioners, regardless of practice setting, can benefit from applying the principles and methods of pharmacoeconomics to their daily practice settings. Applied pharmacoeconomics is defined as putting pharmacoeconomic principles, methods, and theories into practice to quantify the value of pharmacy products and pharmaceu6 tical care services used in real-world environments. Today’s practitioners increasingly are required to justify the value of the products and services they provide. Applied pharmacoeconomics can provide the means or tools for this valuation. One of the primary applications of pharmacoeconomics in clinical practice today is to aid clinical and policy decision making. Through the appropriate application of pharmacoeconomics, practitioners and administrators can make better, more-informed decisions regarding the products and services they provide. Complete pharmacotherapy decisions should contain assessments of three basic outcome areas whenever appropriate: clinical, economic, and humanistic outcomes. Traditionally, most drug therapy decisions were based solely on the clinical outcomes (e.g., safety and efficacy) associated with a treatment alternative. Over the past 10 to 15 years, it has become quite popular also to include an assessment of the economic outcomes associated with a treatment alternative. The current trend is also to

7

MICRO Clinical decisions Formulary management Drug use policy/guidelines Disease management Resource allocation MACRO

FIGURE 1–2. Decisions for pharmacoeconomic applications.

incorporate the humanistic outcomes associated with a treatment alternative, that is, to bring the patient back into this decision-making equation. This ECHO model for medical decision making has become 4 prevalent in current health care settings.14 In today’s health care environment, it is no longer appropriate to make drug-selection decisions based solely on acquisition costs. Thus, through the appropriate application of pharmacoeconomic principles and methods, incorporating these three critical components into clinical decisions can be accomplished. Pharmacoeconomic data can be a powerful tool to support various clinical decisions, ranging from the level of the patient to the 6 level of an entire health care system. Figure 1–2 shows various decisions that may be supported using pharmacoeconomics, including effective formulary management, individual patient treatment, medication policy, and resource allocation.13,21 For discussion purposes, the application of pharmacoeconomics to decision making is divided into two basic areas: drug therapy evaluation and clinical pharmacy service evaluation.

DRUG THERAPY EVALUATION 6 Historically, pharmacoeconomic principles and methods have

been applied commonly to assist clinicians and practitioners in making more informed and complete decisions regarding drug therapy. For example, pharmacoeconomics can provide critical costeffectiveness data to support the addition or deletion of a drug to or from a hospital formulary with or without restriction. In fact, the pharmacoeconomic assessment of formulary actions is becoming a standardized part of many pharmacy and therapeutic (P&T) committees. Selecting the most cost-effective drugs for an organizational formulary is important. However, it is equally important to determine the most appropriate way to use and prescribe these agents. Hence, developing and implementing appropriate use guidelines or policies based on sound pharmacoeconomic data can have a great impact on influencing prescribing patterns. Further, implementing sound drug-use guidelines/policies will ensure the most appropriate and cost-effective use of pharmaceutical agents throughout the health care system. The application of pharmacoeconomics also can be useful for making a decision about an individual patient’s therapy. Evaluating the impact a drug has on a patient’s HRQOL can be useful when deciding between two agents for customizing a patient’s pharmacotherapy. Although this can be one of the most difficult applications of pharmacoeconomics, it is also one of the most important.

CLINICAL PHARMACY SERVICE EVALUATION 6 The most recent application of pharmacoeconomic principles

and methods has been for justifying the value of various health

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care services, particularly pharmacy services. When a specific service is competing for hospital resources, pharmacoeconomics can provide the data necessary to justify that the service maximizes the resources allocated by health care system administrators. Pharmacoeconomics can be useful in determining the value of an existing service, estimating the potential worth of implementing a new service, or capturing the value of a “cognitive” clinical intervention. Practitioners and administrators can then use these data to make more informed resource-allocation decisions. For example, suppose you want to implement a pharmacy-based therapeutic drug monitoring program. It is hypothesized that this service will improve quality of patient care and save money for the health care system. After negotiating with hospital administrators, the funding for this service is approved for a 1-year trial basis, after which you must document and justify the value of this practice. Theoretically, all the relevant costs and benefits of the program should be measured and, if appropriate, converted into dollars using CBA. Potential benefits may include decreased total drug costs and decreased incidence of ADRs. Potential program costs are primarily the salary and benefits for a pharmacist and additional laboratory tests to monitor patients. Data documenting that the benefit of this pharmacy service yields a high return on investment (ROI) should increase the probability of the program continuing to be funded by the health care system. Unfortunately, previous reviews of the literature have revealed a disappointing number of rigorous economic evaluations of clinical pharmacy services published to date.42−44 However, a recently published review shows that the quality of published studies finally may be increasing.45 For example, McGhan and colleagues42 evaluated 35 potential CBAs or CEAs of pharmacy services published before 1978 and concluded that only 5 of these studies were legitimate CBAs or CEAs. MacKeigan and Bootman43 reviewed 22 CBAs or CEAs published between 1978 and 1987 and concluded that CBAs and CEAs have not been adopted extensively for the evaluation of clinical pharmacy services. In 1996, Schumock and associates44 reviewed economic evaluations of pharmacy services published between 1988 and 1995. Of the studies reviewed, only 19 were considered “full” or legitimate economic analyses, and the authors concluded that although the number of articles published has increased over the years, there is still a need for improvement in the quality or rigor of study design. Despite the relatively low number of methodologically sound studies, this review also revealed some results that demonstrate the potential

value of clinical pharmacy services. Of the 109 studies evaluated, the various clinical services reviewed in this study yielded an average C/B ratio of 16:1. In 2003, these authors updated their review and included articles published from 1996 to 2000.45 After reviewing 59 articles, these authors noted an improvement in the overall quality of the research (more studies included comparison groups and measured both costs and outcomes). Studies were conducted in hospital settings (52%), community pharmacies and clinics (41%), and community/clinic settings (18%). For the studies reporting the statistic, B/C ratios ranged from 1.74:1 to 17.01.45

STRATEGIES TO INCORPORATE PHARMACOECONOMICS INTO PHARMACOTHERAPY Various strategies are available to incorporate pharmacoeconomics into pharmacotherapy. Popular strategies for applying pharmacoeconomics to assess the value of pharmaceutical products and services include using the results of published pharmacoeconomic studies, building economic models, and conducting pharmacoeconomic research.46 Advantages and disadvantages of these strategies are summarized in Table 1–3.

USE THE PHARMACOECONOMIC LITERATURE 7 Quantifying the value of pharmaceuticals through pharma-

coeconomics has increased in popularity. Many pharmacoeconomic analyses are published in primary medical and pharmacy literature sources. Over the past 30 or more years, the actual number of pharmacoeconomic studies published exceeded 35,000 in 1993. However, the eagerness to conduct pharmacoeconomic evaluations of drugs often exceeds the quality of these evaluations. Variations in quality and indiscriminate use of pharmacoeconomic terminology are documented in medical and pharmacy literature sources.4,42−45,47−49 To use this literature as an aid in clinical decision making, it must be (1) critically evaluated for quality and rigor and (2) interpreted correctly. Therefore, prior to using pharmacoeconomic data to make clinical and policy decisions, decision makers should recognize the potential limitations of those data.

TABLE 1–3. Advantages and Disadvantages of Pharmacoeconomic Application Strategies Strategy Use published literature

Build an economic model

Conduct a pharmacoeconomic study

RCT, randomized controlled trial.

Advantage

Disadvantage

Quick Inexpensive Subject to peer review Results may be from RCT Variety of results can be examined Quick Relatively inexpensive Yields organization-specific results Bridges efficacy and effectiveness Data collection is unobtrusive Flexible Usually comparative Yields organization-specific data Reflects “usual care” or effectiveness Data from multiple sources can be used

Results from RCT Difficult to generalize results May not be comparative Misuse of pharmacoeconomic terms Variations in rigor/quality Results dependent on assumptions Potential for researcher bias Controversial Reluctance of decision makers to accept results Expensive Time-consuming Difficult to control and randomize Potential for patient selection bias Potential for small sample size

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A primary consideration when evaluating and interpreting a study is the ability to generalize or transfer the results to other health care settings and countries. It can be difficult to generalize and transfer the results of a published study primarily because of wide variations in practice patterns, patient populations, and costs among health care systems and countries. Further, differences in study perspectives, data sources, and analytic styles may present a challenge for practitioners attempting to extrapolate or relate exact cost savings or cost ratios to their own practice settings. To enhance the ability to use pharmacoeconomic results published in the literature, consider the following points: 1. What is the technical merit of the study? 2. Are the results applicable to local decision making? 3. Do the results apply generally in different jurisdictions with different perspectives?50 Various guidelines, criteria, reviews, and consensus-based recommendations for evaluating, conducting, and reporting pharmacoeconomic literature have been published.7,17,31,32,51−60 These guidelines and criteria have been combined and summarized into 11 categories most pertinent to pharmacotherapy.54 A summary of these 11 criteria and pertinent questions for each category are given in Table 1–4. Each evaluation criterion is briefly discussed next.

STUDY OBJECTIVE

of the pharmacoeconomic problem identified. An evaluation may be conducted from single or multiple perspectives as long as the costs and consequences identified are relevant to the perspective(s) chosen.

PHARMACOECONOMIC METHOD It should be clear which pharmacoeconomic method was employed (CEA, CMA, CBA, or CUA), and this method should be appropriate given the problem (e.g., CMA is appropriate if comparing two alternatives equivalent in therapeutic outcome but not if the alternatives differ in therapeutic outcome). Also, a researcher may claim that a specific method was employed (e.g., CEA) but actually employ another method (e.g., CMA).

STUDY DESIGN Pharmacoeconomic evaluations can be prospective or retrospective. Although prospective designs usually are preferred, retrospective evaluations can be rich with information and reflective of usual care. Many pharmacoeconomic evaluations today are conducted as a part of randomized, controlled clinical trials. Two cautions for interpreting pharmacoeconomic data collected in this manner include (1) costs can be protocol-driven, not necessarily reflective of using a drug in common practice,61 and (2) control of subjects and decreased complications may yield greater costs and benefits than those observed in common practice.51

A clear statement of the purpose of the study should be given. This objective should be clear, concise, well defined, and measurable.

STUDY PERSPECTIVE The researcher must select one or more perspectives (e.g., patient, provider, payer, or society) from which the analysis will be conducted.9 This perspective should be appropriate given the scope

9

CHOICE OF INTERVENTIONS All relevant treatment options that are available should be described completely or mentioned. The treatment alternatives and dosages being compared should be those used in common practice, and evidence of their effectiveness should be established. Because pharmacoeconomic methods are tools to aid in choosing among treatment

TABLE 1–4. Basic Criteria for Evaluation of Pharmacoeconomic Literature Objective What is the question(s) being considered? Is the question clear, defined, and measurable? Perspective What is/are the perspective(s) of the analysis? Is the perspective appropriate given the scope of the problem? Pharmacoeconomic Method What pharmacoeconomic tool was used? Is it appropriate given the problem? Is it actually what was conducted? Study Design What was the study design? What were the data sources? Is the evaluation suitable if carried out in a clinical trial? Choice of Interventions Were all appropriate alternatives considered and described? Were any appropriate alternatives omitted? Are the alternatives relevant to the perspective and clinical nature of the study? Is there evidence that the alternatives’ effectiveness has been established? Costs and Consequences What are the costs and consequences (outcomes) included? Are the costs and outcomes relevant to the perspective chosen?

Sensitivity Analysis Are cost ranges for significant variables tested for sensitivity? Are the appropriate and relevant variables varied? Do the findings follow the anticipated trend? Conclusions Are the conclusions of the study justified? Is it possible to extrapolate the conclusions to daily clinical practice? Sponsorship Was there any bias due to the sponsorship of the study? Do they include negative outcomes (failures, ADRs)? How were they valued? Were costs and consequences measured in the appropriate physical units? Discounting Was the study performed over time? Were costs and consequences that occur in the future discounted to their present value? Was any justification given for the discount rate used? Results Are the results accurate and practical for medical decision makers? Were the appropriate statistical analyses performed? Was an incremental analysis performed? Are all the assumptions and limitations of the study discussed?

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alternatives, assessing the cost of a single alternative is considered a partial economic evaluation.

COSTS AND CONSEQUENCES All the important and relevant costs and consequences for each program or treatment alternative should be identified. The costs and consequences identified must be relevant to the study perspective(s) and measured in suitable terms using the appropriate physical units. Costs should include direct, indirect, and intangible costs. Consequences should include the positive and negative clinical and humanistic outcomes associated with the program or treatment alternative. All these costs and consequences must be valued credibly, with the data sources clearly identified.

DISCOUNTING The comparison of programs or treatment alternatives should be made at one point in time; thus any costs and consequences not occurring in the present must be addressed. Discounting, or adjusting for differential timing, is the process of reducing any costs and consequences that may occur in the future back to their present value. If a study is performed over time (more than 1 year), or if future cost savings are projected, discounting should be done using an appropriate discount rate. The rate recommended by most investigators is typically 3% to 8% per annum, representing annual inflation or bank interest rates. However, the modal rates used in pharmacoeconomic evaluations appear to be 5%. Researchers disagree about which discount rate to use, as well as about whether to discount costs and health benefits (simultaneously) using the same discount rate(s).

STUDY RESULTS A full discussion of the study assumptions and limitations and how to interpret the results in the context of different practice settings17 should be provided. This discussion should include all relevant issues of concern to potential users of the study. The results should show that the appropriate statistical analyses were performed. Also, it may be appropriate to express the study results in terms of increases, that is, to use incremental cost analysis (additional cost of gaining an additional benefit by using one drug over another).

results should be justified (internal validity) and able to be generalized (external validity).54 Also, conclusions drawn from results that were statistically significant may or may not be clinically relevant, and vice versa.

SPONSORSHIP Similar to evaluating the quality of a clinical trial, sponsorship of a pharmacoeconomic study should be considered when evaluating the quality and usefulness of that study.52 The quality of studies conducted or funded by different companies or organizations will vary by sponsor, company, product, or evaluation, and the potential for bias should be neither ignored nor assumed. For example, many of the studies sponsored or conducted by the pharmaceutical industry to date have been academically rigorous as well as informative. A clear understanding of how to evaluate, critique, and use the pharmacoeconomic literature appropriately will minimize any potential effects of this criterion on clinical decision making.

CONTROVERSIES WITH PHARMACOECONOMIC LITERATURE Over the years, the literature has highlighted the misuse of pharmacoeconomic terms, inconsistent reporting, and disagreement on the methods used for pharmacoeconomic analyses. Since pharmacoeconomics is a fairly new discipline that lacks strong consensus with respect to its methods and technically appropriate applications, the disagreement between leading researchers in this field has been widespread and evident.60 Unfortunately, this has led to some external skepticism, as well as the inability of clinicians to use the findings of these analyses as extensively as they could to inform their local decision making.60 Creating and implementing a standardized system for conducting and reporting results of pharmacoeconomic analyses are critical to minimize or eliminate some of these controversies. A review of national guidelines for various countries was published and revealed some areas of emerging standarization.63 Such a standardized system would enhance clinicians’ and decision makers’ comprehension of the available data, as well as provide increased assurance that the results reported are methodologically sound.

SENSITIVITY ANALYSIS

BUILD AN ECONOMIC MODEL

It is imperative that researchers test the sensitivity of study results using sensitivity analysis. Using this method, practitioners and researchers can deal with data uncertainties and assumptions and their effect on study conclusions. Sensitivity analysis (SA) is the process of testing the robustness of an economic evaluation by examining changes in results. Specific variables such as percent effectiveness, incidence of ADRs, and dominant resources can be varied over a range of plausible values and the results recalculated. The four general approaches to SA are simple SA, threshold analysis, analysis of extremes, and Monte Carlo simulation analysis.62 SA is of paramount importance because of the very common need for investigators to use assumptions and estimates for unknown variables.49

8 Studies that model the economic impact of a pharmaceutical

STUDY CONCLUSIONS Researchers should assist the reader in extrapolating study conclusions to clinical practice. The conclusions drawn from the study

product or service on a defined population are increasing in popularity. Modeling studies use existing clinical and/or epidemiologic data to project future outcomes.64 Use of economic models can provide support for various clinical decisions, especially those which are time-contingent.46 Identifying assumptions regarding the treatment alternatives being compared, the patient outcomes under study, and the probability of those outcomes occurring can provide the basis for an economic simulation to assist in the medication decision-making process. These studies can use data from various sources available within (internal) and from outside (external) a specific health care organization. Common approaches to modeling are to modify and adapt existing models or to develop a distinct model to answer a specific question.65 Typically, economic modeling in today’s practice settings employs clinical decision analysis, which has been defined as an explicit, quantitative, and prescriptive approach to choosing among

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alternative outcomes.66,67 The tool used in decision analysis is a decision tree. A decision tree provides a framework to display graphically primary variables, including treatment options, outcomes associated with those treatment options, and probabilities of the outcomes. The researcher can then algebraically reduce all these factors into a single value, allowing for comparison. Many examples of decision-analytic models are available in the literature, spanning many therapeutic areas, including the treatment of depression,68 migraine,69 type 2 diabetes,70 and community-acquired pneumonia (CAP).71 In fact, by 1996, more than 80 published articles had been identified that applied decision analysis to questions regarding pharmaceutical products.72 This simple decision-analysis approach is well suited for comparisons of treatment alternatives with relatively immediate consequences, for example, treating a patient with CAP. However, chronic conditions or diseases such as chronic hepatitis C are difficult to model using simple decision trees for various reasons, including time-dependent clinical outcomes, and thus may require alternate modeling techniques. Markov models are another method of decision analysis that provides an alternative way to arrange the decision process so that clinical outcomes and time-dependent risk changes are managed efficiently. The Markov model is designed to simulate the most important aspects of a disease and can be used to estimate the long-term clinical, humanistic, and economic dimensions of the disease.73 There are examples of Markov models available in the literature, including estimates of the cost-effectiveness of interferon-α therapy for the treatment of chronic hepatitis C infection.74−76 Although Markov models can be stand-alone models, they often are combined with simple decision trees to predict the long-term effects of therapies.73 These models can be complex; thus clinicians who attempt to use these data or perform their own Markov modeling should become familiar with these techniques.73,77 Using an economic model can help the clinician to forecast the impact of medication-use decisions on a patient, institution, or health care system. Also, as new drugs are marketed that can displace older agents, an economic model can expedite the reappraisal process for formulary management and drug-use policy decisions.78 For building an economic model to assist in clinical decision making, various published studies and a review can be considered.72,79−83 Further, guidelines for economic modeling are available, and health care practitioners considering using modeling techniques should refer to them.84−86

CONDUCT A PHARMACOECONOMIC EVALUATION 8 Clinicians may need to conduct a pharmacoeconomic evaluation

if there is insufficient literature, if published results cannot be extrapolated to clinical practice, or if building a model is not appropriate. Before conducting a pharmacoeconomic evaluation, clinicians should be familiar with the similarities, differences, and appropriate application of pharmacoeconomic methods (discussed earlier in this chapter). The decision to conduct a local pharmacoeconomic study is not without its own costs. Because both time and monetary resources are consumed by these evaluations, specific pharmacy products and services for pharmacoeconomic evaluation should be targeted. Thus this strategy should be reserved for pharmacy decisions that may have a significant impact on cost or quality of care. Conducting pharmacoeconomic research in a hospital or managed-care environment can be challenging. Lack of institutional

11

resources, small sample sizes, difficulty randomizing, inability to compare with placebo, and difficulty generalizing results all may be limitations. For example, when asked to determine and recommend the most cost-effective antihypertensive agent for a formulary management decision, clinicians may lack monetary and time resources to conduct a scientifically rigorous study. Conducting a pharmacoeconomic evaluation should be guided by the criteria for quality economic evaluations.8,17,32,51−59 A 10-step process identified by Jolicoeur and associates87 and four additional steps that I have added can provide readers with guidance for conducting a local pharmacoeconomic study.88 This process contains 14 fundamental steps for conducting a pharmacoeconomic evaluation in a health care system and can be applied to virtually any therapeutic area or health care service. Although some of these steps are similar to the evaluation criteria detailed earlier in this chapter, they will now be discussed briefly in the context of conducting an evaluation.

STEP 1: DEFINE THE PHARMACOECONOMIC PROBLEM A broad problem might be, “Which antiemetic regimen represents the best value for the prevention of chemotherapy-induced emesis (CIE)?” However, a more succinct and measurable problem would be, “Which regimen is the best value for preventing acute CIE in patients receiving highly emetogenic chemotherapy?”

STEP 2: ASSEMBLE A CROSS-FUNCTIONAL STUDY TEAM The study team can provide early buy-in and additional resources for a pharmacoeconomic evaluation. Team members vary depending on the analysis but may include representatives from medicine, nursing, pharmacy, hospital administration, and information systems.

STEP 3: DEFINE THE APPROPRIATE STUDY PERSPECTIVE Choose a study perspective(s) most relevant to the problem. For example, if the problem is as listed in step 1, then the perspective of the institution or health care system may be most appropriate.

STEP 4: IDENTIFY TREATMENT ALTERNATIVES AND OUTCOMES Treatment alternatives can include pharmacologic and nonpharmacologic options but should include all clinically relevant alternatives. The outcomes identified should include both positive and negative clinical outcomes.

STEP 5: IDENTIFY THE APPROPRIATE PHARMACOECONOMIC METHOD TO EMPLOY Pharmacoeconomic methods to choose from include CMA, CBA, CEA, and CUA. Employing the incorrect method can adversely affect medication decisions influencing both cost and quality of care.

STEP 6: PLACE A MONETARY VALUE ON TREATMENT ALTERNATIVES AND OUTCOMES Placing a monetary value on treatment alternatives and outcomes includes not only drug administration and acquisition costs but also the

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cost of positive and negative clinical outcomes (e.g., determining the cost of ADRs and treatment failures). This can be measured prospectively or retrospectively or estimated using comprehensive databases or expert panels.

ACER option A = $358.30/0.93 = $385

Success (0.93) 247.8

STEP 7: IDENTIFY RESOURCES TO CONDUCT STUDY IN AN EFFICIENT MANNER Resources necessary will vary by study but may include access to medical or computerized records, average medical personnel wages, and specialty medical staff.

Path No ADE (0.89) Success/no ADE 1 222.5 $250

266.5 ADE (0.11)

Success/ADE 44

Drug option A $60 per patient 298.3

$400

No ADE (0.89) Failure/no ADE 578.5 $650

2

3

50.5 Failure (0.07) 721.5

STEP 8: IDENTIFY PROBABILITIES THAT OUTCOMES MAY OCCUR IN THE STUDY POPULATION

ADE (0.11)

Failure/ADE $1,300

143

What are the probabilities of the outcomes identified in step 4 actually occurring in clinical practice? Using primary literature and expert opinion, these probabilities can be obtained and may be manifested as efficacy rates and incidence of ADRs.

No ADE (0.96) Success/no ADE 240 $250

256

STEP 9: EMPLOY DECISION ANALYSIS

ADE (0.04)

Success/ADE $400

16

1. Multiply the cost of path 1 by the probability of no ADE ($250 × 0.89). Repeat for path 2 ($400 × 0.11). 2. Add these two numbers and multiply by the probability of success ($266.50 × 0.93 = $247.80). 3. Repeat the two preceding steps for paths 3 and 4, and then add the resultant values ($247.80 + $50.50 = $298.30). 4. Add the cost of the drug to this value ($298.30 + $60), and divide by the probability of a success (93%, or 0.93); thus $358.30/0.93 = $385. 5. Repeat this process for drug B using paths 5 through 8. Using the values in Table 1–5, another way to calculate the ACER for these treatment options is to multiply the cumulative probabilities (P) by the cumulative costs for each path, then sum the costs for each path 1 through 4 (for drug A) and 5 through 8 (for drug B), and then divide by each drug’s respective effectiveness for acute CIE. On completion, the ACERs for drugs A and B are $385 and $369, respectively. Therefore, despite the 33% increase in the cost of drug B

5

Success (0.97) 248

The use of decision analysis can assist in conducting various economic evaluations, including CEA. Although not necessary for all pharmacoeconomic evaluations, decision analysis and decision trees may provide a solid backbone or platform for the decision at hand. Using a decision tree, treatment alternatives, outcomes, and probabilities may be presented graphically and may be reduced algebraically to a single value for comparison (i.e., cost-effectiveness ratio). When comparing antiemetic agents for the development of a policy for CIE prevention, CEA can be employed. Many of these agents differ with respect to effectiveness, safety, and cost. By performing a thorough CEA, these variables can be reduced to a single number (cost-effectiveness ratio), which will allow for a meaningful comparison. The treatment alternative with a better cost-effectiveness ratio than the others (i.e., lower cost per unit of outcome) would be selected and promoted for use. Figure 1–3 contains an example of a decision tree illustrating how the probabilities of various outcomes can be organized. To calculate the ACER for drug A using “averaging out and folding back,” these steps are followed:

4

6

Drug option B $90 per patient 268

No ADE (0.96) Failure/no ADE 624 $650

7

20 Failure (0.03) 676 ADE (0.04) ACER option B = $358.60/0.97 = $369

Failure/ADE 52

$1,300

8

FIGURE 1–3. Example of a pharmacoeconomic decision tree comparing two drugs. Option B is a drug that is more specific for the target receptor in the body, is more effective, and produces fewer adverse effects than does option A. However, because drug B is more expensive than drug A, the cost of the added benefits must be analyzed using pharmacoeconomic techniques. This figure was completed using the safety and efficacy values for drugs A and B from Table 1–5. Values in color are calculated numbers, only included to illustrate the process of “averaging out and folding back.” ACER = average cost-effectiveness ratio; ADE = adverse drug event; P = probability (a decimal fraction between 0 and 1 indicating the likelihood of a particular event occurring in a given period). (Data from Sanchez LA, Lee JT. Applied pharmacoeconomics: Modeling data from internal and external sources. Am J Health Syst Pharm 2000;57:146– 158.)

over drug A, its increased efficacy for acute CIE and its decreased incidence of ADRs actually make it a more cost-effective option.

STEP 10: DISCOUNT COSTS OR PERFORM A SENSITIVITY OR INCREMENTAL COST ANALYSIS Costs and consequences that occur in the future must be discounted back to their present value. Sensitive variables must be tested over a clinically relevant range and results recalculated. If appropriate, an incremental analysis of the costs and consequences should be performed.

STEP 11: PRESENT STUDY RESULTS Results should be presented to the cross-functional team and the appropriate committees. Presentation style and content may vary depending on the audience.

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TABLE 1–5. Comparison of Costs of Two Drug Options for Preventing Acute Chemotherapy-Induced Emesis Path Drug A 1 2 3 4 Cost of option Drug B 5 6 7 8

Drug Cost ($)

Chemotherapy Cost ($)

Lab Cost ($)

Extra Therapy Cost ($)

60 60 60 60

200 200 200 200

50 100 100 150

100 200 300

Delay in Clinic Cost ($)

150 150

Hospital Cost ($)

Cumulative Cost ($)

Cumulative Probabilities

Cost of path ($)

500

310 460 710 1360

0.827 0.102 0.062 0.007

256.37 46.92 44.02 9.52 $356.83

90 90 90 90

200 200 200 200

50 100 100 150

100 200 300

150 150

500

340 490 740 1390

0.931 0.038 0.028 0.001

Cost of option

316.54 18.62 20.72 1.39 $357.27

STEP 12: DEVELOP A POLICY OR AN INTERVENTION Take the study results and develop a policy or an intervention that can improve or maintain quality of care, possibly at a cost savings.

STEP 13: IMPLEMENT POLICY AND EDUCATE PROFESSIONALS Spend adequate time and resources strategically implementing the policy or intervention. Educate the health care professionals most likely to be affected by this policy using various strategies, including verbal, written, and online communication.

STEP 14: FOLLOW-UP DOCUMENTATION Once the intervention or policy has been implemented for a reasonable period of time, collect follow-up data. These data will provide feedback on the success and quality of the policy or intervention. For additional information and hands-on practice conducting a pharmacoeconomic evaluation in the real world, practitioners should consider a recently published case study. In 2003, Okamoto89 published a case study on conducting a pharmacoeconomic evaluation using 16 steps that readers also may find useful. In this case, clinicians are challenged to conduct a faux economic analysis from an MCO (provider) perspective to support a review of inhaled corticosteroids for formulary management purposes.

CONCLUSIONS The principles and methods of pharmacoeconomics provide the means to quantify the value of pharmacotherapy through balancing costs and outcomes. Providing quality care with minimal resources is the future, and the future is here. By understanding the principles, methods, and application of pharmacoeconomics, health care professionals will be prepared to make better, more-informed decisions regarding the use of pharmaceutical products and services, that is, decisions that ultimately represent the best interests of the patient, the health care system, and society.

ABBREVIATIONS ACER: average cost-effectiveness ratio ADR: adverse drug reaction

AWP: average wholesale price B/C ratio: benefit-to-cost ratio CAP: community-acquired pneumonia CBA: cost-benefit analysis CCA: cost-consequence analysis CEA: cost-effectiveness analysis COI: cost of illness CMA: cost-minimization analysis CUA: cost-utility analysis ECHO: economic, clinical, and humanistic outcomes HRQOL: health-related quality of life ICER: incremental cost-effectiveness ratio MCO: managed-care organization QALY: quality-adjusted life year SA: sensitivity analysis WTP: willingness-to-pay Review Questions and other resources can be found at www.pharmacotherapyonline.com.

REFERENCES 1. Sanchez LA. Expanding the pharmacist’s role in pharmacoeconomics: How and why? Pharmacoeconomics 1994;5:367–375. 2. Townsend RJ. Post-marketing drug research and development. Ann Pharmacother 1987;21:134–136. 3. Drummond M, Smith GT, Wells N. Economic Evaluation in the Development of Medicines. London, Office of Health Economics, 1988:33. 4. Lee JT, Sanchez LA. Interpretation of “cost-effective” and soundness of economic evaluations in the pharmacy literature. Am J Hosp Pharm 1991;48:2622–2627. 5. Bootman JL. Pharmacoeconomics and outcomes research. Am J Health System Pharm 1995;52(suppl 3):S16–S19. 6. Hepler CD, Strand LM. Opportunities and responsibilities in pharmaceutical care. Am J Hosp Pharm 1990;47:533–543. 7. Eisenberg JM. Clinical economics: A guide to economic analysis of clinical practices. JAMA 1989;262:2879–2886. 8. Bootman JL, Townsend RJ, McGhan WF. Principles of Pharmacoeconomics. 3rd ed. Cincinnati, Harvey Whitney Books, 2005. 9. Freund DA, Dittus RS. Principles of pharmacoeconomic analysis of drug therapy. Pharmacoeconomics 1992;1:20–32. 10. Barner J, Rascati K. Cost-benefit analysis. In Grauer D, Lee J, Odom T, et al., eds. Pharmacoeconomics and Outcomes, 2d ed. Kansas City, MO, American College of Clinical Pharmacy, 2003:115–132.

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11. Blumenschein K, Johannesson M. Use of contingent valuation to place a monetary value on pharmacy services: An overview and review of the literature. Clin Ther 1999;21:1402–1417. 12. Glossary of terms used in pharmacoeconomic and quality of life analysis. Pharmacoeconomics 1992;1:151. 13. Detsky AS, Nagiie IG. A clinician’s guide to cost-effectiveness analysis. Ann Intern Med 1990;113:147–154. 14. Kozma CM, Reeder CE, Schulz RM. Economic, clinical, and humanistic outcomes: A planning model for pharmacoeconomic research. Clin Ther 1993;15:1121–1132. 15. Bungay KM, Sanchez LA. Types of economic and humanistic outcomes assessments. In Grauer D, Lee J, Odom T, et al., eds. Pharmacoeconomics and Outcomes, 2d ed. Kansas City, MO, American College of Clinical Pharmacy, 2003:18–60. 16. Draugalis JR, Bootman LJ, Larson LN, McGhan WF. Current Concepts: Pharmacoeconomics. Kalamazoo, MI, Upjohn, 1989. 17. Drummond MF, Stoddart GL, Torrance GW. Methods for the Economic Evaluation of Health Care Programmes, 2d ed. Oxford, England, Oxford University Press, 1997. 18. McGhan WF. Pharmacoeconomics and the evaluation of drugs and services. Hosp Formul 1993;28:365–378. 19. Rice DP, Fox PJ, Max W, et al. The economic burden of Alzheimer’s disease care. Health Affairs 1993;12(2):164–176. 20. Ernst RL, Hay JW. The U.S. economic and social costs of Alzheimer’s disease revisited. Am J Public Health 1994;84:1261–1264. 21. Sanchez LA, Lee JT. Use and misuse of pharmacoeconomic terms. Top Hosp Pharm Manage 1994;13:11–22. 22. Cox E. Cost-minimization analysis. In Grauer D, Lee J, Odom T, et al. (eds.): Pharmacoeconomics and Outcomes, 2d ed. Kansas City, MO, American College of Clinical Pharmacy, 2003:103–114. 23. Sanchez LA. Pharmacoeconomic principles and methods: An introduction for hospital pharmacists. Hosp Pharm 1994;29:1035–1040. 24. Lai LL, Sorkin AL. Cost-benefit analysis of pharmaceutical care in a Medicaid population: From a budgetary perspective. J Manage Care Pharm 1998;4:303–308. 25. Schrand LM, Elliott JM, Ross MB, et al. Cost benefit analysis of RSV prophylaxis in high-risk infants. Ann Pharmacother 2001;35:1186– 1193. 26. Nesbit TW, Shermock KM, Bobek MB, et al. Implementation and pharmacoeconomic analysis of a clinical staff pharmacist practice model. Am J Health Syst Pharm 2001;58:784–790. 27. Sias JJ, Cook S, Wolfe T, et al. An employee influenza immunization initiative in a large university managed care setting. J Manage Care Pharm 2001;7:219–223. 28. Zarnke KB, Levine MAH, O’Brien BJ. Cost-benefit analyses in the health-care literature: Don’t judge a study by its label. Clin Epidemiol 1997;50:813–822. 29. Bootman JL, Larson LN, McGhan WF, Townsend RJ. Pharmacoeconomic research and clinical trials: Concepts and issues. Ann Pharmacother 1989;23:693–697. 30. Bootman JL. The basics of pharmacoeconomic analysis. Pharm Rep 1993;23:14–15. 31. Langley PC. The role of pharmacoeconomic guidelines for formulary approval: The Australian experience. Clin Ther 1993;15:1154–1176. 32. Detsky AS. Guidelines for economic analysis of pharmaceutical products: A draft document for Ontario and Canada. Pharmacoeconomics 1993;3:354–361. 33. Pathak DS. QALYs in health outcomes research: Representation of real preferences or another numerical abstraction? J Res Pharm Econ 1995;6:3–27. 34. Kaplan RM. Quality-of-life assessment for cost/utility studies in cancer. Cancer Treat Rep 1993;19(suppl A):85–96. 35. Gabriel SE, Campion ME, O’Fallon WM. A cost-utility analysis of misoprostol prophylaxis for rheumatoid arthritis patients receiving nonsteroidal anti-inflammatory drugs. Arthritis Rheum 1994;37:333–341. 36. Schipper H, Clinch J, Powell V. Definitions and conceptual issues. In Spilker B (ed.): Quality of Life Assessments in Clinical Trials. New York, Raven Press, 1990.

37. Spilker B. Quality of Life Assessments in Clinical Trials. New York, Raven Press, 1990. 38. Spilker B, White WSA, Simpson RJ, Tilson HN. Quality of life bibliography and indexes—1990 update. Clin Pharmacoepidemiol 1992;6:157– 158. 39. Coons SJ. Quality of life assessment: Understanding its use as an outcome measure. Hosp Formul 1993;28:486–498. 40. Jaeschke R, Guyatt GH, Cook D. Quality of life instruments in the evaluation of new drugs. Pharmacoeconomics 1992;1:84–94. 41. Mackeigan LD, Pathak DS. Overview of health-related quality-of-life measures. Am J Hosp Pharm 1992;49:2236–2245. 42. McGhan WF, Rowland CR, Bootman JL. Cost-benefit and costeffectiveness: Methodologies for evaluating innovative pharmaceutical services. Am J Hosp Pharm 1978;35:133–140. 43. MacKeigan LD, Bootman JL. A review of cost-benefit and costeffectiveness analyses of clinical pharmacy services. J Pharm Market Manage 1988;2:63–84. 44. Schumock GT, Meek PD, Ploetz PA, Vermeulen LC. Economic evaluations of clinical pharmacy services—1988–1995. Pharmacotherapy 1996;16:1188–1208. 45. Schumock GT, Butler MG, Meek PD, et al. Evidence of economic benefit of clinical pharmacy services: 1996–2000. Pharmacotherapy 2003; 23:113–132. 46. Sanchez LA. Pharmacoeconomic principles and methods: Including pharmacoeconomics into hospital pharmacy practice. Hosp Pharm 1994;29:1035–1040. 47. Doubilet P, Weinstein MC, McNeil BJ. The use and misuse of the term ”cost-effective” in medicine. N Engl J Med 1986;314:253–256. 48. Bradley CA, Iskedjian M, Lanctot KL, et al. Quality assessment of economic evaluation in selected pharmacy, medical, and health economic journals. Ann Pharmacother 1995;29:681–689. 49. Udvarhelyi S, Colditz GA, Rai A, et al. Cost-effectiveness and cost-benefit analyses in the medical literature. Ann Intern Med 1992;116:238–244. 50. Mason J. The generalizability of pharmacoeconomic studies. Pharmacoeconomics 1997;11:503–514. 51. Sacristan JA, Soto J, Galende I. Evaluation of pharmacoeconomic studies: Utilization of a checklist. Ann Pharmacother 1993;27:1126–1133. 52. Hillman AL, Eisenberg JM, Pauly MV, et al. Avoiding bias in the conduct and reporting of cost-effectiveness research sponsored by pharmaceutical companies. N Engl J Med 1991;324:1362–1365. 53. McGhan WF, Lewis JV. Guidelines for pharmacoeconomic studies. Clin Ther 1992;14:486–494. 54. Sanchez LA. Pharmacoeconomic principles and methods: Evaluating the quality of published pharmacoeconomic evaluations. Hosp Pharm 1995;30:146–152. 55. Clemans K, Townsend R, Luscombe F, et al. Methodological and conduct principles for pharmacoeconomic research. Pharmacoeconomics 1995;8:169–174. 56. Task Force on Principles for Economic Analysis of Health Care Technology. Economic analysis of healthcare technology: A report on principles. Ann Intern Med 1995;122:61–70. 57. Russell LB, Gold MR, Siegel JE, et al. The role of cost-effectiveness analysis in health and medicine. JAMA 1996;276:1172–1177. 58. Weinstein MC, Siegel JE, Gold MR, et al. Recommendations of the Panel on Cost-effectiveness in Health and Medicine. JAMA 1996;276:1253– 1258. 59. Siegel JE, Weinstein MC, Russell LB, et al. Recommendations for repeating cost-effectiveness analyses. JAMA 1996; 276:1339–1341. 60. Mullins CD, Flowers LR. Evaluating economic outcomes literature. In Grauer D, Lee J, Odom T, et al. (eds.): Pharmacoeconomics and Outcomes, 2d ed. Kansas City, MO, American College of Clinical Pharmacy, 2003:246–273. 61. Eisenberg JM, Glick H, Koffer H. Pharmacoeconomics: Economic evaluation of pharmaceuticals. In Strom BL (ed.): Pharmacoepidemiology. New York, Churchill-Livingstone, 1989:325–350. 62. Armstrong EP. Sensitivity analysis. In Grauer D, Lee J, Odom T, et al. (eds.): Pharmacoeconomics and Outcomes, 2d ed. Kansas City, MO, American College of Clinical Pharmacy, 2003:231–245.

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63. Mullins CD, Ogilvie S. Emerging standardization in pharmacoeconomics. Clin Ther 1998;20(60):1194–1202. 64. Milne RJ. Evaluation of the pharmacoeconomic literature. Pharmacoeconomics 1994;6:337–345. 65. Sanchez LA, Lee JT. Applied pharmacoeconomics: Modeling data from internal and external sources. Am J Health Syst Pharm 2000;57:146–158. 66. Sackett DL, Haynes RB, Tugwell P. Clinical Epidemiology: A Basic Science for Clinical Medicine. Boston, Little Brown, 1985:126. 67. Barr JT, Schumacher GE. Decision analysis and pharmacoeconomic evaluations. In Bootman JL, Townsend RJ, McGhan WF (eds.): Principles of Pharmacoeconomics, 2d ed. Cincinnati, Harvey Whitney Books, 1996. 68. Jones MT, Cockrum PC. A critical review of published economic modeling studies in depression. Pharmacoeconomics 2000;17:555–583. 69. Biddle AK, Shih YC, Kwong WJ. Cost-benefit analysis of sumatriptan tablets versus usual therapy for treatment of migraine. Pharmacotherapy 2000;20:1356–1364. 70. Coyle D, Lee KM, O’Brian BJ. The role of models with economic analysis: Focus on type 2 diabetes mellitus. Pharmacoeconomics 2002;20(suppl 1):11–19. 71. Najib MM, Stein GE, Goss TF. Cost-effectiveness of sparfloxacin compared with other oral antimicrobials in outpatient treatment of communityacquired pneumonia. Pharmacotherapy 2000;20:461–469. 72. Barr JT, Schumacher GE. Using decision analysis to conduct pharmacoeconomic studies. In Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials, 2d ed. Philadelphia, Lippincott-Raven, 1996. 73. Touchette D, Hartung D. Markov modeling. In Grauer D, Lee J, Odom T, et al. (eds.): Pharmacoeconomics and Outcomes, 2d ed. Kansas City, MO, American College of Clinical Pharmacy, 2003:206–230. 74. Bennett WG, Inoue Y, Beck JR, et al. Estimates of the cost-effectiveness of a single course of interferon-α2b in patients with histologically mild chronic hepatitis C. Ann Intern Med 1997;127:855–865. 75. Kim WR, Poterucha JJ, Hermans JE, et al. Cost-effectiveness of 6 and 12 months of interferon-α therapy for chronic hepatitis C. Ann Intern Med 1997;127:866–874. 76. Younossi ZM, Singer ME, McHutchison JG, Shermock KM. Cost effectiveness of interferon-α2b combined with ribavirin for the treatment of chronic hepatitis C. Hepatology 1999;30:1318–1324.

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77. Briggs A, Sculpher M. An introduction to Markov modeling for economic evaluation. Pharmacoeconomics 1998;13:397–409. 78. Schecter CB. Decision analysis in formulary decision making. Pharmacoeconomics 1993;3:454–461. 79. Bjornson DC, Hiner WO, Potyk RP, et al. Effect of pharmacists on health care outcomes in hospitalized patients. Am J Hosp Pharm 1993;50:1875– 1884. 80. Zabinski RA, Burke TA, Johnson J, et al. An economic model for determining the costs and consequences of using various treatment alternatives for the management of arthritis in Canada. Pharmacoeconomics 2001;19(suppl 1):49–58. 81. Harrison DL, Bootman JL, Cox ER. Cost-effectiveness of consultant pharmacists in managing drug-related morbidity and mortality at nursing facilities. Am J Health Syst Pharm 1998;55:1588–1594. 82. Kessler JM. Decision analysis in the formulary process. Am J Health Syst Pharm 1997;54(suppl 1):S5–S8. 83. Paladino JA. Cost-effectiveness comparison of cefepime and ceftazidime using decision analysis. Pharmacoeconomics 1994;5:505–512. 84. Akehurst R, Anderson P, Brazier J, et al. Consensus Conference on Guidelines on Economic Modeling in Health Technology Assessment. Decision analytic modeling in economic evaluation of health technologies: A consensus statement. Pharmacoeconomics 2000;17:443–444. 85. Brennan A, Akehurst R. Modeling in health economic evaluation. What is its place? What is its value? Pharmacoeconomics 2000;17:445– 459. 86. Schulpher M, Fenwick E, Claxton K. Assessing quality in decision analytic cost-effectiveness models: A suggested framework and example of application. Pharmacoeconomics 2000;17:461–477. 87. Jolicoeur LM, Jones-Grizzle AJ, Boyer JG. Guidelines for performing a pharmacoeconomic analysis. Am J Hosp Pharm 1992;49:1741–1747. 88. Sanchez LA. Pharmacoeconomic principles and methods: Conducting pharmacoeconomic evaluations in a hospital setting. Hosp Pharm 1995;30:412–428. 89. Okamoto JL. Case study: Conducting a pharmacoeconomic evaluation. In Grauer D, Lee J, Odom T, et al. (eds.): Pharmacoeconomics and Outcomes, 2d ed. Kansas City, MO, American College of Clinical Pharmacy, 2003:394–403.

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2 HEALTH OUTCOMES AND QUALITY OF LIFE Stephen Joel Coons

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 The evaluation of health care is focused increasingly on assessment of the outcomes of medical interventions.

2 An essential patient-reported outcome is self-assessed

4 Information about the impact of pharmacotherapy

on HRQOL can provide additional data for making medication-use decisions.

function and well-being or health-related quality of life (HRQOL).

5 HRQOL instruments can be categorized as generic/

3 In certain chronic conditions, HRQOL may be the most im-

6 In HRQOL research, the quality of the data-collection tool

portant health outcome to consider in assessing treatment.

Over the past two decades, the medical care marketplace in the United States has undergone unprecedented change.1 This change is evidenced by a variety of developments, including an increase in investorowned organizations, heightened competition, numerous mergers and acquisitions, increasingly sophisticated clinical and administrative information systems, and new financing and organizational structures. In this dynamic and increasingly competitive environment, there is a concern that health care quality is being compromised in the push to 1 contain costs. As a consequence, there has been a growing movement to focus the evaluation of health care on the assessment of the end results, or outcomes, associated with medical care delivery systems, as well as specific medical interventions. The primary objective of this effort is to maximize the net health benefit derived from the use of finite health care resources.2 However, there is a serious lack of critical information as to what value is received for the tremendous amount of resources expended on medical care.3 This lack of critical information as to the outcomes produced is an obstacle to optimal health care decision making at all levels.

general or targeted/specific.

is the major determinant of the overall quality of the results.

TYPES OF OUTCOMES The types of outcomes that result from medical care interventions can be described in a number of ways. One classic list, called the five D’s, although quite negatively worded, captures a wide range of outcomes used in assessing the quality of medical care.7 The five D’s are death, disease, disability, discomfort, and dissatisfaction. A more comprehensive conceptual framework, the ECHO model, places outcomes into three categories: economic, clinical, and humanistic outcomes.8 The model covers the five D’s within the clinical and humanistic outcomes and provides an added economic outcomes dimension. As described by Kozma and associates,8 clinical outcomes are the medical events that occur as a result of the condition or its treatment. Economic outcomes are the direct, indirect, and intangible costs compared with the consequences of a medical 2 intervention. Along with patient satisfaction, an essential humanistic or patient-reported outcome is self-assessed function and wellbeing, or health-related quality of life (HRQOL). This chapter focuses on HRQOL as an outcome of pharmacotherapeutic interventions.

HEALTH OUTCOMES Although the implicit objective of medical care is to improve health outcomes, until relatively recently, little attention was paid to the explicit measurement of outcomes. An outcome is one of the three components of the conceptual framework articulated by Donabedian4 for assessing and ensuring the quality of health care: structure, process, and outcome. Traditionally, the approach to evaluating health care has emphasized the structure and processes involved in medical care delivery rather than the outcomes. However, health care regulators, payers, providers, manufacturers, and patients are placing increasing emphasis on the outcomes that medical care products and services produce.5 As stated by Ellwood,6 outcomes research is “designed to help patients, payers, and providers make rational medical care choices based on better insight into the effect of these choices on the patient’s life.”

QUALITY OF LIFE DEFINITION As mentioned earlier, one of the essential elements of outcomes research is the assessment of patient health-related quality of life. However, there is no consensus on the definition of quality of life (QOL) or its overall conceptual framework.9 In the literature, the term quality of life has been used in a variety of ways. It has been proposed that studies of health outcomes use the term health-related quality of life (HRQOL) to distinguish health effects from the effects of standard of living, family life, friendships, job satisfaction, and other factors on overall quality of life.10 Only health outcomes are discussed in this chapter, so quality of life and health-related quality of life are used interchangeably, along with health status. 17

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HRQOL CONTROVERSY Some observers question whether, when completing HRQOL instruments, respondents are able to distinguish between the impact of health versus the impact of other important life domains on their functioning and well-being. QOL, like other aspects of the human experience, is hard to define. In much of the empirical literature, explicit definitions of QOL are rare; readers must deduce the implicit definition of QOL from the manner in which it is measured. However, some authors have provided definitions. For example, Schron and Shumaker11 define HRQOL as “a multidimensional concept referring to a person’s total well-being, including his or her psychological, social, and physical health status.” Patrick and Erickson12 propose that HRQOL is “the value assigned to duration of life as modified by the impairments, functional states, perceptions, and social opportunities that are influenced by disease, injury, treatment, or policy.” Although the two definitions differ in certain respects, a conceptual characteristic they share is the multidimensionality of QOL. Although the terminology may vary with the author, commonly measured domains of HRQOL include r r r r

Physical health and functioning Mental health and functioning Social and role functioning Perceptions of general well-being

HRQOL CONTROVERSY Should symptoms of a disease or the adverse effects of treatment interventions be assessed explicitly by HRQOL instruments? Although some instruments include items addressing specific symptoms or side effects (particularly in the mental health domain), most HRQOL instruments are developed based on the premise that if a symptom or adverse effect is sufficiently problematic, it will be manifested in one or more of the measured HRQOL domains.

RELEVANCE OF QOL AS AN OUTCOME For medical care providers, HRQOL increasingly is viewed as a therapeutic end point. An overriding factor leading to this has been the gradual shift in the focus of primary medical care from limiting mortality to limiting morbidity and the patient-reported impact of that morbidity. The pattern of illness in the United States has shifted from mostly acute disease to one in which chronic conditions predominate. In the early part of the twentieth century, many individuals died from infectious diseases for which cures (e.g., antibiotics) or effective preventive measures (e.g., vaccines, increased sanitation) were unavailable or underused. Today, although there are many diseases that may shorten life expectancy, it is more likely that a disease will have adverse health consequences leading to dysfunction and decreased well-being. For conditions that shorten life expectancy and for which there are no cures, managing symptoms and maintaining function and well-being should be the primary objectives of medical care. Because therapeutic interventions such as medications have the potential to increase or decrease HRQOL, medical care providers must strive to achieve enhanced HRQOL as an outcome of therapy. Although it must be assumed that HRQOL always has played an implicit role in the provision of health care, it has not always been viewed as equal in importance to the more clinical or physiologic outcome parameters (e.g., blood pressure). The subjective

nature of HRQOL assessment has made many people uneasy with it as a measure of the patient outcomes produced by medical treatment.13 3 However, there is growing awareness that in certain diseases, HRQOL may be the most important health outcome to consider in assessing treatment.14 Physiologic measures may change without improving functioning and well-being. Likewise, patients may feel and function better without measurable change in physiologic values.

QOL AND PHARMACOTHERAPY As described by Smith,15 there are four possible QOL outcomes associated with pharmacotherapy: (1) QOL is improved, (2) QOL is actively maintained, (3) QOL is decreased, or (4) QOL remains unaffected. To assess these possible outcomes effectively, moving beyond consideration of only the biologic or physical manifestations of a disease or its treatment is essential. The use of standardized measurement tools (e.g., self-reported HRQOL instruments) to collect information regarding the impact of pharmacotherapy on the quality of patients’ lives is increasing.16,17 However, the vast majority of HRQOL claims in prescription drug advertisements continue to be based on physiologic parameters and/or clinician-assessed physical function rather than patient-reported functioning and well-being.18 A study by Croog and colleagues19 was one of the first in a growing body of literature reporting the QOL impact of pharmacotherapy, specifically the use of antihypertensive agents. Along with hypertension, examples of other therapeutic areas that are receiving increasing attention are arthritis, asthma, cancer, diabetes, and HIV/AIDS.20−25 The type of condition and type of treatment dictate the importance of HRQOL data in determining the value of pharmacotherapy. As discussed by Badia and Herdman,26 in chronic conditions and palliative treatments (i.e., ameliorating symptoms but not curing the underlying disease), HRQOL may be the primary measure of efficacy. However, with acute conditions and curative treatments, HRQOL is likely to be secondary (although excluding it may underestimate the positive and negative impacts of the treatment). 4 Information about the impact of pharmacotherapy on QOL can provide additional data for making medication-use policy decisions. In fact, the Academy of Managed Care Pharmacy, in its Format for Formulary Submissions, states that manufacturers of pharmaceutical, biologic, and vaccine products should include outcomes data (e.g., QOL data) in their formulary submission dossiers.27 When available, pharmacy and therapeutics committees should incorporate QOL data into the formulary and practice guideline decision-making process. HRQOL as an input to clinical decision making at the patient level is also very important. For example, alternative treatments may have equal efficacy based on traditional clinical parameters (e.g., blood pressure reduction) but produce very different effects on the patient’s HRQOL. Thus a provider’s selection among competing alternatives may hinge on documented differential impact on HRQOL. A perceived decrease in QOL attributed by the patient to an adverse effect of a drug may lead to a decrease in adherence to the medication regimen.15

MEASURING QOL TYPES OF INSTRUMENTS Hundreds of HRQOL instruments are available.28−30 Table 2–1 gives 5 a taxonomy of the different types of instruments.31 A primary distinction among HRQOL instruments is whether they are generic or specific.

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CHAPTER 2 TABLE 2–1. Taxonomy of Quality-of-Life Instruments Generic Instruments Health profiles Preference-based measures Specific Instruments Disease specific (e.g., diabetes) Population specific (e.g., frail older adults) Function specific (e.g., sexual functioning) Condition or problem specific (e.g., pain)

19

TABLE 2–3. SF-36 Scales and Number of Items per Scale (SF-36/SF-12) Physical functioning (10/2) Role limitations attributed to physical problems (4/2) Bodily pain (2/1) General health (5/1) Vitality (4/1) Social functioning (2/1) Role limitations attributed to emotional problems (3/2) Mental health (5/2) Health transition (1/0)

Adapted from Ref. 32.

Compiled from Refs. 38 and 42.

GENERIC INSTRUMENTS Generic, or general, HRQOL instruments are designed to be applicable across all diseases or conditions, across different medical interventions, and across a wide variety of populations.32 Table 2–2 lists the dimensions or domains of five generic instruments. In choosing or evaluating the use of an instrument, the specific dimensions of functioning and well-being covered must be considered. The instruments in Table 2–2 share common dimensions, but they also reflect the diversity and range of dimensions covered. The two main types of generic instruments are health profiles and preference-based measures.

HEALTH PROFILES Health profiles provide an array of scores representing individual dimensions or domains of HRQOL or health status. An advantage of a health profile is that it provides multiple outcome scores that may be useful to clinicians and/or researchers attempting to measure differential effects of a condition or its treatment on various QOL domains. TABLE 2–2. Domains Included in Selected Generic Instruments EuroQol Group’s EQ-SD33 Mobility Usual activity Anxiety/depression

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Self-care Pain/discomfort

Nottingham Health Profile (NHP)34 Part I: Distress within the following domains Emotions Energy Sleep Pain Social isolation Mobility Part II: Health-related problems within the following domains Occupation Sex life Housework Hobbies Social life Holidays Home life Quality of Well-Being Scale (QWB)35 Symptoms/problems Mobility

Physical activity Social activity

Sickness Impact Profile (SIP)36 Sleep and rest Eating Work Ambulation Mobility Communication

Home management Recreation and pastimes Body care and movement Alertness behavior Emotional behavior Social interaction

Health Utilities Index (HUI)—Mark III37 Vision Hearing Speech Ambulation

Dexterity Cognition Pain and discomfort Emotion

A commonly used profile instrument is the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36).38 This instrument includes nine health concepts or scales (Table 2–3). The SF-36 can be self-administered or administered by a trained interviewer (face to face or via telephone). This instrument has several advantages. For example, it is brief (it takes about 5–10 minutes to complete), and its reliability and validity have been documented in many clinical situations and disease states.39,40 A means of aggregating the items into physical (PCS) and mental (MCS) component summary scores is available.41 In addition, an abbreviated version of the SF-36 containing only 12 items (SF-12) has been introduced.42 However, the scale scores and mental and physical component summary scores derived from the SF-12 are based on fewer items and fewer defined levels of health and, as a result, are estimated with less precision and less reliability. The loss of precision and reliability in measurement can be a problem in small samples and/or with small expected effect sizes for an intervention.

PREFERENCE-BASED MEASURES HRQOL as assessed by preference-based measures is a single overall index score on a scale anchored by 1.0 (full health) and 0.0 (dead). Health states considered worse than dead can be reflected by negative numbers on the scale. This approach combines the measurement of an individual’s health status with an adjustment for the relative desirability of or preference for that health state. The preferences are measured or assigned empirically through a variety of procedures. Although often called health state utilities, the term preferences will be used in this chapter as the broader term because it subsumes both utilities and values.43 Preference-based measures are useful in pharmacoeconomic research, specifically cost-utility analysis (CUA).44 CUA, an economic technique discussed in Chapter 1, involves comparing the costs of an intervention (e.g., a medication) with its outcomes expressed in units such as quality-adjusted life years (QALYs) gained. QALYs gained is an outcome measure that incorporates both quantity and quality of life. This can be a key outcome measure, especially in diseases such as cancer, where the treatment itself can have a major impact on patient functioning and well-being. Numerous published studies have used CUA to evaluate the economic efficiency of health care interventions. A review of CUAs published from 1976 to 1997 by Neumann and colleagues45 found that the number increased markedly during that time. Of the 228 articles reviewed, about one-third focused on pharmaceutical interventions. CUA data compiled during this extensive review can be accessed on the Web (http://www.hsph.harvard.edu/cearegistry). QALYs can be produced by increases in QOL and/or length of life. Figure 2–1 represents a case in which QALYs were gained

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FIGURE 2–2. Standard gamble for a chronic health status. The subject is offered the choice between A and B. A involves the certainty of living in health state i (a suboptimal health state) for a specified period of time. B involves an intervention that could lead to full health for the same period of time or immediate death. The probabilities associated with the outcomes of healthy and dead are p and 1 − p, respectively. As p is varied, the indifference point between choices A and B represents the utility of state i. 0

Death Years

FIGURE 2–1. QALYs gained (i.e., area between the curves) as the outcome of a hypothetical health care intervention, such as a drug.

through an increase in QOL alone. The top curve represents the hypothetical life course of a cohort of individuals receiving a specific health care intervention compared with the life course of a cohort (i.e., lower curve) that did not receive the intervention. Average age at death did not differ between the two cohorts, but the intervention led to improvements in QOL in the treatment cohort. The area between the curves represents the QALYs gained through the intervention. This hypothetical case reflects a chronic disease, such as osteoarthritis, in which functioning and well-being are increased, but survival remains unchanged. Other hypothetical combinations of quality and quantity of life can be graphed in this manner. For example, an alternative scenario could reflect a temporary decrease in QOL but an increase in survival that may result from a chemotherapeutic regimen for cancer. HRQOL CONTROVERSY Although the QALY is the most commonly used health outcome summary measure, it is not the only one. Other conceptually equivalent outcomes include years of healthy life (YHL), well years (WYs), health-adjusted person-years (HAPYs), and health-adjusted life expectancy (HALE). An alternative concept called healthy year equivalents (HYEs) has been proposed as theoretically superior to QALYs, but its practical significance has been limited.

0 and 100 on the scale, that subject’s preference for that health state is 0.5.

Standard Gamble. The standard gamble offers a choice between two alternatives: choice A, living in health state i with certainty, or choice B, taking a gamble on a new treatment for which the outcome is uncertain. Figure 2–2 shows this gamble.43 The subject is told that a hypothetical treatment will lead to perfect health, for a defined remaining lifetime, with a probability of p or immediate death with a probability of 1 − p. The subject can choose between remaining, for the same defined lifetime, in state i, which is intermediate between healthy and dead, or taking the gamble and trying the new treatment. The probability p is varied until the subject is indifferent between choices A and B. For example, if a subject is indifferent between the choices A and B when p = 0.75, the preference (i.e., utility) of state i is 0.75. Time Tradeoff. Figure 2–3 represents the time-tradeoff technique for a chronic disease state.47 Here, the subject is offered a choice of living for a variable amount of time x in perfect health or a defined amount of time t in a health state i that is less desirable. By reducing the time x of being healthy (at 1.0) and leaving the time t in the suboptimal health state fixed, an indifference point can be determined (hi = x/t). For example, a subject may indicate that undergoing chronic

Healthy 1.0

Alternative 2

Direct Measures of Health-State Preferences The most commonly used direct measurement techniques include visual analog scales, standard gamble, and time tradeoff.46

Visual Analog Scales. The visual analog scale is a line, typically 10 to 20 cm in length, with the end points well defined (e.g., 0 = worst imaginable health state and 100 = best imaginable health state). The respondent is asked to mark the line where he or she would place a real or hypothetical health state in relation to the two end points. In addition, since death may not always be considered the worst possible health state, the subject’s placement of death on the scale in relation to the other health states must be explicitly elicited. If a subject has placed death at 0 and rates a health state at the midpoint between

State i

hi

Dead

0

Alternative 1

x

t

Time

FIGURE 2–3. Time tradeoff for a chronic health state. The subject chooses between living a varying amount of time in full health (x) and living a specified amount of time (t) in state i. The length of time in full health is shortened until the subject is indifferent between the two choices. The value of health state i(hi ) is then calculated by dividing x/t.

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hemodialysis for 2 years is equivalent to perfect health for 1 year. Therefore, the value of that health state would be 0.5 (hi = 1/2 ). HRQOL CONTROVERSY There is considerable debate regarding the best approach to the direct measurement, or elicitation, of health-state preferences. The empirical literature consistently shows that there are differences in the preferences derived through the different elicitation methods. Although there have been calls for the development of standardized preference-elicitation protocols, it is likely that the lack of consensus will continue into the foreseeable future.

Multiattribute Health-Status Classification Systems In addition to direct measures, instruments are available for which the health-state preferences have been derived empirically through population studies. The instruments are administered to measure respondents’ health status, which is then mapped onto a multiattribute health status classification system. Examples of such instruments include the Quality of Well-Being Scale (QWB),35 the Health Utilities Index (HUI),37 and the EuroQOL Group’s EQ-5D.33 Although each will be described briefly below, more thorough descriptions of these three instruments are provided elsewhere.43,48 The QWB is a generic HRQOL instrument that includes symptoms or problems plus three dimensions of functional health status (see Table 2–2). Standardized preference values for the health states represented by the QWB have been measured (via the category rating scale method, a technique related to visual analog scales) and validated on a general population sample.35 The QWB was available originally only as an interviewer-administered version, but a self-administered version is now available.49 The HUI is another generic instrument that describes the health status of a person at a point in time in terms of his or her ability to function on a set of attributes or dimensions of health status. The HUI Mark II/III is available as a 15-item self-administered form. The measurements for the development of the health-state preference system were made with visual analog scales (VASs) and the standard gamble technique. The dimensions covered in the most recent version of the HUI (Mark III) are listed in Table 2–2.37 The EQ-5D was developed concurrently in five languages (Dutch, English, Finnish, Norwegian, and Swedish) by a multidisciplinary team of European researchers.33 It was designed to be selfadministered and short enough to be used in conjunction with other measures. The first of two parts classifies subjects into one of 243 health states within five dimensions. The most commonly used set of health-state preferences was estimated using the time-tradeoff technique in a random sample of adults in the United Kingdom. A set of preference weights derived from the general U.S. adult population is forthcoming. The second part of the EQ-5D is a 20-cm VAS that has end points labeled “best imaginable health state” and “worst imaginable health state” anchored at 100 and 0, respectively. Respondents are asked to indicate how they rate their own health state by drawing a line from an anchor box to that point on the VAS that best represents their own health on that day. HRQOL CONTROVERSY Whose preferences should be used in the calculation of QALYs for CUA? Some authors have argued that health-state preferences elicited from the general population should not

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TABLE 2–4. Selected Disease-Specific Quality-of-Life Instruments Arthritis Impact Measurement Scales (AIMS)50 Asthma Quality of Life Questionnaire (AQLQ)51 Diabetes Quality of Life (DQOL)52 Kidney Disease Quality of Life (KDQOL) Instrument53 Quality of Life in Epilepsy (QOLIE)54 Medical Outcomes Study HIV Health Survey (MOS-HIV)55

be applied to specific patient groups. However, when public resource-allocation decisions are being made, general population preferences may be the most appropriate.

SPECIFIC INSTRUMENTS Specific or targeted instruments are intended to provide greater detail concerning particular outcomes, in terms of functioning and wellbeing, uniquely associated with a condition and/or its treatment. Several selected examples of disease-specific instruments are listed in Table 2–4. One of the instruments listed is the Asthma Quality of Life Questionnaire (AQLQ), a 32-item instrument developed to assess the impact of asthma on patients’ everyday functioning and well-being.51 Results from research in which the AQLQ was used have appeared in promotional materials for the salmeterol inhaler (GlaxoSmithKline). As opposed to prior prescription drug advertisements that involved predominantly physiologic-based QOL claims,18 this was one of the first times a pharmaceutical firm has promoted a product based on data from trials involving QOL as a primary outcome measure. This is likely to occur with increasing frequency as pharmaceutical firms look for ways to demonstrate value and differentiate their products from those of the competition.56,57 Leidy and colleagues58 have provided useful recommendations for evaluating the validity of QOL claims for labeling and promotion of pharmaceuticals. Although not always, disease- or condition-specific instruments can be more sensitive than a generic measure to particular changes in HRQOL secondary to the disease or its treatment. In addition, specific measures may appear to be more clinically relevant to patients and health care providers.31 However, a concern regarding the use of only specific instruments is that by focusing on the specific impact, the general or overall impact on functioning and well-being may be overlooked. In studies involving pharmacotherapy, the use of both a generic and a specific instrument may be the best approach. The generic instrument provides a more general outcome assessment and allows comparability across other disease states or conditions in which it has been used. An appropriately selected specific instrument should provide more detailed outcome information regarding expected changes in the particular patient population.

MEASUREMENT ISSUES A number of issues must be considered when evaluating existing HRQOL research and/or choosing the appropriate instrument to use when designing a study involving QOL assessment. A thorough review of these issues is not within the scope of this chapter; more in-depth reviews of methodologic considerations are available in the 6 literature.12,59,60 Of particular concern are the psychometric properties of a chosen instrument. Psychometrics refers to the measurement of psychological constructs, such as QOL. Instruments should be developed and tested such that one can place confidence in the

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measurement made. Psychometric properties of measures (e.g., reliability and validity) are considered in the review criteria developed by the Scientific Advisory Committee of the Medical Outcomes Trust (MOT).61 The MOT is a depository and distributor of standardized health outcomes measurement instruments. Every instrument that is proposed for addition to the MOT list of approved instruments is reviewed against a rigorous set of eight attributes. These attributes provide a useful evaluative framework. The eight attributes of an instrument addressed by the review criteria are as follows: (1) conceptual and measurement model, (2) reliability, (3) validity, (4) responsiveness, (5) interpretability, (6) respondent and administrative burden, (7) alternate forms, and (8) cultural and language adaptations.

CONCEPTUAL AND MEASUREMENT MODELS A conceptual model is the rationale for and description of the concepts that a measurement instrument is intended to assess and the interrelationships of those concepts. A measurement model is an instrument’s scale and subscale structure and the procedures followed to create scale and subscale scores. An example is the well-defined conceptual and measurement models for the scales and scale structure of the SF-36.62 The SF-36 contains 36 items that cover nine theorybased health concepts. Eight of these health concepts are measured by multi-item scales. There is a clearly defined means of creating the individual scale scores and the physical and mental component summary scales.41

RELIABILITY Reliability refers to the extent to which measures give consistent or accurate results. The purpose of evaluating the reliability of a QOL instrument is to estimate how much of the variation in a score is real as opposed to random. The two reliability assessment methods discussed most often in the HRQOL literature are internal consistency and test-retest reliability. Internal consistency is an assessment of the performance of items within a scale. It is a function of the number of items and their covariation.63 Internal consistency is commonly measured using Cronbach’s alpha coefficient. Alpha coefficients above 0.90 are recommended for making comparisons between individuals and above 0.70 for comparisons between groups.64 Test-retest reliability refers to the relationship between scores obtained from the same instrument on two or more separate occasions when all pertinent conditions remain relatively unchanged. It is usually evaluated using the intraclass correlation coefficient (ICC).60 However, QOL is not assumed to be constant over the course of time. In fact, most clinical studies attempt to assess how QOL changes. Test-retest reliability estimates may have limited value in evaluating measures that are designed to assess a dynamic process. Interrater reliability and equivalent-forms reliability are two other approaches to reliability assessment that are not used as commonly in QOL research. More in-depth discussions of these and the other reliability assessment methods are found elsewhere.60,65

Criterion validity is demonstrated when a new measure corresponds to an established measure or observation that accurately reflects the phenomenon of interest. By definition, the criterion must be a superior measure of the phenomenon if it is to serve as a comparative norm. However, in QOL assessment, “gold standards,” or criterion measures, rarely exist against which a new measure can be compared. Content validity, which is tested infrequently statistically, refers to how adequately the questions/items capture the relevant aspects of the domain or concept being measured. Construct validity refers to the relationship between measures purporting to measure the same underlying theoretical construct (convergent evidence) or purporting to measure different constructs (discriminant evidence). For example, convergent evidence for the validity of a new measure of emotional well-being could be established by showing a strong association between the new scale and the Beck Depression Inventory.66 Evidence for the construct validity of other aspects of the measure might be established through comparisons with physiologic measures, organ pathology, or clinical signs.

RESPONSIVENESS Responsiveness, or sensitivity to change, is the ability or power of the measure to detect clinically important change when it occurs.67 Although some authors have suggested that responsiveness is a psychometric property of a measure distinct from validity,68 others argue that responsiveness is an aspect of validity rather than a separate property.63,69 HRQOL CONTROVERSY What constitutes a minimally important difference on an HRQOL measure? Although the statistical significance of a change, or difference score, is used often to denote important change, it may over- or underestimate the true impact of the disease and/or its treatment in terms of change that is perceptible and important to patients. Discussions regarding the concept of minimally important difference are appearing increasingly in the literature.

INTERPRETABILITY Interpretability is the degree to which one can assign qualitative meaning to an instrument’s quantitative scores. Interpretability is facilitated by comparison of a score or change in scores to a qualitative category that has clinical or commonly understood meaning. For example, it would be helpful to know how scale scores obtained in a specific patient sample compare with the scale scores of the general population. Ware and colleagues62 have provided very useful U.S. populationbased normative data for the SF-36.

RESPONDENT AND ADMINISTRATIVE BURDEN VALIDITY Reliability is necessary but not sufficient for valid measurement.63 Validity is an estimation of the extent to which the instrument is measuring what it is supposed to be measuring. Validity is not an absolute property of an instrument. Hence a measurement instrument is not “valid,” but empirical data can provide evidence to support its validity. Three types of validity commonly considered are criterion, content, and construct.

Respondent burden refers to the time, energy, and other demands placed on those to whom the instrument is administered. Administrative burden refers to the demands placed on those who administer the instrument. A practical aspect of the measurement of HRQOL is length of the instrument or the administration time involved. Instruments should be as brief as possible without severely compromising the validity and reliability of the measurement. The longer an instrument, the greater is the respondent burden. This can lead to an

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individual’s unwillingness or refusal to complete the instrument or to incomplete responses.

ALTERNATE FORMS Alternate forms of an instrument include all modes of administration other than the original source instrument. Evidence should be provided that supports the comparability of the alternate mode of administration with that of the original instrument.70 Many QOL measures can be administered in different ways. The primary modes of administration are (1) interviewer-administered, either in person or over the telephone, or (2) self-administered questionnaires.31 Other self-completed modes include computer-based (using the keyboard or touch screen to respond) and telephone touchtone administration. Used but not recommended are proxy responders (i.e., using a health care provider, family member, or friend to respond for the subject when the subject is unable to complete the instrument). Because QOL is such a subjective concept, patients must have the opportunity to provide their perspective on the impact of illness and/or medical care on their functioning and well-being. The patient’s perspective has been shown to be quite different from that of outside observers, including physicians, family members, or others close to the patient.71

CULTURAL AND LANGUAGE ADAPTATIONS Methods used to achieve conceptual and linguistic equivalence of cross-culturally adapted instruments should be stated explicitly.72 Evidence should be provided that the measurement properties of the adaptation are comparable with those of the original instrument. It is obvious that this is an extremely important issue when planning crossnational QOL assessment projects. However, it is also very important within countries that are multicultural, such as the United States.73 Many of the English-language instruments have been developed for the dominant U.S. culture and may not be appropriate for all patients.

OTHER MEASUREMENT ISSUES SELECTION OF AN APPROPRIATE INSTRUMENT It is essential that the purpose of the measurement be well defined before selection of an HRQOL instrument. Is the purpose of the measurement to describe the health status or HRQOL of a patient population at a particular time or over time?74 Is it to document change in health outcomes associated with a particular intervention? These and other questions should be answered before HRQOL instruments are selected. Too many practitioner-researchers attempting to demonstrate improvements in outcomes resulting from a pharmaceutical product or service select a commonly used generic instrument, such as the SF-36, with the expectation that it will be sufficiently responsive to changes that may occur. The best approach may be to use the SF-36 or other generic instrument in conjunction with a more targeted, disease-specific instrument.

AVAILABILITY OF INSTRUMENTS Many HRQOL instruments are in the public domain. However, although they can be used for no or little cost, there may be a fee associated with the purchase of a user’s guide or scoring manual. The MOT (www.outcomes-trust.org) is a source for a number of instruments, including the Duke Health Profile, QWB, MOS-HIV Health Survey, Migraine Specific Quality of Life (MSQOL), and Sickness

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Impact Profile (SIP). For information on availability of the SF-36 and SF-12, go to http://www.sf36.org. The Functional Assessment of Chronic Illness Therapy (FACIT) Web site (http://www.facit.org) provides an extensive array of cancer- and chronic-disease–targeted instruments. Developers of particular instruments often can be contacted through addresses provided in other books referenced at the end of this chapter.28−30,60

CONCLUSIONS The concept of HRQOL has gained increasing attention in the evaluation of the outcomes associated with medical care, including pharmacotherapy. In fact, in certain diseases, HRQOL may be the most important outcome to consider in assessing the effectiveness of health care interventions. Health care practitioners and policymakers must remember that efforts to increase length of life must not outstrip the ability to maintain or improve QOL. HRQOL assessment is a relatively new field of endeavor, and a number of theoretical and methodologic issues remain unresolved. However, some general concepts in the measurement of HRQOL outcomes should be considered carefully when designing a study, evaluating existing research, or evaluating new programs or services. This chapter has provided only a brief overview of the concepts in an effort to sensitize students and health care practitioners to the importance of the area, as well as to provide insight as to how these concepts can and should be incorporated into their practices.

ABBREVIATIONS AIMS: Arthritis Impact Measurement Scales AQLQ: Asthma Quality of Life Questionnaire CUA: cost-utility analysis DQOL: Diabetes Quality of Life ECHO: economic, clinical, and humanistic outcomes FACIT: Functional Assessment of Chronic Illness Therapy HALE: health-adjusted life expectancy HAPYs: health-adjusted person years HRQOL: health-related quality of life HIV/AIDS: human immunodeficiency virus/acquired immunodeficiency syndrome HUI: Health Utilities Index HYEs: healthy-year equivalents ICC: intraclass correlation coefficient KDQOL: Kidney Disease Quality of Life instrument MCS: mental component summary scale of the SF-36 MOS-HIV: Medical Outcomes Study HIV Health Survey MOT: Medical Outcomes Trust MSQOL: Migraine Specific Quality of Life NHP: Nottingham Health Profile PCS: physical component summary scale of the SF-36 QALY: quality-adjusted life year QOL: quality of life QOLIE: Quality of Life in Epilepsy QWB: Quality of Well-Being scale SF-36: MOS 36-Item Short-Form Health Survey SIP: Sickness Impact Profile VAS: visual analog scale WY: well year YHL: years of healthy life

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Review Questions and other resources can be found at www.pharmacotherapyonline.com.

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25. Delate T, Coons SJ. The use of two health-related quality-of-life measures in a sample of persons infected with human immunodeficiency virus. Clin Infect Dis 2001;32(3):e47–e52. 26. Badia X, Herdman M. The importance of health-related quality-of-life data in determining the value of drug therapy. Clin Ther 2001;23:168– 175. 27. Academy of Managed Care Pharmacy. Format for Formulary Submissions, Version 2.0. Alexandria, VA, The Foundation for Managed Care Pharmacy, October 2002; available at http://www.fmcpnet.org/fmcp.cfm? c = resources#a3. 28. Bowling A. Measuring Health: A Review of Quality of Life Measurement Scales, 2d ed. Buckingham, England, Open University Press, 1997. 29. Bowling A. Measuring Disease: A Review of Disease-Specific Quality of Life Measurement Scales, 2d ed. Buckingham, England, Open University Press, 2001. 30. McDowell I, Newell C. Measuring Health: A Guide to Rating Scales and Questionnaires, 2d ed. New York, Oxford University Press, 1996. 31. Guyatt GH, Feeny DH, Patrick DL. Measuring health-related quality of life. Ann Intern Med 1993;118:622–629. 32. Patrick DL, Deyo RA. Generic and disease-specific measures in assessing health status and quality of life. Med Care 1989;27:S217–S232. 33. Kind P. The EuroQOL instrument: An index of health-related quality of life. In Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials, 2d ed. Philadelphia, Lippincott-Raven, 1996:191–201. 34. Hunt SM, McEwen J, McKenna SP. Measuring health status: A new tool for clinicians and epidemiologists. J R Coll Gen Pract 1985;35:185–188. 35. Kaplan RM, Anderson JP. The general health policy model: An integrated approach. In Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials, 2d ed. Philadelphia, Lippincott-Raven, 1996:309–322. 36. Bergner M, Bobbitt RA, Carter WB, Gilson BS. The Sickness Impact Profile: Development and final revisions of a health status measure. Med Care 1976;14:57–67. 37. Furlong WJ, Feeny DH, Torrance GW, Barr RD. The Health Utilities Index (HUI) system for assessing health-related quality of life in clinical studies. Ann Med 2001;33:375–384. 38. Ware JE Jr, Sherbourne CD. The MOS 36-Item Short-Form Health Survey (SF-36): I. Conceptual framework and item selection. Med Care 1992;30:473–483. 39. McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993;31:247– 263. 40. McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): III. Tests of data quality, scaling assumptions, and reliability across diverse patient groups. Med Care 1994;32:40–66. 41. Ware JE Jr, Kosinski M, Keller SD. SF-36 Physical and Mental Health Summary Scales: A User’s Manual. Boston, The Health Institute, 1994. 42. Ware JE Jr, Kosinski M, Keller SD. A 12-item short-form health survey: Construction of scales and preliminary test of reliability and validity. Med Care 1996;34:220. 43. Drummond MF, O’Brien B, Stoddart GL, Torrance GW. Methods for the Economic Evaluation of Health Care Programmes, 2d ed. Oxford, England, Oxford University Press, 1997. 44. Coons SJ, Kaplan RM. Cost-utility analysis. In Bootman JL, Townsend RJ, McGhan WF, eds. Principles of Pharmacoeconomics, 2d ed. Cincinnati, Harvey Whitney, 1996:102–126. 45. Neumann PJ, Stone PW, Chapman RH, et al. The quality of reporting in published cost-utility analyses, 1976–1997. Ann Intern Med 2000;132:964–972. 46. Feeny DH, Torrance GW, Labelle R. Integrating economic evaluations and quality of life assessments. In Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials, 2d ed. Philadelphia, LippincottRaven, 1996:85–95. 47. Torrance GW, Thomas WH, Sackett DL. Utility maximization model for evaluation of health care programmes. Health Serv Res 1972;7:118–133. 48. Coons SJ, Rao S, Keininger DL, Hays RD. A comparative review of generic quality of life instruments. Pharmacoeconomics 2000;17: 13–35.

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CHAPTER 2 49. Kaplan RM, Sieber WJ, Ganiats TG. The quality of well-being scale: Comparison of an interviewer-administered version with a self-administered questionnaire. Psychol Health 1997;12:783–791. 50. Meenan RF, Gertman PM, Mason JH. Measuring health status in arthritis: The arthritis impact measurement scales. Arthritis Rheum 1980;23: 146–152. 51. Juniper EF, Guyatt GH, Epstein RS, et al. Evaluation of impairment of health-related quality of life in asthma: Development of a questionnaire for use in clinical trials. Thorax 1992;47:76–83. 52. Parkerson GR, Connis RT, Broadhead WE, et al. Disease-specific versus generic measurement of health-related quality of life in insulin-dependent diabetic patients. Med Care 1993;7:629–639. 53. Hays RD, Kallich JD, Mapes DL, et al. Development of the kidney disease quality of life (KDQOL) instrument. Qual Life Res 1994;3:329–338. 54. Perrine KR. A new quality of life inventory for epilepsy patients: Interim results. Epilepsia 1993;34(suppl 4):S28–S33. 55. Wu AW, Revicki DA, Jacobson D, Malitz FE. Evidence for reliability, validity and usefulness of the medical outcomes study HIV health survey (MOS-HIV). Qual Life Res 1997;6:481–493. 56. Santanello NC, Baker D, Cappelleri JC, et al. Regulatory issues for healthrelated quality of life–-PhRMA Health Outcomes Committee Workshop, 1999. Value Health 2002;5:14–25. 57. Revicki DA, Osoba D, Fairclough D, et al. Recommendations on healthrelated quality of life research to support labeling and promotional claims in the United States. Qual Life Res 2000;9:887–900. 58. Leidy NK, Revicki DA, Geneste B. Recommendations for evaluating the validity of quality of life claims for labeling and promotion. Value Health 1999;2:113–127. 59. Staquet MJ, Hays RD, Fayers PM. Quality of Life Assessment in Clinical Trials: Methods and Practice. Oxford, England, Oxford University Press, 1998. 60. Fayers PM, Machin D. Quality of Life: Assessment, Analysis and Interpretation. Chichester, England, Wiley, 2000. 61. Scientific Advisory Committee of the Medical Outcomes Trust. Assessing

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health status and quality-of-life instruments: Attributes and review criteria. Qual Life Res 2002;11:193–205. Ware JE Jr, Snow KK, Kosinski M, Gandek B. SF-36 Health Survey: Manual and Interpretation Guide. Boston, The Health Institute, 1993. Hays RD, Anderson R, Revicki D. Psychometric considerations in evaluating health-related quality of life measures. Qual Life Res 1993;2:441–449. Nunnally J. Psychometric Theory, 2d ed. New York, McGraw-Hill, 1978. Streiner DL, Norman GR. Health Measurement Scales: A Practical Guide to Their Development and Use, 2d ed. Oxford, England, Oxford University Press, 1995. Beck AT, Steer RA, Brown GK. Beck Depression Inventory Manual, 2d ed (BDI-II). San Antonio, The Psychological Corporation, 1996. Juniper EF, Guyatt GH, Jaeschke R. How to develop and validate a new health-related quality of life instrument. In Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials, 2d ed. Philadelphia, Lippincott-Raven, 1996:49–56. Guyatt G, Walter S, Norman G. Measuring change over time: Assessing the usefulness of evaluative instruments. J Chron Dis 1987;40:171–178. Hays RD, Hadorn D. Responsiveness to change: An aspect of validity, not a separate dimension. Qual Life Res 1992;1:73–75. Cook DJ, Guyatt GH, Juniper E, et al. Interviewer versus self-administered questionnaires in developing a disease-specific, health-related quality of life instrument for asthma. J Clin Epidemiol 1993;46:529–534. Jachuck SJ, Brierly H, Jachuck S, Wilcox PM. The effect of hypotensive drugs on the quality of life. J R Coll Gen Pract 1982;32:103–105. Bullinger M, Power MJ, Aaronson NK, et al. Creating and evaluating cross-cultural instruments. In Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials, 2d ed. Philadelphia, Lippincott-Raven, 1996:659–668. Yu J, Coons SJ, Draugalis JR, et al. Equivalence of the Chinese and U.S.English versions of the SF-36 health survey. Qual Life Res 2003;12:449– 457. Fairclough DL. Design and Analysis of Quality of Life Studies in Clinical Trials. Boca Raton, FL, Chapman & Hall/CRC, 2002.

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3 EVIDENCE-BASED MEDICINE Elaine Chiquette and L. Michael Posey

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 The best current evidence integrated into clinical expertise ensures optimal care for patients.

2 The four steps in the process of applying evidence-based

medicine (EBM) in practice are (a) formulate a clear question from a patient’s problem, (b) identify relevant information, (c) critically appraise available evidence, and (d) implement the findings in clinical practice.

3 The decision as to whether to implement the results of a

In the information age, clinicians are presented with a daunting number of diseases and possible treatments to consider as they care for patients each day. As knowledge increases and as the technology for accessing information becomes widely available, health care professionals are expected to stay current in their fields of expertise and to remain competent throughout their careers. In addition, the number of information sources for the typical practitioner has ballooned, and clinicians must sort out information from many sources: college courses and continuing education (including seminars and journals), pharmaceutical representatives, and colleagues, as well as guidelines from committees of health care facilities, governmental agencies, and expert committees and organizations. 1 How does the health care professional find valid information from such a cacophony? Increasingly, clinicians are turning to the principles of evidence-based medicine (EBM) to identify the best course of action for each patient. EBM strategies help health care professionals to ferret out these gold nuggets, enabling them to integrate the best current evidence into their pharmacotherapeutic decision making. These strategies can help physicians, pharmacists, and other health care professionals to distinguish reliably beneficial pharmacotherapies from those which are ineffective or harmful. Also, EBM approaches can be applied to keep up to date and to make an overwhelming task seem more manageable. This chapter describes for the reader the principles of EBM, offers guidance for finding EBM sources on the World Wide Web, provides a model for applying EBM in patient care, and explains how EBM strategies can help a practitioner stay current.

WHAT IS EVIDENCE-BASED MEDICINE? EBM is an approach to medical practice that uses the results of patient care research and other available objective evidence as a component of clinical decision making. Similarly, evidence-based pharmacotherapy, defined by Etminan and colleagues,1 is an approach to decision

specific study, conclusions of a review article, or another piece of evidence in clinical practice depends on the quality (i.e., internal validity) of the evidence, its clinical importance, whether benefits outweigh risks and costs, and its relevance in the clinical setting and patient’s circumstances.

4 EBM strategies can be applied to help in keeping current. 5 EBM is realistic.

making whereby clinicians appraise the scientific evidence and its strength in support of their therapeutic decisions. While few would argue against the necessity for basing clinical decisions on the best possible evidence available, considerable controversy actually surrounds the practice of EBM. Critics note that not all questions relevant to the care of a patient are of a scientific nature and that EBM favors a “cookbook” approach. In fact, EBM integrates knowledge from research with other factors affecting clinical decision making. EBM does not replace clinical judgment. Rather, it informs clinical judgment with the current best evidence. The expertise and experience of the clinician who understands the disease are crucial in determining whether the external evidence applies to the patient and whether it should be integrated in the therapeutic plan. Also, nonmedical factors affect decision making, such as the patient’s preferences and readiness and the health care delivery system’s characteristics. Other critics state that EBM considers randomized, controlled trials (RCTs) as the only evidence to be used in clinical decision making. Actually, EBM seeks the best existing evidence from basic science to clinical research with which to inform clinical decision. For example, a decision about the accuracy of a diagnostic test is best informed by evidence from a cross-sectional study, not an RCT. A cohort study, not an RCT, best answers a question about prognosis. However, in selecting a treatment, the randomized trial is the best study design to provide the most accurate estimate of treatment efficacy and safety. EBM opponents note that RCTs usually are conducted in idealized environments or situations that are not sufficiently similar to the conditions of the “real world.” In addition, errors can be made when results of an RCT of one drug are extrapolated to all members of that class of drugs.2,3 Regardless of one’s view, RCTs have confirmed the value of many therapeutic options today and have disproved or clarified the usefulness of others. For example, in 1970, observational studies had indicated a possible association between the occurrence of premature ventricular contractions (PVCs) in patients after myocardial infarction 27

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(MI) and sudden death. As a result, the eighth edition of Harrison’s Principles of Internal Medicine recommended the use of antiarrhythmic agents to eradicate post-MI PVCs and thereby minimize the risk of sudden death. However, an RCT tested the antiarrhythmic therapy in patients with frequent PVCs, and it showed that class 1 antiarrhythmic agents increased rather than decreased the risk of sudden death.4,5 Today, guidelines discourage the use of antiarrhythmic agents to suppress PVCs in post-MI patients.6 More recently, the 1996 guidelines for the management of patients with acute MI concluded that observational studies “indicate that estrogen therapy does reduce mortality in women with moderate and severe coronary disease.”7 Subsequently, an RCT found no reduction in overall risk for nonfatal MI or coronary death with estrogen therapy. Rather, significantly more coronary events occurred during the first year of the trial among women receiving estrogen therapy compared with women taking placebo.8 These results prompted revision of the guidelines to conclude: “On the basis of the finding of no overall cardiovascular benefit and a pattern of early increase in risk of coronary events, starting estrogen plus progestin is not recommended for the purpose of secondary prevention of coronary disease.”6 In both these examples, conventional wisdom was wrong. Results from observational studies proved incorrect. Only through careful assessment using RCT methodology was the true estimate of the efficacy and safety of the therapeutic options discovered. CLINICAL CONTROVERSY In many ways, EBM is controversial, with some people feeling that it prevents the application of common sense and experience-based reasoning to clinical care. Some joke that a clinician called an EBM center and asked whether parachutes are effective when jumping from a plane. We do not know came the response—there are no randomized, controlled trials comparing jumping from a plane with and without one!

EBM ON THE WORLD WIDE WEB For additional information and resources relevant to EBM, several comprehensive EBM sites exist on the World Wide Web. These sites include information on the history and development of EBM, glossaries of EBM terms, tutorials, training programs, software, links to EBM organizations and practice centers, guides to searching the medical literature, and results of evidence-based studies. For an excellent list of EBM links, access “Netting the Evidence: A ScHARR Introduction to Evidence Based Practice” (http://www.shef.ac.uk/∼scharr/ ir/netting/). A specialized EBM site dedicated to pharmacotherapy deserves special mention. It is provided by the Centre for EvidenceBased Pharmacotherapy (http://www.aston.ac.uk/pharmacy/cebp/). The mission of the center, created in 1995 by pharmacy professor Alain Li Wan Po, is to undertake research into the methodology of medicines assessment, pharmacoepidemiology, and pharmacoeconomics. In addition, the center offers postgraduate and distance learning in evidence-based pharmacotherapy.

section, the four steps involved in applying the EBM process to a pharmacotherapeutic decision are described9 : 1. Recognize information needs and convert them into answerable questions. 2. Conduct efficient searches for the best evidence with which to answer these questions. 3. Critically appraise the evidence for its validity and usefulness. 4. Apply the results to patient situations to best assist clinical decision making.

BUILDING A FOCUSED QUESTION Clinicians constantly balance the benefits and risks of various therapeutic choices. The questions they face are patient-specific: r r r

Should clopidogrel be prescribed to this 65-year-old man with unstable angina? Should hormone-replacement therapy be prescribed for this postmenopausal woman? Is sildenafil safe in this patient with type 2 diabetes?

When searching for the best evidence to answer such questions, the questions must be rephrased with more precision and specificity. A well-formulated question includes the following elements: the patient or problem being addressed, the intervention being considered, the comparison intervention, and the outcome(s) of interest.10 Using these four elements, the preceding questions can be reframed as follows: r

r

r

Would clopidogrel in addition to aspirin (intervention) prevent death or coronary events (clinically relevant outcome) in this patient with unstable angina (patient with a problem) who is currently on aspirin alone (comparison intervention)? Should we begin hormone-replacement therapy (intervention compared with no intervention) to prevent cardiovascular events (outcome) in this asymptomatic postmenopausal woman with a family history of coronary artery disease (patient)? If sildenafil is begun (intervention), what is the risk of myocardial ischemia (outcome) in this asymptomatic patient with known coronary artery disease (CAD) and newly diagnosed with type 2 diabetes (patient)?

The acronym PICO can be helpful to remember the elements of a well-balanced question11 : P = patient I = intervention C = comparison O = outcome Focusing the question clarifies the target of the literature search and permits use of the appropriate guides for assessing external validity, that is, the applicability of the evidence found in the study to appropriate parts of the “real world.”

CONDUCTING AN EFFICIENT SEARCH INCORPORATING EBM INTO PHARMACOTHERAPEUTIC DECISION MAKING 2 The practice of EBM is to recognize an information need while

caring for a patient, identify the best existing evidence to help resolve the problem, consider the evidence in light of the actual circumstances, and integrate the evidence into a medical plan. In this

Health care professionals have four options as they try to identify the best evidence available to answer a well-framed question: 1. Ask a colleague for his or her expert opinion. 2. Review practice guidelines (evidence-based or expert-opinion–based) or a textbook for appropriate disease management.

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TABLE 3–1. North American Sources of Evidence-Based Clinical Practice Guidelines Resource/Web Address

Special Features

National Guideline Clearinghouse (NGC) (www.guideline.gov ) NGC is a collaboration of U.S. Department of Health and Human Services and the Agency for Healthcare Research and Quality (AHRQ), in partnership with the American Medical Association (AMA) and the American Association of Health Plans (AAHP). NGC provides access to full text guidelines (when available) produced by a number of different professional medical associations and health care organizations. Each guideline is critically appraised using a standard instrument. The site permits side-by-side comparison of several guidelines. National Library of Medicine’s Health Services/Technology Assessment Text (http://hstat.nlm.nih.gov/hq/Hquest/screen/HquestHome/s/ 55240 ) This World Wide Web resource is a collection of AHRQ Supported Guidelines, AHRQ Technology Assessments and Reviews, ATIS (HIV/AIDS Technical Information), NIH Warren G. Magnuson Clinical Research Studies, NIH Consensus Development Program, Public Health Service (PHS) Guide to Clinical Preventive Services and the Substance Abuse, and Mental Health Services Administration’s Center for Substance Abuse Treatment (SAMHSA/CSAT) Prevention Enhancement and Treatment Improvement Protocols. Primary Care Clinical Practice Guidelines (http://medicine.ucsf.edu/resources/guidelines) This Web resource offers a listing of online guidelines. CDC Prevention Guidelines Database Home Page (http://www.phppo.cdc.gov/cdcrecommends) The site is a comprehensive collection of all the official guidelines and recommendations published by the CDC about prevention of diseases, injuries, and disabilities.

r r r r

966 guideline summaries Weekly e-mail alerts Advanced search queries based on guideline attributes Annotated bibliography of resources relevant to guideline methodology

r 199 full-text guidelines r Metasearch capabilities to PubMed, Centers for Disease Control and Prevention (CDC) Prevention Guidelines Database, and National Guideline Clearinghouse r Access to quick-reference guides for clinicians and consumer brochures.

r Searchable by clinical content and organization r More than 500 prevention guidelines/documents r Searchable r Sort by date, by topic, or alphabetically

Cancer Care Ontario Practice Guidelines Initiative (CCOPGI) (http://www.cancercare.on.ca) This Web page includes published and unpublished guidelines related to cancer care. These guidelines are created by the CCOPGI and are available full text.

r 75 guidelines r When information is scarce, evidence summaries are created to review the best evidence available

Agency for Healthcare Research and Quality’s Evidence-Based Practice Centers (AHRQ EPCs) (http://www.ahcpr.gov/clinic/epcix.htm) AHRQ has established 12 Evidence-Based Practice Centers to analyze and synthesize the scientific literature and develop evidence reports and technology assessments on clinical topics.

3. Consult electronic databases of systematic reviews and/or meta-analyses. 4. Conduct a literature search using an electronic database such as MEDLINE.

r 84 evidence reports r Full text available

Asking an expert or colleague may provide a quick and easy answer to a clinical question. Exercise caution, however. These sources have become less reliable as the volume and complexity of medical information have grown exponentially. Colleagues may be out of date or biased by their own experiences.

Medicine Online electronic textbooks). As their names suggest, evidence-based clinical guidelines are guided by objective data and should be preferred over expert-opinion–based guidelines that refer loosely to evidence to support their opinions. Expert-opinion guidelines vary in their scientific validity and reproducibility.12 One Web site—the National Guideline Clearinghouse on the Web (http://www.guideline.gov)—provides links to many evidencebased clinical practice guidelines. For each guideline, this comprehensive database offers a short summary of the key attributes, including the bibliographic sources, guideline developers and endorsers, status of the guidelines, and major recommendations. In addition, the site provides the ability to generate side-by-side comparisons for any combination of two or more guidelines. Table 3–1 presents an annotated list of additional resources to find and access evidence-based clinical practice guidelines.

OPTION 2

OPTION 3

Online practice guidelines or current textbooks with evidence links are useful if the question relates to a common or well-established issue (e.g., UpToDate, Harrison’s Online, and Scientific American

Consulting electronic databases of systematic reviews and metaanalyses is attractive because of the limited amount of time health care professionals have to research and review the literature before they

Each of these options has advantages and disadvantages, as described below.

OPTION 1

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answer clinical questions or reach patient care decisions. Busy health care professionals prefer summaries of information. Traditional narrative reviews are useful for broad overviews of particular therapies or diseases or for reports on the latest advances in a particular area where research may be limited.13 However, information from narrative reviews is often gathered ad hoc, and the author’s biases may enter into the process of gathering, analyzing, and reporting information. In contrast, systematic reviews employ a comprehensive, reproducible data search and selection process to summarize all the best evidence. They follow a rigorous process to appraise and analyze the information, quantitatively (through the meta-analysis technique) or qualitatively, to best answer a defined clinical question. Systematic reviews are a useful means of assessing whether findings from multiple individual studies are consistent and can be generalized.14 The Cochrane Library represents one of the most comprehensive sources of systematic reviews summarizing the evidence about health care. About 2000 Cochrane reviews are currently available, and another 1441 reviews were in progress when this chapter was finalized in spring 2004. Since new reviews are added quarterly, eventually all areas of health care will be covered. The Cochrane Library includes the Database of Abstracts of Reviews of Effectiveness, which contains more than 2500 structured abstracts of good-quality

published reviews about the effectiveness of health interventions. Table 3–2 lists accessible sources of systematic reviews and provides a search strategy developed by librarians at McMaster University to locate systematic reviews and meta-analyses on MEDLINE efficiently.15

OPTION 4 Consider conducting a literature search on an electronic database such as MEDLINE if the question relates to new developments in therapeutic options. In this case, health care professionals must consult primary literature. Dozens of electronic databases exist as primary sources of original research reports. MEDLINE and PubMed, both produced by the National Library of Medicine (NLM), are the largest and best known bibliographic databases of biomedical journal literature. PubMed’s in-process records provide basic citation information and abstracts before the citations are indexed with NLM’s Medical Subject Headings (MeSH) Terms and added to MEDLINE. To optimize the efficiency of a clinical search, PubMed offers specialized searches using methodologic filters. These filters, based on work by Haynes and colleagues,15 are validated search strategies to identify clinically relevant studies

TABLE 3–2. Selected Resources for Systematic Reviews Resources Best Evidence Electronic version of both American College of Physicians (ACP) Journal Club and Evidence-Based Medicine (http://hiru.mcmaster.ca/acpjc/acpod.htm). Available on CD-ROM. MEDLINE Systematic review search strategy: (meta-analy$ or metanal$ or metaanal$). tw. or Meta-Analysis/or meta-analysis (pt) or (quantitativ$ review$ or quantitativ$ overview$).tw. or (systematic$ review$ or systematic$ overview$).tw. or (methodologic$ review$ or methodologic$ overview$).tw. or medline.tw. or pooled.tw.) and eng.lg. and human/) not (letter or editorial or comment).pt

Advantages

r All review articles are systematic reviews. r Updated every 6 months r Short title includes meta-analysis or review to facilitate identification

Disadvantages

r Includes systematic reviews from only the journal scanned by ACP Journal Club and Evidence-Based Medicine

r Covers more than 4000 journals r Contains 11 million citations

r One-tenth of the citations are

Cochrane Library Electronic library of high-quality reviews (http://www.cochrane.org). Available on CD-ROM.

r Most comprehensive collection of

r Limited access; not all libraries

United Kingdom National Health Services Centre for Reviews and Dissemination (http://agatha.york.ac.uk/welcome.htm ) Includes the Database of Abstracts of Reviews of Effectiveness (DARE), NHS Economic evaluation database, and the Health Technology Assessment (HTA) database

r The DARE Web version, which is

Effective Health Care Bulletins http://www.york.ac.uk/inst/crd/ehcb.htm

r Reports of systematic reviews

systematic reviews r Updated every 3 months r Abstracts of Cochrane Reviews are available free on the Internet at http://www.cochrane.org.

updated monthly, is more current than the Cochrane Library version.

indexed as review articles. Even fewer are indexed as systematic reviews. r Requires search strategy to identify meta-analysis or systematic reviews

subscribe to the Cochrane Library

r NHS economic evaluation, last update 1999

r Limited number of reviews

produced by NHS Centre for Reviews and Dissemination National Institute for Clinical Excellence Part of the UK National Health Service (NHS). Provides guidelines and technology assessments to health care practitioners (http://nice.org.uk).

r Follows Cochrane methodology to develop technology assessments. Twenty-eight have been completed, and 38 are in progress.

r Limited number of guidelines and assessments available

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TABLE 3–3. Metasearch Engines for Web-Based Health Information Turning Research Into Practice (TRIP) Web address: www.update-software.com/trip/about.htm Sources: Fifty-eight sites categorized as evidence-based, peer-reviewed journals, guidelines, or other. Sites include top 20 medical journals, EMB sites such as Bandolier, Critically Appraised Bank, Cochrane Database of Systematic Reviews, Journal Club on the Web, Evidence-Based Medicine series, guideline and systematic review sites such as SIGN, DARE, NICE, and National Guideline Clearinghouse. Special features: Updated monthly. Searches use keywords in the title only. Results are displayed by categories: evidence-based, peer-reviewed journals, guidelines, or other. SUMSearch Web address: http://SUMSearch.uthscsa.edu Sources: Three Internet sites: The National Library of Medicine, the Database of Abstracts of Reviews of Effectiveness, and the National Guideline Clearinghouse. Special features: If the first search resulted in too many or not enough hits, SUMSearch uses metasearching and contingency search techniques to query the sites again. Search.com Web address: http://www.search.com Sources: Twenty-two Internet sites containing health and medical information. Some of these sites are American College of Physicians Online, Centers for Disease Control and Prevention, New England Journal of Medicine, Agency for Healthcare Research and Quality, Journal of the American Medical Association, PubMed, Merck, Mayo Clinic, Food and Drug Administration, World Health Organization, WebMD, and Medical Subject Headings (MeSH). Special features: The site allows customization in choosing search engines and how to display results. Query Server Web address: http://queryserver.com Sources: Twelve sites containing health and medical information. These sites are American Health Consultants, American Heart Association, Centers for Disease Control and Prevention, Department of Health and Human Services, Food and Drug Administration, Johns Hopkins Infectious Diseases, Leukemia and Lymphoma Society, MEDLINE, Medscape Clinical Content, Medscape News, National Institutes of Health, National Library of Medicine. Special features: Results are sorted according to content and/or source.

that answer questions about etiology, prognosis, diagnosis, or therapy of a disease. To facilitate the searches of multiple Internet sources, metasearching is useful. Metasearch tools launch a single query across a set of Web-based health sites. One query returns a merged and often ranked list of hits, allowing the user to search several databases at once. Table 3–3 describes the specifics of new metasearch engines available to search for Internet-based health information. Once the evidence is gathered, the clinician needs to determine whether the identified guideline, review article, or study report will help to answer the clinical problem. This is accomplished by considering the validity and by judging the clinical relevance (usefulness) of the information.16

the scope of this chapter to present extensive details about critical appraisal, here are some questions that must be answered in assessing the internal validity of an RCT: r

ASSESSING VALIDITY 3 The external validity refers to applicability and generalization

and is outlined in the section, “Applying the Results.” The remainder of this section focuses on critically appraising the quality— that is, the internal validity—of individual trials. The internal validity is determined by how well the trial ensures that the known and unknown risk factors are equally distributed between the treatment and control groups. To ensure validity, the conduct of the trial should minimize systematic bias and random error as much as possible to provide results that are as accurate and close to the truth as possible. Four sources of bias are possible in trials of health care interventions: selection bias, performance bias, attrition bias, and detection bias. Bias can result in an overestimation or underestimation of the effectiveness of a drug therapy and mislead the reader. While it is beyond

r

Was the subject’s treatment allocation randomized? To minimize selection bias, all participants should have an equal chance to be allocated to the treatment or control group. Randomization is the best method to create groups of similar known and unknown confounders. If important risk factors known to affect prognosis (such as disease severity or presence of comorbidities) are unevenly distributed between groups, then selection bias could falsely estimate the benefit of the intervention. Furthermore, recruiters should not know which assignment (treatment or control group) is next in line. Recruiters who assess eligibility criteria and are aware of the next random allocation may consciously or unconsciously select the healthiest patient to be enrolled in the control group or vice versa. Approaches to randomization that may allow the recruiters to manipulate the assignment include improper use of record numbers (e.g., if all odd numbers were assigned to control group), dates of birth, day of the week, or open lists of random numbers. Examples of bias-free random allocations include centralized randomization (e.g., a central office unaware of subject characteristics allocates group assignments), pharmacy-controlled randomization (assuming that the pharmacist is not recruiting the subjects), and opaque envelopes that are numbered sequentially and sealed.17 Was the study double-blinded? To minimize performance bias (systematic differences in the care provided, apart from the intervention being evaluated), the subjects and the clinicians should be unaware of the therapy received. The double-blind

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method prevents subjects or clinicians from adding any additional treatments (or cointerventions) to one of the groups. For example, clinicians who know that certain patients are receiving the therapy they perceive to be less effective (control group) may opt to check on those patients more often than is required in the study protocol. A third blind can be applied to the outcome assessor (e.g., a statistician or clinician whose role is to measure the outcome) to minimize detection bias (systematic differences in outcome assessment). The necessity for blinding outcome assessors is controversial at this time. Was intention-to-treat analysis performed? Intention-to-treat analysis means that the results from all subjects randomized in the study were accounted for and attributed to the group to which they were assigned. This strategy minimizes attrition bias and ensures that the known and unknown prognostic factors are kept equally distributed. For example, exclusion of subjects who withdrew early in treatment may bias the

comparison because the reasons people withdraw early are often related to prognosis.18 Excluding early withdrawals from the final analysis may select the subjects most likely to get the best outcome and thereby overestimate the benefit of the intervention. For a more detailed description of the concepts in critical appraisal, a series of articles published in the Journal of the American Medical Association (JAMA) provides a useful tool for practitioners who are evaluating clinical trials.19−50 These users’ guides to the medical literature—developed by The Evidence-Based Medicine Working Group, a group of clinicians at Canada’s McMaster University and colleagues across North America—can help to assess the validity of primary studies as well as review articles. Online materials to support teaching of evidence-based health care, including the Users’ Guides to Evidence-Based Practice, are now supported through the Centres for Health Evidence at http://www.cche.net. Table 3–4 summarizes the key elements to be

TABLE 3–4. Checklist for Critical Appraisal of Articles Addressing Pharmacotherapeutic Decisions Therapy Internal validity r Was subject’s treatment allocation randomized? r Was the study double-blinded? r Was intention-to-treat analysis performed? r Was the randomization successful? Magnitude of the effect r What was the impact of the treatment? r How narrow is the 95% confidence interval range? r Were clinically relevant outcomes considered? Applicability r Does this patient fulfill inclusion criteria for the trial? r Do the treatment benefits outweigh the risks? Harm Internal validity r Were the control subjects similar to the cases? r Was bias minimized while measuring exposure and outcomes? r Was length of follow-up appropriate? r Does exposure precede the adverse outcome? r Is there a dose-response relationship? Magnitude of the effect r How strong is the association between exposure and outcome? r How precise is the estimate? r How many patients must be exposed to the agent to cause an adverse event? Applicability r What is the likelihood of harm in my patient? r What are the consequences of eliminating the agent from my patient’s therapy? Overview, Systematic Reviews, Meta-analysis Internal validity r Did the overview clearly state a well-formulated question? r Were the criteria used to select articles for inclusion appropriate? r Were all relevant studies included? r Were included articles critically appraised for quality? r Was bias minimized in the selection, data extraction, and analysis processes? r Were all clinically important outcomes considered? r Were the studies appropriately combined? Magnitude of the effect r What is the average effect? r How precise are the results? Adapted from Users’ Guide Series (Refs. 19 to 50).

Applicability r Are this patient’s characteristics similar to the subjects included in the studies? r Do the treatment benefits outweigh the risks? Practice Guidelines Internal validity r Were the management options and outcomes clearly specified? r Was all evidence relevant to each arm of the evidence model sought? r Were systematic and explicit methods used to identify, select, and combine evidence? r Were all clinically relevant outcomes evaluated? r Is the guideline up-to-date? r Does the guideline clearly present the evidence to support the benefit of following the recommendations? r Has the guideline been peer-reviewed? Magnitude of the effect r How strong are the recommendations? r What is the impact of uncertainty in the evidence on outcomes? Applicability r Are the guideline recommendations targeting my practice (e.g., family practice setting versus endocrinology setting)? r Is my patient the intended target for this guideline? Economic Analyses Internal validity r Were both costs and outcomes evaluated for all strategies considered? r Were costs and outcomes measured and valued accurately? r Was the potential impact of uncertainties in the analysis evaluated? r Was the potential impact of different baseline risk in the treatment population estimated on costs and outcomes? Magnitude of the effect r What were the incremental costs and outcomes of each strategy considered? r Do incremental costs and outcomes vary between selected groups of patients? r What is the impact of sensitivity analyses on incremental cost? Applicability r Do the treatment benefits outweigh the treatment risk and cost? r Are the results transferable to my practice setting (e.g., similar patient types, similar costs of resources)?

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addressed for each type of evidence to appraise internal validity and usefulness.19−50

CONSIDERING CLINICAL RELEVANCE Once the clinician has gathered all relevant studies, eliminated those which addressed other questions, and identified those with the best methods, one question remains: So what? Also known as the “who cares” test,51 applying this admittedly crude criterion begins the process of asking oneself, “Will these findings change the way I will treat or prevent this disease in my practice—and specifically for the patient sitting in front of me right now?” The first step in making this decision is to consider the clinical value of the beneficial outcomes reported. Are the outcomes demonstrating improvements important to the patients? For example, a drug therapy that improves left ventricular ejection fraction (a surrogate end point) does not have the same clinical value as a drug that is shown to decrease mortality or improve functional status (primary end points) in an individual with heart failure. The usefulness of an intervention depends not only on its efficacy but also on whether the magnitude of the benefit outweighs the risks,

EVIDENCE-BASED MEDICINE

costs, and benefits of existing alternative interventions. In this context, the number needed to treat (NNT) and the number needed to harm (NNH) are clinically useful measures. NNT and NNH describe the number of patients who need to be treated and for how long to achieve one favorable or harmful outcome, respectively (Table 3–5 illustrates the values of NNT and NNH). The NNT strategy provides a way to estimate an intervention’s impact and tradeoffs and to decide whether this therapy should be implemented. The relative risk reduction (RRR), as a measure of the magnitude of an intervention’s effect, can be misleading. It does not discriminate between large and trivial absolute differences between the control and experimental groups. For example, an intervention may result in a 50% risk reduction for the adverse outcome, and this amount of decrease would sound impressive to most clinicians and patients. However, it might represent only a small difference in the risk of a rare event (e.g., 0.2% of patients in a placebo group died compared with 0.1% of patients on active drug). In contrast, a 50% risk reduction might reflect a much more meaningful difference, for instance, when 50% of placebo group died versus 25% of patients in the intervention group (an absolute difference of 25%). The RRR is the same for both examples, but the magnitude of the impact of the intervention is drastically different. The information provided by the RRR is incomplete

TABLE 3–5. Number Needed to Treat and Number Needed to Harm In this example, the clinical question is whether the addition of clopidogrel to the regimen of a 65-year-old man with unstable angina who is already taking aspirin would prevent death or coronary event? A search of published trials and presented papers at scientific meetings uncovered only one relevant study. It was presented in abstract form at the American College of Cardiology meeting on March 19, 2001. In the trial: r 12,562 subjects with coronary syndrome were randomized to aspirin alone or aspirin plus clopidogrel. r On average, patients were followed for 9 months. r The primary endpoint was to prevent cardiovascular (CV) death, myocardial infarction (MI), or stroke. To calculate the number needed to treat (NNT), first calculate the absolute risk reduction (ARR). This is the absolute difference between the event rate in the control group (CER) minus the event rate in the experimental group (EER). The NNT is the inverse of the ARR. The trial reports that 11.47% of the aspirin alone group (control group) had MI, stroke, or CV death. In contrast, 9.28% of the aspirin plus clopidogrel (experimental group) had these events. Control Event Rate (Aspirin-Alone Group) 11.47%

Experimental Event Rate (Aspirin Plus Clopidogrel) 9.28%

33

RRR= (CER − EER)/CER 19%

ARR = (CER − EER)

NNT = 1/ARR

2.19%

46

Thus the NNT is 46. That is, treating 46 patients with unstable angina for 9 months with aspirin with clopidogrel should prevent MI, stroke, or CV death in 1 patient. To balance risks versus benefits of an intervention, we can generate a similar number needed to harm to express the risks associated to the intervention. The trial reports that 2.7% of the aspirin-alone group had major nonfatal bleeding events compared with 3.6% in the intervention group (aspirin plus clopidogrel). To calculate the number needed to harm (NNH), first calculate the absolute risk increase (ARI). This is the absolute difference between the event rate in the experimental group (EER) minus the event rate in the control group (CER). The NNH is the inverse of the ARI. Control Event Rate

Experimental Event Rate

ARI (Absolute Risk Increase)

NNH

2.7%

3.6%

0.9%

111

The NNH is thus 111, meaning that treating 111 patients with both drugs for 9 months would result in 1 major nonfatal bleed. Combining the NNT and NNH and projecting the results to 1000 patients would lead to this conclusion: This randomized, controlled trial suggests that treating 1000 individuals with unstable angina with the combination of aspirin plus clopidogrel would prevent 21 patients from having a stroke, MI, or CV death at the cost of 9 major nonfatal bleeding events.

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because it does not take into account the baseline risk of subjects in the trial. CLINICAL CONTROVERSY NNT and NNH can be a bit nebulous when it comes to applying these values in clinical situations. P values are considered significant routinely when they fall below 0.05, but what is a good NNT in one study may not be so good in another trial. NNT and NNH provide visualizations for how much risk and benefit are present when a group of similar patients—such as those seen by a physician or cared for in a pharmaceutical care clinic—are all treated with a medication or other intervention.

APPLYING THE RESULTS For every health care professional, the ultimate test of which studies are important and which are not comes down to the decision of how to treat each patient. Thus clinical judgment is crucial in assessing the importance of drug-therapy evidence. Several patient-specific factors must be considered in the final analysis: 1. Compare the patient with those in the study (similar disease state and stage, similar baseline characteristics). This assessment should ensure that the population studied has a similar disease state and prognostic factors as the patient now being treated. For instance, the results of a trial assessing the mortality benefit of simvastatin in dyslipidemic men with known coronary artery disease would not likely apply to dyslipidemic women with no other coronary risk factors. 2. Consider the patient’s baseline risk for the outcome of interest and other potential risks associated with the therapy. If this patient has a higher baseline risk for the outcome than the population studied, then treatment may yield an even higher benefit. In contrast, if the patient has a lower baseline risk than the population studied, then treatment-associated risks may outweigh the potential benefit. For example, premenopausal women, in general, have a lower cardiovascular mortality risk than do men. Therefore, an intervention shown to prevent cardiovascular mortality in men may result in a smaller benefit in women. 3. Consider the patient’s values, beliefs, concerns, and readiness for the intervention. In addition, health care delivery characteristics (cost and accessibility) must be factored in. While not very long ago health care professionals were considered patriarchal figures who directed the patient’s treatment, today patients are fully engaged partners in decisions about therapy. The evidence must be discussed and integrated with the specific patient’s circumstances to result in successful outcomes.

KEEPING UP TO DATE BY USING EBM 4 The same combination of clinical experience and EBM skills that enables health care professionals to resolve patient-specific

pharmacotherapeutic questions also aids health care professionals’ continued efforts to keep up to date. The process is the same: (1) Recognize information needs (the areas of one’s practice), (2) identify literature relevant to clinical practice, (3) critically appraise the evidence for validity and utility, and (4) devise a mechanism to implement new evidence in daily practice. As with human knowledge in general, medical information is growing exponentially. Clinicians have difficulty staying current; a few statistics explain why. The National Library of Medicine contains more than 11 million citations covering nearly 4500 biomedical journals.52 The number of citations doubled in just 6 years, from 1995 to 2001. Each year, 10,000 RCTs addressing the impact of health care interventions are published. Some influence how clinicians practice, others provide preliminary evidence that is too early to act on or is irrelevant to clinical practice, and others are seriously flawed and should not be implemented. Who has time to read it all and separate the good from the bad? A literature-sorting strategy, using the EBM approach, is one solution. First, the clinician must recognize the areas important in his or her practice (e.g., internal medicine, cardiology, nuclear medicine, nutrition, psychiatry, or pharmacokinetics). Second, scan the literature for clinically relevant studies in that area of interest or practice. These are studies addressing clinical outcomes likely to be relevant to clinical practice and possibly change prescribing behaviors, such as those which report the effect of a pharmacotherapy on quality of life, costeffectiveness, mortality, or morbidity. In contrast, trials addressing the impact of drug therapy on surrogate end points (e.g., biochemical markers) most often are irrelevant to current clinical practice and rarely would result in a change in practice. When in a “keeping up-todate mode,” choose the studies reporting clinically relevant outcomes over those with surrogate end points. Third, critically appraise the evidence for validity and usefulness. When addressing therapeutic efficacy, RCTs are considered the “gold standard” and should be preferred over observational studies for most clinical questions. Scan the abstracts of RCTs for obvious design flaws and size of the effect before appraising further. Shaughnessy and colleagues53 have created a formula to help determine the usefulness of medical information (Fig. 3–1). Finally, integrate the new findings into one’s daily practice. If this process seems too labor-intensive for keeping pace with the medical literature, consider an evidence-based abstraction service. These services, which have grown tremendously in the past 10 years, claim to reduce by 98% the amount of clinical literature a clinician needs to read, enabling the busy health care professional to concentrate on the 2% that is most methodologically rigorous and useful to his or her practice.54 In general, abstraction services consist of an editorial team that scans dozens of journals, usually organized by specialty. They identify articles of potential clinical relevance, critically appraise the studies, and provide commentary on the quality/validity and clinical significance of the results reported. Table 3–6 presents a selected list of translation journals offering evidence-based abstracts of original research.

Usefulness of Medicine Information ⫽

Relevance ⫻ Validity Work Factor

FIGURE 3–1. In this usefulness formula, relevance represents patient-oriented evidence that matters and affects health care, validity refers to a true estimate of the effect, and work factor describes the effort required to review the information.

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TABLE 3–6. Evidence-Based Abstraction Services ACP Journal Club (http://www.acponline.org/journals/acpjc/jcmenu.htm) Audience: Internal medicine, primary care Selection criteria: Original articles, systematic reviews, English, adult, clinically relevant with important outcomes, randomized controlled trials for treatment questions Journals scanned: 26 journals Bandolier (http://www.jr2.ox.ac.uk/bandolier/) Audience: Internal medicine Selection criteria: Those which look remotely interesting are read, and where they are both interesting and make sense, they are summarized Journal scanned: Each month PubMed and the Cochrane Library are searched for systematic reviews and meta-analyses published in the recent past Evidence-Based Cardiovascular Medicine (http://www.harcourt-international.com/journals/ebcm/ ) Audience: Cardiology (adult and pediatric) Selection criteria: Original articles, English, clinically relevant, adult or pediatric humans randomized controlled trials, double blinded Journals scanned: 25 journals mostly cardiology specialty journals Evidence-Based Health Care (http://www.harcourt-international.com/journals/ebhc/ ) Audience: Managers Selection criteria: Articles providing evidence for decision making; articles that are likely to be widely applicable Journals scanned: More than 50 journals mostly with economics and public health focus Evidence-Based Medicine (http://www.evidence-basedmedicine.com) Audience: Internal medicine, general and family practice, surgery, psychiatry, pediatrics, and obstetrics and gynecologists Selection criteria: Original articles, Cochrane Reviews, randomized controlled trial or therapeutic efficacy trial, clinically relevant outcomes, 80% follow-up Journals scanned: More than 30 journals Evidence-Based Mental Health (http://www.ebmentalhealth.com/ ) Audience: Mental health clinicians Selection criteria: Original articles, Cochrane Reviews, randomized controlled trial or therapeutic efficacy trial, clinically relevant outcomes, 80% follow-up Journals scanned: Not available Journal Watch series (http://www.jwatch.org/ ) Audience: General medicine, dermatology, cardiology, psychiatry, women’s health, emergency medicine, infectious disease, neurology, gastroenterology (specialty Journal Watch for each audience) Selection criteria: Not given Journals scanned: More than 50 journals Journal of Family Practice (http://www.jfp.msu.edu) Audience: Family practice, pharmacists Selection criteria: High-quality articles with patient-oriented outcomes that have the greatest potential to change the way that primary care clinicians practice Journals scanned: 80 journals Journal Club on the Web (http://www.journalclub.org ) Audience: Internal medicine Selection criteria: Not given Journals scanned: New England Journal of Medicine, Annals of Internal Medicine, Journal of the American Medical Association, The Lancet

CONCLUSIONS 5 Is EBM realistic? The needed skills for practicing EBM may ap-

pear daunting, but once acquired, they can help health care professionals to better use available resources and time by knowing how to focus a search and be more critical in what reading and information to integrate into their knowledge base. Several sites have demonstrated that EBM can be incorporated into practice successfully.55−58 Why practice EBM? Implementing EBM in a practice provides a framework and the skills to strengthen confidence in pharmacotherapeutic decisions and results in better communication with colleagues involved in the decision-making process. Furthermore, an

evidence-based pharmaceutical care plan facilitates dialogue with patients about the rationale for the management decisions. Finally, using EBM principles enables practicing health care professionals to update their knowledge continuously. This chapter provides tools for health care professionals to 1. Identify rapidly evidence-based clinical practice guidelines 2. Identify rapidly systematic reviews 3. Conduct validated searches to identify studies answering pharmacotherapy questions 4. Critically appraise the literature found 5. Assess relevance and applicability of the evidence

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6. Develop strategies to triage the most useful literature and help to keep pace with the evidence that makes a difference in one’s practice

ABBREVIATIONS CAD: coronary artery disease EBM: evidence-based medicine MeSH: medical subject headings MI: myocardial infarction NLM: National Library of Medicine NNH: number needed to harm NNT: number needed to treat PICO: patient, intervention, comparison, outcome PVC: premature ventricular contraction PCT: randomized, controlled trial RRR: relative risk reduction Review Questions and other resources can be found at www.pharmacotherapyonline.com.

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CHAPTER 3 35. Drummond MF, Richardson WS, O’Brien BJ, et al. Users’ guides to the medical literature: XIII. How to use an article on economic analysis of clinical practice. A. Are the results of the study valid? Evidence-Based Medicine Working Group. JAMA 1997;277:1552–1557. 36. O’Brien BJ, Heyland D, Richardson WS, et al. Users’ guides to the medical literature: XIII. How to use an article on economic analysis of clinical practice. B. What are the results and will they help me in caring for my patients? Evidence-Based Medicine Working Group. JAMA 1997;277:1802–1806. 37. Dans AL, Dans LF, Guyatt GH, Richardson S. Users’ guides to the medical literature: XIV. How to decide on the applicability of clinical trial results to your patient. Evidence-Based Medicine Working Group. JAMA 1998;279:545–549. 38. Richardson WS, Wilson MC, Guyatt GH, et al. Users’ guides to the medical literature: XV. How to use an article about disease probability for differential diagnosis. Evidence-Based Medicine Working Group. JAMA 1999;281:1214–1219. 39. Guyatt GH, Sinclair J, Cook DJ, Glasziou P. Users’ guides to the medical literature: XVI. How to use a treatment recommendation. Evidence-Based Medicine Working Group and the Cochrane Applicability Methods Working Group. JAMA 1999;281:1836–1843. 40. Barratt A, Irwig L, Glasziou P, et al. Users’ guides to the medical literature: XVII. How to use guidelines and recommendations about screening. Evidence-Based Medicine Working Group. JAMA 1999;281:2029–2034. 41. Randolph AG, Haynes RB, Wyatt JC, et al. Users’ guides to the medical literature: XVIII. How to use an article evaluating the clinical impact of a computer-based clinical decision support system. JAMA 1999;282:67–74. 42. Bucher HC, Guyatt GH, Cook DJ, et al. Users’ guides to the medical literature: XIX. Applying clinical trial results. A. How to use an article measuring the effect of an intervention on surrogate end points. EvidenceBased Medicine Working Group. JAMA 1999;282:771–778. 43. McAlister FA, Laupacis A, Wells GA, Sackett DL. Users’ guides to the medical literature: XIX. Applying clinical trial results. B. Guidelines for determining whether a drug is exerting (more than) a class effect. JAMA 1999;282:1371–1377. 44. Hunt DL, Jaeschke R, McKibbon KA. Users’ guides to the medical literature: XXI. Using electronic health information resources in evidence-based practice. Evidence-Based Medicine Working Group. JAMA 2000;283:1875–1879. 45. McAlister FA, Straus SE, Guyatt GH, Haynes RB. Users’ guides to the medical literature: XX. Integrating research evidence with the care of

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the individual patient. Evidence-Based Medicine Working Group. JAMA 2000;283:2829–2836. McGinn TG, Guyatt GH, Wyer PC, et al. Users’ guides to the medical literature: XXII. How to use articles about clinical decision rules. Evidence-Based Medicine Working Group. JAMA 2000;284:79–84. Giacomini MK, Cook DJ. Users’ guides to the medical literature: XXIII. Qualitative research in health care. A. Are the results of the study valid? Evidence-Based Medicine Working Group. JAMA 2000;284:357–362. Giacomini MK, Cook DJ. Users’ guides to the medical literature: XXIII. Qualitative research in health care. B. What are the results and how do they help me care for my patients? Evidence-Based Medicine Working Group. JAMA 2000;284:478–482. Richardson WS, Wilson MC, Williams JW Jr, et al. Users’ guides to the medical literature: XXIV. How to use an article on the clinical manifestations of disease. Evidence-Based Medicine Working Group. JAMA 2000;284:869–875. Guyatt GH, Haynes RB, Jaeschke RZ, et al. Users’ guides to the medical literature: XXV. Evidence-based medicine: Principles for applying the users’ guides to patient care. Evidence-Based Medicine Working Group. JAMA 2000;284:1290–1296. Huth EJ. Writing and Publishing in Medicine, 3d ed. Baltimore, Williams & Wilkins, 1999:10–12. National Library of Medicine, Bethesda, MD; accessed at http://www.nlm.nih.gov/pubs/factsheets/pubmed.html, April 12, 2004. Shaughnessy AF, Slawson DC, Bennet JH. Becoming an information master: A guidebook to the medical information jungle. J Fam Pract 1994;39:484–499. Sackett DL, Haynes RB. 13 steps, 100 people, 1,000,000 thanks. Evidence Based Med 1997;2:101–102. Ellis J, Mulligan I, Rower J, Sackett DL. Inpatient general medicine is evidence-based. Lancet 1995;346:407–410. Geddes JR, Game D, Jenkins NE, et al. What proportion of primary psychiatric interventions are based on randomised evidence? Qual Health Care 1996;5:215–217. Gill P, Dowell AC, Neal RP, et al. Evidence-based general practice: A retrospective study of interventions in our training practice. Br Med J 1996;312:819–821. Kenny SE, Shankar KR, Rentala R, et al. Evidence-based surgery: Interventions in a regional pediatric surgical unit. Arch Dis Child 1997;76: 50–53.

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4 DOCUMENTATION OF PHARMACY SERVICES George E. MacKinnon III and Neil J. MacKinnon

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Documentation of pharmacists’ interventions and intent

4 Integrated electronic information systems can facilitate pro-

2 Unless pharmacists in all practice settings document their

5 Federal systems of documentation are becoming increas-

and their actions and impact on patient outcomes is central to the process of pharmaceutical care. activities and communicate with other health professionals, they may not be considered an essential and integral part of the health care team.

3 Manual systems of documentation for pharmacists have

been described in detail, but increasingly electronic systems are used to facilitate integration with payer records and health care systems.

As the opportunities to become more patient-focused increase and market pressures exert increased accountability for pharmacists’ actions, the importance of documenting pharmacists’ professional activities related to patient care will become paramount in the years to come. Processes to document the clinical activities and therapeutic interventions of pharmacists have been described extensively in the pharmacy literature, yet universal adoption of documentation throughout pharmacy practice remains inconsistent, incomplete, and misunderstood. is central to the provision of pharmaceutical 1 Documentation care.1 Pharmaceutical care is provided through a “system” in which feedback loops are established for monitoring purposes. This has advantages compared with the traditional medication-use process because the system enhances communication among members of the health care team and the patient. Pharmaceutical care requires responsibility by the provider to identify drug-related problems (DRPs), provide a therapeutic monitoring plan, and ensure that patients receive the most appropriate medicines and ultimately achieve their desired level of health-related quality of life (HRQOL). To provide pharmaceutical care, the pharmacist, patient, and other providers enter a covenantal relationship that is considered to be mutually beneficial to all parties. The patient grants the pharmacist the opportunity to provide care, and the pharmacist, in turn, must accept this and the responsibility it entails. Documentation enables the pharmaceutical care model of pharmacy practice to be maximized and communicated to vested parties. Communication among sites of patient care must be accurate and timely to facilitate pharmaceutical care. As discussed by Hepler,1 documentation supports care that is coordinated, efficient, and cooperative. Conversely, failure to document activities and patient outcomes can directly affect patients’ quality of care. There are several reasons for failure to document in the medication-use system, and these are

vision of seamless care as patients move among ambulatory, acute, and long-term care settings. ingly important models in the United States as the Medicare Part D (oral prescription drug) benefit is implemented.

6 Electronic medical records have several advantages over manual systems that will facilitate access by community pharmacists and their participation as fully participating members of the health care team.

related to the process of documentation, the specific data collected on a consistent basis, how documentation is shared (e.g., other pharmacists, health care providers, patients, insurers), and methods by which the data are shared. In describing the medication-use system, Grainger-Rousseau and colleagues2,3 have proposed eight essential structures, or elements, that must be in place for drug therapy to be both safe and effective (Table 4–1). When interventions are being planned to improve the medication-use system, all eight elements must be considered. When one or more of these eight essential elements are missing in the care of a patient, that patient is at a high risk of experiencing a DRP. One of these elements (number 7) is documentation and communication. The lack of a universal reimbursement model for cognitive services provided by pharmacists can serve as a roadblock for initiating documentation; however, the opportunity to demonstrate contributions to patient outcomes and safety should serve as a catalyst for pharmacists to document their services provided in all practice settings. While a reimbursement model associated with professional services for the profession may emerge as Medicare Part D is implemented, its description is beyond the scope of this chapter. The reasons why pharmacists should document their patient care activities, along with the specific information that should be recorded, as well as examples of documentation systems and forms that have been used successfully, are illustrated in this chapter.

NEED FOR PHARMACIST DOCUMENTATION The 1999 Institute of Medicine (IOM) Report (To Err Is Human: Building a Safer Health System) detailed the finding that as many as 98,000 Americans die unnecessarily every year as a result of medical 39

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TABLE 4–1. Eight Elements of a Safe and Effective Drug Therapy System2,3 Element

Examples

Timely recognition of drug indications and other signs and symptoms relevant to drug use with accurate identification of underlying disease

“Correct” therapy for a late or incorrect diagnosis cannot improve a patient’s quality of life

Safe, accessible, and cost-effective medicines

Safe and cost-effective (efficient) drug products must be legally and financially available Explicit therapeutic objectives simplify the assessment of prescribing appropriateness and are necessary for assessing (monitoring) therapeutic outcomes Including (1) ensuring that a patient actually obtained the medicine, (2) negotiating a regimen that the patient can tolerate and afford, (3) ensuring that a patient (or caregiver) can correctly use the medicine and administration devices, (4) advising to empower the patient or caregiver to cooperate in his or her own care as much as possible The ambulatory patient or caregiver should consent to therapeutic objectives and know the signs of therapeutic success, adverse effects, and toxicities; when to expect them; and what to do if they appear Many failures can be detected while they are still problems and before they become adverse outcomes or treatment failures Communication and documentation are necessary for cooperation in a system Practice guidelines, performance indicators, and databases are a useful approach to achieving and maintaining improved system performance (outcomes)

Appropriate prescribing for explicit (clear, measurable, and communicable) objectives Drug product distribution, dispensing, and administration with appropriate patient advice

Patient participation in care (intelligent adherence)

Monitoring (problem detection and resolution) Documentation and communication of information and decisions Product and system performance evaluation and improvement

mistakes and errors, of which 7000 deaths were attributable to medication errors, costing upwards of $9 billion.4 Handwritten prescriptions, orders, notes, and other methods of communication, unless transcribed electronically, are fraught with potential for misinterpretation and are error-prone. Through professional obligations, pharmacists in all settings (e.g., community, hospital, long-term care) play a pivotal role in ensuring the appropriate use of medications through prescription procurement or compounding, verification of the appropriateness of prescribed products (e.g., dose, duration, dosage form, and intended use) with prescribers, processing of prescription insurance-related claims, counseling of patients, and ultimately, follow-up and monitoring. The ability to continue to support uncompensated professional services and act as a critical safety net with respect to medication use in the health care system is now at a critical juncture and requires the profession’s immediate attention and subsequent action. 2 Documentation is the primary method to demonstrate value within an organized health care system. More importantly, it is the accepted method by which health care providers communicate with one another with respect to patient care decision making and clinical outcomes. Thus, if pharmacists in all practice settings are not communicating data/information routinely with other providers, they may not be considered an essential and integral part of the health care team. FORCES AFFECTING CLINICAL D O C U M E N TAT I O N

r The need for enhanced communication among health care providers

r A focus on reducing redundancy and the potential for fatal and nonfatal medical errors and preventable drug-related morbidity in all practice settings

r The emergence of electronic medical records (EMRs) in health care, thereby facilitating the sharing of data and aiding in clinical decision making r The need to maintain secure patient and provider data while also making this information available to other key individuals r The desire of patients to communicate more regularly with health care providers and to obtain health care information in a more convenient manner In the community setting, pharmacists may be one of the most accessible health care providers seen by patients on a regular basis (e.g., when medications are dispensed or over-the-counter products and diagnostics are purchased). By actively participating in the management of prescribed and nonprescribed drug products, as well as monitoring associated clinical outcomes, pharmacists can make a valuable contribution to patient care and demonstrate their impact on clinical and economic outcomes. While such activities presently are occurring in community practice, the provision of timely documentation to other providers and patients alike often is lacking.

STRUCTURE AND ORGANIZATION OF DOCUMENTATION 3 A great deal has been written about manual documentation sys-

tems in the pharmacy literature, both in clinical practice and in education, but these systems tend to be individualized applications in which the transfer of data to other providers is nonexistent or quite limited.5−8 Many documentation systems in pharmacy focus on the generation of reports for workload analysis or accreditation purposes. Unfortunately, the information gathered and analyzed in such

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applications does little, if anything, to improve patient care if it is not in a real-time format. The principal purpose of clinical documentation is to provide a record of what a practitioner does, why it is done, and when possible, what outcomes are achieved. It is essential to document succinctly the patient-specific recommendations and actions taken by pharmacists and why these decisions were made. Functions performed by pharmacists, such as obtaining medication histories, counseling patients, performing limited patient assessment and monitoring, conducting drug regimen reviews, and providing drug information are direct services that benefit patients, pharmacists, and other health care providers in various practice settings. The provision of these services by pharmacists and their associated outcomes need to be documented and communicated on a consistent basis. Documentation that occurs in a vacuum and devoid of real-time dissemination ultimately may not benefit patient care. KEY CHARACTERISTICS OF CLINICAL D O C U M E N TAT I O N

r The primary purpose of clinical documentation is to provide a record of what a practitioner does, why it is done, and where possible, what outcomes are achieved. r Clinical documentation should provide a real-time trail of care provided to patients. r Documentation systems and applications must be easy to use, portable, produce useful reports, be replicated by others consistently, and allow for knowledge sharing with other providers. While convenient and easy to use, paper documentation forms can be time-consuming to complete accurately, are inefficient in terms of producing useful information, and often result in inconsistent reporting because there is great variance in their format and use among practitioners. Efficient and effective documentation systems capable of capturing data supporting the involvement of the profession in direct patient care activities must be developed, tested in clinical settings, and used uniformly in practice.

TYPES OF PATIENT INFORMATION TO DOCUMENT A well-designed documentation system serves a multitude of purposes. It encompasses a complete and comprehensive archive of the patient’s drug-related information, a record of pharmaceutical care interventions, and all care plans and outcomes, and it also may serve as a legal record of the care that has been provided.9

PROBLEM-ORIENTED MEDICAL RECORD Information within a patient’s file must be organized in a fashion that facilitates quick retrieval. One commonly used and efficient method of organization is the problem-oriented medical record (POMR) format, whereby documents within a patient’s file are organized according to a list of problems.10 This process, pioneered by Dr. Lawrence Weed, consists of four major components: a defined database, a problem list, an initial plan, and progress notes. Each document is to be filed according to the source from which it comes, typically physician orders, nursing notes, and laboratory and diagnostic results. The clinical notes for each medical problem commonly are organized according to the SOAP approach: subjective and objective data, assessment, and therapeutic plan.

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Subjective data are related to the identified problem and associated symptoms as described by the patient himself or herself (or in some cases by the caregivers of the patient). Objective data include observations made and information acquired by the health care practitioner that is determined to be relevant to the identified patient problems. The assessment refers to the practitioner’s clinical opinion or judgment about the problem based on subjective and objective data, as well as the practitioner’s previous experiences related to similar clinical problems and patients. The plan is the course of action deemed appropriate for each identified problem given the data available to the clinician.

DRUG-RELATED PROBLEMS While the SOAP approach is very practical and systematic, it may not be appropriate for many pharmacists because there are limitations with respect to consistent access to certain data elements available in many practice settings. Additional concerns relate to the redundancy created in a patient record if the pharmacy documentation is to become part of an existing record. Such patient medical records are already voluminous, and only succinct, essential information needs to be added. Thus the contributions of pharmacist-generated documentation should be supportive of a patient’s care plan to assist in achieving defined therapeutic objectives and/or avoiding drug-related problems (DRPs) where appropriate.11 D R U G - R E L AT E D P R O B L E M S

r r r r r r r r

Untreated indication Improper drug selection Subtherapeutic dosage Overdosage/toxicity Failure to receive drug Adverse drug reactions/events Interactions Drug use without indication

When a pharmacist identifies a DRP, it may be listed and counted among the documents for an existing problem (e.g., subtherapeutic dose of a proton pump inhibitor for treatment of an ulcer), or if the cause is not readily identifiable, it may be listed as a new problem. All patient files established by a pharmacist should contain similar basic elements. For example, to provide pharmaceutical care, such as identification of DRPs, pharmacists need specific knowledge about the patient, such as demographic characteristics, social and medical history, general appearance, health status, and third-party insurance or billing information.9 Currie and colleagues12 devised a tool to assess the quality of pharmacists’ documentation. These researchers created a list of data elements after a comprehensive literature search and input from practitioners and expert panels. The elements are divided into two groups: those essential to each individual patient encounter and those essential to a patient record (Table 4–2). The acquisition of each of these elements is critical to the provision of pharmaceutical care.

COMMUNICATION OF DOCUMENTATION AND FINDINGS 4 Once patient information has been documented appropriately, it

should be made available to other health care providers for review when necessary. Without a universal electronic documentation

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TABLE 4–2. Elements to Be Documented by the Pharmacist12 Status of Element Essential

To be included if relevant

For Patient Encounters*

For Patient Records

Patient identifier Date of encounter Reason for encounter Pharmacist identifier History of present illness Relevant prescription, over-the-counter, and alternative mediations (history and compliance) Assessment (conclusions reached by the pharmacists after assessment of the drug therapy) Plan(s)/action(s) to correct problem(s) (A listing of planned steps to achieve the goals established with the patient for the patient’s drug therapy; the goal of the therapy should be implicitly or explicitly stated) Monitoring plan and follow-up (steps to monitor the outcomes of actions taken) Past medical history Family history Social history (diet, alcohol, tobacco use, caregiver status, etc.) Objective information (e.g., vital signs, laboratory results, diagnostic signs or physical examination results)

Patient identifier Date of birth Sex Contact information Allergies and adverse drug reactions Medical problem(s), current and past Prescription, nonprescription, and alternative medications (history and adherence) Payment method and economic situation

Family history Social history Ethnic background Objective information (a compilation of testing results from the pharmacy practice or other testing site) Special needs of patient (e.g., need for assistive devices, special educational needs) Nonmedication therapy

*The essential elements may be present in the chart and referred to in the note and not repeated in the encounter note itself. If there is a follow-up encounter, the note could be abbreviated.

system in place for pharmacists, various means of communication (e.g., mail, fax, phone, or e-mail) can be used to communicate with other health care providers and patients where appropriate. One patient may have several patient files at different sites of care (e.g., in the hospital, in various physicians’ offices, and in community pharmacies), thus complicating the manner of communication. However, it is critical to determine what information must be passed on to fellow health care workers. An integral part of providing pharmaceutical care is monitoring patient outcomes. To follow patients effectively throughout the course of their therapy, monitoring parameters and desired outcomes must be determined and documented. Examples of monitoring parameters include reducing the blood pressure in a hypertensive post–myocardial infarction patient to less than 120/80 mm Hg and reducing the lowdensity lipoprotein cholesterol to less than 100 mg/dL. Properly documenting this information assists other pharmacists and health care professionals during follow-up appointments because the preestablished monitoring parameters and recommended changes (based on collected data from all providers) can be reviewed readily.

DOCUMENTATION AND SEAMLESS CARE Although the exact terminology may vary, seamless care is a concept that has been viewed widely as a fundamental component of the optimal delivery of health care services. Several different health professions, including nursing, occupational therapy, and others, have published studies in which seamless care was provided within the context of their own practice environments.13 Where seamless care is provided, effort is placed on developing multidisciplinary teams that work together across any transitions of care that may arise.14

In recent years, the average length of hospital stays has shortened, and consequently, patients are being discharged into the ambulatory setting and long-term care facilities at a higher level of acuity. Regrettably, in most health systems, an effective means of communication regarding patients’ drug therapy has not been established across the continuum of care. Such communication is vital since drugs may be added to or discontinued from a patient’s drug regimen during hospitalization, or dosing may be altered. One study that tracked changes in medications over a hospitalization period in the elderly (age 65 and over) reported that 71% of patients had at least one of their admission medications discontinued by the time they were discharged from hospital, accounting for 40% of all admission medications.15 Patients, caregivers, and community pharmacists may be unclear as to what medication changes have been made in the inpatient setting and the reasons for these changes. Subsequently, there may be DRPs in the patient’s medication regimen that will not be identified or resolved in a timely fashion. The community pharmacist, who may fill discharge prescriptions, generally is not privy to information regarding the patient’s diagnosis and laboratory test results. In essence, the community pharmacist is uninformed and at a disadvantage to monitor for future DRPs that may result from previous medication regimen alterations. A study in the United Kingdom indicated that 95.7% of community pharmacists surveyed would not even know if one of their patients had been admitted recently to a hospital.16 Problems stemming from care that is not seamless are not limited to patients who are moving from a hospital to the community. Equally important is the provision of seamless care from the hospital to long-term care setting and the community pharmacy to the hospital pharmacy setting.

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TABLE 4–3. Seven Principles of the Australian National Seamless Care Guidelines20 Principle 1

Principle 2 Principle 3

Principle 4

Principle 5

Principle 6

Principle 7

It is the responsibility of the admitting institution to ensure the development and coordination of a medication discharge plan for each patient. The person responsible for coordinating the development, implementation, and monitoring of the medication discharge plan, including medication supply and medication information, should be identified as soon as practicable after admission. Hospital staff should obtain an accurate medication history, including prescription and nonprescription medicines and other therapies such as herbal products, at the time of admission. Hospital staff should evaluate the current medication at the time of admission, in consultation with the patient’s general practitioner, with a view to (1) identifying the appropriateness and effectiveness of current medication and rationalizing current medications if appropriate, (2) paying particular attention to any problems associated with current drug therapy, including any possible relationship with the current medical conditions, and (3) documenting allergies and any previous adverse drug reactions. During the hospital stay, treatment plans relating to the probable medication management during the stay and, where applicable, at discharge should be developed in consultation with the patient and/or caregiver. Hospital staff should negotiate with the patient issues relating to treatment and the development of a discharge plan, and these discussions should be documented in the patient’s notes. This plan should form part of the overall care plan or critical pathway. Prior to discharge, predischarge medication review and dispensing of adequate medication should take place in a planned and timely fashion. Adequate medication means sufficient medication to carry the patient through to the next arranged review or to complete course of treatment. At the time of discharge, each patient should be provided with a discharge folio containing relevant information such as consumer medicine information, a medication record, patient/care plan, and information on the availability and future supply of medication. No patient should be discharged from hospital until the details of the admission, medication changes, and arrangements for follow-up have been communicated to the health care provider(s) identified by the patient as being responsible for his or her ongoing care.

STUDIES INVOLVING THE EVALUATION OF DOCUMENTATION BY PHARMACISTS ACROSS THE CONTINUUM OF CARE Several studies evaluating the impact of the provision of proper documentation by pharmacists across the continuum of care have been conducted in Australia, Canada, the United Kingdom, the United States, and beyond. Examples of such studies are presented. The examples are not meant to be a comprehensive list of all such activities but rather are reviewed to give an indication of the state of pharmacist documentation in each country.

PHARMACIST-DIRECTED DOCUMENTATION INITIATIVES IN AUSTRALIA Pharmacist-directed documentation activities in Australia have been the center of considerable attention in recent years. The need for these services has been articulated in the Australian Journal of Hospital Pharmacy: “. . . hospital-based services developed with little thought to what happens to patients before they come to the hospital and after they leave. This has placed hospital pharmacy in a dangerously isolated position,” and “presently Australia has no system that effectively manages information relating to medications. This lack of timely and accurate medication information remains a significant barrier to ensuring the quality use of medications by the community at large.”17 The Department of Pharmacy at the Royal North Shore Hospital in Sydney reported on a practice guide for the provision of pharmaceutical care that, among other things, helped to educate the patient at the time of discharge to promote seamless care as the patient returned back into the community.18 The Pharmacy Continuity of Care Project, a study by the Faculty of Pharmacy at the University of Sydney, promoted the use of patient discharge forms that were sent by the hospital pharmacist to (1) the community pharmacist and (2) case conferences between these two individuals and the patient’s general practitioner.19

One of the more significant developments in Australia has been the publication of the Australian Pharmaceutical Advisory Council’s National Guidelines to Achieve the Continuum of Quality Use of Medicines Between Hospital and Community. This 1998 publication contained seven principles that are recommended to be followed to help to attain a high level of seamless pharmaceutical care20 (Table 4–3).

PHARMACIST-DIRECTED DOCUMENTATION INITIATIVES IN CANADA The profession of pharmacy in Canada also has been active in documentation activities across the continuum of care. In 1994, Cameron21 reported on the findings of a pilot project in Halifax, Nova Scotia, in which forms completed by the hospital pharmacist that contained either the rationale for inpatient medication changes or recommendations for future changes were sent to family physicians and community pharmacists. Austin22 provided an overview of seamless care issues in Canada in 1995, including the description of a seamless care program called Palliative At-Home Care Team at the Scarborough General Hospital in Ontario. More recently, other researchers have evaluated the use of hospital discharge prescription summary forms in Halifax, Nova Scotia,23 and Montreal, Quebec.24 Seamless care pilot projects also have been undertaken in Calgary; Alberta; Montreal, Quebec; and Pictou County, Nova Scotia, as described in the cases at the end of this chapter. A randomized controlled study was carried out at the Moncton Hospital in Moncton, New Brunswick, to determine the impact of a pharmacist-directed seamless care program on economic, clinical, and humanistic outcomes and processes of care.25 A total of 253 patients (119 in the control group and 134 in the intervention group) completed the study. A mean of 3.59 drug therapy problems for seamless monitoring per intervention patient was identified, and 72.1% of these problems were scored as having a significant or very significant

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clinical impact level. Participating community pharmacists who were surveyed believed that seamless care service helped them to provide better pharmaceutical care and improved efficiency in their pharmacies. In conclusion, the study researchers argued that a pharmacistdirected seamless care service can effectively resolve many drug therapy problems and improve drug-related processes of care in hospital and community pharmacies. On a national level, the Canadian Society of Hospital Pharmacists and the Canadian Pharmacists Association have had a joint task force on seamless care in operation for several years.

PHARMACIST-DIRECTED DOCUMENTATION INITIATIVES IN THE UNITED KINGDOM In the United Kingdom, some health researchers have concluded that the medication-use system requires seamless care services to improve communication and safety. A study conducted in a large general hospital in England showed that breakdowns in the present discharge system can create problems for patients.26 Thus 13% of participants had at least one discrepancy in their take-home prescriptions transcribed from the discharge notes. When the discharge letter was compared with the discharge notes, 27% of the patients’ letters had a drug discrepancy. The researchers found that the mean time for the discharge letter to arrive from the hospital to the general practitioner’s office was 26.9 days, and one-half took longer than 32 days. At follow-up, 57% of patients were experiencing a DRP that by clinical pharmacists’ standards required intervention. The results of the completed surveys from 163 U.K. Trust Hospitals showed that a wide variation still exists among various institutions in their ability to meet patients’ needs.27 Pharmacists were involved in the preparation of discharge prescriptions in only onethird of the hospitals, and their impact there was close to negligible. Alarmingly, 95% of institutions did not have their clinical pharmacists communicating with their community counterparts. The authors made the following recommendations: implementation of medication compliance charts, telephone medicine help lines, additional copies of discharge prescriptions for the general practitioner and the community pharmacist, regular involvement of the pharmacist in preparation of discharge medications (checking against the ward chart), and directly faxing copies of the prescriptions (complete with reasons for changes) to the general practitioner’s office. Studies that have evaluated pharmacist-directed seamless care services in the United Kingdom have had mixed results. In a randomized controlled trial of 362 patients that evaluated the effectiveness of a pharmacy discharge plan in hospitalized older adults, no impact on patient outcomes was found.28 A smaller study of 32 patients found a positive impact on unintentional medication discrepancies in the intervention group,29 whereas a seamless care feasibility study was received positively by participating community pharmacists.30 Pharmacists in the United Kingdom also have begun to take an expanded role in primary care groups, working closely with physicians and nurses. In 1993, the Royal Pharmaceutical Society of Great Britain created checklists for pharmacists that served as a guide to the types of communication that should occur between hospital and community pharmacists regarding patients’ medication and pharmaceutical needs.31 These checklists contained information that should be completed by the community pharmacist to the hospital pharmacist on hospital admission of a patient, such as the medication history and domiciliary circumstances and known adverse drug reactions (ADRs),

and information to be provided by the hospital pharmacist to the community pharmacist, such as the medication plan.

PHARMACIST-DIRECTED DOCUMENTATION INITIATIVES IN THE UNITED STATES Many of the activities in the United States in this area relate to initiatives regarding the expanded scope of practice of pharmacists in the hospital, community, and managed-care settings. Most states now allow pharmacists to enter into collaborative prescribing agreements with physicians. The American Society of Health-System Pharmacists’ Statement on the Pharmacist’s Role in Primary Care advocates a larger role for pharmacists, including participation in multidisciplinary reviews of patients’ progress, initiating or modifying medication therapy on the basis of patient responses, and performing limited physical assessments.32 The American College of Physicians– American Society of Internal Medicine also has put forward a pharmacist’s scope of practice, including the pharmacist’s role in collaborative practice with physicians; pharmacist involvement in patient education and hospital medical rounds; pharmacist prescribing, immunizing, and therapeutic substitution; and reimbursement for pharmacists’ cognitive services.33 This expanded scope of practice also has legal implications; as Brushwood and Belgado explain, “The expanding availability of knowledge will expand professional responsibilities—and legal duties will not be far behind.”34 Some pharmacist-directed seamless care evaluation studies have been conducted in the United States. Community and ambulatory care pharmacists who received a referral form from the hospital pharmacist when patients were discharged believed that the form helped them to better tailor patient counseling to the needs of the patients and positively affected the pharmacist–patient relationship.35 Two studies that evaluated the impact of a hospital pharmacist providing pharmaceutical care at the time of discharge revealed the service to be well received by physicians and nurses36 and patients.37 Kuehl, Chrischilles, and Sorofman reported on a novel pharmacist-directed seamless care program among ambulatory care, hospital care, and long-term care pharmacists in five pharmacies in the midwestern United States.38 In this study of 156 patients, patient-specific information significantly increased the number of interventions by the hospital and ambulatory care pharmacists.

HOSPITAL PHARMACY TO COMMUNITY PHARMACY Most research projects to date have focused on the transfer of information from hospital pharmacies to community-based facilities primarily involving the general practitioner and the community pharmacist. These projects have clearly addressed a real need. In a survey of community pharmacists in the United Kingdom, 95.7% indicated that they would not know if one of their patients had been admitted to a hospital, and almost one-third had never seen a copy of the discharge information provided to patients and their general practitioners.16

COMMUNITY PHARMACY TO HOSPITAL PHARMACY Far fewer initiatives have focused on the transfer of information from the community pharmacist to other members of the health care team. This is unfortunate because the community pharmacist often possesses valuable patient information by virtue of seeing the patient regularly for prescription refills and other self-care needs. Developing stronger ties between the community pharmacy and other sites of

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care can only serve to increase communication to improve the quality of patient care delivered.

COMMUNICATION WITH PHYSICIANS Communication between the pharmacists and a patient’s physician or physicians is crucial to the delivery of high-quality care, but such relationships can be threatened by perceived turf battles and misunderstandings. As discussed by Buerger,39 improving the pharmacist– physician relationship requires effort and understanding on the part of both parties. Various stresses inherent in health care delivery make effective communication rather challenging in certain situations. To strengthen ties between physicians and pharmacists, all parties should focus on improving their communication skills and exercising their conflict-resolution skills.39

COMMUNICATION WITH PATIENTS In this era of an ever-increasing desire on the part of patients to be involved in their own health care, an increasing number of self-care products (e.g., diagnostic, pharmaceutical, and nutraceutical) in the marketplace, and advanced communication technologies available to consumers (e.g., cell phones, personal digital assistants, electronic mail, and the Internet), community pharmacists have a unique opportunity to assume a pivotal role among other health care providers and patients in communicating, interpreting, and monitoring for the desired health outcomes. While not commonplace today, pharmacists should begin to communicate more regularly with their patients with respect to their health care needs and, where possible, should refer those patients back to health care providers when necessary. For example, how often has a patient presented himself or herself to a community pharmacy describing a condition or possible DRP in which the recommendation of the pharmacist following a brief triage is to refer the patient to his or her physician or other caregivers (e.g., dentist or optometrist) for follow-up? Unfortunately, this interaction seldom involves documentation by the pharmacist to the patient or other provider involved, and more than likely, follow-up with either party is by serendipity. This situation in the medical community would result in what is commonly known as a referral from one health care provider to another. Clearly, anecdotal reports of patients who have presented to a pharmacist, and describe significantly negative health outcomes and possibly death were averted because of this interaction with the pharmacist. However, such actions commonly went undocumented and therefore were not reported or traceable and possibly underappreciated or undervalued. Many patients have not experienced such formal and consistent documentation from the pharmacy profession, and it would prove valuable. Once these activities are consistent and valued by patients and providers alike, this may begin to set the parameters for patient payments directly to pharmacists while ultimately contributing to beneficial health outcomes of the patients served.

BILLING CONSIDERATIONS AND DOCUMENTATION SYSTEMS MEDICAL BILLING SYSTEMS IN THE UNITED STATES 5 The Centers for Medicare and Medicaid Services (CMS) uni-

versal claim form is used by health care providers for third-party billing related to the provision of services. This form is required by Medicare and other third-party payers in the United States and uses

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the International Classification for Disease, 9th Revision, Clinical Modification (ICD-9-CM) coding system by providers for reimbursement, and this system is becoming increasingly important as Medicare Part D (oral prescription drug) coverage is implemented. Categories 1 to 15 (codes 001–779) identify diseases and related common medical conditions. Category 16 (codes 780–799) designates symptoms, signs, and ill-defined conditions. Category 19 (codes 800–999) relates to injury and poisoning. Each category contains additional codes that provide greater specificity and precision in terms of the condition or illness. There are two additional subsets of codes: V codes, which are used to classify routine screening examinations, and E codes, which are related to environmental injury or illness. Use of Current Procedural Terminology (CPT) codes or the Common Procedure Coding System is required for completion of the universal claims form. CPT codes were created to be a listing of descriptive terms and identifying codes for medical services and procedures performed. Codes 99201 to 99205 are used for an office visit with a new patient, and codes 99211 to 99215 are used for an office visit with an existing patient. The differentiation among codes used is based on the intensity of service provided by the health care provider and the time involved. While not used commonly in pharmacy, these codes have been used by pharmacists to document the provision of patientcentered services in ambulatory and community settings when completing the universal claims form for billing purposes to third-party payers.

PHARMACY BILLING SYSTEMS Recognizing issues related to nomenclature, compatibility, and transmission of data, some organizations have created guidelines to assist in the standardization of documentation systems for pharmacy. Historically, these efforts have been centered on the outpatient arena, focusing primarily on prescription claims related to the procurement and dispensing of prescription pharmaceutical products to patients from community pharmacies and by mail order. Founded in 1976, the National Council for Prescription Drug Programs (NCPDP) developed standards that allow for electronic data interchange (EDI) among providers of pharmaceuticals (e.g., pharmacies) and third-party administrators [e.g., pharmacy benefit management (PBM) organizations] primarily for the adjudication (i.e., financial approval) of prescriptions. This adjudication historically has centered on the assessment of the formulary status of a prescribed medication, resulting in verification or denial of the prescription and resulting payment to the dispensing pharmacy. The payment formula for pharmaceuticals (and not professional services) typically has included a discounted cost of ingredients [e.g., the average wholesale price (AWP) discounted by a given percentage] plus a dispensing fee. The dispensing fee, often in the range of $1 to $2 per prescription, is paid irrespective of the pharmacist time involved in processing the prescription (procuring/compounding the product, verifying with the prescriber patient- and product-specific concerns identified, addressing insurance-related claims issues, and conducting patient counseling/follow-up monitoring). Arguably, no uniform standard has been adopted by pharmacists and third-party administrators to allow for billing and financial compensation associated with the provision of professional services by pharmacists both in scope and in intensity of services provided. Having a reimbursement system tied only to product dispensing is fraught with problems. For example, in community pharmacy practice, if a pharmacist provides a recommendation to discontinue

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therapy and this recommendation is followed, no reimbursement to the pharmacy will take place because no product would be dispensed (although the third-party administrator and the patient would save money). However, if the recommendation is ignored and the product is dispensed, the third-party payer would incur a cost related to dispensing the prescription. Clearly, the issue related to the appropriateness of the prescription is somewhat lost. Recent efforts by the NCPDP and other professional organizations such as the National Community Pharmacists Association have recognized the need for allowing the transmission and adjudication not only of electronic prescriptions but also of requests for refills and other transactions among prescribers (e.g., physicians) and pharmacists. As a result, various initiatives have been undertaken to allow for such levels of transmission among pharmacists, physicians and other health care providers, payers, and ultimately, patients.

a PC as opposed to a PDA because the internal workflow would necessitate this. In contrast, a consultant pharmacist who travels among various long-term care facilities may prefer a portable device for documentation. C O N S I D E R AT I O N S W H E N S E L E C T I N G E L E C T R O N I C D O C U M E N TAT I O N S Y S T E M S FOR PHARMACISTS

r Cost to implement and support the system r Ability to interface with pharmacy billing, dispensing, and drug information systems

r Compatibility with other operating systems in the organization

r Ability to ensure private and secure data r Support for enhancements and updates to the software and hardware

ROLE OF TECHNOLOGY IN CLINICAL DOCUMENTATION 6 Emerging technologies will have a profound effect on health care, thus offering opportunities for the pharmacy profession in maintaining constant vigilance related to the procurement, preparation, and distribution of pharmaceuticals and allowing for more consistent provision of pharmaceutical care. Digital documentation, such as computer-stored medical records or electronic medical records (EMRs), is one vehicle that, if adapted universally, would assist in enhancing the communication among providers in all settings. EMRs must be implemented by 2009 under the new Medicare Part D regulations, and this is expected to drive adoption of the new technologies by prescribers. Significant benefits to EMRs have been described as the following: (1) improved logistics and organization of the medical record to speed care and improve efficiency, (2) automatic computer review of the medical record to limit errors and control costs, and (3) systematic analysis of past clinical experience to guide future practices and policies.40 The use of EMRs that include pharmacyspecific data (e.g., history of medication usage, both prescription and over the counter; history of refills; assessment of adherence and persistence; and other information deemed appropriate for inclusion by pharmacists) allows for improved communication, enhanced decision making, and the ability to follow up on outcomes associated with care plans. Advances in technology can facilitate the generation and transfer of patient documentation. As more pharmacies use the Internet as a means of communication, information can be transferred quickly and accurately over greater distances. Handheld computers and specialty software allow health care practitioners to document information in an electronic format that can be transformed immediately for rapid transfer to others. Reports in the literature have described methods to assess pharmacist interventions related to medication errors,5 the use of computer-based systems,6 and recently, the use of personal digital assistants (PDAs) in specific patient care areas.7 Many of these documentation systems tend to be individualized applications in which the transfer of data to other providers is not possible or quite limited. Often these systems focus on the generation of reports for workload analysis or accreditation purposes. The internal pharmacy environment may dictate the method for data collection and documentation as well. While pharmacists in some practice settings routinely use personal computers (PCs), others tend to be more mobile, and therefore, access to portable technology is more crucial (e.g., laptops and PDAs). For example, a community pharmacist may be more likely to document his or her activities on

r Compatibility with the workflow of pharmacists Internal operating systems and their incompatibility with other operating systems present challenges as well. The inability to interface with other systems can create redundancies that potentially can lead to serious misinterpretations and mistakes in the translation of data that can compromise patient care. In choosing an electronic documentation program for pharmacists, consideration must be given to the ability to interface not only with the pharmacy system (billing and automated dispensing) but also with other electronic records throughout an organization. When a pharmacy system does not interface with the laboratory system of the EMRs of a hospital, the ability of providers to communicate effectively is reduced. Pharmacists in community settings must communicate more regularly with hospital pharmacists, and vice versa, yet this is often not the case.14,27 Interventions often need to be shared with other pharmacists at shift changes, transfer of patients from one care area to another, or even transfer of patients to new health systems altogether. One study assessed the use of computerized reminders to physicians to increase preventive care in inpatient settings for pneumococcal and influenza vaccinations and prophylactic heparin and prophylactic aspirin at discharge with the use of a computerized order-entry system. The investigators concluded that computerized reminders significantly increased the rate of delivery of the intended therapies.41 Future digital technologies not only will prompt and remind practitioners of situations that require their attention but also will prevent such occurrences. Likewise, electronic mail and the Internet can be used as vehicles to communicate not only among health care providers but also with patients. Electronic reminders aiding medication adherence, answering medication- and disease-related questions, and providing product comparisons can be sent via e-mail from pharmacy providers. Access to the Internet in the work setting, however, may be a limiting factor for many community pharmacists, in particular, those in chain pharmacies,42 and must be overcome to allow for universal adoption in community pharmacy practice. The benefits to allowing Internet access in community pharmacies far outweigh potential concerns for inappropriate use in the work setting when patients’ lives may depend on the information contained within resources available through the Internet. PDAs are efficient tools that can be used to collect, process, and transmit data that ultimately have an impact on the care delivered to patients, although they do have limitations, such as their memory capabilities, screen size, and overall functionality.43 In some software applications, a synchronization interface can be written to allow for

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an automatic link to a Web site to deposit and collate aggregate data from PDA users or directly from a computer linked to the Internet.44 An example of an electronic documentation system is provided in the case study.

TRAINING CONSIDERATIONS FOR PHARMACISTS AND SUPPORT STAFF IN DOCUMENTATION Pharmacists often are not comfortable in documenting their activities related to patient care within the pharmacy setting and are even more uncomfortable in communicating this information to other health care providers. All too often communications from pharmacists to physicians relate to pharmaceutical product usage and restrictions (i.e., nonformulary issues) and do not focus on patient care issues. Thus attention must be directed toward practicing pharmacists and providing them with education and training related to why documentation is necessary, how to document, and use of technology to assist in the documentation process. The training of support staff, such as pharmacy technicians, must not be overlooked because these individuals can assist in the routine collection of both pharmaceutical data and retrievable patient information (e.g., from medical charts and laboratory reports) that can be presented to pharmacists for assessment and needed follow-up. Although the concepts of documentation are consistent irrespective of practice settings, the process by which data are collected and the tools for documentation can be quite different. Thus the training associated with documentation must be specific to the respective practice environments of pharmacists. For example, access to health care providers, medical records, laboratory data, and patients is more common in hospital pharmacy practice than in community pharmacy practice, where direct access to patients is often the only source of information. As a result, data collection, documentation, and communication with other health care providers and patients will vary based on the practice setting. However, as the use of EMRs and digital documentation becomes more common, the ability of pharmacists to interface with these systems will become less of a logistical barrier.

CONCLUSIONS While the common maxim, “If it wasn’t documented, it wasn’t done,” applies to all providers of health care, for the pharmacy profession, this is the mantra the profession needs to embrace if it is to remain

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an active and valued participant in the health care systems of industrialized countries. The profession must not wait for the creation and implementation of a universal billing system related to the provision of cognitive services by pharmacists; rather, the focus should remain centrally on the patient; one in which pharmacists universally assume a pivotal role between other health care providers and patients in communicating, interpreting, and monitoring the desired health outcomes associated with prescription and nonprescription therapies and all actions are documented and communicated effectively to all stakeholders in a convenient, consistent, and interpretable manner.

CASE STUDY This case could be seen in either a community or hospital setting (if the prescription was a handwritten order in the medical chart of the patient). A 59-year-old African-American man who has atrial fibrillation presents a handwritten prescription that appears to read, “warfarin sodium 25 mg PO qd.” The pharmacist identifies this as too high of a dose (most likely missing the decimal point for the dose of 2.5 mg) and contacts the prescriber immediately. The pharmacist would proceed to log this intervention as shown in Fig. 4–1. Continuing, in the box on the first “Reasons” page under the subheading of “Order Clarification,” “Illegible writing” would be checked. and under “Drug Regimen Selection,” “Dose” would be checked (Fig. 4–2), given that the prescription was written poorly (e.g., illegibly) and the dose appeared incorrect. As with most interventions by pharmacists, typically, recommendations are made to health care providers, patients, or caregivers. Using the preceding example with the warfarin prescription, the box under the recommendation subheading “Medication Related” would be checked, and “Change dose” would be indicated (Fig. 4–3). In this case, additional “Patient Care Related” recommendations could have been made, such as the ordering of “laboratory tests” and “therapeutic drug monitoring.” The next step would be to check the box under the subheading “Contact” entitled, “Contact health care provider,” to ensure that the illegible prescription and the incorrect dose were interpreted correctly and that the appropriate medication and strength were verified by the pharmacist and dispensed to the patient (Fig. 4–4). With respect to outcomes, the following items would be indicated for the prescription if the prescriber agreed with (accepted) the interpretation that the prescription was in fact for “Warfarin sodium

FIGURE 4–1. PSDS initial patient screen.

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FIGURE 4–2. PSDS reason for intervention screen.

FIGURE 4–3. PSDS intervention recommendation screen.

FIGURE 4–4. PSDS intervention action screen.

FIGURE 4–5. PSDS intervention outcomes screen.

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FIGURE 4–6. PSDS professional services screen.

2.5 mg PO qd” and not “Warfarin sodium 25 mg PO qd” as written in the “Result of Intervention” section. The intervention required 10 minutes of the pharmacist’s time, captured in “Time Involved.” It was assumed that this action by the pharmacist would have an “Anticipated Outcome” of “Increased safety” for the patient (Fig. 4–5). In a situation where point-of-care diagnostic monitoring for anticoagulation is available to the pharmacist, under the “Professional Services” subheading, “Laboratory tests” could have been checked (Fig. 4–6). In many instances, this interaction and others quite similar take place on a daily basis, but the valuable contributions pharmacists make in averting potentially lethal medication-related errors are never captured. More importantly, without this systematic approach to documentation of specific classes of agents, most common reasons for interventions and outcomes of recommendations would not be known or available for follow-up.

ABBREVIATIONS DRPs: drug-related problems HRQOL: health-related quality of life IOM: Institute of Medicine POMR: problem-oriented medical record SOAP: subjective–objective–assessment–plan CMS: Centers for Medicare & Medicaid Services ICD-9-CM: International Classification for Disease, 9th edition, Clinical Modification CPT: Current Procedural Terminology NCPDP: National Council for Prescription Drug Programs EDI: electronic drug interchange AWP: average wholesale price EMRs: electronic medical records PDAs: personal digital assistants PCs: personal computers

REFERENCES 1. Hepler CD, Stand LM. Opportunities and responsibilities in pharmaceutical care. Am J Hosp Pharm 1990;47:533–543. 2. Grainger-Rousseau TJ, Miralles MA, Hepler CD, et al. Therapeutic outcomes monitoring: Application of pharmaceutical care guidelines to community pharmacy. J Am Pharm Assoc 1997;NS37:647–661.

3. MacKinnon NJ. Risk assessment of preventable drug-related morbidity in older persons. Ph.D. dissertation, University of Florida, Gainesville, 1999. 4. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err Is Human: Building a Safer Health System. Committee on Quality of Health Care in America, Institute of Medicine. Washington, National Academy Press, 1999. 5. Overhage JM, Lukes A. Practical, reliable, comprehensive method for characterizing pharmacists’ clinical activities. Am J Health Syst Pharm 1999;56:2444–2449. 6. Sauer BL, Heeren DL, Walker RG, et al. Computerized documentation of activities of Pharm.D. clerkship students. Am J Health Syst Pharm 1997;54:1727–1732. 7. Lau A, Balen RM, Lam, R, Malyuk, DL. Using a personal digital assistant to document clinical pharmacy services in an intensive care unit. Am J Health Syst Pharm 2001;58:1229–1232. 8. MacKinnon GE III. Documenting pharmacy student interventions via scannable patient care activity records (PCAR). Pharm Educ 2002;2:191– 197. 9. Rovers JP, Currie JD, Hagel HP, et al. Documentation. In Meade V, ed. A Practical Guide to Pharmaceutical Care. Washington, American Pharmaceutical Association, 1998:103–115. 10. Weed LL. Medical Records, Medical Education, and Patient Care. Cleveland, Case Western University Press, 1971. 11. Strand LM, Morley PC, Cipolle RJ, et al. Drug-related problems: Their structure and function. DICP 1990;24:1093–1097. 12. Currie J, Kuhle J, Doucette WR, et al. Quality Assessment for Documentation of Pharmaceutical Care Final Report. Iowa City, Iowa, American Pharmaceutical Foundation Quality Center, 1999. 13. Naylor MD, Brooten D, Campbell R, et al. Comprehensive discharge planning and home follow-up of hospitalized elders: A randomized controlled trial. JAMA 1999;281:613–620. 14. MacKinnon NJ, Zwicker LA. Review of seamless care: Backgrounder. In MacKinnon NJ, ed. Seamless Care: A Pharmacist’s Guide to Continuous Care Programs. Ottawa, Canada, Canadian Pharmacists Association, 2003:1–12. 15. Beers MH, Dang J, Hasegawa J, et al. Influence of hospitalization on drug therapy in the elderly. J Am Geriatr Soc 1989;37:679–683. 16. Al-Rashid SA, Wright DJ, Reeves JA, Chrystyn H. Opinions about hospital discharge information: 2. Community pharmacists. J Soc Admin Pharm 2001;18:129–135. 17. Low J. Seamless care anyone. Aust J Hosp Pharm 1997;27:356–357. 18. Wilcox C, Duguid MJ. The medication chart as an integral tool in the pharmaceutical care plan. Aust J Hosp Pharm 2001;31:268–274. 19. Editorial Staff. Continuity of care between hospital and the community. Aust J Pharm 2002;83:136–138. 20. Australian Pharmaceutical Advisory Council. National Guidelines to Achieve the Continuum of Quality Use of Medicines Between Hospital and Community. Canberra: Publications Production Unit, Commonwealth Department of Health and Family Services, 1998.

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21. Cameron B. The impact of pharmacy discharge planning on continuity of care. Can J Hosp Pharm 1994;47:101–119. 22. Austin Z. Towards seamless care. Hosp Pharm Pract 1995;3:17–21. 23. Cole DL, Slayter KL. Evaluation by patients and pharmacists of a summary form for seamless pharmaceutical care. Can J Hosp Pharm 1999;52: 162–166. 24. Lamontagne-Paquette N, McLean WM, Besse L, Cusson J. Evaluation of a new integrated discharge prescription form. Ann Pharmacother 2001;35:935–938. 25. MacKinnon NJ, Nickerson A, Roberts N, Saulnier L. Outcomes analysis of a pharmacist-directed seamless care service (abstract). J Can Geriatr Soc 2002;5:119–120. 26. Sexton J, Brown A. Problems with medicines following hospital discharge: Not always the patient’s fault? J Soc Admin Pharm 1999;16: 199–207. 27. Sexton J, Ho YJ, Green CF, et al. Ensuring seamless care at hospital discharge: A national survey. J Clin Pharmcol Ther 2000;25: 385–393. 28. Nazareth I, Burton A, Shulman S, et al. A pharmacy discharge plan for hospitalized elderly patients: A randomized, controlled trial. Age Ageing 2001;30:33–40. 29. Pickrell L, Duggan C, Dhillon S. From hospital admission to discharge: An exploratory study to evaluate seamless care. Pharm J 2001;267:650–653. 30. Cook H. Transfer of information between hospital and community pharmacy: A feasibility study. Pharm J 1995;254:736–737. 31. Communication Between Hospital and Community Pharmacists Concerning Patients’ Medication and Pharmaceutical Needs. London, Royal Pharmaceutical Society of Great Britain, 1993. 32. American Society of Health-System Pharmacists. ASHP statement on the

33. 34. 35. 36.

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pharmacist’s role in primary care. Am J Health Syst Pharm 1999;56:1665– 1667. American College of Physicians–American Society of Internal Medicine. Pharmacist scope of practice. Ann Intern Med 2002;136:79–85. Brushwood DB, Belgado BS. Judicial policy and expanded duties for pharmacists. Am J Health Syst Pharm 2002;59:455–457. Dvorak SR, McCoy RA, Voss GD. Continuity of care from acute to ambulatory care setting. Am J Health Syst Pharm 1998;55:2500–2504. Wernick A, Possidente CJ, Keller EG, et al. Enhancing continuity of care through pharmacist review of discharge medications. Hosp Pharm 1996;31:672–676. Lucas KS. Outcomes evaluation of a pharmacists discharge medication teaching service. Am J Health Syst Pharm 1998;55:S32–S35. Kuehl AK, Chrischilles EA, Sorofman BA. System for exchanging information among pharmacists in different practice environments. J Am Pharm Assoc 1998;38:317–324. Buerger D. Basic steps to better pharmacist–physician communication. Consult Pharm 1994;14:95–96. McDonald CJ, Tierney WM. Computer-based medical records: Their future role in medical practice. JAMA 1988;259:3433–3440. Dexter PR, Perkins S, Overhage JM, et al. A computerized reminder system to increase the use of preventive care for hospitalized patients. N Engl J Med 2001;345:965–970. MacKinnon GE III, Mologousis NM. Preliminary survey of pharmacists’ use of the Internet. Am J Health Syst Pharm 1999;56:1675–1676. MacKinnon GE III. Development of a personal digital assistant application for pharmacy documentation. Pharm Educ 2003;3:11–16. MacKinnon GE III. Evaluation of an Internet-based system to document pharmacy student interventions. Am J Pharm Educ 2003;67:90.

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5 CLINICAL PHARMACOKINETICS AND PHARMACODYNAMICS Larry A. Bauer

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Clinical pharmacokinetics is the discipline that describes

the absorption, distribution, metabolism, and elimination of drugs in patients requiring drug therapy.

constants such as clearance, volume of distribution, and half-life. The simplest case uses a single compartment to represent the entire body.

2 Clearance is the most important pharmacokinetic param-

9 Factors to be taken into consideration when deciding on the

eter because it determines the steady-state concentration for a given dosage rate. Physiologically, clearance is determined by blood flow to the organ that metabolizes or eliminates the drug and the efficiency of the organ in extracting the drug from the bloodstream.

3 The volume of distribution is a proportionality constant that relates the amount of drug in the body to the serum concentration. The volume of distribution is used to calculate the loading dose of a drug that will immediately achieve a desired steady-state concentration. The value of the volume of distribution is determined by the physiologic volume of blood and tissues and how the drug binds in blood and tissues. 4 Half-life is the time required for serum concentrations to

decrease by one-half after absorption and distribution are complete. Half-life is important because it determines the time required to reach steady state and the dosage interval. Half-life is a dependent kinetic variable because its value depends on the values of clearance and volume of distribution.

5 The fraction of drug absorbed into the systemic circulation

after extravascular administration is defined as its bioavailability.

6 Most drugs follow linear pharmacokinetics, whereby steady-state serum drug concentrations change proportionally with long-term daily dosing.

7 Some drugs do not follow the rules of linear pharmacoki-

netics. Instead of steady-state drug concentration changing proportionally with dose, serum concentration changes more or less than expected. These drugs follow nonlinear pharmacokinetics.

8 Pharmacokinetic models are useful to describe data sets, to

predict serum concentrations after several doses or different routes of administration, and to calculate pharmacokinetic

best drug dose for a patient include age, gender, weight, ethnic background, other concurrent disease states, and other drug therapy.

10 Cytochrome P450 is a generic name for the group of en-

zymes that are responsible for most drug metabolism oxidation reactions. Several P450 isozymes have been identified, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.

11 The importance of transport proteins in drug bioavailabil-

ity and elimination is now better understood. The principal transport protein involved in the movement of drugs across biologic membranes is P-glycoprotein. P-glycoprotein is present in many organs, including the gastrointestinal tract, liver, and kidney.

12 When deciding on initial doses for drugs that are renally

eliminated, the patient’s renal function should be assessed. A common, useful way to do this is to measure the patient’s serum creatinine concentration and convert this value into an estimated creatinine clearance (CrClest ). For drugs that are eliminated primarily by the kidney (≥60% of the administered dose), some agents will need minor dosage adjustments for CrClest between 30 and 60 mL/ min, moderate dosage adjustments for CrClest between 15 and 30 mL/min, and major dosage adjustments for CrClest less than 15 mL/min. Postdialysis supplemental doses of some medications also may be needed for patients receiving hemodialysis if the drug is removed by the artificial kidney.

13 When deciding on initial doses for drugs that are hepati-

cally eliminated, the patient’s liver function should be assessed. The Child-Pugh score can be used as an indicator of a patient’s ability to metabolize drugs that are eliminated by the liver. In the absence of specific pharmacokinetic dosing guidelines for a medication, a Child-Pugh score equal to 8 or 9 is grounds for a moderate decrease (∼25%) 51

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in initial daily drug dose for agents that are metabolized primarily hepatically (≥60%), and a score of 10 or greater indicates that a significant decrease in initial daily dose (∼50%) is required for drugs that are metabolized mostly hepatically. 14 For drugs that exhibit linear pharmacokinetics, steady-

state drug concentration (Css ) changes proportionally with dose (D). To adjust a patient’s drug therapy, a reasonable starting dose is administered for an estimated three to five half-lives. A serum concentration is obtained, assuming that it will reflect Css . Independent of the route of administration, the new dose (Dnew ) needed to attain the desired Css (Css,new ) is calculated: Dnew = Dold (Css,new /Css,old ),

Pharmacokinetic concepts have been used successfully by pharmacists to individualize patient drug therapy for about a quarter of a century. Pharmacokinetic consultant services and individual clinicians routinely provide patient-specific drug dosing recommendations that increase the efficacy and decrease the toxicity of many medications. Laboratories routinely measure patient serum or plasma samples for many drugs, including antibiotics (e.g., aminoglycosides and vancomycin), theophylline, antiepileptics (e.g., phenytoin, carbamazepine, valproic acid, phenobarbital, and ethosuximide), methotrexate, lithium, antiarrhythmics (e.g., lidocaine, procainamide, quinidine, and digoxin), and immunosuppressants (e.g., cyclosporine and tacrolimus). Combined with a knowledge of the disease states and conditions that influence the disposition of a particular drug, kinetic concepts can be used to modify doses to produce serum drug concentrations that result in desirable pharmacologic effects without unwanted side effects. This narrow range of concentrations within which the pharmacologic response is produced and adverse effects prevented in most patients is defined as the therapeutic range of the drug. Table 5–1 lists the therapeutic ranges for commonly used medications.

TABLE 5–1. Selected Therapeutic Ranges Drug

Therapeutic Range

Digoxin Lidocaine Procainamide/N-acetylprocainamide Quinidine Amikacina

0.5–2 ng/mL 1.5–5 mcg/mL 10–30 mcg/mL (total) 2–5 mcg/mL 20–30 mcg/mL (peak) 65 yr) Decompensated CHF, cor pulmonale, cirrhosis

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TABLE 5–4. Theophylline Pharmacokinetic Parameters for Selected Disease States/Conditions Disease State/Condition

CLINICAL PHARMACOKINETICS AND PHARMACODYNAMICS

Mean volume of distribution = 0.5 L/kg. Adapted from Ref. 49.

is required for drugs that are metabolized mostly by the liver. As in any patient with or without liver dysfunction, initial doses are meant as starting points for dosage titration based on patient response and avoidance of adverse effects. Since there are no good markers of liver function, clinicians have come to rely on pharmacokinetic parameters derived in various patient populations to compute initial doses of drugs that are eliminated hepatically. Table 5–4 contains average pharmacokinetic parameters for theophylline in several disease states. Initial doses of many livermetabolized drugs are computed by determining which disease states and/or conditions the patient has that are known to alter the kinetics of the drug and by using these average pharmacokinetic constants to calculate doses. The patient is then monitored for therapeutic and adverse effects, and drug serum concentrations are obtained to ensure that concentrations are appropriate and to adjust doses, if necessary. The following computations illustrate the estimated intravenous loading dose and the intravenous continuous infusion necessary to achieve a theophylline concentration of 10 mg/L for a 55-year-old, 70-kg male with liver cirrhosis (mean kinetic parameters obtained from Table 5–4): VD = (0.5 L/kg)(70 kg) = 35 L LD = Css VD = (10 mg/L)(35 L) = 350 mg theophylline infused over 20 to 30 min (0.35 mL/min/kg)(70 kg)(60 min/h) Cl(in L/h) = 1000 mL/L = 1.5 L/h k0 = Css Cl = (10 mg/L)(1.5 L/h) = 15 mg/h of theophylline to begin after loading dose is given If theophylline is to be given as the aminophylline salt form, each dose would need to be changed to reflect the fact that aminophylline contains only 85% theophylline (LD = 350 mg of theophylline/0.85 = 410 mg of aminophylline infused over 20 to 30 minutes, k0 = 15 mg/h of theophylline/0.85 = 18 mg/h of aminophylline to begin after loading dose is given). Heart failure is often overlooked as a disease state that can alter drug disposition. Severe heart failure decreases cardiac output and therefore reduces liver blood flow. Theophylline,26 lidocaine,27 and drugs with high extraction ratios are compounds whose clearance declines with decreased liver blood flow. Initial dosages of these drugs should be reduced in patients with moderate to severe heart failure (New York Heart Association class III or IV) by 25% to 50% until steady-state concentrations and response can be determined.

Serum drug concentrations are readily available to clinicians to use as guides for the individualization of drug therapy. The therapeutic ranges for several drugs have been identified, and it is likely that new drugs also will be monitored using serum concentrations. Although several individualization methods have been advocated for specific 14 drugs, one simple, reliable method is used commonly. For drugs that exhibit linear pharmacokinetics, Css changes proportionally with dose. To adjust a patient’s drug therapy, a reasonable starting dose is administered for an estimated three to five half-lives. A serum concentration is obtained, assuming that it will reflect Css . Independent of the route of administration, the new dose (Dnew ) needed to attain the desired Css (Css,new ) is calculated: Dnew = Dold (Css,new /Css,old ), where Dold and Css,old are the old dose and old Css , respectively. To use this method, Css,old must reflect steady-state conditions. Often patients are noncompliant with regard to their drug dosage and therefore are not at steady state. This occurs not only in outpatients but also in hospital inpatients. Inpatients can spit out oral doses or alter the infusion rates on intravenous pump rates after the nurse leaves the hospital room. Doses also can be missed if the patient is absent from his or her room at the time medications are to be administered. If Css,old is much larger or smaller than expected for the Dold the patient is taking, one should suspect noncompliance and repeat the serum concentration determination after another three to five half-lives or change the patient’s dose cautiously and monitor for signs of toxicity or lack of effect.

MEASUREMENT OF PHARMACOKINETIC PARAMETERS IN PATIENTS 15 If it is necessary to determine the kinetic constants for a patient

to individualize his or her dose, a small kinetic evaluation is conducted in the individual. In these cases, the number of serum concentrations obtained from the patient is held to the minimum needed to calculate accurate pharmacokinetic parameters and doses. The reason for using fewer serum drug concentration determinations is to be as cost-effective as possible because these laboratory tests generally cost $20 to $50 each. Although many drugs follow two-compartment-model pharmacokinetics (especially after intravenous administration), a onecompartment model is used to compute kinetic parameters in patients because too many serum concentration determinations would be needed to determine accurately both the distribution and elimination phases found in the two-compartment model. Because of this, serum concentrations usually are not measured in patients during the distribution phase. Another important reason serum concentrations are not measured during the distribution phase for therapeutic drugmonitoring purposes in patients is that drug in the blood and drug in the tissues are not in equilibrium during this time so that serum concentrations do not reflect tissue concentrations. When drug serum concentrations are obtained in patients for the purpose of assessing efficacy or toxicity, it is important that they be measured in the postdistribution phase when drug in the blood is in equilibrium with drug at the site of action. In the case where the patient has received enough doses to be at steady state, pharmacokinetic parameters can be computed using a predose minimum concentration and a postdose maximum concentration. Under steady-state conditions, serum concentrations after each dose are identical, so the predose minimum concentration is the same before each dose (Fig. 5–10). This situation allows the predose concentration to be used to compute both the patient’s t1/2 and V. If the drug was given extravascularly or has a significant distribution

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concentrations can be calculated using one-compartment-model equations. Specific examples of these methods to calculate initial doses and individualized doses using serum concentrations are discussed later in this chapter for the aminoglycoside antibiotics, vancomycin, digoxin, theophylline, phenytoin, and cyclosporine.

Cmax, ss t1/2

∗

1 Cmin, ss

Cmin, ss (extrapolated)

COMPUTER PROGRAMS

0.1 0

1

2

3

4

5

6

7

8

9

10

Time (h)

FIGURE 5–10. When a patient has received enough doses to be at steady state, steady-state maximum (Cmax,ss ) and minimum (Cmin,ss ) concentrations can be used to compute clearance, volume of distribution, and half-life. At steady state, consecutive Cmin,ss values are equal, so the predose value can be extrapolated to the time before the next dose and be used to calculate half-life (dashed line).

phase, the postdose concentration should be determined after absorption or distribution is finished. To ensure that steady-state conditions have been achieved, the patient needs to receive the drug on schedule for at least three to five estimated half-lives. To make sure that this is the case, inpatients should have their medication administration records checked, and the patient’s nurse should be consulted regarding missed or late doses. Outpatients should be interviewed about compliance with the prescribed dosage regimen. When compliance with the dosage regimen has been verified, steady-state conditions reasonably can be assumed. If the patient is not at steady state, an additional postdose serum concentration determination should be done to compute the patient’s pharmacokinetic parameters. Ideally, the third concentration (C3 ) should be acquired approximately one estimated half-life after the postdose maximum concentration. Determining serum concentrations too close together will hamper the drug assay’s ability to measure differences between them, and getting the third sample too late could result in a concentration too low for the assay to detect. In this situation, the predose minimum and postdose maximum concentrations are used to compute V, and both postdose concentrations are used to calculate t1/2 (Fig. 5–11). After Cl, V, and t1/2 have been computed for a patient, the dose and dosage interval necessary to achieve desired steady-state serum

Computer programs that aid in the individualization of therapy are available for many different drugs. The most sophisticated programs use nonlinear regression to fit Cl and VD to actual serum concentrations obtained in a patient.28 After drug doses and serum concentrations are entered into the computer, nonlinear least-squares regression programs adjust Cl and VD until the sum of the squared error between actual (Cact ) and computer-estimated concentrations (Cest ) is at a minimum [(Cest – Cact )2 ]. Once estimates of Cl and VD are available, doses are calculated easily. Many programs also take into account what the Cl and VD should be on the basis of disease states and conditions present in the patient.29 Incorporation of expected population-based parameters allows the computer to use a limited number of serum concentrations (one or two) to provide estimates of Cl and VD . This type of computer program is called Bayesian because it incorporates portions of Bayes’ theorem during the fitting routine.30 Bayesian pharmacokinetic dosing programs are used widely to adjust the dose of a variety of drugs. In the case of renally eliminated drugs (e.g., aminoglycosides, vancomycin, and digoxin), population estimates for kinetic parameters are generated by entering the patient’s age, weight, height, gender, and serum creatinine concentration into the computer program. For hepatically eliminated drugs (e.g., theophylline and phenytoin), population estimates for kinetic parameters are computed using the patient’s age, weight, and gender, as well as other factors that might change hepatic clearance, such as the presence or absence of disease states (e.g., cirrhosis or congestive heart failure) or other drug therapy that might cause a drug interaction. The Bayesian estimates of the pharmacokinetic parameters are then modified using nonlinear least-squares regression fits of serum concentrations to result in individualized parameters for the patient. The individualized parameters are used to compute doses for the patient that will result in desired steady-state concentrations of the drug.

AMINOGLYCOSIDES 10

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Cmin

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1

2

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4

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10

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FIGURE 5–11. If a patient has not received enough doses to be at steady state, or doses have been given on an irregular schedule, the minimum concentration (Cmin ), maximum concentration (Cmax ), and an additional postdose concentration (C3 ) can be used to compute clearance, volume of distribution, and half-life.

Although aminoglycoside pharmacokinetics follow multicompartment models,31 a one-compartment model appears sufficient to individualize doses in patients.32 Aminoglycosides usually are given as short-term intermittent intravenous infusions and administered as a single daily dose or multiple doses per day. Initial doses for aminoglycosides can be computed using estimated kinetic parameters derived from population pharmacokinetic data. The elimination rate constant is estimated using the patient’s creatinine clearance in the following formula: k (in h−1 ) = 0.00293(CrCl) + 0.014, where CrCl is the measured or estimated creatinine clearance in milliliters per minute. The volume of distribution is estimated using the average population value for normal-weight (within 30% of ideal weight) individuals equal to 0.26 L/kg [V = 0.26(Wt), where Wt is the patient’s weight] or for obese individuals (over 30% ideal weight)33 by taking into account the patient’s excess adipose tissue: V = 0.26[IBW + 0.4(TBW – IBW)], where IBW is ideal body weight [IBWmales (in kilograms) = 50 + 2.3(Ht – 60) or IBWfemales (in kilograms) = 45 + 2.3(Ht – 60), where Ht is the patient’s height in inches]. Additional

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volume-of-distribution population estimates are available for other disease states and conditions such as cystic fibrosis,34 ascites,35 and neonates.36 Appropriate Cmax,ss and Cmin,ss values are selected for the patient based on the site and severity of the infection and the sensitivity of the known or suspected pathogen, as well as avoidance of adverse effects. For example, Cmax,ss values of 8 to 10 mg/L generally are selected for gram-negative pneumonia patients, whereas Cmin,ss values of less than 2 mg/L usually are chosen to avoid aminoglycoside-induced nephrotoxicity when tobramycin and gentamicin are prescribed using conventional multiple-daily-dosing regimens. Once appropriate steady-state serum concentrations are selected, the dosage interval required to achieve those concentrations is calculated, and τ is rounded to a clinically acceptable value (e.g., 8, 12, 18, 24, 36, or 48 hours): τ = [(ln Cmax,ss – ln Cmin,ss )/k] + T. Finally, a dose is computed for the patient using the one-compartment-model intermittent intravenous infusion equation at steady state, and the dose is rounded off to the nearest 5 to 10 mg: D = T kVD Cmax,ss

1 − e−kτ 1 − e−kT

The Hull and Sarrubi aminoglycoside dosage nomogram (Table 5–5) is based on this dosage-calculation method and includes precalculated doses and dosage intervals for a variety of creatinine clearance values.22 The nomogram assumes that VD = 0.26 L/kg and should not be used to compute doses for disease states with altered VD . For extended-interval therapy, Cmax,ss values of 20–30 mg/L and Cmin,ss values less than 1 mg/L generally are accepted as appropriate for gram-negative pneumonia patients. A minimum 24-hour dosage interval is chosen for this dosing technique, and the dosing interval is increased in 12- to 24-hour increments for patients with renal dysfunction. An example of this initial dosage scheme for a typical case is provided to illustrate the use of the various equations. Mr. JJ is a 65-year-old, 80-kg, 6-ft-tall man with the diagnosis of gram-negative pneumonia. His serum creatinine concentration is 2.1 mg/dL and is stable. Compute a conventional gentamicin dosage regimen (infused over 1 hour) that would provide approximate peak and trough concentrations of Cmax,ss = 8 mg/L and Cmin,ss = 1.5 mg/L, respectively. The patient is within 30% of his ideal body weight [IBWmale = 50 + 2.3(72 in – 60) = 78 kg] and has stable renal function, so the Cockcroft-Gault creatinine clearance estimation equation can be used: CrClest = [(140 – 65 yrs)80 kg]/[72(2.1 mg/dL)] = 40 mL/min. The patient’s weight and estimated creatinine clearance are used to compute his V and k, respectively: V = 0.26 L/kg(80 kg) = 20.8 L; k = 0.00293(40 mL/min) + 0.014 = 0.131 h−1 or t1/2 = 0.693/0.131 h−1 ) = 5.3 h. The dosage interval and dose for the desired serum concentrations would then be calculated: τ = [(ln 8 mg/L – ln 1.5 mg/ L)/0.131 h−1 ] + 1 h = 13.7 h rounded to 12 h; D = (1 h)(0.131 −1 −1 h−1 )(20.8 L)(8 mg/L)[(1 – e−(0.131h )(12h) )/(1 – e−(0.131h )(1h) )] = 140 mg. Thus the prescribed dose would be gentamicin 140 mg every 12 hours administered as a 1-hour infusion. If a loading dose were deemed necessary, it would be given as the first dose [LD = (20.8 L)(8 mg/L) = 166 mg rounded to 170 mg infused over 1 hour], and the first maintenance dose would be administered 12 hours (e.g., one dosage interval) later. Using the Hull and Sarrubi nomogram for the same patient, the loading dose is 160 mg (gentamicin loading dose for serious gram-negative infection is 2 mg/kg: 2 mg/kg × 80 kg = 160 mg), and the maintenance dose is 115 mg every 12 hours (for a 12-hour dosage interval and CrClest = 40 mL/min, maintenance dose is 72% of the loading dose: 0.72 × 160 mg = 115 mg).

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TA B L E 5 – 5 . Aminoglycoside Dosage Chart 1. Compute patient's creatinine clearance (CrCl) using Cockcroft–Gault method: CrCl = [(140 = age)BW]/(Scr × 72). Multiply by 0.85 for females. 2. Use patient's weight if within 30% of IBW; otherwise use adjusted dosing weight = IBW + [0.40(TBW = IBW)]. 3. Select loading dose in mg/kg to provide peak serum concentrations in range listed below for the desired aminoglycoside antibiotic: Aminoglycoside Tobramycin Gentamicin Netilmicin Amikacin Kanamycin

Usual Loading Doses

Expected Peak Serum Concentrations

1.5 to 2.0 mg/kg

4 to 10 mcg/mL

5.0 to 7.5 mg/kg

15 to 30 mcg/mL

4. Select maintenance dose (as percentage of loading dose) to continue peak serum concentrations indicated above according to desired dosage interval and the patient's creatinine clearance. To maintain usual peak/trough ratio, use dosage intervals in clear areas. Percentage of Loading Dose Required for Dosage Interval Selected CrCl (mL/min)

Est. HalfLife (h)

8 h (%)

>90 90 80 70 60 50 40 30 25 20 17 15 12 10a 7a 5a 2a 0a

2=3 3.1 3.4 3.9 4.5 5.3 6.5 8.4 9.9 11.9 13.6 15.1 17.9 20.4 25.9 31.5 46.8 69.3

90 84 80 76 71 65 57 48 43 37 33 31 27 24 19 16 11 8

a Note:

Dosing for patients with CrCl measuring serum concentrations. Adapted from Ref. 22.

12 h (%) – – 91 88 84 79 72 63 57 50 46 42 37 34 28 23 16 11

24 h (%) – – – – – – 92 86 81 75 70 67 61 56 47 41 30 21

mL/min should be assisted by

CLINICAL CONTROVERSY Some clinicians use conventional dosing or extended-interval dosing exclusively for patients requiring aminoglycosides, whereas others use a mix of both approaches according to the perceived benefit to the patient. Definitive, authoritative recommendations to guide the choice of one method of aminoglycoside dosing over the other are not available. If appropriate aminoglycoside serum concentrations are available, kinetic parameters can be calculated at any point in therapy. When the patient is not at steady state, serum aminoglycoside concentrations are obtained before a dose (Cmin ), after a dose administered

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as an intravenous infusion of about 1 hour or as a 1/2 -hour infusion followed by a 1/2 -hour waiting period to allow for drug distribution (Cmax ), and at one additional postdose time (C3 ) approximately one estimated half-life after Cmax . The t1/2 and k values are computed using Cmax and C3 : k = (ln Cmax – ln C3 )/t and t1/2 = 0.693/k, where t is the time that expired between the times Cmax and C3 were obtained. If the patient is at steady state, serum aminoglycoside concentrations are obtained before a dose (Cmin,ss ) and after a dose administered as an intravenous infusion of about 1 hour or as a 1/2 -hour infusion followed by a 1/2 -hour waiting period to allow for drug distribution (Cmax,ss ). The t1/2 and k values are computed using Cmax,ss and Cmin,ss : k = (ln Cmax,ss – ln Cmin,ss )/(τ – T) and t1/2 = 0.693/k, where τ is the dosage interval and T is the dose infusion time or dose infusion time plus waiting time. Assuming a one-compartment model, the following equation is used to compute VD 32 : VD =

(D/T )(1 − e−kT ) k(Cmax − Cmin e−kT )

where D is dose and T is duration of infusion. Once these are known, the dose and dosage interval (τ ) can be calculated for any desired maximum Css (Cmax,ss ) and minimum Css (Cmin,ss ): ln Cmax,ss − ln Cmin,ss +T k 1 − e−kτ D = T kVD Cmax,ss 1 − e−kT τ =

The dose and dosage interval should be rounded to provide clinically accepted values (every 8, 12, 18, 24, 36, and 48 hours for dosage interval, nearest 5 to 10 mg for conventional dosing or every 24, 36, and 48 hours for dosage interval, nearest 10 to 25 mg for extended interval dosing). This method also has been used to individualize intravenous theophylline dosage regimens.37 To provide an example of this technique, the problem given previously will be extended to include steady-state concentrations. Mr. JJ was prescribed gentamicin 140 mg every 12 hours (infused over 1 hour) for the treatment of gram-negative pneumonia. Steadystate trough (Cmin,ss ) and peak (Cmax,ss ) values were obtained before and after the fourth dose was given (more than three to five estimated half-lives), respectively, and equaled Cmin,ss = 2.8 mg/L and Cmax,ss = 8.5 mg/L. Clinically, the patient was improving with decreased white blood cell counts and body temperatures and a resolving chest x-ray. However, the serum creatinine value had increased to 2.5 mg/dL. Because of this, a new dosage regimen with a similar peak (to maintain high intrapulmonary levels) but lower trough (to decrease the risk of drug-induced nephrotoxicity) concentrations was suggested. The patient’s elimination rate constant and half-life can be computed using the following formulas: k = (ln 8.5 mg/L – ln 2.8 mg/L)/(12 h – 1 h) = 0.101 h−1 and t1/2 = 0.693/0.101 h−1 = 6.9 h. The patient’s volume of distribution can be calculated using the following equation: −1

V=

(140 mg/1 h)[1 − e−(0.101 h )(1 h) ] = 22.3 L −1 (0.101 h ){8.5 mg/L − [(2.8 mg/L)e−(0.101 h−1 )(1 h) ]}

Thus the patient’s volume of distribution was larger and half-life was longer than originally estimated, and this led to higher serum concentrations than anticipated. To achieve the desired serum concentrations (Cmin,ss = 1.5 mg/L and Cmax,ss = 8 mg/L), the patient’s actual kinetic parameters are used to compute a new dose and dosage interval: τ = [(ln 8 mg/L – ln 1.5 mg/L)/0.101 h−1 ] + 1 h = 17.6 h, rounded

to 18 h and −1

D = (1 h)(0.101 h−1 )(22.3 L)(8 mg/L)

(1 − e−(0.101 h )(18 h) ) (1 − e−(0.101 h−1 )(1 h) )

= 157 mg, rounded to 160 mg Thus the new dose would be gentamicin 160 mg every 18 hours and infused over 1 hour; the first dose of the new dosage regimen would be given 18 hours (e.g., the new dosage interval) after the last dose of the old dosage regimen. Because aminoglycoside antibiotics exhibit concentrationdependent bacterial killing and the postantibiotic effect is longer with higher concentrations, investigators studied the possibility of giving a higher dose of aminoglycoside using an extended-dosage interval (24 hours or longer, depending on renal function). Generally, these studies have shown comparable microbiologic and clinical cure rates for many infections and about the same rate of nephrotoxicity (approximately 5% to 10%) as with conventional dosing. Ototoxicity has not been monitored using audiometry in most of these investigations, but loss of hearing in the conversational range, as well as signs and symptoms of vestibular toxicity, usually has been assessed and found to be similar to that with aminoglycoside therapy dosed conventionally. Based on these data, clinicians have begun using extendedinterval dosing in selected patients. For Pseudomonas aeruginosa infections where the organism has an expected MIC ≈ 2 mg/L, peak concentrations between 20 and 30 mg/L and trough concentrations of less than 1 mg/L for gentamicin or tobramycin have been suggested.38 At the present time, there is not a consensus on how to approach concentration monitoring using this mode of administration. Some clinicians obtain steady-state peak and trough concentrations and use the kinetic equations given earlier to adjust the dose and dosage interval in order to attain appropriate target levels. Other clinicians measure only trough concentrations, trusting that the large doses administered to patients achieve adequate peak concentrations. Also, a nomogram that adjusts extended-interval doses based on a single postdose concentration to achieve these steady-state concentration goals has been proposed (Fig. 5–12). The dose is 7 mg/kg of gentamicin or tobramycin. The initial dosage interval is set according to the patient’s creatinine clearance (see Fig. 5–12). The Hartford nomogram includes a method to adjust doses based on serum concentrations. This portion of the nomogram contains average serum concentration time lines for gentamicin or tobramycin in patients with creatinine clearances of 60, 40, and 20 mL/min. A serum concentration is measured 6 to 14 hours after the first dose is given, and this concentration/time point is plotted on the graph (see Fig. 5–12). The modified dosage interval is indicated by which zone the serum concentration/time point falls in. Because cystic fibrosis patients have a different volume of distribution (0.35 L/kg) than assumed by this dosing technique and extended-interval dosing has not been tested adequately in patients with endocarditis, the Hartford nomogram should not be used in these situations. To illustrate how the nomogram is used, the same patient example used previously will be repeated for this dosage approach. Mr. JJ is an 80-kg man with a CrClest of 40 mL/min. Using the Hartford nomogram, the patient would receive gentamicin 560 mg every 36 hours (7 mg/kg × 80 kg = 560 mg, initial dosage interval for CrClest = 40 mL/min is 36 hours). Ten hours after the first dose was given, the serum gentamicin concentration is 8.2 mg/L. According to the graph contained in the nomogram, the dosage interval should be changed to 48 hours. The new dose is 560 mg every 48 hours.

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TABLE 5–5. Vancomycin Dosage Chart

14 13 12 11 10 9 8 7 6 5 4 3 2

1. Compute patient’s creatinine clearance (CrCl) using Cockcroft-Gault method: CrCl = [(140 – age)BW]/(SCr × 72). Multiply by 0.85 for females. 2. Use patient’s total body weight to compute doses. 3. Dosage chart designed to achieve peak serum concentrations of 30 µg/mL and trough concentrations of 7.5 µg/mL. 4. Compute loading dose of 25 mg/kg. 5. Compute maintenance dose of 19 mg/kg given at the dosage interval listed in the following chart for the patient’s CrCl:

q48h q36h q24h

6

7 8 9 10 11 12 13 Time between start of infusion and sample draw (h)

14

1. Administer 7 mg/kg gentamicin with initial dosage interval: Estimated CrCl (mL/min)

Initial dosage interval

ⱖ60 mL/min

q24h

40–59 mL/min

q36h

20–39 mL/min

q48h

⬍20 mL/min

Monitor serial concentrations and administer next dose when ⬍1 ␮g/mL.

2. Obtain timed serum concentration 6 to 14 hours after dose (ideally first dose). 3. Alter dosage interval to that indicated by the nomogram zone (above q48h zone, monitor serial concentrations and administer next dose when ⬍1 ␮g/mL)

FIGURE 5–12. Hartford nomogram for extended-interval aminoglycosides. (Adapted with permission from ref. 38.)

CLINICAL CONTROVERSY “Trough only” measurement of steady-state vancomycin concentrations is becoming a mainstream method to monitor therapy. The exact range for this value is uncertain. Some clinicians recommend 5 to 10 mcg/mL, whereas others suggest 5 to 15 mcg/mL. Many clinicians continue to measure both steady-state peak and trough vancomycin concentrations.

VANCOMYCIN Vancomycin requires multicompartment models to completely describe its serum-concentration-versus-time curves. However, if peak serum concentrations are obtained after the distribution phase is completed (usually 1/2 to 1 hour after a 1-hour intravenous infusion), a onecompartment model can be used for patient dosage calculations. Also, since vancomycin has a relatively long half-life compared with the infusion time, only a small amount of drug is eliminated during infusion, and it is usually not necessary to use more complex intravenous infusion equations. Thus simple intravenous bolus equations can be used to calculate vancomycin doses for most patients. Although a recent review paper39 questioned the clinical usefulness of measuring vancomycin concentrations on a routine basis, research articles40,41 have shown potential benefits in obtaining vancomycin concentrations

CrCl (mL/min)

Dosage Interval (Days)

≥120 100 80 60 40 30 20 10 5 0

0.5 0.6 0.75 1.0 1.5 2.0 2.5 4.0 6.0 12.0

Adapted from Ref. 45.

in selected patient populations. Some clinicians advocate monitoring only steady-state trough concentrations of vancomycin.42 The decision to conduct vancomycin concentration monitoring should be made on a patient-by-patient basis. Initial doses of vancomycin can be computed for adult patients using estimated kinetic parameters derived from population pharmacokinetic data. Clearance is estimated using the patient’s creatinine clearance in the following equation41 : Cl (in mL/min/kg) = 0.695(CrCl in mL/min/kg) + 0.05. The volume of distribution is computed assuming the standard value of 0.7 L/kg: VD = 0.7(Wt), where Wt is the patient’s weight. In the case of obese patients, actual or total body weight is used in the calculations of clearance, but ideal body weight is used to compute volume of distribution.44 The elimination rate constant is calculated using clearance and volumeof-distribution estimates, correcting for possible differences in units for these parameters: k = Cl/VD . A nomogram that uses this type of approach for vancomycin therapy is available to determine initial doses rapidly for patients45 (Table 5–6). Steady-state peak and trough concentrations are chosen for the patient based on the site and severity of the infection, as well as the known or suspected pathogen and avoidance of potential side effects. Cmax,ss values of between 20 and 40 mg/L and Cmin,ss values of between 5 and 10 mg/L typically are used for patients with moderate to severe methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, or penicillin-resistant enterococcal infections. After appropriate steady-state concentrations are chosen, the dosage interval required to attain those concentrations is computed, and τ is rounded to a clinically acceptable value (12, 18, 24, 36, 48, or 72 hours): τ = (ln Cmax,ss – ln Cmin,ss )/k. Finally, the maintenance dose is computed for the patient using a one-compartment-model intravenous bolus equation at steady state, and the dose is rounded off to the nearest 100 to 250 mg: D = Cmax,ss VD (1 − e−kτ ) If desired, a loading dose can be computed using the following equation: LD = VD Cmax,ss

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The following case will illustrate the use of this dosage methodology. Ms HJ is a 65-year-old, 68-kg, 5-ft, 4-in-tall coronary artery bypass graft surgery patient who has developed a surgical wound infection with S. aureus the suspected pathogen. Her serum creatinine concentration is 1.8 mg/dL and stable. Compute a vancomycin dosage regimen that would provide approximate peak (obtained 1 hour after a 1-hour infusion) and trough concentrations of 30 and 7 mg/L, respectively. The patient is within 30% of her ideal body weight [IBWfemale = 45 + 2.3(64 in – 60) = 54 kg] and has stable renal function, so the Cockcroft-Gault creatinine clearance estimation formula can be used: CrClest = 0.85[(140 – 65 yrs)68 kg]/[72(1.8 mg/dL)] = 33 mL/min. The patient’s weight and estimated creatinine clearance are used to calculate her estimated Cl, VD , and k, respectively: Cl = 0.695 (33 mL/min/68 kg) + 0.05 = 0.387 mL/min/kg; VD = 0.7 L/kg(68 kg) = 48 L; and k = [(0.387 mL/min/kg)(68 kg)(60 min/h)]/[(48 L)(1000 mL/L)] = 0.033 h−1 or t1/2 = 0.693/0.033 h−1 = 21 h. The dosage interval, maintenance dose, and loading dose for the desired serum concentrations then can be computed: τ = (ln 30 mg/L – ln 7 mg/L)/0.033 h−1 = 44 h, rounded to 48 h; D = (30 mg/L) (48 L)(1 −1 – e−(0.033h )(48h) ) = 1145 mg, rounded to 1200 mg; LD = (48 L)(30 mg/L) = 1440 mg, rounded to 1450 mg. Therefore, the prescribed doses would be vancomycin 1200 mg every 48 hours administered as a 1-hour infusion. If a loading dose was used, it would be given as the first dose, and the first maintenance dose would be administered 48 hours (one dosage interval) later. Using the Matzke nomogram for the same patient, the loading dose would be 1700 mg (vancomycin loading dose is 25 mg/kg: 25 mg/kg × 68 kg = 1700 mg), followed by a maintenance dose of 1300 mg every 48 hours (for CrClest = 30 mL/ min, maintenance dose is 19 mg/kg every 2 days: 19 mg/kg × 68 kg = 1292 mg, rounded to 1300 mg). If appropriate vancomycin serum concentrations are available, kinetic parameters can be computed at any point in therapy. When the patient is not at steady state, serum vancomycin concentrations are obtained before a dose (Cmin ), after a dose administered as an intravenous infusion of 1 hour followed by a 1/2- to 1-hour waiting period to allow for drug distribution (Cmax ), and at one additional postdose time (C3 ) approximately one estimated half-life after Cmax . The t1/2 and k values are computed using Cmax and C3 : k = (ln Cmax – ln C3 )/t and t1/2 = 0.693/k, where t is the time that expired between the times Cmax and C3 were obtained. If the patient is at steady state, serum vancomycin concentrations are obtained before a dose (Cmin,ss ) and after a dose administered as an intravenous infusion of about 1 hour followed by a 1/2- to 1-hour waiting period to allow for drug distribution (Cmax,ss ). The t1/2 and k values are computed using Cmax,ss and Cmin,ss : k = (ln Cmax,ss – ln Cmin,ss )/(τ – Tmax ) and t1/2 = 0.693/k, where τ is the dosage interval and Tmax is the dose infusion time plus waiting time. Assuming a one-compartment model, the following equation is used to compute VD : VD =

D Cmax − Cmin

where D is dose. Once these are known, the dose and dosage interval (τ ) can be calculated for any desired maximum Css (Cmax,ss ) and minimum Css (Cmin,ss ): ln Cmax,ss − ln Cmin,ss k D = Cmax,ss VD (1 − e−kτ )

τ=

The dose and dosage interval should be rounded to provide clinically accepted values (every 12, 18, 24, 36, 48, or 72 hours for dosage interval, nearest 100 to 250 mg for dose).

To provide an example for this dosage-calculation method, the preceding problem will be extended to include steady-state concentrations. Ms HJ was prescribed vancomycin 1200 mg every 48 hours (infused over 1 hour) for the treatment of a surgical wound infection. Steady-state trough (Cmin,ss ) and peak (Cmax,ss ) values (Cmax,ss obtained 1 hour after the end of the infusion) were obtained before and after the third dose was given (more than three to five estimated half-lives), respectively, and equaled Cmin,ss = 2.5 mg/L and Cmax,ss = 22.4 mg/L. Clinically, the patient had improved somewhat, but her white blood cell count was still elevated, and the patient was still febrile. Because of this, a modified dosage regimen with a Cmax,ss = 30 mg/L and Cmin,ss = 7 mg/L was suggested to maintain trough concentrations three to five times above the minimal inhibitory concentration (MIC) for the suspected pathogen. The patient’s actual elimination rate constant and half-life can be calculated using the following formulas: k = (ln 22.4 mg/L – ln 2.5 mg/L)/(48 h – 2 h) = 0.048 h−1 and t1/2 = 0.693/0.048 h−1 = 14.4 h. The patient’s volume of distribution can be calculated using the following equation: VD =

1200 mg = 60 L 22.4 mg/L − 2.5 mg/L

Thus the patient’s volume of distribution was larger and halflife shorter than originally estimated, and this led to lower serum concentrations than anticipated. To achieve the desired serum concentrations (Cmax,ss = 30 mg/L and Cmin,ss = 7 mg/L), the patient’s actual kinetic parameters are used to calculate a new dose and dosage interval: ln 30 mg/L − ln 7 mg/L τ = 0.048 h−1 = 30 h, rounded to 36 h −1 )(36 h)

D = (30 mg/L)(60 L)(1 − e−(0.048 h

)

= 1480 mg, rounded to 1500 mg The new dose would be vancomycin 1500 mg every 36 hours (infused over 1 hour); the first dose of the new dosage regimen would be given 36 hours (the new dosage interval) after the last dose of the old dosage regimen. Some clinicians measure only steady-state vancomycin trough concentrations in patients. The justification for this approach is that since vancomycin exhibits time-dependent bacterial killing, the minimum concentration is the most important with regard to therapeutic outcome. Vancomycin pharmacokinetics also support this approach because the volume of distribution is relatively stable and is not changed by many disease states or conditions. Because of this important point, it is difficult to attain peak steady-state concentrations in the toxic range when the steady-state vancomycin trough is in the therapeutic range if typical doses are used (15 mg/kg or ∼1000 mg for average-weight individuals). Also, toxic peak concentrations (generally greater than 80 to 100 mg/L) are quite a bit higher than therapeutic peak concentrations, which adds a safety margin between effective concentrations and those yielding adverse drug effects. Coupled with trough-only vancomycin concentration monitoring is a widening of the therapeutic steady-state trough concentration range from 5 to 15 mg/L. The justification for increasing the top of the range from 10 to 15 mg/L comes from limited retrospective41 and prospective42 studies and until more clinical evidence is available should be reserved for severely ill patients, infections caused by bacteria with higher MICs, and patients not responding to trough concentrations within the usual 5- to 10-mg/L range. When trough-only monitoring of vancomycin concentrations is chosen by a clinician, a simple variant of linear pharmacokinetics can

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be used to adjust the dose (D) and dosage interval (τ ): (Dnew /τ new ) = (Dold /τ old )(Css,new /Css,old ), where new and old indicate the new target trough concentration and the old measured trough concentration, respectively. This equation is an approximation of the actual new steady-state trough concentration that will be attained in the patient because, mathematically, Css,new is an exponential function of τ . An example of this approach is given in the following case. Mr. MK (72 years old, 72 kg weight, 5 ft, 9 in tall) was prescribed vancomycin 1000 mg every 12 hours (infused over 1 hour) for the treatment of an S. epidermidis central venous catheter infection. A steady-state trough (Cmin,ss ) value was obtained before the fifth dose was given (more than three to five estimated half-lives), and Cmin,ss equaled 19 mg/L. Clinically, the patient was improving, but the trough concentration was judged to be too high. Because of this, a modified dosage regimen with a Cmin,ss = 10 mg/L was suggested to maintain trough concentrations three to five times above the minimal inhibitory concentration (MIC) for the suspected pathogen: (Dnew /τ new ) = (1000 mg/12 h)(10 mg/L/19 mg/L) = 44 mg/h. Because the patient is near his ideal weight, a new dose of 1000 mg can be used (Dnew ), and the new dosage interval (τ new ) can be computed: τ = 1000 mg/44 mg/h = 23 h, rounded to 24 h. The new prescribed dose for the patient would be 1000 mg every 24 hours.

DIGOXIN Digoxin pharmacokinetics are best described by a two-compartment model. However, because digoxin has a long half-life compared with its dosage interval and a very long distribution phase, simple pharmacokinetic equations can be used to individualize dosing when postdistribution serum concentrations are used. Digoxin can be given as an intravenous injection and orally as elixir (F = 0.8), tablets (F = 0.7), or capsules (F = 0.9). When given orally, the appropriate bioavailability fraction must be used to compute the correct dose. Initial doses of digoxin can be computed using population pharmacokinetic data obtained from published studies. Digoxin clearance is estimated using the patient’s creatinine clearance in the following formula20 : Cl (in milliliters per minute) = 1.303(CrCl in milliliters per minute) + Clm , where Clm is metabolic clearance and equals 40 mL/min for patients with no or mild heart failure or 20 mL/min for patients with moderate to severe heart failure. The volume of distribution decreases with declining renal function and is estimated using the following equation20 : VD (in liters) = 226 + [298(CrCl in milliliters per minute)]/(29.1 + CrCl in milliliters per minute). The elimination rate constant can be computed by taking the product of Cl and VD : k = Cl/VD . For obese individuals, digoxin dosing should be based on ideal body weight.46 Appropriate Css values are chosen for the patient based on the disease state being treated, the goal of therapy, and avoidance of adverse effects. The inotropic effects of digoxin occur at lower concentrations than do the chronotropic effects. Therefore, initial serum concentrations of digoxin for the treatment of heart failure generally are 1 ng/mL or less and for the treatment of atrial fibrillation are 1–1.5 ng/mL. Once the appropriate Css is selected, a dose is computed for the patient: D/τ = (Css Cl)/F. An example of this initial dosage scheme is provided in the following case. Mr. PO is a 72-year-old, 83-kg, 5-ft, 11-in man admitted to the hospital for the treatment of community-acquired pneumonia. While in the hospital, Mr. PO develops atrial fibrillation, and the decision is made to treat him with digoxin to provide ventricular rate control. His serum creatinine concentration is 2.5 mg/dL and stable. Calculate an intravenous loading dose and oral maintenance dose that will achieve a Css of 1.5 ng/mL. The Cockcroft-Gault equation can be

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used to estimate the patient’s creatinine clearance because his serum creatinine concentration is stable and he is within 30% of his ideal weight [IBWmale = 50 + 2.3(71 in – 60) = 75 kg]: CrCl = [(140 – 72 yrs)83 kg]/[72(2.5 mg/dL)] = 31 mL/min. Using the estimated CrCl, both Cl and VD can be computed: Cl = 1.303(31 mL/min) + 40 = 80 mL/min VD = 226 +

298(31 mL/min) = 380 L 29.1 + 31 mL/min

The maintenance dose will be given as digoxin tablets, so F = 0.7 in the dosing equation: D/τ = [(1.5 mcg/L)(80 mL/min)(60 min/h) (24 h/day)]/[0.7(1000 mL/L)] = 247 mcg/day, rounded to 250 mcg/ day. The loading dose will be given intravenously as a digoxin injection: LD = (1.5 mcg/L)(380 L) = 570 mcg, rounded to 500 mcg. The loading dose would be given 50% now (250 mcg), 25% (125 mcg) in 4 to 6 hours after monitoring the patient’s heart rate and blood pressure and assessing the patient for digoxin adverse effects, and the final 25% (125 mcg) 4 to 6 hours later after monitoring the same clinical parameters. The first maintenance dose would be given one dosage interval (in this case 24 hours) after the first part of the loading dose was given. Adjustment of digoxin doses using steady-state concentrations is accomplished using linear pharmacokinetics and dosage ratios: Dnew = Dold (Css,new /Css,old ). For example, Mr. PO’s atrial fibrillation responded to digoxin therapy, and he was discharged after resolution of his pneumonia. A month later he was followed up in the clinic with moderate nausea, possibly due to digoxin toxicity. His heart rate was 55 beats per minute. A steady-state digoxin concentration was determined and reported by the clinical laboratory as 2.2 mcg/L. Compute a new dose for the patient to achieve a Css of 1.5 mcg/L. The digoxin Css and old dose would be used to calculate a new dose using the linear pharmacokinetic equation: Dnew = 250 mcg/day[(1.5 mcg/L)/ (2.2 mcg/L)] = 170 mcg/day. This approximate average daily dose could be achieved by having the patient alternate take two 125-mcg tablets (250 mcg) and one 125-mcg tablet daily, giving an average dose equal to 187.5 mcg/day [(250 mcg + 125 mcg)/2 = 187.5 mcg/day].

THEOPHYLLINE Theophylline disposition is described most accurately by nonlinear kinetics.47,48 However, at the usual doses, theophylline acts as if it obeys linear kinetics in most patients. Initial theophylline doses are computed by taking a detailed medical history of the patient and noting disease states and conditions that are known to change theophylline disposition. Age, smoking of tobacco-containing products, heart failure, and liver disease are among the important factors that alter theophylline kinetic parameters and dosage requirements. Once the patient has been assessed, average theophylline kinetic parameters obtained from the literature for patients similar to the one being currently treated are used to compute either oral or intravenous doses. Dosage guidelines that take into account most common disease states and conditions that change theophylline kinetic parameters are available49 (see Table 5–4). Once theophylline is administered, the patient is monitored for the therapeutic effect and potential adverse effects. Theophylline concentrations then are used to individualize the theophylline dose that the patient receives. An example of this approach was given previously for a patient in the section on drug dosing in patients with liver disease. Continuous intravenous infusions of theophylline (or its salt, aminophylline) can be individualized rapidly by determining the

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patient’s Cl before steady state occurs.50 Assuming that the patient receives theophylline only by continuous intravenous infusion (previous doses of sustained-release oral theophylline are completely absorbed), two serum theophylline concentration determinations are done 4 hours or more apart. The infusion rate (k0 ) cannot be changed between the times the samples are drawn. With one-compartment model equations, the first (C1 ) and second (C2 ) theophylline concentrations are used to calculate theophylline Cl: Cl =

2k0 2VD (C1 − C2 ) + C1 + C2 (C1 + C2 )(t2 − t1 )

VD is assumed to be 0.5 L/kg, and t1 and t2 are the times at which C1 and C2 , respectively, are obtained. Once Cl is known, k0 can be computed easily for any desired Css (Css = k0 /Cl). This method probably can be applied to other drugs that are administered as continuous intravenous infusions, such as intravenous antiarrhythmics, when rapid individualization of drug dosage is desirable. An example of this approach can be obtained by continuing the theophylline patient case from the section on drug dosing in liver disease. In this example, a 55-year-old, 70-kg man with liver cirrhosis was prescribed a loading dose of theophylline 350 mg intravenously over 20 to 30 minutes, followed by a maintenance dose of 15 mg/h of theophylline as a continuous infusion. The infusion began at 9 A.M., blood samples were obtained at 10 A.M. and 4 P.M., and the clinical laboratory reported the theophylline serum concentrations as 10.9 and 12.3 mg/L, respectively. The patient’s theophylline clearance and revised continuous infusion to maintain a Css of 15 mg/L can be computed as follows (patient’s VD estimated at 0.5 L/kg): Cl = +

2(15 mg/h) 10.9 mg/L + 12.3 mg/L 2(0.5 L/kg × 70 kg)(10.9 mg/L − 12.3 mg/L) = 0.59 L/h (10.9 mg/L + 12.3 mg/L)(16 − 10 h)

k0 = Css Cl = (15 mg/L)(0.59 L/h) = 9 mg/h theophylline If theophylline is to be given as the aminophylline salt form, the doses would need to be changed to reflect the fact that aminophylline contains only 85% theophylline (k0 = 9 mg/h theophylline/0.85 = 11 mg/h aminophylline). If continuous intravenous infusions or oral dosage regimens are given long enough for steady state to occur (three to five estimated half-lives based on previous studies conducted in similar patients), linear pharmacokinetics can be used to adjust doses for either route of administration: Dnew = Dold (Css,new /Css,old ). For example, a patient receiving 200 mg of sustained-release oral theophylline every 12 hours with a theophylline steady-state serum concentration of 9.5 mcg/mL can have the dose required to achieve a new steady-state concentration equal to 15 mcg/mL computed by applying linear pharmacokinetics: Dnew = 200 mg[(15 mcg/mL)/(9.5 mcg/mL)] = 316 mg, rounded to 300 mg. Thus the new theophylline dose would be 300 mg every 12 hours.

PHENYTOIN Phenytoin doses are very difficult to individualize because the drug follows Michaelis-Menten kinetics, and there is a large amount of interpatient variability in Vmax and Km . Initial maintenance doses of phenytoin in adults usually range between 4 and 7 mg/kg per day, yielding starting doses of 300 to 400 mg/day in most individuals. If

needed, loading doses of phenytoin or fosphenytoin (a prodrug of phenytoin used intravenously) can be administered in adults at a dose of 15 mg/kg, which is approximately 1000 mg in many individuals. Loading doses of phenytoin can be given orally but need to be administered in divided doses separated by several hours in order to avoid decreased bioavailability and gastrointestinal intolerance (400 mg, 300 mg, and then 300 mg with each dose separated by 4 to 6 hours). Since phenytoin is metabolized hepatically, decreased doses may be needed in patients with liver disease. Because phenytoin follows dosedependent pharmacokinetics, the half-life of phenytoin increases for a patient as the maintenance dose increases. Therefore, the time to steady-state phenytoin concentrations increases with dose. On average, at a phenytoin dose of 300 mg/day, it takes approximately 5 to 7 days to achieve steady state; at a dose of 400 mg/day, it takes approximately 10 to 14 days to achieve steady state; and at a dose of 500 mg/day, it takes approximately 21 to 28 days to achieve steady state. It should be noted that the injectable and capsule dosage forms of phenytoin are phenytoin sodium, and the labeled dosage amounts contain 92% of active phenytoin [300-mg phenytoin sodium capsules contain 276 mg (300 mg × 0.92 = 276 mg) of active phenytoin]. Unbound phenytoin concentrations are useful in patients with hypoalbuminemia (e.g., liver disease, nephrotic syndrome, pregnancy, cystic fibrosis, burns, trauma, and malnourishment, as well as the elderly), in patients in whom displacement with endogenous compounds is possible (e.g., hyperbilirubinemia, liver disease, or endstage renal disease), or in patients receiving other drugs that may displace phenytoin from plasma-protein-binding sights (e.g., valproic acid, aspirin therapy of more than 2 g/day, warfarin, and nonsteroidal anti-inflammatory drugs with high albumin binding). After steady state has occurred, phenytoin serum concentrations can be obtained as an aid to dosage adjustment. A simple, easy way to approximate new serum concentrations after a dosage adjustment with phenytoin is to temporarily assume linear pharmacokinetics and then add 15% to 33% for a dosage increase or subtract 15% to 33% for a dosage decrease to account for Michaelis-Menten kinetics. To avoid large disproportionate changes in phenytoin concentrations when using this empirical method, dosage adjustments should be limited to 50 to 100 mg/day. For example, Ms PP is a 35-year-old, 65-kg patient with grand mal seizures who is receiving phenytoin capsules 300 mg orally at bedtime. A steady-state concentration of 9.2 mcg/mL is measured. It is observed that her seizure frequency decreased by only about 15% and that she has had no adverse effects due to phenytoin treatment. Because of this, her phenytoin dose is increased to 400 mg orally at bedtime. The expected phenytoin steady-state concentration would be estimated using linear pharmacokinetics [Cnew = (Dnew /Dold )Cold = (400 mg/300 mg)/(9.2 mcg/mL) = 12.3 mcg/mL] and then increased by 15% to 33% to account for nonlinear kinetics [Cnew = 1.15(12.3 mcg/mL) = 14.1 mcg/mL or Cnew = 1.33 (12.3 mcg/mL) = 16.4 mcg/mL]. Thus the patient would be expected to have a steady-state phenytoin concentration of approximately 14 to 16 mcg/mL due to the dosage increase. An alternative approach would be to use a graphic Bayesian method that allows an estimate of Vmax and Km from one steady-state phenytoin concentration and the prediction of new steady-state concentrations when doses are changed.51 Other methods used to individualize phenytoin doses involve rearrangements of the Michaelis-Menten equation [DR = Vmax Css /(Km + Css ), in which DR is the dosage rate at steady state] so that two or more doses and Css values can be used to obtain graphic solutions for Vmax and Km . One rearrangement52 is DR = –Km (DR/Css ) + Vmax . When DR is plotted on the y axis and DR/Css is plotted on the x axis of Cartesian graph paper, a straight line with a y intercept of Vmax

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to change cyclosporine doses using steady-state concentrations and assuming that the drug follows linear pharmacokinetics:

Vmax

Dnew = Dold Slope = −Km DR

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DR/Css

FIGURE 5–13. Relationship between dosage rate (DR) and steady-state serum concentrations (Css ).

and slope equal to –Km is found (Fig. 5–13). To use this method, patients are prescribed an initial phenytoin dose, and Css is obtained. The phenytoin dose is then changed, and a second Css from the new dose is obtained. Each dose is divided by its respective Css to derive DR/Css values. The DR/Css and Css values are plotted on the graph to calculate Vmax (y intercept) and Km (minus slope). The steady-state Michaelis-Menten equation can be used to compute Css for a given DR or a DR for any Css .

CYCLOSPORINE Because of the large amount of variability in cyclosporine pharmacokinetics, even when concurrent disease states and conditions are identified, many clinicians believe that the use of standard cyclosporine doses for various situations is warranted. Indeed, most transplant centers use doses that are determined employing a locally derived cyclosporine dosage protocol. The original computations of these doses were based on the pharmacokinetic dosing methods described in preceding sections and subsequently modified based on clinical experience. In general, the expected cyclosporine steady-state concentration used to compute these doses depends on the type of transplanted tissue and the posttransplantation time line. Generally speaking, initial oral doses of 8 to 18 mg/kg per day or intravenous doses of 3 to 6 mg/kg per day (one-third the oral dose to account for approximately 30% oral bioavailability) are used and vary greatly from institution to institution. For obese individuals (more than 30% over ideal body weight), ideal body weight should be used to compute initial doses. It is likely that doses computed using patient population characteristics will not always produce cyclosporine concentrations that are expected or desirable. Additionally, there is a very high amount of interday variation in cyclosporine concentrations. Because of pharmacokinetic variability, the narrow therapeutic index of cyclosporine, and the severity of cyclosporine adverse side effects, measurement of cyclosporine concentrations is mandatory for patients to ensure that therapeutic, nontoxic levels are present. When cyclosporine concentrations are measured in patients and a dosage change is necessary, clinicians should seek to use the simplest, most straightforward method available to determine a dose that will provide safe and effective treatment. In most cases, a simple dosage ratio can be used

Css,new Css,old

Css,new 200 ng/mL = 800 mg/day = 427 mg/day, Css,new 375 ng/mL

rounded to 400 mg/day The new suggested dose would be 400 mg/day or 200 mg every 12 hours of cyclosporine capsules to be started at the next scheduled dosing time.

CLINICAL PHARMACODYNAMICS 16 Pharmacodynamics is the study of the relationship between the

concentration of a drug and the response obtained in a patient. Originally, investigators examined the dose-response relationship of drugs in humans but found that the same dose of a drug usually resulted in different concentrations in individuals because of pharmacokinetic differences in clearance and volume of distribution. Examples of quantifiable pharmacodynamic measurements include changes in blood pressure during antihypertensive drug therapy, decreases in heart rate during β-blocker treatment, and alterations in prothrombin time or international normalized ratio during warfarin therapy. For drugs that exhibit a direct and reversible effect, the following diagram describes what occurs at the level of the drug receptor: Drug + receptor ↔ drug − receptor complex ↔ response According to this scheme, there is a drug receptor located within the target organ or tissue. When a drug molecule “finds” the receptor, it forms a complex that causes the pharmacologic response to occur. The drug and receptor are in dynamic equilibrium with the drug-receptor complex.

THE Emax AND SIGMOID Emax MODELS The mathematical model that comes from the classic drug receptor theory shown previously is known as the Emax model: E=

E max × C EC50 + C

where E is the pharmacologic effect elicited by the drug, Emax is the maximum effect the drug can cause, EC50 is the concentration causing one-half the maximum drug effect (Emax /2), and C is the concentration of drug at the receptor site. EC50 can be used as a measure of drug potency (a lower EC50 indicating a more potent drug), whereas Emax reflects the intrinsic efficacy of the drug (a higher Emax indicating greater efficacy). If pharmacologic effect is plotted versus concentration in the Emax equation, a hyperbola results with an asymptote equal to Emax (Fig. 5–14). At a concentration of zero, no measurable effect is present.

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100

100

80

80

60

60 Effect

Effect 40

40

20

20

0

50

100

150 200 Concentration

250

300

350

FIGURE 5–14. The Emax model [E = (Emax × C )/(EC50 + C )] has the shape of a hyperbola with an asymptote equal to Emax . EC50 is the concentration where effect = Emax /2.

When dealing with human studies in which a drug is administered to a patient and pharmacologic effect is measured, it is very difficult to determine the concentration of drug at the receptor site. Because of this, serum concentrations (total or unbound) usually are used as the concentration parameter in the Emax equation. Therefore, the values of Emax and EC50 are much different than if the drug were added to an isolated tissue contained in a laboratory beaker. The result is that a much more empirical approach is used to describe the relationship between concentration and effect in clinical pharmacology studies. After a pharmacodynamic experiment has been conducted, concentration-effect plots are generated. The shape of the concentration-effect curve is used to determine which pharmacodynamic model will be used to describe the data. Because of this, the pharmacodynamic models used in a clinical pharmacology study are deterministic in the same way that the shape of the serumconcentration-versus-time curve determines which pharmacokinetic model is used in clinical pharmacokinetic studies. Sometimes a hyperbolic function does not describe the concentration-effect relationship at lower concentrations adequately. When this is the case, the sigmoid Emax equation may be superior to the Emax model:

0

50

150 200 Concentration

100

250

300

350

n FIGURE 5–15. The sigmoid Emax model [E = (Emax × C n )/(EC50 + C n )] has an S-shaped curve at lower concentrations. In this example, Emax and EC50 have the same values as in Fig. 5–14.

LINEAR MODELS When serum concentrations obtained during a pharmacodynamic experiment are between 20% and 80% of Emax , the concentration-effect curve may appear to be linear (Fig. 5–16). This occurs often because lower drug concentrations may not be detectable with the analytic technique used to assay serum samples, and higher drug concentrations may be avoided to prevent toxic side effects. The equation used is that of a simple line: E = S × C + I, where E is the drug effect, C is the drug concentration, S is the slope of the line, and I is the y intercept. In this situation, the value of S can be used as a measure of drug potency (the larger the value of S, the more potent the drug). The linear model can be derived from the Emax model. When EC50 is much greater than C, E = (Emax /EC50 )C = S × C, where S = Emax /EC50 . The linear model allows a nonzero value for effect when the concentration equals zero. This may be a baseline value for the effect that is present without the drug, the result of measurement error when determining effect, or model misspecification. Also, this model does not allow the prediction of a maximum response.

80

E max × C n E= n EC50 + Cn 60

where n is an exponent that changes the shape of the concentrationeffect curve. When n > 1, the concentration-effect curve is S- or sigmoid-shaped at lower serum concentrations. When n < 1, the concentration-effect curve has a steeper slope at lower concentrations (Fig. 5–15). With both the Emax and sigmoid Emax models, the largest changes in drug effect occur at the lower end of the concentration scale. Small changes in low serum concentrations cause large changes in effect. As serum concentrations become larger, further increases in serum concentration result in smaller changes in effect. Using the Emax model as an example and setting Emax = 100 units and EC50 = 20 mg/L, doubling the serum concentration from 5 to 10 mg/L increases the effect from 20 to 33 units (a 67% increase), whereas doubling the serum concentration from 40 to 80 mg/L only increases the effect from 67 to 80 units (a 19% increase). This is an important concept for clinicians to remember when doses are being titrated in patients.

Effect

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10

20

30

40

50

60

70

80

Concentration

FIGURE 5–16. The linear model (E = S × C + I ) is often used as a pharmacodynamic model when the measured pharmacologic effect is 20% to 80% of Emax . In this situation, the determination of Emax and EC50 is not possible. To illustrate this, effect measurements from Fig. 5–14 between 20% and 80% of Emax are graphed using the linear pharmacodynamic model.

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Some investigators have used a log-linear model in pharmacodynamic experiments: E = S × (log C) + I, where the symbols have the same meaning as in the linear model. The advantages of this model are that the concentration scale is compressed on concentration-effect plots for experiments where wide concentration ranges were used, and the concentration values are transformed so that linear regression can be used to compute model parameters. The disadvantages are that the model cannot predict a maximum effect or an effect when the concentration equals zero. With the increased availability of nonlinear regression programs that can compute the parameters of nonlinear functions such as the Emax model easily, use of the log-linear model has been discouraged.53

BASELINE EFFECTS At times, the effect measured during a pharmacodynamic study has a value before the drug is administered to the patient. In these cases, the drug changes the patient’s baseline value. Examples of these types of measurements are heart rate and blood pressure. In addition, a given drug may increase or decrease the baseline value. Two basic techniques are used to incorporate baseline values into pharmacodynamic data. One way incorporates the baseline value into the pharmacodynamic model; the other way transforms the effect data to take baseline values into account. Incorporation of the baseline value into the pharmacodynamic model involves the addition of a new term to the previous equations. E0 is the symbol used to denote the baseline value of the effect that will be measured. The form that these equations takes depends on whether the drug increases or decreases the pharmacodynamic effect. When the drug increases the baseline value, E0 is added to the equations: E max × C EC50 + C E max × C n E = E0 + n EC50 + Cn

E = E0 +

E = S × C + E0 When E0 is not known with any better certainty than any other effect measurement, it should be estimated as a model parameter similar to the way that one would estimate the values of Emax , EC50 , S, or n.54,55 If the baseline effect is well known and has only a small amount of measurement error, it can be subtracted from the effect determined in the patient during the experiment and not estimated as a model parameter. This approach can lead to better estimates of the remaining model parameters.55 Using the linear model as an example, the equation used would be E – E0 = S × C. If the drug decreases the baseline value, the drug effect is subtracted from E0 in the pharmacodynamic models: E max × C E = E0 − I C50 + C E max × C n E = E0 − n I C50 + Cn E = E0 − S × C where Emax represents the maximum reduction in effect caused by the drug, and IC50 is the concentration that produces a 50% inhibition of Emax . These forms of the equations have been called the inhibitory Emax and inhibitory sigmoidal Emax equations, respectively. In this arrangement of the pharmacodynamic model, E0 is a model parameter and can be estimated. If the baseline effect is well known and has little measurement error, the effect in the presence of the drug can be subtracted from the baseline effect and not estimated as a model

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parameter. Using the inhibitory Emax model as an example, the formula would be E0 − E = (Emax × C)/(IC50 + C). When using the inhibitory Emax model, a special situation occurs if the baseline effect can be obliterated completely by the drug (e.g., decreased premature ventricular contractions during antiarrhythmic therapy). In this situation, Emax = E0 , and the equation simplifies to a rearrangement known as the fractional Emax equation:   C E = E0 1 − I C50 + C This form of the model relates drug concentration to the fraction of the maximum effect. An alternative approach to the pharmacodynamic modeling of drugs that alter baseline effects is to transform the effect data so that they represent a percentage increase or decrease from the baseline value.55 For drugs that increase the effect, the following transformation equation would be used: percent effectt = [(treatmentt – baseline)/baseline] × 100. For drugs that decrease the effect, the following formula would be applied to the data: percent inhibitiont = [(baseline – treatmentt )/baseline] × 100. The subscript indicates the treatment, effect, or inhibition that occurred at time t during the experiment. If the study included a placebo control phase, baseline measurements made at the same time as treatment measurements (i.e., heart rate determined 2 hours after placebo and 2 hours after drug treatment) could be used in the appropriate transformation equation.55 The appropriate model (excluding E0 ) then would be used.

HYSTERESIS Concentration-effect curves do not always follow the same pattern when serum concentrations increase as they do when serum concentrations decrease. In this situation, the concentration-effect curves form a loop that is known as hysteresis. With some drugs the effect is greater when serum concentrations are increasing, whereas with other drugs the effect is greater while serum concentrations are decreasing (Fig. 5–17). When individual concentration-effect pairs are joined in

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FIGURE 5–17. Hysteresis occurs when effect measurements are different at the same concentration. This is commonly seen after short-term intravenous infusions or extravascular doses where concentrations increase and subsequently decrease. Counterclockwise hysteresis loops are found when concentration-effect points are joined as time increases (shown by arrows) and effect is larger at the same concentration but at a later time. Clockwise hysteresis loops are similar, but the concentration-effect points are joined in clockwise order and the effect is smaller at a later time.

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time sequence, this results in clockwise and counterclockwise hysteresis loops. Clockwise hysteresis loops usually are caused by the development of tolerance to the drug. In this situation, the longer the patient is exposed to the drug, the smaller is the pharmacologic effect for a given concentration. Therefore, after an extravascular or short-term infusion dose of the drug, the effect is smaller when serum concentrations are decreasing compared with the time when serum concentrations are increasing during the infusion or absorption phase. Accumulation of a drug metabolite that acts as an antagonist also can cause clockwise hysteresis. Counterclockwise hysteresis loops can be caused by the accumulation of an active metabolite, sensitization to the drug, or delay in time in equilibration between serum concentration and concentration of drug at the site of action. Combined pharmacokineticpharmacodynamic models have been devised that allow equilibration lag times to be taken into account.

CONCLUSIONS The availability of inexpensive, rapidly achievable serum drug concentrations has changed the way clinicians monitor drug therapy in patients. The therapeutic range for many drugs is known, and it is likely that more drugs will be monitored using serum concentrations in the future. Clinicians need to remember that the therapeutic range is merely an average guideline and to take into account interindividual pharmacodynamic variability when treating patients. Individual patients may respond to smaller concentrations or require concentrations that are much greater to obtain a therapeutic effect. Conversely, patients may show toxic effects at concentrations within or below the therapeutic range. Serum concentrations should never replace clinical judgment. Three kinetic constants determine the dosage requirements of patients. Clearance determines the maintenance dose (MD = ClCss ), volume of distribution determines the loading dose (LD = VD Css ), and half-life determines the time to steady state and the dosage interval. Several methods are available to compute these parameters. Methods available to individualize drug therapy range from clinical pharmacokinetic techniques using simple mathematical relationships that hold for all drugs that obey linear pharmacokinetics to very complex computer programs that are specific to one drug. New techniques for monitoring serum drug concentrations are available on an experimental basis and may revolutionize clinical pharmacokinetics in the future. Review Questions and other resources can be found at www.pharmacotherapyonline.com.

REFERENCES 1. Koup JR, Gibaldi M. Some comments on the evaluation of bioavailability data. Drug Intell Clin Pharm 1980;14:327–330. 2. Gibaldi M, Boyes RN, Feldman S. Influence of first pass effect on availability of drugs on oral administration. J Pharm Sci 1971;60:1338–1340. 3. Wu C-Y, Benet LZ, Hebert MF, el al. Differentiation of absorption and firstpass gut and hepatic metabolism in humans: Studies with cyclosporine. Clin Pharmacol Ther 1995;58:492–497. 4. Wagner JG, Northam JI, Alway CD, el al. Blood levels of drug at the equilibrium state after multiple dosing. Nature 1965;207:1301–1302. 5. Rowland M, Benet LZ, Graham GG. Clearance concepts in pharmacokinetics. J Pharmacokinet Biopharm 1973;1:123–136.

6. Wilkinson GR, Shand DG. A physiological approach to hepatic drug clearance. Clin Pharmacol Ther 1975;18:377–390. 7. Nies AS, Shand DG, Wilkinson GR. Altered hepatic blood flow and drug disposition. Clin Pharmacokinet 1976;1:135–155. 8. Gibaldi M, Koup JR. Pharmacokinetic concepts: Drug binding, apparent volume of distribution and clearance. Eur J Clin Pharmacol 1981;20:299– 305. 9. Bowdle TA, Patel IH, Levy RH, el al. Valproic acid dosage and plasma protein binding and clearance. Clin Pharmacol Ther 1980;28:486–492. 10. Lima JJ, Boudonlas H, Blanford M. Concentration-dependence of disopyramide binding to plasma protein and its influence on kinetics and dynamics. J Pharmacol Exp Ther 1981;219:741–747. 11. Gibaldi M, Perrier D. Pharmacokinetics, 2d ed. New York, Marcel Dekker, 1980. 12. Gibaldi M. Estimation of the pharmacokinetic parameters of the twocompartment open model from post-infusion plasma concentration data. J Pharm Sci 1969;58:1133–1135. 13. Loo JCK, Riegelman S. Assessment of pharmacokinetic constants from postinfusion blood curves obtained after IV infusion. J Pharm Sci 1970;59:53–55. 14. Wagner JG. Model-independent linear pharmacokinetics. Drug Intell Clin Pharm 1976;10:179–180. 15. Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2003 ed. Edmonds, WA, H&H Publications, 2003. 16. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. 17. Traub SL, Johnson CE. Comparison of methods of estimating creatinine clearance in children. Am J Hosp Pharm 1980;37:195–201. 18. Salazar DE, Corcoran GB. Predicting creatinine clearance and renal drug clearance in obese patients from estimated fat-free body mass. Am J Med 1988;84:1053–1060. 19. Jelliffe RW, Jelliffe SM. A computer program for estimation of creatinine clearance from unstable serum creatinine levels, age, sex, and weight. Math Biosci 1972;14:17–24. 20. Koup JR, Jusko WJ, Elwood CM, Kohli RK. Digoxin pharmacokinetics: Role of renal failure in dosage regimen design. Clin Pharmacol Ther 1975;18:9–21. 21. Matzke GR, McGory RW, Halstenson CE, Keane WF. Pharmacokinetics of vancomycin in patients with various degrees of renal function. Antimicrob Agents Chemother 1984;25:433–437. 22. Sarubbi FA, Hull JH. Amikacin serum concentrations: Predictions of levels and dosage guidelines. Ann Intern Med 1978;89:612–618. 23. Sivan SK, Bennett WM. Drug dosing guidelines in patients with renal failure. West J Med 1992;156:633–638. 24. Aronoff GR, Berns JS, Brier ME, el al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults, 4th ed. Philadelphia, American College of Physicians, 1999. 25. Pugh RNH, Murray-Lyon IM, Dawson JL, el al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646– 649. 26. Jusko WJ, Gardner MJ, Mangione A, el al. Factors affecting theophylline clearances: Age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and ethanol. J Pharm Sci 1979;68:1358–1366. 27. Thomson PD, Melmon KL, Richardson JA, el al. Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans. Ann Intern Med 1973;78:499–508. 28. Koup JR, Killen T, Bauer LA. Multiple-dose nonlinear regression analysis program: Aminoglycoside dose prediction. Clin Pharmacokinet 1983;8:456–462. 29. Sheiner LB, Beal S, Rosenberg B, el al. Forecasting individual pharmacokinetics. Clin Pharmacol Ther 1979;26:294–305. 30. Sheiner LB, Beal SL. Bayesian individualization of pharmacokinetics: Simple implementation and comparison with non-Bayesian methods. J Pharm Sci 1982;71:1344–1348. 31. Schentag JJ, Jusko WJ. Renal clearance and tissue accumulation of gentamicin. Clin Pharmacol Ther 1977;22:364–370. 32. Sawchuk RJ, Zaske DE, Cipolle RJ, el al. Kinetic model for gentamicin

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33.

34.

35. 36. 37.

38.

39.

40. 41.

42.

43.

dosing with the use of individual patient parameters. Clin Pharmacol Ther 1977;21:362–369. Bauer LA, Edwards WAD, Dellinger EP, Simonowitz DA. Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients. Eur J Clin Pharmacol 1983;24:643–647. Bauer LA, Piecoro JJ, Wilson HD, Blouin RA. Gentamicin and tobramycin pharmacokinetics in patients with cystic fibrosis. Clin Pharm 1983; 2:262–264. Sampliner R, Perrier D, Powell R, Finley P. Influence of ascites on tobramycin pharmacokinetics. J Clin Pharmacol 1984;24:43–46. Zank KE, Miwa L, Cohen JL, et al. Effect of body weight on gentamicin pharmacokinetics in neonates. Clin Pharm 1984;3:170–173. Pancorbo S, Sawchuk RJ, Dashe C, el al. Use of a pharmacokinetic model for individual intravenous doses of aminophylline. Eur J Clin Pharmacol 1979;16:251–254. Nicolau DP, Freeman CD, Belliveau PP, el al. Experience with a once-daily aminoglycoside program administered to 2184 adult patients. Antimicrob Agents Chemother 1995;39:650–655. Cantu TG, Yamanaka-Yuen NA, Lietman PS. Serum vancomycin concentrations: Reappraisal of their clinical value. Clin Infect Dis 1994;18: 533–543. Welty TE, Copa AK. Impact of vancomycin therapeutic drug monitoring on patient care. Ann Pharmacother 1994;28:1335–1339. Zimmermann AE, Katona BG, Plaisance KI. Association of vancomycin serum concentrations with outcomes in patients with gram-positive bacteremia. Pharmacotherapy 1995;15:85–91. Karam CM, McKinnon PS, Neuhauser MM, Rybak MJ. Outcome assessment of minimizing vancomycin monitoring and dosage adjustments. Pharmacotherapy 1999;19:257–266. Moellering RC Jr, Krogstad DJ, Greenblatt DJ. Vancomycin therapy in patients with impaired renal function: A nomogram for dosage. Ann Intern Med 1981;94:343–346.

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44. Blouin RA, Bauer LA, Miller DD, el al. Vancomycin pharmacokinetics in normal and morbidly obese subjects. Antimicrob Agents Chemother 1982;21:575–580. 45. Matzke GR, McGory RW, Halstenson CE, Keane WF. Pharmacokinetics of vancomycin in patients with various degrees of renal function. Antimicrob Agents Chemother 1984;25:433–437. 46. Abernethy DR, Greenblatt DJ, Smith TW. Digoxin disposition in obesity: Clinical pharmacokinetic investigations. Am Heart J 1981;102: 740–744. 47. Sarrazin E, Hendeles L, Weinberger M, et al. Dose-dependent kinetics for theophylline: Observations among ambulatory asthmatic children. J Pediatr 1980;97:825–828. 48. Tang-Liu DDS, Williams RL, Riegelman S. Nonlinear theophylline elimination. Clin Pharmacol Ther 1982;31:358–369. 49. Edwards DJ, Zarowitz BJ, Slaughter RL. Theophylline In: Evans E, Schentag JJ, Jusko WJ, eds. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. Vancouver, WA, Applied Therapeutics, 1992. 50. Vozeh S, Kewitz G, Wenk M, et al. Rapid prediction of steady-state serum theophylline concentrations in patients treated with intravenous aminophylline. Eur J Clin Pharmacol 1980;18:473–477. 51. Vozeh S, Muir KT, Sheiner LB, Follath F. Predicting individual phenytoin dosage. J Pharmacokinet Biopharm 1991;9:131–146. 52. Ludden TM, Allen JP, Valutsky WA, el al. Individualization of phenytoin dosage regimens. Clin Pharmacol Ther 1977;21:287–293. 53. Holford NHG, Sheiner LB. Understanding the dose-effect relationship: Clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 1981;6:429–453. 54. Schwinghammer TL, Kroboth PD. Basic concepts in pharmacodynamic modeling. J Clin Pharmacol 1988;28:388–394. 55. Sheiner LB, Stanski DR, Vozeh S, el al. Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d-tubocurarine. Clin Pharmacol Ther 1979;25:358.

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6 PHARMACOGENETICS Larisa H. Cavallari and Y. W. Francis Lam

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Genetic variations contribute to interpatient differences in

5 The goals of pharmacogenetics are to optimize drug effi-

2 Genetic variations occur for drug metabolism, drug trans-

6 Single-nucleotide polymorphisms are the most common

drug response.

porter, and drug target proteins, as well as diseaseassociated genes.

3 Genetic polymorphisms may be linked to drug efficacy and toxicity. 4 Pharmacogenetics is the study of the impact of genetic polymorphisms on drug response.

Great variability exists among individuals in response to drug therapy, and it is often difficult to predict how effective or safe a medication will be for a particular patient. For example, when treating a patient with hypertension, it may be necessary to try several agents or a combination of agents before achieving adequate blood pressure control with acceptable tolerability. A number of factors may influence drug response, including pharmacokinetics, age, ethnicity, and concomitant drug use. However, these alone do not predict the likelihood of drug efficacy or safety sufficiently for a given patient. For instance, identical antihypertensive therapy in two patients with similar demographic characteristics, medical histories, and concomitant drug therapy may produce inadequate blood pressure reduction in one patient and symptomatic hypotension in the other. 1 2 The observed interpatient variability in drug response may result largely from genetically determined differences in drug metabolism, drug distribution, and drug target proteins. The influence of hereditary factors on drug response was demonstrated as early as 1956 with the discovery that an inherited deficiency of glucose-6-phosphate dehydrogenase was responsible for hemolytic reactions to the antimalarial drug primaquine.1 Variations in the genetic makeup of cytochrome P450 (CYP) and other drug-metabolizing enzymes are now well recognized as causes of interindividual differences in plasma concentrations of certain drugs. These variations may have serious implications for narrow-therapeutic-index drugs such as warfarin, phenytoin, and mercaptopurine.2−4 More recently, interest has been generated in the associations between drug response and genetic polymorphisms for drug transporters such as P-glycoprotein and drug targets such as receptors, enzymes, and proteins involved in intracellular signal transduction. Genetic variations for drugmetabolizing enzymes and drug transporter proteins may influence drug disposition, thus altering pharmacokinetic drug properties. Drug target genes may alter pharmacodynamic mechanisms by affecting sensitivity to a drug at its target site. Finally, genes associated

cacy and limit drug toxicity based on an individual’s DNA. variations in the human genome.

7 Gene therapy aims to cure disease caused by genetic defects by changing gene expression.

8 Inadequate gene delivery and expression and serious adverse effects are obstacles to successful gene therapy.

with disease severity have been correlated with drug efficacy despite having no direct effect on pharmacokinetic or pharmacodynamic mechanisms.

PHARMACOGENETICS: A DEFINITION 3

4 Pharmacogenetics involves the search for genetic variations

that lead to interindividual differences in drug response. The term pharmacogenetics often is used interchangeably with the term pharmacogenomics. However, pharmacogenetics generally refers to monogenetic variants that affect drug response, whereas pharmacogenomics refers to the entire spectrum of genes that interact to determine drug efficacy and safety. For example, a pharmacogenetic study would be one that examines the influence of the β 1 -adrenergic receptor gene on blood pressure response to carvedilol. A pharmacogenomic study might examine the interaction between the CYP2D6, β 1 -, β 2 -, and α 1 -adrenergic receptor genes on carvedilol effects. To date, most studies of gene-drug responses are pharmacogenetic in nature. However, given that multiple proteins are involved in determining the ultimate response to most drugs, many investigators are now taking a more pharmacogenomic approach to elucidating genetic contributions to drug response. For simplicity, this chapter treats pharmacogenetics and pharmacogenomics as synonymous. 5 The goals of pharmacogenetics are to optimize drug therapy and limit drug toxicity based on an individual’s genetic profile. Thus pharmacogenetics aims to use genetic information to choose a drug, drug dose, and treatment duration that will have the greatest likelihood for achieving therapeutic outcomes with the least potential for harm in a given patient. The results of pharmacogenetic research ultimately will provide opportunities for clinicians to use genetic tests to predict individual responses to drug treatments, specifically to select medications for patients based on DNA profiles, and to develop 75

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1953: Watson and Crick describe DNA’s double helix. 1956: Investigators discover a genetic link to hemolytic reactions to primaquine. 1957: Motulsky proposes that “inheritance might explain many individual differences in the efficacy of drugs and in the occurrence of adverse drug reactions.” 1959: Fredrich Vogel introduces the term “pharmacogenetics.” Human Genome Project is started.

1950

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FIGURE 6–1. Timeline of genomic discoveries.

novel strategies for disease treatment and prevention based on an understanding of genetic control of cellular functions. Although there has been considerable interest in genetic influences of drug response in recent years, pharmacogenetics is not a new area. As shown in Fig. 6–1, in 1957, shortly after the discovery of a genetic predisposition toward primaquine-induced toxicity, Arno Motulsky proposed that inheritance might underlie much of the disparity among individuals in drug response.5 Fredrich Vogel first introduced the term pharmacogenetics 2 years later.6 With the advent of the Human Genome Project in 1990 came a resurgence of interest in determining genetic contributions to drug response.

HUMAN GENOME PROJECT In 1988, Congress commissioned the Department of Energy and the National Institutes of Health to plan and implement the Human Genome Project. The goal of the Human Genome Project was to determine the entire sequence of the human genome by 2005. The mapping of the human genome, which officially began in 1990, has led to a better understanding of genetic contributions to disease susceptibility. To encourage research and ultimately maximize the societal benefits of the Human Genome Project, sequence data from the Human Genome Project have been deposited into a freely accessible database run by the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov). As a consequence of these shared data, research efforts in the 1990s accelerated the discovery of genetic variations affecting treatment response and development of new treatments and preventive strategies for human disease. Largely because of advances in biotechnology, the initial working draft of the human genome sequence was completed in 2000, well ahead of schedule.7 In April of 2003, 50 years after James Watson and Francis Crick described the double-helix structure of DNA and over 2 years ahead of schedule, researchers announced the completion of the Human Genome Project.8 The final version contains 99% of the gene-containing sequence, with 99.9% accuracy. Following completion of the Human Genome Project, the National Human Genome Research Institute announced its vision for the future of genomic research with the goal of improving human health and well-being.9 One of the challenges set forth to meet this goal is to develop genome-based approaches to predict drug response. This challenge will involve the accurate, unbiased determination of genetic variants linked to drug response, advanced technology to

Renewed interest in pharmacogenetics

reduce genotyping costs, and appropriate integration of genetic testing into the therapeutic decision process. The National Human Genome Research Institute also challenges investigators to develop new, genebased approaches to disease management, which will require a thorough understanding of genetic determinants of disease susceptibility and progression.

GENETIC CONCEPTS The human genome contains approximately 3 billion nucleotide bases, which code for approximately 30,000 genes. Two purine nucleotide bases, adenine (A) and guanine (G), and two pyrimidine nucleotide bases, cytosine (C) and thymidine (T), are present in DNA, with purines and pyrimidines always pairing together as A-T and C-G in the two strands that make up the DNA structure. Most nucleotide base pairs are identical from person to person, with only 0.1% contributing to individual differences. According to the central dogma, when one strand of DNA is transcribed into RNA and translated to make proteins, three consecutive nucleotides form a codon. Each codon specifies an amino acid or amino acid chain termination. For example, the nucleotide sequence, or codon, GGA specifies the amino acid glycine. The genetic code has substantial redundancy, in that two or more codons code for the same amino acid. For example, both GGA and GGC code for glycine. Amino acids are the basic constituents of proteins, which mediate all cellular functions. Only 20 different amino acids, in various arrangements, form the basic units of all the proteins in the human body. A gene is a series of codons that specifies a particular protein. Genes contain several regions: exons that encode for the final protein, introns that consist of intervening noncoding regions, and promoter regions that regulate gene transcription. At each gene locus, an individual carries two alleles, one from each parent. An allele is defined as the sequence of nucleic acid bases at a given gene chromosomal locus. Two identical alleles make up a homozygous genotype, and two different alleles make up a heterozygous genotype. A phenotype refers to the outward expression of the genotype.

TYPES OF GENETIC VARIATIONS Genetic variations occur as either rare defects or polymorphisms. Polymorphisms are defined as variations occurring at a frequency of

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at least 1% in the human population. For example, the genes encoding the CYP enzymes 2A6, 2C9, 2C19, 2D6, and 3A4 are polymorphic, with functional mutations of greater than 1% occurring in different ethnic groups. In contrast, rare mutations occur in less than 1% of the population and cause inherited diseases such as cystic fibrosis, hemophilia, and Huntington’s disease. Common diseases, such as essential hypertension and diabetes mellitus, are polygenic in that multiple genetic polymorphisms likely interact to contribute to the disease susceptibility. 6 Single-nucleotide polymorphisms, abbreviated as SNPs and pronounced “snips,” are the most common genetic variations in human DNA, occurring approximately once in every 1000 base pairs. Approximately 3.7 million SNPs have been mapped thus far in the human genome. SNPs occur when one nucleotide base pair replaces another, as illustrated in Fig. 6–2. Thus SNPs are single-base differences that exist between individuals. Nucleotide substitution results in two possible alleles. One allele, typically either the most commonly occurring allele or the allele originally sequenced, is considered the wild type, and the alternative allele is considered the variant allele. A SNP may change the codon resulting in amino acid substitution, which may or may not alter gene expression. For example, in Fig. 6–2, guanine (G) is substituted for adenine (A) at nucleotide 46. This results in the substitution of glycine for arginine at amino acid position 16. SNPs such as this that result in amino acid substitution are referred to as nonsynonymous. SNPs that do not result in amino acid substitution are called synonymous. Referring to a previous example of redundancy in the genetic code, replacement of adenine (A) with cytosine (C) in the codon GGA is an example of a synonymous SNP because the resulting amino acid is still glycine. Synonymous SNPs usually are abbreviated based on the nucleotides involved and the nucleotide base position. For example, A1166C or A1166→C indicates that cytosine is substituted for adenine at nucleotide position 1166 of a given gene region. Nonsynonymous SNPs usually are designated by the amino acids and codon involved. For example, Arg16Gly or

A. "Wild type" allele Codon Nucleotide

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Arg16→Gly indicates that glycine is substituted for arginine at codon 16. If a SNP changes the expression of a protein that contributes to drug response, it may alter a patient’s sensitivity to a drug or predispose a patient to adverse reactions to drug therapy. Other examples of genetic variants include r

r

r

r

r r

Insertion-deletion polymorphisms, in which a nucleotide or nucleotide sequence is either added to or deleted from a DNA sequence Tandem repeats, in which a nucleotide sequence repeats in tandem (i.e., if “AG” is the nucleotide repeat unit, “AGAGAGAGAG” is a five-tandem repeat) Frameshift mutation, in which there is an insertion/deletion polymorphism, and the number of nucleotides added or lost is not a multiple of 3, resulting in disruption of the gene’s reading frame Defective splicing, in which an internal polypeptide segment is abnormally removed, and the ends of the remaining polypeptide chain are joined Aberrant splice site, in which processing of the protein occurs at an alternate site Premature stop codon polymorphisms, in which there is premature termination of the polypeptide chain by a stop codon (specific sequence of three nucleotides that do not code for an amino acid but rather specify polypeptide chain termination)

For more detailed information about genetic concepts, refer to the recommended genetics textbook.10 As mentioned earlier, most common diseases are polygenic in nature. For example, independent studies have demonstrated associations between gene variants for proteins involved in the reninangiotensin system, sympathetic nervous system, and renal sodium transport and the risk for essential hypertension.11 Environmental factors are also well-known risk factors for diseases such as hypertension and often interact with genetic factors to influence disease susceptibility and progression. Given the complex pathophysiology of most common diseases, genes linked to disease susceptibility will not be discussed in this chapter. Rather, this chapter will focus on genetic variations linked to responses to pharmacologic agents.

19

AGA AGC CAT Ser

PHARMACOGENETICS

POLYMORPHISMS IN GENES FOR DRUG-METABOLIZING ENZYMES 3 Polymorphisms in the drug-metabolizing enzymes represent the

B. "Variant" allele Codon Nucleotide Amino acid

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Pro

Asn

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GCG . . .

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FIGURE 6–2. Nucleotide sequence of the β 2 -adrenergic receptor gene from codons 13 through 19. A. Nucleotide sequence of the wild-type allele with adenine (A) at nucleotide position 46 (underlined ) located in codon 16 of the β 2 -adrenergic receptor gene. The AGA codon designates the amino acid arginine (Arg), with an average frequency of 39% in the human population. B. Nucleotide sequence of the variant allele with guanine (G) at nucleotide position 46 (underlined ), located in codon 16. The GGA codon designates the amino acid glycine (Gly), which occurs at an average frequency of 61%. Although the Arg16 polymorphism occurs less commonly than the Gly16 polymorphism, it is referred to as the wild type because it was identified first.

first recognized and, so far, the most documented examples of genetic variants with consequences in drug response and toxicity. The major phase I enzymes are the CYP superfamily of isoenzymes. N-acetyltransferase, thiopurine S-methyltransferase, and glutathione S-transferase are examples of phase II metabolizing enzymes that exhibit genetic polymorphisms. Table 6–1 lists selected examples of polymorphic metabolizing enzymes, corresponding drug substrates, and the consequences of altered enzyme function as a result of gene mutation.

CYTOCHROME P450 ENZYMES Currently, 57 different CYP isoenzymes have been documented to be present in humans, with 42 involved in the metabolism of xenobiotics, including drugs, and endogenous substances such as steroids and prostaglandins.12 Fifteen of these isoenzymes are known to be involved in the metabolism of xenobiotics, and functional

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BASIC CONCEPTS TABLE 6–1. Selected Examples of Genetic Polymorphisms in Drug-Metabolizing Enzymes and Response to Drug Therapy Genetic Variants/Genes CYP2D6 ∗4, CYP2D6 ∗5 CYP2D6 ∗2 (n >l) CYP2D6 ∗10 CYP2C9 ∗3 CYP2C9, CYP2C19 CYP2C19 Glutathione-S -transferase Thiopurine methyltransferase N-Acetyltransferase slow acetylator

UDP-glucuronosyltransferase

Drug Perhexiline Codeine Tramadol Tricyclic antidepressants (e.g., desipramine, nortriptyline) Antipsychotics (e.g., haloperidol) Warfarin Phenytoin Omeprazole Primaquine Mercaptopurine Isoniazid Procainamide Hydralazine Sulfonamides Irinotecan

genetic polymorphism has been discovered for CYP2A6, CYP2C9, CYP2C19, CYP2D6,13 and more recently, CYP3A4/5.14,15 A polymorphism in the regulatory region of the gene encoding for CYP1A216 has been identified, but its functional importance remains to be determined.

CYP2D6 Polymorphisms in the CYP2D6 gene are the best characterized of the CYP variants. Over the years, at least 48 gene variants and 53 alleles have been identified in the CYP2D6 gene.17 Nevertheless, the CYP2D6 extensive-metabolizer (EM) and poor-metabolizer (PM) phenotypes (outward expression of genotypes) can be predicted with up to 99% confidence with six genotypic variants. CYP2D6*1 is considered the wild-type variant and exhibits normal enzyme activity. CYP2D6*2 has the same activity as CYP2D6*1 but is capable of duplication or amplification. Both these variants are present in EMs. The CYP2D6*4 (defective splicing) and CYP2D6*5 (gene deletion) variants are present in PMs and result in an inactive enzyme and absence of enzyme, respectively. The predominant variants in people of Asian and African heritage are CYP2D6*10 (Pro34Ser) and CYP2D6*17 (Arg296Cys), respectively, both resulting in single-amino-acid substitution and consequent reduction in enzyme activity. Poor CYP2D6 metabolizers carry two defective alleles, such as CYP2D6*3, CYP2D6*4 (more common), CYP2D6*5, and CYP2D6*6, resulting in a total absence of active enzyme and an impaired ability to metabolize CYP2D6-dependent substrates. Examples of CYP2D6 substrates include neuroleptic medications, antidepressants such as tricyclic antidepressants and mianserin, antiarrhythmic drugs such as propafenone, and β-adrenergic antagonists such as metoprolol (see Table 6–1). Depending on the importance of the affected CYP2D6 pathway to overall drug metabolism and the drug’s therapeutic index, clinically significant side effects may occur in PMs as a result of elevated parent drug concentrations. For example, compared with EMs, PMs have been shown to develop

Drug Effect Associated with Polymorphism Neuropathy18 Significant reduction in analgesic effect22,23 Inadequate antidepressant response29,30

Elevated plasma concentrations and exaggerated responses33 Hemorrhage2 Phenytoin toxicity3 Improved cure rates for Helicobacter pylori 41 Hemolytic reactions1 Bone marrow depression4 More prone to peripheral neuropathy119 More prone to development of SLE-like syndrome120,121 Increased hematologic and gastrointestinal adverse reactions122 Increased severity of diarrhea and neutropenia in carrier of (TA)7 TAA allele59

neuropathy after treatment with the antianginal agent perhexiline18 and have experienced more adverse effects with propafenone19 and neuroleptic agents such as perphenazine.20,21 The therapeutic implication of CYP2D6 polymorphism is different if the substrate in question is a prodrug. In this case, PMs would not be able to convert the drug into the therapeutically active metabolite. Two examples of prodrugs dependent on CYP2D6-mediated conversion to active forms are codeine and tramadol. Codeine and tramadol are converted by CYP2D6 to morphine and O-desmethyltramadol, respectively, and thus poor CYP2D6 metabolizers would experience little or no analgesic relief after taking these drugs.22,23 Although PMs are at a disadvantage from the standpoint of drug toxicity and lack of efficacy for most CYP2D6 substrates and prodrugs, data suggest that they may be “protected” from abusing opiates such as codeine, oxycodone, and hydrocodone. This is primarily based on an observation that no PMs were found among opiate-dependent subjects, which likely reflects their inability to convert these drugs of abuse into their respective “pharmacologically active” moieties.24 Given the reduced potential for opiate abuse among CYP2D6 PMs, investigators have used daily doses of fluoxetine 20 mg, a CYP2D6 inhibitor, as adjunctive therapy in the management of opiate abuse to “metabolically convert” drug abusers who are EMs to PMs.25 Furthermore, the potential and magnitude of drug interactions involving competitive inhibition of CYP2D6 are much greater in EMs versus PMs, who have either deficient or absent enzyme activity.26,27 For example, Hamelin and colleagues28 showed that in EMs, but not PMs, hemodynamic responses to metoprolol (a CYP2D6 substrate) were pronounced and prolonged during concomitant diphenhydramine administration. Thus potent CYP2D6 inhibitors may reduce the metabolic capacity of EMs significantly so that EMs appear phenotypically as PMs. Patients who are EMs have a wide range of CYP2D6 activity, with ultrarapid metabolizers (UMs) on one end of the spectrum and subjects with diminished activity on the other end. Both have clinical implications in terms of dosage adjustment for CYP2D6 substrates.

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UMs carry a duplicated or amplified mutant allele, resulting in two or multiple copies of the functional CYP2D6*2 allele, and therefore show very high CYP2D6 activity. Nontherapeutic plasma concentrations of nortriptyline, a CYP2D6 substrate, were observed in a UM given normal doses of the drug.29 The CYP2D6 enzyme converts nortriptyline to 10-hydroxynortriptyline, and one study demonstrated a directly proportional relationship between the number of functional CYP2D6 genes and the concentration of 10-hydroxynortriptyline after nortriptyline ingestion.30 A patient with three copies of CYP2D6*2 was shown to require nortriptyline doses three- to fivefold higher than normally recommended to achieve therapeutic plasma concentrations (50–150 mcg/mL).29,31 In the same report, another patient with duplicated CYP2D6*2 required twice the usual recommended daily dose (300 mg versus 25–150 mg) to achieve adequate therapeutic response.31 The UM genotype also has been reported to affect the potential for drug interaction with paroxetine, a CYP2D6 substrate as well as a potent CYP2D6 inhibitor.32 The high prevalence of CYP2D6*10 (associated with lower enzyme activity) in the Asian population provides a biologic and molecular explanation for the higher drug concentrations and/or lower dosage requirements of neuroleptic medications and mianserin in people of Asian heritage.33,34 The widespread presence of the CYP2D6*17 variant among people of African heritage suggests that native African populations would metabolize CYP2D6 substrates at a slower rate than do other ethnic or racial groups.35,36 However, there are no current genotype- and phenotype-based data to document the need for prescribing lower doses of psychotropics and other CYP2D6 substrates in native African populations. In addition to the therapeutic implications of genetic polymorphisms, a recent study showed that the CYP2D6 polymorphism also has an economic impact.37 The annual cost of treating UMs and PMs (carriers of two nonfunctional CYP2D6 alleles) was $4,000–$6,000 higher than the cost of treating EMs or intermediate metabolizers (carriers of one nonfunctional allele and one allele associated with diminished activity). The cost of genotyping can be considerably less than that incurred in a patient with a serious adverse drug reaction. Brockmoller and colleagues38 recently suggested how CYP2D6 genotyping can be used to achieve higher therapeutic success with the CYP2D6 substrate haloperidol.

CYP2C19 The principal defective alleles for the CYP2C19 genetic polymorphism are CYP2C19*2 (aberrant splice site) and CYP2C19*3 (premature stop codon), resulting in inactive CYP2C19 enzymes and the PM phenotype. The clinical implication of the CYP2C19 polymorphism has not been examined as extensively as that of the CYP2D6 polymorphism. However, PMs for the CYP2C19 polymorphism showed more than a 12-fold increase in the area under the curve (AUC) of the CYP2C19 substrate omeprazole compared with EMs.39 In a separate study, the steady-state AUC of omeprazole and other CYP2C19 substrate proton-pump inhibitors was 5-fold higher in PMs versus EMs.40 The presence of a defective CYP2C19 allele has been associated with improved Helicobacter pylori cure rates after dual (omeprazole and amoxicillin)41 or triple therapy (omeprazole, amoxicillin, and clarithromycin) with omeprazole,42 as well as with lansoprazole.43 This difference likely reflects the higher achievable intragastric pH in the PM group.44 The cure rate achieved with dual therapy was 100% in PMs compared with 60% and 29% in heterozygous and homozygous EMs, respectively.41 In two studies, EMs had H. pylori

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eradication rates of 41% with dual therapy and 74% to 83% with triple therapy.42,43 In contrast, both dual- and triple-therapy regimens produced 100% cure rates in all 15 PMs included in the same studies. Interestingly, EMs who failed initial triple therapy (lansoprazole, clarithromycin, and amoxicillin) and were retreated with high-dose lansoprazole (30 mg four times daily) and amoxicillin achieved a 97% H. pylori eradication.45 Similar to the CYP2D6 polymorphism, people of Asian heritage also metabolize most CYP2C19 substrates at a slower rate than do Caucasians.46 This is a reflection of a higher prevalence of both PMs (13% to 20% versus 2% to 6% in Caucasians) and heterozygotes for the defective CYP2C19 allele in Asians.47 This genotypic difference may explain the practice of prescribing lower diazepam dosages for patients of Chinese heritage.48

CYP2C9 Warfarin, phenytoin, and tolbutamide are examples of narrowtherapeutic-index drugs that are metabolized by CYP2C9. Warfarin is a racemic mixture, and the S-isomer, which possesses about three times the anticoagulant effects of the R-isomer, is metabolized by CYP2C9. CYP2C9*2 and CYP2C9*3 are the two most common CYP2C9 variants, and both exhibit single-amino-acid substitutions at positions critical for enzyme activity.49 This could have clinically important consequences in warfarin-treated patients. For example, a 90% reduction in S-warfarin clearance was reported in CYP2C9*3 homozygotes compared with subjects homozygous for the wild-type variant.50 In another study, an overrepresentation of CYP2C9 mutant alleles was observed in 81% of patients requiring low-dose warfarin therapy (≤1.5 mg/day).2 The low-dose group was reported to have more difficulty with warfarin induction, requiring longer hospital stays to stabilize the warfarin regimen and experiencing a higher incidence of bleeding complications. In addition, a profound therapeutic response to usual doses of warfarin was observed in a patient homozygous for the CYP2C9*3 allele, necessitating dose reduction to 0.5 mg/day.51

CYP2A6 A recent polymorphism was characterized for CYP2A6, with several variants identified: CYP2A6*1 (wild type), CYP2A6*2 (singleamino-acid substitution), CYP2A6*3 (gene conversion), and three gene-deletion alleles: CYP2A6*4A, CYP2A6*4B, and CYP2A6*4D.52 Deletion of the CYP2A6 gene is very common in Asian patients,52,53 which likely accounts for the dramatic difference in the frequency of PMs in Asian (20%) versus European and Caucasian populations (≤1%). Nicotine is metabolized by CYP2A6, and the clinical relevance of the CYP2A6 polymorphism lies in management of tobacco abuse.54 Investigators reported that nonsmokers were more likely to carry the defective CYP2A6 allele than were smokers. Smokers who had the defective CYP2A6 allele smoked fewer cigarettes and were more likely to quit.54 The inability to metabolize nicotine, secondary to the presence of a defective CYP2A6 allele, likely leads to enhanced nicotine tolerance and increased adverse effects from nicotine. Based on these observations, CYP2A6 inhibition may have a role in the management of tobacco dependency.55

CYP3A4/5 Within the CYP3A subfamily, at least three isoenzymes, namely, CYP3A4, CYP3A5, and CYP3A7, have been characterized. Despite

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as much as 40-fold interindividual variability in its expression, functional CYP3A4 is expressed in most adults. CYP3A4 variants with amino acid substitutions in exons 7 and 12 have been associated with altered catalytic activity for a CYP3A4 substrate, nifedipine.14 The clinical importance of this finding needs to be further elucidated and confirmed. CYP3A5 is reported to be polymorphic in 60% of AfricanAmericans and 33% of Caucasians. In contrast to individuals with the CYP3A5*1 allele, subjects with variant alleles such as CYP3A5*3 (aberrant splice site) in intron 3 have no functional CYP3A5 enzyme.15 It remains unknown whether there are clinically used drugs that are substrates for CYP3A5 but not CYP3A4 and vice versa.

PHASE II METABOLIZING ENZYMES The clinical relevance of genetic polymorphisms in thiopurineS-methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), and UDP-glucuronosyl transferase (UGT) enzymes has been demonstrated in the treatment of cancer.4,56,57 The TPMT gene has three mutant alleles: TPMT*3A (the most common), TPMT*2, and TPMT*3C. Patients who are homozygous or heterozygous for the TPMT mutant alleles are at higher risk for developing serious anemias during mercaptopurine treatment.4 DPD mediates the metabolism of 5-fluorouracil, and patients with a defective allele of the DPD gene cannot metabolize 5-fluorouracil and thus may experience enhanced drug-related neurotoxicity.56 The camptothecin derivative irinotecan (CPT-11) is activated by carboxylesterase to SN-38, which is a potent topoisomerase I inhibitor. SN-38 is inactivated by glucuronidation via the polymorphic UDP-glucouronosyl transferase (UGT1A1) enzyme, which may play a role in CPT-11–related toxicity. A polymorphism in the promoter region of the UGT1A1 gene results in the (TA)7 TAA allele, which possesses lower enzyme activity than the wild-type (TA)6 TAA allele. A patient homozygous for the (TA)7 TAA allele had impaired SN-38 glucuronidation.57 Since abnormally high SN-38 concentrations have been associated with diarrhea,58 likely resulting from increased SN-38 excretion into the gut lumen, patients with the (TA)7 TAA allele may be predisposed to developing diarrhea with usual CPT-11 doses. This observation has been confirmed in a prospective clinical trial that demonstrated more severe diarrhea and neutropenia in patients who are homozygous or heterozygous carriers of the (TA)7 TAA allele.59

POLYMORPHISMS IN DRUG TRANSPORTER GENES Certain membrane-spanning proteins facilitate drug transport across the gastrointestinal tract, drug excretion into the bile and urine, and drug distribution across the blood-brain barrier. Genetic variations for drug transport proteins may affect the distribution of drugs that serve as substrates for these proteins and alter drug concentrations at their therapeutic sites of action. P-glycoprotein is one of the most recognized of the drug transport proteins that exhibit genetic polymorphism. P-glycoprotein is an energy-dependent transmembrane efflux pump encoded by the multidrug-resistance 1 (MDR-1) gene. P-glycoprotein was first recognized for its ability to actively export anticancer agents from cancer cells and promote multidrug resistance to cancer chemotherapy. Later, it was discovered that P-glycoprotein is also widely distributed on normal cell types, including intestinal enterocytes, hepatocytes, renal proximal tubule cells, and endothelial cells lining the blood-brain barrier. At these locations, P-glycoprotein serves a protective role by transporting toxic substances or metabolites out of cells. P-glycoprotein also affects the distribution of some

Anthracyclines Vinca alkaloids Digoxin Cyclosporine Protease inhibitors Dexamethasone

Extracellular

Plasma membrane NH2

COOH

Intracellular

P-glycoprotein FIGURE 6–3. Active transport of drugs out of the cell by P-glycoprotein.

nonchemotherapeutic agents, including digoxin, the immunosuppressants cyclosporine and tacrolimus, and antiretroviral protease inhibitors (Fig. 6–3). Increased intestinal expression of P-glycoprotein can limit the absorption of P-glycoprotein substrates, thus reducing their bioavailability and preventing attainment of therapeutic plasma concentrations. Conversely, decreased P-glycoprotein expression may result in supratherapeutic plasma concentrations of relevant drugs and drug toxicity. CLINICAL CONTROVERSY Much of the data on individual variations in the multidrug resistance gene and response to P-glycoprotein substrates are inconsistent and even conflicting. The combination of multiple variations in the multidrug resistance gene eventually may prove to be a stronger predictor of drug response than any individual variation. A number of polymorphisms have been identified in the promoter and exon regions of the MDR-1 gene. Common SNPs occur in exons 12 (C1236T), 21 (G2677T), and 26 (C3435T). The exon 21 and 26 SNPs have been associated with intestinal MDR-1 expression, P-glycoprotein activity, and digoxin plasma concentrations in healthy volunteers.60 These data imply that the MDR-1 genotype may be useful in predicting digoxin concentrations in patients with atrial arrhythmias or heart failure and in choosing initial digoxin doses accordingly. The MDR-1 exon 26 polymorphism also has been associated with plasma concentrations and clinical effects of protease inhibitors in patients infected with the human immunodeficiency virus (HIV).61 Specifically, following therapy with efavirenz or nelfinavir for 6 months, a greater rise in CD4 cell counts was observed in individuals with the exon 26 TT genotype compared with CC homozygotes. This findings suggest a role for MDR-1 genotyping in predicting hematologic responses to protease inhibitors and individualizing antiretroviral drug therapy for HIV-infected patients. Other examples of polymorphic drug transporter proteins include the dipeptide transporter, organic anion and cation transporters, and L-amino acid transporter. Their effects on drug distribution are the focus of ongoing research.

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POLYMORPHISMS IN DRUG TARGET GENES 5 Genetic polymorphisms occur commonly for drug target pro-

teins, including receptors, enzymes, and intracellular signaling proteins. Drug target genes may work in concert with genes that affect pharmacokinetic properties to contribute to overall drug response. Table 6–2 provides examples of drug target genes linked to drug response in clinical studies. The following section highlights some of the receptor, enzyme, and cell-signaling protein genes shown to influence the efficacy and safety of various pharmacologic agents.

RECEPTOR GENOTYPES AND DRUG RESPONSE The β 1 - and β 2 -adrenergic receptor genes have been the focus of much research into genetic determinants of responses to β-agonists and β-antagonists. β 1 -Receptors are located in the heart and kidney, where they participate in blood pressure regulation. Two nonsynonymous SNPs commonly occur in the β 1 -receptor gene at codons 49 (Ser→Gly) and 389 (Arg→Gly), and there is evidence of their involvement in blood pressure control.62 Recently, investigators examined the influence of the β 1 -receptor gene on blood pressure response to β 1 -receptor blockade with metoprolol. Hypertensive patients who were homozygous for both the Ser49 and Arg389 alleles were found to have greater reductions in diastolic blood pressure with metoprolol monotherapy compared with carriers of the Gly49 and/or Gly389 alleles.63 These data suggest that β 1 -receptor genotype may be an important determinant of blood pressure response to β-blockers in the management of hypertension. Given that a significant percentage of hypertensive patients fail to derive adequate blood pressure reduction with β-blocker monotherapy,64 the ability to predict the likelihood of response based on genotype would have important clinical implications. Specifically, β-blockers could be started in patients expected to respond well to this drug class based on their β 1 -receptor genotype, whereas other classes of antihypertensive agents could be used in those expected to respond poorly to β-blockers.

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β 2 -Receptors are located on vascular and bronchial smooth muscle cells, where they mediate vasodilation and bronchodilation, respectively, on exposure to the β 2 -receptor agonists. Inhaled β 2 -agonists are the most effective agents for the acute reversal of bronchospasm; however, the magnitude of their effects varies substantially among asthmatic patients.65 More than 11 SNPs have been identified in the β 2 -receptor gene, 3 of which occur frequently and result in amino acid changes. Two common nonsynonymous SNPs are found in the gene’s coding block region, at codons 16 and 27, and a third occurs upstream from the coding block in the gene’s promoter region. Three groups of investigators have examined the influence of the β 2 -receptor codon 16 (Arg→Gly) polymorphism on vasodilatory response to β 2 -agonist therapy. Two of these groups reported greater vasodilation with the homozygous Arg genotype, whereas the third reported greater response with the Gly/Gly form.66−68 A fourth group of investigators found that the combination of SNPs in the gene’s coding block and promoter region was a better determinant of β 2 agonist response than any individual SNP.69 These data suggest that an individual SNP in the β 2 -receptor gene is an insufficient predictor of β 2 -agonist effects and that multiple receptor gene variations more accurately correlate with β 2 -agonist response. Clozapine is an example of a drug for which there is evidence that multiple receptor genes interact to influence its effects. Clozapine is an atypical antipsychotic used in the treatment of schizophrenia. Because of its potential to produce agranulocytosis in 0.5% to 2% of treated patients, clozapine is reserved for schizophrenic patients who are unresponsive to other drug therapies. However, only 30% to 60% of patients with refractory schizophrenia respond to clozapine.70 Clozapine’s effects are believed to be mediated through dopaminergic, serotoninergic, adrenergic, and histaminergic receptors in the central nervous system.71 Although several studies have demonstrated relationships between single genetic variants for these receptor subtypes and clozapine response, the data are inconsistent.72 In a more recent study, a combination of six polymorphisms in the histamine and serotonin 2A and 2C receptor genes and the serotonin transporter gene

TABLE 6–2. Genetic Polymorphisms in Drug Targets and Response to Drug Therapy Gene

81

Drug/Drug Class

Drug Effect Associated with Polymorphism

α-Adducin

Hydrochlorothiazide

ACE

ACE inhibitors

Angiotensinogen β1 -Adrenergic receptor β 2 -Adrenergic receptor Bradykinin B2 receptor Dopamine D2 receptor Dopamine D3 receptor Estrogen receptor Inhibitory GTP-binding protein β 3 subunit 5-Lipoxygenase Combination of H2 , 5HT2A , 5-HT2C , 5-HT transporter Stimulatory G-protein α subunit

ACE inhibitors β-Blockers β 2 -Agonists ACE inhibitors Levodopa Levodopa, neuroleptics Estrogen Antidepressants

Blood pressure reduction91 and clinical outcomes92 Blood pressure reduction,74 regression of left ventricular hypertrophy,77 renoprotective effects,123 drug-induced cough81 Blood pressure reduction80 Blood pressure lowering63 Bronchodilation69,124−126 Cough127 Peak-dose dyskinesias128 Akathisia129 Bone mineral density130 Antidepressant response88,89

Leukotriene modifier Clozapine

Change in FEV1 131 Response in schizophrenia70

β-Blockers

Blood pressure lowering85

Key: ACE, angiotensin-converting enzyme; H, histamine; FEV1 , forced expiratory volume in 1 second; 5-HT, serotonin.

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were 77% predictive of antipsychotic response to clozapine.70 These findings imply that, similar to other drug target gene–drug response relationships, a combination of polymorphisms, rather than any single polymorphism, provides a more accurate prediction of clozapine response.

ENZYME GENES AND DRUG RESPONSE The angiotensin-converting enzyme (ACE) is an example of an enzyme with genetic contributions to drug response. An insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene results in the presence or absence of a 287-base-pair fragment. This polymorphism has been linked consistently to plasma concentrations of ACE, the enzyme responsible for the conversion of angiotensin I to the potent vasoconstrictor angiotensin II.73 ACE inhibitors are among the most commonly prescribed antihypertensive agents. However, ACE inhibitors fail to sufficiently lower blood pressure in over 50% of patients.64 Given its association with ACE concentrations, a number of investigators have examined whether the ACE I/D polymorphism contributes to the interpatient variability in ACE inhibitor response. To date, much of the data with the ACE gene and response to ACE inhibitors are inconsistent and even conflicting. While some studies have demonstrated greater blood pressure reductions with ACE inhibitor therapy among individuals with the ACE DD genotype, others have shown greater blood pressure reductions with the II genotype.74−76 Still other investigators have reported no association between the ACE I/D genotype and the antihypertensive effects of ACE inhibition.77,78 Numerous proteins are involved in the complex signaling pathway of the renin-angiotensin system, and multiple genetic polymorphisms have been identified for many of these proteins (Fig. 6–4). Thus one explanation for the inconsistent and conflicting ACE gene– drug response data is that a single polymorphism contributes little to the overall response to ACE inhibition. Rather, response to ACE inhibition is best determined by a combination of multiple polymorphisms occurring in multiple genes involved in the renin-angiotensin

pathway. Indeed, other renin-angiotensin system genes, including the angiotensinogen and aldosterone synthase genes, have been correlated with antihypertensive responses to ACE inhibitors and angiotensin receptor blockers,79,80 suggesting that ACE, angiotensinogen, aldosterone synthase, and probably other genes encoding for renin-angiotensin system proteins interact to influence ACE inhibitor response. Thus, before genotype may be used as a predictor of response to renin-angiotensin antagonists, the combination of genetic variants in the renin-angiotensin system that best determines drug response first must be elucidated. The ACE gene also may predict the likelihood of adverse reactions of ACE inhibitors. Approximately 10% of patients receiving ACE inhibitors develop a cough that persists for the duration of treatment.81 The ACE I/D polymorphism was correlated with the ACE inhibitor–induced cough in one small study.81 However, a larger study found no such association.82 Given the proven benefits of ACE inhibitors in diseases such as hypertension, diabetes, and heart failure, it is unlikely that genes associated with the ACE inhibitor–induced cough, even if validated, would influence drug prescribing. This is so because the development of a cough during ACE inhibitor treatment may be bothersome and a potential threat to drug adherence, but it is unlikely that the cough will result in any serious outcomes. Thus one should not deprive a patient of the potential benefits from ACE inhibitor therapy on the basis of a genetic predisposition for drug-induced cough. On the other hand, in cases where an adverse drug effect may have serious consequences, knowledge of a genetic propensity for such an effect would be of great clinical significance. Angioedema is an example of a serious and potentially life-threatening adverse drug effect that may have genetic influences. Angioedema is estimated to occur in approximately 0.1% to 0.2% of ACE inhibitor–treated patients.83 Given its infrequent occurrence, genetic data from a relatively large number of affected patients would be necessary to establish a definite genetic cause for ACE inhibitor–induced angioedema. Investigators for many multicenter clinical drug trials are now asking study participants to provide consent for the collection of genetic material so that

Angiotensinogen (78) Bradykinin B1 receptor (36)

Renin (27) Bradykinin

Angiotensin I ACE (101) Angiotensin II

AT1 receptor (131)

FIGURE 6–4. Single-nucleotide polymorphisms (SNPs) identified for reninangiotensin system genes. The number of polymorphisms identified for each protein is shown in parenthesis after the protein name (http://snp.cshl.org). ACE, angiotensinconverting enzyme; ARB, angiotensin receptor blocker.

G-protein signaling pathways (numerous)

Cellular response

Bradykinin B2 receptor (86)

ACE inhibitor Inactive fragments

ARB

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in the future, genetic contributions to rare but serious adverse drug effects may be elucidated. There is evidence of racial differences in antihypertensive response to ACE inhibitors. Specifically, African-Americans in general are believed to have diminished antihypertensive responses to ACE inhibitors compared with Caucasians.64 The frequencies of many SNPs in the renin-angiotensin system vary between African-American and white populations and may contribute to the observed racial differences in ACE inhibitor response.84 Indeed, most racial differences in drug response probably can be attributed to racial differences in genotype frequencies, although this is yet to be determined.

that hydrochlorothiazide produced greater blood pressure reductions in hypertensive individuals with at least one 460Trp allele (Trp/Trp homozygotes or Gly/Trp heterozygotes) compared with Gly/Gly homozygotes.91 In a subsequent population-based case-control study, hypertensive patients with at least one 460Trp allele appeared to derive superior protection against stroke and myocardial infarction from diuretic therapy compared with treatment with alternative agents.92 These findings suggest that the α-adducin genotype may be an important determinant not only of antihypertensive response to diuretic therapy but also, more important, of the effects of diuretic therapy on hypertension-related target-organ damage.

GENES FOR INTRACELLULAR SIGNALING PROTEINS, ION TRANSPORTERS, AND DRUG RESPONSE

DISEASE-ASSOCIATED GENES

Cellular responses to many drugs are mediated through GTP-binding proteins also called G-proteins. The β 1 -adrenergic receptor is an example of a G-protein–coupled receptor in which a stimulatory G-protein (Gs -protein) couples the receptor to intracellular signaling mechanisms to elicit a cellular response (Fig. 6–5). Receptor-coupled Gs -proteins contain α, β, and γ subunits that mediate the activation of adenylyl cyclase and the generation of cyclic AMP following receptor stimulation. A SNP in the α subunit of Gs -protein has been linked to the blood pressure response to β-blockers.85 Whether the Gs -protein α-subunit gene interacts with the β 1 -adrenergic receptor gene or other intracellular signaling-protein genes to determine β-blocker response remains to be determined. Disturbances in G-protein–mediated signal transduction have been implicated in the pathophysiology of depressive disorders.86 In addition, data suggest that abnormalities in signal-transduction proteins contribute to antidepressant drug response.87 A common SNP (C825→T) occurs in the gene for the inhibitory G-protein (Gi -protein) β 3 subunit and has been associated with enhanced intracellular signal transduction. In a study of patients treated with either tricyclic antidepressants or serotonin reuptake inhibitors, the TT genotype was correlated with greater improvement in depression symptoms,88,89 implying that the Gi -protein β 3 subunit gene may have a future role in therapeutic decisions for depression management. There is evidence that the gene for α-adducin, a cytoskeletal protein involved in renal tubular ion transport, contributes to thiazide diuretic response. Substitution of tryptophan for glycine at codon 460 of the α-adducin gene has been associated with enhanced renal tubular sodium reabsorption.90 Two separate studies demonstrated

␤-blocker

Cell membrane

␤-receptor

␥ Gs protein

␤

Adenylyl cyclase

␣ ATP

cAMP

FIGURE 6–5. β 1 -receptor coupled to intracellular signaling mechanisms by a stimulatory G-protein.

Numerous genes have been correlated with disease outcomes, and many of these have been found subsequently to influence response to pharmacologic disease management. These gene–drug response associations often occur despite the lack of a direct effect on pharmacokinetic or pharmacodynamic drug properties. Examples of such disease-associated genes are given below.

FACTOR V AND PROTHROMBIN GENES AND ORAL CONTRACEPTION The use of oral contraceptives is associated with an increased risk for developing thromboembolic disorders, including deep venous thrombosis, pulmonary embolism, and thrombotic stroke. Variations in the genes for the coagulation factors prothrombin and factor V Leiden also have been identified as risk factors for thromboembolic disorders.93,94 In case-control studies, the presence of a factor V Leiden or prothrombin gene variation significantly increased the risk for deep vein thrombosis and cerebral vein thrombosis among oral contraceptive users.93,94 Thus it appears as though carrier status for either the prothrombin or factor V Leiden mutation markedly increases the risk of thrombosis with oral contraceptive use. These data suggest that alternative birth control measures should be employed in women with the prothrombin or factor V Leiden mutations.

CONGENITAL LONG-QT SYNDROME AND DRUG-INDUCED TORSADES DE POINTES Drug-induced QT-interval prolongation and torsades de pointes are serious, potentially life-threatening adverse effects of many drugs. It is well recognized that many antiarrhythmic drugs can cause torsades de pointes. In addition, numerous noncardiovascular agents can induce torsades de pointes, and many have been withdrawn from the market as a result. Such drugs include the antihistamines terfenadine and astemizole, the fluoroquinolone antibiotic grepafloxacin, and the motility agent cisapride. Given the serious and unpredictable nature of torsades de pointes, there has been great interest in identifying genetic markers that predispose individuals to its occurrence. Abnormalities in ion flux across the cardiac cell membrane resulting in an excess of intracellular positive ions and delayed ventricular repolarization are characteristic of long-QT syndromes. Mutations in genes for the pore-forming channel proteins that affect potassium and sodium transport across the cardiac cell membrane underlie congenital long-QT syndromes.95 There is evidence that these mutations also may increase the risk for drug-induced torsades de pointes.96,97 The ability to screen for mutations associated with druginduced torsades de pointes would be of clinical significance in that

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individuals with a genetic predisposition for this life-threatening arrhythmia could be spared exposure to potentially causative agents and treated with alternative therapies.

examining these gene as targets for future drug therapy in psychiatric and neurologic diseases.

GENE THERAPY CORONARY DISEASE PROGRESSION GENE AND RESPONSE TO STATIN THERAPY Several large clinical trials in patients with coronary heart disease, including the Scandinavian Simvastatin Survival Study (4S), have demonstrated significant reductions in coronary events and mortality with HMG-CoA reductase inhibitors, or statins. The gene for apolipoprotein E has been correlated with hepatic cholesterol uptake and the risk for coronary heart disease.98 Its contribution to coronary heart disease progression and statin response was examined in the 4S population.99 Investigators found that the variant ε4 allele was associated with increased risk for all-cause mortality among placebo-treated study participants. However, no such association was observed in the simvastatin group, suggesting that simvastatin abolished the excess mortality risk associated with the ε4 allele. Several other genes have been associated with responses to statins in coronary heart disease. These include the genes for the cholesteryl ester transfer protein, which is involved in the metabolism of high-density lipoprotein cholesterol; β-fibrinogen, which influences plasma fibrinogen concentrations; and stromelysin-1, which is involved in remodeling of the extracellular matrix of atherosclerotic plaques.100−102 In each case, the gene linked to worse disease progression or clinical outcomes also was associated with the greatest response to statin therapy. These data imply that genotype may be useful in identifying which coronary heart disease patients are at an increased risk for coronary events and death, in whom treatment with a statin would be of particular benefit.

NOVEL SITES FOR DRUG DEVELOPMENT The discovery of genes that confer disease has led to an improved understanding of the molecular mechanisms involved in disease pathophysiology. Once associations between genes and diseases are discovered, scientists can elucidate the functions of the encoded proteins and more clearly define the consequences of genetic mutations. Insight into the genetic control of cellular functions may reveal new strategies for disease treatment and prevention. For example, researchers have discovered that the gene for the cysteine protease calpain-10 confers susceptibility to type 2 diabetes and may serve as a new target for treatment intervention.103 While the exact function of calpain-10 remains to be determined, it is expressed in tissues involved in the pathophysiology of type 2 diabetes mellitus, including the pancreatic islet cells, skeletal myocytes, and hepatocytes. These sites are important for controlling insulin secretion, peripheral insulin uptake, and hepatic glucose production, suggesting that the product of calpain-10 protein may influence glucose homeostasis.104 Multiple SNPs have been identified in the calpain10 gene, one of which has been correlated with reduced calpain-10 levels in skeletal muscle and insulin resistance.103 The discovery of calpain-10 as a candidate gene for type 2 diabetes identifies a potential new drug target for glucose control and an opportunity to improve glucose homeostasis permanently in patients with diabetes through pharmacogenetics. Similarly, the discovery that the apolipoprotein E gene is strongly linked to late-onset Alzheimer’s disease105 and that the α-synuclein gene is associated with Parkinson’s disease106 raises the possibility of

7 Gene therapy has emerged as a possible approach to treating

and curing disease by altering gene expression. The goal of gene therapy is to correct genetic defects permanently and thereby restore normal cellular function. Most gene therapy techniques attempt to replace defective genes with normally functioning ones. Exogenous genes, called transgenes, can be transferred into either somatic (body) or germ line (egg or sperm) cells of the recipient. In somatic cell gene transfer, genetic changes do not affect future generations. In contrast, germ line cell transfer, which is currently prohibited by the Food and Drug Administration (FDA),107 results in the passage of genetic alterations to offspring. Initially, the focus of gene therapy was for the treatment of inherited disorders such as cystic fibrosis, sickle cell anemia, hemophilia, and adenosine deaminase deficiency.108 Gene therapy trials were later expanded to include patients with acquired diseases such as cancer and heart disease. The first clinical gene therapy trial began in 1990 for the treatment of adenosine deaminase deficiency.107 B and T lymphocytes fail to develop in this autosomal recessive disease, resulting in a severe combined immunodeficiency syndrome (SCID) made famous by the “bubble boys” whose lives were confined to tents in an effort to keep them in a germ-free environment. Only two patients were included in this trial, and although both continued to demonstrate clinical improvement 10 years later, gene therapy did not cure the disease, as investigators had hoped. Since then, the FDA has approved more than 350 clinical gene therapy trials.108 Most of these trials involve cancer patients; however, a number of studies also target inherited disorders. The results of gene therapy trials to date have been largely disappointing, with reports of serious toxicities and few therapeutic successes.

OBSTACLES TO SUCCESS Reasons for limited success with gene therapy include inefficient gene delivery to target cells, inadequate gene expression, and unacceptable adverse effects.107 Sufficient amounts of the transgene must be inserted into a sufficient number of recipient cells to produce a therapeutic response. In addition, the transgene must be inserted into the correct chromosomal position of the correct cell nucleus so as not to disrupt normal gene function and expression. Incorrect chromosomal insertion of the transgene is a problem referred to as insertional mutagenesis. Once the therapeutic gene is integrated correctly into host DNA, it must be expressed at adequate levels and at appropriate times to restore normal cell function. Finally, the gene delivery system and delivery technique should lack any potential to cause unwanted effects in the transgene recipient.

RETROVIRAL GENE DELIVERY 8 Because of their efficiency in integrating into human DNA,

viruses are the most common vectors used to deliver therapeutic genes to recipient cell targets. Disease-causing genes are replaced with the desired therapeutic genes; the viral genes that control delivery mechanisms are retained.

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The first viral vectors introduced were retroviruses, which are RNA viruses that integrate into the host cell genome and replicate during cell division. Thus retroviral gene transfer is capable of permanently altering gene expression. Retroviruses may be used to deliver genes through either direct infusion into target organs or ex vivo manipulation of harvested cells followed by reinfusion into the recipient. The disadvantages of retroviral vectors are the limited size of the gene they can carry, relatively low efficiency, and the risk of insertional mutagenesis. In fact, the FDA temporarily halted retroviral gene delivery into hematopoietic tissue in early 2003 after leukemia developed as a result of insertional mutagenesis in two SCID-affected children treated with retroviral gene therapy.109

ADENOVIRAL GENE DELIVERY Unlike retroviruses, adenoviruses do not integrate into the host genome and thus do not replicate. As a result, genes delivered by adenoviruses are only active temporarily. Adenoviral-mediated gene therapy is employed commonly in cancer patients because permanent gene expression is unnecessary in this patient population. Tumor cells have been infused with adenoviral vectors carrying the herpes simplex virus-1 thymidine kinase gene and then exposed to ganciclovir as a mode of cancer chemotherapy.110 Thymidine kinase converts ganciclovir to its active, cytotoxic form, which is incorporated in the DNA of tumor cells, leading to their death. Adenoviruses can be grown in high titers and do not carry the risk of insertional mutagenesis. The major disadvantage of adenoviruses is their immunogenic potential, which has resulted in one death and prompted federal oversight of gene therapy trials.111

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ETHICAL CONSIDERATIONS PHARMACOGENETICS Traditionally, genetic testing refers to screening human genetic material to identify genotypes associated with disease susceptibility or carrier status for inherited diseases, such Huntington’s disease, Alzheimer’s disease, or breast cancer. This kind of testing can have profound legal, ethical, and social implications. For example, knowledge that a patient is at risk for developing a genetic disorder could result in discrimination by employers or insurance companies. In addition, this information likely would cause emotional distress for the individual at risk and his or her family members. Within the context of pharmacogenetics, however, testing involves searching for genetic variations linked to drug efficacy or toxicity rather than to disease susceptibility. This form of testing carries little risk for ethical, legal, and social concerns. To prevent public wariness and confusion, genetic testing in reference to pharmacogenetics needs to be defined or renamed so that it can be distinguished from genetic testing for susceptibility to inherited disorders. CLINICAL CONTROVERSY Many individuals are wary of the term genetic testing because this term is usually associated with determining genetic risk for serious diseases. Therefore, clinicians may cause unnecessary anxiety among patients if they refer to the screening for genetic variants associated with drug response as genetic testing.

GENE THERAPY OTHER MEANS OF GENE DELIVERY Adeno-associated viruses are human DNA-containing viruses that appear neither to cause disease in humans nor to trigger immune responses on injection. Similar to retroviruses, adeno-associated viruses are incapable of carrying a large amount of genetic material, and their use entails the risk of insertional mutagenesis. Investigators have had some success in treating hemophilia B using intramuscular injections of an adeno-associated virus vector that expresses the human coagulation factor IX gene.112 Scientists are also experimenting with nonviral delivery methods such as the use of direct DNA injection, liposomes, and electroporation. There has been some success with intramyocardial transfection of plasmid DNA encoding for vascular endothelial growth factor into patients with severe, intractable angina.113 Initially, the procedure improved myocardial perfusion and angina in this patient population with few major adverse events. One year later, patients continued to report some improvement in their angina symptoms.114 Scientists have enjoyed few successes with gene therapy in recent years, and it is unlikely that gene therapy will progress to have a lasting impact on medicine during the next decade. Improvements in gene delivery techniques and a better understanding of molecular processes controlling gene expression are necessary before gene therapy can correct genetic defects successfully and thus cure associated diseases without inducing adverse effects. Because of limited success with traditional approaches to gene therapy, scientists are exploring other strategies, such as repairing defective genes rather than replacing them.115 It is important that gene therapy eventually succeeds so that diseases such as Huntington’s disease, sickle cell anemia, and inherited immunodeficiency disorders may be cured and their associated morbidity and mortality alleviated.

Many of the ethical concerns with gene therapy center on transgenic manipulation of somatic versus germ line cells. Somatic gene therapy only affects the recipient. That is, genetic alterations introduced by gene therapy are not passed on to future generations. In contrast, with manipulation of germ line cells, alterations are passed on to future children of the treated patient. Some argue that this is unethical because it violates the rights of future generations. Thus it appears that most gene therapy in the foreseeable future will focus on somatic gene transfer.

ROLE OF PHARMACISTS Although pharmacogenetics provides opportunities to improve drug therapy outcomes, it likely will increase the complexity of drug prescribing. In addition to considering factors such as age, concomitant drug therapy, and renal and hepatic function, prescribers also will have to interpret the results of genetic analyses when making drug therapy decisions. Further complicating the drug-prescribing process are many medications whose effects are not determined by single polymorphisms in single genes. Rather, pharmacologic effects for most medications likely are determined by the interaction of polymorphisms in multiple genes that encode proteins involved in the various pathways of drug metabolism, distribution, and effects. For example, the immunosuppressants cyclosporine and tacrolimus are believed to be substrates for both P-glycoprotein and the CYP450 3A4 and possibly 3A5 enzymes.116 Thus it is possible that genes for both MDR-1 and CYP450 enzymes interact to influence cyclosporine and tacrolimus distribution and plasma concentrations. Pharmacists are broadly trained in a number of medicationrelated areas, including pharmacology, pharmacokinetics, and

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pharmacodynamics. This places pharmacists in an extremely valuable position in dealing with the complexities of the drug-decision process in the age of pharmacogenetics. Pharmacists will be in key positions to interpret the results of genetic tests, determine the ultimate effects of multiple genetic variations on drug response, and choose the most appropriate drug for a given patient based on the individual’s DNA. Thus it will be essential for pharmacists to stay abreast of significant discoveries in genotype–drug response relationships and understand how best to incorporate this genomic information into pharmacotherapeutic decisions. Recognizing the challenges in health care delivery with advancing genetic discoveries, the National Coalition for Health Professional Education in Genetics established core competencies related to genetics for health care professionals that are available through the coalition’s Web site (www.nchpeg.org). The objective of these competencies is to encourage clinicians to incorporate genetics knowledge, skills, and attitudes into their clinical practices. Subsequently, the American Association of Colleges of Pharmacy developed recommendations to guide academic institutions in instilling these competencies in future pharmacists so that pharmacists will be prepared to provide appropriate pharmacotherapy in the age of genomics.117

APPLICATION OF PHARMACOGENETIC DATA TO DISEASE MANAGEMENT Pharmacogenetics has the potential to greatly improve the pharmacologic management of disease. Clinicians may be able to predict the

likelihood that an individual will respond to a particular medication based on the patient’s genotype. Medications may be avoided or prescribed in lower doses with careful monitoring in patients genetically predisposed to their adverse effects. This would be of particular benefit for narrow-therapeutic-index drugs. For example, in warfarin candidates with a CYP2C9*2 or CYP2C9*3 allele, warfarin may be initiated at lower doses with closer monitoring. If the anticipated benefit from warfarin is low in a patient homozygous for the CYP2C9*2 or CYP2C9*3 alleles, it may be safer to withhold warfarin and institute alternative anticoagulant therapy. With pharmacogenetics, it also may be possible to eliminate the trial-and-error approach to drug prescribing for many diseases. Instead, clinicians may be able to use genetic information to match the right drug to the right patient at the right dose while minimizing adverse effects. For example, the current approach to hypertension management involves the trial of various antihypertensives until blood pressure goals are achieved with acceptable drug tolerability. Commonly, the initial agent(s) fails to lower blood pressure to goal or produces intolerable adverse effects (Fig. 6–6). Trials of additional or alternative antihypertensive medications must be undertaken until treatment is deemed successful. In the interim, the patient remains hypertensive and at risk for hypertension-related target-organ damage. With pharmacogenetics, clinicians may choose the antihypertensive drug expected to provide the greatest response with the best tolerability for a particular patient based on his or her DNA. For example, if a hypertensive patient is found to have the 460Trp allele of the α-adducin gene, a thiazide diuretic may be the most appropriate initial antihypertensive agent because evidence suggests that diuretic

Same therapy for all patients

Individualized therapy based on genotype

Adverse effects: Initiate alternative therapy

Therapeutic success: Continue current therapy

Population with a given disease

Therapeutic success: Continue current therapy

Nonresponders: Initiate alternative therapy

FIGURE 6–6. Current and future approaches to pharmacologic management of disease.

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therapy in 460Trp allele carriers will lower blood pressure effectively and potentially improve clinical outcomes. New drugs may be developed based on knowledge about genetic control of cellular functions. For example, the discovery that chronic myeloid leukemia (CML) was caused by chromosome translocation and consequent production of an enzyme capable of producing lifethreatening lymphocyte levels led to accelerated FDA approval of Gleevec (also known as STI-571), an inhibitor of the translocationcreated enzyme, for treatment of CML.118 In addition, future drug development may focus on treating specific genetic subgroups instead of broadly treating all individuals with a particular disease. Ultimately, pharmacogenetics may improve the quality and reduce the overall costs of health care by decreasing the number of treatment failures and the number of adverse drug reactions and leading to the discovery of new genetic targets and therapeutic interventions for disease management. CLINICAL CONTROVERSY For some drugs, variations in genes affecting both pharmacokinetic and pharmacodynamic drug properties may interact to determine the ultimate effects from drug therapy. Thus the challenge for researchers will be to identify the combination of gene variations that best predicts response for these drugs.

4.

5. 6. 7. 8. 9. 10. 11. 12.

13. 14.

15.

ABBREVIATIONS 16.

CYP: cytochrome P450 SNPs: single-nucleotide polymorphisms A: adenine C: cytosine G: guanine T: thymidine EM: extensive metabolizer PM: poor metabolizer UM: ultrarapid metabolizer AUC: area under the curve TPMT: thiopurine-S-methyltransferase DPD: dihydropyrimidine dehydrogenase UGT: UDP-glucuronosyl transferase MDR-1: multidrug resistance 1 HIV: human immunodeficiency virus ACE: angiotensin-converting enzyme I/D: insertion/deletion FDA: Food and Drug Administration SCID: severe combined immunodeficiency syndrome CML: chronic myeloid leukemia Review Questions and other resources can be found at www.pharmacotherapyonline.com.

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CHAPTER 6 69. Drysdale CM, McGraw DW, Stack CB, et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 2000; 97:10483–10488. 70. Arranz MJ, Munro J, Birkett J, et al. Pharmacogenetic prediction of clozapine response. Lancet 2000;355:1615–1616. 71. Ashby CR Jr, Wang RY. Pharmacological actions of the atypical antipsychotic drug clozapine: A review. Synapse 1996;24:349–394. 72. Masellis M, Basile VS, Ozdemir V, et al. Pharmacogenetics of antipsychotic treatment: Lessons learned from clozapine. Biol Psychiatry 2000; 47:252–266. 73. Turner ST, Schwartz GL, Chapman AB, et al. Antihypertensive pharmacogenetics: Getting the right drug into the right patient. J Hypertens 2001;19:1–11. 74. Stavroulakis GA, Makris TK, Krespi PG, et al. Predicting response to chronic antihypertensive treatment with fosinopril: The role of angiotensin-converting enzyme gene polymorphism. Cardiovasc Drugs Ther 2000;14:427–432. 75. Ohmichi N, Iwai N, Uchida Y, et al. Relationship between the response to the angiotensin-converting enzyme inhibitor imidapril and the angiotensin-converting enzyme genotype. Am J Hypertens 1997;10: 951–955. 76. Ueda S, Meredith PA, Morton JJ, et al. ACE (I/D) genotype as a predictor of the magnitude and duration of the response to an ACE inhibitor drug (enalaprilat) in humans. Circulation 1998;98:2148–2153. 77. Sasaki M, Oki T, Iuchi A, et al. Relationship between the angiotensinconverting enzyme gene polymorphism and the effects of enalapril on left ventricular hypertrophy and impaired diastolic filling in essential hypertension: M-mode and pulsed Doppler echocardiographic studies. J Hypertens 1996;14:1403–1408. 78. Kohno M, Yokokawa K, Minami M, et al. Association between angiotensin-converting enzyme gene polymorphisms and regression of left ventricular hypertrophy in patients treated with angiotensinconverting enzyme inhibitors. Am J Med 1999;106:544–549. 79. Kurland L, Melhus H, Karlsson J, et al. Aldosterone synthase (CYP11B2) −344 C/T polymorphism is related to antihypertensive response: Result from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial. Am J Hypertens 2002;15:389– 393. 80. Hingorani AD, Jia H, Stevens PA, et al. Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensinconverting enzyme inhibition. J Hypertens 1995;13:1602–1609. 81. Takahashi T, Yamaguchi E, Furuya K, Kawakami Y. The ACE gene polymorphism and cough threshold for capsaicin after cilazapril usage. Respir Med 2001;95:130–135. 82. Zee RY, Rao VS, Paster RZ, et al. Three candidate genes and angiotensinconverting enzyme inhibitor-related cough: A pharmacogenetic analysis. Hypertension 1998;31:925–928. 83. Vleeming W, van Amsterdam JG, Stricker BH, de Wildt DJ. ACE inhibitor–induced angioedema: Incidence, prevention and management. Drug Saf 1998;18:171–188. 84. Wang JG, Staessen JA. Genetic polymorphisms in the renin-angiotensin system: Relevance for susceptibility to cardiovascular disease. Eur J Pharmacol 2000;410:289–302. 85. Jia HHA, Sharma P, Hopper R, et al. Association of the G(s)alpha gene with essential hypertension and response to beta-blockade. Hypertension 1999;34:8–14. 86. Hudson CJ, Young LT, Li PP, Warsh JJ. CNS signal transduction in the pathophysiology and pharmacotherapy of affective disorders and schizophrenia. Synapse 1993;13:278–293. 87. Rasenick MM, Chaney KA, Chen J. G-protein-mediated signal transduction as a target of antidepressant and antibipolar drug action: Evidence from model systems. J Clin Psychiatry 1996;57(suppl 13):49–55; discussion 56–58. 88. Serretti A, Lorenzi C, Cusin C, et al. SSRIs antidepressant activity is influenced by G beta 3 variants. Eur Neuropsychopharmacol 2003;13:117– 122. 89. Zill P, Baghai TC, Zwanzger P, et al. Evidence for an association

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between a G-protein beta3-gene variant with depression and response to antidepressant treatment. Neuroreport 2000;11:1893–1897. Manunta P, Cusi D, Barlassina C, et al. Alpha-adducin polymorphisms and renal sodium handling in essential hypertensive patients. Kidney Int 1998;53:1471–1478. Glorioso N, Manunta P, Filigheddu F, et al. The role of alpha-adducin polymorphism in blood pressure and sodium handling regulation may not be excluded by a negative association study. Hypertension 1999;34:649– 654. Psaty BM, Smith NL, Heckbert SR, et al. Diuretic therapy, the alphaadducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension. JAMA 2002;287:1680–1689. Aznar J, Vaya A, Estelles A, et al. Risk of venous thrombosis in carriers of the prothrombin G20210A variant and factor V Leiden and their interaction with oral contraceptives. Haematologica 2000;85:1271– 1276. Martinelli I, Sacchi E, Landi G, et al. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med 1998;338:1793–1797. Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias: Impact on clinical management parts I and II. Circulation 1999;99:518–528. Yang P, Kanki H, Drolet B, et al. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 2002;105:1943–1948. Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999;97:175–187. Wilson PW, Schaefer EJ, Larson MG, Ordovas JM. Apolipoprotein E alleles and risk of coronary disease: A meta-analysis. Arterioscler Thromb Vasc Biol 1996;16:1250–1255. Gerdes LU, Gerdes C, Kervinen K, et al. The apolipoprotein ε4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction: A substudy of the Scandinavian simvastatin survival study. Circulation 2000;101:1366–1371. Kuivenhoven JA, Jukema JW, Zwinderman AH, et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N Engl J Med 1998;338:86–93. de Maat MP, Kastelein JJ, Jukema JW, et al. −455G/A polymorphism of the beta-fibrinogen gene is associated with the progression of coronary atherosclerosis in symptomatic men: Proposed role for an acute-phase reaction pattern of fibrinogen. REGRESS group. Arterioscler Thromb Vasc Biol 1998;18:265–271. de Maat MP, Jukema JW, Ye S, et al. Effect of the stromelysin-1 promoter on efficacy of pravastatin in coronary atherosclerosis and restenosis. Am J Cardiol 1999;83:852–856. Baier LJ, Permana PA, Yang X, et al. A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest 2000;106:R69–73. Horikawa Y, Oda N, Cox NJ, et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nature Genet 2000; 26:163–175. Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: High-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 1993;90:1977–1981. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alphasynuclein gene identified in families with Parkinson’s disease. Science 1997;276:2045–2047. Fibison WJ. Gene therapy. Nurs Clin North Am 2000;35:757–772. Williams DA, Smith FO. Progress in the use of gene transfer methods to treat genetic blood diseases. Hum Gene Ther 2000;11:2059–2066. Marshall E. Gene therapy: Second child in French trial is found to have leukemia. Science 2003;299:320. Morris JC, Ramsey WJ, Wildner O, et al. A phase I study of intralesional administration of an adenovirus vector expressing the HSV-1 thymidine kinase gene (AdV.RSV-TK) in combination with escalating doses of

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ganciclovir in patients with cutaneous metastatic malignant melanoma. Hum Gene Ther 2000;11:487–503. Marshall E. Gene therapy death prompts review of adenovirus vector. Science 1999;286:2244–2245. Manno CS, Chew AJ, Hutchison S, et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 2003;101:2963–2972. Symes JF, Losordo DW, Vale PR, et al. Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Ann Thorac Surg 1999;68:830–836; discussion 836–837. Fortuin FD, Vale P, Losordo DW, et al. One-year follow-up of direct myocardial gene transfer of vascular endothelial growth factor-2 using naked plasmid deoxyribonucleic acid by way of thoracotomy in nooption patients. Am J Cardiol 2003;92:436–439. Sullenger BA. Targeted genetic repair: An emerging approach to genetic therapy. J Clin Invest 2003;112:310–311. Hesselink DA, van Schaik RH, van der Heiden IP, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 2003;74:245–254. Johnson JA, Bootman JL, Evans WE, et al. Pharmacogenomics: A scientific revolution in pharmaceutical sciences and pharmacy practice. Report of the 2001–2002 Academic Affairs Committee. Am J Pharm Educ 2002;66:12S–15S. Johnson JR, Bross P, Cohen M, et al. Approval summary: Imatinib mesylate capsules for treatment of adult patients with newly diagnosed Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase. Clin Cancer Res 2003;9:1972–1979. Devadatta S, Gangadharam PRJ, Andrews RH. Peripheral neuritis due to isoniazid. Bull WHO 1960;23:587–598. Henningsen NC, Cederberg A, Hanson A, Johansson BW. Effects of long-term treatment with procaine amide: A prospective study with special regard to ANF and SLE in fast and slow acetylators. Acta Med Scand 1975;198:475–482. Strandberg I, Boman G, Hassler L, Sjoqvist F. Acetylator phenotype in

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patients with hydralazine-induced lupoid syndrome. Acta Med Scand 1976;200:367–371. Pullar T, Hunter JA, Capell HA. Effect of acetylator phenotype on efficacy and toxicity of sulphasalazine in rheumatoid arthritis. Ann Rheum Dis 1985;44:831–837. Jacobsen P, Rossing K, Rossing P, et al. Angiotensin-converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy. Kidney Int 1998;53:1002–1006. Kotani Y, Nishimura Y, Maeda H, Yokoyama M. Beta2-adrenergic receptor polymorphisms affect airway responsiveness to salbutamol in asthmatics. J Asthma 1999;36:583–590. Lima JJ, Thomason DB, Mohamed MH, et al. Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharmacol Ther 1999;65:519–525. Martinez FD, Graves PE, Baldini M, et al. Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest 1997;100:3184–3188. Mukae S, Aoki S, Itoh S, et al. Bradykinin B(2) receptor gene polymorphism is associated with angiotensin-converting enzyme inhibitorrelated cough. Hypertension 2000;36:127–131. Oliveri RL, Annesi G, Zappia M, et al. Dopamine D2 receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD. Neurology 1999;53:1425–1430. Eichhammer P, Albus M, Borrmann-Hassenbach M, et al. Association of dopamine D3-receptor gene variants with neuroleptic induced akathisia in schizophrenic patients: A generalization of Steen’s study on DRD3 and tardive dyskinesia. Am J Med Genet 2000;96:187–191. Ongphiphadhanakul B, Chanprasertyothin S, Payatikul P, et al. Oestrogen-receptor-alpha gene polymorphism affects response in bone mineral density to oestrogen in post-menopausal women. Clin Endocrinol (Oxf ) 2000;52:581–585. Drazen JM, Yandava CN, Dube L, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet 1999;22:168–170.

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7 PEDIATRICS Milap C. Nahata and Carol Taketomo

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Children are not just “little adults,” and lack of data on

important pharmacokinetic and pharmacodynamic differences has led to several disastrous situations in pediatric care.

2 Variations in absorption of medications from the gastroin-

testinal tract, intramuscular injection sites, and skin are important in pediatric patients, especially in premature and other newborn infants.

3 The rate and extent of organ function development and the

distribution, metabolism, and elimination of drugs differ not only between pediatric versus adult patients but also among pediatric age groups.

4 The effectiveness and safety of drugs may vary among various age groups and from one drug to another in pediatric versus adult patients.

Remarkable progress has been made in the clinical management of disease in pediatric patients. This chapter highlights important principles of pediatric pharmacotherapy that must be considered when the diseases discussed in other chapters of this book occur in pediatric patients, defined as those younger than 18 years of age. Newborn infants born before 37 weeks of gestational age are termed premature; those between 1 day and 1 month of age are neonates; 1 month to 1-yearold, infants; 1 year to 11 years of age, children; and 12 to 16 years, adolescents. Covered are notable examples of problems in pediatrics, pharmacokinetic differences in pediatric patients, drug efficacy and toxicity in this patient group, and various factors affecting pediatric pharmacotherapy. Specific examples of problems and special considerations in pediatric patients are cited to enhance understanding. 1 Infant mortality has declined from 200 per 1000 births in the nineteenth century to 75 per 1000 births in 1925 to 6.8 per 1000 births in 2001.1 This success has resulted largely from improvements in identification, prevention, and treatment of diseases once common during delivery and the period of infancy. Although most marketed drugs are used in pediatric patients, only one-fourth of the drugs approved by the Food and Drug Administration (FDA) have indications specific for use in the pediatric population. Data on the pharmacokinetics, pharmacodynamics, efficacy, and safety of drugs in infants and children are scarce. Lack of this type of information led to such disasters as gray baby syndrome from chloramphenicol, phocomelia from thalidomide, and kernicterus from sulfonamide therapy. Gray baby syndrome was first reported in two neonates who died after excessive chloramphenicol doses (100–300 mg/kg per day); the serum

5 Concomitant diseases may influence dosage requirements to achieve a targeted effect for a specific disease in children.

6 The myth that neonates and young children do not experi-

ence pain has led to inadequate pain management in this population.

7 Special methods of drug administration are needed for infants and young children.

8 Many medicines needed for pediatric patients are not available in appropriate dosage forms, and thus the dosage forms of drugs marketed for adults may have to be modified for infants and children, requiring assurance of potency and safety of drug use.

9 The pediatric medication-use process is complex and error-

prone owing to multiple steps required in calculating, verifying, preparing, and administering doses.

concentrations of chloramphenicol immediately before death were 75 and 100 mcg/mL. Patients with gray baby syndrome usually have abdominal distention, vomiting, diarrhea, a characteristic gray color, respiratory distress, hypotension, and progressive shock. Thalidomide is well known for its teratogenic effects. Clearly implicated as the cause of multiple congenital fetal abnormalities (particularly limb deformities), it also can cause polyneuritis, nerve damage, and mental retardation. Isotretinoin (Accutane) is another teratogen. Because it is used to treat acne vulgaris, common in teenage patients who may be sexually active but not willing to acknowledge that activity to health care professionals, isotretinoin has presented a difficult problem in patient education since its marketing in the 1980s. Kernicterus was reported in neonates receiving sulfonamides, which displaced bilirubin from protein-binding sites in the blood to cause a hyperbilirubinemia. This results in deposition of bilirubin in the brain and induces encephalopathy in infants. Another area of concern in pediatrics is identifying an optimal dosage. Dosage regimens cannot be based simply on body weight or surface area of a pediatric patient extrapolated from adult data. Bioavailability, pharmacokinetics, pharmacodynamics, efficacy, and adverse-effect information can differ markedly between pediatric and adult patients, as well as among pediatric patients, because of differences in age, organ function, and disease state. Significant progress has been made in the area of pediatric pharmacokinetics during the last two decades, but few such studies have correlated pharmacokinetics with the outcomes of efficacy, adverse effects, or quality of life. 91

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Several additional factors should be considered in optimizing pediatric drug therapy. Many drugs prescribed widely for infants and children are not available in suitable dosage forms. For example, extemporaneous liquid dosage forms of amiodarone, captopril, omeprazole, and spironolactone are prepared for infants and children who cannot swallow tablets or capsules, and injectable dosage forms of aminophylline, methylprednisolone, morphine, and phenobarbital are diluted to accurately measure small doses for infants. Alteration (dilution or reformulation) of dosage forms intended for adult patients raises questions about the bioavailability, stability, and compatibility of these drugs. Because of low fluid volume requirements and limited access to intravenous sites, special methods must be used for the delivery of intravenous drugs to infants and children. As simple as it may seem, administration of oral drugs to young patients continues to be a difficult task for nurses and parents. Similarly, ensuring adherence to pharmacotherapy in pediatric patients poses a special challenge. Finally, the need for additional pharmacologic or therapeutic research brings up the issue of ethical justification for conducting research. The investigators proposing studies and institutional review committees approving human studies must assess the risk-benefit ratio of each study to be fair to children who are not in a position to accept or reject the opportunity to participate in the research project. Enormous progress has been made in pharmacokinetics in pediatric patients. Two factors have contributed to this progress: (1) the availability of sensitive and specific analytic methods to measure drugs and their metabolites in small volumes of biologic fluids and (2) awareness of the importance of clinical pharmacokinetics in optimization of drug therapy. Absorption, distribution, metabolism, and elimination of many drugs are different in premature infants, full-term infants, and older children, and this topic is discussed in detail in the next few sections.

INTRAMUSCULAR SITES Drug absorption from an intramuscular site also may be altered in premature infants. Differences in relative muscle mass, poor perfusion to various muscles, peripheral vasomotor instability, and insufficient muscular contractions in premature infants compared with older children and adults can influence drug absorption from the intramuscular site. The net effect of these factors on drug absorption is impossible to predict; phenobarbital has been reported to be absorbed rapidly,10 whereas diazepam absorption may be delayed.11 Thus intramuscular dosing is used rarely in neonates except in emergencies or when an intravenous site is inaccessible.

SKIN Percutaneous absorption may be increased substantially in newborns because of an underdeveloped epidermal barrier (stratum corneum) and increased skin hydration. The increased permeability can produce toxic effects after the topical use of hexachlorophene soaps and powders,12 salicylic acid ointment, and rubbing alcohol.13 Interestingly, a study has shown that a therapeutic serum concentration of theophylline can be achieved to control apnea in premature infants of less than 30 weeks’ gestation after a topical application of gel containing a standard dose of theophylline.14 The use of this route of administration may minimize the unpredictability of oral and intramuscular absorption and complications of intravenous drug administration for certain drugs.

DISTRIBUTION 3 Drug distribution is determined by the physicochemical prop-

ABSORPTION GASTROINTESTINAL TRACT 2 Two factors affecting the absorption of drugs from the gastroin-

testinal tract are pH-dependent passive diffusion and gastric emptying time. Both processes are strikingly different in premature infants compared with older children and adults. In a full-term infant, gastric pH ranges from 6 to 8 at birth but declines to 1 to 3 within 24 hours.2 In contrast, the gastric pH is elevated in premature infants because of immature acid secretion.3 In premature infants, higher serum concentrations of acid-labile drugs—such as penicillin,4 ampicillin,5 and nafcillin6 —and lower serum concentrations of a weak acid such as phenobarbital7 can be explained by higher gastric pH. Because of a lack of extensive data comparing serum concentration-time profiles after oral versus intravenous drug administration, differences in the bioavailability of drugs in premature infants are poorly understood. Although little is known about the influence of developmental changes with age on drug absorption in pediatric patients, a few studies with drugs (e.g., digoxin and phenobarbital) and nutrients (e.g., arabinose and xylose) have suggested that the processes of both passive and active transport may be fully developed by about 4 months of age.8 No data are available about the development and expression of the efflux transporter P-glycoprotein in the intestine. Studies have shown that gastric emptying is slow in a premature infant.9 Thus drugs with limited absorption in adults may be absorbed efficiently in a premature infant because of prolonged contact time with gastrointestinal mucosa.

erties of the drug itself (pKa , molecular weight, partition coefficient) and the physiologic factors specific to the patient. Although the physicochemical properties of the drug are constant, the physiologic functions often vary in different patient populations. Some important patient-specific factors include extracellular and total body water, protein binding by the drug in plasma, and the presence of pathologic conditions modifying physiologic function. Total body water, as a percentage of total body weight, has been estimated to be 94% in the fetus, 85% in premature infants, 78% in full-term infants, and 60% in adults.14 Extracellular fluid volume is also markedly different in premature infants compared with older children and adults; the extracellular fluid volume may account for 50% of body weight in premature infants, 35% in 4- to 6-month-old infants, 25% in children 1 year of age, and 19% in adults.15 This conforms to the observed gentamicin distribution volumes of 0.48 L/kg in neonates and 0.20 L/kg in adults.16 Studies have shown that the distribution volume of tobramycin is largest in the most premature infants and decreases with increases in the gestational age and birth weight of the infant.17 Binding of drugs to plasma proteins is also decreased in newborn infants because of the decreased plasma protein concentration, lower binding capacity of protein, decreased affinity of proteins for drug binding, and competition for certain binding sites by endogenous compounds such as bilirubin. The plasma protein binding of many drugs—including phenobarbital, salicylates, and phenytoin— is significantly less in the neonate than in the adult.18 The decrease in plasma protein binding of drugs can increase their apparent volumes of distribution. Therefore, premature infants require a larger loading dose than older children and adults to achieve a therapeutic serum concentration of such drugs as phenobarbital19 and phenytoin.20

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The consequences of increased concentrations of free or unbound drug in the serum and tissues must be considered. Pharmacologic and toxic effects are related directly to the concentration of free drug in the body. Increases in free drug concentrations may result directly from decreases in plasma protein binding or indirectly from, for example, drug displacement from binding sites. The increased mortality from the development of kernicterus secondary to displacement of bilirubin by sulfisoxazole in neonates has been well documented.21 However, because drug bound to plasma proteins cannot be eliminated by the kidney, an increase in free drug concentration also may increase its clearance.22 The amount of body fat is substantially lower in neonates compared with adults, which may affect drug therapy. Certain highly lipidsoluble drugs are distributed less widely in infants than in adults. The apparent volume of distribution of diazepam has ranged from 1.4 to 1.8 L/kg in neonates and from 2.2 to 2.6 L/kg in adults.23 In recent years, the numbers of mothers breast-feeding their infants has climbed. Thus certain drugs distributed in breast milk may pose problems for the infants. The American Academy of Pediatrics recommends that bromocriptine, cyclophosphamide, cyclosporine, doxorubicin, ergotamine, lithium, methotrexate, phenindione, and all drugs of abuse (e.g., amphetamine, cocaine, heroin, marijuana, and phencyclidine, or PCP) be contraindicated during breast-feeding. Further, the use of nuclear medicines should be stopped temporarily during breast-feeding.24 Note that these recommendations are based on limited data; other drugs taken over a prolonged period by the mother also may be toxic to the infant. For example, acebutolol, aspirin, atenolol, clemastine, phenobarbital, primidone, sulfasalazine, and 5-aminosalicylic acid have been associated with adverse effects in some nursing infants.24,25 Unless benefits outweigh the risks, the use of any drug should be avoided by the mother during pregnancy and while breast-feeding.

METABOLISM Drug metabolism is substantially slower in infants compared with older children and adults. There are important differences in the maturation of various pathways of metabolism within a premature infant. For example, the sulfation pathway is well developed but the glucuronidation pathway is undeveloped in infants.26 Although acetaminophen metabolism by glucuronidation is impaired in infants compared with adults, it is partly compensated for by the sulfation pathway. The cause of the tragic chloramphenicol-induced gray baby syndrome in newborn infants is a decreased metabolism of chloramphenicol by glucuronyl transferases to the inactive glucuronide metabolite.27 This metabolic pathway appears to be age-related28 and may take several months to a year to develop fully. Evidence for this is the increase in clearance with age up to 1 year.29 Interestingly, higher serum concentrations of morphine are required to achieve efficacy in premature infants than in adults in part because infants are not able to metabolize morphine adequately to its 6-glucuronide metabolite (20 times more active than morphine).30 This is balanced to some degree by the fact that the clearance of morphine quadruples between 27 and 40 weeks of postconceptional age. Metabolism of drugs such as theophylline, phenobarbital, and phenytoin by oxidation is also impaired in newborn infants. The rate of metabolism, however, is more rapid with phenobarbital and phenytoin than with theophylline, perhaps owing to the involvement of different cytochrome P450 isozymes. Total clearance of phenytoin by CYP2C9 and to a lesser extent by CYP2C19 surpasses adult values by 2 weeks

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of age, whereas theophylline clearance is not fully developed for several months.18 Two additional observations should be noted about theophylline metabolism by CYP1A2 in pediatric patients. First, in premature infants receiving theophylline for the treatment of apnea, a significant amount of its active metabolite caffeine may be present, unlike in older children and adults.18 Second, theophylline clearance in children 1 to 9 years of age exceeds the values in infants as well as adults. Thus a child with asthma often requires markedly higher doses on a weight basis of theophylline compared with an adult.31 Because of decreased metabolism, doses of such drugs as theophylline, phenobarbital, phenytoin, and diazepam should be decreased in premature infants. The clearance of unbound S-warfarin, a substrate of CYP2C9, was substantially greater in prepubertal children than among pubertal children and adults even after adjustment for total body weight.32 Finally, the clearance of caffeine, metabolized by demethylation, declines to adult values when girls reach Tanner stage 2 (early puberty) and boys reach Tanner stage 4 and 5 (late puberty).33

ELIMINATION Drugs and their metabolites are often eliminated by the kidney. The glomerular filtration rate may be as low as 0.6–0.8 mL/min per 1.73 m2 in preterm infants and about 2–4 mL/min per 1.73 m2 in term infants. The processes of glomerular filtration, tubular secretion, and tubular reabsorption determine the efficiency of renal excretion. These processes may take several weeks to 1 year after birth to develop fully. Studies in infants have shown that tobramycin clearance during the first postnatal week may increase with an increase in gestational age.17 In infants up to 1 month after birth, postnatal age also was correlated directly with aminoglycoside clearance.29 Thus premature infants require a lower daily dose of drugs eliminated by the kidney during the first week of life; the dosage requirement then increases with age. Because of immature renal elimination, chloramphenicol succinate can accumulate in premature infants. Although chloramphenicol succinate is inactive, this accumulation may be the reason for an increased bioavailability of chloramphenicol in premature infants compared with older children.28 These data indicate that dose-related toxicity may result from an underdeveloped glucuronidation pathway, as well as increased bioavailability of chloramphenicol in premature infants.

DRUG EFFICACY AND TOXICITY 4 Besides the pharmacokinetic differences previously identified

between pediatric and older patients, factors related to drug efficacy and toxicity also should be considered in planning pediatric pharmacotherapy. Unique pathophysiologic changes occur in pediatric patients with some disease states. Examples of these pathophysiologic and pharmacodynamic differences are numerous. Clinical presentation of chronic asthma differs in children and adults.34 Children present almost exclusively with a reversible extrinsic type of asthma, whereas adults have nonspecific, nonatopic bronchial irritability.34 This explains the value of adjunctive hyposensitization therapy in the management of pediatric patients with extrinsic asthma.35,36 The maintenance dose of digoxin is substantially higher in infants than in adults. This is explained by a lower binding affinity of receptors in the myocardium for digoxin and increased digoxin-binding

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sites on neonatal erythrocytes compared with adult erythrocytes.37 Insulin requirement is highest during adolescence because of the individual’s rapid growth. Growth hormone therapy has allowed children with growth hormone deficiency to attain greater adult height. However, a recent study has shown that in “normal” short children (without growth hormone deficiency), early and rapid pubertal progression by growth hormone therapy may lead to a shorter final adult height than may have been attained naturally.38 This emphasizes the need for identifying specific indications for the effective and safe use of drugs in pediatric patients. Certain adverse effects of drugs are most common in the newborn period, whereas other toxic effects may continue to be important for many years of childhood. Chloramphenicol toxicity is increased in newborns because of immature metabolism and enhanced bioavailability. Similarly, propylene glycol—added to many injectable drugs, including phenytoin, phenobarbital, digoxin, diazepam, vitamin D, and hydralazine, to increase their stability—can cause hyperosmolality in infants.39 Benzyl alcohol was a popular preservative in intravascular flush solutions until a syndrome of metabolic acidosis, seizures, neurologic deterioration, gasping respirations, hepatic and renal abnormalities, cardiovascular collapse, and death was described in premature infants. A decline in both mortality and the incidence of major intraventricular hemorrhage has been documented after the use of solutions containing benzyl alcohol was stopped in low-birthweight infants.40 Tetracyclines are also contraindicated in pregnant women, nursing mothers, and children younger than 8 years of age because they can cause dental staining and defects in enamelization of deciduous and permanent teeth, as well as a decrease in bone growth.41 CLINICAL CONTROVERSY Are fluoroquinolones safe in pediatric patients younger than 1 year of age? The antibiotics of the fluoroquinolone class (e.g., ciprofloxacin) are not recommended for pediatric patients or pregnant women because of an association between these drugs and development of permanent lesions of the cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species.42 Reversible arthralgia, sometimes accompanied by synovial effusion, was associated with ciprofloxacin therapy in 1.8% of pediatric patients with cystic fibrosis.43 Although these drugs are used to treat certain infections in pediatric populations, further safety data are needed before they can be prescribed routinely, especially in infants.

CLINICAL CONTROVERSY Are antidepressants safe and effective in children and adolescents? Because of observations of an increased suicidality among adolescents (and adults, for that matter), experts are questioning whether these medications merely bring out an increased suicide risk that the patient has suppressed or has been too depressed to act on or actually increase the risk per se through some pharmacologic effect. Fluoxetine is the only selective serotonin reuptake inhibitor (SSRI) currently approved for use in pediatric patients in the United States. The British regulatory agency banned the use of another SSRI, paroxetine, in 2003 after analysis of the data indicated the occurrence of suicidal thoughts or episodes of self-harm at a rate of 1.5 to 3.2 times higher than that with placebo. Subsequently, the

FDA has cautioned about the use of and need for monitoring SSRI therapy in pediatric patients, and this area remained controversial when this chapter was finalized in the spring of 2004. Some drugs may be less toxic in pediatric patients than in adults. Aminoglycosides appear to be less toxic in infants than in adults. In adults, aminoglycoside toxicity is related to both peripheral compartment accumulation and the individual patient’s inherent sensitivity to these tissue concentrations.44 Although neonatal peripheral tissue compartments for gentamicin have been reported to closely resemble those of adults with similar renal function,16 gentamicin is rarely nephrotoxic in infants. This dissimilarity in the incidence of nephrotoxicity implies that newborn infants may have less inherent tissue sensitivity for toxicity than adults. The differences in efficacy, toxicity, and protein binding of drugs in pediatric versus adult patients raise an important question about the acceptable therapeutic range in children. Therapeutic ranges for drugs are first established in adults and often are applied directly to pediatric patients, but specific studies should be conducted in pediatric patients to define optimal therapeutic ranges of drugs.

FACTORS AFFECTING PEDIATRIC THERAPY DISEASES 5 Because most drugs are either metabolized by the liver or elim-

inated by the kidney, hepatic and renal diseases are expected to decrease the dosage requirements in patients. Nevertheless, not all diseases require lower doses of drugs; for instance, patients with cystic fibrosis require larger doses of certain drugs to achieve therapeutic concentrations.45

LIVER DISEASE Because the liver is the main organ for drug metabolism, drug clearance usually is decreased in patients with hepatic disease; however, most studies on the influence of liver disease on dosage requirements have been carried out in adults, and these data may not be extrapolated uniformly to pediatric patients. Drug metabolism by the liver depends on complex interactions among hepatic blood flow, ability of the liver to extract the drug from the blood, drug binding in the blood, and both type and severity of liver disease. Routine liver function tests—such as determinations of serum aspartate aminotransferase, serum alanine aminotransferase, alkaline phosphatase, and bilirubin levels—have not correlated consistently with drug pharmacokinetics. Further, because of different pathologic changes in various types of liver diseases, patients with acute viral hepatitis may have different abilities to metabolize drugs compared with patients with alcoholic cirrhosis.46 On the basis of hepatic extraction characteristics, drugs can be divided into two categories. The first category consists of drugs with a high hepatic extraction ratio (>0.7; such drugs include morphine, meperidine, lidocaine, and propranolol). Clearance of these drugs is affected by hepatic blood flow. A decreased hepatic blood flow in the presence of such disease states as cirrhosis and congestive heart failure is expected to decrease the clearance of drugs with high extraction ratios. The second category consists of drugs with a low extraction ratio ( 60 years, and no clinical risk factors Major surgery, age 40–60 years, with clinical risk factor(s) Acutely ill (e.g., MI, ischemic stroke, CHF exacerbation), with risk factor(s) Highest Major lower extremity orthopedic surgery Hip fracture Multiple trauma Major surgery, age > 40 years, and prior history of VTE Major surgery, age > 40 years, and malignancy Major surgery, age > 40 years, and hypercoagulable state Spinal cord injury or stroke with limb paralysis

Calf Vein Thrombosis,%

Symptomatic PE,%

Fatal PE,%

2

0.2

0.002

10–20

1–2

0.1–0.4

UFH 5000 units SC q12h Dalteparin 2500 units SC q24h Enoxaparin 40 mg SC q24h Tinzaparin 3500 units SC q24h IPC Graduated compression stockings

20–40

2–4

0.4–1.0

UFH 5000 units SC q8h Dalteparin 5000 units SC q24h Enoxaparin 40 mg SC q24h Tinzaparin 75 units/kg SC q24h IPC

40–80

4–10

0.2–5

Prevention Strategies Ambulation

Adjusted dose UFH SC q8h (aPTT > 36 s) Dalteparin 5000 units SC q24h Desirudin 15 mg SC q12h Enoxaparin 30 mg SC q12h Fondaparinux 2.5 mg SC q24h Tinzaparin 75 units/kg SC q24h Warfarin (INR = 2.0–3.0) IPC with UFH 5000 units SC q8h

IPC = intermittent pneumatic compression. From ref. 3.

in the lower extremities.3,74 The technique involves the sequential inflation of a series of cuffs wrapped around the patient’s legs. Using graded pressure, the cuffs inflate in 1- to 2-minute cycles continually throughout the day from the ankles to the thighs. IPC has been shown to reduce the risk of VTE by more than 60% following general surgery, neurosurgery, and orthopedic surgery.3 There is some theoretical concern that external compression may dislodge a previously formed clot.75 Although IPC is well tolerated and safe to use in patients who have contraindications to pharmacologic therapies, it does have a few drawbacks. It is more expensive than the use of graduated compression stockings, it is a relatively cumbersome technique, and some patients may have difficulty sleeping while using it.3 Like graduated compression hose, IPC can increase the effectiveness of pharmacologic prophylaxis. Inferior vena cava (IVC) filters, also known as Greenfield filters, provide short-term protection against pulmonary embolism in very high-risk patients by preventing the embolization of a thrombus formed in the lower extremities into the pulmonary circulation.3,76,77 Percutaneous insertion of a filter into the IVC is a minimally invasive procedure performed via fluoroscopy. Despite the widespread use of IVC filters, there are very limited data regarding their effectiveness and long-term safety. The evidence suggests that IVC filters, particularly in the absence of effective antithrombotic therapy, increase the long-term risk of recurrent DVT. In the only randomized clinical trial examining the short- and long-term effectiveness of the filters in

patients with a documented proximal DVT, treatment with IVC filters in combination with anticoagulation therapy reduced the risk of PE by more than 75% during the first 12 days following insertion.77 However, this benefit was not sustained during 2 years of follow-up, and the long-term risk of recurrent DVT was nearly twofold higher in those who received a filter. Although IVC filters can reduce the shortterm risk of PE in patients at highest risk, they should be reserved for patients in whom other prophylactic strategies cannot be used. Further, to reduce the long-term risk of VTE in association with IVC filters, pharmacologic prophylaxis is necessary, and warfarin therapy should begin as soon as the patient is able to tolerate it.


PHARMACOLOGIC STRATEGIES Several pharmacologic interventions have been evaluated extensively in numerous randomized clinical trials.3 Appropriately selected drug therapies can reduce the incidence of VTE dramatically following hip replacement, knee replacement, general surgery, myocardial infarction, and ischemic stroke (see Table 19–15). The choice of agent and dose to use for VTE prevention must be based on the patient’s level of risk for thrombosis and bleeding complications, as well as cost and the availability of an adequate drug therapy monitoring system.

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CLINICAL CONTROVERSY A recent and widely publicized study found that “low dose” warfarin (INR goal range 1.5 to 2.0) was substantially more effective than placebo for the long-term treatment of patients with an idiopathic DVT following an initial 6 months of “full intensity” therapy (INR goal range 2.0 to 3.0). However, another study found that long-term “full intensity” warfarin was more effective than the “low dose” regimen. Whereas the full-intensity warfarin appears to be slightly more effective in terms of recurrent VTE, the lower-intensity regimen is easier to manage and requires less frequent monitoring (every 8 weeks rather than every 3 to 4 weeks). It remains unclear whether the tradeoff in terms of reduced quality of life justifies long-term “full intensity” treatment.

Although a meta-analysis by the Antiplatelet Trialists’ Collaboration challenges this view, most randomized, controlled trials fail to show a significant benefit from aspirin therapy in the prevention of VTE.3,78 The ACCP Consensus Conference continues to recommend against the use of aspirin as the primary method of VTE prophylaxis. Antiplatelet drugs clearly reduce the risk of coronary artery and cerebrovascular events in patients with arterial disease, but aspirin produces a very modest reduction in VTE following orthopedic surgeries of the lower extremities. The relative contribution of platelets in the pathogenesis of venous thrombosis compared with that of arterial thrombosis can explain the reason for this difference. Venous thrombosis results primarily from venous stasis, whereas arterial thrombosis is most often the result of vascular wall injury. The most extensively studied agents for the prevention of VTE are UFH, the LMWHs, and fondaparinux.3,46 The LMWHs and fondaparinux provide superior protection against VTE compared with low-dose UFH.3,46 Their more predictable absorption when given by subcutaneous injection may be the explanation. Even so, UFH remains a highly effective, cost-conscious choice for many patient populations, provided that it is given in the appropriate dose (see Table 19–15). Low-dose UFH (5000 units every 12 hours or every 8 hours) given subcutaneously has been shown to reduce the risk of VTE by 55% to 70% in patients undergoing a wide range of general surgical procedures and following a myocardial infarction or stroke. For the prevention of VTE following hip and knee replacement surgery, the effectiveness of low-dose UFH is considerably lower.3 Adjusted-dose UFH therapy provided subcutaneously, which requires dose adjustments to maintain the aPTT at the high end of the normal range, appears to be substantially more effective than low-dose UFH in the highest-risk patient populations. However, adjusted-dose UFH has been studied in only a few relatively small clinical trials and requires frequent laboratory monitoring. The LMWHs and fondaparinux appear to provide a high degree of protection against VTE in most high-risk populations. The appropriate prophylactic dose for each LMWH product is indication-specific (see Table 19–10). There is no evidence that one LMWH is superior to another for the prevention of VTE. Fondaparinux was significantly more effective than enoxaparin in several clinical trials that enrolled patients undergoing high-risk orthopedic procedures but has not been shown to reduce the incidence of symptomatic pulmonary embolism or mortality.46 To provide optimal protection, some experts believe that the LMWHs should be initiated prior to surgery.3,79 Warfarin is a commonly used option for the prevention of VTE following orthopedic surgeries of the lower extremities.3 The evidence is equivocal regarding the relative effectiveness of warfarin

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compared with the LMWHs for the prevention of clinically important VTE events in the highest-risk populations. When used to prevent VTE, the dose of warfarin must be adjusted to maintain an INR between 2.0 and 3.0. Oral administration and low drug cost give warfarin some advantages over the LMWHs and fondaparinux. However, warfarin does not achieve its full antithrombotic effect for several days, requires frequent monitoring and periodic dosage adjustments, and carries a substantial risk of major bleeding. For these reasons, warfarin is reserved for the highest-risk patients. Furthermore, warfarin should be recommended only when a well-developed monitoring system is available.6 The optimal duration for VTE prophylaxis following surgery is not well established.3,80 Prophylaxis should be given throughout the period of risk. For general surgical procedures and medical conditions, once the patient is able to ambulate regularly and other risk factors are no longer present, prophylaxis can be discontinued. Because of the relatively high incidence of VTE in the first month following hospital discharge among patients who have undergone a lower extremity orthopedic procedure, extended prophylaxis following hospital discharge with either an LMWH, fondaparinux, or warfarin appears to be beneficial. Most clinical trials support the use of antithrombotic therapy for 21 to 35 days following total hip replacement, hip fracture repair, and knee replacement surgeries.43,81,82


PHARMACOECONOMIC CONSIDERATIONS Only a handful of studies have formally evaluated the costeffectiveness of VTE prevention strategies. The acquisition costs of graduated compression stockings, heparin, and warfarin are considerably less than those of the LMWHs, DTIs, and fondaparinux. However, the acquisition cost for drug therapy is relatively small when compared with the overall cost of care. Economic analyses must take into account the efficacy of the strategy, treatment complications, and monitoring costs. Determination of the cost-effectiveness of VTE prophylaxis is based on the premise that a reduction in future VTE events will reduce future costs.83 Furthermore, the incremental cost per patient will decrease proportionally with an increase in the frequency of VTE in the population. Stated another way, the cost of providing prophylaxis to 1000 patients will decline as the incidence of VTE in the given population increases. More expensive and effective strategies, therefore, become more cost-effective in higher-risk populations. In populations at low risk for VTE, early ambulation appears to be the most cost-effective strategy. In populations at moderate risk, the use of graduated compression stockings, the least expensive intervention, results in a lower overall cost of care, whereas low-dose UFH is estimated to increase the cost by $50 (1990 U.S. dollars) per patient when compared with no prophylaxis.84 This compares favorably with the incremental costs associated with other routinely employed preventative measures. While the LMWHs provide slightly greater reductions in the risk of VTE in patients at moderate risk of VTE, the additional cost is estimated to be $107 (1999 U.S. dollars) per patient when compared with low-dose UFH.85 Whether universal use of LMWHs in moderate-risk patients is a cost-effective strategy remains controversial. In high-risk patients, the cost-effectiveness of prevention is far greater because the incidence of VTE is higher. Following hip replacement surgery, regardless of the strategy selected, prophylaxis saves money when compared with no prophylaxis.83 The LMWHs and fondaparinux slightly increase the total mean cost of care after total hip and knee replacement when compared with low-dose

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-If VTE not objectively confirmed order appropriate diagnostic testing -Consider giving UFH 5000 units IV Objectively confirmed VTE

Consider vena cava filter

Yes

Anticoagulant contraindicated?

No

No

Contraindication to thrombolytic therapy?

Yes

Consider thrombolytic therapy

PE with evidence of shock?

No

Initiate anticoagulation therapy with: UFH or LMWH or Fondaparinux and warfarin

Yes Consider embolectomy in critically ill patients

Consider longterm warfarin therapy

Yes

SBP < 90 mm Hg vasopressor therapy

Consider outpatient treatment if patient is: -Hemodynamically stable -Free of severe renal disease -Low bleeding risk -Free of coexisting conditions that would require hospitalization

Hypercoagulable state or idiopathic VTE?

No

Warfarin therapy for 3 to 6 months

FIGURE 19–10. Treatment of venous thromboembolism.

UFH and warfarin.86,87 However, because of their superior effectiveness, the LMWHs have a significantly lower cost per DVT and PE avoided.83 Based on typical drug acquisition costs, the LMWHs and fondaparinux appear to be a cost-effective choice in the highest-risk patient populations.88


GENERAL APPROACH TO THE TREATMENT OF VTE 7 Anticoagulation therapy remains the mainstay of treatment for VTE. DVT and PE are manifestations of the same disease

process and are treated similarly.12 Full “therapeutic” doses of antithrombotic drugs not only prevent thrombus extension and embolization but also reduce the risk of long-term sequelae such as the postthrombotic syndrome, pulmonary hypertension, and recurrent thromboembolism.12,89 The standard approach is to initiate therapy with UFH by continuous intravenous infusion or a LMWH by subcutaneous injection and to make the transition to warfarin for maintenance therapy (Fig. 19–10 and Table 19–16). Newer approaches using ximelagatran alone or fondaparinux plus warfarin have been investigated recently in phase III clinical trials11,44,45,90 (Table 19–17). In rare circumstances, elimination of the obstructing thrombus is warranted, and the use of venous thrombectomy or thrombolysis can be considered.12 IVC interruption with a filter is also an option in those

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TABLE 19–16. Consensus Guidelines for VTE Treatment

Acute anticoagulation

Duration of acute treatment

Long-term anticoagulation

Recommendation

Gradea

Acute treatment of DVT or PE should be with LMWH, fondaparinux, intravenous UFH, or adjusted-dose subcutaneous UFH. The dose of UFH should be sufficient to prolong the aPTT to a range that correlates to an anti-Xa activity of 0.3 to 0.6 units mL. LMWH or fondaparinux are preferred over UFH. A LMWH is preferred in patients with cancer. Treatment with UFH, LMWH, or fondaparinux should be overlapped with warfarin for at least 5 days and can be stopped when the INR is >2.0. Most patients should have warfarin started at the same time as UFH, LMWH, or fondaparinux. Patients with cancer should be treated with a LMWH for at least 6 months. A longer period of heparin therapy (approximately 10 days) is recommended for massive PE or severe iliofemoral thrombosis. Oral anticoagulation therapy (target INR 2.5; range 2.0–3.0) should be continued for at least 3 months. If oral anticoagulation therapy is contraindicated (e.g., pregnancy), a treatment dose of LMWH or adjusted-dose UFH should be used. Patients with an idiopathic VTE, an inherited disorder of hypercoagulability, or antiphospholipid antibodies should be treated for at least 6 to 12 months and considered for indefinite therapy. Patients with two or more episodes of documented DVT should be treated indefinitely.

1A

1C +

1A 1A 1C

1A 1C

1A

1A

1A

a Refers to grade of recommendation (1A = strong recommendation applying to most patients without reservation; 1C = intermediate-strength recommendation that may change when stronger evidence becomes available; 1C + = strong recommendation that applies to most patients in most circumstances. From ref. 12.

with contraindications to anticoagulation therapy or in whom anticoagulant therapy has failed. Once the diagnosis of VTE has been confirmed objectively (see “Clinical Presentation and Diagnosis” section), anticoagulant therapy with either UFH, LMWH, or fondaparinux should be instituted as soon as possible. Although LMWHs and fondaparinux are highly effective and can be administered in the outpatient setting, most patients in the United States continue to receive intravenous UFH for the initial treatment of VTE.11 The decision to initiate therapy with an LMWH or fondaparinux on an outpatient basis should

be based on institutional resources and patient-specific variables (Table 19–18).


UNFRACTIONATED HEPARIN (UFH) The parenteral administration of UFH followed by warfarin has been the conventional treatment of patients with VTE for more than 40 years.11,89,91 Although UFH can be given by either subcutaneous or intravenous injection, continuous intravenous infusion is preferable

TABLE 19–17. Emerging Treatment Options for VTE: Major Findings from Recent Phase III Clinical Trials Trial Matisse-DVT44

Matisse-PE45

Thrive treatment90

Treatments

Duration of Trial

Recurrent VTE

Major Bleeding

Fondaparinux 7.5 mg SC q24h versus enoxaparin 1 mg/kg SC q12h All patients received warfarin (INR = 2.0–3.0) for 3 months Fondaparinux 7.5 mg SC q24h versus adjusted-dose UFH IV infusion All patients received warfarin (INR = 2.0–3.0) for 3 months Ximelagatran 36 mg PO q12h for 6 months versus enoxaparin 1 mg/kg SC q12h followed by warfarin (INR = 2.0–3.0) for 6 months

3 months

3.9% versus 4.1% (p = NS)

1.1% versus 1.2% (p = NS)

3 months

2.4% versus 3.6% (p = NS)

1.3% versus 1.1% (p = NS)

6 months

2.0% versus 2.1% (p = NS)

1.3% versus 2.2% (p = NS)

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TABLE 19–18. Outpatient Treatment Protocol for Venous Thrombosis (Kaiser Permanente of Colorado) Target Population Inclusion Relative exclusion Exclusion

Inclusion/exclusion criteria for outpatient VTE treatment Patients with objectively diagnosed VTE Patients with clinical evidence of pulmonary embolus or suspected embolism who are hemodynamically stable Arterial thromboembolism or patients who are currently receiving dialysis, actively bleeding, have had recent (within 2 weeks) major surgery/trauma, or have other severe uncompensated co-morbid conditions Recommended Procedure May vary depending on the patient’s clinical condition A. Confirm diagnosis of VTE by objective testing 1. Venous ultrasound ˙ Q ˙ scan 2. V/ 3. CT scan B. Day 1 1. Baseline laboratory evaluation a. Prothrombin time (PT) and calculated international normalized ratio (INR) b. Activated partial thromboplastin time (aPTT) c. Serum creatinine (Crs ) d. Complete blood count (CBC) with platelets 2. Medication a. LMWH or fondaparinux injections i. Enoxaparin 1 mg/kg SC q12h or ii. Enoxaparin 1.5 mg/kg SC q24h (not recommended for patients with cancer and obese patients) iii. Dalteparin 100 units/kg SC q12h or iv. Dalteparin 200 units/kg SC q24h or v. Tinzaparin 175 units/kg SC q24h or vi. Fondaparinux 7.5 mg SC q24h (5 mg if < 50 kg and 10 mg if > 100 kg) b. Warfarin sodium 5–10 mg orally every evening c. Pain medication if necessary (avoid NSAIDs) 3. Patient education a. Clinical pharmacy/nursing i. Educate patient regarding the importance of proper monitoring of anticoagulation therapy and indications for additional medical evaluation. Document activities in the medical record. ii. Teach patient how to self-administer LMWH or fondaparinux (if patient or family member unwilling or unable to self-administer LMWH injection, visiting nurse services should be arranged). Initial LMWH or fondaparinux injection should be administered in the medical office or hospital. iii. Instruct patient regarding local therapy: elevation of affected extremity, localized heat, antiembolic exercises (flexion/extension of ankle for lower extremity VTE, or hand squeezing/relaxation for upper extremity VTE). b. Pharmacy operations i. Provide back up for clinical pharmacy/nursing. Reinforce patient education regarding indication, use, monitoring, side effects, and drug interactions with antithrombotic therapy ii. Repackage LMWH or fondaparinux syringes (if indicated) in patient-specific doses and dispense 5 to 7 days of therapy. iii. Screen patient’s pharmacy profile for potential drug-drug interactions with anticoagulation therapy. c. Clinical pharmacy anticoagulation service (CPAS) enrollment i. The physician should forward outpatient VTE treatment orders to the anticoagulation service. C. Day 2 1. Laboratory evaluation: Not required on day 2 of therapy. 2. Medications: Continue LMWH or fondaparinux and warfarin as directed. 3. Anticoagulation service a. Contact patient and evaluate for symptoms of PE, clot extension, and/or bleeding. b. Arrange for visiting nursing services if family or family member is having difficulty with outpatient therapy. c. Continue reduced activity as long as pain persists (when possible, elevate extremity); increase activity as tolerated. d. Document activities in medical record. D. Day 3 1. Laboratory evaluation: Check INR. 2. Medications: Continue LMWH or fondaparinux and warfarin as directed. 3. Anticoagulation service a. Contact patient and evaluate for symptoms of PE, clot extension, and/or bleeding. b. Interpret results of INR and adjust dose of warfarin to achieve a target INR of 2.5. c. Patient activity: Continue reduced activity as long as pain persists (when possible, elevate extremity); increase activity as tolerated. d. Document activities in medical record. E. Day 4 1. Laboratory evaluation: Check INR. 2. Medications: Continue LMWH or fondaparinux and warfarin as directed. 3. Anticoagulation service a. Contact patient and evaluate for symptoms of PE, clot extension, and/or bleeding. b. Interpret results of INR and adjust dose of warfarin to achieve a target INR of 2.5. c. Patient activity: No restrictions; if pain increases, contact anticoagulation service or provider. d. Document activities in medical record.

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TABLE 19–18. (Continued) F. Day 5 1. Laboratory evaluation: Check INR and CBC with platelets. 2. Medications: Continue LMWH or fondaparinux if indicated and warfarin as directed. 3. Anticoagulation service a. Contact patient and evaluate for symptoms of PE, clot extension, and/or bleeding. b. Interpret results of INR and adjust dose of warfarin to achieve a target INR of 2.5. c. Patient activity: No restrictions; if pain increases, contact CPAS or provider. d. Document activities in medical record. G. Day 6 1. Laboratory evaluation: Check INR. 2. Medications: Continue LMWH or fondaparinux if indicated and warfarin as directed. 3. Anticoagulation service a. Contact patient and evaluate for symptoms of PE, clot extension, and/or bleeding. b. Interpret results of INR and adjust dose of warfarin to achieve a target INR of 2.5. c. If LMWH or fondaparinux has not been discontinued, continue until INR > 2.0. d. Patient activity: No restrictions; if pain increases, contact CPAS or provider. e. Document activities in medical record.

because of improved dosing precision and a lower risk of major bleeding12 (see Table 19–7). The aPTT or a suitable coagulation study should be used to monitor the effect of UFH. The infusion rate should be adjusted to maintain an appropriate therapy range corresponding to a heparin concentration of 0.2 to 0.4 units/mL or an anti-factor Xa level of 0.3 to 0.7 units/mL. Weight-based dosing of UFH achieves a therapeutic aPTT in the vast majority of patients in the first 24 hours11,29 (see Table 19–7). Failure to give a sufficient dose of heparin increases the risk of VTE recurrence. Intravenous UFH requires hospitalization with frequent monitoring and dose adjustment.12 Well-organized inpatient anticoagulation management services have been shown to improve patient care by increasing the proportion of aPTT values in the therapeutic range, reducing the length of hospital stay, and lowering total hospital costs when compared with usual care.9 However, despite the widespread use of weight-based dosing protocols, as many as 25% of patients still fail to achieve an adequate response to UFH therapy.11 There is also evidence that UFH does not prevent thrombus progression in some patients with DVT. These limitations of UFH in the acute treatment of VTE have led to the use of alternative agents.

when LMWH is given in this setting. There appears to be no difference in the efficacy or safety of once-daily versus twice-daily dosing regimens.39,93 However, a subgroup analysis in one study suggested that patients with cancer and obese patients have higher recurrence rates with once-daily enoxaparin.93 CLINICAL CONTROVERSY Some clinicians advocate strict criteria for the outpatient management of VTE in order to minimize the potential for treatment failure and bleeding complications. These criteria often exclude patients with cancer and the morbidly obese. Proponents of a less restrictive approach argue that strict exclusion criteria unnecessarily withhold outpatient treatment with LMWHs or fondaparinux from those patients who may benefit the most; namely, those with cancer. Each health care system must develop outpatient DVT criteria that fit its resources, philosophy, and patient population best.

8 Given the predictable response and the reduced need for labo-


LOW-MOLECULAR-WEIGHT HEPARIN Because of their improved pharmacokinetic and pharmacodynamic profile, as well as ease of use, the LMWHs have replaced UFH for the treatment of VTE in many institutions. The LMWHs given subcutaneously in fixed, weight-based doses (see Table 19–10) are at least as effective as UFH given intravenously for the treatment of VTE.12 A number of meta-analyses comparing LMWHs with UFH in the treatment of VTE have been conducted.12,39 These analyses demonstrate no differences in clinically important end points, including recurrent VTE, PE, major or minor bleeding, and thrombocytopenia. Surprisingly, patients who received LMWH have a significantly lower mortality rate. The reduction in mortality was seen primarily in patients with cancer. The explanation for this survival advantage is unknown, but studies are underway to further examine this observation.92 There appears to be no difference in the risk of recurrent VTE among patients who are treated on an inpatient or outpatient basis with an LMWH for DVT.39 However, outpatient treatment was associated with a slightly greater risk of major bleed, indicating the need for close monitoring

ratory monitoring with the LMWHs, stable patients with DVT who have normal vital signs, low bleeding risk, and no other comorbid conditions requiring hospitalization can be discharged early or treated entirely on an outpatient basis12,94 (see Table 19–18). The efficacy and safety of LMWHs in the home-based treatment of proximal DVT was established initially in large clinical studies.91 The results of randomized, controlled clinical trials, as well as the experience of several successful outpatient DVT treatment programs in a variety of health care settings, have led to an increased acceptance of outpatient management.11,91,94 Indeed, surveys of patients who received outpatient DVT treatment indicate a high degree of satisfaction and comfort, with 96% preferring at-home treatment. Patients presenting with PE and no evidence of hemodynamic instability are at low risk of subsequent morbidity and mortality. Recent evidence suggests that patients with submassive PE who are hemodynamically stable can be managed safely as outpatients with LMWHs or fondaparinux. However, hemodynamically unstable patients with PE should be admitted and treated with intravenous UFH.92 Patients with PE who present with shock have the highest risk of mortality and require aggressive interventions such as volume expansion,

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TABLE 19–19. Patient Education for Outpatient VTE Therapy General Information Regarding VTE and the Goals of Treatment Anticoagulant medications injections and tablets have been prescribed to prevent the blood clot from growing larger so that the body can begin to dissolve the clot. Your body may be able to completely dissolve the clot, but in some cases the clot never goes completely away; even with adequate anticoagulation therapy, some people will have chronic pain and swelling in the affected extremity; people who have had one clot are at increased risk of having future clots. Warfarin tablets take several days to begin to work; LMWH or fondaparinux injections work right away, so at first, LMWH or fondaparinux injections and warfarin tablets are used together. When the warfarin has become effective, you will be able to stop the LMWH or fondaparinux injections; you will continue to take warfarin tablets for 3 to 6 months or more to prevent blood clots from returning. It is important for you to administer your LMWH or fondaparinux and warfarin exactly as directed. Subcutaneous Injection Technique You must learn to give yourself a subcutaneous injection of LMWH or fondaparinux. Alternatively, you may have a family member or visiting nurse give it to you. If your LMWH or fondaparinux syringes were filled by the manufacturer, they can be stored at room temperature; if your syringes were filled by the pharmacy, they should be stored in the refrigerator; if you were instructed to fill your own syringes, you should prepare the syringe immediately prior to injecting its contents. If you see a bubble in the syringe, do not try to get it out; you may accidentally squirt out part of your dose. Choose an injection site on your abdomen; clean the area with alcohol; then position an uncapped syringe at a 90-degree angle; pinch the skin, stick the needle in as far as it will go, and gently but firmly push the plunger down; this will inject the medicine into the skin; when all the medication has been injected, remove the needle and dispose of it in an appropriate container. You likely will experience a burning sensation when the medication is injected; this will go away after a few minutes. Rotate injection sites from side to side; do not inject into the same site more than once; avoid the area around your navel; do not inject into any bruises. Blood Test Monitoring Regular blood tests will be required to make sure that your medication is working properly. The prothrombin time tells how quickly your blood forms a clot; it is used to tell how well warfarin is working. The INR is a way to standardize the prothrombin time between laboratories; your goal INR range is between 2.0 and 3.0; if your INR is less than 2.0, you are at higher risk for clotting, if your INR is greater than 3.0, you are at higher risk for bleeding; your dose of warfarin will be adjusted based on the results of this test. You will need to have a complete blood count test before you begin therapy and after you have been on LMWH or fondaparinux for about 5 days; this will help detect internal bleeding and the occurrence of a rare side effect of heparin therapy that can decrease a component of your blood called platelets. Warfarin Information Each strength of warfarin has a unique color; each time your refill your prescription, make sure that your new tablets are the same color as the ones you have been taking; if they are not the same color, ask your pharmacist why. Warfarin should be taken at approximately the same time each day. The most common and serious side effect of warfarin is bleeding; you should be careful to avoid situations or activities that increase your risk of injury; apply direct pressure to control bleeding from superficial cuts. Warfarin has many drug interactions; always check with your provider before taking any new medications (including over-the-counter medication and dietary supplements). Foods rich in vitamin K (green leafy vegetables, etc.) may interfere with warfarin; you do not need to avoid foods rich in vitamin K, but you should try to maintain consistent dietary habits. Alcohol can increase your risk for bleeding and interfere with warfarin therapy; drink alcohol in moderation (one to two drinks per day); avoid binge drinking. Contact Your Provider If You Experience: Persistent bleeding from a cut or scrape Blood in your urine Blood in your stool Persistent nose bleeding Increased swelling or pain in your affected extremity Go to the Emergency Department If You Experience: Shortness of breath Chest pain Coughing up blood Black, tarry-appearing stool Severe headache of sudden onset Slurred speech LMWH = low-molecular-weight heparin.

vasopressor therapy, intubation, and mechanical ventilation, in addition to antithrombotic therapy.95 Not all patients are appropriate candidates for outpatient VTE treatment. At a minimum, patients must be reliable or have adequate caregiver support.12 Patients and their caregivers must be willing and

active participants in the outpatient management of VTE (Table 19– 18 and Table 19–19). Patients who are unable or decline at-home treatment should be admitted to the hospital. These patients may opt subsequently for early discharge on LMWH or fondaparinux. Daily patient contact either in person or via telephone is essential to

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identify potential complications and to address questions and concerns promptly. During daily contacts, patients must be asked about symptoms that may indicate bleeding, thrombus extension, and PE.94 Once acute treatment with a LMWH or fondaparinux has been transitioned to long-term warfarin therapy (approximately 5 to 10 days), patient contact can occur less frequently.


FONDAPARINUX Fondaparinux has been shown in two recent clinical trials to be a safe and effective alternative to enoxaparin and intravenous UFH for the treatment of VTE (see Table 19–17). In the MATISSE DVT trial, a fixed-dose regimen of fondaparinux (7.5 mg/day) given by subcutaneous injection was compared with the standard weight-adjusted dosing of enoxaparin (1 mg/kg every 12 hours) for the acute treatment of DVT followed by 3 months of warfarin therapy. In the MATISSE PE trial, fondaparinux (7.5 mg subcutaneously every 24 hours) was compared with UFH administered by intravenous infusion. In both trials, the dose of fondaparinux was increased to 10 mg subcutaneously every 24 hours for patients who weighed more than 100 kg and reduced to 5 mg every 24 hours for those who weighed less than 50 kg. Fondaparinux received FDA approval for the acute treatment of DVT and PE in 2004. CLINICAL CONTROVERSY In a series of large, well-designed phase III clinical trials, fondaparinux was superior to enoxaparin for the prevention of VTE in patients undergoing lower extremity orthopedic surgery. However, the rate of symptomatic PE and death was not different between the two treatments in any of these studies. Furthermore, fondaparinux has not been compared with warfarin for the prevention of VTE in high-risk patients. Based on these findings, some experts contend that fondaparinux offers no clinical advantages over enoxaparin or warfarin. In addition, although there was no difference in the risk of major hemorrhage seen in the clinical trials compared with enoxaparin, some clinicians worry about the potential for bleeding with fondaparinux because it has a long half-life and cannot be reversed with protamine sulfate. Despite these concerns, some experts believe that fondaparinux should be used preferentially because asymptomatic DVTs and PEs may increase the future risk of recurrent thrombotic events and the postthrombotic syndrome.


WARFARIN Warfarin monotherapy is an unacceptable choice for the acute treatment of VTE because it does not produce a rapid anticoagulation effect and is associated with a high incidence of recurrent thromboembolism.91 However, warfarin is very effective in the longterm management of VTE and should be started concurrently with UFH, LMWH, or fondaparinux therapy.12 The acute treatment regimen should overlap with warfarin therapy for at least 5 days and until a therapeutic INR has been achieved. The initial dose of warfarin should be 5 to 10 mg (see Fig. 19–8), and it should be adjusted periodically to achieve and maintain an INR between 2.0 and 3.0. The appropriate duration of warfarin maintenance therapy requires careful consideration of the circumstances surrounding the initial thromboembolic event, the presence of ongoing thromboembolic risk factors, and the risk of bleeding.12 A major consideration in

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determining the risk of recurrent VTE once anticoagulation therapy is stopped is whether the initial thrombotic event was associated with a transient or reversible risk factor (e.g., trauma, prolonged immobility, surgery, pregnancy, estrogen use, or major medical illness). For patients in this situation, the risk of recurrence is relatively small, approximately 3% per year, and only short-term anticoagulation treatment is warranted.12 Six to 12 weeks of warfarin therapy is sufficient for patients with symptomatic isolated calf vein DVT.12 For patients with a proximal vein DVT, warfarin should be continued for at least 3 months. If the patient has a large iliofemoral DVT or PE, most experts recommend at least 6 months of therapy.96 If the patient has ongoing risk factors for recurrent VTE, such as malignancy, antiphospholipid antibodies, or an inherited disorder of hypercoagulability, the risk of recurrence during the first year after stopping treatment exceeds 10%.97 In this situation, long-term anticoagulation therapy should be considered. Several recent clinical trials provide clear evidence that long-term treatment with warfarin reduces the risk of recurrent VTE by 70% to 90% in patients with inherited deficiencies of coagulation factors (e.g., protein C or S and antithrombin) or an idiopathic VTE.63,97,98 Similar results have been observed with the long-term use of ximelagatran.99 The optimal duration for long-term anticoagulation therapy for patients with ongoing risk factors for VTE or an idiopathic VTE remains unknown.63,98 The benefit of continuing warfarin therapy longer than 2.5 years has not been studied. Further, the data supporting long-term warfarin therapy in patients with factor V Leiden, prothrombin 20210A gene mutation, increased factor VIII activity, and hyperhomocysteinemia is less compelling. For patients with stable INRs who are able to obtain follow-up blood tests at recommended intervals and who are at low risk for developing bleeding complications, long-term anticoagulation therapy can be continued indefinitely but should be reassessed annually. A decision with the patient to continue anticoagulation therapy should consider the patient’s long-term prognosis, financial resources, lifestyle, and quality of life. For patients who are unable to keep follow-up appointments every 3 to 4 weeks, low-intensity warfarin therapy (goal INR 1.5 to 2.0) can be considered following the first 6 months of therapy.63


THROMBOLYSIS AND THROMBECTOMY Most cases of VTE require only anticoagulation therapy. In some cases, however, removal of the occluding thrombus by either pharmacologic or surgical means may be warranted.12 There is a relative paucity of data supporting either thrombolysis or thrombectomy in the management of VTE, and more study clearly is needed to clarify their precise role.100 Thrombolytic agents are proteolytic enzymes that enhance the conversion of plasminogen to plasmin, which subsequently degrades the fibrin matrix. Thrombolytic therapy for DVT was once believed to improve long-term outcomes by preventing the postthrombotic syndrome.12 While thrombolytic therapy has been shown to improve venous patency, clinical trials have failed to demonstrate any sustained benefit from the routine use of thrombolytic therapy. There is no evidence that thrombolytic therapy is superior to anticoagulation therapy alone in preventing the postthrombotic syndrome. Patients who present with massive DVT and limb gangrene despite anticoagulation therapy are candidates for thrombolysis (Table 19–20). Some authorities recommend thrombolytic treatment for patients with massive iliofemoral venous thromboembolism who are at low risk for bleeding. Catheterdirected instillation of a thrombolytic agent directly into the clot has been used in recent years.101 The risk of bleeding associated with catheter-directed drug administration appears to be less than systemic

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TABLE 19–20. Thrombolysis for the Treatment of VTE Thrombolytic therapy should be reserved for patients who present with shock, hypotension, right ventricular strain, or massive DVT with limb gangrene. Diagnosis must be confirmed objectively before initiating thrombolytic therapy. Thrombolytic therapy is most effective when administered as soon as possible after PE diagnosis, but benefit may extend up to 14 days after symptom onset. Approved PE Thrombolytic Regimens Streptokinase 250,000 units intravenously over 30 minutes followed by 100,000 units/h for 24 ha Urokinase 4400 units/kg intravenously over 10 min followed by 4400 units/kg/h for 12 to 24 ha Alteplase 100 mg intravenously over 2 h Factors that increase the risk of bleeding must be evaluated before thrombolytic therapy is initiated (i.e., recent surgery, trauma or internal bleeding, uncontrolled hypertension, recent stroke or intracranial hemorrhage). Baseline laboratory tests should include CBC and blood typing in case transfusion is needed. UFH should not be used during thrombolytic therapy. The aPTT or any other anticoagulation parameter should not be monitored during the thrombolytic infusion. aPTT should be measured following the completion of thrombolytic therapy. If aPTT is less than 2.5 times control value, UFH infusion should be started and adjusted to maintain aPTT in therapeutic range. If aPTT is greater than 2.5 times control value, remeasure every 2 to 4 hours and start UFH infusion when aPTT is less than 2.5. Avoid phlebotomy, arterial puncture, and other invasive procedures during thrombolytic therapy to minimize the risk of bleeding. a

Two-hour infusions of streptokinase and urokinase are as effective and safe as alteplase. From ref. 102.

administration. Prospective clinical trials are necessary to clarify the clinical utility of catheter-directed thrombolysis in the treatment of DVT. In the management of acute PE, alteplase, streptokinase, and urokinase all have been shown to restore pulmonary artery patency more rapidly than UFH alone.102 However, this early benefit does not improve long-term patient outcomes. One week following acute treatment, clot lysis and vessel patency are similar with or without thrombolytic therapy. Thrombolytic therapy has never been shown to improve morbidity or mortality but has been associated with a substantial risk of hemorrhage. Admittedly, clinical trials to date have been underpowered to detect a benefit from thrombolytic therapy. The association of thrombolytic therapy with hemorrhage is particularly problematic because PE frequently occurs following a surgical procedure and the risk of bleeding is high.101 Given the relative lack of data to support their routine use, thrombolytic agents should be reserved for patients with PE who are most likely to benefit (see Table 19–20). Patients who have hemodynamic compromise, as evidenced by significant hypotension (systolic blood pressure 90 mm Hg or less) or severe right ventricular strain due to a large clot burden, may benefit from thrombolytic therapy.12,102 Between 5% and 10% of patients diagnosed with PE present with shock. Mortality among these patients is as high as 50%, thus justifying the risks associated with thrombolytic therapy. Although thrombolytic therapy for patients with massive PE manifested by shock and cardiovascular collapse is considered the standard of care, only one trial has demonstrated a mortality benefit.95 A significant number of hemodynamically stable patients with PE have evidence of right ventricular dysfunction and appear to be at higher risk for recurrent PE and death when treated with heparin alone.102 Some experts believe that thrombolytic therapy is beneficial in patients with evidence of right ventricular dysfunction because it restores pulmonary blood flow and reduces pulmonary artery pressure. However, convincing data are lacking.95,102 Although it is an uncommon choice, venous thrombectomy is a reasonable approach to remove a massive obstructive thrombus in a patient with significant iliofemoral venous thrombosis, particularly if the patient is either not a candidate for, or has not responded to, thrombolysis.12 In cases of chronic PE—where persistent emboli produce progressive pulmonary hypertension, hypoxemia, and rightsided heart failure—surgical embolectomy offers greater benefit than

anticoagulants and may be the treatment of choice. The surgical technique has been refined over the past 20 years. The procedure uses a balloon catheter to extract the thrombus while the patient is under general anesthesia. Fluoroscopy and venography guide the procedure. Balloon angioplasty, with or without stent placement, can be used if a focal iliac vein stenosis is discovered. Full-dose anticoagulation therapy is essential during the entire operative and postoperative periods. These patients still need chronic anticoagulation therapy for the usual recommended duration.


VENA CAVA INTERRUPTION Anticoagulation therapy is the accepted standard for treating DVT and PE. However, an IVC filter may be indicated in special situations when anticoagulants are ineffective or unsafe, including (1) in patients with an absolute contraindication to anticoagulation therapy due to active bleeding or anticipated bleeding from a predisposing lesion, (2) in patients with a massive PE who survive but in whom recurrent embolism may be fatal, or (3) in patients who have recurrent VTE despite adequate anticoagulation therapy.103 Interruption of the IVC can be accomplished with an occlusive filter, often called a Greenfield filter, inserted percutaneously through the femoral or jugular vein. There is little evidence to support the widespread use of IVC filters. IVC filters have not been shown to reduce the risk of rehospitalization for PE. Indeed, the permanent IVC interruption appears to increase the long-term risk for recurrent DVT presumably owing to the accumulation of thrombus on the filter resulting in venous stasis.103 Whether patients with permanent IVC filters should receive anticoagulant therapy remains unresolved, but many clinicians opt to continue warfarin therapy indefinitely whenever possible. Given these concerns, retrievable filters that can be removed after the period of greatest risk for PE have been developed.


ANCILLARY THERAPY In addition to anticoagulant therapy for patients with proximal DVT, wearing graduated compression stockings can reduce the risk of developing the postthrombotic syndrome by as much as 50%.89 To be

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TABLE 19–21. UFH and LWMH Use During Pregnancy Acute treatment

LMWH Enoxaparin 1 mg/kg SC q12h or 1.5 mg/kg q24h or Dalteparin 100 units/kg SC q12h or 200 units/kg q24h or Tinzaparin 175 units/kg SC q24h or UFH Initiate using weight-based intravenous therapy, and adjust dose to achieve therapeutic aPTT for at least 5 days. Transition to SC adjusted-dose UFH administered q8–12h with midinterval aPTT in the therapeutic range.a

Long-term treatmentb

LMWH Maintain initial LMWH dose regimen throughout pregnancy or Alter LMWH dose in proportion to any weight change (usually gain) or Obtain monthly anti-Xa level measurements 4 to 6 hours after morning dose and adjust LMWH dose to achieve an anti-Xa level of 0.5 to 1.2 units/mL if twice-daily dosing or 1.0 to 2.0 units/mL if once-daily dosing or UFH Obtain monthly aPTT at the midpoint of the dosing interval and adjust UFH dose as indicated. Elective induction of labor Discontinue UFH or LMWH 24 hours prior to induction. Initiate therapeutic doses of UFH by IV infusion and discontinue 4 to 6 hours prior to expected time of delivery if risk of recurrent VTE is deemed high. Spontaneous labor For LMWH, if there is a reasonable expectation that significant anticoagulant effect will be present at time of delivery, (1) epidural should be avoided, and (2) reversal with protamine sulfate may be considered. For UFH, monitor the aPTT and reverse with protamine sulfate if aPTT is prolonged near the time of delivery. Postpartum Commence UFH or LMWH as soon as safely possible (usually 12 hours following delivery). Concurrently initiate warfarin therapy and discontinue UFH or LMWH when the INR is 2.0 or greater. Continue anticoagulants for at least 4 weeks following delivery. Warfarin can be used safely by women who are breast-feeding.

Issues at time of delivery

a

Anti-Xa monitoring is preferred because the relationship between aPTT and heparin levels differs in pregnant compared with nonpregnant patients. As pregnancy progresses, the volume of distribution of LMWH changes; golmerular filtration rate increases, and most women gain weight. From ref. 121. b

effective, graduated compression stockings must fit properly. Antiembolic leg exercise also may be useful. To perform the exercise, patients should elevate the legs above the hips (7 to 10 degrees) with feet supported. The patient then flexes one foot at a time back and forth for 3 to 5 minutes or until the calf muscle group is fatigued. This exercise should be repeated four to six times daily.104 Patients also should be instructed not to remain in a sitting position for more than 20 minutes without ambulating briefly or stretching the leg for a few minutes. Strict bed rest traditionally was recommended following acute DVT based on the assumption that leg movement would dislodge the clot, resulting in PE. However, the evidence contradicts this assumption. Ambulation in conjunction with graduated compression stockings results in faster reduction in pain and swelling with no apparent increase in the rate of clot embolization.12 Patients should be encouraged to ambulate as much as their symptoms permit. If pain and swelling increase with ambulation, the patient should be instructed to lie down and elevate the affected leg until symptoms subside.


TREATMENT OF VTE IN SPECIAL POPULATIONS
Pregnancy The use of anticoagulation therapy for the treatment of DVT or PE in pregnant women is common.22 UFH and LMWHs are the preferred

anticoagulants for use during pregnancy (Table 19–21). They do not cross the placenta, and evidence suggests that they are safe for the fetus.22,105 Warfarin should be avoided because it crosses the placenta and can produce fetal bleeding, central nervous system abnormalities, and embryopathy. The DTIs also cross the placenta. To date, fondaparinux has not been formally evaluated in pregnant patients. Long-term UFH therapy has been linked to significant bone loss and osteoporosis, requires multiple daily injections, and must be monitored frequently (every 1 to 2 weeks) throughout pregnancy. Because of these limitations, many experts recommend the use of LMWHs over UFH throughout pregnancy.22


Pediatric Patients VTE in children has become increasingly common secondary to prematurity, cancer, trauma, surgery, congenital heart disease, and SLE.35 Children often develop DVTs associated with an indwelling central venous catheter. In contrast to adults, children rarely develop idiopathic VTE. Anticoagulation with UFH and warfarin remains the most frequently used approach for the treatment of VTE in pediatric patients.35 The recommended target aPTT and INR ranges, as well as the duration of therapy, are extrapolated from clinical trials in adults. The

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recommended initial bolus dose of UFH is 75 to 100 units/kg given intravenously over 10 minutes, followed by a maintenance infusion of 28 units/kg per hour for infants 2 to 12 months of age and 20 units/kg per hour for children 1 year of age or older. Subsequent adjustments should be made every 4 to 6 hours to maintain the aPTT within the institution-specific therapeutic range. The usual warfarin starting dose is 0.2 mg/kg, with a maximum of 10 mg.35,106 Infants require higher doses of warfarin per kilogram to maintain a therapeutic INR compared with teenagers and adults (mean doses 0.33 mg/kg, 0.09 mg/kg, and 0.04 to 0.08 mg/kg, respectively). The INR target range is 2.0 to 3.0. Frequent INR monitoring and warfarin dose adjustments typically are required. When compared with adults, only 10% to 20% of pediatric patients can be monitored safely once monthly. Obtaining coagulation monitoring tests in pediatric patients is problematic because many have poor or nonexistent venous access. To address this problem, many clinicians recommend using finger-stick blood samples with a portable PT monitor. Since LMWHs have low drug-interaction potential, are less likely to cause HIT or osteoporosis, and require less frequent laboratory testing, they are an attractive alternative in pediatric patients.35 Enoxaparin, dalteparin, tinzaparin, and reviparin have been evaluated in pediatric patients. Most experts recommend that anti-factor Xa activity be monitored and the dose adjusted to maintain anti-factor Xa levels between 0.5 and 1.0 unit/mL. Compared with adults, children younger than 2 to 3 years of age or weighing less than 5 kg have higher per-kilogram dose requirements to achieve a “therapeutic” response. The doses of LMWH for older children generally are similar to the weight-adjusted doses used in adults.35 Warfarin can be initiated concurrently with UFH or LMWH therapy. Therapy should be overlapped for a minimum of 5 days and until the INR is therapeutic. Warfarin should be continued for at least 3 months. Thrombolysis and thrombectomy have been employed successfully in pediatric patients, but published data are very limited.

altering tumor angiogenesis and metatasis.20 In vitro data suggest that small to midsized heparin molecules have antiangiogenic properties. Warfarin therapy in cancer patients is often complicated by drug interactions (e.g., chemotherapy and antibiotics) and the need to frequently interrupt therapy for invasive procedures (e.g., thoracentesis, percutaneous biopsy, and abdominal paracentesis).107 Maintaining stable INR control is more difficult in this patient population due to nausea, anorexia, and vomiting. Two recent randomized trials provide evidence that long-term LMWH therapy for VTE in cancer patients significantly decreases the rate of recurrent VTE without increasing bleeding risks compared with traditional therapy with oral anticoagulants.108,109 In one relatively small study in cancer patients with VTE, fixed-dose subcutaneous enoxaparin for 3 months appeared to be more effective than conventional warfarin therapy, with only 10.5% of enoxaparintreated patients compared with 21% warfarin-treated patients reaching the composite outcome of major bleeding and recurrent VTE ( p = .09).108 In the Comparison of LMWH versus Oral Anticoagulation Therapy for the Prevention of Recurrent Venous Thrombosis (CLOT) trial, continuous treatment with dalteparin for 6 months was compared with conventional therapy with dalterparin followed by warfarin in cancer patients following an acute VTE.109 The probability of recurrent VTE was reduced by nearly 50% in the long-term dalteparin treatment group, from 17.4% to 8.8% ( p = .0017). There was no difference in the rate of major bleeding. While this provides compelling data that cancer patients should be given LMWH instead of warfarin for the long-term treatment of VTE, the economic implications of this strategy have not yet been evaluated. In the absence of insurance coverage to offset the relatively high cost of long-term LMWH therapy, most patients are unable to afford it.


PHARMACOECONOMIC CONSIDERATIONS
Patients with Cancer VTE is a frequent complication of malignancy.92 Further, compared with patients without cancer, the rate of recurrent VTE in patients with cancer is threefold higher, and the risk of bleeding is two- to sixfold higher.107 Several meta-analyses and one randomized clinical trial comparing LMWH with UFH for the treatment of VTE have shown a survival advantage for patients with cancer who received LMWHs. While the reduction in mortality may be attributable to a decline in fatal PE, several other mechanisms have been postulated, including

Hospitalization is the main cost driver in the management of VTE.94 Although the drug acquisition cost for the LMWHs is substantially higher than UFH, avoiding hospitalization dramatically decreases the overall costs of VTE treatment. A number of cost-effectiveness analyses using decision modeling suggest that the treatment of DVT with LMWHs is more cost effective than the treatment with UFH in both inpatient and outpatient settings.110 Based on this decision model, the LMWHs will reduce overall health care cost if as few as 8% of patients are treated entirely on an outpatients basis or 13% of patients are discharged from the hospital early.

HEPARIN-INDUCED THROMBOCYTOPENIA

ETIOLOGY AND PATHOPHYSIOLOGY OF HIT

9 Heparin-induced thrombocytopenia (HIT) is an uncommon

but extremely serious adverse effect associated with heparin use.34,111 The immune-mediated platelet activation and thrombin generation seen during HIT can lead to severe and unusual thrombotic complications. Morbidity and mortality associated with HIT are disturbingly high—up to 50% of patients who develop the disorder will suffer a thrombotic complication or die within 30 days in the absence of treatment. The diagnosis of HIT is based on clinical and laboratory findings that confirm heparin antibody formation and platelet activation. To prevent the thrombotic complications associated with HIT, prompt discontinuation of heparin and initiation of an alternative anticoagulant therapy is imperative.

Two types of thrombocytopenia associated with heparin use have been described.7,34,111 As many as of 25% of patients receiving heparin therapy develop a benign, mild reduction in platelet counts referred to as non-immune-mediated heparin-associated thrombocytopenia (HAT) or previously called HIT type 1. HAT produces a transient fall in platelet count that occurs early, typically between days 2 and 4, during the course of therapy. The degree of thrombocytopenia is usually mild, with platelet counts rarely going below 100,000/mm3 . It is not necessary to discontinue heparin therapy in these patients because platelet counts generally rebound to baseline values despite continued use. The exact mechanism of HAT is unknown, but it may be the result of platelet aggregation, a dilutional effect, or diminished platelet

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Heparin

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PF4 Endothelium

5

1 4 3 2

IgG

Platelet

FIGURE 19–11. Pathogenesis of heparininduced thrombocytopenia.

production often seen in acutely ill patients. No clinical sequelae are associated with this benign phenomenon. The second type of thrombocytopenia associated with heparin use is known as immune-mediated HIT (formally known as HIT type 2).7,34,111 HIT is a severe pathologic adverse effect of heparin with a significant potential to cause thrombotic complications. The time course and magnitude of thrombocytopenia associated with HIT differ from those of HAT. Platelets counts typically begin to fall after 5 or more days of continuous heparin use, most often between days 7 and 14 of therapy. The development of thrombocytopenia can be delayed up to 20 days in patients naive to heparin therapy. Conversely, so-called rapid-onset HIT can occur in 24 to 48 hours in patients with recent exposure to heparin (i.e., in the previous 3 to 6 months).112 Platelet counts commonly fall below 100,000/mm3 but rarely nadir lower than 20,000/mm3 . In some cases, overt thrombocytopenia may not occur, but a drop in platelet count greater than 50% from baseline is considered indicative of HIT. The frequency of immune-mediated HIT is related most powerfully to the duration and type of heparin used and, to a lesser extent, to the dose and route of administration.111 The incidence of HIT associated with intravenous full-dose UFH given for prolonged periods is significantly higher than that of low-dose subcutaneous UFH or LMWHs. The estimated overall incidence of HIT after 5 days of UFH use is 1% to 3%, but the cumulative incidence may be as high as 6% after 14 days of continuous intravenous use. LMWHs are associated with a significantly lower risk of HIT (110 mm Hg at time of treatment


GENERAL INFORMATION REGARDING SAFETY AND EFFICACY (INCLUDING PIVOTAL CLINICAL TRIALS)
tPA The effectiveness of intravenous (IV) tPA in the treatment of ischemic stroke was demonstrated in the National Institutes of Neurologic Disorders and Stroke (NINDS) rt-PA Stroke Trial, published in 1995.21

In 624 patients treated in equal numbers with either tPA 0.9 mg/kg IV or placebo within 3 hours of the onset of their neurologic symptoms, 39% of the treated patients achieved an “excellent outcome” at 3 months compared with 26% of the placebo patients. An “excellent outcome” was defined as minimal or no disability by several different neurologic scales. This beneficial effect was reported despite a 10-fold increase in the risk of symptomatic intracerebral hemorrhage in the tPA-treated patients (0.6% versus 6.4%). Overall mortality was not different between the two groups (17% with tPA and 21% with placebo). Patients with very severe symptoms at baseline (NIH Stroke Scale [NIHSS] > 20) and early ischemic changes on CT scan were shown to be at highest risk for the development of symptomatic intracranial hemorrhage. Even in patients at highest risk for bleeding, however, those receiving tPA had better outcomes at 90 days than those who received placebo.21 The publication of the NINDS trial results significantly changed the way in which acute stroke is managed in the community, promoting the development of acute stroke teams and emphasis on the early diagnosis and treatment of acute stroke. Currently, only 2% to 3% of ischemic stroke patients in the United States receive tPA, primarily owing to failure of patients to present in time to facilities equipped to administer the therapy safely.24,25 Hemorrhage rates associated with tPA use in the community have been reported to be similar to those reported in the NINDS trial (5%),24 but significantly higher rates (up to 15%) have been reported when a strict protocol is not followed.25


Aspirin 5 The use of early aspirin to reduce long-term death and disability

owing to ischemic stroke is supported by two large, randomized clinical trials. In the International Stroke Trial (IST),23 aspirin 300 mg/day significantly reduced stroke recurrence within the first 2 weeks without effect on early mortality, resulting in a significant decrease in death and dependency at 6 months. In the Chinese Acute Stroke Trial (CAST),22 aspirin 160 mg/day reduced the risk of recurrence and death in the first 28 days, but long-term death and disability were not different than with placebo. In both trials, a small but significant increase in hemorrhagic transformation of the infarction was demonstrated. Overall, the beneficial effects of early aspirin have been embraced and adopted into clinical guidelines.

TABLE 20–4. Recommendations for Pharmacotherapy of Ischemic Stroke

Acute Treatment

Secondary Prevention Noncardioembolic

Cardioembolic (esp. atrial fibrillation) All

Primary Agents

Alternatives

tPA 0.9 mg/kg IV6,17 (maximum 90 kg) over 1 hour in selected patients within 3 hours of onset. ASA 160–325 mg daily6,17 started within 48 hours of onset

tPA (various doses) intraarterially up to 6 hours after onset in selected patients

Aspirin 50–325 mg daily6 Clopidogrel 75 mg daily6 Asprin 25 mg + extended-release dipyridamole 200 mg twice daily6 Warfarin (INR = 2.5)6

Ticlopidine 250 mg twice daily6

ACE inhibitor + diuretic or ARB45 blood pressure lowering33,34 Statin39

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Antiplatelet Agents All patients who have had an acute ischemic stroke or TIA should receive long-term antithrombotic therapy for secondary prevention.6 In patients with noncardioembolic stroke, this will be some form of antiplatelet therapy. In a recent meta-analysis, the overall benefit of antiplatelet therapy in patients with atherothrombotic disorders was estimated to be 22%.26 Aspirin is the best-studied of the available agents and, until recently, was considered the sole first-line agent. However, published literature has supported the use of clopidogrel and the aspirin plus extended-release dipyridamole combination product (ERDP + ASA) as additional first-line agents in secondary stroke prevention. The efficacy of clopidogrel as an antiplatelet agent in atherothrombotic disorders was demonstrated in the CAPRIE trial.27 In this study of more than 19,000 patients with a history of either myocardial infarction (MI), stroke, or peripheral arterial disease (PAD), clopidogrel 75 mg/day was compared with aspirin 325 mg/day for its ability to decrease MI, stroke, or cardiovascular death. In the final analysis, clopidogrel was slightly (8% relative risk reduction [RRR]) more effective than aspirin (p = .043) and had a similar incidence of adverse effects. It is not associated with the blood dyscrasias (neutropenia) common with its congener, ticlopidine, and is used widely in patients with atherosclerosis. In the European Stroke Prevention Study 2 (ESPS-2), aspirin 25 mg and extended-release dipyridamole (ERDP) 200 mg twice daily were compared alone and in combination with placebo for their ability to reduce recurrent stroke over a 2-year period.28 In a total of more than 6600 patients, all three treatment groups were shown to be superior to placebo—aspirin alone, 18% RRR; ERDP alone, 16% RRR; and the combination, 37% RRR. Importantly, this study was the first to show a significant benefit of combination antiplatelet therapy in stroke prevention, with the combination demonstrating a significant advantage over the aspirin-alone group (23% RRR; p = .006) and the ERDPalone group (24% RRR; p = .002). Headache resulting in discontinuation occurred in about 15% of the ERDP groups (four times more common than in the placebo group), and the aspirin-treated patients, even at the low dose of 50 mg/day, experienced significantly more bleeding than the other groups. The combination of aspirin 25 mg and ERDP 200 mg twice daily is a highly effective treatment to prevent recurrence in patients with stroke or TIA. No data exist on the ability of this combination to reduce MI and/or cardiovascular death in patients with other indications for antiplatelet therapy.


Warfarin for the prevention of 6 Warfarin is the most effective treatment 10,11,29,30

stroke in patients with atrial fibrillation. In patients with atrial fibrillation and a recent history of stroke or TIA, the risk of recurrence places these patients in one of the highest risk categories known. In the European Atrial Fibrillation Trial (EAFT), 669 patients with nonvalvular atrial fibrillation (NVAF) and a prior stroke or TIA were randomized to either warfarin (INR = 2.5–4), aspirin 300 mg/day, or placebo. Patients in the placebo group experienced stroke, MI, or vascular death at a rate of 17% per year compared with 8% per year in the warfarin group and 15% per year in the aspirin group. This represents a 53% reduction in risk with anticoagulation.10 Subsequent studies in the primary prevention of stroke in patients with NVAF have demonstrated that targeting an international normalization ratio (INR) of 2.5 prevents stroke with the lowest bleeding risk (SPAF III); therefore,

STROKE

421

a target INR of 2.5 is recommended in the secondary prevention of stroke.11,29,30 Use of warfarin in the secondary prevention of noncardioembolic stroke was addressed in the Warfarin Aspirin Recurrent Stroke Study.31 In 2206 patients with recent stroke, warfarin (INR = 1.4–2.8) was not superior to aspirin 325 mg/day in the prevention of recurrent events. This led many clinicians to abandon the practice of using warfarin as an alternative agent in patients who suffered recurrent events while on antiplatelet therapy in favor of combination or alternate antiplatelet therapy.


Blood Pressure Lowering 7 Elevated blood pressure is very common in ischemic stroke

patients, and treatment of hypertension in these patients is associated with a decreased risk of stroke recurrence.32 In the PROGRESS study, a multinational stroke population (40% Asian) was randomized to receive either blood pressure lowering with the angiotensinconverting enzyme (ACE) inhibitor perindopril (with or without the thiazide diuretic indapamide) or placebo.33 Treated patients achieved an overall 9/4 mm Hg blood pressure reduction, and this was associated with a 28% reduction in stroke recurrence. In the patients who received the combination treatment (clinician’s discretion), the blood pressure lowering achieved was 12/5 mm Hg, and this was associated with an even larger reduction in stroke recurrence (43%). Similar results were achieved in patients with and without hypertension. Based on the results of this study and other evidence of the tolerability and vascular protective properties of the ACE inhibitors, the Joint National Committee (JNC7) recommends an ACE inhibitor and a diuretic for the reduction of blood pressure in patients with stroke or TIA.34 8 Blood pressure lowering in the acute stroke period (first 7 days) may result in decreased cerebral blood flow and worsened symptoms; therefore, recommendations are limited to patients out of the acute stroke period.


Statins 9 The statins have been shown to reduce the risk of stroke by ap-

proximately 30% in patients with coronary artery disease and elevated plasma lipids.35−37 The National Cholesterol Education Program (NCEP) considers ischemic stroke or TIA to be a coronary “equivalent” and has recommended the use of statins to achieve a lowdensity lipoprotein (LDL) concentration of less than 100 mg/dL.38 More recently, the Heart Protection Study was published, and it provided evidence that simvastatin 40 mg/day reduced stroke risk in high-risk individuals (including patients with prior stroke) by 25% (p < .0001), even in patients with LDL concentrations of less than 116 mg/dL.39 The investigators also showed that this practice is extremely safe, with an excess incidence of myopathy of 0.01%. The study even recommended abandoning the routine monitoring of liver function tests in these individuals because elevations are rarely significant or sustained. Other evidence in primary prevention of patients with hypertension suggests that similar stroke risk reduction can be achieved with other statins in patients with normal total cholesterol values.40 Statin therapy is an effective way to reduce stroke risk and should be considered in all ischemic stroke patients.


Heparin for Prophylaxis of Deep Vein Thrombosis (DVT) The use of low-molecular-weight heparins or low-dose subcutaneous unfractionated heparin (5000 units twice daily) can be recommended

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for the prevention of DVT in hospitalized patients with decreased mobility owing to their stroke and should be used in all but the most minor strokes.6


ALTERNATIVE DRUG TREATMENTS
ASPIRIN PLUS CLOPIDOGREL In the MATCH study, clopidogrel in combination with aspirin 75 mg daily was no better than clopidogrel alone in secondary stroke prevention.43 However, the combination has been studied in patients with acute coronary syndromes and patients undergoing percutaneous coronary interventions and shown to be significantly more effective than aspirin alone in reducing MI, stroke, and cardiovascular death.41,42 Also, when clopidogrel was used with aspirin, the risk of life-threatening bleeding increased from 1.3% to 2.6%.43 This combination can only be recommended in patients with ischemic stroke and a recent history of MI or other coronary events and only with ultra-low-dose aspirin to minimize bleeding risk.44


ANGIOTENSIN II RECEPTOR ANTAGONISTS (ARBS) Angiotensin II receptor antagonists (ARBs) also have been shown to reduce the risk of stroke. In the LIFE study, losartan and metoprolol were compared for their ability to reduce blood pressure and prevent cardiovascular events in a group of severely hypertensive patients.45 Despite similar reductions in blood pressure of approximately 30/16 mm Hg, the losartan group experienced a 24% reduction in the risk of stroke. The ARBs should be considered in patients unable to tolerate ACE inhibitors (LIFE) after acute ischemic stroke.


HEPARINS The use of full-dose unfractionated heparin in the acute stroke period has never been proved to positively affect stroke outcome, and it significantly increases the risk of intracerebral hemorrhage.6 Trials of low-molecular-weight heparins or heparinoids have been largely negative and do not support their routine use in stroke patients.46−48 Other potential but unproven uses for treatment doses of either unfractionated or low-molecular-weight heparins include bridge therapy in patients being initiated on warfarin, carotid dissection, or continuous worsening of ischemia despite adequate antiplatelet therapy.6


DRUG CLASS INFORMATION
Aspirin Aspirin exerts its antiplatelet effect by irreversibly inhibiting cyclooxygenase, which, in platelets, prevents conversion of arachidonic acid to thromboxane A2 (TXA2 ), which is a powerful vasoconstrictor and stimulator of platelet aggregation. Platelets remain impaired for their life span (5 to 7 days) after exposure to aspirin. Aspirin also inhibits prostacyclin (PGI2 ) activity in the smooth muscle of vascular walls. PGI2 inhibits platelet aggregation, and the vascular endothelium can synthesize prostacyclin such that the platelet antiaggregating effect is maintained. The suppression of PGI2 production by aspirin has been found to be dose- and duration-related; the higher the dose, the longer the cyclooxygenase production is suppressed. Therefore, the lower the aspirin dose, the less effect on prostacyclin.6 The optimal dose of aspirin is still under study, but it should be the dose that inhibits TXA2 with the least amount of prostacyclin inhibition. It has been shown that an aspirin dose of 325 mg/day will inhibit TXA2 but will not significantly inhibit PGI2 production. There is probably a point at which lower doses of aspirin do not completely block TXA2 , and recent studies indicate that the lowest effective dose may be in the range of 50 mg/day.50 Upper gastrointestinal (GI) discomfort and bleeding are the most common adverse effects of aspirin and have been shown to be dose-related. The highest rates of GI bleeding (5%) have been reported in patients receiving 1200 mg/day as compared with rates of 2% in patients taking the more commonly prescribed, 300 mg/day. Upper GI symptoms are much more common than frank bleeding, however, with 40% of patients affected at 1200 mg/day and 25% at 300 mg/day.51 In the ESPS-2 study, even 50 mg/day of aspirin was associated with a twofold increase in bleeding over the placebo group.28 Low doses ( 8.5 (>750)

Chylomicrons, VLDL

I, V

VLDL, LDL

IIb

VLDL, IDL; LDL normal

III

Hypertriglyceridemia and Hypercholesterolemia Combined hyperlipidemia TG = 2.8–8.5 (250–750); TC = 6.5–13 (250–500)

Dysbetalipoproteinemia

TG = 2.8–8.5 (250–750); TC = 6.5–13 (250–500)

Elevated

Phenotype

Clinical Signs Usually develop xanthomas in adulthood and vascular disease at 30–50 years Usually develop xanthomas in adulthood and vascular disease in childhood Usually asymptomatic until vascular disease develops; no xanthomas Asymptomatic; may be associated with increased risk of vascular disease May be asymptomatic; may be associated with pancreatitis, abdominal pain, hepatosplenomegaly As above

Usually asymptomatic until vascular disease develops; familial form also may present as isolated high TG or an isolated high LDL cholesterol Usually asymptomatic until vascular disease develops; may have palmar or tuboeruptive xanthomas

TC = total cholesterol; TG = triglycerides; LPL = lipoprotein lipase.

or, rarely, a defect of internalizing the LDL-R complex into the cell after normal binding. Homozygotes have essentially no functional LDL receptors. This leads to a lack of LDL degradation by cells and unregulated biosynthesis of cholesterol, with total cholesterol and LDL cholesterol levels being inversely proportional to the deficit in LDL receptors. Heterozygotes have only about one-half the normal number of LDL receptors, total cholesterol levels in the range of 300–600 mg/dL, and cardiovascular events beginning in the third and fourth decades of life. Familial LPL deficiency is a rare, autosomal recessive trait characterized by a massive accumulation of chylomicrons and a corresponding increase in plasma triglycerides, or a type I lipoprotein pattern. VLDL concentration is normal. The presenting manifestations include repeated attacks of pancreatitis and abdominal pain, eruptive cutaneous xanthomatosis, and hepatosplenomegaly beginning in childhood. Symptom severity is proportional to dietary fat intake and, consequently, to the elevation of chylomicrons. LPL normally is released from vascular endothelium or by heparin and hydrolyzes chylomicrons and VLDL (see Fig. 21–3). Diagnosis is based on low or absent enzyme activity with normal human plasma or apolipoprotein C-II, a cofactor of the enzyme. Accelerated atherosclerosis is not associated with this disease. Abdominal pain, pancreatitis, eruptive xanthomas, and peripheral polyneuropathy characterize type V (VLDL and chylomicrons). Symptoms may occur in childhood, but usually the disorder is expressed at a later age. The risk of atherosclerosis is increased with this disorder. These patients commonly are obese, hyperuricemic, and diabetic, and alcohol intake, exogenous estrogens, and renal insufficiency tend to be exacerbating factors. Patients with familial type III hyperlipoproteinemia (also called dysbetalipoproteinemia, broad-band, or β-VLDL) develop these

clinical features after 20 years of age: xanthoma striata palmaris (yellow discoloration of the palmar and digital creases), tuberous or tuberoeruptive xanthomas (bulbous cutaneous xanthomas), and severe atherosclerosis involving the coronary arteries, internal carotids, and abdominal aorta. A defective structure of apolipoprotein E does not allow normal hepatic surface receptor binding of remnant particles derived from chylomicrons and VLDL (known as IDL); aggravating factors such as obesity, diabetes, or pregnancy may promote overproduction of apo-B–containing lipoproteins. Although homozygosity for the defective allele (E2 /E2 ) is common (1 in 100), only 1 in 10,000 express the full-blown picture, and interaction with other genetic or environmental factors, or both, is needed to produce clinical disease. Familial combined hyperlipidemia is characterized by elevations in total cholesterol and triglycerides, decreased HDL, increased apolipoprotein B, and small, dense LDL.25 It is associated with premature CHD and may be difficult to diagnose because the lipid levels do not consistently display the same pattern. Type IV hyperlipoproteinemia is common and occurs in adulthood primarily in patients who are obese, diabetic, and hyperuricemic and do not have xanthomas. It may be secondary to alcohol ingestion and can be aggravated by stress, progestins, oral contraceptives, thiazides, or β-blockers. Two genetic patterns occur in type IV hyperlipoproteinemia: familial hypertriglyceridemia, which does not carry a great risk for premature CAD, and familial combined hyperlipidemia, which is associated with increased risk of cardiovascular disease. Rare forms of lipoprotein disorders may include hypobetalipoproteinemia, abetalipoproteinemia, Tangier disease, LCAT deficiency (fish-eye disease), cerebrotendinous xanthomatosis (CTX),

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CHAPTER 21 TABLE 21–5. Secondary Causes of Lipoprotein Abnormalities Hypercholesterolemia

Hypertriglyceridemia

Hypocholesterolemia

Low HDL

Hypothyroidism Obstructive liver disease Nephrotic syndrome Anorexia nervosa Acute intermittent porphyria Drugs: Progestins, thiazide diuretics, glucocorticoids, β-blockers, isotretinoin, protease inhibitors, cyclosporine, mirtazapine, sirolimus Obesity Diabetes mellitus Lipodystrophy Glycogen storage disease Ileal bypass surgery Sepsis Pregnancy Acute hepatitis Systemic lupus erythematosus Monoclonal gammopathy: multiple myeloma, lymphoma Drugs: Alcohol, estrogens, isotretinoin, beta blockers, glucocorticoids, bile-acid resins, thiazides; asparaginase, interferons, azole antifungals, mirtazapine, anabolic steroids, sirolimus, bexarotene Malnutrition Malabsorption Myeloproliferative diseases Chronic infectious diseases: AIDS, tuberculosis Monoclonal gammopathy Chronic liver disease Malnutrition Obesity Drugs: non-ISA β-blockers, anabolic steroids, probucol, isotretinoin, progestins

and sitosterolemia. Most of these rare lipoprotein disorders do not result in premature atherosclerosis, with the exceptions of familial LCAT deficiency, cerebrotendinous xanthomatosis, and sitosterolemia with xanthomatosis. Their treatment consists of dietary restriction of plant sterols (sitosterolemia with xanthomatosis) and chenodeoxycholic acid (CTX) or, potentially, blood transfusion (LCAT deficiency). C L I N I C A L P R E S E N TAT I O N GENERAL

r Most patients are asymptomatic for many years prior to clinically evident disease.

r Patients with the metabolic syndrome may have three or more of the following: abdominal obesity, atherogenic dyslipidemia, raised blood pressure, insulin resistance with or without glucose intolerance, prothrombotic state, or proinflammatory state. SYMPTOMS

r None to chest pain, palpitations, sweating, anxiety, shortness of breath, loss of consciousness or difficulty with speech or movement, abdominal pain, and sudden death.

HYPERLIPIDEMIA

435

SIGNS

r None to abdominal pain, pancreatitis, eruptive xanthomas, peripheral polyneuropathy, high blood pressure, body mass index greater than 30 kg/m2 , or waist size greater than 40 inches in men (35 inches in women). LABORATORY TESTS

r Elevations in total cholesterol, LDL, triglycerides, apolipoprotein B, and C-reactive protein.

r Low HDL.

OTHER DIAGNOSTIC TESTS

r Lipoprotein(a), homocysteine, serum amyloid A, and small, dense LDL (pattern B).

r Various screening tests for manifestations of vascular disease (ankle-brachial index, exercise testing, magnetic resonance imaging) and diabetes (fasting glucose, oral glucose tolerance test).

PATIENT EVALUATION A fasting lipoprotein profile (FLP) including total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides should be measured in all adults 20 years of age or older at least once every 5 years.1 If the profile is obtained in the nonfasted state, only total cholesterol and HDL cholesterol will be usable because LDL cholesterol usually is a calculated value; if total cholesterol is 200 mg/dL or more, or if HDL cholesterol is less than 40 mg/dL, a follow-up fasting lipoprotein profile should be obtained. After a lipid abnormality is confirmed (Table 21–6), major components of the evaluation are the history (including age, gender, and if female, menstrual and estrogenreplacement status), physical examination, and laboratory investigations. A complete history and physical examination should assess (1) presence or absence of cardiovascular risk factors (Table 21–7) or definite cardiovascular disease in the individual, (2) family history of

TABLE 21–6. Classification of Total, LDL, and HDL Cholesterol and Triglycerides Total cholesterol duodenum Less dependent Often asymptomatic Deep More severe, single vessel

Acute Stomach > duodenum Less dependent Asymptomatic Most superficial More severe, superficial mucosal capillaries

H. pylori, Helicobacter pylori; NSAID, nonsteroidal anti-inflammatory drug; SRMD, stress-related mucosal damage.

EPIDEMIOLOGY

ETIOLOGY AND RISK FACTORS

Approximately 10% of Americans develop chronic PUD during their lifetime.1 The incidence varies with ulcer type, age, gender, and geographic location. Race, occupation, genetic predisposition, and societal factors may play a minor role in ulcer pathogenesis, but are attenuated by the importance of HP infection and NSAID use. The prevalence of PUD in the United States has shifted from predominance in men to nearly comparable prevalence in men and women. Recent trends suggest a declining rate for younger men and an increasing rate for older women.1 Factors that have influenced these trends include the declining smoking rates in younger men and the increased use of NSAIDs in older adults. Since 1960, ulcer-related physician visits, hospitalizations, operations, and deaths have declined in the United States by more than 50%, primarily because of decreased rates of PUD among men.1 The decline in hospitalizations has resulted from a reduction in hospital admissions for uncomplicated duodenal ulcer. However, hospitalizations of older adults for ulcer-related complications (bleeding and perforation) have increased.1 Although the overall mortality from PUD has decreased, death rates have increased in patients older than 75 years of age, most likely a result of increased consumption of NSAIDs and an aging population. Patients with gastric ulcer have a higher mortality rate than those with duodenal ulcer because gastric ulcer is more prevalent in older individuals. Despite these trends, PUD remains one of the most common GI diseases, resulting in impaired quality of life, work loss, and high-cost medical care. To date, H2 -receptor antagonists (H2 RAs), proton pump inhibitors (PPIs), and drugs that promote mucosal defense have not altered PUD complication rates.1

Most peptic ulcers occur in the presence of acid and pepsin when HP, NSAIDs, or other factors (see Table 33–2) disrupt normal mucosal defense and healing mechanisms.1 Hypersecretion of acid is the primary pathogenic mechanism in hypersecretory states such as ZES.4 Ulcer location is related to a number of etiologic factors. Benign gastric ulcers can occur anywhere in the stomach, although most are located on the lesser curvature, just distal to the junction of the antral and acid-secreting mucosa (see Fig. 33–1). Most duodenal ulcers occur in the first part of the duodenum (duodenal bulb).

HELICOBACTER PYLORI Helicobacter pylori infection causes chronic gastritis in all infected individuals and is causally linked to PUD, gastric cancer, and mucosaassociated lymphoid tissue (MALT) lymphoma (Fig. 33–2).1,5−7 However, only a small number of infected individuals will develop symptomatic PUD (about 20%) or gastric cancer (less than 1%).1,6 The pattern and distribution of gastritis correlates strongly with the risk of a specific gastrointestinal disorder. The development of atrophic gastritis and gastric cancer is a slow process that occurs over 20 to 40 years. Serologic studies confirm an association between HP and gastric cancer.1,6 Supportive evidence for PUD is based on the fact that most non-NSAID ulcers are infected with HP, and that HP eradication markedly decreases ulcer recurrence.5,6 Host-specific cofactors and HP strain variability play an important role in the pathogenesis of PUD and gastric cancer.5−7 Although an association between HP and PUD bleeding is less clear, eradication of HP decreases recurrent bleeding.8 No specific link has been established between HP and dyspepsia, nonulcer dyspepsia (NUD), or gastroesophageal reflux disease.9−11

Esophagus Diaphragm

Duodenal ulcer

Lesser curvature

Fundus Lower esophageal sphincter Body

Stomach Greater curvature Gastric ulcer

Duodenum Pylorus

Antrum

FIGURE 33–1. Anatomic structure of the stomach and duodenum and most common locations of gastric and duodenal ulcers.

TABLE 33–2. Potential Causes of Peptic Ulcer Common causes Helicobacter pylori infection Nonsteroidal anti-inflammatory drugs Critical illness (stress-related mucosal damage) Uncommon causes Hypersecretion of gastric acid (e.g., Zollinger-Ellison syndrome) Viral infections (e.g., cytomegalovirus) Vascular insufficiency (crack cocaine–associated) Radiation Chemotherapy (e.g., hepatic artery infusions) Rare genetic subtypes Idiopathic

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CHAPTER 33

Acquisition of Helicobacter pylori Acute gastritis

Asymptomatic or symptomatic acquisition

Chronic active gastritis

Nonsalicylates Nonselective (traditional) NSAIDs: indomethacin, piroxicam, ibuprofen, naproxen, sulindac, ketoprofen, ketorolac, flurbiprofen, diclofenac Partially selective NSAIDs: etodolac, nabumetone, meloxicam Selective COX-2 inhibitors: celecoxib, valdecoxib Salicylates Acetylated: aspirin Nonacetylated: salsalate, trisalicylate

Corpus-predominant gastritis with multifocal atrophy Environmental Factors

Duodenal ulcer

631

TABLE 33–3. Selected Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Cyclooxygenase-2 (COX-2) Inhibitors

Normal gastric mucosa

Antral-predominant gastritis

PEPTIC ULCER DISEASE

MALT lymphoma

Gastric ulcer

Gastric cancer

FIGURE 33–2. The natural history of Helicobacter pylori infection in the pathogenesis of gastric ulcer and duodenal ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer.

Approximately 50% of the world’s population is colonized by HP.6 The prevalence of HP varies by geographic location, socioeconomic conditions, ethnicity, and age. In developing countries, HP prevalence exceeds 80% in adults and correlates with lower socioeconomic conditions.5 In industrialized countries, the prevalence of HP in adults is between 20% and 50%.5 The prevalence of HP in the United States is 30% to 40%, but remains higher in ethnic groups such as African and Latin Americans.6 There is a decreasing frequency of infection, especially in regions with improving sanitation and socioeconomic conditions.6 In developed countries, there is an increased HP prevalence with age.1,6 However, this reflects a more intense transmission when older generations were children, as younger generations have been less likely to acquire the infection. Infection rates do not differ with gender or smoking status. HP is transmitted person-to-person by three different pathways; fecal-oral, oral-oral, and iatrogenic.1,6 Transmission of the organism is thought to occur by the fecal-oral route, either directly from an infected person, or indirectly from fecal-contaminated water or food.1 Members of the same household are likely to become infected when someone in the same household is infected.1 Risk factors include crowded living conditions, a large number of children, unclean water, and consumption of raw vegetables.6 Transmission by the oral-oral route has been postulated because HP has been isolated from the oral cavity.6 Transmission of HP can occur iatrogenically when infected instruments such as endoscopes are used.1

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS NSAIDs are one of the most widely prescribed classes of medications in the United States, particularly in individuals 60 years of age and older.1 There is overwhelming evidence linking chronic nonselective NSAID (including aspirin) use to a variety of GI tract injuries (Table 33–3).1,12−14 Subepithelial gastric hemorrhages occur within 15 to 30 minutes of ingestion, and progress to gastric erosions with continued ingestion.1,12 These lesions heal within a few days with continued NSAID use and do not lead to GI complications. Gastroduodenal ulcers occur in 15% to 30% of regular NSAID users and may develop

within a week or with continued treatment (6 months or longer).12 Gastric ulcers are most common, occur primarily in the antrum (see Fig. 33–1), and are of greater concern than erosions because of their potential to bleed or perforate (see Table 33–1). NSAID-induced ulcers may occur in the esophagus and colon, but are less common.1,15 Each year, nonselective NSAIDs account for at least 16,500 deaths and 107,000 hospitalizations in the United States.1,14 Clinically important upper GI events occur in 3% to 4.5% of arthritis patients taking NSAIDs, and 1.5% have a serious complication (major GI bleeding, perforation, or obstruction).12 The risk factors for NSAID-induced ulcers and GI-related complications are presented in Table 33–4. Combinations of factors confer an additive risk. The risk of NSAID complications is increased as much as 14-fold in patients with a previous history of an ulcer or ulcer-related bleeding.1 Advanced age is an independent risk factor and increases linearly with the age of the patient.1 The high incidence of ulcer complications in older individuals may be explained by age-related changes in gastric mucosal defense. The risk for NSAID-induced ulcers and complications is dose related, although both can occur with low dosages of nonprescription NSAIDs and the low dosages of aspirin taken for cardioprotective purposes (81 to 325 mg/day).1,12−14,16,17 The use of corticosteroids alone does not increase the risk of ulcer or complications, but ulcer risk is

TABLE 33–4. Risk Factors for Nonsteroidal Anti-Inflammatory Drug (NSAID)-Induced Ulcers and Upper Gastrointestinal Complicationsa Established risk factors Age over 60 years Previous peptic ulcer disease Previous upper GI bleeding Concomitant corticosteroid therapy High-dose and multiple NSAID use Concomitant anticoagulant use or coagulopathy Chronic major organ impairment (e.g., cardiovascular disease) Possible risk factors NSAID-related dyspepsia Duration of NSAID use Helicobacter pylori infection Rheumatoid arthritis (extent of disability) Questionable risk factors Cigarette smoking Alcohol consumption a

Combinations of risk factors are additive. Compiled from Del Valle et al,1 Suerbaum and Michetti,5 Laine,12 and Gleeson and Davis.15

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increased twofold in corticosteroid users who are also taking concurrent NSAIDs.1 The use of low-dose aspirin in combination with another NSAID increases the risk of upper GI complications to a greater extent than the use of either drug alone.1,17 The risk of bleeding is markedly increased when NSAIDs are used in combination with anticoagulants.1 NSAID-related dyspepsia that is not relieved by antiulcer medications may indicate an ulcer or ulcer complication, but dyspepsia does not correlate directly with mucosal injury or clinical events. Whether HP infection is a risk factor for NSAID-induced ulcers remains controversial.18−20 Most evidence indicates that both HP and NSAIDs are independent risk factors and that HP does not potentiate the risk of ulcer formation in NSAID users.18 However, recent data suggest that HP may potentiate the effects of NSAIDs and low-dose aspirin with regard to ulcer bleeding.19,20 Cigarette smoking and alcohol ingestion contribute to increased ulcer risk but do not appear to be independent factors.1 There is little evidence to support clinically important differences with regard to the frequency of ulcers and upper GI complications among most available nonaspirin, nonselective NSAIDs (see Table 33–3) when used in equipotent anti-inflammatory dosages.1 However, the nonacetylated salicylates (e.g., salsalate) and newer NSAIDs (e.g., etodolac, nabumetone, and meloxicam) may be associated with a decreased incidence of GI toxicity.1,21,22 NSAIDs that selectively inhibit cyclooxygenase-2 (COX-2) decrease the incidence of gastroduodenal ulcers and related GI complications when compared to the nonselective NSAIDs.21,22 The use of buffered or enteric-coated aspirin confers no added protection from ulcer or GI complications.23

CIGARETTE SMOKING There is epidemiologic evidence that links cigarette smoking to PUD, impaired ulcer healing, and ulcer-related GI complications.1 The risk is proportional to the number of cigarettes smoked and is modest when fewer than 10 cigarettes are smoked per day. Smoking does not increase ulcer recurrence after HP eradication. Death rates are higher among patients who smoke than among nonsmoking patients, although it is not known whether the increase in mortality reflects PUD or the cardiac and pulmonary sequelae of smoking. The exact mechanism by which cigarette smoking contributes to PUD remains unclear. Possible mechanisms include delayed gastric emptying of solids and liquids, inhibition of pancreatic bicarbonate secretion, promotion of duodenogastric reflux, and reduction in mucosal prostaglandin (PG) production. Although smoking increases gastric acid secretion, this effect is not consistent. It is uncertain whether nicotine or other components of smoke are responsible for these physiologic alterations. Cigarette smoking may provide a favorable milieu for HP infection.

PSYCHOLOGICAL STRESS The importance of psychological factors in the pathogenesis of PUD remains controversial.1 Clinical observation suggests that ulcer patients are adversely affected by stressful life events. However, results from controlled trials are conflicting and have failed to document a cause-and-effect relationship.1 It is possible that emotional stress induces behavioral risks such as smoking and the use of NSAIDs, or alters the inflammatory response or resistance to HP infection. The role of stress and how it affects PUD is complex and probably multifactorial.

DIETARY FACTORS The role of diet and nutrition in PUD is uncertain, but may explain regional variations.1 Coffee, tea, cola beverages, beer, milk, and spices may cause dyspepsia, but do not increase the risk for PUD. Beverage restrictions and bland diets do not alter the frequency of ulcer recurrence. Although caffeine is a gastric acid stimulant, constituents in decaffeinated coffee or tea, caffeine-free carbonated beverages, beer, and wine are also responsible for increasing gastric acid secretion. In high concentrations, alcohol ingestion is associated with acute gastric mucosal damage and upper GI bleeding; however, there is insufficient evidence to confirm that alcohol causes ulcers.

DISEASES ASSOCIATED WITH PEPTIC ULCERS There is epidemiologic evidence to suggest an increased prevalence of duodenal ulcers in patients with certain chronic diseases, but the pathophysiologic mechanisms of these associations are uncertain.1 A strong association exists in patients with systemic mastocytosis, multiple endocrine neoplasia type 1, chronic pulmonary diseases, chronic renal failure, kidney stones, hepatic cirrhosis, and α 1 -antitrypsin deficiency. An association may exist in patients with cystic fibrosis, chronic pancreatitis, Crohn’s disease, coronary artery disease, polycythemia vera, and hyperparathyroidism.

PATHOPHYSIOLOGY Gastric and duodenal ulcers occur because of an imbalance between aggressive factors (gastric acid and pepsin) and mechanisms that maintain mucosal integrity (mucosal defense and repair).

GASTRIC ACID AND PEPSIN The potential for producing mucosal damage is related to the secretion of gastric (hydrochloric) acid and pepsin. Hydrochloric acid is secreted by the parietal cells, which contain receptors for histamine, gastrin, and acetylcholine. Acid (as well as HP infection and NSAID use) is an independent factor that contributes to the disruption of mucosal integrity. Increased acid secretion has been observed in patients with duodenal ulcers and may be a consequence of HP infection.24,25 Patients with ZES (described later in the chapter) have gastric acid hypersecretion resulting from a gastrin-producing tumor.4 Patients with gastric ulcer usually have normal or reduced rates of acid secretion (hypochlorhydria). Acid secretion is expressed as the amount of acid secreted under basal or fasting conditions, basal acid output (BAO); after maximal stimulation, maximal acid output (MAO); or in response to a meal.24 Basal, maximal, and meal-stimulated acid secretion varies according to time of day and the individual’s psychological state, age, gender, and health status. The BAO follows a circadian rhythm, with the highest acid secretion occurring at night and the lowest in the morning. An increase in the BAO:MAO ratio suggests a basal hypersecretory state such as ZES. A review of gastric acid secretion and its regulation can be found elsewhere.24 Pepsinogen, the inactive precursor of pepsin, is secreted by the chief cells located in the gastric fundus (see Fig. 33–1). Pepsin is activated by acid pH (optimal pH of 1.8 to 3.5), inactivated reversibly at pH 4, and irreversibly destroyed at pH 7. Pepsin appears to play a role in the proteolytic activity involved in ulcer formation.24

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MUCOSAL DEFENSE AND REPAIR Mucosal defense and repair mechanisms protect the gastroduodenal mucosa from noxious endogenous and exogenous substances.1 Mucosal defense mechanisms include mucus and bicarbonate secretion, intrinsic epithelial cell defense, and mucosal blood flow.1,25 The viscous nature and near-neutral pH of the mucus-bicarbonate barrier protect the stomach from the acidic contents in the gastric lumen. Mucosal repair after injury is related to epithelial cell restitution, growth, and regeneration. The maintenance of mucosal integrity and repair is mediated by the production of endogenous prostaglandins. The term cytoprotection is often used to describe this process, but mucosal defense and mucosal protection are more accurate terms, as prostaglandins prevent deep mucosal injury and not superficial damage to individual cells. Gastric hyperemia and increased prostaglandin synthesis characterize adaptive cytoprotection, the short-term adaptation of mucosal cells to mild topical irritants. This phenomenon enables the stomach to initially withstand the damaging effects of irritants. Alterations in mucosal defense that are induced by HP or NSAIDs are the most important cofactors in the formation of peptic ulcers.

HELICOBACTER PYLORI Helicobacter pylori is a spiral-shaped, pH-sensitive, gram-negative, microaerophilic bacterium that resides between the mucus layer and surface epithelial cells in the stomach, or any location where gastrictype epithelium is found.1,5,6 The combination of its spiral shape and flagellum permits it to move from the lumen of the stomach, where the pH is low, to the mucus layer, where the local pH is neutral. The acute infection is accompanied by transient hypochlorhydria, which permits the organism to survive in the acidic gastric juice.25 The exact method by which HP initially induces hypochlorhydria is unclear. One theory is that HP produces large amounts of urease, which hydrolyzes urea in the gastric juice and converts it to ammonia and carbon dioxide.5,6 The local buffering effect of ammonia creates a neutral microenvironment within and surrounding the bacterium, which protects it from the lethal effect of acid.6 HP also produces acid-inhibitory proteins, which allows it to adapt to the low-pH environment of the stomach.25 HP attaches to gastric-type epithelium by adherence pedestals, which prevent the organism from being shed during cell turnover and mucus secretion. Colonization of the corpus (body) of the stomach is associated with gastric ulcer (see Fig. 33–2). Antral organisms are hypothesized to colonize gastric metaplastic tissue (which is thought to arise secondary to changes in acid or bicarbonate secretion, products of HP, or host inflammatory responses) in the duodenal bulb, leading to duodenal ulcer.1 A number of bacterial and host factors contribute to the ability of HP to cause gastroduodenal mucosal injury. Pathogenic mechanisms include: (a) direct mucosal damage, (b) alterations in the host immune/inflammatory response, and (c) hypergastrinemia leading to increased acid secretion.1,5 In addition, HP enhances the carcinogenic conversion of susceptible gastric epithelial cells.6,7 Direct mucosal damage is produced by virulence factors (vacuolating cytotoxin, cytotoxin-associated gene protein, and growthinhibitory factor), elaborating bacterial enzymes (lipases, proteases, and urease), and adherence.1,5 About 50% of HP strains produce a protein toxin (Vac A) that is responsible for cellular vacuole formation. Strains with cytotoxin-associated gene (cagA) protein are associated with duodenal ulcer, atrophic gastritis, and gastric cancer.1,5,7 Lipases and proteases degrade gastric mucus, ammonia produced by urease may be toxic to gastric epithelial cells, and bacterial adherence enhances the uptake of toxins into gastric epithelial cells. HP infection

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alters the host inflammatory response and damages epithelial cells directly by cell-mediated immune mechanisms, or indirectly by activated neutrophils or macrophages attempting to phagocytose bacteria or bacterial products.1,5 HP infection may increase gastric acid secretion in patients with duodenal ulcer, or diminish acid output in patients with gastric cancer.1 Antral-predominant infection is associated with hypergastrinemia and increased gastric acid secretion. Responsible mechanisms include cytokines, such as tumor necrosis factor-α released in HP gastritis; products of HP, such as ammonia; and diminished expression of somatostatin. Why somatostatin is diminished is unclear, but cytokines may be involved.1 Corpus (body)-predominant infection promotes gastric atrophy and decreases acid output.1,6,7

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS Nonselective NSAIDs including aspirin (see Table 33–3) cause gastric mucosal damage by two important mechanisms: (a) direct or topical irritation of the gastric epithelium and (b) systemic inhibition of endogenous mucosal prostaglandin synthesis.1,13,14 Although the initial injury is initiated topically by the acidic properties of many of the NSAIDs, systemic inhibition of the protective prostaglandins plays the predominant role in the development of gastric ulcer.1,13,14 Cyclooxygenase (COX) is the rate-limiting enzyme in the conversion of arachidonic acid to prostaglandins and is inhibited by NSAIDs (Fig. 33–3). Two similar COX isoforms have been identified: cyclooxygenase-1 (COX-1) is found in most body tissue, including the stomach, kidney, intestine, and platelets; cyclooxygenase-2 (COX-2) is undetectable in most tissues under normal physiologic conditions, but its expression can be induced during acute inflammation and arthritis (Fig. 33–4).13,14 COX-1 produces protective prostaglandins that regulate physiologic processes such as GI mucosal integrity, platelet homeostasis, and renal function. COX-2 is induced (upregulated) by inflammatory stimuli such as cytokines, and produces prostaglandins involved with inflammation, fever, and pain. COX-2 is also constitutionally expressed in organs such as the brain, kidney, and reproductive tract. Adverse effects (e.g., GI toxicity or renal toxicity) of NSAIDs are associated with the inhibition of COX-1, whereas anti-inflammatory actions result from NSAID inhibition of COX-2.13,14 Nonselective NSAIDs including aspirin (see Table 33–3) inhibit both COX-1 and COX-2 to varying degrees.1,13,14 Aspirin irreversibly inhibits platelet COX-1 for as long as 18 hours, resulting in decreased platelet aggregation and prolonged

Membrane Phospholipids Phospholipase A2 Arachidonic acid

Lipoxygenase

NSAIDs ASA Cyclooxygenase PG endoperoxide

15-HPETE

5-HPETE

Lipoxin A1B

Leukotrienes A4-E4

12-HPETE

Thromboxane A2

PGE2 PG1 (prostacyclin) PGD2 PGF2

FIGURE 33–3. Metabolism of arachidonic acid after its release from membrane phospholipids. ASA, aspirin; HPETE, hydroperoxyeicosatetraenoic acid; NSAIDs, nonsteroidal antiinflammatory drugs; PG, prostaglandin. Broken arrow indicates inhibitory effects.

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Cyclooxygenase

COX-1 Constitutively expressed

COX-2 Induced at inflammation site

Nonselective NSAID/ASA

Stomach Kidney Platelets Intestinal endothelium

Selective COX-2 inhibitor

Macrophages Leukocytes Fibroblasts Endothelial cells Other

FIGURE 33–4. Tissue distribution and actions of cyclooxygenase (COX) isoenzymes. Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin (ASA) inhibit COX-1 and COX-2 to varying degrees; COX-2 inhibitors inhibit only COX-2. Broken arrow indicates inhibitory effects.

bleeding times, which may potentiate upper and lower GI bleeding.1 Similar effects are observed with the nonselective NSAIDs. A number of other mechanisms may contribute to the development of NSAID-induced mucosal injury. Neutrophil adherence may damage the vascular endothelium and may lead to a reduction in mucosal blood flow, or may liberate oxygen-derived free radicals and proteases. Leukotrienes, products of lipoxygenase metabolism, are inflammatory substances that may contribute to mucosal injury through stimulatory effects on neutrophil adherence (see Fig. 33–3). Topical irritant properties are predominantly associated with acidic NSAIDs (e.g., aspirin) and their ability to decrease the hydrophobicity of the mucous gel layer in the gastric mucosa.1,13,14 Most nonaspirin NSAIDs have topical irritant effects, but aspirin appears to be the most damaging. Although NSAID prodrugs, enteric-coated aspirin tablets, salicylate derivatives, and parenteral or rectal preparations are associated with less-acute topical gastric mucosal injury, they can cause ulcers and related GI complications as a result of their systemic inhibition of endogenous PGs.

COMPLICATIONS Upper GI bleeding, perforation, and obstruction occur with HPassociated and NSAID-induced ulcers and constitute the most serious, life-threatening complications of chronic PUD.1,2,26 Bleeding is caused by the erosion of an ulcer into an artery and occurs in approximately 10% to 15% of patients.1,2 The bleeding may be occult (hidden) and insidious, or may present as melena (black-colored stools) or hematemesis (vomiting of blood). The use of NSAIDs (especially in older adults) is the most important risk factor for upper GI bleeding. Deaths occur primarily in patients who continue to bleed, or in those patients who rebleed after the initial bleeding has stopped (see section on upper GI bleeding). Ulcer-related perforation into the peritoneal cavity occurs in about 7% of patients with PUD.1 The incidence of perforation is increasing with the increased use of NSAIDs. Mortality is usually higher for perforated gastric ulcer than duodenal ulcer. The pain of perforation is usually sudden, sharp, and severe, beginning first in the epigastrium, but quickly spreading over the entire abdomen. Most patients experience ulcer symptoms prior to perforation. However, older patients who experience perforation in association with NSAID use may be asymptomatic. Penetration occurs when an ulcer burrows

into an adjacent structure (pancreas, biliary tract, or liver) rather than opening freely into a cavity. Gastric outlet obstruction occurs in about 2% of patients with peptic ulcers.1 Mechanical obstruction is caused by scarring or edema of the duodenal bulb or pyloric channel and can lead to gastric retention. Symptoms usually occur over several months and include early satiety, bloating, anorexia, nausea, vomiting, and weight loss. Perforation, penetration, and gastric outlet obstruction occur most often in patients with long-standing PUD. Treatment of PUD has improved so dramatically that even the most virulent ulcers can be managed with medication. Intractability to drug therapy is now an infrequent manifestation of PUD and an infrequent indication for surgery.

CLINICAL PRESENTATION SIGNS AND SYMPTOMS The clinical presentation of PUD varies depending on the severity of abdominal pain and the presence of complications (Table 33–5).1

TABLE 33–5. Presentation of Chronic Peptic Ulcer Disease General r Mild epigastric pain or acute life-threatening upper gastrointestinal complications Symptoms r Abdominal pain that is often epigastric and described as burning, but may present as vague discomfort, abdominal fullness, or cramping r A typical nocturnal pain that awakens the patient from sleep (especially between 12 AM and 3 AM) r The severity of ulcer pain varies from patient to patient, and may be seasonal, occurring more frequently in the spring or fall; episodes of discomfort usually occur in clusters lasting up to a few weeks followed by a pain-free period or remission lasting from weeks to years r Changes in the character of the pain may suggest the presence of complications r Heartburn, belching, and bloating often accompany the pain r Nausea, vomiting, and anorexia, are more common in patients with gastric ulcer than with duodenal ulcer, but may also be signs of an ulcer-related complication Signs r Weight loss associated with nausea, vomiting, and anorexia r Complications, including ulcer bleeding, perforation, penetration, or obstruction Laboratory tests r Gastric acid secretory studies r Fasting serum gastrin concentrations are only recommended for patients unresponsive to therapy, or for those in whom hypersecretory diseases are suspected r The hematocrit and hemoglobin are low with bleeding, and stool hemoccult tests are positive r Tests for Helicobacter pylori (see Table 33–6) Other diagnostic tests r Fiberoptic upper endoscopy (esophagogastroduodenoscopy) detects more than 90% of peptic ulcers and permits direct inspection, biopsy, visualization of superficial erosions, and sites of active bleeding r Routine single-barium contrast techniques detect 30% of peptic ulcers; optimal double-contrast radiography detects 60% to 80% of ulcers

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Ulcer-related pain in duodenal ulcer often occurs 1 to 3 hours after meals and is usually relieved by food, but this is variable. In gastric ulcer, food may precipitate or accentuate ulcer pain. Antacids usually provide immediate pain relief in most ulcer patients. The abdominal pain usually diminishes or disappears during treatment; however, recurrence of pain after healing often suggests an unhealed or recurrent ulcer. Abdominal pain does not always correlate with the presence or absence of acid or an ulcer. Asymptomatic patients may have an ulcer at endoscopy, and patients with endoscopically proven healed ulcers may have persistent symptoms. Many patients, particularly older adults, with an NSAID-induced ulcer-related complication may not have prior abdominal symptoms. The reasons for this are unclear, but may relate to the analgesic effect of the NSAID or differences in the way older individuals perceive pain. Dyspepsia may or may not be associated with an ulcer, and in itself is of little clinical value when trying to identify subsets of patients who are most likely to have an ulcer. As many as 50% of patients who take NSAIDs report having dyspepsia.14 Patients with dyspeptic symptoms may have either uninvestigated (no upper endoscopy) dyspepsia or investigated (underwent upper endoscopy) dyspepsia. If an ulcer is not confirmed in a patient with ulcer-like symptoms at the time of endoscopy, the disorder is referred to as nonulcer dyspepsia.3

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Ulcer-like symptoms may also occur in the absence of peptic ulceration in association with HP gastritis or duodenitis.

DIAGNOSIS Routine laboratory tests are not helpful in establishing the diagnosis of uncomplicated PUD (see Table 33–5).1

TESTS FOR HELICOBACTER PYLORI The diagnosis of HP infection can be made using endoscopic or nonendoscopic tests (Table 33–6).1,5,27 The tests that require upper endoscopy are more expensive, uncomfortable, and require a mucosal biopsy for histology, culture, or detection of urease activity. Recommendations to maximize the diagnostic yield include taking at least three tissue samples from specific areas of the stomach, as patchy distribution of HP infection can lead to false-negative results. Because certain medications may decrease the sensitivity of these tests, antibiotics and bismuth salts should be withheld for 4 weeks and PPIs for 1 to 2 weeks prior to endoscopic testing. The nonendoscopic tests (see Table 33–6) include serologic antibody detection tests, the urea breath test (UBT), and the stool antigen

TABLE 33–6. Tests for Detection of Helicobacter pylori Test Endoscopic tests Histology

Description Microbiologic examination using various stains

Culture

Culture of biopsy

Biopsy (rapid) urease

HP urease generates ammonia, which causes a color change

Nonendoscopic tests Antibody detection (laboratory-based)

Detects antibodies to HP in serum; in the U.S., only FDA-approved anti-HP lgG antibody should be used

Antibody detection (can be performed in office or near patient)

Detects lgG antibodies to HP in whole blood or fingerstick

Urea breath test

HP urease breaks down ingested labeled C-urea, patient exhales labeled CO2

Stool antigen

Identifies HP antigen in stool, leading to color change that can be detected visually or by spectrophotometer

Comments Gold standard; >95% sensitive and specific; permits classification of gastritis; results are not immediate; not recommended for initial diagnosis; tests for active HP infection; antibiotics, bismuth, and PPIs may cause false-negative results Enables sensitivity testing to determine appropriate treatment or antibiotic resistance; 100% specific; results are not immediate; not recommended for initial diagnosis, but may be used after failure of second-line treatment; tests for active HP infection; antibiotics, bismuth, and PPIs may cause false-negative results Test of choice at endoscopy; >90% sensitive and specific; easily performed; rapid results (usually within 24 hours); tests for active HP infection; antibiotics, bismuth, and PPIs may cause false-negative results; test may yield false-negatives in active ulcer bleeding; available as gel tests, paper tests, and tablets Quantitative; less sensitive and specific than endoscopic tests; more accurate than in-office or near-patient tests; unable to determine if antibody is related to active or cured infection; antibody titers vary markedly between individuals and take 6 months to 1 year to return to the uninfected range; not affected by PPIs or bismuth; antibiotics given for unrelated indications may cure the infection but antibody test will remain positive Qualitative; quick (within 15 minutes); unable to determine if antibody is related to active or cured infection; most patients remain seropositive for at least 6 months to 1 year post HP eradication; not affected by PPIs, bismuth, or antibiotics Tests for active HP infection; 95% sensitive and specific; results take about 2 days; antibiotics, bismuth, PPIs, and H2 RAs may cause false-negative results; withhold PPIs or H2 RAs (1 to 2 weeks) and bismuth or antibiotics (2 to 4 weeks) before testing; may be used posttreatment to confirm eradication Tests for active HP infection; sensitivity and specificity comparable to urea breath test when used for initial diagnosis; antibiotics, bismuth, and PPIs may cause false-negative results, but to a lesser extent than with the urea breath test; may be used posttreatment to confirm eradication

HP, Helicobacter pylori; H2 RA, H2 -receptor antagonist; PPI, proton pump inhibitor. Compiled from Del Valle et al,1 Suerbaum and Michetti,5 Vaira et al,27 Oderda et al,28 and Bilardi et al.29

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test.1,5,27−29 These tests are more convenient and less expensive than the endoscopic tests. Serologic tests are of limited use in evaluating posttreatment eradication and are not reliable in young children.1,5,27 The UBT is based on HP urease activity. The 13 carbon (nonradioactive isotope) and 14 carbon (radioactive isotope) tests require that the patient ingest radiolabeled urea, which is then hydrolyzed by HP (if present in the stomach) to ammonia and radiolabeled bicarbonate. The radiolabeled bicarbonate is absorbed in the blood and excreted in the breath. A mass spectrometer is used to detect 13 carbon, whereas14 carbon is measured using a scintillation counter. The stool antigen test is approved by the Food and Drug Administration (FDA), but availability in the United States is limited. It is less expensive and easier to perform than the UBT, and may be useful in children.28 Although comparable to the UBT in the initial detection of HP, the stool antigen test is less accurate when used to confirm HP eradication posttreatment.29 Salivary and urine antibody tests are under investigation.1,27 Testing for HP is only recommended if eradication therapy is considered. If endoscopy is not planned, serologic antibody testing is a reasonable choice to determine HP status. Posttreatment evaluation to confirm eradication is unnecessary in most patients with PUD unless they have recurrent symptoms, complicated ulcer, MALT lymphoma, or gastric cancer.1 The UBT is the preferred nonendoscopic method to verify HP eradication after treatment. To avoid confusing bacterial suppression with eradication, the UBT must be delayed at least 4 weeks after the completion of treatment. The term “eradication” or “cure” is used when posttreatment tests conducted 4 weeks after the end of treatment do not detect the organism. Quantitative antibody tests are considered impractical for posttreatment eradication as antibody titers remain elevated for long periods of time.

IMAGING AND ENDOSCOPY The diagnosis of PUD depends on visualizing the ulcer crater either by upper GI radiography or endoscopy (see Table 33–5).1 Because of its lower cost, greater availability, and greater safety, many physicians believe that radiography should be the initial diagnostic procedure in patients with suspected uncomplicated PUD. If complications are thought to exist, or if an accurate diagnosis is warranted, upper endoscopy is the diagnostic procedure of choice. If a gastric ulcer is found on radiography, malignancy should be excluded by direct endoscopic visualization and histology.

CLINICAL COURSE AND PROGNOSIS The natural history of PUD is characterized by periods of exacerbations and remissions.1 Ulcer pain is usually recognizable and episodic, but symptoms are variable, especially in older adults and in patients taking NSAIDs. Antiulcer medications, including the H2 RAs, PPIs, and sucralfate, relieve symptoms, accelerate ulcer healing, and prevent ulcers from recurring, but they do not cure the disease. Both duodenal ulcers and gastric ulcers recur unless the underlying cause (HP or NSAID) is removed. Successful HP eradication markedly decreases ulcer recurrence and complications. Prophylactic therapy or COX-2 inhibitors dramatically decrease the risk for ulcers and ulcer-related complications in high-risk patients taking NSAIDs. About 20% of patients with chronic PUD experience upper GI bleeding, perforation, or obstruction. Mortality in patients with gastric ulcer is slightly higher than in duodenal ulcer and the general population. The lifetime risk of gastric adenocarcinoma in HP-infected patients is less than 1%.1,6


TREATMENT: Peptic Ulcer Disease
DESIRED OUTCOME The treatment of chronic PUD varies depending on the etiology of the ulcer (HP or NSAID), whether the ulcer is initial or recurrent, and whether complications have occurred (Fig. 33–5). Overall treatment is aimed at relieving ulcer pain, healing the ulcer, preventing ulcer recurrence, and reducing ulcer-related complications. The goal of therapy in HP-positive patients with an active ulcer, a previously documented ulcer, or a history of an ulcer-related complication, is to eradicate HP, heal the ulcer, and cure the disease. Successful eradication heals ulcers and reduces the risk of recurrence to less than 10% at 1 year.1 The goal of therapy in a patient with a NSAID-induced ulcer is to heal the ulcer as rapidly as possible. Patients at high risk of developing NSAID ulcers should be switched to a COX-2 inhibitor or receive prophylactic drug cotherapy to reduce ulcer risk and ulcerrelated complications. When possible, the most cost-effective drug regimen should be utilized.


GENERAL APPROACH TO TREATMENT The treatment of PUD centers on the eradication of HP in HP-positive patients and reducing the risk of NSAID-induced ulcers and ulcerrelated complications. Drug regimens containing antimicrobials such as clarithromycin, metronidazole, amoxicillin, and bismuth salts and antisecretory drugs such as the PPIs or H2 RAs are used to relieve

ulcer symptoms, heal the ulcer, and eradicate HP infection. Successful eradication will alter the natural history of PUD and cure the disease. PPIs, H2 RAs, and sucralfate are used to heal HP-negative NSAID-induced ulcers, but ulcer recurrence is likely in high-risk patients if the NSAID is continued. Prophylactic cotherapy with a PPI or misoprostol is used to decrease the risk of an ulcer and upper GI complications in patients taking nonselective NSAIDs. COX-2 inhibitors are often used in place of a nonselective NSAID to reduce the risk of ulcers and complications. Dietary modifications may be important for some patients, especially those who are unable to tolerate certain foods and beverages. Lifestyle modifications such as reducing stress and decreasing or stopping cigarette smoking is often encouraged. Some patients may require radiographic or endoscopic procedures for a definitive diagnosis or for complications such as bleeding. Surgery may be necessary in patients with ulcer-related bleeding or other complications such as perforation.


NONPHARMACOLOGIC THERAPY 1 Patients with PUD should eliminate or reduce psychological

stress, cigarette smoking, and the use of nonselective NSAIDs (including aspirin). Although there is no “antiulcer diet,” the patient should avoid foods and beverages (e.g., spicy foods, caffeine, and alcohol) that cause dyspepsia or that exacerbate ulcer symptoms. If possible, alternative agents such as acetaminophen, nonacetylated

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Patient presents with ulcer-like symptoms

Alarm symptoms present, e.g., bleeding, anemia, weight loss

Dyspepsia, no alarm symptoms On NSAID?

Endoscopy to assess ulcer status Yes

No

Stop NSAID; if not possible, decrease dose or change to COX-2 inhibitor

Previously treated for HP?

Ulcer present

Symptoms resolve No further treatment

Consider other etiologies for symptoms, e.g., GERD, NUD

Test for HP

Positive

Yes

No

Symptoms persist

Ulcer absent

Perform serology

Negative

Treat with PPIbased HP eradication regimen

Initiate H2RA or PPI

On NSAID?

Continue NSAID

Discontinue NSAID

Negative Symptoms resolve

Symptoms persist

Consider continuation of H2RA or PPI

Treat with H2RA or PPI

Positive

No further treatment

No

Signs/symptoms 1–2 weeks post-treatment? Yes

Discontinue NSAID

On NSAID?

Treat with H2RA or PPI

Continue NSAID

salicylate (e.g., salsalate), or COX-2 inhibitors should be used for relief of pain. Elective surgery for PUD is rarely performed today because of highly effective medical management such as the eradication of HP and the use of potent acid inhibitors.30 A subset of patients, however, may require emergency surgery for bleeding, perforation, or obstruction. In the past, surgical procedures were performed for medical treatment failures and included vagotomy with pyloroplasty or vagotomy with antrectomy.30 Vagotomy (truncal, selective, or parietal cell) inhibits vagal stimulation of gastric acid. A truncal or selective vagotomy frequently results in postoperative gastric dysfunction and requires a pyloroplasty or antrectomy to facilitate gastric drainage. When an antrectomy is performed, the remaining stomach is anastomosed with the duodenum (Billroth I) or with the jejunum (Billroth II). A vagotomy is unnecessary when an antrectomy is performed for gastric ulcer. The postoperative consequences associated with these procedures include postvagotomy diarrhea, dumping syndrome, anemia, and recurrent ulceration.


PHARMACOLOGIC THERAPY
RECOMMENDATIONS 2 Guidelines for the eradication of infection in HP-positive individuals are presented in Table 33–7. Recommended HP

Treat with PPI followed by cotherapy with PPI or misoprostol or switch NSAID to COX-2 inhibitor

FIGURE 33–5. Algorithm: Guidelines for the evaluation and management of a patient who presents with dyspeptic or ulcer-like symptoms. COX-2, cyclooxygenase-2; GERD, gastroesophageal reflux disease; HP, Helicobacter pylori; H2 -RA, H2 -receptor antagonist; PPI, proton pump inhibitor; NSAID, nonsteroidal anti-inflammatory drug; NUD, nonulcer dyspepsia.

eradication regimens are presented in Table 33–8. First-line therapy should be initiated with a PPI-based three-drug regimen for a minimum of 7 days, but preferably 10 to 14 days. If a second course of treatment is required, the PPI-based three-drug regimen should contain different antibiotics or a four-drug regimen with bismuth subsalicylate, metronidazole, tetracycline, and a PPI should be used. 3 Treatment with a conventional antiulcer drug (H2 RA, PPI, or sucralfate) is an alternative to HP eradication, but is discouraged because of the high rate of ulcer recurrence and ulcer-related complications associated with these regimens. Concomitant therapy (e.g., an H2 RA and sucralfate or an H2 RA and a PPI) is not recommended because it adds to drug costs without enhancing efficacy. Maintenance therapy with a PPI or H2 RA is recommended for high-risk patients with ulcer complications, patients who fail eradication, or those with HPnegative ulcers. 4 Patients with NSAID-induced ulcers should be tested to determine their HP status. If HP-positive, treatment should be initiated with a PPI-based three-drug eradication regimen. If HP-negative, the NSAID should be discontinued and the patient treated with either a PPI, H2 RA, or sucralfate. If the NSAID must be continued, treatment should be initiated with a PPI (if HP-negative) or with a PPI-based three-drug eradication regimen (if HP-positive). Prophylactic cotherapy with a PPI or misoprostol or switching to a selective COX-2 inhibitor is recommended for patients at risk of developing ulcer-related upper GI complications (see Table 33–4). PPI cotherapy should be considered in high-risk patients taking a COX-2 inhibitor.

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TABLE 33–7. Guidelines for the Eradication of Helicobacter pylori (HP) Infection in HP-Positive Individuals Strongly recommended r Gastric and duodenal ulcer (active or inactive), including complicated ulcers, and following gastric surgery for peptic ulcer r Mucosa-associated lymphoid tissue (MALT) lymphoma r Atrophic changes in the gastric mucosa (atrophic gastritis) r Following resection of gastric cancer r Infected patients who are first-degree relatives of patients with gastric cancer r Infected patients who are aware and concerned about the risks of infection Recommended r Use of nonsteroidal anti-inflammatory drugs (HP infection and the use of nonsteroidal anti-inflammatory drugs or aspirin are independent risk factors for peptic ulcer disease) r Nonulcer dyspepsia r Patients with gastroesophageal reflux disease receiving long-term proton pump inhibitor therapy Compiled from Del Valle et al,1 Suerbaum and Michetti,5 Malfertheiner et al,36 and Qasim and O’Morain.37


TREATMENT OF HELICOBACTER PYLORI–ASSOCIATED ULCERS The following discussion focuses on the eradication of HP in adults. Guidelines for the treatment of HP infection in older adults,31,32 children,33,34 and patients with chronic renal insufficiency35 can be found elsewhere. 5 The goal of HP drug therapy is eradication of the organism. Treatment should be effective, well-tolerated, easy to comply with, and cost-effective. HP regimens should have eradication (cure) rates of at least 80% based on intention-to-treat analysis, or at least 90% based on per protocol analysis, and should minimize the potential for antimicrobial resistance.1,5,36,37 The use of a single antibiotic, bismuth salt, or antiulcer drug does not achieve this goal.1,5 However,

clarithromycin is the single most effective antibiotic.1 Two-drug regimens that combine a PPI and either amoxicillin or clarithromycin have yielded marginal and variable eradication rates in the United States and are not recommeded.1,5 In addition, the use of only one antibiotic is associated with a higher rate of antimicrobial resistance.38 Eradication regimens (see Table 33–8) that combine two antibiotics and one antisecretory drug (triple therapy) or a bismuth salt, two antibiotics, and an antisecretory drug (quadruple therapy) increase eradication rates to an acceptable level and reduce the risk of antimicrobial resistance.1,5,36,38 When selecting a first-line eradication regimen, an antibiotic combination should be used that permits second-line treatment (if necessary) with different antibiotics. The antibiotics that have been most extensively studied and found to be effective in various combinations include clarithromycin, amoxicillin, metronidazole, and tetracycline.1,5 Although other antibiotics may be effective, they should not be used as part of the initial HP regimen. Because of insufficient data, ampicillin should not be substituted for amoxicillin, doxycycline should not be substituted for tetracycline, and azithromycin or erythromycin should not be substituted for clarithromycin. Amoxicillin should not be used in penicillin-allergic patients and metronidazole should be avoided if alcohol is consumed.36 Bismuth salts have a topical antimicrobial effect.1 Explanations as to why antisecretory drugs enhance the efficacy of antibiotics include increased activity or stability of the antibiotic at a higher intragastric pH and enhanced topical antibiotic concentration resulting from decreased intragastric volume.


PROTON PUMP INHIBITOR–BASED THREE-DRUG REGIMENS Proton pump inhibitor–based three-drug regimens with two antibiotics (see Table 33–8) constitute first-line therapy for eradication of HP.1,5,36 A meta-analysis39 of 666 studies indicates that PPI-based regimens that combine clarithromycin and amoxicillin, clarithromycin and metronidazole, or amoxicillin and metronidazole yield similar eradication rates (78.9% to 82.8%) using intent-to-treat analysis; however, other studies suggest that the amoxicillin-metronidazole combination is less effective.1 Eradication rates were improved when the

TABLE 33–8. Drug Regimens to Eradicate Helicobacter Pylori a Drug #1

Drug #2

Proton pump inhibitor–based three-drug regimens Omeprazole 20 mg twice daily Clarithromycin 500 mg twice or lansoprazole 30 mg twice daily daily or pantoprazole 40 mg twice daily or esomeprazole 40 mg daily or rabeprazole 20 mg daily Bismuth-based four-drug regimens b Omeprazole 40 mg twice daily Bismuth subsalicylate 525 mg or lansoprazole 30 mg twice daily four times daily or pantoprazole 40 mg twice daily or esomeprazole 40 mg daily or rabeprazole 20 mg daily or Standard ulcer-healing dosages of an H2 -receptor antagonist taken for 4–6 weeks (see Table 33–9)

Drug #3

Drug #4

Amoxicillin 1 g twice daily or metronidazole 500 mg twice daily

Metronidazole 250–500 mg four times daily

Tetracycline 500 mg four times daily or amoxicillin 500 mg four times daily, or, clarithromycin 250–500 mg four times daily

a Although treatment is minimally effective if used for 7 days, 10–14 days of treatment is recommended. The antisecretory drug may be continued beyond antimicrobial treatment in the presence of an active ulcer. b In the setting of an active ulcer, acid suppression is added to hasten pain relief.

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clarithromycin dose was increased to 1.5 g/day, but increasing the dosage of the other antibiotics did not increase eradication rates.39 Most clinicians prefer to initiate triple therapy with clarithromycin and amoxicillin rather than clarithromycin and metronidazole. Reserving metronidazole as an alternative or second-line agent leaves an effective back-up agent and reduces exposure and adverse effects from metronidazole. Alternatively, the PPI-clarithromycin-metronidazole regimen is an excellent alternative in penicillin-allergic patients (see Table 33–8). An initial 7-day course of therapy provides minimally acceptable eradication rates and has been approved by the FDA and is recommended in Europe.1,5 The duration of therapy, however, remains controversial in the United States, as longer treatment periods (10day and 14-day) favor higher eradication rates and are less likely to be associated with antimicrobial resistance.1,5,38,40 One meta-analysis reports a 7% to 9% increase in eradication rates with a 14-day treatment regimen when compared to a 7-day regimen.40 A number of other antibiotics and antibiotic combinations have been evaluated as part of the PPI-based three-drug regimen with varying degrees of success.1,5,41 The PPI is an integral part of the three-drug regimen and should be taken 15 to 30 minutes before a meal (see section on PPIs) along with the two antibiotics (see Table 33–8). Although gastric acid inhibition is necessary to influence HP eradication rates, the specific level of inhibition remains unknown. A single daily dose of a PPI may be less effective than a double dose when used as part of a triple-therapy HP eradication regimen.42 Substitution of one PPI for another is acceptable and does not appear to enhance or diminish HP eradication.43 An H2 RA should not be substituted for a PPI, as better eradication rates have been demonstrated with a PPI.44 CLINICAL CONTROVERSY Some clinicians favor an initial 7-day HP regimen, while others favor a 10-day or 14-day treatment course. The duration of therapy is controversial, as shorter periods may enhance compliance, but longer treatment periods in compliant patients favor higher eradication rates and are less likely to be associated with antimicrobial resistance. Patients receiving a second course of therapy after an unsuccessful eradication should receive treatment for 14 days.


BISMUTH-BASED FOUR-DRUG REGIMENS The bismuth-based four-drug regimens presented in Table 33–8 were originally used as first-line therapy to eradicate HP. Eradication rates for a 14-day regimen containing bismuth, metronidazole, tetracycline, and an H2 -receptor antagonist are similar to those achieved with PPI-based triple therapy.1,5,45 Increasing the duration of treatment to 1 month does not substantially increase eradication. Substitution of amoxicillin for tetracycline lowers the eradication rate and is usually not recommended.1,45 Substitution of clarithromycin 250 to 500 mg four times a day for tetracycline yields similar results, but increases adverse effects. The antisecretory drug is also used to hasten pain relief in patients with an active ulcer. Although the original bismuth-based four-drug regimen is effective and inexpensive, it is associated with frequent adverse effects and poor compliance. A capsule containing bismuth, metronidazole, and tetracycline is under investigation. First-line treatment with quadruple therapy using a PPI (with bismuth, metronidazole, and tetracycline) in place of the H2 RA achieves

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similar eradication rates as those of PPI-based triple therapy and permits a shorter treatment duration (7 days).1,45 Although evidence supports the efficacy of bismuth-based quadruple therapy as first-line treatment, it is often recommended as second-line treatment when a clarithromycin-amoxicillin regimen is used initially (see section on eradication regimens after initial treatment failure). All medications except the PPI (see section on PPIs) should be taken with meals and at bedtime.


ERADICATION REGIMENS AFTER INITIAL TREATMENT FAILURE HP eradication is often more difficult after initial treatment fails and eradication rates are extremely variable.5,37 Because there are limited data on second attempts to eradicate HP, treatment failures should be handled on a case-by-case basis. Failure of first- and second-line regimens in primary care requires referral to a specialist. Second-line empiric treatment should: utilize antibiotics that were not previously used during initial therapy; use antibiotics that do not have resistance problems; use a drug that has a topical effect such as bismuth; and the duration of treatment should be extended 10 to 14 days.46 Thus after unsuccessful initial treatment with a PPI-amoxicillin-clarithromycin regimen, empiric second-line therapy should be instituted with bismuth subsalicylate, metronidazole, tetracycline, and a PPI for 10 to 14 days (see Table 33–8).5,46,47 When metronidazole resistance is suspected, metronidazole may be replaced by furazolidone (100 mg four times a day) in either the proton pump inhibitor-based three-drug regimen or the bismuth-based four-drug regimen.46 When furazolidone is used, patients should be counseled not to ingest alcohol or monoamine oxidase inhibitors.1 Other successful second-line regimens are discussed elsewhere.46,47


FACTORS THAT CONTRIBUTE TO UNSUCCESSFUL ERADICATION Factors that contribute to unsuccessful eradication include poor patient compliance, resistant organisms, low intragastric pH, and a high bacterial load.37,38,46,48 Poor patient compliance is an important factor influencing successful therapy. Compliance decreases with multiple medications, increased frequency of administration, increased length of treatment, intolerable adverse effects, and costly drug regimens. Although a longer treatment duration may contribute to noncompliance, missed doses in a 7-day regimen may also lead to failed eradication.46 Tolerability varies with different regimens. Metronidazole-containing regimens increase the frequency of adverse effects (especially when the dose is >1 g/day). Other common adverse effects include taste disturbances (metronidazole and clarithromycin), nausea, vomiting, abdominal pain, and diarrhea. Antibiotic-associated colitis, a serious complication, occurs occasionally. Oral thrush and vaginal candidiasis may also occur. An important determinant of successful HP eradication therapy is the presence of preexisting antimicrobial resistance.1,37,38,46,49 Metronidazole resistance is most common (10% to 60%), but varies depending on prior antibiotic exposure and geographic region.1.37,38,49 The clinical importance of metronidazole resistance in eradicating HP remains uncertain, as the synergistic effect of combining metronidazole with other antibiotics appears to render resistance to metronidazole less important. Primary resistance to clarithromycin is lower (10% to 15%) than with metronidazole, but it is more likely to affect

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GASTROINTESTINAL DISORDERS TABLE 33–9. Oral Drug Regimens Used to Heal Peptic Ulcers or Maintain Ulcer Healing Drug Proton pump inhibitors Omeprazole Lansoprazole Rabeprazole Pantoprazole Esomeprazole H2 -receptor antagonists Cimetidine

Famotidine Nizatidine Ranitidine Promote mucosal defense Sucralfate (g/dose)

Duodenal or Gastric Ulcer Healing (mg/dose)

Maintenance of Duodenal or Gastric Ulcer Healing (mg/dose)

20–40 daily 15–30 daily 20 daily 40 daily 20–40 daily

20–40 daily 15–30 daily 20 daily 40 daily 20–40 daily

300 four times daily 400 twice daily 800 at bedtime 20 twice daily 40 at bedtime 150 twice daily 300 at bedtime 150 twice daily 300 at bedtime

400–800 at bedtime

1 four times daily 2 twice daily

20–40 at bedtime 150–300 at bedtime 150–300 at bedtime

1–2 twice daily 1 four times daily

the clinical outcome.1,38,46 Secondary resistance occurs in up to twothirds of treatment failures. Resistance to tetracycline and amoxicillin is uncommon.1 Resistance to bismuth has not been reported. The role of antibiotic sensitivity testing before initiating HP treatment has not been established.

Switching to a selective COX-2 inhibitor also decreases ulcer risk and complications.1,12−14,21,50−52


TREATMENT OF NSAID-INDUCED ULCERS

Misoprostol, 200 mcg four times a day, markedly reduces the risk of NSAID-induced gastric ulcer, duodenal ulcer, and ulcer-related GI complications, but diarrhea and abdominal cramping limit its use.12−14,21 Because a dosage of 200 mcg three times a day is comparable in efficacy to 800 mcg/day, the lower dosage should be considered in patients unable to tolerate the higher dose.1,12−14 Reducing the misoprostol dosage to 400 mcg/day or less to minimize diarrhea may compromise its prophylactic effects. A fixed combination of misoprostol 200 mcg and diclofenac (50 mg or 75 mg) is available and may enhance compliance, but the flexibility to individualize drug dosage is lost. A large double-blind clinical trial in rheumatoid arthritis patients receiving misoprostol 200 mcg four times a day provides the most compelling evidence that serious upper GI complications can be prevented, especially in high-risk patients.53 However, the reduction in complications was less than the prevention of endoscopic lesions, indicating that it is not appropriate to extrapolate from ulcer prevention to a reduction in GI complications.

Nonselective NSAIDs should be discontinued (when possible) if an active ulcer is confirmed. If the NSAID is stopped, most uncomplicated ulcers will heal with standard regimens of an H2 -receptor antagonist, PPI, or sucralfate (Table 33–9).1,12,14 PPIs are usually preferred because they provide more rapid ulcer healing than H2 RAs or sucralfate. If the NSAID must be continued in a patient despite ulceration, consideration should be given to reducing the NSAID dose, or switching to acetaminophen, a nonacetylated salicylate, a partially selective COX-2 inhibitor, or a selective COX-2 inhibitor (see Table 33–3). The PPIs are the drugs of choice when the NSAID must be continued, as potent acid suppression is required to accelerate ulcer healing.1,12,14 H2 RAs are less effective in the presence of continued NSAID use; sucralfate does not appear to be effective. If HP is present, treatment should be initiated with an eradication regimen that contains a PPI.1,12−14

STRATEGIES TO REDUCE THE RISK OF NSAID-INDUCED ULCERS AND ULCER-RELATED UPPER GI COMPLICATIONS A number of strategies are used to reduce the risk of NSAID-related ulcers and GI complications. Strategies aimed at reducing the topical irritant effects of nonselective NSAIDs—prodrugs, slow-release formulations, and enteric-coated products—do not prevent ulcers or GI complications such as bleeding or perforation. Medical cotherapy with misoprostol or a PPI decreases the risk of ulcers and GI complications in high-risk patients (see Table 33–3).1,12−14,21,50,51

MISOPROSTOL COTHERAPY WITH A NONSELECTIVE NSAID

H2 -RECEPTOR ANTAGONIST COTHERAPY WITH A NONSELECTIVE NSAID Standard H2 -receptor antagonist dosages (e.g., famotidine 40 mg/day) are effective in reducing the risk of NSAID-induced duodenal ulcer, but not gastric ulcer (the most frequent type of ulcer associated with NSAIDs).1,12−14,21 Therefore standard H2 RA dosages should not be used as cotherapy with a nonselective NSAID for prophylaxis. There is evidence that higher dosages (e.g., famotidine 40 mg twice daily, ranitidine 300 mg twice daily) reduce the risk for gastric ulcer and duodenal ulcer.1,21 However, there are no studies that have evaluated whether higher H2 RA dosages reduce the risk of ulcer-related upper

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GI complications. The H2 RAs may be used when necessary to relieve NSAID-related dyspepsia.

PROTON PUMP INHIBITOR COTHERAPY WITH A NONSELECTIVE NSAID Standard PPI dosages (e.g., omeprazole 20 mg/day and lansoprazole 30 mg/day) reduce the risk of NSAID-induced gastric ulcer and duodenal ulcer.1,12−14,21 In a large comparative multicenter trial, omeprazole 20 mg/day was superior to ranitidine 150 mg twice daily in preventing NSAID-induced gastroduodenal ulcers.54 Two randomized controlled trials have compared PPIs with misoprostol and placebo. 6 In the first study,55 omeprazole 20 mg/day was as effective as misoprostol 400 mcg/day in reducing the incidence of gastric ulcer; however, if a higher dosage of misoprostol had been used it might have been more effective. In the second study of HP-negative NSAIDusers with a history of gastric ulcer,56 misoprostol 800 mcg/day was more effective than lansoprazole (15 mg or 30 mg/day) and placebo. When withdrawals from the study (primarily related to the side effects of misoprostol) were regarded as “treatment failures,” lansoprazole and full-dose misoprostol were considered clinically equivalent. Although there are no large clinical studies to prove that PPIs decrease the risk for NSAID-related upper GI complications, two small studies have reported a reduction in serious upper GI complications in patients with a history of upper GI bleeding.57,58 Proton pump inhibitor cotherapy is considered an alternative to misoprostol in high-risk patients taking nonselective NSAIDs (including low-dose aspirin).

SELECTIVE COX-2 INHIBITORS Of the oral selective COX-2 inhibitors now available in the U.S. (see Table 33–3) only celecoxib was investigated in arthritic patients, in a large, long-term, randomized controlled trial (named CLASS), that was specifically designed to evaluate upper gastrointestinal complications versus nonselective NSAIDs.59,60 Patients in the CLASS trial, were permitted to take low-dose aspirin for cardioprotection.59 The initial analysis of the CLASS trial indicated that, when compared to nonselective NSAIDs, celecoxib had 50% fewer symptomatic ulcers and serious upper GI complications in patients not taking concomitant low-dose aspirin. However, in the CLASS trial, these benefits were negated in the aspirin users. Although a systematic review61 of celecoxib found that it is safer than nonselective NSAIDs, a re-evaluation of the CLASS data by the FDA concluded that celecoxib does not have a GI safety advantage over nonselective NSAIDs.21,52 The manufacturer of celecoxib argued (and the FDA acknowledged) that confounding factors in study design, including the use of low-dose aspirin, account for these discrepant results. Concerns about the cardiovascular safety of selective COX-2 inhibitors (e.g., thrombotic events and myocardial infarction) have arisen.21,52,60 GI effects such as dyspepsia and abdominal pain, fluid retention, hypertension, and renal toxicity can also occur with the COX-2 inhibitors.21,52 7 Two small comparative trials in HP-negative patients with histories of NSAID-related ulcer complications suggested that a standard dosage of a PPI and a nonselective NSAID have a GI safety profile similar to that observed with a selective COX-2 inhibitor.62,63 However, the comparative benefits and cost effectiveness of these regimens remain controversial. Cotherapy with a PPI and a selective COX-2 inhibitor should be considered in patients with multiple or life-threatening risk factors.1

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CLINICAL CONTROVERSY Some clinicians favor the use of a PPI and a nonselective NSAID, while others favor a selective COX-2 inhibitor when treating a patient at risk of NSAID-related GI complications. High-risk patients taking a nonselective NSAID should receive cotherapy with a PPI or be switched to a COX-2 inhibitor. The comparative benefits and cost effectiveness of these regimens remains controversial. Some clinicians favor the concomitant use of an NSAID and low-dose aspirin in a high-risk patient, while others favor the use of a selective COX-2 inhibitor and low-dose aspirin. Ulcer risk is increased when a nonselective NSAID and aspirin are used concomitantly, but the benefit of the COX-2 inhibitor may be reduced in a patient taking low-dose aspirin. The comparative risks and benefits of these two methods to reduce ulcer complications has not been studied and remains controversial.


CONVENTIONAL TREATMENT OF ACTIVE DUODENAL AND GASTRIC ULCERS AND LONG-TERM MAINTENANCE OF ULCER HEALING Conventional treatment with standard dosages of H2 -receptor antagonists or sucralfate relieves ulcer symptoms and heals the majority of gastric and duodenal ulcers in 6 to 8 weeks (see Table 33–9).1,64 Proton pump inhibitors provide comparable ulcer healing rates over a shorter treatment period (4 weeks).1,64 A higher daily dose or a longer treatment duration is sometimes needed to heal larger gastric ulcers. Antacids, although effective, are not used as single agents to heal ulcers because of the high volume and frequent doses required (100 to 144 mEq of acid-neutralizing capacity 1 hour and 3 hours after meals and at bedtime), as well as associated adverse effects.1 When conventional antiulcer therapy is discontinued after ulcer healing, most HP-positive patients develop a recurrent ulcer within 1 year.1,5 Continuous antiulcer therapy (see Table 33–9) is aimed at the long-term maintenance of ulcer healing and at preventing ulcer-related complications. Because HP eradication dramatically decreases ulcer recurrence (35% of body surface area), head injury, traumatic spinal cord injury, major surgery, or history of GI bleeding.90,91,100

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Although the relative importance of the various risk factors remains controversial, most clinicians concur that patients with respiratory failure (mechanical ventilation for >48 hours) or coagulopathy should receive prophylaxis, as these two factors were shown to be independent risk factors in a large observational study.91 In the absence of these two risk factors, some clinicians only use prophylaxis in patients who have two of the aforementioned risk factors.90 Although exactly who should receive prophylaxis remains controversial, not all patients in a hospital or ICU are at increased risk of SRMB. A cost-effective approach is to target prophylactic therapy at high-risk patients. Prevention of SRMB includes resuscitative measures which restore mucosal blood.90 Although the benefits of enteral nutrition to patient outcome (e.g., improved nutritional status enhances mucosal integrity) are of overall clinical importance, its precise role as a sole modality to prevent SRMB remains controversial.103 Therapeutic options for the prevention of SRMB include antacids (which are of historical interest, as they are no longer used because of cumbersome dosage schedules and side effects), antisecretory drugs (H2 RAs and PPIs), and sucralfate, a mucosal protectant.90,104 Cimetidine, given as a continuous intravenous infusion, is the only regimen that is FDAlabeled for the prevention of SRMB. However, in clinical practice, intermittent intravenous H2 RAs are more commonly used. H2 -receptor antagonists are preferred for prophylaxis of SRMB. A large landmark study demonstrated that intravenous ranitidine was superior to oral sucralfate in preventing SRMB.101 Moreover, ranitidine did not increase the risk for nosocomial pneumonia, as the incidence of pneumonia was no different between the two treatment groups. In itself, critical illness places the patient at risk for nosocomial pneumonia. Also there are potential problems associated with sucralfate therapy (e.g., constipation, clogging tubes, hypophosphatemia, and drug interactions).104 Proton pump inhibitors should only be used as alternatives to H2 RAs or sucralfate for preventing SRMB, as their superiority has not been firmly established.105 Only a limited number of studies have evaluated their effectiveness.95,105,106 Only one published randomized controlled trial has demonstrated that omeprazole (40 mg/day oral or nasogastric) is superior to ranitidine (150 mg/day intravenous) in preventing SRMB.106 Although the superiority of omeprazole may be related to its greater antisecretory potency, the possibility of study bias exists, as the population that received ranitidine was at greater risk for SRMB. The optimal dosage of the various intravenous PPIs as well as the preferred route of administration for this indication remains to be defined. Improvement in the patient’s overall medical condition (discharge from the ICU, extubation, and oral intake) suggests that prophylactic therapy can be discontinued. If a patient develops clinically significant bleeding, endoscopic evaluation of the GI tract is indicated along with aggressive drug therapy.

CONCLUSIONS The eradication of HP infection has dramatically changed the way in which chronic PUD is treated. Although substantial progress has been made, there is still no ideal treatment, and much of what has been learned has not yet been instilled into clinical practice. The widespread use of NSAIDs and their associated GI complications remains a major concern, especially in older adults. Cotherapy with misoprostol or a PPI, or switching to a selective COX-2 inhibitor reduces NSAID-related GI events, but studies are needed to determine their comparative cost effectiveness.

ABBREVIATIONS BAO: basal acid output COX-1: cyclooxygenase-1 COX-2: cyclooxygenase-2 CYP450: cytochrome P450 ECL: enterochromaffin-like HP: Helicobacter pylori H2 RA: histamine-2 receptor antagonist ICU: intensive care unit MALT: mucosa-associated lymphoid tissue MAO: maximal acid output NSAID: nonsteroidal antiinflammatory drug NUD: nonulcer dyspepsia PG: prostaglandin PPI: proton pump inhibitor PUD: peptic ulcer disease SRMB: stress-related mucosal bleeding SRMD: stress-related mucosal damage UBT: urea breath test ZES: Zollinger-Ellison syndrome Review Questions and other resources can be found at www.pharmacotherapyonline.com.

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38. Meyer JM, Silliman NP, Wang W, et al. Risk factors for Helicobacter pylori resistance in the United States; the surveillance of H. pylori antimicrobial resistance partnership (SHARP) study, 1993–1999. Ann Intern Med 2002;136:13–20. 39. Laheij RJ, Rossum LG, Janser JB, et al. Evaluation of treatment regimens to cure Helicobacter pylori infection—a meta-analysis. Aliment Pharmacol Ther 1999;13:857–864. 40. Calvet X, Garcia N, Lopez T, et al. A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and either metronidazole or amoxycillin for treating Helicobacter pylori infection. Aliment Pharmacol Ther 2000;14:603–609. 41. Chey WE, Fisher L, Barnett J, et al. Low-versus high-dose azithromycin triple therapy for Helicobacter pylori infection. Aliment Pharmacol Ther 1998;12:1263–1267. 42. Vallve M, Vergara M, Gisbert JP, et al. Single vs. double dose of a proton pump inhibitor in triple therapy for Helicobacter pylori eradication: A meta-analysis. Aliment Pharmacol Ther 2002;16:1149–1156. 43. Vergara M, Vallve M, Gisbert JP, et al. Meta-analysis: Comparative efficacy of different proton-pump inhibitors in triple therapy for Helicobacter pylori eradication. Aliment Pharmacol Ther 2003;18:647–654. 44. Gisbert JP, Khorrami S, Calvet X, et al. Meta-analysis: Proton pump inhibitors vs. H2 -receptor antagonists—their efficacy with antibiotics in Helicobacter pylori eradication. Aliment Pharmacol Ther 2002;18:757– 766. 45. Gene E, Calvet X, Azagra R, et al. Triple vs quadruple therapy for treating Helicobacter pylori infection: A meta-analysis. Aliment Pharmacol Ther 2003;17:1137–1143. 46. Megraud F, Lamouliatte H. Review article: The treatment of refractory Helicobacter pylori infection. Aliment Pharmacol Ther 2003;17:1333– 1343. 47. Gisbert JP, Pajares JM. Review article: Helicobacter pylori “rescue” regimen when proton pump inhibitor-based triple therapies fail. Aliment Pharmacol Ther 2002;16:1047–1057. 48. Lee M, Kemp JA, Canning A, et al. A randomized controlled trial of an enhanced patient compliance program for Helicobacter pylori therapy. Arch Intern Med 1999;159:2312–2316. 49. Van Der Wouden EJ, Thijs JC, Van Zwet AA, et al. Nitroimidazole resistance in Helicobacter pylori. Aliment Pharmacol Ther 2000;14:7– 14. 50. Chan FKL, Leung WK. Peptic ulcer disease. Lancet 2002;360:933–941. 51. Fennerty MB. NSAID-related gastrointestinal injury: Evidence-based approach to a preventable complication. Postgrad Med 2001;110:87–94. 52. Fitzgerald GA, Patrono C. Coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2002;345:433–442. 53. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: A randomized, doubleblind, placebo-controlled trial. Ann Intern Med 1995;123:241–249. 54. Yeomans ND, Tulassay Z, Juhasz L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1998;338:719–726. 55. Hawkey CJ, Karrasch JA, Szcepanski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal anti-inflammatory drugs. N Engl J Med 1998;338:727–734. 56. Graham DY, Agrawal NM, Campbell DR, et al. Ulcer prevention in longterm users of nonsteroidal anti-inflammatory drugs: Results of a doubleblind, randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole. Arch Intern Med 2002;152:169–175. 57. Chan PKI, Chung SCS, Suen BY, et al. Preventing recurrence of upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med 2001;344: 967–973. 58. Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of upper gastrointestinal complications from long-term lowdose aspirin use. N Engl J Med 2002;346:2033–2038. 59. Silverstein F, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal antiinflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: A randomized controlled trial. JAMA 2000;284:1247–1255.

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60. Bombardier C, Laine L, Reicin A, et al. Comparison of upper intestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343:1520–1528. 61. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: Systematic review of randomized controlled trials. BMJ 2002;325:619–626. 62. Chan FD, Huang LC, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347:2104–2111. 63. Lai KC, Chu KM, Hui WM, et al. COX-2 inhibitor compared with proton pump inhibitor in the prevention of recurrent ulcer complications in high-risk patients taking NSAIDs. Gastroenterology 2001;120:A104. Abstract. 64. Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases. J Am Pharm Assoc 2000;40:52–62. 65. Richardson P, Hawkey CJ, Stack WA. Proton pump inhibitors: Pharmacology and rationale for use in gastrointestinal disorders. Drugs 1998;56:307–335. 66. Welage L. Pharmacologic properties of proton pump inhibitors. Pharmacotherapy 2003;23(10 Pt 2):74S–80S. 67. Matheson AJ, Jarvis B. Lansoprazole: An update of its place in the management of acid-related disorders. Drugs 2001;61:1801–1833. 68. Scott LJ, Dunn CJ, Mallarkey G, et al. Esomeprazole: A review of its use in the management of acid-related disorders. Drugs 2002;62:1503–1538. 69. Cheer SM, Prakash A, Faulds D, et al. Pantoprazole: An update of its pharmacological properties and therapeutic use in the management of acid related disorders. Drugs 2003;63:101–132. 70. Carswell CI, Goa KL. Rabeprazole: An update of its use in acid related disorders. Drugs 2001;61:2327–2356. 71. Stedman CAM, Barclay ML. Review article: Comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors. Aliment Pharmacol Ther 2000;14:963–978. 72. Hatlebakk JG, Katz PO, Camacho-Lobato L, et al. Proton pump inhibitors: Better acid suppression when taken before a meal than without a meal. Aliment Pharmacol Ther 2000;14:1267–1272. 73. Baldi F, Malfertheiner P. Lansoprazole fast disintegrating tablet: A new formulation for an established proton pump inhibitor. Digestion 2003;67:1–5. 74. Sharma VK. Comparison of 24-hour intragastric pH using four liquid formulations of lansoprazole and omeprazole. Am J Health-Syst Pharm 1999;(Suppl 4):518–521. 75. Sostek MB, Chen Y, Skammer W, et al. Esomeprazole administered through a nasogastric tube provides bioavailability similar to oral dosing. Aliment Pharmacol Ther 2003;18:581–586. 76. Laine L, Ahnen D, McClain C, et al. Review article: Potential gastrointestinal effects of long term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000;14:651–668. 77. Wade EE, Rebuck JA, Healey MA, et al. H2 antagonist-induced thrombocytopenia: Is this a real phenomenon? Intensive Care Med 2002;28:459– 465. 78. Monroe ML, Doering PL. Effect of common over the counter medications on blood alcohol levels. Ann Pharmacother 2001;35:918–924. 79. Welage LS, Berardi RR. Drug interactions with antiulcer agents: Considerations in the treatment of acid-peptic disease. J Pharm Pract 1994;VII:177–195. 80. Kamiya S, Yamaguchi H, Osaki T, et al. Effect of an aluminum hydroxide-magnesium hydroxide combination drug on adhesion, IL-8 inducibility, and expression of HSP60 by Helicobacter pylori. Scand J Gastroenterol 1999;34:663–670. 81. Maton PN, Burton ME. Antacids revisited: A review of their clinical pharmacology and recommended therapeutic use. Drugs 1999;57:855– 870. 82. Sonnenberg A, Schwartz JS, Cutler AF, et al. Cost savings in duodenal ulcer therapy through Helicobacter pylori eradication compared with conventional therapies: Results of a randomized, double-blind, multicenter trial. Arch Intern Med 1998;158:852–860.

83. Maetzel A, Ferraz MB, Bombardier C. The cost-effectiveness of misoprostol in preventing serious gastrointestinal events associated with the use of nonsteroidal anti-inflammatory drugs. Arthritis Rheum 1998;41:16–25. 84. El-Serag HP, Graham DY, Richardson P, et al. Prevention of complicated ulcer disease among chronic users of nonsteroidal antiinflammatory drugs: The use of a nomogram in cost-effectiveness analysis. Arch Intern Med 2002;162:2105–2110. 85. Hirschowitz BI. Zollinger-Ellison syndrome: Pathogenesis, diagnosis, and management. Am J Gastroenterol 1997;92(Suppl 4):44S–50S. 86. Corleto VD, Annibale B, Gibril F, et al. Does the widespread use of proton pump inhibitors mask, complicate and/or delay the diagnosis of Zollinger-Ellison syndrome? Aliment Pharmacol Ther 2001;15:1555– 1561. 87. Fu F, Venzon DJ, Serrano J, et al. Prospective study of the clinical course, prognostic factors, causes of death and survival in patients with longstanding Zollinger-Ellison syndrome. J Clin Oncol 1999;17:615–630. 88. Tomassetti P, Migliori M, Corinaldesi R, Gullo L. Treatment of gastroenteropancreatic neuroendocrine tumors with octreotide LAR. Aliment Pharmacol Ther 2000;14:557–560. 89. Barkun AN, Coceram AW, Plourde V, Fedorak RN. Review article: Acid suppression in non-variceal acute upper gastrointestinal bleeding. Aliment Pharmacol Ther 1999;13:1565–1584. 90. American Society of Health-System Pharmacists Therapeutic Guidelines on Stress Ulcer Prophylaxis. Am J Health Syst Pharm 1999;56:347–379. 91. Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. N Engl J Med 1994;330:377–381. 92. Laine L, Peterson WL. Bleeding peptic ulcer. N Engl J Med 1994;331: 717–727. 93. Barkun A, Bardou M, Marshall JK. Consensus recommendations for managing patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2003;139:843–857. 94. Levine JE, Leontiadis GI, Sharma VK, Howden CW. Meta-analysis: The efficacy of intravenous H2-receptor antagonists in bleeding peptic ulcer. Aliment Pharmacol Ther 2002;16:1137–1142. 95. Van Leerdam ME, Rauws EAJ. The role of acid suppressants in upper gastrointestinal ulcer bleeding. Best Pract Res Clin Gastroenterol 2001;15:463–475. 96. Lau JYW, Sung JJY, Lee KKC, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 2000;343:310–316. 97. Sung JJY, Chan FKL, Lau JYW. The effect of endoscopic therapy in patients receiving omeprazole for bleeding ulcers with nonbleeding visible vessels or adherent clots. Ann Intern Med 2003;139:237–243. 98. Javid G, Masoodi I, Zargar SA, et al. Omeprazole as adjuvant therapy to endoscopic combination injection sclerotherapy for treating bleeding peptic ulcer. Am J Med 2001;111:280–284. 99. Kaviani MJ, Hashemi MR, Kazemifar AR, et al. Effect of oral omeprazole in reducing re-bleeding in bleeding peptic ulcers: A prospective, double-blind, randomized, clinical trial. Aliment Pharmacol Ther 2003;17:211–216. 100. Cook D, Heyland D, Griffith L, et al. Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical ventilation. Crit Care Med 1999;27:2812–2817. 101. Cook D, Guyatt G, Marshall J, et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. N Engl J Med 1998;338:791–797. 102. Cook DJ, Griffith LE, Walter SD, et al. The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Crit Care 2001;5:368–375. 103. MacLaren R, Jarvis CL, Fish DN. Use of enteral nutrition for stress ulcer prophylaxis. Ann Pharmacother 2001;35:1614–1623. 104. Lam NP, Le PDT, Crawford SY, et al. National survey of stress ulcer prophylaxis. Crit Care Med 1999;27:98–103. 105. Jung R, MacLaren R. Proton-pump inhibitors for stress ulcer prophylaxis in critically ill patients. Ann Pharmacother 2002;36:1929–1937. 106. Levy MJ, Seelig CB, et al. Comparison of omeprazole and ranitidine for stress ulcer prophylaxis. Dig Dis Sci 1997;42:1255–1259.

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34 INFLAMMATORY BOWEL DISEASE Joseph T. DiPiro and Robert R. Schade

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 The exact cause of inflammatory bowel disease (IBD) is un-

known, although there are components that appear to be infectious and other components that suggest immune dysregulation. Genetic variations explain some of the increased risk of disease occurrence.

2 Ulcerative colitis is confined to the rectum and colon,

causes continuous lesions, and affects primarily the mucosa and the submucosa. Crohn’s disease can involve any part of the GI tract, often causes discontinuous (skip) lesions, and is a transmural process that can result in fistulas, perforations, or strictures.

3 Common complications of IBD include rectal fissures,

5 The goals of treatment of IBD are resolution of acute inflam-

mation and complications, alleviation of systemic manifestations, maintenance of remission, and in some patients, surgical palliation or cure.

6 The first-line of treatment for mild to moderate ulcerative colitis or Crohn’s colitis consists of oral sulfasalazine or mesalamine; mesalamine or steroid enemas may be used for rectosigmoid disease. Delayed-release oral formulations of mesalamine may be used for Crohn’s ileitis.

7 Corticosteroids are often required for acute ulcerative colitis or Crohn’s disease. The duration of steroid use should be minimized and the dose tapered gradually over 3 to 4 weeks.

fistulas (Crohn’s disease), perirectal abscess (ulcerative colitis), and colon cancer, in addition to hepatobiliary complications, arthritis, uveitis, skin lesions (including erythema nodosum and pyoderma gangrenosum), and aphthous ulcerations of the mouth.

8 Intravenous continuous infusion of cyclosporine is effective

4 The severity of ulcerative colitis may be assessed by fac-

currence of acute disease in many patients, while steroids are ineffective for this purpose.

tors such as stool frequency, presence of blood in stool, fever, pulse, hemoglobin, erythrocyte sedimentation rate, C-reactive protein, abdominal tenderness, and radiologic or endoscopic findings. The severity of Crohn’s disease can be assessed by the Crohn’s disease activity index, which includes stool frequency, presence of blood in stool, endoscopic appearance, and physician’s global assessment.

There are two forms of idiopathic inflammatory bowel disease (IBD): (a) ulcerative colitis, a mucosal inflammatory condition confined to the rectum and colon; and (b) Crohn’s disease, a transmural inflammation of the gastrointestinal tract that can affect any part, from the mouth to the anus. The etiologies of both conditions are unknown, but they may have some common pathogenetic mechanisms.

EPIDEMIOLOGY At least 1 million Americans are believed to have IBD, with 15,000 to 30,000 new cases diagnosed annually.1 Crohn’s disease has a reported incidence of 3.6 to 8.8 per 100,000 persons in the United States and a prevalence of 20 to 40 per 100,000 people.2 The rates of IBD are highest in Scandinavia, Great Britain, and North America.3 The incidence of Crohn’s disease varies considerably among studies, but

in treating severe colitis that is refractory to steroids.

9 Sulfasalazine and mesalamine derivatives can prevent re-

10 Other drugs that are useful for treatment of Crohn’s disease

include metronidazole (for perineal disease), azathioprine or mercaptopurine (for inadequate response or to reduce steroid dosage), cyclosporine (for refractory disease), and infliximab for refractory or fistulizing disease.

has clearly increased dramatically over the last 3 or 4 decades.3,4 Ulcerative colitis incidence ranges from 3 to 15 cases per 100,000 persons per year among the white population with a prevalence of 80 to 120 per 100,000.2 The incidence of ulcerative colitis has remained relatively constant over many years.3,4 Although most epidemiologic studies combine ulcerative proctitis with ulcerative colitis, from 17% to 49% of cases are proctitis. Both sexes are affected equally with inflammatory bowel disease,1,2 although some studies show slightly greater numbers of women with Crohn’s disease and males with ulcerative colitis.6,7 Ulcerative colitis and Crohn’s disease have bimodal distributions in age of initial presentation. The peak incidence occurs in the second or third decades of life, with a second peak occurring between 50 and 80 years of age.4 A significantly increased incidence of ulcerative colitis (four to five times normal) has been observed in Ashkenazi Jews, while blacks and Asians have a relatively low incidence of occurrence.5

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TABLE 34–1. Proposed Etiologies for Inflammatory Bowel Disease Infectious agents Viruses (e.g., measles) L-Forms of bacteria Mycobacteria Chlamydia Genetics Metabolic defects Connective tissue disorders Environmental Factors Diet Smoking (Crohn’s disease) Immune defects Altered host suceptibility Immune-mediated mucosal damage Psychologic factors Stress Emotional or physical trauma Occupation

ETIOLOGY 1 Although the exact etiology of ulcerative colitis and Crohn’s

disease is unknown, similar factors are believed responsible for both conditions (Table 34–1). The major theories of the cause of IBD involve a combination of infectious, genetic, and immunologic factors.8 The inflammatory response with IBD may indicate abnormal regulation of the normal immune response or an autoimmune reaction to self-antigens. The microflora of the gastrointestinal tract may provide an environmental trigger to activate inflammation.9 Crohn’s disease has been described as “a disorder mediated by T lymphocytes which arises in genetically susceptible individuals as a result of a breakdown in the regulatory constraints on mucosal immune responses to enteric bacteria.”10

INFECTIOUS FACTORS Microorganisms are a likely factor in the initiation of inflammation in IBD.11 However, no definitive infectious cause of IBD has been found, even though the presentation is similar to that caused by some invasive microbial pathogens. Patients with inflammatory bowel diseases have increased numbers of surface-adherent and intracellular bacteria.12 IBD may involve a loss of tolerance toward normal bacterial flora.13 Suspect infectious agents include the measles virus, protozoans, mycobacteria, and other bacteria. Also, certain strains of bacteria produce toxins (necrotoxins, hemolysins, and enterotoxins) that cause mucosal damage. Bacteria elaborate peptides (e.g., formyl-methionylleucyl-phenylalanine) that have chemotactic properties and that cause an influx of inflammatory cells with subsequent release of inflammatory mediators and tissue destruction. Microbes may elaborate superantigens, which are capable of global T-lymphocyte stimulation and subsequent inflammatory response.11 Through luminal exposure to potent nonspecific stimulatory bacterial products, the state of activation of the immune system pathways may be upregulated.14 As many as 70% of patients with Crohn’s disease have circulating antibody to Saccharomyces cerevisiae, but this may not be a disease mechanism.15

GENETIC FACTORS Genetic factors predispose patients to inflammatory bowel diseases, particularly Crohn’s disease. In studies of monozygotic twins, there has been a high concordance rate, with both individuals of the pair having an IBD (particularly Crohn’s disease). Also, first-degree relatives of patients with IBD had a 13-fold increase in the risk of disease.16 Other investigators have observed genetic markers that are found more frequently in those with IBD (particularly major histocompatability complex, HLA-DR2 for ulcerative colitis and HLA-A2 for Crohn’s disease).3 Multiple genes have been associated with IBDs; however, the nature of the gene products has not been established.

IMMUNOLOGIC MECHANISMS The immunologic basis of IBD is supported by a number of observations.9 First is the pathology of the lesions. With Crohn’s disease, the bowel wall is infiltrated with lymphocytes, plasma cells, mast cells, macrophages, and neutrophils. Similar infiltration has been observed in the mucosal layer of the colon in patients with ulcerative colitis. Inflammation in IBDs is maintained by an influx of leukocytes from the vascular system into sites of active disease. This influx is promoted by expression of adhesion molecules (such as alpha-4 integrins) on the surface of endothelial cells in the microvasculature in the area of inflammation.12 Second, many of the systemic manifestations of IBD have an immunologic etiology (e.g., arthritis or uveitis). Finally, IBD is responsive to immunosuppressive drugs (e.g., corticosteroids and azathioprine). The immune theory of IBD assumes that IBD is caused by an inappropriate reaction of the immune system. This may involve an immunodeficiency, such as a defect in cell-mediated immunity or of macrophages or neutrophils. Autoimmunity may be involved. Also, oxidant injury in colon epithelial crypt cells can be demonstrated from inflamed mucosa of patients with IBD.17 Potential immunologic mechanisms include both autoimmune and nonautoimmune phenomena.11 Autoimmunity may be directed against mucosal epithelial cells or against neutrophil cytoplasmic elements. Some patients with IBD have abnormal structural features for colonic epithelial cells even in the absence of active disease. Autoantibodies to these structures have been reported. Also, antineutrophil cytoplasmic antibodies are found in a high percentage of patients with ulcerative colitis (70%) and much less frequently with Crohn’s disease.12 Presence of antineutrophil cytoplasmic antibodies in left-sided ulcerative colitis is associated with resistance to medical therapy.18 Dysregulation of cytokines is a component of IBD. Specifically, Th1 cytokine activity (which enhances cellmediated immunity and suppresses humoral immunity) is excessive with Crohn’s disease, whereas Th2 cytokine activity (which inhibits cell-mediated immunity and enhances humoral immunity) is excessive with ulcerative colitis.19 The result is that patients have inappropriate T-cell responses to antigens from their own intestinal microflora.19 Expression of interferon-γ (a Th1 cytokine) in intestinal mucosa of diseased patients is increased, while interleukin-4 (a Th2 cytokine) is reduced.20−22 Tumor necrosis factor-α (TNF-α) is a pivotal proinflammatory cytokine in Crohn’s disease. TNF-α can recruit inflammatory cells to inflamed tissues, activate coagulation, and promote the formation of granulomas. Production of TNF-α is increased in the mucosa and intestinal lumen of patients with Crohn’s disease.23 Eicosanoids such as leukotriene B4 are increased in rectal dialysates and tissues of IBD patients and are related to disease activity. Leukotriene B4 enhances neutrophil adherence to vascular endothelium and acts as a

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CHAPTER 34

neutrophil chemoattractant. These findings have led to the consideration of leukotriene inhibitor strategies for therapy.

TABLE 34–2. Comparison of the Clinical and Pathologic Features of Crohn’s Disease and Ulcerative Colitis Feature

PSYCHOLOGICAL FACTORS Mental health changes appear to correlate with remissions and exacerbations, especially of ulcerative colitis, but psychological factors overall are not thought to be an etiologic factor. There is a weak association between the number of stressful events experienced and the time to relapse of ulcerative colitis.24

DIET, SMOKING, AND NSAID USE Changes in diet by people in industrialized countries where Crohn’s disease is more common have not been consistently associated with the disease. Studies of increased intake of refined sugars or chemical food additives and reduced fiber intake have provided conflicting results regarding risk for Crohn’s disease. Smoking plays an important but contrasting role in ulcerative colitis and Crohn’s disease. Smoking is protective for ulcerative colitis.12 The risk of developing ulcerative colitis in smokers is about 40% of that in nonsmokers.25 Clinical relapses are associated with smoking cessation, and nicotine transdermal administration has been effective in improving symptoms in patients with ulcerative colitis.26,27 In contrast, smoking is associated with a twofold increased frequency of Crohn’s disease.3 Crohn’s disease patients who stop smoking have a more benign course than patients who continue smoking.28 The mechanisms of these differing effects have not been identified. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) can trigger disease occurrence or lead to disease flares.12,29 The effect of NSAIDs to inhibit prostaglandin production through cyclooxygenase inhibition may impair mucosal barrier protective mechanisms. The increased risk seems to be present for cyclooxygenase-2 inhibitors as well as cyclooxygenase-1 inhibitors.

PATHOPHYSIOLOGY Ulcerative colitis and Crohn’s disease differ in two general respects: anatomic sites and depth of involvement within the bowel wall. There is, however, overlap between the two conditions, with a small fraction of patients showing features of both diseases. Confusion can occur, particularly when the inflammatory process is limited to the colon. Table 34–2 compares pathologic and clinical findings of the two diseases.

ULCERATIVE COLITIS 2 Ulcerative colitis is confined to the rectum and colon, and af-

fects the mucosa and the submucosa. In some instances, a short segment of terminal ileum may be inflamed; this is referred to as backwash ileitis. Unlike Crohn’s disease, the deeper longitudinal muscular layers, serosa, and regional lymph nodes are not usually involved.6 Fistulas, perforation, or obstruction are uncommon because inflammation is usually confined to the mucosa and submucosa. The primary lesion of ulcerative colitis occurs in the crypts of the mucosa (crypts of Lieberkuhn) in the form of a crypt abscess. Here, frank necrosis of the epithelium occurs; it is usually visible only with microscopy, but may be seen grossly when coalescence of ulcers occurs. Extension and coalescence ulcers may surround areas of uninvolved mucosa. These islands of mucosa are called pseudopolyps.

INFLAMMATORY BOWEL DISEASE 651

Clinical Malaise, fever Rectal bleeding Abdominal tenderness Abdominal mass Abdominal pain Abdominal wall and internal fistulas Distribution Aphthous or linear ulcers Pathologic Rectal involvement Ileal involvement Strictures Fistulas Transmural involvement Crypt abscesses Granulomas Linear clefts Cobblestone appearance

Crohn’s Disease

Ulcerative Colitis

Common Common Common Common Common Common

Uncommon Common May be present Absent Unusual Absent

Discontinuous Common

Continuous Rare

Rare Very common Common Common Common Rare Common Common Common

Common Rare Rare Rare Rare Very common Rare Rare Absent

Other typical ulceration patterns include a “collar-button ulcer,” which results from extensive submucosal undermining at the ulcer edge.6 The extensive mucosal damage seen in ulcerative colitis can result in significant diarrhea and bleeding, although a small percentage of patients experience constipation. 3 Ulcerative colitis can be accompanied by complications that may be local (involving the colon or rectum) or systemic (not directly associated with the colon). With either type the complications may be mild, serious, or even life threatening. Local complications occur in the majority of ulcerative colitis patients. Relatively minor complications include hemorrhoids, anal fissures, or perirectal abscesses, and are more likely to be present during active colitis. Enteroenteric fistulas are rare. A major complication is toxic megacolon, which is a segmental or total colonic distension of >6 cm with acute colitis and signs of systemic toxicity.30 It is a severe condition that occurs in up to 7.9% of ulcerative colitis patients admitted to hospitals and results in death rates up to 50%. With toxic megacolon, ulceration extends below the submucosa, sometimes even reaching the serosa. Vasculitis, swelling of the vascular endothelium, and thrombosis of small arteries occurs; involvement of the muscularis propria causes loss of colonic tone, which leads to dilatation and potential perforation.6 The patient with toxic megacolon usually has a high fever, tachycardia, distended abdomen, and elevated white blood cell count, and a dilated colon is observed on x-ray. Colonic perforation, however, may occur with or without toxic megacolon and is a greater risk with the first attack. Another infrequent major local complication is massive colonic hemorrhage. Colonic stricture, sometimes with clinical obstruction, may also complicate long-standing ulcerative colitis. The risk of colonic carcinoma is much greater in patients with ulcerative colitis as compared to the general population. The risk of colon cancer begins to increase 10 to 15 years after the diagnosis of ulcerative colitis. The absolute risk may be as high as 30% 35 years after diagnosis, and as high as 49% for patients who have a long history of disease and who were less than 15 years of age at the time of diagnosis.

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The inflammatory response seen in IBD has also been blamed for the systemic complications seen in both Crohn’s disease and ulcerative colitis. The systemic extraintestinal complications of ulcerative colitis are summarized in the next section.

HEPATOBILIARY COMPLICATIONS Approximately 11% of patients with ulcerative colitis are reported to have hepatobiliary complications with frequencies ranging from 5% to 95% in IBD patients overall.31,32 Hepatic complications include fatty liver, pericholangitis, chronic active hepatitis, and cirrhosis. Biliary complications include sclerosing cholangitis, cholangiocarcinoma, and gallstones. Fatty infiltration of the liver may be a result of malabsorption, protein-losing enteropathy, or concomitant steroid use. The most common hepatic complication is pericholangitis (acute inflammation surrounding the intrahepatic portal venules, bile ducts, and lymphatics), which occurs in up to one-third of ulcerative colitis patients. This is associated with progressive fibrosis of intrahepatic and extrahepatic bile ducts in a small percentage of ulcerative colitis patients, and is referred to as primary sclerosing cholangitis. Cirrhosis may be a sequela of cholangitis or of chronic active hepatitis. Often the severity of hepatic disease does not correlate with gastrointestinal disease activity. Gallstones occur commonly in patients with Crohn’s disease (particularly with terminal ileal disease) and may be related to bile salt malabsorption. Also, cholangiocarcinoma occurs 10 to 20 times more frequently in IBD patients as compared to the general population.31

JOINT COMPLICATIONS Arthritis commonly occurs in IBD patients and is typically asymmetric (unlike rheumatoid arthritis) and migratory, involving one or a few usually large joints. The joints most often affected, in decreasing frequency, are the knees, hips, ankles, wrists, and elbows. Sacroiliitis also occurs commonly. Arthritis associated with ulcerative colitis is generally related to the severity of colonic disease, and resolution without recurrence is seen with proctocolectomy. Also, arthritis in this setting is different from rheumatoid arthritis in that rheumatoid factors are generally not detected. It is nondeforming and nondestructive, even after multiple episodes. Another potential joint complication is ankylosing spondylitis, which is often unresponsive to treatment. The incidence of ankylosing spondylitis in patients with ulcerative colitis is 30 times that of the general population and occurs most commonly in patients with the HLA-B27 phenotype.

OCULAR COMPLICATIONS Ocular complications including iritis, uveitis, episcleritis, and conjunctivitis occur in up to 10% of patients with IBD. The most commonly reported symptoms with iritis and uveitis include blurred vision, eye pain, and photophobia. Episcleritis is associated with scleral injection, burning, and increased secretions. These complications may parallel the severity of intestinal disease, and recurrence after colectomy with ulcerative colitis is uncommon.

DERMATOLOGIC AND MUCOSAL COMPLICATIONS Skin and mucosal lesions associated with IBD include erythema nodosum, pyoderma gangrenosum, and aphthous ulceration. Five to

ten percent of IBD patients experience dermatologic or mucosal complications.33 Raised, red, tender nodules that vary in size from 1 cm to several centimeters are manifestations of erythema nodosum. They are typically found on the tibial surfaces of the legs and arms. These lesions are more commonly observed in Crohn’s disease patients and are noted to correlate with disease severity. Pyoderma gangrenosum occurs more commonly in patients with ulcerative colitis (1% to 5% incidence) and is characterized by discrete skin ulcerations that have a necrotic center and a violaceous color of the surrounding skin.33 They can be seen on any part of the body but are more commonly found on the lower extremities. Oral lesions are found in 6% to 20% of patients with Crohn’s disease and 8% of patients with ulcerative colitis.33 The most common lesion is aphthous stomatitis, seen with Crohn’s disease. The severity of these lesions tends to parallel GI disease.

CROHN’S DISEASE 2 Crohn’s disease is best characterized as a transmural inflamma-

tory process. The terminal ileum is the most common site of the disorder, but it may occur in any part of the GI tract from mouth to anus. About two-thirds of patients have some colonic involvement, and 15% to 25% of patients have only colonic disease.11 Patients often have normal bowel separating segments of diseased bowel; that is, the disease is discontinuous. Regardless of the site, bowel wall injury is extensive and the intestinal lumen is often narrowed. The mesentery first becomes thickened and edematous and then fibrotic. Ulcers tend to be deep and elongated and extend along the longitudinal axis of the bowel, at least into the submucosa. The “cobblestone” appearance of the bowel wall results from deep mucosal ulceration intermingled with nodular submucosal thickening. 3 Complications of Crohn’s disease may involve the intestinal tract or organs unrelated to it. Small bowel stricture and subsequent obstruction is a complication that may require surgery. Fistula formation is common and occurs much more frequently than with ulcerative colitis.11 Fistulae often occur in the areas of worst inflammation, where loops of bowel have become matted together by fibrous adhesions. Fistulae may connect a segment of the GI tract to skin (enterocutaneous fistula), two segments of the GI tract (enteroenteric fistula), or the intestinal tract with the bladder (enterovesicular fistula) or vagina. Crohn’s disease fistulae or abscesses associated with them frequently require surgical treatment. Bleeding with Crohn’s disease is usually not as severe as with ulcerative colitis, although patients with Crohn’s disease may have hypochromic anemia. Also, as with ulcerative colitis, the risk of carcinoma is increased but not as greatly as with ulcerative colitis. Systemic complications of Crohn’s disease are common, and similar to those found with ulcerative colitis. Arthritis, iritis, skin lesions, and liver disease often accompany Crohn’s disease. Renal stones occur in up to 10% of patients with Crohn’s disease (less frequently with ulcerative colitis) and are caused by fat malabsorption, which allows for greater oxalate absorption and formation of calcium oxalate stones. Gallstones also occur with greater frequency in patients with ileitis, possibly because of bile acid malabsorption at the terminal ileum. Nutritional deficiencies are common with Crohn’s disease.34 Reported frequencies of various nutritional parameters are: weight loss, 40% to 80%; growth failure in children, 15% to 88%; iron deficiency anemia, 25% to 50%; vitamin B12 deficiency, 20% to 37%; folate

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deficiency, 13% to 37%; hypoalbuminemia, 25% to 76%; hypokalemia, 33%; and osteomalacia, 36%. There are usually decreased fat stores and lean tissue. Growth failure in children may be associated with hypozincemia.

CLINICAL PRESENTATION The patterns of clinical presentation of IBD can vary widely. Patients may have a single acute episode that resolves and does not recur, but most patients experience acute exacerbations after periods of remission. With more severe disease, prolonged illness may occur.

ULCERATIVE COLITIS Although a typical clinical picture of ulcerative colitis can be described, there is a wide range of presentation, from mild abdominal cramping with frequent small-volume bowel movements to profuse diarrhea (Table 34–3). Most patients with ulcerative colitis experience intermittent bouts of illness after varying intervals with no symptoms. Only a small percentage of patients have continuous unremitting symptoms or have a single acute attack with no subsequent symptoms. 4 Complex disease classifications are generally not used in clinical practice for ulcerative colitis. The arbitrarily determined distinctions of mild, moderate, and severe disease activity are generally used, and these are determined largely by clinical signs and symptoms.6 Mild—Fewer than four stools daily, with or without blood, with no systemic disturbance and a normal erythrocyte sedimentation rate (ESR). Moderate—More than four stools per day but with minimal systemic disturbance. Severe—More than six stools per day with blood, with evidence of systemic disturbance as shown by fever, tachycardia, anemia, or ESR of >30. It is also important to determine disease extent; that is, which part of the colon is involved—rectum, descending colon only, or the entire colon.

TABLE 34–3. Clinical Presentation of Ulcerative Colitis Signs and symptoms r Abdominal cramping r Frequent bowel movements, often with blood in the stool r Weight loss r Fever and tachycardia in severe disease r Blurred vision, eye pain, and photophobia with ocular involvement r Arthritis r Raised, red, tender nodules that vary in size from 1 cm to several centimeters Physical examination r Hemorrhoids, anal fissures, or perirectal abscesses may be present r Iritis, uveitis, episcleritis, and conjunctivitis with ocular involvement r Dermatologic findings with erythema nodosum, pyoderma gangrenosum, or aphthous ulceration Laboratory tests r Decreased hematocrit/hemoglobin r Increased erythrocyte sedimentation rate r Leukocytosis and hypoalbuminemia with severe disease

INFLAMMATORY BOWEL DISEASE 653

Two-thirds of patients with ulcerative colitis have mild disease, which almost always starts in the rectum. Occasionally, the mild form may progress to severe disease, which may be called “fulminant” if it occurs acutely. Systemic signs and symptoms of the disease (e.g., arthritis, uveitis, or pyoderma gangrenosum) may be present in these patients, and in fact may be the reason the patient seeks medical attention. Patients with mild disease are believed to be at lower risk of colon cancer. Moderate disease is observed in one-fourth of patients. With severe disease, the patient is usually found to be in acute distress, has profuse bloody diarrhea, and often has a high fever with leukocytosis and hypoalbuminemia. Often, the patient is dehydrated, and therefore may be tachycardic and hypotensive. This presentation may have a sudden onset with rapid progression. The diagnosis of ulcerative colitis is made on clinical suspicion and confirmed by biopsy, stool examinations, sigmoidoscopy or colonoscopy, or barium radiographic contrast studies. The presence of extracolonic manifestations such as arthritis, uveitis, and pyoderma gangrenosum may also aid in establishing the diagnosis.

CROHN’S DISEASE As with ulcerative colitis, the presentation of Crohn’s disease is highly variable. A single episode may not be followed by further episodes, or the patient may experience continuous, unremitting disease. The time between the onset of complaints and the initial diagnosis may be as long as 3 years. The patient typically presents with diarrhea and abdominal pain. Hematochezia occurs in about one-half of the patients with colonic involvement and much less frequently when there is no colonic involvement. Commonly, a patient may first present with a perirectal or perianal lesion (Table 34–4). The diagnosis should also be suspected in children with growth retardation, especially with abdominal complaints. The course of Crohn’s disease is characterized by periods of remission and exacerbation. Some patients may be free of symptoms for years, while others experience chronic problems in spite of medical therapy. Nearly all patients have a recurrence of Crohn’s disease within 10 years of the initial episode.17 As with ulcerative colitis, the diagnosis of Crohn’s disease involves a thorough evaluation using laboratory, endoscopic, and radiologic testing to detect the extent and characteristic features of the disease. Because of similarities that may exist between ulcerative colitis and Crohn’s disease confined to the colon, a definitive diagnosis cannot be made in up to 15% of cases, even with pathologic specimens in hand. Small bowel involvement and strictures detected on radiographs are characteristic of Crohn’s disease.

TABLE 34–4. Clinical Presentation of Crohn’s Disease Signs and symptoms r Malaise and fever r Abdominal pain r Frequent bowel movements r Hemotachezia r Fistula r Weight loss r Arthritis Physical examination r Abdominal mass and tenderness r Perianal fissure or fistula Laboratory tests r Increased white blood cell count and erythrocyte sedimentation rate

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TREATMENT: Inflammatory Bowel Disease
DESIRED OUTCOME


NONPHARMACOLOGIC THERAPY
NUTRITIONAL SUPPORT

5 To treat IBD properly, the clinician must have a clear concept

of realistic therapeutic goals for each patient. These goals may relate to resolution of acute inflammatory processes, resolution of attendant complications (e.g., fistulas and abscesses), alleviation of systemic manifestations (e.g., arthritis), maintenance of remission from acute inflammation, or surgical palliation or cure. The approach to the therapeutic regimen differs considerably with varying goals as well as with the two diseases, ulcerative colitis and Crohn’s disease. When determining goals of therapy and selecting therapeutic regimens it is important to understand the natural history of IBD.35 Some cases of acute ulcerative colitis are self-limited. With mild to moderate acute colitis without systemic symptoms, 20% of patients may experience spontaneous improvement in their disease within a few weeks; however, a small percentage of patients may go on to experience more serious disease. With severe colitis, improvement without treatment cannot be expected. For instance, the response to medical management of toxic megacolon is variable and emergent colectomy may be required. When remission of ulcerative colitis is achieved, it is likely to last at least 1 year with medical therapy. In the absence of medical therapy, one-half to two-thirds of patients are likely to relapse within 9 months.35 In some reports, remission rates with placebo have approached those found with active treatment. A considerable number of patients with active Crohn’s disease may achieve at least temporary remission without drug therapy. In two large trials, 26% and 42% of ambulatory patients on placebo achieved remission.36,37 Once remission is achieved, two-thirds to three-fourths of patients remain in remission up to 2 years without drug therapy.35 The implication of these data is that up to 40% of patients with active Crohn’s disease improve in 3 to 4 months with observation alone, and that most patients remain in remission for prolonged periods without medical intervention. These observations apply more to mild or moderate disease than to severe disease.


GENERAL APPROACH TO TREATMENT 6 Treatment of IBD centers on agents used to relieve the inflam-

matory process. Salicylates, corticosteroids, antimicrobials, and immunosuppressive agents such as azathioprine and mercaptopurine are commonly used to treat active disease, and for some agents, to lengthen the time of disease remission. In addition to the use of drugs, surgical procedures are sometimes performed when active disease is inadequately controlled or when the required drug dosages pose an unacceptable risk of adverse effects. For most patients with IBD, nutritional considerations are also important, because these patients are often malnourished. Finally, a variety of therapies may be used to address complications or symptoms of IBD. For example, antidiarrheals may be used in some patients, although these are generally to be avoided in severe ulcerative colitis because they may contribute to the development of toxic colonic dilatation. Antimicrobial agents may be used in conjunction with drainage when abscesses are present. Iron may be required, particularly with ulcerative colitis, where blood loss from the colon can be significant.

Proper nutritional support is an important aspect of the treatment of patients with IBD, not because specific types of diets are useful in alleviating the inflammatory conditions, but because patients with moderate to severe disease are often malnourished either because the inflammatory process results in significant malabsorption or maldigestion, or because of the catabolic effects of the disease process. Malabsorption may occur in the patient with Crohn’s disease with inflammatory involvement of the small bowel, where many nutrients are absorbed, as well as in patients who have undergone multiple small bowel resections with subsequent reduction in absorptive surface (“short gut”). Maldigestion can occur if there is a bile salt deficiency in the gut. Many specific diets have been tried to improve the condition of patients with IBD, but none has gained widespread acceptance. With each individual it is helpful to eliminate specific foods that exacerbate symptoms. This elimination process must be conducted cautiously, as patients have been known to exclude a wide range of nutritious products without adequate justification. Some patients with IBD, although not the majority, have lactase deficiency; therefore diarrhea may be associated with milk intake. In these patients, avoidance of milk or supplementation with lactase generally improves the patient’s symptoms. The nutritional needs of the majority of patients can be adequately addressed with enteral supplementation.38 Patients who have severe disease may require a course of parenteral nutrition to attain a reasonable nutritional status or in preparation for surgery. In severe acute ulcerative colitis, enteral nutrition resulted in a significantly greater increase in serum albumin, fewer adverse effects related to the nutritional regimen, and fewer postoperative infections, as compared to isocaloric, isonitrogenous parenteral nutrition.39 The regimens were similar with regard to remission rate and the need for colectomy.39 Consideration should be given to lipid administration for its caloric value, as well as in recognition of depleted peripheral fat stores in many IBD patients and the greater potential for fatty acid deficiency. Parenteral nutrition is an important component of the treatment of severe Crohn’s disease or ulcerative colitis. The use of parenteral nutrition allows complete bowel rest in patients with severe ulcerative colitis, which may alter the need for proctocolectomy. Parenteral nutrition has also been valuable in Crohn’s disease, because remission may be achieved with parenteral nutrition in about 50% of patients.40 In some patients, the disease may worsen when parenteral nutrition is stopped. Patients with enterocutaneous fistulas of various etiologies benefit from parenteral nutrition.40 Parenteral nutrition may also be valuable in children or adolescents with growth retardation associated with Crohn’s disease, but surgery is often necessary with severe disease. Finally, when possible, home parenteral nutrition should be used for patients requiring long-term therapy, particularly those with “short gut” as a consequence of surgical resection. There is a growing interest in using probiotic approaches for IBD. Probiotics involves the reestablishment of normal bacterial flora within the gut by oral administration of live bacteria such as nonpathogenic Escherichia coli, bifidobacteria, lactobacilli, or Streptococcus thermophilus. Probiotic formulations have been effective in maintaining remission in ulcerative colitis.41−43

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SURGERY Surgical procedures have an established place in the treatment of IBD. Although surgery (proctocolectomy) is curative for ulcerative colitis, this is not the case for Crohn’s disease. Surgical procedures involve resection of segments of intestine that are affected, as well as correction of complications (e.g., fistulas) or drainage of abscesses. For ulcerative colitis, colectomy may be necessary when the patient has disease uncontrolled by maximum medical therapy or when there are complications of the disease such as colonic perforation, toxic dilatation (megacolon), uncontrolled colonic hemorrhage, or colonic strictures. Colectomy may be indicated in patients with longstanding disease (greater than 8 to 10 years), as a prophylactic measure against the development of cancer, and in patients with premalignant changes (severe dysplasia) on surveillance mucosal biopsies. The most common surgical procedures include proctocolectomy, after which the patient is left with a permanent ileostomy, and abdominal colectomy, with removal of the mucosa of the rectum and anastomosis of an ileal pouch to the anus (ileoanal pull-through). The risk from surgery in these patients is relatively low if the operations are performed on a nonemergent basis. The indications for surgery with Crohn’s disease are not as well established as for ulcerative colitis, and surgery is usually reserved for the complications of the disease. A recognized problem with intestinal resection for Crohn’s disease is the high recurrence rate. Surgery may be appropriate in well-selected patients who have severe or incapacitating disease or obstruction in spite of aggressive medical management. The surgical procedures performed include resections of the major intestinal areas of involvement. In some patients with severe rectal or perineal disease, diversion of the fecal stream is performed with a colostomy. Other indications for surgery include the finding of colon cancer, an inflammatory mass, or intestinal perforations.


PHARMACOLOGIC THERAPY Drug therapy plays an integral part in the overall treatment of IBD. None of the drugs used for IBD is curative; at best they serve to control the disease process. Therefore a reasonable goal of drug therapy is resolution of disease symptoms such that the patient can carry on normal daily functions. The major types of drug therapy used in IBD include aminosalicylates, corticosteroids, immunosuppressive agents (azathioprine, mercaptopurine, cyclosporine, and methotrexate), antimicrobials (metronidazole and ciprofloxacin), and agents to inhibit TNF-α (anti-TNF-α antibodies).

INFLAMMATORY BOWEL DISEASE 655

Sulfasalazine, an agent that combines a sulfonamide (sulfapyridine) antibiotic and mesalamine (5-aminosalicylic acid) in the same molecule, has been used for many years to treat IBD but was originally intended to treat arthritis. Sulfasalazine is cleaved by gut bacteria in the colon to sulfapyridine (which is mostly absorbed and excreted in the urine) and mesalamine (which mostly remains in the colon and is excreted in stool).44 The active component of sulfasalazine is mesalamine.44 The mechanism of action of mesalamine is not well understood. Cyclooxygenase or lipoxygenase inhibition alone do not account for the agent’s effects. Aminosalicylates may block production of prostaglandins and leukotrienes, inhibit bacterial peptide-induced neutrophil chemotaxis and adenosine-induced secretion, scavenge reactive oxygen metabolites, and inhibit activation of the nuclear regulatory factor NF-κB.12 Because the mechanism of action of sulfasalazine is not related to the sulfapyridine component, and since sulfapyridine is believed to be responsible for many of the adverse reactions to sulfasalazine, mesalamine alone can be used. Mesalamine can be used topically as an enema for the treatment of proctitis, or given orally in slowrelease formulations that deliver mesalamine to the small intestine and colon (Table 34–5 and Fig. 34–1). Slow-release oral formulations of mesalamine such as Pentasa release mesalamine from the duodenum to the ileum, with about 75% of the drug passing into the colon.45 Olsalazine is a dimer of two 5-aminosalicylate molecules linked by an azo bond. Mesalamine is released in the colon after colonic bacteria cleave olsalazine. Balsalazide is a mesalamine prodrug that is enzymatically cleaved in the colon to produce mesalamine. The recommended daily doses of the oral mesalamine derivatives are intended to approximate the molar equivalent of mesalamine present in 4 g of sulfasalazine. At present, sulfasalazine is used in preference to oral mesalamine derivatives, mainly because it costs much less. However, it is not tolerated as well as the mesalamine alternatives. Because the oral mesalamine formulations are coated tablets or granules, they should not be crushed or chewed. Corticosteroids and adrenocorticotropic hormone have been widely used for the treatment of ulcerative colitis and Crohn’s disease, given parenterally, orally, or rectally. Corticosteroids are believed to modulate the immune system and inhibit production of cytokines and mediators. It is not clear whether the most important steroid effects are systemic or local (mucosal). Budesonide is a corticosteroid that is administered orally in a controlled-release formulation. The drug undergoes extensive first-pass metabolism, so systemic exposure is thought to be minimized. Immunosuppressive agents such as azathioprine, mercaptopurine (a metabolite of azathioprine), methotrexate, or cyclosporine are sometimes used for the treatment of IBD.46

TABLE 34–5. Mesalamine Derivatives for Treatment of Inflammatory Bowel Disease Product Sulfasalazine Mesalamine

Trade Name(s) Azulfidine Rowasa, Salofalk, Claversal, Pentasa Asacol Pentasa

Olsalazine Balsalazide

Dipentum Colazal

Formulation

Dose/Day

Site of Action

Tablet Enema

4–6 g 1–4 g

Colon Rectum, terminal colon

Mesalamine tablet coated with Eudragit-S (delayed-release acrylic resin) Mesalamine capsules encapsulated in ethylcellulose microgranules Dimer of 5-aminosalicylic acid oral capsule Capsule

2.4–4.8 g

Distal ileum and colon

2–4 g

Small bowel and colon

1.5–3 g 6.75 g

Colon Colon

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Distal colon

Proximal colon

Terminal ileum

Ileum Jejunum

Product Rowasa suppository Steroid enema Rowasa enema Sulfasalazine balsalazide Asacol Pentasa

FIGURE 34–1. Site of activity of various agents used to treat inflammatory bowel disease.

Azathioprine and mercaptopurine are effective for long-term treatment of Crohn’s disease and ulcerative colitis.47 These agents are generally reserved for patients who are refractory to steroids, and they may be associated with serious adverse effects such as lymphomas, pancreatitis, or nephrotoxicity. They are usually used in conjunction with mesalamine derivatives and/or steroids, and must be used for long periods of time (from a few weeks up to 6 months) before benefits may be observed.48 Remission can be prolonged by azathioprine in steroid-dependent patients with ulcerative colitis.49 Cyclosporine

Disease severity Mild

Moderate

has also been of short-term benefit in treatment of acute, severe ulcerative colitis when used in a continuous intravenous infusion. Oral doses are ineffective. The agent poses a risk of nephrotoxicity and neurotoxicity. Methotrexate given 15 to 25 mg intramuscularly once weekly is useful for treatment and maintenance of Crohn’s disease but not ulcerative colitis. Antimicrobial agents, particularly metronidazole, are frequently used in attempts to control Crohn’s disease but are not useful in ulcerative colitis. Metronidazole is of value in some patients with active Crohn’s disease, particularly involving the perineal area or fistulas.50 The mechanism of metronidazole’s effect on Crohn’s disease has not been determined but is theorized to relate to interruption of a bacterial role in the inflammatory process. Ciprofloxacin has also been used for treatment of IBD. Infliximab is an IgG1 chimeric monoclonal antibody that binds TNF-α and inhibits its inflammatory effect in the gut. The agent is useful for steroid-dependent or fistulizing disease, but the cost far exceeds that of other regimens.


ULCERATIVE COLITIS
Mild to Moderate Disease Most patients with active ulcerative colitis have mild to moderate disease and do not require parenteral medications (Fig. 34–2). The first line of drug therapy for these patients is oral sulfasalazine or an oral mesalamine derivative, or topical mesalamine or steroids for distal

Proctitis As above or mesalamine enema 2– 4 g/day or corticosteroid enema Colitis Sulfasalazine 4–6 g/day or oral mesalamine 2– 4.8 g/day

Sulfasalazine 4– 6 g/day or oral mesalamine 3–6 g/day PLUS prednisone 40–60 mg/day

Remission

Remission

Remission

Severe Inadequate or no response Hydrocortisone IV 100 mg every 6–8 h Fulminant

Remission

No response in 5–7 days Cyclosporine IV 4 mg/kg/day

As above or mesalamine enema 4 g every 1–2 days

Reduce sulfasalazine or mesalamine dose up to 2 g/day

Taper prednisone, then after 1–2 mo reduce sulfasalazine or mesalamine dose to those listed above Add azathioprine or mercaptopurine

Change to prednisone Add sulfasalazine or mesalamine and attempt to withdraw steroid after 1–2 mo Remission

FIGURE 34–2. Treatment approaches for ulcerative colitis.

Maintenance dose of sulfasalazine

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disease.51 When given orally, usually 4 g/day, and up to 8 g/day, of sulfasalazine is required to attain control of active inflammation. There does not appear to be an increased rate of response with increased dosage over 4 g/day, although side effects increase. Even with the use of adequate doses, patient improvement usually takes 2 to 3 weeks, and sometimes longer. The dosage of sulfasalazine that can be given is usually limited by the patient’s tolerance of the agent; most adverse effects of sulfasalazine are dose related (GI disturbances, headache, and arthralgia).48 Sulfasalazine therapy should be instituted at 500 mg/day and increased every few days up to 4 g/day or the maximum tolerated. It should not be used in patients with allergy to sulfa drugs. Oral mesalamine derivatives (such as those listed in Table 34–5) are reasonable alternatives to sulfasalazine for treatment of ulcerative colitis. These agents are clearly more effective than placebo but no more effective than sulfasalalzine. However, mesalamine preparations are better tolerated.52 For many patients the dose of mesalamine can be increased without an increase in adverse effects. The majority of patients intolerant to sulfasalazine should tolerate one of the other oral mesalamine derivatives. While the dosage range for Pentasa is 2 to 4 g/day, 4 g/day appears to be more effective.53 Olsalazine (a dimer of 5-aminosalicylic acid that is given orally) is effective for treatment of mild to moderate ulcerative colitis. However, of patients taking olsalazine, 15% to 25% experience severe diarrhea, often necessitating discontinuation of the drug. This results from a direct osmotic effect of the drug to induce small bowel fluid secretion. For this reason it is not the drug of first choice. Balsalazide is another mesalamine derivative that is effective for treatment of mild to moderate ulcerative colitis.54 For patients with distal disease, combination therapy of oral mesalamine derivatives and topical (enema) mesalamine therapy may be beneficial for induction of remission as well as for maintenance.12,55 7 Steroids have a place in the treatment of moderate to severe ulcerative colitis that is unresponsive to maximal doses of oral and topical mesalamine derivatives. Oral steroids (usually up to 1 mg/kg per day of prednisone equivalent) may be used for patients who do not have an adequate response to sulfasalazine or mesalamine. Overall, steroids and sulfasalazine appear to be equally efficacious; however, the response to steroids may be evident sooner. Oral steroids should not be used as initial therapy for mild to moderate ulcerative colitis, mainly because of the known risks of steroid use. If steroids are used to attain remission, tapered drug withdrawal should be accomplished to minimize long-term steroid exposure. Rectally administered steroids or mesalamine can be used as initial therapy for patients with ulcerative proctitis or distal colitis. Rectal agents are also beneficial for treatment of tenesmus. With these agents, local actions are believed to be responsible for drug effects. Rectal steroids are effective in the treatment of active, distal ulcerative colitis. However, rectal mesalamine is more effective than rectal steroids for inducing remission.56,57 CLINICAL CONTROVERSY The choice of rectally administered steroid is a subject of debate, as there is varying potential for systemic steroid absorption with different products. Although many steroids have been administered rectally, certain agents such as betamethasone-17-valerate, beclomethasone dipropionate, prednisolone metasulfobenzoate, prednisolone-21phosphate, and budesonide have been used in attempts to reduce systemic steroid effects. Systemic side effects may be the least severe with beclomethasone dipropionate, because

INFLAMMATORY BOWEL DISEASE 657

the gut wall and liver rapidly metabolize this agent.56 Most patients do not experience adrenal suppression from rectal steroids. The use of rectal steroids may often result in reduction of the required oral dose. Nicotine has been proposed as a treatment for ulcerative colitis (but not as a treatment for Crohn’s disease) based on the observation of the onset of a flare of ulcerative colitis after smoking cessation in some individuals. When used in the highest tolerated dose, transdermal nicotine improved symptoms of patients with mild to moderate active ulcerative colitis.58


Severe or Intractable Disease Patients with uncontrolled severe colitis or who have incapacitating symptoms require hospitalization for effective management. Under these conditions, patients generally receive nothing by mouth to put the bowel at rest. Most medication is given by the parenteral route. With severe colitis, there is a much greater reliance on parenteral steroids (intravenous hydrocortisone) and surgical procedures. Sulfasalazine or mesalamine derivatives are not beneficial for treatment of severe colitis because of rapid elimination of these agents from the colon with diarrhea, thereby not allowing sufficient time for gut bacteria to cleave the molecules. Overall it is difficult to evaluate drugs in this setting, because patients with severe disease almost always receive additional medications including steroids. Steroids have been valuable in the treatment of severe disease because the use of these agents may allow some patients to avoid colectomy. A trial of steroids is warranted in most patients before proceeding to colectomy, unless the condition is grave or rapidly deteriorating. The dose of steroid generally used is 1 mg/kg of prednisone equivalent daily (up to 60 mg/day), although some patients may require much less or much more for satisfactory control. With higher doses, however, steroid side effects may limit drug benefits. The length of the medical trial before consideration of surgery is open to debate. Steroids increase surgical risk, particularly infectious risk, if an operation is required later. After a colectomy is performed, steroids should no longer be required for the disease; however, they must be withdrawn gradually (usually over 3 to 4 weeks) to avoid hypoadrenal crisis due to adrenal suppression. 8 Patients who are unresponsive to parenteral corticosteroids after 7 to 10 days should receive cyclosporine by intravenous infusion. Most hospitalized patients who are unresponsive to corticosteroids will respond to cyclosporine.59−61 Continuous intravenous infusion of cyclosporine (4 mg/kg per day) was rapidly effective in steroid-resistant acute severe ulcerative colitis and reduced the need for emergent colectomy.62 Intravenous cyclosporine has been recommended as an alternative to steroids in patients with severe attacks of ulcerative colitis (fulminant colitis).63 Patients who are controlled on intravenous cyclosporine can then be switched to an oral cyclosporine taper regimen.


Maintenance of Remission 9 After remission from active disease is achieved, the goal of ther-

apy is to maintain remission. The major agents used for maintenance of remission are sulfasalazine and the mesalamine derivatives; steroids do not have a role. The value of sulfasalazine in preventing recurrences has been documented in placebo-controlled trials.

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One-fourth of patients taking sulfasalazine (2 g/day) had a relapse within 1 year, while three-fourths of patients taking placebo had a relapse.64 Mesalamine preparations and olsalaizine are effective for maintaining remission. A meta-analysis of trials concluded that mesalalmine was more effective than placebo, but not as effective as sulfasalazine for maintaining remission.65 CLINICAL CONTROVERSY A major question about the use of sulfasalazine for maintenance of remission with ulcerative colitis is the duration of the preventive regimen. Maintenance of remission has been well documented up to 1 year and may last as long as 3 years. The efficacy of sulfasalazine appears to be related to the dose administered, up to a point. Although 4 g/day has a lower recurrence rate than 2 g or 1 g, a 4-g dose will result in intolerable side effects in about one-fourth of patients. Therefore 2 g/day is recommended. Steroids do not have a role in the maintenance of remission with ulcerative colitis because they are ineffective.48 Steroids should be gradually withdrawn after remission is induced (over 3 to 4 weeks). If they are continued, the patient will be exposed to steroid side effects without likelihood of benefits. For patients who require chronic steroid use (>20 mg/day), there is a strong justification for alternative therapies or colectomy. Azathioprine is effective in preventing relapse of ulcerative colitis for periods of up to 2 years.66 However, 3 to 6 months may be required before beneficial effects are noted. Oral azathioprine also maintains long-term remission after IV cyclosporine induction.67


CROHN’S DISEASE Management of Crohn’s disease often proves more difficult than management of ulcerative colitis, partly because of the greater complexity of presentation with Crohn’s disease (Fig. 34–3). The disease may

involve any segment of the GI tract, from mouth to anus, and may involve other visceral structures and soft tissues through fistulization. There is a greater reliance on drug therapy with Crohn’s disease, because resection of all involved intestine may not be possible and disease recurrence after surgery is common.


Active Crohn’s Disease The goal of treatment for active Crohn’s disease is to achieve remission; however, in many patients, reduction of symptoms so the patient may carry out normal activities, or reduction of the steroid dose required for control, is a significant accomplishment. In the majority of patients, active Crohn’s disease is treated with sulfasalazine, mesalamine derivatives, or steroids, although azathioprine, mercaptopurine, methotrexate, or metronidazole are frequently used. The role of sulfasalazine in the treatment of active Crohn’s disease is not as well established as its role in the treatment of ulcerative colitis. Sulfasalazine is more effective when Crohn’s disease involves the colon.36 In these circumstances, sulfasalazine is as effective as prednisone.36,68 A trial of sulfasalazine or an oral mesalamine derivative should be initiated in patients with mild to moderate Crohn’s disease, particularly when the colon is involved. Mesalamine products such as Pentasa or Asacol, that release mesalamine in the small bowel, are more effective than sulfasalazine for ileal involvement. In a trial of 310 patients with active Crohn’s disease, Pentasa alone was more effective than placebo in achieving remission in a 16-week trial (43% vs. 18%, respectively).69 This beneficial effect was dose dependent and greatest with a dose of 4 g/day. A course of steroids is appropriate in patients who cannot be controlled with mesalamine. However, when a patient is maintained on steroids, there appears to be no benefit from the addition of sulfasalazine. 7 Steroids are frequently used for the treatment of active Crohn’s disease, particularly with more severe presentations. In the National Cooperative Crohn’s Disease Study,36 prednisone was more effective than placebo in achieving remission (60% remission rate after 17 weeks vs. a 30% remission rate for placebo). In this trial, the prednisone doses were 0.25 mg/kg per day for mild disease,

Disease severity Mild Ileocolonic or colonic Sulfasalazine 3–6 g/day or oral mesalamine 3–4 g/day

Perianal Sulfasalazine or oral mesalamine and/or metronidazole up to 10–20 mg/kg/day

Small bowel Oral mesalamine 3–4 g/day or metronidazole

Moderate Response As above plus prednisone 40–60 mg/day

Refractory and fistulizing disease add Infliximab

Severe Hydrocortisone 100 mg IV every 6–8 h

FIGURE 34–3. Treatment approaches for Crohn’s disease.

Fulminant

No response in 7 days

Taper prednisone after 2–3 wk Add azathioprine, mercaptopurine, or methotrexate

Cyclosporine IV 4 mg/kg/day

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0.5 mg/kg per day for moderate disease, and 0.75 mg/kg per day for severe disease. Prednisone was effective for disease limited to the small bowel. The major limitation of steroids is the risk of adverse effects with long-term use. Steroids are preferred for treatment of severe Crohn’s disease, mainly because these agents can be given parenterally and response to therapy may occur sooner than with other agents. However, once remission is achieved, it is difficult to reduce the steroid dosage without a flare of active disease. 10 Metronidazole (given orally up to 20 mg/kg per day in divided doses) may be useful in some patients with Crohn’s disease, particularly in patients with colonic involvement, or in those patients with perineal disease.50 For most patients, metronidazole would be added to a mesalamine product, or steroid therapy when those agents alone are not effective. The role for metronidazole is not fully defined. It may deserve a trial as adjunctive therapy for patients with colonic or perineal disease, where satisfactory control of Crohn’s disease is not gained with first-line agents, or in attempts to reduce steroid dosage.70 Ciprofloxacin has gained attention as an alternative to metronidazole and appears to be effective.71 The immunosuppressive agents (azathioprine and mercaptopurine) are generally limited to use in patients not achieving adequate response to standard medical therapy, or to reduce steroid doses when high steroid doses are required. Azathioprine and mercaptopurine demonstrated long-term benefits in patients with Crohn’s disease.47 The usual doses of azathioprine are 2 to 2.5 mg/kg per day, and for mercaptopurine 1 to 1.5 mg/kg per day. They are begun at 50 mg/day and increased at 2-week intervals while monitoring white blood cell and platelet counts. Treatment with azathioprine may need to be continued for up to 6 months to observe a response.48 In one trial of patients already receiving sulfasalazine or prednisone, mercaptopurine decreased steroid requirement and healed fistulas. One problem noted with mercaptopurine was that more than 3 months was required to observe a response in 32% of patients. In a report of 20 years of experience with 148 patients, mercaptopurine (50 mg/day, mean 34 months) was judged effective for reduction of steroid dosage or elimination of the need for steroids, healing of fistulas and abscesses, and healing of Crohn’s disease of the stomach and duodenum.72 Some investigators have suggested that azathioprine or mercaptopurine should be started earlier in the course of treatment than has been traditional. Clinical response to mercaptopurine is related to whole-blood concentrations of the metabolite 6-thioguanine, and hepatotoxicity is correlated with another metabolite, 6-methylmercaptopurine.73 Metabolic inactivation of azathioprine and mercaptopurine occurs by thiopurine S-methyltransferase, which exhibits genetic polymorphism. Enzyme-deficient patients are at greater risk of bone marrow suppression from these agents.74,75 Determination of enzyme activity may be necessary to determine which patients require lower doses of these agents. Cyclosporine is not recommended for treatment of Crohn’s disease except for patients with symptomatic and severe perianal or cutaneous fistulas.12 Approximately 80% of patients with refractory fistulas responded to intravenous cyclosporine (4 mg/kg per day) within a mean of 7.9 days.76 The dose of cyclosporine is important in determining efficacy. An oral dose of 5 mg/kg per day was ineffective,77 whereas 7.9 mg/kg per day was effective.78 However, toxic effects limit application of the higher dosage. At present, the therapeutic blood or plasma concentration range for cyclosporine has not been established for Crohn’s disease, but whole-blood trough concentrations of 200 to 800 ng/mL (by monoclonal radioimmunoassay) or 200 to 400 ng/mL (by high-performance liquid chromatography) have been recommended.3 When using cyclosporine, however, clinicians should

INFLAMMATORY BOWEL DISEASE 659

recognize the accompanying long-term risk of renal toxicity as well as the potential for drug interactions. Methotrexate given as a weekly injection of 5 to 25 mg has demonstrated efficacy for induction of remission in Crohn’s disease as well as for maintenance therapy.79,80 It is also useful for corticosteroidsparing effects.81,82 While there are risks of bone marrow suppression, hepatotoxicity, and pulmonary toxicity, low-dose methotrexate appears relatively safe.79 Infliximab is approved for treating refractory or fistulizing Crohn’s disease. A 5 mg/kg single infusion of infliximab resulted in clinical improvement in 80% of patients with chronic Crohn’s disease who were receiving steroids.83 The benefit lasted 8 to 12 weeks with reinfusion producing a sustained response. Infliximab also significantly reduced fistula drainage. Additional studies have demonstrated the effectiveness of long-term use (10 mg/kg every 8 weeks for 32 weeks).84 Patients who receive infliximab often develop antibodies to infliximab, which can result in infusion reactions and loss of response to the drug. Administration of a second dose within 8 weeks of the first dose and concurrent administration of hydrocortisone (200 mg intravenously) significantly reduced antibody formation.85,86 Smoking reduces the response to infliximab, both the percentage of patients responding (73% in nonsmokers and 22% in smokers) and the duration of response.87


Maintenance of Remission 9 Prevention of recurrence of disease is clearly more difficult with

Crohn’s disease than with ulcerative colitis. There is evidence that some agents, particularly sulfasalazine and oral mesalamine derivatives, are effective in preventing acute recurrences in quiescent Crohn’s disease.88 The support for sulfasalazine has been largely anecdotal;88 however, a trial of 232 patients demonstrated a lower relapse rate compared with placebo for up to 2 years when given 3 g/day.89 There is support for the use of oral mesalamine derivatives for maintenance of symptomatic remission. On average, oral mesalamine derivatives decrease recurrence rates by 40% as compared to placebo in long-term studies.77 In one trial of 161 patients in remission, 2 g/day of mesalamine (Pentasa) for 2 years resulted in a significantly reduced relapse rate when begun within 3 months of achieving remission.90 In another trial of mesalamine (Asacol), 125 patients received 2.4 g/day or placebo for 12 months, resulting in a significantly reduced relapse rate with Asacol.91 Steroids also have no place in the prevention of recurrence of Crohn’s disease; these agents do not appear to alter the long-term course of the disease. However, a study of oral budesonide 6 mg/day demonstrated prolongation of time to relapse in ileal and ileocecal disease.92 Azathioprine, mercaptopurine, and methotrexate are useful in some patients to maintain remission. Although the published data are inconsistent, there is evidence to suggest that azathioprine and mercaptopurine are effective in maintaining remission in Crohn’s disease and are documented to increase quality-adjusted life expectancy.48,49,93 Low-dose methotrexate (15 mg intramuscularly once weekly) is also effective in maintaining remission.94 These agents should be reserved for patients who cannot tolerate the dosages of steroids required to control their disease and who are not good surgical candidates. Infliximab infusion given every 8 weeks is more effective than placebo in maintaining remission in patients who initially respond to infliximab for active Crohn’s disease. It can be administered 5 or 20 mg/kg every 8 weeks.95

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SELECTED COMPLICATIONS TOXIC MEGACOLON The treatment required for toxic megacolon includes general supportive measures to maintain vital functions, consideration for early surgical intervention, and drugs (steroids, cyclosporine, and antimicrobials). Aggressive fluid and electrolyte management is required for dehydration. Fluids and electrolytes may be lost through vomiting, diarrhea, and nasogastric intubation, as well as through fluid accumulation in the bowel. When the patient has lost significant amounts of blood (through the rectum), blood replacement is also necessary. Opiates and anticholinergics should be discontinued because these agents enhance colonic dilatation, thereby increasing the risk of bowel perforation. Broad-spectrum antimicrobials that include coverage for gram-negative bacilli and intestinal anaerobes should be used. Steroids in high dosages should be administered intravenously to reduce acute inflammation. Doses as high as 2 mg/kg per day of prednisone equivalent have been recommended (generally administered as hydrocortisone).6 The duration of steroid administration is not certain; however, most clinicians continue the high-dose steroids for up to 2 weeks after improvement is observed, and then reduce the dosage (approximately 0.5 to 1 mg/kg per day) for a few additional weeks. Antimicrobial regimens that are effective against enteric aerobes and anaerobes (e.g., an aminoglycoside with clindamycin or metronidazole, imipenem, or an extended-spectrum penicillin with β-lactamase inhibitor) should be administered from the time of diagnosis and continued until patient improvement is assured. The duration of the antimicrobial regimen (often 2 to 3 weeks) should be determined with consideration that there may be significant intraabdominal contamination with signs and symptoms hidden by steroid effects. Emergent surgical intervention, mainly an abdominal colectomy with formation of an ileostomy, is an important consideration in patients with toxic megacolon and prevents death in some patients. In most cases in which colectomy is performed in the face of toxic megacolon, there is a significant risk of operative complications, including postoperative infection.

SYSTEMIC MANIFESTATIONS The common systemic manifestations of IBD include arthritis, anemia, skin manifestations such as erythema nodosum and pyoderma gangrenosum, uveitis, and liver disease. These problems may be related to the inflammatory process. For some of these manifestations specific therapies can be instituted, whereas for others the treatment that is used for the GI inflammatory process also addresses the systemic manifestations. Anemia occurs when there is significant blood loss from the GI tract. If the patient can consume oral medication, ferrous sulfate should be administered. If the patient is unable to take oral medication and the patient’s hematocrit is sufficiently low, blood transfusions or intravenous iron infusions may be required. Anemia may also be related to malabsorption of vitamin B12 or folic acid, so these may also be required. There are no consistently recommended therapies for liver disease, skin manifestations, or uveitis associated with IBD. Some reports suggest that these manifestations are worse during exacerbations of the intestinal disease and that measures improving intestinal disease will improve these systemic manifestations. Unfortunately, this association has not been demonstrated consistently. Liver transplantation

is being used more frequently for definitive treatment of primary sclerosing cholangitis. For arthritis associated with IBD, aspirin or another NSAID may be beneficial, as might be steroids.

SPECIAL CONSIDERATIONS PREGNANCY Either the occurrence or consideration of pregnancy may cause significant concerns in the patient with IBD. Patients with IBD do not appear to be less fertile than women in general.6,96 The rate of normal childbirth is similar to that for healthy populations. Some studies have noted a greater risk of spontaneous abortions in patients with IBD. Also, there is a greater incidence of low birth weight infants in mothers with chronic idiopathic ulcerative colitis.97 Pregnancy does not affect the course of IBD. Patients who are pregnant experience recurrence rates similar to those of nonpregnant females. Also, there is no justification for therapeutic abortion with IBD because termination of the pregnancy has not been observed to improve the disease. There is also unfounded concern that the drugs required to treat IBD may be teratogenic. Steroids and sulfasalazine should be administered during pregnancy with the same guidelines that would be applied to the nonpregnant patient.6,97 Steroids given systemically do not appear to be detrimental to the fetus. Sulfasalazine is generally well tolerated; however, there has been suggestion of increased frequency of congenital abnormalities when it is given during pregnancy.98 Interestingly, sulfasalazine has also been reported to cause decreased sperm counts and reduced fertility in males.99 This effect is reversible on discontinuation of the drug, and it is not reported with mesalamine. Immunosuppressive drugs (azathioprine and mercaptopurine) may be associated with fetal deformities in humans; however, they have been used without detriment in some patients.96 Metronidazole should not be used in those contemplating pregnancy, as it may be teratogenic. Overall, drug therapy for IBD is not a contraindication for pregnancy, and most pregnancies are well managed in patients with these diseases. The indications for medical and surgical treatment are similar to those in the nonpregnant patient. If a patient has an initial bout of IBD during pregnancy, a standard approach to treatment should be initiated. Recommendations for the use of drugs in nursing mothers vary. Although prednisone and prednisolone can be detected in breast milk, breast-feeding is believed to be safe for the infant when low doses of prednisone are used.100 Sulfasalazine does not pose a risk of kernicterus, as levels of sulfapyridine in breast milk are low or undetectable. Metronidazole should not be given to nursing mothers because it is excreted into breast milk.100

ADVERSE DRUG EFFECTS Drug intolerance often limits the usefulness of agents used to treat IBD. Many patients receiving sulfasalazine, mesalamine, corticosteroids, metronidazole, azathioprine, mercaptopurine, or infliximab experience some undesired effects. In some cases, these adverse effects can be significant and require discontinuation of the therapy. Knowledge of the common or important adverse reactions will assist in avoiding or minimizing their effects. Sulfasalazine is often associated with adverse drug effects and these effects may be classified as either dose related or idiosyncratic. Dose-related side effects usually include GI disturbances such as nausea, vomiting, diarrhea, or anorexia, but may also include headache

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and arthralgia. These adverse reactions tend to occur more commonly on initiation of therapy and decrease in frequency as therapy is continued. Patients may experience these adverse effects at the commonly used dosages. One approach to the management of these reactions is to discontinue the agent for a short period and then reinstitute therapy at a reduced dosage. The sulfapyridine portion of the sulfasalazine molecule is believed to be responsible for much of the sulfasalazine toxicity.101 Folic acid absorption is impaired by sulfasalazine, which may lead to anemia. Patients receiving sulfasalazine should receive oral folic acid supplementation. Adverse effects that are not dose related most commonly include rash, fever, or hepatotoxicity, as well as relatively uncommon but serious reactions such as bone marrow suppression, thrombocytopenia, pancreatitis, and hepatitis. For most patients with idiosyncratic reactions, sulfasalazine must be discontinued. In some patients who have experienced allergic reactions to sulfasalazine, a desensitization procedure can be instituted. By gradually increasing sulfasalazine dosage over weeks to months, patient tolerance has been improved.102 Most of the idiosyncratic reactions observed with sulfasalazine are similar to those with the class of sulfonamides in general. Oral mesalamine derivatives may impose a lower frequency of adverse effects as compared to sulfasalazine.52 Up to 80% to 90% of patients who are intolerant to sulfasalazine will tolerate oral mesalamine derivatives.101 Olsalazine, however, may frequently (in as many as 25% of patients) cause watery diarrhea, sometimes requiring drug discontinuation.103 Adverse reactions to corticosteroids are well recognized and may occur when corticosteroids are used for any indication. However, there is a greater potential for adverse effects when corticosteroids are used for the treatment of IBD because high doses must often be used for extended periods. In the National Cooperative Crohn’s Disease Study, half of patients receiving high-dose steroid therapy experienced side effects, as did one-third of the patients on the lower-dose regimens for maintenance.36 The well-appreciated adverse effects of corticosteroids include hyperglycemia, hypertension, osteoporosis, acne, fluid retention, electrolyte disturbances, myopathies, muscle wasting, increased appetite, psychosis, and reduced resistance to infection. In addition, corticosteroid use may cause adrenocortical suppression. To minimize corticosteroid effects, clinicians have used alternate-day steroid therapy; however, some patients do not do well on the days when no steroid is given. For most patients a single daily corticosteroid dose suffices, and divided daily doses are unnecessary. Another problem with corticosteroids is adrenal insufficiency after abrupt steroid withdrawal. Patients sometimes discontinue prescribed medications when they feel better. Immunosuppressants such as azathioprine and mercaptopurine have a significant potential for adverse reactions. Azathioprine causes bone marrow suppression and has been associated with lymphomas (in renal transplant patients), skin cancer, and pancreatitis (about 3% of patients). Some investigators believe that induction of leukopenia may be necessary for therapeutic effect.104,105 Mercaptopurine causes adverse reactions similarly to azathioprine; however, there are fewer reports of lymphomas with this agent. In one cohort of IBD patients, adverse effects from mercaptopurine were as follows: pancreatitis, 1.2%; allergic reactions, 3.9%, significant leukopenia, 11.5%; and infectious complications, 14%.106 Ten percent of patients who received azathioprine or mercaptopurine required discontinuation of treatment because of adverse effects.107 Allopurinol inhibits the metabolism of mercaptopurine, and a dosage reduction of the latter is required when the two are used in combination. Myelosuppression resulting in leukopenia from azathioprine and mercaptopurine is related to a deficiency of thiopurine S-

INFLAMMATORY BOWEL DISEASE 661

methyltransferase (TPMT) due to excessive accumulation of toxic metabolites.108 Approximately 0.1% of people are homozygous for a nonfunctional TPMT gene, which causes TPMT deficiency. These patients have a much greater risk of toxicity, and should not receive either drug. Heterozygous patients have an increased risk of toxicity and may receive either drug with careful monitoring of white blood cell counts. Most patients receiving metronidazole for Crohn’s disease tolerate the agent fairly well; however, mild adverse effects occur frequently. They commonly include paresthesias and reversible peripheral neuropathy, metallic taste, urticaria, and glossitis.51 Other effects include a disulfiram-like reaction if alcohol is ingested in conjunction. Infliximab has been related to adverse effects such as infusion reactions, serum sickness, sepsis, and reactivation of tuberculosis. Infusion reactions and serum sickness relate to the immune response to foreign protein. Patients often develop anti-infliximab antibodies with multiple infusions. Serum sickness has occurred in patients who received infliximab doses separated by a long period of time. Sepsis and tuberculosis may occur because of the inhibition of TNF-protective mechanisms.

EVALUATION OF THERAPEUTIC OUTCOMES The success of therapeutic regimens to treat IBD can be measured by patient-reported complaints, signs, and symptoms; by direct physician examination (including endoscopy); by history and physical examination; by selected laboratory tests; and by quality-of-life measures. Evaluation of IBD severity is difficult because much of the assessment is subjective. To create more objective measures, disease rating scales or indices have been created. The Crohn’s Disease Activity Index is a commonly used scale, particularly for evaluation of patients during clinical trials.109 The scale incorporates eight elements: (1) number of stools in the past 7 days; (2) sum of abdominal pain ratings from the past 7 days; (3) rating of general well-being in the past 7 days; (4) use of antidiarrheals; (5) body weight; (6) hematocrit; (7) finding of abdominal mass; and (8) a sum of symptoms present in the past week. Elements of this index provide a guide for those measures that may be useful in assessing the effectiveness of treatment regimens. Standardized assessment tools have also been constructed for ulcerative colitis.110 Elements in these scales include (1) stool frequency; (2) presence of blood in the stool; (3) mucosal appearance (from endoscopy); and (4) physician’s global assessment based on physical examination, endoscopy, and laboratory data. Additional studies that are often useful include direct endoscopic examination of affected areas and/or radiocontrast studies. For patients with acute disease, assessment of fluid and electrolyte status is important, because these may be lost during diarrheal episodes. Other laboratory tests, such as serum albumin, transferrin, or other markers of visceral protein status, as well as markers of inflammation (erythrocyte sedimentation rate) may be used. Assessment of the IBD patient must include consideration of adverse drug effects. Because many of the agents used have a relatively high probability of causing adverse effects, particularly corticosteroids and other immunosuppressive agents, patient assessment should include collection of history and physical and laboratory data that are necessary to prevent or recognize adverse drug effects. Finally, a patient quality-of-life assessment should be performed regularly.111 Agents that appear clinically equivalent may differ substantially in resulting quality of life. Inquiry should be made regarding general well-being, emotional function, and social function. Social function may include assessment of the ability to perform routine

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daily functions, maintain occupational activities, sexual function, and recreation. Quality-of-life studies have been conducted with infliximab. To balance the exceptionally high cost of this therapy, Crohn’s disease patients who receive infliximab have improved quality of life, fewer emergency room visits, a reduced requirement for surgery, and are more likely to be employed.112,113

ABBREVIATIONS ESR: erythrocyte sedimentation rate IBD: inflammatory bowel disease NSAID: nonsteroidal anti-inflammatory drug TPMT: thiopurine S-methyltransferase TNF-α: tumor necrosis factor-alpha Review Questions and other resources can be found at www.pharmacotherapyonline.com.

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treatment of patients with ulcerative colitis. Aliment Pharmacol Ther 1999;13:1103–1109. Klotz U, Maier K, Fischer C, et al. Therapeutic efficacy of sulfasalazine and its metabolites in patients with ulcerative colitis and Crohn’s disease. N Engl J Med 1980;303:1499–1502. DeVos M. Clinical pharmacokinetics of slow release mesalamine. Clin Pharmacokinetics 2000;39:85–97. Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: Azathioprine, 6-mercaptopurine, cyclosporine. Am J Gastroenterol 1996;91:423–433. Pearson DC, May GR, Fick GH, et al. Azathioprine and 6mercaptopurine in Crohn’s disease: A meta analysis. Ann Intern Med 1995;123:134–142. Hanauer SB, Baert F. Medical therapy of inflammatory bowel disease. Med Clin North Am 1994;78:1413–1426. Paoluzi OA, Pica R, Marcheggiano A, et al. Azathioprine or methotrexate in the treatment of patients with steroid-dependent or steroid-resistant ulcerative colitis: Results of an open-label study on efficacy and tolerability in inducing and maintaining remission. Aliment Pharmacol Ther 2003;17:479–480. Sutherland L, Singleton J, Sessions J, et al. Double-blind, placebo controlled trial of metronidazole in Crohn’s disease. Gut 1991;32:1071– 1075. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults. Am J Gastroenterol 1997;92:204–211. Sutherland L, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2003;3:CD000543. Clemett D, Markham A. Prolonged-release mesalamine: a review of its therapeutic potential in ulcerative colitis and Crohn’s disease. Drugs 2000;59:929–956. Pruitt R, Hanson J, Safdi M, et al. Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mildto-moderate ulcerative colitis. Am J Gastroenterol 2002;97:3078– 3086. D’Albasio G, Pacini F, Camarri E, et al. Combined therapy with 5-aminosalicylic acid tablets and enemas for maintaining remission in ulcerative colitis: A randomized double-blind study. Am J Gastroenterol 1997;92:1143–1147. Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative treatments in ulcerative colitis: A meta-analysis. Gut 1997;40:775–781. Lee FI, Jewell DP, Mani V, et al. A randomized trial comparing mesalamine and prednisone foam enemas in patients with acute distal ulcerative colitis. Gut 1996;38:229–233. Sandborn WJ, Tremaine WJ, Offord KP, et al. Transdermal nicotine for mild to moderately active ulcerative colitis. A randomized, double-blind, placebo controlled trial. Ann Intern Med 1997;126:364–371. Sandborn WJ, Tremaine WJ. Cyclosporine treatment of inflammatory bowel disease. Mayo Clin Proc 1992;67:981–990. Present DH, Lichtiger S. Efficacy of cyclosporine in treatment of fistula of Crohn’s disease. Dig Dis Sci 1994;39:374–380. Carbonnel F, Boruchowicz A, Duclos B, et al. Intravenous cyclosporine in attacks of ulcerative colitis: Short-term and long-term responses. Dig Dis Sci 1996;41:2471–2476. Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841– 1845. D’Haens G, Lemmens L, Geboes K, et al. Intravenous cyclosporine versus corticosteroids as single therapy for severe attacks of ulcerative colitis. Gastroenterology 2001;120:1323–1329. Misiewicz JJ, Lennard-Jones JE, Connell AM, et al. Controlled trial of sulphasalazine in maintenance therapy for ulcerative colitis. Lancet 1965;1:185–188. Sutherland L, Roth D, Beck P, et al. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2002;4:CD000544. Hawthorne AB, Logan RFA, Hawkey CJ. Randomized controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992;305:20–22.

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67. Fernandez-Banares F, Bertran X, Esteve-Comas M, et al. Azathioprine is useful in maintaining long-term remission induced by intravenous cyclosporine in steroid-refractory severe ulcerative colitis. Am J Gastroenterol 1996;91:2498–2499. 68. Salomon P, Kornbluth A, Aisenberg J, et al. How effective are current therapies for Crohn’s disease? A meta-analysis. Am J Gastroenterol 1992;14:211–215. 69. Singleton JW, Hanauer SB, Gitnick GL, et al. Mesalamine capsules for the treatment of active Crohn’s disease: Results of a 16-week trial. Gastroenterology 1993;104:1293–1301. 70. Ewe K, Press AG, Singe CC, et al. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn’s disease. Gastroenterology 1993;105:367–372. 71. Colombrel JF, Lemann M, Bouhnik Y, et al. A controlled trial comparing ciprofloxacin with mesalamine for the treatment of active Crohn’s disease. Gastroenterology 1997;112:A951. 72. Korelitz BI, Adler DJ, Mendelsohn RA, Sacknoff AL. Long-term experience with 6-mercaptopurine in the treatment of Crohn’s disease. Am J Gastroenterol 1993;88:1198–1205. 73. Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000;18:705–713. 74. Yates CR, Krnetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: Genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997;126:608–614. 75. Colombel JF, Ferrari N, Debuysere H, et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology 2000;118:1025–1030. 76. Hanauer SB, Smith MB. Rapid closure of Crohn’s disease fistulas with continuous intravenous cyclosporin A. Am J Gastroenterol 1993;88:646– 649. 77. Stark ME, Tremaine WJ. Maintenance of symptomatic remission in patients with Crohn’s disease. Mayo Clin Proc 1993;68:1183–1190. 78. Brynskov J, Freund L, Rasmussen SN, et al. A placebo-controlled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn’s disease. N Engl J Med 1989;321:845–850. 79. Schroder O, Stein J. Low dose methotrexate in inflammatory bowel disease: current status and future directions. Am J Gastroenterol 2003;98:530–537. 80. Vandell AG, DiPiro JT. Low-dose methotrexate for treatment and maintenance of remission in patients with inflammatory bowel disease. Pharmacotherapy 2002;22:613–620. 81. Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn’s disease. N Engl J Med 1995;332:292–297. 82. Egan LJ, Sandborn WJ. Methotrexate for inflammatory bowel disease: Pharmacology and preliminary results. Mayo Clin Proc 1996;71: 69–80. 83. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody to CA2 to tumor necrosis factor alpha for Crohn’s disease. N Engl J Med 1997;337:1029–1035. 84. Rutgeerts P, D’Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 1999;117:761–769. 85. Farrell RJ, Alsahi M, Jeen YT, et al. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology 2003;124:917–924. 86. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348:601–608. 87. Parsi MA, Achkar JP, Richardson S, et al. Predictors of response to infliximab in patients with Crohn’s disease. Gastroenterology 2002;123:707– 713. 88. Goldstein F. Maintenance treatment for Crohn’s disease: Has the time arrived? Am J Gastroenterol 1992;87:551–556. 89. Ewe K, Herfarth C, Malchow H, Jesdinsky HJ. Postoperative recurrence of Crohn’s disease in relation to radicality of operation and sulfasalazine prophylaxis: A multicenter trial. Digestion 1989;42:224–232.

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90. Gendre JP, Mary JY, Florent C, et al. Oral mesalamine (Pentasa) as maintenance treatment in Crohn’s disease: A multicenter placebo-controlled study. Gastroenterology 1993;104:435–439. 91. Prantera C, Pallone F, Brunetti G, et al. Oral 5-aminosalicylic acid (Asacol) in the maintenance treatment of Crohn’s disease. Gastroenterology 1992;103:363–368. 92. Lofberg R, Rutgeerts P, Malchow H. Budesonide prolongs time to relapse in ileal and ileocecal Crohn’s disease. A placebo controlled, one-year study. Gut 1996;39:82–86. 93. Lewis JD, Schwatrz JS, Lichtenstein GR. Azathioprine for maintenance of remission in Crohn’s disease: Benefits outweigh the risk of lymphoma. Gastroenterology 2000;118:1018–1024. 94. Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn’s disease. North America’s Crohn’s Study Group. N Engl J Med 2000;342:1627–1632. 95. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENTS I randomized trial. Lancet 2002;359:1541–1549. 96. Hanan IM. Inflammatory bowel disease in the pregnant woman. Compr Ther 1993;19:91–95. 97. Schade RR, Van Thiel DH, Gavaler JS. Chronic idiopathic ulcerative colitis: Pregnancy and fetal outcome. Dig Dis Sci 1984;29:614–619. 98. Willoughby CP, Truelove SC. Ulcerative colitis and pregnancy. Gut 1980;21:469–474. 99. Toovey S, Hudson E, Hendry WF, et al. Sulfasalazine and male infertility: Reversibility and possible mechanism. Gut 1981;22:445–451. 100. Farraye FA. Pregnancy and nursing. In: Peppercorn MA, ed. Therapy of Inflammatory Bowel Disease. New York, Marcel Dekker, 1990. 101. Ardizzone S, Porro GB. Comparative tolerability of therapies for ulcerative colitis. Drug Saf 2002;25:561–582. 102. Korelitz BI, Present DH, Rubin PH, et al. Desensitization to sulfasalazine after hypersensitivity reactions in patients with inflammatory bowel disease. J Clin Gastroenterol 1984;6:27–31. 103. Zinberg J, Molinas S, Das KM. Double-blind placebo-controlled study

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of olsalazine in the treatment of ulcerative colitis. Am J Gastroenterol 1990;85:562–566. Haber CJ, Meltzer SJ, Present DH, et al. Nature and course of pancreatitis caused by 6-mercaptopurine in the treatment of inflammatory bowel disease. Gastroenterology 1986;91:982–986. Colonna T, Korelitz BI. The role of leukopenia in the 6-mercaptopurineinduced remission of refractory Crohn’s disease. Am J Gastroenterol 1994;89:362–366. Warman JI, Korelitz BI, Fleisher MR, Janardhanam R. Cumulative experience with short- and long-term toxicity to 6-mercaptopurine in the treatment of Crohn’s disease and ulcerative colitis. J Clin Gastroenterol 2003;37:220–225. O’Brien JJ, Bayless TM, Bayless JA. Use of azathioprine or 6mercaptopurine in the treatment of Crohn’s disease. Gastroenterology 1991;101:39–46. Lennard L. TPMT in the treatment of Crohn’s disease with azathioprine. Gut 2002;51:143–146. Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn’s disease activity index. Gastroenterology 1976;70:439–444. Sanborn WJ, Tremaine WJ, Schroeder KW, et al. Cyclosporine enemas for treatment-resistant, mildly to moderately active, left sided ulcerative colitis. Am J Gastroenterol 1993;88:640–645. Irvine EJ, Zhou Q, Thompson AK. The short inflammatory bowel disease questionnaire: A quality of life instrument for community physicians managing inflammatory bowel disease. CERPT investigators. Canadian Crohn’s relapse prevention trial. Am J Gastroenterol 1996;91:1571– 1578. Lichtenstein GR, Yan S, Balla M, Hanauer S. Remission in patients with Crohn’s disease is associated with improvement in employment and quality of life and a decrease in hospitalizations and surgeries. Am J Gastroenterol 2004;99:91–96. Rubenstein JH, Chong RY, Cohen RD. Infliximab decreases resource use among patients with Crohn’s disease. J Clin Gastroenterol 2002;35: 151–156.

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35 NAUSEA AND VOMITING Cecily V. DiPiro and A. Thomas Taylor

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Nausea and vomiting may be a part of the symptom complex for a variety of gastrointestinal, cardiovascular, infectious, neurologic, metabolic, or psychogenic processes.

Optimal control of acute nausea and vomiting positively impacts the incidence and control of delayed and anticipatory nausea and vomiting.

2 Nausea and vomiting may be caused by a variety of medi-

6 The emetogenic potential of the chemotherapeutic regimen

cations or other noxious agents.

3 The overall goal of treatment should be to prevent or eliminate nausea and vomiting regardless of etiology.

4 Treatment options for nausea and vomiting include drug and nondrug modalities.

5 The primary goal with chemotherapy-induced nausea and vomiting (CINV) is to prevent nausea and/or vomiting.

Nausea and vomiting are common complaints among many individuals with gastrointestinal (GI) disorders. However, because of the variable etiologies of these problems, management may be quite simple or detailed and complex, essentially innocuous or associated with therapy-induced adverse reactions. This chapter provides an overview of nausea and vomiting, two multifaceted problems. Nausea is usually defined as the inclination to vomit or as a feeling in the throat or epigastric region alerting an individual that vomiting is imminent. Vomiting is defined as the ejection or expulsion of gastric contents through the mouth and is often a forceful event. Either condition may occur transiently with no other associated signs or symptoms; however, these conditions also may be only part of a more complex clinical presentation.

ETIOLOGY 1 Nausea and vomiting may be associated with a variety of clini-

cal presentations. In addition to GI diseases, either or both may accompany cardiovascular, infectious, neurologic, or metabolic disease processes. Nausea and vomiting may be a feature of such conditions as pregnancy or may follow operative procedures or administration of certain medications such as those used in cancer chemotherapy. Psychogenic etiologies of these symptoms may be present, especially in young women with an underlying emotional disturbance. Anticipatory etiologies may be involved, such as in patients who have previously received cytotoxic chemotherapy. Specific etiologies associated with nausea and vomiting are presented in Table 35–1.1 In addition to identifying conditions associated with nausea and vomiting, it is important to address the specific causative medical

is the primary factor to consider when selecting prophylactic antiemetics for CINV.

7 Patients at high risk of vomiting should receive prophylactic

antiemetics for postoperative nausea and vomiting (PONV).

8 Patients receiving single-exposure, high-dose radiation therapy to the upper abdomen or receiving total or hemibody irradiation should receive prophylactic antiemetics for radiation-induced nausea and vomiting (RINV).

problems. For example, nausea and vomiting may occur in as many as 70% of patients with inferior myocardial infarction or diabetic ketoacidosis. Eighty to ninety percent of patients with an Addisonian crisis, acute pancreatitis, or acute appendicitis may present with nausea and vomiting. The etiology of nausea and vomiting may vary with the age of the patient. For example, vomiting in the newborn during the first day of life suggests upper digestive tract obstruction or an increase in intracranial pressure. Other illnesses associated with vomiting in children include pyloric stenosis, duodenal ulcer, stress ulcer, adrenal insufficiency, septicemia, or diseases of the pancreas, liver, or biliary tree. Also, the hepatocellular failure seen in Reye’s syndrome may lead to profound cerebral edema followed by persistent emesis. A common etiology of vomiting in children is viral gastroenteritis caused by rotavirus. Vomiting in infants may be associated with something as simple as overfeeding, rapid feeding, inadequate burping, or lying down too soon after feeding. It should be recognized that these types of vomiting are usually indicative of minor problems and may be altered by changing the approach to feeding. 2 Drug-induced nausea and vomiting are of particular concern, especially with the increasing number of patients receiving cytotoxic treatment and the number of agents implicated. Included in Table 35–2 are specific cytotoxic agents categorized by their emetogenic potential. Although some agents may have greater emetogenic potential than others, combinations of agents, high doses, clinical settings, psychological conditions, prior treatment experiences, and unusual stimulus of sight, smell, or taste may alter a patient’s response to drug treatment. In this setting, nausea and vomiting may be unavoidable and potentially devastating to the patient’s desire to continue treatment. Indeed, some patients experience these problems so 665

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GASTROINTESTINAL DISORDERS TABLE 35–1. Specific Etiologies of Nausea and Vomiting Gastrointestinal Mechanisms Mechanical gastric outlet obstruction Peptic ulcer disease Gastric carcinoma Pancreatic disease Motility disorders Gastroparesis Drug-induced gastric stasis Chronic intestinal pseudo-obstruction Postviral gastroenteritis Irritable bowel syndrome Postgastric surgery Idiopathic gastric stasis Anorexia nervosa Intra-abdominal emergencies Intestinal obstruction Acute pancreatitis Acute pyelonephritis Acute cholecystitis Acute cholangitis Acute viral hepatitis Acute gastroenteritis Viral gastroenteritis Salmonellosis Shigellosis Staphylococcal gastroenteritis (enterotoxins) Cardiovascular Diseases Acute myocardial infarction Congestive heart failure Shock and circulatory collapse

Neurologic Processes Midline cerebellar hemorrhage Increased intracranial pressure Migraine headache Vestibular disorders Head trauma Metabolic Disorders Diabetes mellitus (diabetic ketoacidosis) Addison’s disease Renal disease (uremia) Psychogenic Causes Self-induced Anticipatory Therapy-induced Causes Cytotoxic chemotherapy Radiation therapy Theophylline preparations (intolerance, toxic) Anticonvulsant preparations (toxic) Digitalis preparations (toxic) Opiates Amphotericin B Antibiotics Drug Withdrawal Opiates Benzodiazepines Miscellaneous Causes Pregnancy Any swallowed irritant (foods, drugs) Noxious odors Operative procedures

From Hanson and McCallum.1

intensely that chemotherapy is postponed or discontinued. In addition to the emetogenic potential of various cytotoxic regimens, a variety of other common etiologies have been proposed for the development of nausea and vomiting in cancer patients. These are presented in Table 35–3.2

PATHOPHYSIOLOGY The three consecutive phases of emesis include nausea, retching, and vomiting. Nausea, the imminent need to vomit, is associated with gastric stasis and may be considered a separate and singular symptom. Retching is the labored movement of abdominal and thoracic muscles before vomiting. The final phase of emesis is vomiting, the forceful expulsion of gastric contents caused by GI retroperistalsis. The act of vomiting requires the coordinated contractions of the abdominal muscles, pylorus, and antrum, a raised gastric cardia, diminished lower esophageal sphincter pressure, and esophageal dilatation.3 Vomiting should not be confused with regurgitation, an act in which the gastric or esophageal contents rise to the pharynx because of pressure differences caused by, for example, an incompetent lower esophageal sphincter. Accompanying autonomic symptoms of pallor, tachycardia, and diaphoresis account for many of the distressing feelings associated with emesis. Vomiting is triggered by afferent impulses to the vomiting center, a nucleus of cells in the medulla. Impulses are received from sensory centers, such as the chemoreceptor trigger zone (CTZ), cerebral cortex, and visceral afferents from the pharynx and GI tract.

When excited, afferent impulses are integrated by the vomiting center, resulting in efferent impulses to the salivation center, respiratory center, and the pharyngeal, GI, and abdominal muscles, leading to vomiting. The CTZ, located in the area postrema of the fourth ventricle of the brain, is a major chemosensory organ for emesis and is usually associated with chemically induced vomiting. Because of its location, blood-borne and cerebrospinal fluid toxins have easy access to the CTZ. Therefore cytotoxic agents stimulate primarily this area rather than the cerebral cortex and visceral afferents. Similarly, pregnancyassociated vomiting probably occurs through stimulation of the CTZ. Numerous neurotransmitter receptors are located in the vomiting center, CTZ, and GI tract. Examples of such receptors include cholinergic and histaminic, dopaminergic, opiate, serotonergic, neurokinin, and benzodiazepine receptors. Chemotherapeutic agents, their metabolites, or other emetic compounds theoretically trigger the process of emesis through stimulation of one or more of these receptors. Effective antiemetics are able to antagonize or block the emetogenic receptors.

CLINICAL PRESENTATION Because it is impossible to discuss all clinical settings in which the presence of nausea and vomiting might be a pertinent finding, these processes are presented in Table 35–4 as they might occur together and also as simple or complex in presentation.

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TABLE 35–2. Emetogenicity of Chemotherapeutic Agents Level 1 (less than 10% frequency) Androgens Bleomycin Busulfan (oral 90% frequency) Carmustine (>250 mg/m2 ) Cisplatin (>50 mg/m2 ) Cyclophosphamide (>1500 mg/m2 ) Dacarbazine (≥500 mg/m2 ) Lomustine (>60 mg/m2 ) Mechlorethamine Pentostatin Streptozocin

Adapted from Hesketh et al.34

TABLE 35–3. Nonchemotherapy Etiologies of Nausea and Vomiting in Cancer Patients

TABLE 35–4. Presentation of Nausea and Vomiting

Fluid and electrolyte abnormalities Hypercalcemia Volume depletion Water intoxication Adrenocortical insufficiency Drug-induced Opiates Antibiotics Gastrointestinal obstruction Increased intracranial pressure Peritonitis Metastases Brain Meninges Hepatic Uremia Infections (septicemia, local) Radiation therapy

General Depending on severity of symptoms, patients may present in mild to severe distress Symptoms Simple: Self-limiting, resolves spontaneously and requires only symptomatic therapy Complex: Not relieved after administration of antiemetics; progressive deterioration of patient secondary to fluid-electrolyte imbalances; usually associated with noxious agents or psychogenic events Signs Simple: Patient complaint of queasiness or discomfort Complex: Weight loss; fever; abdominal pain Laboratory tests Simple: None Complex: Serum electrolyte concentrations; upper/lower Gl evaluation Other information Fluid input and output Medication history Recent history of behavioral or visual changes, headache, pain, or stress Family history positive for psychogenic vomiting

From Frytak and Moertel.2

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TREATMENT: Nausea and Vomiting
DESIRED OUTCOME 3 The overall goal of antiemetic therapy is to prevent or to elim-

inate nausea and vomiting. This should be accomplished without adverse effects or with clinically acceptable adverse effects. Although this goal may be accomplished easily in patients with simple nausea and vomiting, patients with more complex problems require greater assistance. In addition to these clinical goals, appropriate cost issues should be considered, particularly in the management of chemotherapy-induced and postoperative nausea and vomiting.


GENERAL APPROACH TO TREATMENT 4 Treatment options for nausea and vomiting include drug and

nondrug modalities. The treatment of nausea and vomiting is quite varied depending on the associated medical situation. Even though a number of potentially effective measures are available, most patients receive a medication at some point in their care. For simple nausea and vomiting, patients may choose to do nothing or to select from a variety of nonprescription drugs. As symptoms become worse or are associated with more serious medical problems, patients are more likely to benefit from prescription antiemetic drugs. When prescribed according to reliable clinical information, these agents often provide acceptable relief. However, some patients will never be totally free of symptoms. This lack of relief is most disabling to the patient when it is associated with an unresolved medical problem or when the necessary therapy for this condition is the cause of the nausea or vomiting, as in the case of patients receiving emetogenic chemotherapy.


NONPHARMACOLOGIC MANAGEMENT Nonpharmacologic management of nausea and vomiting may include a variety of dietary, physical, or psychological changes consistent with the etiology of symptoms. For patients with simple complaints, perhaps resulting from excessive or disagreeable food or beverage consumption, avoidance or moderation in dietary intake may be preferable. Patients suffering symptoms of systemic illness may improve dramatically as their underlying condition resolves. Finally, patients in whom these symptoms result from labyrinthine changes produced by motion may benefit quickly by assuming a stable physical position. Cancer patients undergoing chemotherapy may experience nausea and/or vomiting despite receiving prophylactic antiemetics. The fact that anticipatory side effects rarely occur unless the patient has previously experienced posttreatment nausea or vomiting suggests that the mechanism for anticipatory nausea and vomiting is a learned process involving elements of classic conditioning.4 This conditioning model may also be important in understanding the development of pregnancy-related nausea. Nonpharmacologic interventions are classified as behavioral interventions and include relaxation, biofeedback, self-hypnosis, cognitive distraction, guided imagery, and systematic desensitization.5−7

The management of psychogenic vomiting is greatly dependent on psychological intervention. However, because the underlying problems are so complex and intertwined in personal relationships, psychological therapy may require lengthy, in-depth treatment. Pharmacologic therapy offers only minimal benefit in these patients. Surgery, such as gastroenterostomy, is of no value.


PHARMACOLOGIC THERAPY 4 Although many approaches to the treatment of nausea and vom-

iting have been suggested, antiemetic drugs (nonprescription and prescription) are most often recommended. These agents represent a variety of pharmacologic and chemical classes, as well as dosage regimens and routes of administration. With so many treatment possibilities available, factors that enable the clinician to discriminate among various choices must be recognized. These factors include (a) the suspected etiology of the symptoms; (b) the frequency, duration, and severity of the episodes; (c) the ability of the patient to use oral, rectal, injectable, or transdermal medications; and (d) the success of previous antiemetic medications. Information concerning commonly available antiemetic preparations is given in Table 35–5. The treatment of simple nausea and vomiting usually requires minimal therapy. For these symptoms, patients may choose from a lengthy list of nonprescription products. Both nonprescription and prescription drugs useful in the treatment of simple nausea and vomiting are usually effective in small, infrequently administered doses. Side effects and toxic effects in these settings are also usually minimal. Although suitable for occasional simple nausea and vomiting, nonprescription agents are often abandoned by the patient as symptoms continue or become progressively worse. As the patient’s condition warrants, prescription medications may be chosen, either as single-agent therapy or in combination. The management of complex nausea and vomiting, for example, in patients receiving cytotoxic chemotherapy, may require combination therapy. In combination regimens, agents are prescribed in small-to-moderate dosages, achieving symptomatic control through different pharmacologic mechanisms while avoiding the untoward effects caused by high doses.


ANTACIDS Patients who are experiencing simple nausea and vomiting may use various antacids. In this setting, single or combination nonprescription antacid products, especially those containing magnesium hydroxide, aluminum hydroxide, and/or calcium carbonate, may provide sufficient relief, primarily through gastric acid neutralization. Common antacid regimens for the relief of acute or intermittent nausea and vomiting include one or more small doses of single- or multiple-agent products. Depending on dose, common products usually supply sufficient ingredients to allow a range of approximately 40 to 180 mEq of acid-neutralizing capacity.8−10 Potential adverse effects from antacids are usually related to the presence of magnesium, aluminum, or calcium salts. Specifically, osmotic diarrhea from magnesium and constipation from aluminum or calcium salts may be of concern to patients, particularly those self-medicating with high or frequently administered antacid doses. Generally, however, when

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TABLE 35–5. Common Antiemetic Preparations and Adult Dosage Regimens Drug

Adult Dosage Regimen

Dosage Form/Route

Availability

Antacids Antacids (various)

15–30 mL every 2–4 h prn

Liquid

OTC

Histamine H2 Antagonists Cimetidine (Tagamet HB) Famotidine (Pepcid AC) Nizatidine (Axid AR) Ranitidine (Zantac 75)

200 mg twice daily prn 10 mg twice daily prn 75 mg twice daily prn 75 mg twice daily prn

Tab Tab Tab Tab

OTC OTC OTC OTC

Antihistaminic-Anticholinergic Agents Buclizine (Bucladin-S) Cyclizine (Marezine) Dimenhydrinate (Dramamine) Diphenhydramine (Benadryl) Hydroxyzine (Vistril, Atarax) Meclizine (Bonine, Antivert) Pyrilamine (Nisaval) Scopolamine (Transderm Scop) Trimethobenzamide (Tigan)

50 mg twice daily 50 mg every 4–6 h prn 50–100 mg every 4–6 h prn 10–50 mg every 4–6 h prn 25–100 mg every 6 h prn 25–50 mg every 24 h prn 25–50 mg 3 to 4 times daily 0.5 mg every 72 h prn 200–250 mg 3 to 4 times daily prn

Tab Tab, IM Tab, Chew tab, cap, liquid, IM, IV Tab, cap, liquid, IM, IV Tab, cap, liquid, IM Tab, chew tab, cap Tab Transdermal patch Cap, IM, supp

Rx Rx/OTC Rx/OTC Rx/OTC Rx Rx/OTC Rx/OTC Rx Rx

Promazine (Sparine) Promethazine (Phenergan) Thiethylperazine (Torecan)

10–25 mg every 4–6 h prn 50–100 mg every 6–8 h prn 5–10 mg 3 to 4 times daily prn 25 mg twice daily prn 25–50 mg every 4–6 h prn 12.5–25 mg every 4–6 h prn 10 mg 3 times daily

SR, cap, tab, liquid, IM, IV Supp SR, cap, tab, liquid IM, IV Supp Tab, IM Tab, liquid, IM, IV, supp Tab, IM, supp

Rx Rx Rx Rx Rx Rx Rx

Cannabinoids Dronabinol (Marinol) Nabilone (Cesamet)

5–7.5 mg/m2 every 2–4 h prn 1–2 mg 2 to 3 times daily prn

Cap Cap

Rx (C-II) Rx (C-II)

Butyrophenones Haloperidol (Haldol) Droperidol (Inapsine)a

1–5 mg every 12 h prn 2.5–5 mg every 4–6 h prn

Tab, liquid, IM, IV IM, IV

Rx Rx

IV

Rx

Methylprednisolone (Solu-Medrol)

10 mg prior to chemotherapy, repeat with 4–8 mg every 6 h for total of 4 doses 125–500 mg every 6 h for total of 4 doses

IV

Rx

Benzodiazepines Lorazepam (Ativan)

0.5–2 mg prior to chemotherapy

IV

Rx (C-IV)

125 mg on day 1, 1 hour prior to chemotherapy, 80 mg on days 2 and 3

Cap

Rx

1.8 mg/kg 30 min prior to chemotherapy (undiluted, up to 100 mg over 30 min, or diluted, over 30 min) OR 100 mg within 1 h before chemotherapy 10 mcg/kg prior to chemotherapy (diluted, infuse over 5 min or undiluted over 30 seconds)

IV

Rx

Tab IV

Rx Rx

Tab

Rx

IV

Rx

Tab

Rx

Phenothiazines Chlorpromazine (Thorazine) Prochlorperazine (Compazine)

Corticosteroids Dexamethasone-(Decadron) for CINV

Substance P/Neurokinin1 Receptor Inhibitor Aprepitant (Emend) Selective Serotonin Antagonists for CINVb Dolasetron (Anzemet)

Granisetron (Kytril)

Ondansetron (Zofran)

OR 1 mg up to 1 h prior to chemotherapy and 1 mg 12 h after the first dose, or, 2 mg up to 1 h prior to chemotherapy 32 mg prior to chemotherapy as a single dose (diluted, give over 15 min), or 0.15 mg/kg prior to chemotherapy, repeat at 4 and 8 h OR 8 mg 30 min prior to chemotherapy, repeat at 4 and 8 h and every 12 h for 1–2 days after chemotherapy completion

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TABLE 35–5. (continued) Drug Palonestron (Aloxi)

Miscellaneous Agents Metoclopramide (Reglan), for CINV Metoclopramide (Reglan), for PONV Metoclopramide (Reglan), for delayed CINV

Adult Dosage Regimen

Dosage Form/Route

Availability

0.25 mg 30 min prior to chemotherapy (undiluted over 30 seconds; do not repeat within 7 days)

IV

Rx

1–2 mg/kg every 2 h × 2, then every 3 h × 3 10–20 mg about 10 min prior to anesthesia 0.5 mg/kg or 20 mg every 6 h prn, days 2 to 4

IV IV Tab

Rx Rx Rx

a

See text for current warnings. See Table 35–7 for PONV dosing. C-II, C-IV = controlled substance schedule 2 and 4, respectively; cap, capsule; chew tab, chewable tablet; CINV, chemotherapy-induced nausea and vomiting; liquid, oral syrup, concentrate, or suspension; OTC, over the counter; PONV, postoperative nausea and vomiting; Rx, prescription; SR cap, sustained-release capsule; supp, rectal suppository; tab, tablet. b

used occasionally for acute episodic relief of nausea and vomiting, antacids do not produce serious toxicities.


H2 -RECEPTOR ANTAGONISTS Patients may use histamine2 -receptor antagonists in low doses to manage simple nausea and vomiting associated with heartburn or gastroesophageal reflux. Individual dosages of cimetidine 200 mg, famotidine 10 mg, nizatidine 75 mg, or ranitidine 75 mg may be used for brief periods. Except for potential drug interactions with cimetidine, these agents cause few side effects when used for episodic relief.


ANTIHISTAMINE-ANTICHOLINERGIC DRUGS Antiemetic drugs from the antihistaminic-anticholinergic category appear to interrupt various visceral afferent pathways that stimulate nausea and vomiting and may be appropriate in the treatment of simple nausea and vomiting. Adverse reactions that may be apparent with the use of the antihistaminic-anticholinergic agents primarily include drowsiness, confusion, blurred vision, dry mouth, and urinary retention, and possibly tachycardia, particularly in elderly patients. Also, as doses are increased or are more frequently administered, patients with narrow-angle glaucoma, prostatic hyperplasia, or asthma are at greater risk of complications from the anticholinergic effects of these drugs.


PHENOTHIAZINES Historically, phenothiazines have been the most widely prescribed antiemetic agents. These agents appear to block dopamine receptors, most likely in the CTZ. Phenothiazines are marketed in an array of dosage forms, none of which appears to be more efficacious than another. These agents may be most practical for long-term treatment and are inexpensive in comparison with newer drugs. Rectal administration is a reasonable alternative in patients in whom oral or parenteral administration is not feasible. In an open-label, randomized, crossover comparison between promethazine in oral syrup and rectal suppositories, the pharmacokinetics were highly variable, but in general the suppositories produced a lower maximum concentration and a later time of maximum concentration than the oral syrup.11 Phenothiazines are most useful in patients with simple nausea and vomiting or in those receiving mildly emetogenic doses of chemotherapy. Intravenous prochlorperazine provides quicker and

more complete relief with less drowsiness than intravenous promethazine in adult patients treated in an emergency department for nausea and vomiting associated with uncomplicated gastritis or gastroenteritis.12 There are numerous potential side effects with these medications, including extrapyramidal reactions, hypersensitivity reactions with possible liver dysfunction, bone marrow aplasia, and excessive sedation.


BUTYROPHENONES Two butyrophenone compounds that have antiemetic activity are haloperidol and its congener droperidol. Each agent blocks dopaminergic stimulation of the CTZ. Although each agent is effective in relieving nausea and vomiting, haloperidol is not considered first-line therapy, although it has been used in palliative care situations.13 After 30 years of clinical use, a “black box” warning was recently added to the labeling for droperidol stating that QT prolongation and/or torsades de pointes have been reported in patients receiving droperidol at doses at or below recommended doses. Some of these cases occurred in patients with no known risk factors for QT prolongation and have been fatal. The warning recommends that droperidol should be reserved for use in the treatment of patients who fail to show an acceptable response to other adequate treatments and that all patients should undergo a 12-lead electrocardiogram prior to administration of droperidol, followed by cardiac monitoring for 2 to 3 hours postadministration.14 As a result of this change in labeling, the clinical use of droperidol has effectively ceased. After review of the cases, several authors have questioned the justification of this warning.15,16


CORTICOSTEROIDS Corticosteroids have demonstrated antiemetic efficacy since the initial recognition that patients receiving prednisone as part of their Hodgkin’s disease protocol appeared to develop less nausea and vomiting than those patients treated with protocols that excluded this agent. Other corticosteroids showing antiemetic efficacy include methylprednisolone and dexamethasone. Dexamethasone has been used successfully in the management of chemotherapy-induced and postoperative nausea and vomiting, either as a single agent or in combination with selective serotonin receptor inhibitors (SSRIs). For chemotherapy-induced nausea and vomiting, dexamethasone has demonstrated efficacy in the prevention of both cisplatin-induced acute emesis17 and delayed nausea and

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vomiting associated with moderately emetogenic chemotherapy.18 For patients with simple nausea and vomiting, steroids are not indicated and may be associated with unacceptable risks.


METOCLOPRAMIDE Metoclopramide, procainamide’s congener, provides significant antiemetic effects by blocking the dopaminergic receptors centrally in the CTZ. Peripherally, metoclopramide increases lower esophageal sphincter tone, aids gastric emptying, and accelerates transit through the small bowel, possibly through the release of acetylcholine. Metoclopramide is used for its antiemetic properties in patients with diabetic gastroparesis and as a component of multiagent therapy for prophylaxis of delayed nausea and vomiting associated with chemotherapy administration. Its use as prophylaxis for acute chemotherapy-induced nausea and vomiting was supplanted by the introduction of the SSRIs in the early 1990s. These agents have greater efficacy and decreased toxicity compared with metoclopramide in patients receiving cisplatin-based regimens.19−21


CANNABINOIDS Thirty randomized, controlled trials from 1975 to 1996 were analyzed to quantify the antiemetic efficacy and adverse effects of cannabis when given to 1366 patients receiving chemotherapy.22 Oral nabilone, oral dronabinol, and intramuscular levonantradol were compared with conventional antiemetics (prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, and alizapride) or placebo. Across all trials, cannabinoids were slightly more effective than active comparators and placebo when the chemotherapy regimen was of moderate emetogenic potential, and patients preferred them. No dose-response relationships were evident to the authors. The cannabinoids were also more toxic; side effects included euphoria, drowsiness, sedation, somnolence, dysphoria, depression, hallucinations, and paranoia. The efficacy of cannabinoids as compared to SSRIs has not been studied. Use of these agents should be considered when other regimens do not provide desired efficacy.


SUBSTANCE P/NEUROKININ 1 RECEPTOR ANTAGONISTS Substance P is a peptide neurotransmitter in the neurokinin (NK) family whose preferred receptor is the NK1 receptor.23 The acute phase of CINV is believed to be mediated by both serotonin and substance P, whereas substance P is believed to be the primary mediator of the delayed phase. NK1 antagonists administered as part of a multiple-drug regimen with a SSRI and a corticosteroid improved protection from both acute and delayed emesis.24−26 Aprepitant is the first approved substance P/NK1 receptor antagonist. In two placebocontrolled, randomized trials, patients receiving high-dose cisplatinbased chemotherapy received IV ondansetron on day 1 plus oral dexamethasone on days 1 through 4 with or without oral aprepitant on days 1, 2, and 3. The aprepitant regimen provided significantly superior control of emesis in the overall study period as well as in separate analyses of the acute and delayed phases.27,28 Aprepitant has the potential for numerous drug interactions because it is a substrate, moderate inhibitor, and an inducer of cytochrome isoenzyme CYP3A4 and an inducer of CYP2C9. Aprepitant

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can increase serum concentrations of many drugs metabolized by CYP3A4, including docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vincristine, and vinblastine. In clinical studies, aprepitant was concomitantly administered with etoposide, vinorelbine, or paclitaxel, with no adjustment in the doses of these agents to account for potential drug interactions. The efficacy of oral contraceptives may be reduced. Concomitant administration with warfarin may result in a clinically significant decrease in the International Normalized Ratio.29 The dose of oral dexamethasone should be reduced 50% when coadministered with aprepitant, due to the 2.2-fold increase in observed area under the plasma-concentration-versus-time curve.30 Aprepitant is not indicated for use in children.


SELECTIVE SEROTONIN RECEPTOR INHIBITORS SSRIs block presynaptic serotonin receptors on sensory vagal fibers in the gut wall, effectively blocking the acute phase of CINV. These agents do not completely block the acute phase of CINV and are less efficacious in preventing the delayed phase, but they are the standard of care in the management of chemotherapy-induced, radiationinduced, and postoperative nausea and vomiting. Issues involved in the use of dolasetron, granisetron, ondansetron, and palonosetron are reviewed in detail in the sections that follow. The most common side effects associated with these agents are constipation, headache, and asthenia. Safety and efficacy in children less than 2 years old have not been established.


CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING CINV can be classified as anticipatory, acute, or delayed. As defined earlier, anticipatory nausea and vomiting is a conditioned response linked to experiencing poor emetic control with previously administered chemotherapy.4 The anxiolytic and amnestic properties of lorazepam 1 to 2 mg given orally the evening before and the morning of chemotherapy may help prevent anticipatory nausea and vomiting, but efficacy has not been demonstrated in large, randomized trials.31 Use of the most appropriate antiemetic regimen to prevent acute and delayed nausea and vomiting, beginning with the first cycle of chemotherapy, is recommended to prevent future development of anticipatory nausea and vomiting.32 5 Nausea and vomiting that occurs within 24 hours of chemotherapy administration is defined as acute, whereas when it starts more than 24 hours after chemotherapy administration, it is defined as delayed. The primary goal with CINV is to prevent nausea and/or vomiting; optimal control of acute nausea and vomiting positively impacts the incidence and control of delayed and anticipatory nausea and vomiting. Clinical practice guidelines for the use of antiemetics in CINV have been published.31−33 Despite the availability of nationally recommended guidelines, individual practice varies from one institution to the next. Product availability and recommended doses are institution-specific and may vary considerably from the doses listed in Table 35–5. Factors to consider when selecting an antiemetic for CINV include: r r r

The emetogenic potential of the chemotherapy agent or regimen (see Table 35–2). Patient-specific factors. Patterns of emesis after administration of specific chemotherapy agents or regimens.

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Prophylaxis of CINV (Adapted from Reference 31; Used with Permission) 6
Recommendation 1. The emetogenic potential of the chemotherapeutic agent (see Table 35–2) is the primary factor to consider when deciding whether to administer prophylactic agents and which antiemetic(s) to select. When combination therapy is prescribed, the most highly emetogenic agent in the combination should be identified, and the contribution of other agents should be considered by using the following rules:34 r r

r

Level 1 agents do not contribute to the emetogenicity of a given regimen. Adding one or more level 2 agents increases emetogenicity of the combination by one level greater than the most emetogenic agent in the combination. Adding level 3 and 4 agents increases emetogenicity of the combination by one level per agent.

Originally developed for adult patients, these guidelines should be used cautiously in pediatric patients; however, the information is considered generally applicable to children receiving chemotherapy.


Recommendation 2. Adult and pediatric patients receiving chemotherapeutic agent(s) with emetogenic potential classified as level 2 through 5 should receive prophylaxis against nausea and vomiting each day on which chemotherapy is given. Antiemetic prophylaxis is not required for level 1 agents. r

r

r

r

Adult and pediatric patients receiving level 2 regimens can receive a corticosteroid alone for prophylaxis. Prochlorperazine is also an option for adults. Adult and pediatric patients receiving level 3 through 5 regimens should receive a corticosteroid in combination with a SSRI. Orally and intravenously administered antiemetics are generally equivalent in efficacy and safety for both adult and pediatric patients. The decision as to which formulation to use should be based on patient-specific factors and cost. The decision as to which SSRI to use should be based on the acquisition cost of comparable doses. Dosage recommendations for adult and pediatric patients differ.

At the time the American Society of Health-System Pharmacists (ASHP) guidelines were published, the safety and efficacy of ondansetron, granisetron, and dolasetron for prophylaxis of CINV in adult and pediatric patients receiving moderately emetogenic or highly emetogenic chemotherapeutic regimens were supported by more than 50 clinical studies. The superior efficacy and safety of this class of agents over metoclopramide, with or without dexamethasone, in CINV prophylaxis have been demonstrated in numerous studies. When used in comparable dosage regimens, the choice of whether to use ondansetron, granisetron, or dolasetron should be based primarily on acquisition costs. The oral route of administration is preferred.35,36 The efficacy of ondansetron, granisetron, and dolasetron for the prophylaxis of moderately or highly emetogenic chemotherapy regimens is enhanced when used in combination with dexamethasone.


Treatment of CINV
Recommendation 3. All patients receiving chemotherapy should have antiemetics available on as as-needed basis for rescue of

breakthrough nausea and vomiting. Chlorpromazine, prochlorperazine, methylprednisolone, lorazepam, metoclopramide, dexamethasone, and dronabinol are available for adult patients. Chlorpromazine, lorazepam, and methylprednisolone (or dexamethasone) are recommended for pediatric patients. The choice of agent should be based on patient-specific factors, including potential adverse reactions, and cost. Granisetron, dolasetron, and ondansetron are effective in the treatment of breakthrough nausea and vomiting, but they are not superior to conventional, less expensive antiemetics.


Prophylaxis of Delayed CINV
Recommendation 4. For the prevention of delayed emesis after cisplatin therapy in adults, dexamethasone with metoclopramide or a SSRI is recommended. The choice of agent should be based on patientspecific factors and cost. For delayed emesis after cyclophosphamide, doxorubicin, or carboplatin therapy, a SSRI with dexamethasone is recommended. In pediatric patients, chlorpromazine, lorazepam, or a SSRI can be used in combination with a corticosteroid. Since the publication of the ASHP and American Society of Clinical Oncologists (ASCO) clinical guidelines,31,32 two new agents have been released, aprepitant (Emend) and palonestron (Aloxi). Aprepitant has been studied in combination with ondansetron and dexamethasone for the prophylaxis of acute and delayed nausea and vomiting associated with highly emetogenic chemotherapy, including high-dose cisplatin. The National Comprehensive Cancer Network (NCCN) guidelines33 also include aprepitant in their guidelines for moderately emetogenic chemotherapy regimens. Palonestron, an injectable SSRI with a prolonged serum half-life and higher receptor binding affinity, is indicated for the prophylaxis of both acute nausea and vomiting associated with moderately and highly emetogenic chemotherapy regimens, and delayed nausea and vomiting associated with moderately emetogenic chemotherapy. Palonestron 0.25 mg is administered IV over 30 minutes prior to chemotherapy and should not be repeated within 7 days.37 It has not been approved for use in children. Two Phase III trials support the labeled indications.38,39 Although proven safe and efficacious, the design of the trials for these two new agents raises many questions and their eventual place in therapy, and inclusion in clinical practice guidelines, remains to be determined. CLINICAL CONTROVERSY Current published information describes the experience with aprepitant in highly emetogenic cisplatin-based chemotherapy regimens. The NCCN has also included aprepitant for prophylaxis of nausea and vomiting induced by moderately emetogenic chemotherapy regimens.33 This recommendation is not supported by the current literature and has been questioned by clinicians.


POSTOPERATIVE NAUSEA AND VOMITING One of the most common complications of surgery is postoperative nausea and vomiting (PONV). Most patients undergoing an operative procedure do not require preoperative prophylactic antiemetic therapy and universal PONV prophylaxis is not cost effective. Consensus therapeutic guidelines for the prophylaxis and treatment of PONV have recently been published.31,40 Factors to be considered for PONV

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CHAPTER 35 TABLE 35–6. Risk Factors for PONV Patient-specific factors Female gender Nonsmoking status History of motion sickness/PONV Anesthetic risk factors Use of volatile anesthetics Nitrous oxide Use of opioids (intraoperative or postoperative) Surgical risk factors Duration of surgery Operative procedure (intra-abdominal, ear-nose-throat, major gynecologic, orthopedic, or laparoscopic) PONV, postoperative nausea and vomiting.

prophylaxis and treatment include: risk factors, potential morbidity, potential adverse events associated with various antiemetics, efficacy of antiemetics, and costs. Risk factors for PONV are summarized in Table 35–6. The incidence of PONV can be significantly decreased by reducing baseline risk factors among patients at highest risk whenever clinically practical. Strategies to reduce baseline risk include use of regional anesthesia, propofol, supplemental oxygen, and hydration, as well as avoiding nitrous oxide, volatile anesthetics, and opioids.


Prophylaxis of PONV 7 Although the optimal management of PONV is not known,

patients at high risk of vomiting should receive prophylactic antiemetics for PONV. In addition to likely lack of benefit from prophylaxis, patients at low risk for PONV may potentially experience adverse reactions from the medications. Doses for prophylactic antiemetics are summarized in Table 35–7. The consensus panel determined that there is no difference in the efficacy and safety profiles of the SSRIs in the prophylaxis of PONV, and that these drugs are most effective when given at the end of surgery. Furthermore, the panel agreed that with equivalent efficacy and safety profiles, acquisition cost was the primary factor that differentiated the SSRIs from each other.40 Dexamethasone is an effective prophylactic agent when administered either alone or in combination with other antiemetic drugs before the induction of anesthesia.41 Droperidol has been one of the most effective agents for PONV prophylaxis. At a dose of 1.25 mg IV, it was more effective and much less costly than combination therapy with ondansetron 4 mg IV and droperidol 0.625 mg IV.42 As discussed earlier, the recent FDA black box warning has effectively removed droperidol from clinical use. As a result of conflicting data,

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clinicians do not agree on the role of metoclopramide as a prophylactic agent for PONV. Although effective, the use of phenothiazines in ambulatory surgery is limited due to predictable side effects including sedation, dry mouth, and dizziness. Transdermal scopolamine is an effective prophylactic agent for PONV, but its use is limited by the 2- to 4-hour delay in onset of effect in addition to age-related concerns and medical contraindications.43,44 Combination therapy is superior to monotherapy, but optimal dosing of agents used in combination as prophylaxis of PONV has not been determined.45,46


Treatment of PONV When PONV occurs in a patient who did not receive prophylaxis or who only received prophylactic dexamethasone, treatment with a SSRI is indicated. Typical adult treatment doses of SSRIs are as follows: dolasetron 12.5 mg, granisetron 0.1 mg, and ondansetron 1 mg.47 If prophylaxis with a SSRI is not protective, a treatment dose of a SSRI is not recommended within the first 6 hours after surgery due to lack of proven efficacy.48 Patients who experience PONV after receiving prophylactic treatment with a SSRI plus dexamethasone should receive a rescue dose from a different drug class such as a phenothiazine or droperidol.49 If more than 6 hours has elapsed between the administration of a prophylactic dose of a SSRI and an episode of PONV, a treatment or prophylaxis dose of a SSRI or droperidol can be administered, but the optimal readministration dose and interval for these two agents have not been determined. CLINICAL CONTROVERSY Is the lower dose of droperidol used for PONV safer than a higher dose? Several authors have reviewed the cases used by the FDA as justification for the black box warning. One author has hypothesized that droperidol is more hazardous in the presence of acute psychosis, making the acutely psychotic, severely agitated patient at higher risk of dysrhythmia than the typical perioperative patient receiving a dose of 1.25 mg or less.15


RADIATION-INDUCED NAUSEA AND VOMITING Nausea and vomiting associated with radiation therapy is not well understood. It is neither as predictable nor as severe as CINV, and many patients receiving radiation therapy will not experience nausea or vomiting. Risk factors associated with the development of RINV include the site of radiation, the dose, dose rate, and field size. 8 Patients receiving single-exposure, high-dose radiation therapy

TABLE 35–7. Recommended Prophylactic Doses of Antiemetics for PONV Drug Dolasetron Granisetron Ondansetron Dexamethasone Droperidol Dimenhydrinate

Adult Dose (IV)

Pediatric Dose (IV)

Timing of Dosea

12.5 mg 0.35–1 mg 4–8 mg 5–10 mg 0.625–1.25 mg 1–2 mg/kg

350 mcg/kg up to 12.5 mg

At end of surgery At end of surgery At end of surgery Before induction At end of surgery

50–100 mcg/kg up to 4 mg 150 mcg/kg up to 8 mg 50–70 mcg/kg up to 1.25 mg 0.5 mg/kg

a Based on recommendations from consensus guidelines; may differ from manufacturer’s recommendations. PONV, postoperative nausea and vomiting. From Gan et al.40

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to the upper abdomen, or total or hemibody irradiation should receive prophylactic antiemetics for RINV.


Prophylaxis of RINV The ASHP Therapeutic Guidelines31 and the ASCO antiemetic practice guidelines32 recommend preventive therapy in patients receiving total or hemibody irradiation or single-exposure, high-dose radiation therapy to the upper abdomen. The efficacy of oral granisetron 2 mg and ondansetron 8 mg was demonstrated in 34 patients undergoing hyperfractionated total body irradiation.50 Patients undergoing radiation therapy procedures with low to intermediate risk of nausea or vomiting should receive a SSRI or a dopamine receptor antagonist prior to each fraction.32


Treatment of RINV Patients who experience nausea and vomiting after radiation therapy should receive prochlorperazine, metoclopramide, or thiethylperazine as rescue agents, and then receive prophylactic treatment with a SSRI prior to subsequent radiation treatment.31


DISORDERS OF BALANCE A variety of clinical conditions may be associated with vertigo and dizziness. The etiology of these complaints may include diseases that are infectious, postinfectious, demyelinative, vascular, neoplastic, degenerative, traumatic, toxic, psychogenic, or idiopathic. Therefore symptoms of imbalance or imbalance perceived by the patient present a particular clinical challenge. Whether associated with a minor or complex disorder, motion sickness may be associated with nausea and vomiting. Although much progress has been made in the management of other illnesses associated with emesis, motion sickness represents an area in which newer agents have provided little benefit. Beneficial therapy for patients in this setting can most reliably be found among the antihistaminic-anticholinergic agents. However, their precise mechanisms of action are unknown to date. Neither the antihistaminic nor the anticholinergic potency appears to correlate well with the ability of these agents to prevent or treat the nausea and vomiting associated with motion sickness. When used for their depressant effects on labyrinth excitability, these agents produce variable efficacy and safety profiles. Oral regimens of antihistaminicanticholinergic agents given one to several times each day may be effective, especially when the first dose is administered prior to motion. The utility of scopolamine in preventing motion sickness was enhanced with the development of the transdermal system that increased patient satisfaction and decreased untoward side effects. The efficacy of transdermal scopolamine, oral meclizine, and placebo in protection against motion sickness was compared in a double-blind crossover study in 36 healthy subjects. Transdermal applications were made and tablets were taken at least 12 and 2 hours before exposure to three 90-minute periods in a ship-motion simulator. Transdermal scopolamine provided better protection than placebo or meclizine, with dryness of mouth more frequently reported in the transdermal scopolamine subjects.51


ANTIEMETIC USE DURING PREGNANCY More than one-half of pregnant women experience nausea and vomiting to some degree during the first trimester of pregnancy (nausea and vomiting of pregnancy; NVP). Teratogenicity is a major consideration for the use of antiemetic drugs during pregnancy and is the primary factor that guides drug selection. A large body of evidence suggests that the histamine1 -receptor antagonists (dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, and meclizine) have no human teratogenic potential52 and are effective in reducing treatment failure.53 Whether used alone or in combination with doxylamine, pyridoxine has not been found to be teratogenic and significantly decreases the nausea score.54,55 Other commonly prescribed agents that are effective and not teratogenic include the phenothiazines prochlorperazine and promethazine.53 Studies using the SSRIs in NVP are limited. In a randomized controlled trial of 15 patients exposed during the first trimester to intravenous ondansetron versus promethazine for treatment of severe NVP, ondansetron was no more beneficial than promethazine with respect to the following outcome measures: severity of nausea, daily weight gain, days requiring hospitalization, treatment failures, and voluntary use of the drug.56 The limited safety data for ondansetron does not allow it to be recommended as first-line therapy. Nonpharmacologic interventions for NVP include ginger 57 and acupuncture, although safety and efficacy trials for acupuncture are lacking. Although many women experience nausea and vomiting during pregnancy, less than 1% develop hyperemesis gravidarum, a serious condition marked by severe physical symptoms and/or medical complications. The etiology of hyperemesis gravidarum is not well understood. In its most severe state, hyperemesis gravidarum may result in volume contraction, starvation, and electrolyte abnormalities. Other clinical strategies include attention to fluid and electrolyte management, the use of vitamin supplements, reduced intake of dietary fats with increased intake of carbohydrates, and methods aimed at reducing psychosomatic complaints.58


ANTIEMETIC USE IN CHILDREN As discussed previously, the safety and efficacy of SSRIs have been established in pediatric patients receiving chemotherapy. Their side effect profile has promoted their use in children. The best doses or dosing strategies for children (by age, weight, or body surface area) have not been clearly established. Due to the lack of comparative trials in children, the ASCO antiemetic guidelines recommend that clinicians follow the adult guidelines with dosage adjustments for the pediatric population, with the exception that dopamine receptor antagonists should be avoided because of their potential for dystonic reactions.32 Corticosteroids are often used in combination with SSRIs as prophylaxis for CINV. For nausea and vomiting associated with pediatric gastroenteritis, there is greater emphasis on rehydration measures than on pharmacologic intervention. Only two prospective studies have been published on the safety or efficacy of antiemetics in pediatric gastroenteritis since 1966.59,60 A recent survey of physicians revealed that promethazine suppositories were the most commonly prescribed antiemetic for pediatric gastroenteritis, despite the lack of prospective trials for this agent.61

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PHARMACOECONOMIC CONSIDERATIONS There are many important variables to consider when attempting to document the overall costs of using a medication in a particular medical situation. Medication costs alone cannot begin to explain the true pharmacoeconomic outcome associated with the use of antiemetic drugs. For example, the costs associated with an unexpected hospital admission because of vomiting after an outpatient surgical procedure

EVALUATION OF THERAPEUTIC OUTCOMES In accordance with the information presented concerning age and clinical condition, individualized therapy is possible through drug selection and dosage adjustment. Monitoring criteria for drug therapy should include the subjective assessment of the patient’s severity of nausea, as well as objective parameters, such as changes in patient weight, the number of vomiting episodes each day, the volume of vomitus lost, and evaluation of fluid, acid-base balance, and electrolyte status, with particular attention to serum sodium, potassium, and chloride concentrations. In addition, evaluation of renal function may become important, particularly in patients with volume contraction and progressive electrolyte disturbances. Specific parameters include daily urine volume, urine specific gravity, and urine electrolyte concentrations. Physical assessment of patients should include evaluation of mucous membranes and skin turgor, because dryness of these tissues may be indicative of significant volume loss.

ABBREVIATIONS ASCO: American Society of Clinical Oncology ASHP: American Society of Health-System Pharmacists CINV: chemotherapy-induced nausea and vomiting CTZ: chemoreceptor trigger zone NCCN: National Comprehensive Cancer Network NK1 : neurokinin1 NVP: nausea and vomiting of pregnancy PONV: postoperative nausea and vomiting RINV: radiation-induced nausea and vomiting SSRI: selective serotonin receptor inhibitor Review Questions and other resources can be found at www.pharmacotherapyonline.com.

REFERENCES 1. Hanson JS, McCallum RW. The diagnosis and management of nausea and vomiting: A review. Am J Gastroenterol 1985;80:210–218. 2. Frytak S, Moertel CG. Management of nausea and vomiting in the cancer patient. JAMA 1981;245:393–396. 3. Lee M. Nausea and vomiting. In: Feldman M, ed. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/ Diagnosis/Management. St. Louis, Elsevier, 2002:119–130. 4. Montgomery GH, Bovbjerg DH. The development of anticipatory nausea in patients receiving adjuvant chemotherapy for breast cancer. Physiol Behav 1997;61:737–741. 5. Morrow GR, Morrell C. Behavioral treatment for the anticipatory nausea and vomiting induced by cancer chemotherapy. N Engl J Med 1982;307:1476–1480.

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quickly offset the savings related to the selection of an inexpensive antiemetic drug. In this and other similar situations, it is economically and clinically important to develop antiemetic protocols based on appropriate decision analysis and clinical outcomes in order to optimize drug product selection. The clinical practice guidelines that have been previously described are valuable tools when developing institution-specific antiemetic protocols. The availability of new, more expensive agents will only increase the costs associated with the prophylaxis of CINV. The need to control antiemetic costs for hospitals is universal and formulary management strategies have been described.62

6. King CR. Nonpharmacologic management of chemotherapy-induced nausea and vomiting. Oncol Nurs Forum 1997;24:S41–S48. 7. Matteson S, Roscoe J, Hickok J, Morrow GR. The role of behavioral conditioning in the development of nausea. Am J Obstet Gynecol 2002;186:S239–S243. 8. Dutro MP, Amerson AB. Comparison of liquid antacids. N Engl J Med 1980;302: 967–971. 9. Fordtran JS, Morawski S, Richardson C. In vitro and in vivo evaluation of antacids. N Engl J Med 1973;288:923–928. 10. Seipler JK, Mahakian K, Trudeau WT. Current concepts in clinical therapeutics: Peptic ulcer disease. Clin Pharm 1986;5:128–142. 11. Strenkoski-Nix L, Ermer J, DeCleene S, et al. Pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories and oral syrup to healthy subjects. Am J Health-Syst Pharm 2000;57:1499–1505. 12. Ernst A, Weiss SJ, Park S, et al. Prochlorperazine versus promethazine for uncomplicated nausea and vomiting in the emergency department: A randomized, double-blind clinical trial. Ann Emerg Med 2000;36:89–94. 13. Critchley P, Plach N, Grantham M, et al. Efficacy of haloperidol in the treatment of nausea and vomiting in the palliative patient: A systematic review. J Pain Symptom Manage 2001;22:631–634. 14. www.fda.gov/medwatch/SAFETY/2001/inapsine.htm 15. Dershwitz M. Droperidol: Should the black box be light gray? J Clin Anesth 2002;14:598–603. 16. Kao LK, Kirk, MA, Evers SJ, Rosenfeld SH. Droperidol, QT prolongation and sudden death: What is the evidence? Ann Emerg Med 2003;41:546– 558. 17. Italian Group for Antiemetic Research. Double-blind, dose-finding study of four intravenous doses of dexamethasone in the prevention of cisplatininduced acute emesis. J Clin Oncol 1998;16:2937–2942. 18. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy: Italian Group for Antiemetic Research. N Engl J Med 2000;342:1554–1559. 19. De Mulder PH, Seynaeve C, Vermorken JB, et al. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting: A multicenter, randomized, double-blind, crossover study. Ann Intern Med 1990;113:834–840. 20. Heron JF, Goedhals L, Jordaan JP, et al. Oral granisetron alone and in combination with dexamethasone: A double-blind randomized comparison against high-dose metoclopramide plus dexamethasone in prevention of cisplatin-induced emesis. Ann Oncol 1994;5:579–584. 21. Chevallier B, Cappelaere P, Splinter T, et al. A double-blind, multicenter comparison of intravenous dolasetron mesylate and metoclopramide in the prevention of nausea and vomiting in cancer patients receiving high-dose cisplatin chemotherapy. Support Care Cancer 1997;5:22–30. 22. Tramer MR, Carroll D, Campbell FA, et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: Quantitative systematic review. BMJ 2001;323:1–8. 23. Stahl SM. The ups and downs of novel antiemetic drugs, Part 1: Substance P, 5-HT, and the neuropharmacology of vomiting. J Clin Psychol 2003;64:498–499. 24. Kris MG, Radford JE, Pizzo BA, et al. Use of a NK-1 receptor antagonist to prevent delayed emesis following cisplatin. J Natl Cancer Inst 1997; 89:53–54. 25. Hesketh PJ, Gralla RJ, Webb RT, et al. Randomized phase II study of the neurokinin 1 receptor antagonist CJ-11,974 in the control of cisplatininduced emesis. J Clin Oncol 1999;17:338–343.

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26. Navari RM, Reinhardt RR, Gralla RJ, et al. Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. N Engl J Med 1999;340:190–195. 27. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer 2003;97:3090–3098. 28. Hesketh PJ, Grunbert SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: A multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—The aprepitant protocol 052 study group. J Clin Oncol 2003;21:4112–4119. 29. Emend [package insert]. Whitehouse Station, NJ, Merck & Co, March 2003. 30. McCrea JB, Majumdar AK, Goldberg MR, et al. Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther 2003;74:17–24. 31. American Society of Health-System Pharmacists (ASHP) Therapeutic Guidelines on the Pharmacologic Management of Nausea and Vomiting in Adult and Pediatric Patients Receiving Chemotherapy or Radiation Therapy or Undergoing Surgery. Am J Health-Syst Pharm 1999;56:729–764. 32. Gralla RJ, Osoba D, Kris MG, et al. Recommendations for the use of antiemetics:evidence-based, clinical practice guidelines. American Society of Clinical Oncology. J Clin Oncol 1999;17:2971–2994. 33. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Antiemesis Version 2.2003. Available at http://www.nccn.org/ professionals/physician gls/default.asp. Accessed December 1, 2003. 34. Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997;15:103– 109. 35. Lindley C, Blower P. Oral serotonin type 3-receptor antagonists for prevention of chemotherapy-induced emesis. Am J Health-Syst Pharm 2000; 57:1685–1697. 36. Walker PC, Biglin KE, Constance TD, et al. Promoting the use of oral ondansetron in children receiving cancer chemotherapy. Am J HealthSyst Pharm 2001;58:598–602. 37. Aloxi [package insert]. Bloomington, MI, MGI PHARMA Inc., July 2003. 38. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: Results of a phase III, single-dose trial versus dolasetron. Cancer 2003;98:2473–2482. 39. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: Results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol 2003;14:1570–1577. 40. Gan TJ, Meyer T, Apfel CC, et al. Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg 2003;97:62–71. 41. Wang JJ, Ho ST, Tzeng JI, Tang CS. The effect of timing of dexamethasone administration on its efficacy as a prophylactic antiemetic for postoperative nausea and vomiting. Anesth Analg 2000;91:136–139. 42. Hill RP, Lubarsky DA, Phillips-Bute B, et al. Cost-effectiveness of prophylactic antiemetic therapy with ondansetron, droperidol or placebo. Anesthesiology 2000;92:958–967. 43. Kranke P, Morin AM, Roewer N, et al. The efficacy and safety of transdermal scopolamine for the prevention of postoperative nausea and vomiting: A quantitative systematic review. Anesth Analg 2002;95:133–143.

44. Bailey PL, Streisand JB, Pace NL, et al. Transdermal scopolamine reduces nausea and vomiting after outpatient laparoscopy. Anesthesiology 1990;72:977–980. 45. Habib AS, Gan TJ. Combination therapy for postoperative nausea and vomiting: A more effective prophylaxis? Ambulatory Surg 2001;9: 59–71. 46. Eberhart LH, Morin AM, Bothner U, Georgieff M. Droperidol and 5-HT3receptor antagonists alone or in combination, for prophylaxis of postoperative nausea and vomiting: A meta-analysis of randomized controlled trials. Acta Anaesthesiol Scand 2000;44:1252–1257. 47. Tramer M, Moore RA, Reynolds DJM, McQuay HJ. A quantitative systematic review of ondansetron in treatment of established postoperative nausea and vomiting. BMJ 1997;314:1088–1092. 48. Kovac AL, O’Connor TA, Pearman MH, et al. Efficacy of repeat intravenous dosing of ondansetron in controlling postoperative nausea and vomiting: A randomized, double-blind, placebo-controlled multicenter trial. J Clin Anesth 1999;11:453–459. 49. Kreisler NS, Spiekermann BF, Ascari CM, et al. Small-dose droperidol effectively reduces nausea in a general surgical adult patient population. Anesth Analg 2000;91:1256–1261. 50. Spitzer TR, Friedman CJ, Bushnell W, et al. Double-blind, randomized, parallel-group study on the efficacy and safety of oral granisetron and oral ondansetron in the prophylaxis of nausea and vomiting in patients receiving hyperfractionated total body irradiation. Bone Marrow Transplant 2000;26:203–210. 51. Dahl E, Offer-Ohlsen D, Lillevold PE, Sandvik L. Transdermal scopolamine, oral meclizine, and placebo in motion sickness. Clin Pharmacol Ther 1984;36:116–120. 52. Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy Asthma Immunol 1997;78:157–159. 53. Mazzotta P, Magee LA. A risk-benefit assessment of pharmacological and nonpharmacological treatments for nausea and vomiting of pregnancy. Drugs 2000;59:781–800. 54. Sahakian V, Rouse D, Sipes S, et al. Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: A randomized, double-blind placebocontrolled study. Obstet Gynecol 1991;78:33–36. 55. Vutyavanich T, Wongtra-ngan S, Ruangsri R. Pyridoxine for nausea and vomiting of pregnancy: A randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol 1995;173:881–884. 56. Sullivan CA, Johnson CA, Roach H, Martin RW, et al. A pilot study of intravenous ondansetron for hyperemesis gravidarum. Am J Obstet Gynecol 1996;174:1565–1568. 57. Portnoi G, Chng LA, Karimi-Tabesh L, et al. Prospective comparative study of the safety and effectiveness of ginger for the treatment of nausea and vomiting in pregnancy. Am J Obstet Gynecol 2003;189: 1374–1377. 58. Quinlan JD, Hill DA. Nausea and vomiting of pregnancy. Am Fam Physician 2003;68:121–128. 59. Ginsburg CM, Clahsen J. Evaluation of trimethobenzamide hydrochloride (Tigan) suppositories for treatment of nausea and vomiting in children. J Pediatr 1980;96:767–769. 60. Cubeddu LX, Trujillo LM, Talmaciu I, et al. Antiemetic activity of ondansetron in acute gastroenteritis. Aliment Pharmacol Ther 1997;11:185– 191. 61. Kwon KT, Rudkin SE, Langdorf MI. Antiemetic use in pediatric gastroenteritis: A national survey of emergency physicians, pediatricians, and pediatric emergency physicians. Clin Pediatr 2002;41:641–652. 62. Lucarelli CD. Formulary management strategies for type 3 serotonin receptor antagonists. Am J Health-Syst Pharm 2003;60:S4–S11.

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36 DIARRHEA, CONSTIPATION, AND IRRITABLE BOWEL SYNDROME William J. Spruill and William E. Wade

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Diarrhea is caused by many viral and bacterial organisms. It is most often a minor discomfort, not life-threatening, and usually self-limited.

2 The four pathophysiologic mechanisms of diarrhea have been linked to the four broad diarrheal groups, which are secretory, osmotic, exudative, and altered intestinal transit. The three mechanisms by which absorption occurs from the intestines are active transport, diffusion, and solvent drag. 3 Management of diarrhea focuses on preventing exces-

sive water and electrolyte losses, dietary care, relieving symptoms, treating curable causes, and treating secondary disorders.

4 Bismuth subsalicylate is marketed for indigestion, relieving abdominal cramps, and controlling diarrhea, including traveler’s diarrhea, but contains multiple components that might be toxic if given excessively. 5 Underlying causes of constipation should be identified when possible and corrective measures taken (e.g., alter-

DIARRHEA Diarrhea is a troublesome discomfort that affects most individuals in the United States at some point in their lives. Usually diarrheal episodes begin abruptly and subside within 1 or 2 days without treatment. This chapter focuses primarily on noninfectious diarrhea, with only minor reference to infectious diarrhea (see Chap. 111 on gastrointestinal infections). Diarrhea is often a symptom of a systemic disease and not all possible causes of diarrhea are discussed in this chapter. To understand diarrhea, one must have a reasonable definition of the condition; unfortunately, the literature is extremely variable on this. Simply put, diarrhea is an increased frequency and decreased consistency of fecal discharge as compared to an individual’s normal bowel pattern. Frequency and consistency are variable within and between individuals. For example, some individuals defecate as often as three times per day, whereas others defecate only two or three times per week. A Western diet usually produces a daily stool weighing between 100 and 300 g, depending on the amount of nonabsorbable materials (mainly carbohydrates) consumed. Patients with serious diarrhea may have a daily stool weight in excess of 300 g; however, a

ation of diet or treatment of diseases such as hypothyroidism).

6 The foundation of treatment of constipation is dietary fiber or bulk-forming laxatives that provide 10 to 15 g/day of raw fiber.

7 Irritable bowel syndrome is one of the most common gas-

trointestinal disorders, and is characterized by lower abdominal pain, disturbed defecation, and bloating. Many nongastrointestinal manifestations also exist with IBS. Recent studies have found that visceral hypersensitivity is a major culprit in the pathophysiology of the disease.

8 Diarrhea-predominant IBS should be managed by dietary

modification and drugs such as loperamide when diet changes alone are insufficient to control symptoms.

9 Several drug classes are involved in the treatment of the pain associated with IBS, including tricyclic compounds and the gut-selective calcium channel blockers.

subset of patients experience frequent small, watery passages. Additionally, vegetable fiber-rich diets, such as those consumed in some Eastern cultures such as those in Africa, produce stools weighing more than 300 g/day. Diarrhea may be associated with a specific disease of the intestines or secondary to a disease outside the intestines. For instance, bacillary dysentery directly affects the gut, whereas diabetes mellitus causes neuropathic diarrheal episodes. Furthermore, diarrhea can be considered as acute or chronic disease. Infectious diarrhea is often acute; diabetic diarrhea is chronic. Whether acute or chronic, diarrhea has the same pathophysiologic causes that help identification of specific treatments.

EPIDEMIOLOGY The epidemiology of diarrhea varies in developed versus developing countries.1−3 In the United States, diarrheal illnesses are usually not reported to the Centers for Disease Control and Prevention (CDC) unless associated with an outbreak or an unusual organism or condition. For example, the acquired immune deficiency syndrome (AIDS) has been identified with protracted diarrheal illness. Diarrhea is a major 677

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problem in day care centers and nursing homes, probably because early childhood and senescence plus environmental conditions are risk factors. However, an exact epidemiologic profile in the United States is not available through the CDC or published literature. 1 Viral and bacterial organisms account for most episodes of infectious diarrhea. Common causative bacterial organisms include Shigella, Salmonella, Campylobacter, Staphylococcus, and Escherichia coli. Food-borne bacterial infection is a major concern, as several major food poisoning episodes have occurred that were traced to poor sanitary conditions in meat-processing plants. Acute viral infections are attributed mostly to the Norwalk and rotavirus groups. In developing countries, diarrhea is a leading cause of illness and death in children.4 Moreover, diarrhea produces an economic burden because of costs related to hospitalization and loss of productivity. Approximately 1.3 billion episodes occur annually and 4 million deaths result from diarrhea in these countries. Factors associated with these findings include poor sanitation, poor nutrition, and age less than 5 years. Children in underdeveloped countries experience an average of three episodes of diarrhea each year (e.g., 2.7 diarrhea episodes/person/year in Latin America) as compared to 1 episode/ person/year in the United States and Western Europe.

PHYSIOLOGY In the fasting state, 9 L of fluid enters the proximal small intestine each day. Of this fluid, 2 L are ingested through diet, while the remainder consists of internal secretions. Because of meal content, duodenal chyme is usually hypertonic. When chyme reaches the ileum, the osmolality adjusts to that of plasma, with most dietary fat, carbohydrate, and protein being absorbed. The volume of ileal chyme decreases to about 1 L/day upon entering the colon, which is further reduced by colonic absorption to 100 mL daily. If the small intestine water absorption capacity is exceeded, chyme overloads the colon, resulting in diarrhea. In humans, the colon absorptive capacity is about 5 L daily. Colonic fluid transport is critical to water and electrolyte balance. Absorption from the intestines back into the blood occurs by three mechanisms: active transport, diffusion, and solvent drag. Active transport and diffusion are the mechanisms of sodium transport. Because of the high luminal sodium concentration (142 mEq/L), sodium diffuses from the sodium-rich gut into epithelial cells, where it is actively pumped into the blood and exchanged with chloride to maintain an isoelectric condition across the epithelial membrane. Hydrogen ions are transported by an indirect mechanism in the upper small intestine. As sodium is absorbed, hydrogen ions are secreted into the gut. Hydrogen ions then combine with bicarbonate ions to form carbonic acid, which then dissociates into carbon dioxide and water. Carbon dioxide readily diffuses into the blood for expiration through the lung. The water remains in the chyme. Paracellular pathways are major routes of ion movement. As ions, monosaccharides, and amino acids are actively transported, an osmotic pressure is created, drawing water and electrolytes across the intestinal wall. This pathway accounts for significant amounts of ion transport, especially sodium. Sodium plays an important role in stimulating glucose absorption. Glucose and amino acids are actively transported into the blood via a sodium dependent cotransport mechanism. Cotransport absorption mechanisms of glucose-sodium and amino acid-sodium are extremely important for treating diarrhea. Gut motility influences absorption and secretion. The amount of time in which luminal content is in contact with the epithelium is under neural and hormonal control. Neurohormonal substances, such as angiotensin, vasopressin, glucocorticoid, and aldosterone, and neurotransmitters also regulate ion transport.

PATHOPHYSIOLOGY 2 Four general pathophysiologic mechanisms disrupt water and

electrolyte balance, leading to diarrhea, and are the basis of diagnosis and therapy. These are (a) a change in active ion transport by either decreased sodium absorption or increased chloride secretion; (b) change in intestinal motility; (c) increase in luminal osmolarity; and (d) increase in tissue hydrostatic pressure. These mechanisms have been related to four broad clinical diarrheal groups: secretory, osmotic, exudative, and altered intestinal transit. Secretory diarrhea occurs when a stimulating substance either increases secretion or decreases absorption of large amounts of water and electrolytes. Substances that cause excess secretion include vasoactive intestinal peptide (VIP) from a pancreatic tumor, unabsorbed dietary fat in steatorrhea, laxatives, hormones (such as secretin), bacterial toxins, and excessive bile salts. Many of these agents stimulate intracellular cyclic adenosine monophosphate and inhibit Na+ /K+ -ATPase, leading to increased secretion. Also, many of these mediators inhibit ion absorption simultaneously. Clinically, secretory diarrhea is recognized by large stool volumes (>1 L/ day) with normal ionic contents and osmolality approximately equal to plasma. Fasting does not alter the stool volume in these patients. Poorly absorbed substances retain intestinal fluids, resulting in osmotic diarrhea. This process occurs with malabsorption syndromes, lactose intolerance, administration of divalent ions (e.g., magnesiumcontaining antacids), or consumption of poorly soluble carbohydrate (e.g., lactulose). As a poorly soluble solute is transported, the gut adjusts the osmolality to that of plasma; in so doing, water and electrolytes flux into the lumen. Clinically, osmotic diarrhea is distinguishable from other types, as it ceases if the patient resorts to a fasting state. Inflammatory diseases of the gastrointestinal tract discharge mucus, serum proteins, and blood into the gut. Sometimes bowel movements consist only of mucus, exudate, and blood. Exudative diarrhea probably affects other absorptive, secretory, or motility functions to account for the large stool volume associated with this disorder. Altered intestinal motility produces diarrhea by three mechanisms: reduction of contact time in the small intestine, premature emptying of the colon, and bacterial overgrowth. Chyme must be exposed to intestinal epithelium for a sufficient time period to enable normal absorption and secretion processes to occur. If this contact time decreases, diarrhea results. Intestinal resection or bypass surgery and drugs (such as metoclopramide) cause this type of diarrhea. On the other hand, an increased time of exposure allows fecal bacteria overgrowth. A characteristic small intestine diarrheal pattern is rapid, small, coupling bursts of waves. These waves are inefficient, do not allow absorption, and rapidly dump chyme into the colon. Once in the colon, chyme exceeds the colonic capability to absorb water.

ETIOLOGIC EXAMINATION OF THE STOOL Stool characteristics are important in assessing the etiology of diarrhea. A description of the frequency, volume, consistency, and color provides diagnostic clues. For instance, diarrhea starting in the small intestine produces a copious, watery or fatty (greasy), and foul-smelling stool; contains undigested food particles; and is usually free from gross blood. Colonic diarrhea appears as small, pasty, and sometimes bloody or mucoid movements. Rectal tenesmus with flatus accompanies large intestinal diarrhea.

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TABLE 36–1. Clinical Presentation of Diarrhea

TABLE 36–2. Drugs Causing Diarrhea

General r Usually, acute diarrheal episodes subside within 72 hours of onset, whereas chronic diarrhea involves frequent attacks over extended time periods. Signs and symptoms r Abrupt onset of nausea, vomiting, abdominal pain, headache, fever, chills, and malaise. r Bowel movements are frequent and never bloody, and diarrhea lasts 12 to 60 hours. r Intermittent periumbilical or lower right quadrant pain with cramps and audible bowel sounds is characteristic of small intestinal disease. r When pain is present in large intestinal diarrhea, it is a gripping, aching sensation with tenesmus (straining, ineffective and painful stooling). Pain localizes to the hypogastric region, right or left lower quadrant, or sacral region. r In chronic diarrhea, a history of previous bouts, weight loss, anorexia, and chronic weakness are important findings. Physical examination r Typically demonstrates hyperperistalsis with borborygmi and generalized or local tenderness. Laboratory tests r Stool analysis studies include examination for microorganisms, blood, mucus, fat, osmolality, pH, electrolyte and mineral concentration, and cultures. r Stool test kits are useful for detecting gastrointestinal viruses, particularly rotavirus. r Antibody serologic testing shows rising titers over a 3- to 6-day period, but this test is not practical and is nonspecific. r Occasionally, total daily stool volume is also determined. r Direct endoscopic visualization and biopsy of the colon may be undertaken to assess for the presence of conditions such as colitis or cancer. r Radiographic studies are helpful in neoplastic and inflammatory conditions.

Laxatives Antacids containing magnesium Antineoplastics Auranofin (gold salt) Antibiotics Clindamycin Tetracyclines Sulfonamides Any broad-spectrum antibiotic Antihypertensives Reserpine Guanethidine Methyldopa Guanabenz Guanadrel Cholinergics Bethanechol Neostigmine Cardiac agents Quinidine Digitalis Digoxin Nonsteroidal anti-inflammatory drugs Prostaglandins Colchicine

CLINICAL PRESENTATION Table 36–1 outlines the clinical presentation of diarrhea while Table 36–2 shows common drug-induced causes of diarrhea. A medication

history is extremely important in identifying drug-induced diarrhea. Many agents, including antibiotics and other drugs, cause diarrhea, or less commonly, pseudomembranous colitis. Self-inflicted laxative abuse for weight loss is popular. Neurotic or psychotic behavior leads to laxative abuse. Drug side effects (e.g., quinidine side effects) often present as diarrhea. Most acute diarrhea is self-limiting, subsiding within 72 hours. However, infants, young children, the elderly, and debilitated persons are at risk for morbid and mortal events in prolonged or voluminous diarrhea. These groups are at risk for water, electrolyte, and acid-base disturbances, and potentially cardiovascular collapse and death. The prognosis for chronic diarrhea depends on the cause; for example, diarrhea secondary to diabetes mellitus waxes and wanes throughout life.


TREATMENT: Diarrhea
PREVENTION Acute viral diarrheal illness often occurs in day care centers and nursing homes. As person-to-person contact is the mechanism by which viral disease spreads, isolation techniques must be initiated. For bacterial, parasite, and protozoal infections, strict food handling, sanitation, water, and other environmental hygiene practices can prevent transmission. If diarrhea is secondary to another illness, controlling the primary condition is necessary. Antibiotics and bismuth subsalicylate are advocated to prevent traveler’s diarrhea, in conjunction with treatment of drinking water and caution with consumption of fresh vegetables.


DESIRED OUTCOME 3 If prevention is not successful and diarrhea occurs, therapeutic goals are to (a) manage the diet;(b) prevent excessive water, elec-

trolyte, and acid-base disturbances; (c) provide symptomatic relief; (d) treat curable causes; and (e) manage secondary disorders causing diarrhea (Figs. 36–1 and 36–2). Clinicians must clearly understand that diarrhea, like a cough, may be a body defense mechanism for ridding itself of harmful substances or pathogens. The correct therapeutic response is not necessarily to stop diarrhea at all costs.


NONPHARMACOLOGIC MANAGEMENT Dietary management is a first priority in the treatment of diarrhea. Most clinicians recommend discontinuing consumption of solid foods and dairy products for 24 hours. However, fasting is of questionable value, as this treatment modality has not been extensively studied. In osmotic diarrhea, these maneuvers control the problem. If the mechanism is secretory, diarrhea persists. For patients experiencing

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Diarrhea History and physical examination

FIGURE 36–1. Recommendations for treating acute diarrhea. Follow these steps: (1) Perform a complete history and physical examination. (2) Is the diarrhea acute or chronic? If chronic diarrhea, go to Fig. 36–2. (3) If acute diarrhea, check for fever and/or systemic signs and symptoms (i.e., toxic patient). If systemic illness (fever, anorexia, or volume depletion), check for an infectious source. If positive for infectious diarrhea, use appropriate antibiotic/anthelmintic drug and symptomatic therapy. If negative for infectious cause, use only symptomatic treatment. (4) If no systemic findings, then use symptomatic therapy based on severity of volume depletion, oral or parenteral fluid/electrolytes, antidiarrheal agents (see Table 36–4), and diet.

Go to Fig. 36–2 No fever or systemic symptoms

Fever or systemic symptoms

Symptomatic therapy a. Fluid/electrolyte replacement b. Loperamide, diphenoxylate, or absorbent c. Diet

Check feces for WBC/RBC/ ova and parasites

Chronic diarrhea Lasting > 14 days Possible causes: a. Intestinal infection b. Inflammatory bowel disease c. Malabsorption d. Secretory hormonal tumor e. Drug, factitious f. Motility disturbance

History and physical examination

Select appropriate diagnostic studies For example, a. Stool culture/ova/ parasites/WBC/RBC/ fat b. Sigmoidoscopy c. Intestinal biopsy

No diagnosis, symptomatic therapy a. Replete hydration b. Discontinue potential drug inducer c. Adjust diet d. Loperamide or absorbent

Chronic diarrhea ( > 14 days)

Acute diarrhea ( < 3 days)

Diagnosis a. Treat specific cause

FIGURE 36–2. Recommendations for treating chronic diarrhea. Follow these steps: (1) Perform a careful history and physical examination. (2) The possible causes of chronic diarrhea are many. These can be classified into intestinal infections (bacterial or protozoal), inflammatory disease (Crohn’s disease or ulcerative colitis), malabsorption (lactose intolerance), secretory hormonal tumor (intestinal carcinoid tumor or VIPoma), drug (antacid), factitious (laxative abuse), or motility disturbance (diabetes mellitus, irritable bowel syndrome, or hyperthyroidism). (3) If the diagnosis is uncertain, selected appropriate diagnostic studies should be ordered. (4) Once diagnosed, treatment is planned for the underlying cause with symptomatic antidiarrheal therapy. (5) If no specific cause can be identified, symptomatic therapy is prescribed.

Negative

Positive

Symptomatic therapy

Use appropriate antibiotic and symptomatic therapy

nausea and/or vomiting, a mild, digestible low-residue diet should be administered for 24 hours. If vomiting is present and uncontrollable with antiemetics (see Chap. 35 on nausea and vomiting), nothing is taken by mouth. As bowel movements decrease, a bland diet is begun. Feeding should continue in children with acute bacterial diarrhea. Fed children have less morbidity and mortality, whether or not they receive oral rehydration fluids. Studies are not available in the elderly or in other high-risk groups to determine the value of continued feeding in bacterial diarrhea.


WATER AND ELECTROLYTES Rehydration and maintenance of water and electrolytes are primary treatment goals until the diarrheal episode ends. If the patient is volume depleted, rehydration should be directed at replacing water and electrolytes to normal body composition. Then water and electrolyte composition are maintained by replacing losses. Many patients will not develop volume depletion and therefore will only require maintenance fluid and electrolyte therapy. Parenteral and enteral routes may be used for supplying water and electrolytes. If vomiting and dehydration are not severe, enteral feeding is the less costly and preferred method. In the United States, many commercial oral rehydration preparations are available (Table 36–3). Because of concerns about hypernatremia, physicians continue to hospitalize and intravenously correct fluid and electrolyte deficits in severe dehydration. Oral solutions are strongly recommended.5,6 In developing countries, the World Health Organization Oral Rehydration Solution (WHO-ORS) saves the lives of millions of children annually. During diarrhea, the small intestine retains its ability to actively transport monosaccharides such as glucose. Glucose actively carries sodium with water and other electrolytes. Because the WHO-ORS has a high sodium concentration, U.S. physicians have been reluctant to use it in well-nourished children. Yet controlled comparative studies describe more favorable results with the WHO-ORS than with parenteral fluids.7 Amino acids promote sodium transport and act as

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TABLE 36–3. Oral Rehydration Solutions

Osmolality (mOsm/L) Carbohydratesb (g/L) Calories (cal/L) Electrolytes (mEq/L) Sodium Potassium Chloride Citrate Bicarbonate Calcium Magnesium Sulfate Phosphate

WHO-ORSa

Pedialyteb (Ross)

Rehydralyteb (Ross)

Infalyte (Mead Johnson)

Resolb (Wyeth)

333 20 85

249 25 100

304 25 100

200 30c 126

269 20 80

90 20 80 — 30 — — — —

45 20 35 30 — — — — —

75 20 65 30 — — — — —

50 25 45 34 — — — — —

50 20 50 34 — 4 4 — 5

a

World Health Organization Oral Rehydration Solution. Carbohydrate is glucose. c Rice syrup solids are carbohydrate source. b

Various drugs have been used to treat diarrheal attacks (Table 36–4). These drugs are grouped into several categories: antimotility, adsorbents, antisecretory compounds, antibiotics, enzymes, and intestinal microflora. Usually these drugs are not curative but palliative.

products), is suggested for managing acute and chronic diarrhea. The usual adult dose is initially 4 mg orally, followed by 2 mg after each loose stool, up to 16 mg/day. Used correctly, this agent has rare side effects such as dizziness and constipation. If the diarrhea is concurrent with a high fever or bloody stool, the patient should be referred to a physician. Also, diarrhea lasting 48 hours beyond initiating loperamide warrants medical attention. Loperamide can also be used in traveler’s diarrhea. It is comparable to bismuth subsalicylate for treatment of this disorder.8 Diphenoxylate is available as 2.5-mg tablets and as a 2.5 mg/ 5 mL solution. A small amount of atropine (0.025 mg) is included to discourage abuse. In adults, when taken as 2.5 to 5 mg three or four times daily, not to exceed a 20-mg total daily dose, diphenoxylate is rarely toxic. Some patients may complain of atropinism (blurred vision, dry mouth, and urinary hesitancy). Like loperamide, it should not be used in patients at risk of bacterial enteritis with Escherichia coli, Shigella, or Salmonella. Difenoxin, a diphenoxylate derivative, is also combined with atropine and has the same uses, precautions, and side effects. Marketed as 1-mg tablet, the adult dosage is 2 mg initially followed by 1 mg after each loose stool, not to exceed 8 mg/day. Paregoric, tincture of opium, is marketed as a 2 mg/5 mL solution and is indicated for managing both acute and chronic diarrhea. It is not widely prescribed today because of its abuse potential.


OPIATES AND THEIR DERIVATIVES


ADSORBENTS

Opiates and opioid derivatives (a) delay the transit of intraluminal contents or (b) increase gut capacity, prolonging contact and absorption. Enkephalins, endogenous opioid substances, regulate fluid movement across the mucosa by stimulating absorptive processes. Limitations to the use of opiates include an addiction potential (a real concern with long-term use) and worsening of diarrhea in selected infectious diarrhea. Most opiates act through peripheral and central mechanisms with the exception of loperamide, which acts only peripherally. Loperamide is antisecretory; it inhibits the calcium-binding protein calmodulin, controlling chloride secretion. Loperamide, available as 2-mg capsules or 1 mg/5 mL solution (both are nonprescription

Adsorbents are used for symptomatic relief. These products, many not requiring a prescription, are nontoxic, but their effectiveness remains unproven. Adsorbents are nonspecific in their action; they adsorb nutrients, toxins, drugs, and digestive juices. Coadministration with other drugs reduces their bioavailability. The Food and Drug Administration over-the-counter review panel recommends only polycarbophil as an effective adsorbent. Polycarbophil absorbs 60 times its weight in water and can be used to treat both diarrhea and constipation. It is a nonprescription product and is sold as 500-mg chewable tablets. This hydrophilic nonabsorbable product is safe and may be taken four times daily, up to 6 g/day in adults.

an antisecretory agent. Researchers have added glycine to ORS in an attempt to create a “super-ORS.” Reports, however, are disappointing, because glycine causes an osmotic diarrhea and diuresis in experimental concentrations. Rice-based oral solution is a hyposmotically active substrate that elutes glucose without increasing stool or urine outflows. Pizarro and associates7 reported effective rehydration of infants with acute diarrhea using a rice-based solution. They also reported decreased stool output and greater absorption and retention of fluid and electrolytes. In summary, oral rehydration solution is a lifesaving treatment for millions afflicted in developing countries. Acceptance in developed countries is less enthusiastic; however, the advantage of this product in reducing hospitalizations may prove its use as a cost-effective alternative, saving millions of dollars in health care expenditures.


PHARMACOLOGIC THERAPY

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TABLE 36–4. Selected Antidiarrheal Preparations Dose Form Antimotility Diphenoxylate Loperamide

2.5 mg/tablet 2.5 mg/5 mL 2 mg/capsule

Paregoric Opium tincture Difenoxin

1 mg/5 mL 2 mg/5 mL (morphine) 5 mg/mL (morphine) 1 mg/tablet

Adsorbents Kaolin–pectin mixture Polycarbophil Attapulgite

Antisecretory Bismuth subsalicylate

Enzymes (lactase) Bacterial replacement (Lactobacillus acidophilus, Lactobacillus bulgaricus) Octreotide

5 mg four times daily; do not exceed 20 mg/day Initially 4 mg, then 2 mg after each loose stool; do not exceed 16 mg/day 5–10 mL 1–4 times daily 0.6 mL four times daily Two tablets, then one tablet after each loose stool; up to 8 tablets/day

5.7 g kaolin + 130.2 mg pectin/30 mL 500 mg/tablet 750 mg/15 mL 300 mg/7.5 mL 750 mg/tablet 600 mg/tablet 300 mg/tablet 1050 mg/30 mL 262 mg/15 mL 524 mg/15 mL 262 mg/tablet 1250 neutral lactase units/4 drops 3300 FCC lactase units per tablet

0.05 mg/mL 0.1 mg/mL 0.5 mg/mL


ANTISECRETORY AGENTS Bismuth subsalicylate appears to have antisecretory, antiinflammatory, and antibacterial effects. As a nonprescription product, it is marketed for indigestion, relieving abdominal cramps, and controlling diarrhea, including traveler’s diarrhea. Bismuth subsalicylate dosage strengths are 262-mg chewable tablets, 262 mg/5 mL liquid, and 524 mg/15 mL liquid. The usual adult dose is 2 tablets or 30 mL every 30 minutes to 1 hour up to 8 doses per day. 4 Bismuth subsalicylate contains multiple components that might be toxic if given excessively to prevent or treat diarrhea. For instance, an active ingredient is salicylate, which may interact with anticoagulants or may produce salicylism (tinnitus, nausea, and vomiting). Bismuth reduces tetracycline absorption and may interfere with select gastrointestinal radiographic studies. Patients may complain of a darkening of the tongue and stools with repeat administration. Salicylate can induce gout attacks in susceptible individuals. Bismuth subsalicylate suspension has been evaluated in the treatment of secretory diarrhea of infectious etiology as well. In a dose of 30 mL every 30 minutes for eight doses, unformed stools decrease in the first 24 hours. Bismuth subsalicylate may also be effective in preventing traveler’s diarrhea. Octreotide, a synthetic octapeptide analog of endogenous somatostatin, is prescribed for the symptomatic treatment of carcinoid tumors and vasoactive intestinal peptide–secreting tumors (VIPomas).9 Metastatic intestinal carcinoid tumors secrete excessive

Adult Dose

30–120 mL after each loose stool Chew 2 tablets four times daily or after each loose stool; do not exceed 12 tablets/day 1200–1500 mg after each loose bowel movement or every 2 hours; up to 9000 mg/day

Two tablets or 30 mL every 30 min to 1 h as needed up to 8 doses/day

3–4 drops taken with milk or dairy product 1 or 2 tablets as above 2 tablets or 1 granule packet 3 to 4 times daily; give with milk, juice, or water Initial: 50 mcg subcutaneously 1–2 times per day and titrate dose based on indication up to 600 mcg/day in 2–4 divided doses

amounts of vasoactive substances, including histamine, bradykinin, serotonin, and prostaglandins. Primary carcinoid tumors occur throughout the gastrointestinal tract, with most in the ileum. Predominant signs and symptoms experienced by patients with these tumors are attributable to excessive concentrations of 5-hydroxytryptophan and serotonin. The totality of their clinical effects is termed the carcinoid syndrome. Paroxysmal vasomotor attacks characterize carcinoid syndrome, most notably sudden red to purple flushing of the face and neck. These attacks are often caused by emotional outbursts or by ingestion of food or alcohol. Some patients have a violent, watery diarrhea with abdominal cramping. Initially, diarrhea might be managed with various agents such as codeine, diphenoxylate, cyproheptadine, methysergide, phenoxybenzamine, or methyldopa. Recently, octreotide has become the drug of choice. Octreotide blocks the release of serotonin and many other active peptides and has been effective in controlling diarrhea and flushing. It is reported to have direct inhibitory effects on intestinal secretion and stimulatory effects on intestinal absorption. Non–gastrin-secreting adenomas of the pancreas are tumors associated with profuse watery diarrhea. This condition has been referred to as Verner-Morrison syndrome, WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, pancreatic cholera, watery diarrhea syndrome, and VIPoma. Excessive secretion of VIP from a retroperitoneal or pancreatic tumor produces most of the clinical features. Excessive VIP is isolated in about half of patients, along with numerous other peptide hormones (peptide histidine methionine [PHM], serotonin,

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somatostatin, gastrin, and glucagon). Surgical tumor dissection is the treatment of choice. In nonsurgical candidates, the profuse watery diarrhea and other symptoms commonly encountered are managed with octreotide. The dose of octreotide varies with the indication, disease severity, and patient response.9 For managing diarrhea and flushing associated with carcinoid tumors in adults, the initial dosage range is 100 to 600 mcg/day in two to four divided doses subcutaneously for 2 weeks. For controlling secretory diarrhea of VIPomas, the dosage range is 200 to 300 mcg/day in two to four divided doses for 2 weeks. Some patients may require higher doses for symptomatic control. Patients responding to these initial doses may be switched to Sandostatin LAR Depot, a long-acting octreotide formulation. This product consists of microspheres containing the drug. Initial doses consist of 20 mg given intramuscularly intragluteally at 4-week intervals for 2 months. It is recommended that during the first 2 weeks of therapy the short-acting formulation also be administered subcutaneously. At the end of 2 months, patients with good symptom control may have the dose reduced to 10 mg every 4 weeks, while those without sufficient symptom control may have the dose increased to 30 mg every 4 weeks. For patients experiencing recurrence of symptoms on the 10-mg dose, dosage adjustment to 20 mg should be made. It is not uncommon for patients with carcinoid tumors or VIPomas to experience periodic exacerbation of symptoms. Subcutaneous octreotide for several days should be reinstituted in these individuals. In socalled carcinoid crisis, octreotide is given as an intravenous infusion at 50 mcg/h for 8 to 24 hours. Because octreotide inhibits many other gastrointestinal hormones, it has a variety of intestinal side effects. With prolonged use, gallbladder and biliary tract complications such as cholelithiasis have been reported. About 5% to 10% of patients complain of nausea, diarrhea, and abdominal pain. Local injection pain occurs with about an 8% incidence. With high doses, octreotide may reduce dietary fat absorption, leading to steatorrhea. Two other somatostatin analogs, lanreotide and vapreotide, have been studied.10 Lanreotide is indicated for patients with carcinoid tumors in a dose of 30 mg intramuscularly (as a depot) every 14 days. If necessary the dose can be increased to 30 mg intramuscular every 7 to 10 days. Vapreotide is an orphan drug that is indicated for pancreatic and gastrointestinal fistulas.


MISCELLANEOUS PRODUCTS Lactobacillus preparations replace colonic microflora. This supposedly restores normal intestinal function and suppresses the growth of pathogenic microorganisms. However, a dairy product diet containing 200 to 400 g of lactose or dextrin is equally effective in producing recolonization of normal flora. The dosage varies depending on the brand used and lactobacillus preparations should be administered with milk, juice, water, or cereal. Intestinal flatus is the primary patient complaint experienced with this modality. Anticholinergic drugs such as atropine block vagal tone and prolong gut transit time. Drugs with anticholinergic properties are present in many nonprescription products. Their value in controlling diarrhea is questionable and limited due to side effects. To stop diarrhea, clinicians have been falsely taught to dose anticholinergics until they decrease salivary and sweat secretion. Angle-closure glaucoma, selected heart diseases, and obstructive uropathies are relative contraindications to the use of anticholinergic agents. Lactase enzyme products are helpful for patients experiencing diarrhea secondary to lactose intolerance. Lactase is required for

carbohydrate digestion. When a patient lacks this enzyme, eating dairy products causes an osmotic diarrhea. Several products are available for use each time a dairy product, especially milk or ice cream, is consumed. CLINICAL CONTROVERSY Long-term use of oral opiates is not routinely recommended for several pharmacologic reasons. Some opioids such as morphine and codeine have the tendency to cause constipation by slowing down the peristaltic action of the bowels, which can also result in a functional ileus. This effect can be minimized by administering laxatives and/or stool softeners in patients who require longer-term opiate therapy. Prokinetic agents may also be helpful in treating opiate-related constipation.


INVESTIGATIONAL DRUGS Many experimental drugs have been used to control diarrhea. Phenothiazines, β-blockers, nonsteroidal anti-inflammatory drugs, calcium channel blockers, and α-adrenergic agonists are only a few agents under investigation in either animals or humans. Nifalatide is an enkephalin analog that delays the onset of castor oil–induced diarrhea and decreases stool frequency. Dizziness and dry mouth are frequent side effects. Enkephalinase inhibitors (e.g., acetorphan or racecadotril) are other therapeutic options that reduce hypersecretion of water and electrolytes into the intestinal lumen. Prostaglandin inhibitors, aspirin and its analogs, and indomethacin are safe and effective in childhood gastroenteritis; studies in animals support indomethacin use in enteropathogen secretory states such as Vibrio cholerae infection. Vaccines are a new therapeutic frontier in controlling infectious diarrheas, especially in developing countries.11,12 Cholera vaccine, which is available in the United States in the parenteral form of wholecell inactivated bacteria, yields some protection but is not totally effective and does not prevent transmission. However, live oral vaccine is thought to be protective against V. cholerae. Oral Shigella vaccine, although effective under field conditions, requires five doses and repeat booster doses, thereby limiting its practicality for use in developing nations. With about 1,500 serotypes for Salmonella, a vaccine is not currently available. There are three parenteral typhoid vaccine formulations available in the United States. In addition, an oral vaccine of S. typhi (Tyza) is now available and is administered in 4 doses on days 1, 3, 5, and 7, to be completed at least 1 week before exposure. Rotavirus vaccine is effective in infants and children, and is administered as a three–oral dose sequence.


EVALUATION OF THERAPEUTIC OUTCOMES
GENERAL OUTCOMES MEASURES Therapeutic outcomes are directed toward key symptoms, signs, and laboratory studies. Constitutional symptoms usually improve within 24 to 72 hours. Monitoring for changes in the frequency and character of bowel movements on a daily basis in conjunction with vital signs and improvement in appetite are of utmost importance. Also, the clinician needs to monitor body weight, serum osmolality, serum electrolytes, complete blood cell counts, urinalysis, and culture results (if appropriate).

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ACUTE DIARRHEA


SEVERE DIARRHEA

Most patients with acute diarrhea experience mild to moderate distress. In the absence of moderate to severe dehydration, high fever, and blood or mucus in the stool, this illness is usually self-limiting within 3 to 7 days. Mild to moderate acute diarrhea is usually managed on an outpatient basis with oral rehydration, symptomatic treatment, and diet. Elderly persons with chronic illness and infants may require hospitalization for parenteral rehydration and close monitoring.

In the urgent/emergent situation, restoration of the patient’s volume status is the most important outcome. Toxic patients (fever, dehydration, hematochezia, or hypotension) require hospitalization, intravenous fluids and electrolyte administration, and empiric antibiotic therapy while awaiting culture and sensitivity results. With timely management, these patients usually recover within a few days.

CONSTIPATION

older than 65 years of age in a Florida community,17 26% of women and 15.8% of men reported recurrent constipation. Factors found to correlate with self-reported constipation were age, sex (higher frequency in females), total number of drugs taken, abdominal pain, and hemorrhoids.

Constipation is a commonly encountered medical condition in the United States for which many patients initiate self-treatment. One reason constipation continues to be a frequent problem in this country is lack of adequate dietary fiber. Another unfortunate problem is that many people have misconceptions about normal bowel function, and think that daily bowel movements are required for health and well being. Others believe that the lack of a daily bowel movement contributes to the accumulation of toxic substances or is associated with various somatic complaints. These misconceptions often lead to the inappropriate use of laxatives by the general public. Constipation does not have a single, generally agreed upon definition. When using the term, the lay public or health care professional may be referring to several difficult-to-quantify variables: bowel movement frequency, stool size or consistency, and such symptoms as the sensation of incomplete defecation. Stool frequency is most often used to describe constipation; however, the frequency of bowel movements used to define constipation is not well established. Normal people pass at least three stools per week. Some of the definitions of constipation used in clinical studies include (a) less than three stools per week for women and five stools per week for men despite a high-residue diet, or a period of more than 3 days without a bowel movement; (b) straining at stool greater than 25% of the time and/or two or fewer stools per week; or (c) straining at defecation and less than one stool daily with minimal effort. These varying definitions demonstrate the difficulty in characterizing this problem. An international committee defined and classified constipation on the basis of stool frequency, consistency, and difficulty of defecation.13,14 Functional constipation is defined as two or more of the following complaints present for at least 12 months in the absence of laxative use: (a) straining at least 25% of the time; (b) lumpy or hard stools at least 25% of the time; (c) a feeling of incomplete evacuation at least 25% of the time; or (d) two or fewer bowel movements in a week. Rectal outlet delay is defined as anal blockage more than 25% of the time and prolonged defecation or manual disimpaction when necessary.

EPIDEMIOLOGY As many as 40% of patients older than 65 years of age report experiencing constipation.15 The results from 42,375 participants of the National Health Interview Survey on Digestive Disorders demonstrated that there is not an age-related increased incidence of infrequent bowel movements; however, there is an age-related increased incidence of laxative use.16 The frequency of subjects reporting two or fewer bowel movements per week was 5.9% for those younger than 40 years of age; 3.8% for subjects 60 to 69 years of age; and 6.3% for subjects older than 80 years of age. In a prospective study of 3166 people

PATHOPHYSIOLOGY 5 Constipation is not a disease, but a symptom of an underlying

disease or problem. Approaches to the treatment of constipation should begin with attempts to determine its cause. Disorders of the GI tract (irritable bowel syndrome or diverticulitis), metabolic disorders (diabetes), or endocrine disorders (hypothyroidism) may be involved. Constipation commonly results from a diet low in fiber or from use of constipating drugs such as opiates. Finally, it is believed that constipation may sometimes be psychogenic in origin.18 Each of these causes is discussed in the following sections. Constipation is a frequently reported problem in the elderly, probably the result of improper diets (low in fiber and liquids), diminished abdominal wall muscular strength, and possibly diminished physical activity. However, as previously stated, the frequency of bowel movements is not decreased with normal aging. In addition, diseases that may cause constipation, such as colon cancer and diverticulitis, are more common with increasing age. Table 36–5 lists common causes of constipation in specific disease states.

DRUG-INDUCED CONSTIPATION Use of drugs that inhibit the neurologic or muscular function of the GI tract, particularly the colon, may result in constipation (Table 36–6). The majority of cases of drug-induced constipation are caused by opiates, various agents with anticholinergic properties, and antacids containing aluminum or calcium. With most of the agents listed in Table 36–6, the inhibitory effects on bowel function are dose dependent, with larger doses clearly causing constipation more frequently. Opiates have effects on all segments of the bowel, but effects are most pronounced on the colon. The major mechanism by which opiates produce constipation has been proposed to be prolongation of intestinal transit time by causing spastic, nonpropulsive contractions. An additional contributory mechanism may be an increase in electrolyte absorption. All opiate derivatives are associated with constipation, but the degree of intestinal inhibitory effects seems to differ between agents. Orally administered opiates appear to have greater inhibitory effects than parenterally administered products. Orally administered enkephalins (endogenous opiate-like polypeptides) are recognized to have antimotility properties.

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TABLE 36–5. Possible Causes of Constipation Conditions GI disorders

Metabolic and endocrine disorders

Pregnancy

Neurogenic causes

Psychogenic causes Drug-induced

Possible Causes Irritable bowel syndrome Diverticulitis Upper GI tract diseases Anal and rectal diseases Hemorrhoids Anal fissures Ulcerative proctitis Tumors Hernia Volvulus of the bowel Syphilis Tuberculosis Helminthic infections Lymphogranuloma venereum Hirschsprung’s disease Diabetes mellitus with neuropathy Hypothyroidism Panhypopituitarism Pheochromocytoma Hypercalcemia Enteric glucagon excess Depressed gut motility Increased fluid absorption from colon Decreased physical activity Dietary changes Inadequate fluid intake Low dietary fiber Use of iron salts CNS diseases Trauma to the brain (particularly the medulla) Spinal cord injury CNS tumors Cerebrovascular accidents Parkinson’s disease Ignoring or postponing urge to defecate Psychiatric diseases See Table 36–6

Agents with anticholinergic properties inhibit bowel function by parasympatholytic actions on innervation to many regions of the GI tract, particularly the colon and rectum. Many types of drugs possess anticholinergic action, and these agents are used commonly in both hospitalized and nonhospitalized patients. One study demonstrated that amitriptyline, diphenhydramine, and thioridazine use were associated with laxative needs in 800 nursing home patients.15 In patients older than 65 years of age, drugs that correlate most often with constipation are anticholinergics, aspirin, furosemide, ni-

TABLE 36–6. Drugs Causing Constipation Analgesics Inhibitors of prostaglandin synthesis Opiates Anticholinergics Antihistamines Antiparkinsonian agents (e.g., benztropine or trihexaphenidyl) Phenothiazines Tricyclic antidepressants Antacids containing calcium carbonate or aluminum hydroxide Barium sulfate Calcium channel blockers Clonidine Diuretics (non–potassium-sparing) Ganglionic blockers Iron preparations Muscle blockers (D-tubocurarine, succinylcholine) Nonsteroidal anti-inflammatory agents Polystyrene sodium sulfonate

TABLE 36–7. Clinical Presentation of Constipation Signs and symptoms r It is important to ascertain whether the patient perceives the problem as infrequent bowel movements, stools of insufficient size, a feeling of fullness, or difficulty and pain on passing stool. r Signs and symptoms include hard, small or dry stools, bloated stomach, cramping abdominal pain and discomfort, straining or grunting, sensation of blockade, fatigue, headache, and nausea and vomiting. Laboratory tests r A series of examinations, including proctoscopy, sigmoidoscopy, colonoscopy, or barium enema, may be necessary to determine the presence of colorectal pathology. r Thyroid function studies may be performed to determine the presence of metabolic or endocrine disorders. r With laxative abuse, fluid and electrolyte imbalances (most commonly hypokalemia), protein-losing gastroenteropathy with hypoalbuminemia may be present.

troglycerin, and amitriptyline.22 Serum chloride and aspartate aminotransferase, as well as alcohol consumption, are negatively related to constipation.

CLINICAL PRESENTATION Table 36–7 shows the general clinical presentation of constipation.


TREATMENT: Constipation
GENERAL APPROACH TO TREATMENT The patient should be asked about the frequency of bowel movements and the chronicity of constipation. Constipation occurring recently in an adult may indicate significant colon pathology such as malignancy; constipation present since early infancy may be indicative of neurologic disorders. The patient also should be carefully questioned about

usual diet and laxative regimens. Does the patient have a diet consistently deficient in high-fiber items and containing mainly highly refined foods? What laxatives or cathartics has the patient used to attempt relief of constipation? The patient should be questioned about other concurrent medications, with interest focused on agents that might cause constipation. For most patients complaining of constipation, a thorough physical examination is not required after it is established that constipation

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TABLE 36–8. Constipation Treatment Algorithm History r Stool frequency r Stool consistency r Difficulty of defecation Possible causes r Diet deficient in high-fiber items and consisting mainly of highly refined foods r GI disorders r Metabolic and endocrine disorders r Pregnancy r Neurogenic r Psychogenic r Drug-Induced r Laxative abusers Symptoms seen with chronic constipation r Fluid and electrolyte imbalances (hypokalemia) r Protein-losing gastroenteropathy with hypoalbuminemia r Syndromes resembling colitis Select appropriate diagnostic studies r Protoscopy r Sigmoidoscopy r Colonoscopy r Barium enema Diagnosis 1. Treat specific cause 2. No diagnosis, symptomatic therapy A. Bulk-forming agents B. Dietary modification C. Alter lifestyle (exercise) D. Increase fluid intake E. Discontinue potential drug inducer

(a) is not a chronic problem, (b) is not accompanied by signs of significant GI disease (e.g., rectal bleeding or anemia), and (c) does not cause severe discomfort. In these circumstances, the patient may be referred directly to the first-line therapies for constipation described in the next section (mainly bulk-forming laxatives and dietary fiber with occasional use of saline or stimulant laxatives). Table 36–8 presents a general treatment algorithm for the management of constipation. 6 The proper management of constipation requires a number of different modalities; however, the basis for therapy should be dietary modification. The major dietary change should be an increase in the amount of fiber consumed daily. In addition to dietary management, patients should be encouraged to alter other aspects of their lifestyles if necessary. Important considerations are to encourage patients to exercise (achieved even by brisk walking after dinner) and to adjust bowel habits so that a regular and adequate time is made to respond to the urge to defecate. Another general measure is to increase fluid intake. This is generally recommended and believed beneficial, although there is little objective evidence to support this measure. If an underlying disease is recognized as the cause of constipation, attempts should be made to correct it. GI malignancies may be removed via surgical resection. Endocrine and metabolic derangements should be corrected by the appropriate methods. For example, when hypothyroidism is the cause of constipation, cautious institution of thyroid-replacement therapy is the most important treatment measure. As discussed earlier, many drug substances may cause constipation. If a patient is consuming medications well known to cause constipation, consideration should be given to alternative agents. For

some medications (e.g., antacids), nonconstipating alternatives exist. If no reasonable alternatives exist to the medication thought to be responsible for constipation, consideration should be given to lowering the dose. If a patient must remain on constipating medications, then more attention must be given to general measures for prevention of constipation, as discussed in the next section.


NONPHARMACOLOGIC THERAPY
DIETARY MODIFICATION AND BULK-FORMING AGENTS The most important aspect of therapy for constipation for the majority of patients is dietary modification to increase the amount of fiber consumed. Fiber, the portion of vegetable matter not digested in the human GI tract, increases stool bulk, retention of stool water, and rate of transit of stool through the intestine. The result of fiber therapy is an increased frequency of defecation. Also, fiber decreases intraluminal pressures in the colon and rectum, which is thought to be beneficial for diverticular disease and for irritable bowel syndrome. The specific physiologic effects of fiber are not well understood. Patients should be advised to include at least 10 g of crude fiber in their daily diets.19 Fruits, vegetables, and cereals have the highest fiber content. Bran, a by-product of milling of wheat, is often added to foods to increase fiber content. Raw bran is generally 40% fiber. Medicinal products, often called “bulk-forming agents,” such as psyllium hydrophilic colloids, methylcellulose, or polycarbophil, have properties similar to those of dietary fiber and may be taken as tablets, powders, or granules (Table 36–9). A trial of dietary modification with high-fiber content should be continued for at least 1 month before effects on bowel function are determined. Most patients begin to notice effects on bowel

TABLE 36–9. Dosage Recommendations for Laxatives and Cathartics Agent

Recommended Dose

Agents that cause softening of feces in 1–3 days Bulk-forming agents Methylcellulose 4–6 g/day Polycarbophil 4–6 g/day Psyllium Varies with product Emollients Docusate sodium 50–360 mg/day Docusate calcium 50–360 mg/day Docusate potassium 100–300 mg/day Lactulose 15–30 mL orally Sorbitol 30–50 g/day orally Mineral oil 15–30 mL orally Agents that result in soft or semifluid stool in 6–12 h Bisacodyl (oral) 5–15 mg orally Phenolphthalein 30–270 mg orally Cascara sagrada Dose varies with formulation Senna Dose varies with formulation Magnesium sulfate (low dose) 3 stools/day r Extreme urgency r Mucus passage r Constipation symptoms, 500 units/L, and higher values should alert the clinician to complicating problems.20 The ratio of AST to ALT also provides information in patients with suspected alcoholic liver disease. Seventy percent of patients with alcoholic liver disease had ratios greater than 2, compared to 4% of patients with viral hepatitis.24

ALKALINE PHOSPHATASE AND GAMMA-GLUTAMYL TRANSPEPTIDASE Elevated levels of alkaline phosphatase and GGT occur with obstructive disorders that disrupt the flow of bile from the hepatocytes to the bile ductules, or from the biliary tree to the intestines. Examples of the former include primary biliary cirrhosis and drug-induced cholestasis; examples of the latter include gallstone disease and malignancies of the pancreas and bile ducts. In liver disease, the levels of GGT correlate well with elevations of the alkaline phosphatase, and their combination is a sensitive and specific marker for biliary tract disease.22

PORTAL HYPERTENSION AND CIRRHOSIS

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TABLE 37–5. Etiology of Hyperbilirubinemia Etiology

Diagnosis

Unconjugated bilirubin Excessive production Immature enzyme systems

Hemolysis Jaundice of newborn Jaundice of prematurity Gilbert syndrome Crigler-Najjar syndrome

Inherited defects Drug effects Conjugated bilirubin Impaired intrahepatic excretion Hepatocellular disease Intrahepatic cholestasis Congenital Obstruction Extrahepatic Intrahepatic

Hepatitis, cirrhosis, drugs Drugs, pregnancy Dubin-Johnson syndrome Rotor’s syndrome Calculus, stricture, neoplasm Sclerosing cholangitis, cirrhosis, neoplasm

BILIRUBIN Bilirubin is a breakdown product of hemoglobin derived from senescent red blood cells. Elevations of the serum bilirubin are common in end-stage liver disease and obstruction of the common bile duct due to gallstones or malignancy; however, there are other causes of an elevated bilirubin (Table 37–5). When cirrhosis has been established, the degree of bilirubin elevation has prognostic significance and is used as a component of the Child-Pugh scoring system for quantifying the degree of cirrhosis. Figure 37–4 describes a general algorithm for the interpretation of liver function tests. The algorithm first separates the tests into two categories based on the underlying pathology (pattern of elevations): obstructive (alkaline phosphatase, GGT, and bilirubin) versus hepatocellular (AST and ALT). If a hepatocellular pattern predominates, the magnitude of elevation provides diagnostic assistance. If the degree of elevation is >20 times normal, the etiology is likely a result of drugs or other toxins, ischemia, or acute viral hepatitis. Elevations 3.5 None None 1–4

2–3 2.8–3.5 Mild 1 and 2 4–6

>3 6

Grade A, 12 mm Hg, are the best candidates for prophylactic β-adrenergic blocker therapy.34 β-Adrenergic blocker therapy should be lifelong unless it is not tolerated, because bleeding can occur when β-blocker therapy is abruptly discontinued.35 C L I N I C A L C O N T R O V E R S Y: T H E U S E O F N I T R AT E S Nitrates are known to cause smooth muscle vasodilation and to reduce portal pressures; however, the role of nitrates in primary prophylaxis is controversial. Isosorbide-5-mononitrate was compared with propranolol for primary prophylaxis in cirrhosis.36 Equivalent reductions in bleeding were reported, but short-term survival was improved with isosorbide therapy. This report was met with great enthusiasm because it offered an effective alternative for patients who did not tolerate β-adrenergic blockers. Follow-up on the patients in the study was continued for up to 7 years with the finding that the early mortality benefit was lost. In fact, the use of isosorbide5-mononitrate resulted in higher long-term mortality than propranolol in patients >50 years of age.37 These findings are not entirely surprising because it was appreciated that a potential existed for nitrates to increase portal blood flow and consequently portal pressure by enhancing nitric oxide–mediated vasodilation of the mesenteric vasculature. Considering that vasodilation in liver disease is the hemodynamic expression of liver failure and is a prognostic indicator of morbidity and mortality, this may explain, at least in part, the negative effects on long-term survival.38

PORTAL HYPERTENSION AND CIRRHOSIS

699

Another therapeutic issue arises because β-adrenergic blockers alone do not adequately lower portal pressure in all patients. A number of trials have shown that the combination of nitrates and β-adrenergic blockers is superior to β-adrenergic blockers alone in lowering portal pressures.38 β-Adrenergic blocker therapy may suppress the neurohormonal activation associated with the relative hypovolemia induced by the vasodilation from the nitrate therapy and thereby minimize its detrimental effects.32 With such disparate study findings the role of nitrates in primary prophylaxis is controversial and firm recommendations are difficult. Nevertheless, for patients with an inadequate response to β-adrenergic blockers alone, a long-acting nitrovasodilator should be added to try to achieve adequate lowering of portal pressure. For patients with contraindications or intolerance to β-adrenergic blockers, treatment decisions are uncertain. Groszmann suggests that nitrates can probably be used safely in this situation in younger patients who have wellcompensated cirrhosis.38


Treatment Recommendations: Variceal Bleeding-Primary Prophylaxis 2 All patients with cirrhosis and portal hypertension should

be considered for endoscopic screening, and patients with large varices should receive primary prophylaxis with β-adrenergic 3 blockers. Initiate therapy with oral propranolol 10 mg three times daily or nadolol 20 mg once daily and titrate to a reduction in the resting heart rate of 20% to 25%, an absolute heart rate of 55 to 60 beats per minute (bpm), or the development of adverse effects. Patients with contraindications or intolerance to β-adrenergic blockers should be considered for trials of alternative prophylactic therapy.39 Nitrates may be considered for these patients provided they are younger than 50 years of age and have well-compensated cirrhosis. Initiate therapy with isosorbide-5-mononitrate 20 mg orally twice daily and increase to 20 mg three times a day after 1 week if tolerated. Combination therapy with β-blockers and nitrates is recommended for patients with an inadequate lowering of portal pressure in response to β-adrenergic blockers alone. Currently, no evidence supports the use of sclerotherapy, band ligation, surgical shunting, or transjugular intrahepatic portosystemic shunt (TIPS) as primary prophylaxis.31,39 However, one recent study comparing variceal band ligation versus β-blockers as a primary prophylaxis did show a decreased rate of bleeding at 1 year in the banding group.40


ACUTE VARICEAL HEMORRHAGE Variceal hemorrhage typically presents with hematemesis or melena. Important risk factors include active alcohol abuse, use of nonsteroidal anti-inflammatory agents or aspirin, or previous variceal hemorrhage.39 It is important to note, however, that variceal bleeding secondary to portal hypertension can occur in patients without signs of liver disease; for example, in patients with portal vein thrombosis. The initial assessment should determine the severity of the bleeding, severity of other organ dysfunction, and the severity of the liver disease. The Child-Pugh scoring system (see Table 37–4) is the most reliable means of assessing the severity of chronic liver disease.39

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MANAGEMENT OF ACUTE VARICEAL HEMORRHAGE Initial treatment goals include: (a) adequate fluid resuscitation; (b) correction of coagulopathy and thrombocytopenia; (c) control of bleeding; (d) prevention of rebleeding; and (e) preservation of liver function. Prompt stabilization and aggressive fluid resuscitation of patients with active bleeding is followed by endoscopic examination. General resuscitation measures should be applied in the initial management of variceal hemorrhage. Airway management is critical in patients with variceal hemorrhage because of depressed reflexes and/or combative behavior associated with drug and alcohol use. The endoscopic approach to bleeding also requires a quiet and cooperative patient, and elective intubation for airway control and adequate sedation is often necessary. Clinical practice guidelines approved by the American College of Gastroenterology recommend esophagogastroduodenoscopy (EGD) employing endoscopic injection sclerotherapy (EIS) or endoscopic band ligation (EBL) of varices as the primary diagnostic and treatment strategy for upper GI tract hemorrhage secondary to portal hypertension and varices.41 Fluid resuscitation involves colloids initially and subsequent blood products after blood bank matching procedures are completed. Packed red blood cells, fresh frozen plasma, and platelets may be employed both as volume expanders and corrective therapy for underlying clotting abnormalities. Vasoactive drug therapy (somatostatin, octreotide, or terlipressin) to stop or slow bleeding is routinely employed early in patient management to allow stabilization of the patient and to permit endoscopy to proceed under more favorable conditions. Antibiotic therapy to prevent sepsis should also be implemented early, especially for patients with signs of infection or ascites. Figure 37–5 presents an algorithm for the management of variceal hemorrhage.


DRUG THERAPY Drug therapy for acute variceal bleeding is based on the principle that it is possible to reduce portal, and consequently variceal, pressure by

reducing portal vein blood flow via splanchnic vasoconstriction.42 Drugs employed to manage acute variceal bleeding include octreotide or somatostatin, vasopressin, and terlipressin (triglycyl-lysine vasopressin).


Somatostatin and Octreotide Somatostatin is a naturally occurring 14-amino acid peptide and octreotide is a synthetic octapeptide analog that is significantly more potent than native somatostatin. Octreotide shares four amino acids with somatostatin and these moieties are responsible for its pharmacologic activity. Somatostatin increases vascular tone in the gastrointestinal tract by inhibiting vasodilatory peptides such as vasoactive intestinal peptide, producing mesenteric vasoconstriction.43 Both somatostatin and octreotide are widely used in the treatment of variceal hemorrhage because of their reported ability to decrease splanchnic blood flow, and thereby reduce portal and variceal pressures, without significant adverse effects.30,39 Unlike vasopressin, systemic vasoconstriction and elevations in blood pressure are not seen because the vasoconstriction that occurs with somatostatin and octreotide is selective for the mesenteric circulation. Other reports, however, have failed to demonstrate reductions in gastric mucosal blood flow or intravariceal pressure.39 Consequently, the precise mechanism of action by which these agents may beneficially impact variceal bleeding still remains unclear.44 Placebo-controlled clinical trials found somatostatin to be no more effective than placebo, whereas other studies show a clear benefit with somatostatin.45−47 A meta-analysis of clinical trials comparing somatostatin and octreotide with vasopressin or terlipressin has demonstrated equivalent efficacy, but the side effect profile of somatostatin and octreotide was superior to vasopressin.48 This analysis also reported that somatostatin was more effective in achieving initial and sustained control of bleeding. Vasopressin (also known as antidiuretic hormone) is a potent, nonselective vasoconstrictor that has been recommended for many

Acute bleed Resuscitation ABC's Sedation Somatostatin Octreotide Prophylactic antibiotic therapy Endoscopy: Diagnostic and therapeutic

Non-portal hypertension source

Portal hypertension gastropathy

Isolated gastric varices

Esophageal varices

Treat

Somatostatin Octreotide

Tamponade Octreotide TIPS

Octreotide for 5 days and endoscopy banding or sclerotherapy

If unresolved—TIPS Rebleeding

No rebleeding

Child’s A or early B

Child’s

Surgical shunt/TIPS

TIPS

FIGURE 37–5. Management of acute variceal hemorrhage.

Continue endoscopy -blockers

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years for the management of acute variceal bleeding. Vasopressin reduces portal pressure by causing splanchnic vasoconstriction, which reduces splanchnic blood flow. Unfortunately, the vasoconstrictive effects of vasopressin are nonselective—the vasoconstriction produced is not restricted to the splanchnic vascular bed. Potent systemic vasoconstriction occurs in the coronary and mesenteric circulation as well, resulting in hypertension, severe headaches, coronary ischemia, myocardial infarction, and arrhythmias. A meta-analysis of 15 randomized controlled clinical trials of vasopressin for variceal hemorrhage demonstrated that vasopressin was significantly more effective than no treatment; however, control of hemorrhage was achieved in only 50% of the bleeding episodes.48 Adverse effects were reported in 45% of patients, and vasopressin was discontinued in 25% of patients secondary to adverse effects. To minimize adverse effects associated with the peripheral vasoconstriction secondary to vasopressin, and to further lower portal pressure, the combination of vasopressin and intravenous nitroglycerin has been evaluated.13 The combination trended toward improved control of hemorrhage with reduced side 4 effects when compared to vasopressin alone. However, with the recent addition of safer and equally effective treatment alternatives, vasopressin, alone or combined with nitroglycerin, can no longer be recommended as first-line therapy for the management of variceal hemorrhage.39 Terlipressin (Glypressin), triglycyl-lysine vasopressin, is a synthetic prodrug of vasopressin with intrinsic vasoconstrictor activity that was developed in an attempt to provide an analogue of vasopressin with lower toxicity. The glycl residues are enzymatically cleaved in vivo, resulting in the slow conversion into lysine vasopressin. This process results in the availability of lysine vasopressin with a longer half-life, permitting bolus dosing every 4 hours.39 In a number of unblinded clinical trials, terlipressin was associated with a significantly lower rate of adverse effects as compared to vasopressin alone, or as compared to vasopressin combined with nitroglycerin.45 Terlipressin produces a marked and sustained reduction in portal pressures. This prolonged biologic effect allows intravenous administration as an intermittent infusion every 4 hours, whereas somatostatin requires administration as a continuous intravenous infusion.49 In clinical trials that have been criticized for small sample size and unclear timing of treatments, terlipressin has demonstrated a beneficial effect on the control of bleeding compared with placebo, and is the only drug that has been shown to reduce mortality.39 Terlipressin, the preferred drug in Europe for acute variceal bleeding, is not currently available in the United States. Cirrhotic patients with active bleeding are at high risk of infection and sepsis secondary to aspiration, the placement of multiple intravascular access devices, sclerotherapy, translocation, and defects in humoral and cellular immunity.39 Prophylactic antibiotic therapy to reduce the risk of sepsis during episodes of bleeding is reported to decrease the incidence of rebleeding and to increase short-term survival.50 All patients with variceal hemorrhage should be screened for infection and pan-cultured. Patients should be evaluated at admission and observed throughout therapy for signs and symptoms of spontaneous bacterial peritonitis.31

PORTAL HYPERTENSION AND CIRRHOSIS

of the varices to tamponade blood flow. EBL consists of placement of rubber bands around the varix through a clear plastic channel attached to the end of the endoscope. After the rubber bands are in place, the varix will slough off after 48 to 72 hours. Endoscopic approaches can successfully stop bleeding in up to 95% of cases, but rebleeding may occur in 50% of cases. A recent meta-analysis of comparative clinical trials found both techniques equally effective in controlling acute variceal bleeding, but indicated that EBL was superior to EIS in reducing the rebleeding rate, and that EBL was associated with fewer posttreatment complications.39 Sclerosing agents employed in EIS include ethanolamine, sodium tetradecyl sulfate, polidocanol, and sodium morrhuate. There are no data establishing clinical superiority of any of the sclerosants.51 Eight published clinical trials have compared endoscopic sclerotherapy with vasoactive drug therapy for active variceal bleeding. Drug treatment controlled bleeding in 58% to 95% of cases, and sclerotherapy controlled bleeding in 68% to 94% of cases. Rebleeding was slightly less common in patients receiving sclerotherapy, and sclerotherapy was associated with a lower mortality rate. Clinical trials of sclerotherapy plus vasoactive drugs versus sclerotherapy alone show a significant advantage for combination therapy; however, there was no beneficial effect on mortality.39


INTERVENTIONAL AND SURGICAL TREATMENT APPROACHES If standard therapy fails to control bleeding (after two failed endoscopic procedures, further attempts are unlikely to be of benefit) a salvage procedure, such as balloon tamponade, TIPS, or surgical shunting is necessary. Sengstaken-Blakemore tubes are balloon devices designed to tamponade gastric and esophageal varices that can be effective in 70% to 90% of cases of variceal bleeding.39 However, these devices have a 10% to 30% complication rate and will be ineffective if the bleeding source is nonvariceal, a situation which occurs in 10% to 50% of patients with portal hypertension.39 Balloon tamponade should be reserved as a temporizing measure until a TIPS procedure or surgical shunt can be performed.31 The development of the TIPS provided a major improvement in the management of refractory or severe cases of esophagogastric variceal bleeding and other complications of portal hypertension.52 The TIPS procedure involves the placement of one or more stents between the hepatic vein and the portal vein (Fig. 37–6). This procedure is widely used because it provides an effective decompressive shunt without laparotomy, and can be employed regardless of ChildPugh score. Survival rates with TIPS in patients refractory to endoscopic treatment are comparable to rates achieved with portacaval

Hepatic vein

Inferior vena cava

Stent


ENDOSCOPIC INTERVENTIONS: SCLEROTHERAPY AND BAND LIGATION The American College of Gastroenterology published clinical practice guidelines in 1997 recommending EGD employing EIS or EBL of varices as the primary diagnostic and treatment strategy for upper GI tract hemorrhage secondary to portal hypertension and varices.41 EIS involves injection of 1 to 4 mL of a sclerosing agent into the lumen

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Portal vein

FIGURE 37–6. Transjugular intrahepatic portosystemic shunt (TIPS).

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shunts.39 Patients undergoing TIPS experience a 30% incidence of encephalopathy, and approximately 50% of shunts malfunction.31 Various surgical shunts have been developed and are effective for the prevention of recurrent variceal hemorrhage in patients refractory to β-adrenergic blockade and endoscopy.31


TREATMENT RECOMMENDATIONS: VARICEAL HEMORRHAGE Patients require prompt resuscitation with colloids and blood products to correct intravascular losses and to reverse existing coagu4 lopathies. Drug therapy with octreotide or somatostatin should be initiated early to control bleeding and facilitate diagnostic and therapeutic endoscopy. Based on availability octreotide is preferred. Therapy is initiated with an IV bolus of 50 to 100 mcg and is followed by a continuous infusion of 25 mcg/h, up to a maximum rate of 50 mcg/h. Monitor patients for hypo- or hyperglycemia, especially patients with diabetes, and assess for cardiac conduction abnormalities. Vasopressin is no longer recommended for control of variceal bleeding. Endoscopy employing EBL or EIS is the primary therapeutic tool in the management of acute variceal bleeding.30,39,53 Antibiotic prophylaxis is recommended if ascites is present and EIS is planned. Appropriate choices include a third-generation cephalosporin (e.g., ceftazidime or ceftriaxone), a penicillin/ β-lactamase inhibitor combination (e.g., piperacillin-tazobactam), or a fluoroquinolone (e.g., ofloxacin). Surgical shunts and TIPS are employed as salvage therapy in patients who have failed repeated endoscopy and vasoactive drug therapy.


Secondary Prophylaxis: Prevention of Rebleeding Because the risk of rebleeding after initial control of variceal hemorrhage can approach 80%, and rebleeding significantly increases the risk of death, it is inappropriate to simply observe patients for evidence of further bleeding. Traditionally, pharmacologic therapy using β-adrenergic blockers was recommended as the initial approach for prevention of rebleeding. A major shift in therapy is underway; endoscopic therapy using EBL or EIS, repeated at regular intervals with the goal of obliteration of varices, is emerging as the preferred treatment option. Alternatives for the secondary prevention of rebleeding include surgical or interventional shunting. The objective of both EIS and EBL in prevention of rebleeding is the obliteration of esophageal varices. The majority of rebleeding occurs in the interval between the primary endoscopic session and the time to complete obliteration. Therefore the patient should have repeat endoscopy with either EIS or EBL every 2 weeks until no further varices are identified. After this is achieved, repeat exams at 3 and 6 months are appropriate. The rebleeding rate after EBL is less than EIS, 27% versus 45%.54


Drug Therapy. Drug therapy of variceal hemorrhage is less expensive, offers fewer serious complications, and is usually preferred by patients. In patients without contraindications, β-adrenergic blocking agents should be the initial step in secondary prophylaxis, along with endoscopy.39,54 A meta-analysis of 11 randomized controlled clinical trials demonstrated a significant 21% reduction in rebleeding with β-blockers as compared to untreated controls, and a 5.4% improvement in the 2-year overall survival rate.55 Secondary prophylaxis with β-adrenergic blockade therapy also resulted in a significant

7.4% reduction in death as a consequence of rebleeding. Propranolol was used in 10 trials; nadolol was used in one trial. Patients treated with β-adrenergic blocking agents experienced significantly more adverse events, 22% versus 9% compared to untreated controls,55 with 5.7% requiring discontinuation of β-adrenergic blockade therapy. When considering the benefits associated with β-adrenergic blockers, it is important to appreciate that approximately 25% of cirrhotic patients either have contraindications or exhibit intolerance to β-adrenergic blockers, and portal pressures are not adequately lowered in all patients treated with β-adrenergic blockade.56 Use of a long-acting β-blocker (such as nadolol) is usually recommended to improve compliance, and gradual, individualized dose escalation may help to minimize side effects. Ideally, portal pressure monitoring can help to assess the response to β-adrenergic blocker therapy and identify nonresponders earlier in the treatment course. This is important because patients with sinusoidal portal hypertension (the type encountered in cirrhosis) do not bleed when the hepatic venous pressure gradient is 250 >10 >5 6

2 >500

Compiled from Topazian and Gorelick,2 Grendell,4 Dervenis et al,5 and Banks.6

diagnosis depends on the recognition of an etiologic factor, the clinical signs and symptoms, abnormal laboratory tests, and imaging techniques that predict the severity of the disease. In most patients, the diagnosis of AP is based on the clinical presentation, an elevated serum amylase or lipase, and the results of either computed tomography (CT) or an ultrasound of the pancreas.1,2 Evaluation of the patient with recurrent AP requires systematic identification and elimination of correctable inciting factors.39

Prognostic Indicators of Disease Severity Patients should be categorized into either prognostically mild or severe disease using any one of a number of validated multiple-factor scoring systems (Table 39–4).2,4−6 Two widely used measures include Ranson’s criteria and the Acute Physiology and Chronic Health Evaluation (APACHE II). The APACHE II (≥8 points) system is more sensitive and specific than Ranson’s criteria (≥3 criteria), but it is also more complex.2,6 The APACHE II system uses 14 indicators of physiological and biochemical function that can be readily calculated upon admission to an intensive care unit. Ranson’s criteria includes 11 variables that must be monitored at the time of admission and during the initial 48 hours of hospitalization. Patients with fewer than three Ranson criteria have a mortality rate of less than 1%, while

PANCREATITIS 725

those with six or more have a 100% mortality rate.2,5 Some modifications of Ranson’s criteria have dropped the base deficit and fluid requirements, while others have added obesity as an independent risk factor.2 Additional criteria enhance the predictability of these scoring systems (see Table 39–4).

Laboratory Tests Laboratory test results vary depending on the severity of the inflammatory process, whether damage is confined to the pancreas or involves contiguous organs, and the time course from the onset of the acute attack (see Table 39–3). Serum concentrations of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6 are markers of disease severity, but elevations are not specific for pancreatitis and the tests are not widely available.37,38

Markers of Pancreatic Injury. Serum amylase and lipase are most widely used to detect elevations of pancreatic enzymes in AP, but elevations do not necessarily correlate with either the etiology or severity of the disease (see Table 39–3). In addition, many nonpancreatic diseases may be associated with hyperamylasemia, including salivary, renal, hepatobiliary, metabolic, female reproductive tract, and neoplastic diseases.2 Pancreatic isoamylase studies assist in determining the origin of elevated serum amylase concentrations, but are not useful for the diagnosis of AP because the diseases that simulate pancreatitis cause pancreatic rather than nonpancreatic amylase concentration to rise. Newer markers (e.g., urinary trypsinogen activation peptide) provide both diagnostic and prognostic information, but are not routinely used in practice. A number of other tests have been used to detect pancreatic enzymes in the serum (e.g., elastase) and urine (e.g., amylase), but most of these are not considered useful in the diagnosis of AP.1,2 Imaging A number of radiologic imaging techniques reveal pancreatic abnormalities during the disease course (see Table 39–3). Although no single imaging technique provides a positive diagnosis for AP, CT is considered the gold standard.

CLINICAL COURSE AND PROGNOSIS The majority of patients with mild AP recover uneventfully. Mortality increases with unfavorable early prognostic signs, organ failure, and local complications. The mortality of patients with infected pancreatic necrosis approximates 30% and is higher than in sterile necrotizing pancreatitis or interstitial pancreatitis.2,4−6 Mortality rates are also influenced by the etiology, as patients with idiopathic or postoperative AP have higher mortality rates than those with gallstone- or alcoholicinduced disease. Mortality is higher during the first or second attacks than during recurrent acute episodes. Death during the first few days often results from systemic complications. When death occurs after this period, it is usually associated with local complications.


TREATMENT: Acute Pancreatitis
DESIRED OUTCOME Treatment of AP is aimed at relieving abdominal pain, replacing fluids, minimizing systemic complications, and preventing pancreatic necrosis and infection. Management varies depending on the severity

of the attack (see Table 39–4; Fig. 39–3). In patients with mild AP, the disease is usually self-limiting and subsides spontaneously within 2 to 7 days of the initiation of supportive care and the reduction of pancreatic secretions. Patients with severe AP typically follow a more fulminant course and should be treated aggressively and monitored closely.

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Acute pancreatitis

Mild disease Favorable prognosis No systemic complications Supportive care Analgesics Nutrition

Severe disease Unfavorable prognosis Systemic complications

Interstitial Intensive care required Fluid resuscitation Treat systemic complication ERCP for gallstones? Parenteral/enteral nutrition? Consider octreotide

Necrotizing Intensive care required Fluid resuscitation Treat systemic complication ERCP for gallstones? Parenteral/enteral nutrition? Consider antibiotics Consider octreotide

Improvement

No improvement

Continue treatment

Rule out infected pancreatic necrosis

FIGURE 39–3. Algorithm of guidelines for evaluation and treatment of acute pancreatitis. ERCP, endoscopic retrograde cholangiopancreatography.


GENERAL APPROACH TO TREATMENT All patients with AP should receive supportive care, including effective pain control, fluid resuscitation, and nutritional support. However, initial treatment usually involves withholding foods or liquids in order to minimize exocrine stimulation of the pancreas. The use of nasogastric aspiration offers no clear advantage in patients with mild AP, but is beneficial in patients with profound pain, severe disease, paralytic ileus, and intractable vomiting.2,4 Patients predicted to follow a severe course will require treatment of any cardiovascular, respiratory, renal, and metabolic com1 plications. Aggressive fluid resuscitation is essential to correct intravascular volume. The prognosis of the patient often depends on the rapidity and adequacy of volume restoration, as large quantities of fluid are sequestered within the peritoneal and retroperitoneal spaces. Vasodilation from the anti-inflammatory response, vomiting, and nasogastric suction contribute to hypovolemia and fluid and electrolyte losses. Intravenous colloids may be required to maintain intravascular volume and blood pressure because fluid losses are rich in protein. Patients with pancreatitis and systemic inflammatory response syndrome may benefit from treatment with drotrecogin alfa. Intravenous potassium, calcium, and magnesium are used to correct deficiency states. Insulin is used to treat hyperglycemia. Local complications resolve as the inflammatory process subsides; however, patients with necrotizing pancreatitis may require antibiotics and surgical intervention.

If infected, surgical débridement If sterile, continue treatment

patients, it can cause serious problems such as catheter sepsis and hyperglycemia.40 In the past, there was concern that enteral feeding would stimulate pancreatic enzyme secretion and exacerbate the underlying disease. However, studies in patients with pancreatitis have demonstrated that the stimulatory effect of nutrients is minimized if administered distally into the jejunum.40 Results of clinical trials in patients with AP confirm that jejunal feedings are safer and less expensive than parenteral nutrition.40−42 Enteral feedings may also prevent infection by decreasing translocation of bacteria across the gut wall.43 Preliminary data suggest that probiotics such as lactobacillus (along with a fiber supplement) may reduce bacterial translocation and possibly decrease pancreatic necrosis and abscess.44 If enteral feeding is not possible, total parenteral nutrition (TPN) should be implemented before protein and calorie depletion becomes advanced. Intravenous lipids should not be withheld unless the serum triglyceride concentration is greater than 500 mg/dL.2,6 At present, there is no clear evidence that nutritional support alters outcome in most patients with AP unless malnutrition exists.42 Removal of an underlying biliary tract gallstone with ERCP or surgery usually resolves AP and reduces the risk of recurrence. Surgery may be indicated in AP to treat pseudocyst, pancreatic abscess, and to drain the pancreatic bed if hemorrhagic or necrotic material is present.


PHARMACOLOGIC THERAPY


NONPHARMACOLOGIC THERAPY


RECOMMENDATIONS

Patients with mild AP can begin oral feeding within several days of the onset of pain.1 In severe disease, nutritional deficits develop rapidly and are complicated by tissue necrosis, organ failure, and surgery. Enteral or parenteral nutrition should be initiated if it is anticipated that oral nutrition will be withheld for more than 1 week, as nutritional depletion can impair recovery and increase the risk of complications.6 Although total parenteral nutrition is very effective in critically ill

Patients with AP should receive aggressive supportive care, including effective pain control, fluid resuscitation, and nutritional support. 2 When possible, discontinue medications listed in Table 39–2. Antisecretory drugs may be used to prevent stress-related mucosal bleeding. Octreotide may be tried in severe AP, but its efficacy remains uncertain (see Fig. 39–3). Antibiotics should not be used in the absence of signs of infection except in patients with biliary tract gallstones, or in severe AP when pancreatic necrosis or abscess is

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likely. Patients with life-threatening complications require additional intensive medical therapy or surgery.


RELIEF OF ABDOMINAL PAIN Analgesics are administered to reduce the severity of abdominal pain. The most important factors to consider in selecting an analgesic are efficacy and safety. Although the administration of some narcotics is associated with mild and transient increases in serum amylase and lipase, these effects are not deleterious to the patient. In the past, treatment was usually initiated with parenteral meperidine (50 to 100 mg every 3 to 4 hours) because it does not cause pancreatitis or significantly alter the function of the sphincter of Oddi.4,45 Today 3 many hospitals have either restricted or eliminated the use of meperidine because it is not as effective as other narcotics and because it is contraindicated in patients with renal failure. Because meperidine is less effective than other narcotics in relieving pain, higher and more frequent daily dosages are generally required. Most importantly, active metabolites of meperidine accumulate in patients with renal impairment and may cause seizures or psychosis. The maximum recommended parenteral dose of meperidine is 600 mg/day in patients with normal renal function, but it should not be used in patients with renal failure. Parenteral morphine is often recommended for pain control, but its use in AP is sometimes avoided because it can cause spasm of the sphincter of Oddi, increases in serum amylase, and rarely pancreatitis.2 Although not as well-studied, hydromorphone is often preferred because it has a longer half-life than meperidine and can be given parenterally by a patient-controlled analgesia pump. Patientcontrolled analgesia should be considered in patients who require frequent narcotic dosing (e.g., every 2 to 3 hours) and usually achieves adequate pain control. Dosing should be monitored carefully and adjusted daily. There is no evidence that antisecretory drugs (such as H2 -receptor antagonists or proton pump inhibitors) prevent an exacerbation of abdominal pain.6


LIMITATION OF SYSTEMIC COMPLICATIONS AND PREVENTION OF PANCREATIC NECROSIS Vigorous fluid resuscitation and support of respiratory, renal, cardiovascular, and hepatobiliary function may limit systemic complications.2,46−48 However, there is no proven method to prevent these complications.6 While hemoconcentration (decreased intravascular volume) is strongly associated with pancreatic necrosis, it is not clear whether aggressive fluid resuscitation alone during the first 24 hours can prevent pancreatic necrosis.49 Procedures such as ERCP, hypothermia, nasogastric suction, pancreatic irradiation, peritoneal lavage, and thoracic duct drainage remain unproven.2,6 A number of drugs have been investigated to determine their efficacy in limiting the severity of AP by either directly or indirectly reducing pancreatic secretion, inhibiting the action of circulating inflammatory mediators, or increasing pancreatic microcirculation. The use of parenteral H2 -receptor antagonists or proton pump inhibitors is no more effective than nasogastric suction to diminish pancreatic exocrine secretion. Corticosteroids are not helpful in limiting systemic complications and altering the course of the disease.47 Clinical studies with protease inhibitors such as aprotinin and gabexate fail to reduce mortality in AP.46−48 However, the results of two metaanalyses and a multicenter comparative study with gabexate demonstrate a decrease in complications.2,50 Clinical trials fail to demonstrate a decrease in mortality with lexipafant, a platelet-activating

PANCREATITIS 727

factor antagonist.47 Low-molecular-weight dextran increases pancreatic microcirculation in experimental animal models, but its efficacy in preventing pancreatic necrosis in humans requires further study.51 Conflicting or inconclusive data exist regarding the efficacy of antioxidants, glucagon, calcitonin, atropine, α-aminocaproic acid, 5-fluorouracil, and indomethacin.48


Somatostatin and Octreotide The use of somatostatin and its synthetic analog octreotide in severe AP may reduce mortality, but does not appear to decrease complication rates.2,52 Although these agents are potent inhibitors of pancreatic enzyme secretion, they may have detrimental effects in patients with AP because they may increase sphincter of Oddi pressure and decrease splanchnic blood flow.47 Many of the studies that evaluated the efficacy of somatostatin and octreotide in AP have yielded conflicting results. Most of these studies had small numbers of patients, were not placebo-controlled, and included patients with mild disease. Preliminary results of a randomized, open-label trial in severe AP indicates that octreotide 0.1 mg subcutaneously every 8 hours decreased mortality, sepsis, and length of hospital stay.53 In a study using higher dosages (0.5 mcg/kg per hour given by continuous intravenous infusion), octreotide provided a more pronounced decrease in serum amylase, greater improvement in pancreatic edema, and earlier return to oral intake than controls.54 Until there is evidence to support its 4 efficacy in patients with mild disease, the use of octreotide should be limited to patients with severe AP, as it may decrease mortality and possibly the length of hospital stay. CLINICAL CONTROVERSY Some clinicians believe that octreotide should be used to decrease pancreatic secretions in patients with AP, while others believe that this is unnecessary. Octreotide should only be used in patients with severe AP.


PREVENTION OF INFECTION 5 Patients with severe AP complicated by necrosis should receive

prophylactic treatment with a broad-spectrum antibiotic (Fig. 39–4).1,2,55 Pancreatic infections occur in about 30% of patients who have greater than 30% necrosis and account for 80% of the deaths associated with AP.46 However, the use of antibiotics in patients without definite proof of an infection remains controversial. Prophylactic antibiotics do not offer any benefit in mild AP or those who do not have necrosis. Early clinical trials showed no benefit from antibiotic prophylaxis, but studies were flawed, as they included patients with all degrees of disease severity and did not have a sufficient number of patients with severe necrotizing AP.1,47 In addition, the studies utilized ampicillin, which does not penetrate well into pancreatic tissue.47 Imipenem-cilastatin, metronidazole, cefotaxime, piperacillin, mezlocillin, ofloxacin, and ciprofloxacin all achieve satisfactory bactericidal tissue concentrations, whereas aminoglycosides have poor penetration.46,47 However, the importance of antibiotic penetration into pancreatic tissue has been debated, as it is the peripancreatic retroperitoneal necrotic fat and debris, not the pancreas itself, that becomes infected. At present there is sufficient evidence to recommend that patients with severe acute necrotizing pancreatitis should receive antibiotic prophylaxis as soon as possible after diagnosis. Three

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Chronic abdominal pain Tests to exclude anatomic causes

Positive

Negative

Treat complications

Abstain from ethanol Low-fat diet (50–75 g/day) Non-narcotic analgesics

Pain

No pain

4-week trial of high-dose pancreatic enzymes (in tablet form) plus acid suppression

Continue treatment

No pain

Pain

Observe

Consider octreotide? Consider ERCP

Discuss with patient watchful waiting vs narcotic analgesics with risk of addiction vs benefits and risks of surgery

No

ERCP performed? Yes

Celiac nerve block?

FIGURE 39–4. Algorithm of guidelines for the treatment of chronic abdominal pain in chronic pancreatitis. ERCP, endoscopic retrograde cholangiopancreatography.

randomized clinical trials have compared antibiotic prophylaxis with no antibiotics in patients with acute necrotizing pancreatitis, with varying results.56−58 In one study, prophylaxis with cefuroxime 4 to 5 g/day lowered mortality, length of hospital stay, and the overall infection rate, but a decrease in the total number of infections was attributed to fewer urinary tract infections in the antibiotic group.56 In contrast, prophylaxis with either ceftazidime, amikacin, and metronidazole or imipenem-cilastatin decreased the incidence of sepsis and reduced the length of stay, but had no effect on mortality.57,58 Despite differences among the studies, the results of two meta-analyses conclude that prophylaxis with broad-spectrum antibiotics decreases sepsis and mortality in patients with severe AP and necrosis.59,60 In a randomized comparison of perfloxacin and imipenem-cilastatin, pancreatic sepsis was reduced in the imipenem group, but mortality did not differ between groups.61 Selective gut decontamination may be of benefit, but randomized controlled trials are needed to confirm its effectiveness when compared to parenteral antibiotic prophylaxis.1,2,47 Because the source of bacterial contamination is most likely the colon, the choice of antibiotic should be broad-spectrum, covering the range of enteric aerobic gram-negative bacilli and anaerobic microorganisms. Treatment should be initiated within the first 48 hours and continued for 2 to 3 weeks. Imipenem-cilastatin (500 mg every 8 hours) is probably the most effective agent, but a quinolone (such as ciprofloxacin or levofloxacin) with metronidazole should be considered for the penicillin-allergic patient.1,47 Antibiotic prophylaxis is not always effective in eliminating the risk of infected pancreatic necrosis. Widespread use of antibiotics may lead to multiresistant bacterial and fungal infections, thus worsening the course of the disease. There appears to be a shift toward gram-positive infections (primarily enterococci and staphylococci) in AP patients who receive antibiotic prophylaxis as compared to

Endoscopic therapy Pancreatic surgery

earlier studies when patients did not receive antibiotic prophylaxis.62 The use of prophylactic antibiotics may also alter the bacteriology of infected necrosis and is associated with an increase in the incidence of fungal and β-lactam–resistant gram-positive organisms.63 The rise in fungal infections has led some clinicians to consider the addition of an antifungal agent to the prophylactic regimen.64 Although fluconazole demonstrated adequate penetration of pancreatic tissue, there is no evidence to support its efficacy in the prophylaxis of pancreatic fungal infections in patients with acute necrotizing pancreatitis. CLINICAL CONTROVERSY Some clinicians believe that antibiotic prophylaxis is necessary in patients with severe AP in order to prevent pancreatic infection, while others believe that this practice is unnecessary. Antibiotic use in AP remains controversial in patients without definite proof of an infection. Patients with severe AP complicated by necrosis should receive prophylactic treatment with a broad-spectrum antibiotic.


POST-ERCP PANCREATITIS The clinical characteristics of post-ERCP pancreatitis are similar to those of AP from other causes. In most cases the pancreatitis is mild and resolves in several days. Pretreatment with octreotide, calcium channel blockers, and aprotinin has been disappointing, but somatostatin and gabexate have shown some benefit.1,66 To date, there have not been any studies to evaluate the cost effectiveness of prophylactic therapy.

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CHRONIC PANCREATITIS CP is an inflammatory condition that usually results in functional and structural damage to the pancreas. In most patients CP is progressive and loss of pancreatic function is irreversible. Permanent destruction of pancreatic tissue usually leads to exocrine and endocrine insufficiency.7−10 Cystic fibrosis may be associated with pancreatic exocrine insufficiency in children and is discussed in Chap. 30.

ETIOLOGY Etiologic risk factors associated with CP are identified in Table 39–5. Prolonged alcohol consumption accounts for 70% of all cases in the United States, about 20% are idiopathic, and the remaining 10% constitute other less frequent causes.7−10 Recent evidence suggests that there is a strong association between cigarette smoking and CP.7,8 Autoimmune pancreatitis may be isolated or occur in association with immune-mediated disorders. Although cholelithiasis may coexist with CP, gallstones rarely lead to chronic disease.

PATHOPHYSIOLOGY The exact mechanism by which alcohol causes CP is uncertain. It appears that alcohol-induced pancreatitis progresses from inflammation to cellular necrosis, and that fibrosis occurs over time. Chronic alcoholism results in a number of changes in pancreatic fluid that creates an environment for the formation of intraductal protein plugs that block small ductules.7 Blockage of the ductules produces progressive structural damage in the ducts and the acinar tissue. Calcium complexes to the protein plugs, first in the small ductules and then in the main pancreatic duct (see Fig. 39–1), eventually resulting in injury and destruction of pancreatic tissue. Other theories have been hypothesized, all of which lead to pancreatic destruction and insufficiency.7 The pathogenesis of the abdominal pain associated with CP is multifactorial and related in part to increased intraductal pressure secondary to continued pancreatic secretion, pancreatic inflammation, and abnormalities involving pancreatic nerves. Malabsorption of protein and fat occurs when the capacity for enzyme secretion is reduced by 90%.7 Lipase secretion decreases more rapidly than the proteolytic enzymes. Bicarbonate secretion may be decreased, leading to a duodenal pH of less than 4.7 A minority of patients develop

TABLE 39–5. Etiologic Risk Factors Associated with Chronic Pancreatitis Toxic Metabolic

Obstructive Idiopathic Genetic Autoimmune

Other etiologies

Alcohol (ethanol), tobacco, organotin compounds (e.g., di-n-butyltin dichloride) Chronic hypercalcemia associated with hyperparathyroidism, chronic hypertriglyceridemia (controversial), chronic renal failure Pancreas divisum, pancreatic duct obstruction (e.g., tumor), sphincter of Oddi (controversial) Tropical pancreatitis Autosomal dominant, autosomal recessive/modifier genes (e.g., cystic fibrosis) Isolated autoimmune, syndromic autoimmune ¨ (e.g., Sjogren syndrome, inflammatory bowel disease, primary biliary cirrhosis) Postirradiation, postnecrotic pancreatitis, vascular diseases

Compiled from Owyang,7 Etemad and Whitcomb,8 Toskes,9 and Steer et al.10

PANCREATITIS 729

complications, including pancreatic pseudocyst, abscess, and ascites or common bile duct obstruction, leading to cholangitis or secondary biliary cirrhosis. Bleeding is associated with a variety of causes.

CLINICAL PRESENTATION SIGNS AND SYMPTOMS The clinical presentation of CP varies depending on the etiology of the disease, the severity of the inflammatory process, and the extent of irreversible damage to the pancreas (Table 39–6).7−10 The classic features of CP are abdominal pain, malabsorption, weight loss, and diabetes. Most alcoholic patients have chronic pain, while others have intermittent attacks or painless pancreatitis. Abstinence from ethanol may provide relief from pain, but does not prevent exocrine TABLE 39–6. Presentation of Chronic Pancreatitis General r The patient may appear well-nourished or have coexistent signs of malnutrition and chronic alcoholic liver disease. Symptoms r Dull epigastric or abdominal pain that radiates to the back is seen. Pain is the most prominent clinical feature and may be either consistent or episodic. r Characteristically the pain is deep-seated, positional, frequently nocturnal, and unresponsive to medication. The intensity of the pain varies from mild to severe, and does not usually correlate directly with the inflammatory process or other physical findings. Severe attacks last from several days to several weeks and may be aggravated by eating. r Nausea and vomiting often accompany the pain. Signs r Steatorrhea (excessive loss of fat in the feces) and azotorrhea (excessive loss of protein in the feces) are seen in most patients. Steatorrhea is often associated with diarrhea and bloating. r Weight loss may be seen. r About 50% of patients with advanced pancreatic insufficiency present with vitamin B12 malabsorption. r Jaundice occurs in about 10% of patients. r Pancreatic diabetes is usually a late manifestation that is commonly associated with pancreatic calcification. Ketoacidosis, vascular complications, and nephropathy are uncommon with this form of diabetes. r Neuropathy is sometimes seen. r Complications, including pancreatic pseudocysts, pleural effusions, and ascites, may be detected on physical examination. Laboratory tests r The white blood cell count, fluids, and electrolytes usually remain normal unless fluids and electrolytes are lost as a result of vomiting and diarrhea. r Serum amylase and lipase concentrations usually remain normal unless the pancreatic duct is blocked or a pseudocyst is present. Other diagnostic tests r Malabsorption of fat can be detected by Sudan staining of the feces or by a 72-hour quantitative measurement of fecal fat. r Ultrasound is the simplest and least expensive of the imaging techniques. Abdominal computed tomography is often used in patients who have a negative or unsatisfactory ultrasound examination. r Endoscopic retrograde cholangiopancreatography is the most sensitive and specific test for the diagnosis of CP. However, because it is expensive and is associated with complications, it is reserved for patients for whom the diagnosis cannot be established by imaging techniques.

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dysfunction.7,10 The course of pain is unpredictable, but it frequently lessens as pancreatic insufficiency progresses.67

complicated and require intubation and special collection techniques, they are not routinely performed.

DIAGNOSIS

CLINICAL COURSE AND PROGNOSIS

Most patients with CP have a history of heavy alcohol use and attacks of recurrent upper abdominal pain. The classic triad of calcification, steatorrhea, and diabetes usually confirms the diagnosis.7,10 Surgical biopsy of pancreatic tissue through laparoscopy or laparotomy is the gold standard for confirming the diagnosis of CP.7 In the absence of histologic samples, imaging techniques (see Table 39–6) are helpful in detecting calcification of the pancreas, other causes of pain (ductal obstruction secondary to stones, strictures, or pseudocysts), and in differentiating CP from pancreatic cancer. Direct tests of pancreatic exocrine function involve the collection of pancreatic fluid after stimulation with exogenous hormones such as secretin or cholecystokinin. These functional tests are not diagnostic of CP, but serve as a sign of CP and a measure of the severity of injury.7,8 Because these tests are

Patients with alcoholic CP usually present with an initial acute attack followed by successive attacks that are slower to resolve. Continued alcohol use leads to chronic abdominal pain and progressive exocrine and endocrine insufficiency. In about 50% of patients, the pain diminishes 5 to 10 years after the onset of symptoms.68 Steatorrhea, calcification, and diabetes usually develop after 10 to 20 years of heavy ethanol ingestion. Most patients present with varying degrees of pain, malnutrition, and glucose intolerance. The mortality rate of CP is approximately 50% within 20 to 25 years of the diagnosis.10 About 15% to 20% actually die of complications associated with acute attacks. Most deaths occur as a consequence of malnutrition, infection, or ethanol, narcotic, and tobacco use. The clinical course of idiopathic CP is more favorable than that of alcoholic pancreatitis.7,8


TREATMENT: Chronic Pancreatitis
DESIRED OUTCOME The treatment of uncomplicated CP is aimed primarily at the control of chronic abdominal pain (see Fig. 39–4) and the correction of malabsorption with pancreatic enzymes (Fig. 39–5). Diabetes associated with CP may require exogenous insulin.


GENERAL APPROACH TO TREATMENT The majority of patients with alcohol-related CP require pain control and pancreatic enzyme supplementation.7,9,10,68−71 Avoidance

of alcohol usually decreases pain, but oral analgesics remain the cornerstone of therapy. Non-narcotic analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, or tramadol should be tried initially. The dose and frequency of administration should be increased before the patient is switched to a narcotic. Patients unresponsive to non-narcotic analgesics should be given a trial of pancreatic enzymes prior to using narcotics. Narcotics are required for patients with severe pain. Specific endoscopic or surgical procedures may be necessary in patients refractory to drug therapy. Patients with malabsorption require pancreatic enzymes to reduce steatorrhea and azotorrhea. Most patients achieve satisfactory results with standard-dosage regimens. In patients who remain symptomatic, dietary fat should be reduced. Consideration may also be given to increasing the pancreatic

Pancreatic steatorrhea

UCT/C/P with meals

FIGURE 39–5. Algorithm of guidelines for the treatment of pancreatic steatorrhea in chronic pancreatitis. UCT, uncoated tablet; C, capsule; P, powder; ECS, enteric-coated sphere; ECMS, entericcoated microsphere; ECMT, enteric-coated microtablet; H2 RA, H2 receptor antagonist; PPI, proton pump inhibitor.

ECS/ECMS/ECMT

No symptoms

Symptoms

Continue treatment

Decrease fat to 50–75 g/day

No symptoms Continue treatment

Symptoms Decrease dietary fat to 50–75 g/day

No symptoms

Symptoms

No symptoms

Continue treatment

Switch to ECS/ECMS/ECMT

Continue treatment

No symptoms

Symptoms

Continue treatment

Add H2RA or PPI

Symptoms

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enzyme dose or switching from an uncoated tablet to a microencapsulated enteric-coated dosage form. The addition of an antisecretory drug should be reserved for those patients who do not respond to these maneuvers or who have documented low duodenal pH levels.

PANCREATITIS 731


RELIEF OF CHRONIC ABDOMINAL PAIN
Analgesics 7 Non-narcotic analgesics such as acetaminophen, NSAIDs, or


NONPHARMACOLOGIC THERAPY 6 Abstinence from alcohol is the most important factor in prevent-

ing abdominal pain in the early stages of alcoholic CP, although reports of the effect of abstinence from alcohol have varied.7,19,68 Small and frequent meals (six meals per day) and a diet restricted in fat (50 to 75 g/day) are recommended to minimize postprandial pancreatic secretion and resulting pain.71 Parenteral or enteral nutrition (elemental diets) may be necessary, especially if the patient is chronically debilitated, and these nutritional approaches are less likely than oral ingestion of ordinary food to simulate pancreatic secretion, as stimulation of the pancreas is of some concern in that it may contribute to pain.41 In some patients pain may be associated with pseudocysts, peptic ulcer, cholelithiasis, biliary or duodenal obstruction, or pancreatic cancer, and if detected may be amenable to other forms of treatment (see Fig. 39–4), including endoscopic procedures such as sphincterotomy, pancreatic duct stenting, and lithotriptic destruction of pancreatic calculi.7,10,68,72 The most common indication for surgery is abdominal pain that is refractory to medical therapy. Surgical procedures that alleviate pain include a subtotal pancreatectomy, decompression of the main pancreatic duct, or interruption of the splanchnic nerves.7,10,68,72 Although the pain may diminish as the gland deteriorates, it is unreasonable that a patient wait years for spontaneous relief. A percutaneous injection of a corticosteroid or local anesthetic into the celiac ganglion (celiac nerve block) may be attempted. Unfortunately, pain relief obtained by this procedure lasts only a few months, and repeated treatments are not as effective.68,72,73


PHARMACOLOGIC THERAPY
RECOMMENDATIONS Pain management should begin with non-narcotic analgesics such as acetaminophen, NSAIDs, or selective COX-2 inhibitors (see Fig. 39–4). If pain persists, the response to exogenous pancreatic enzymes should be evaluated in patients with mild to moderate CP. If these measures fail, an oral narcotic should be added to the drug regimen. Parenteral narcotics should be reserved for patients with severe pain that is unresponsive to oral analgesics. Non-narcotic modulators of chronic pain should be considered in patients with difficult-to-manage pain. Most patients with malabsorption will require pancreatic enzyme supplementation and a reduction in dietary fat in order to achieve satisfactory nutritional status and become relatively asymptomatic. An initial prandial dose of 30,000 international units of lipase (uncoated tablet, capsule, or powder) is recommended to be given with each meal (see Fig. 34–5). Alternatively, the use of microencapsulated entericcoated dosage forms may be used. The total daily lipase dose should be titrated to reduce steatorrhea. In some patients a reduction in dietary fat may be necessary. The addition of an antisecretory drug should be reserved for patients resistant to enzyme therapy (see Fig. 39–5). If these measures are ineffective, documentation of the diagnosis and exclusion of other diseases should be undertaken.

selective COX-2 inhibitors should be given before meals to prevent postprandial exacerbation of pain (Table 39–7).7,9,69−72 Treatment should be individualized and should begin with the lowest effective dose. The dosage regimen should be maximized before switching to narcotic alternatives. Analgesics should be scheduled around the clock, because they may be more effective and the total amount of medication required over 24 hours may be less. If the non-narcotic analgesic is ineffective, consideration should be given to using tramadol or adding a low-dose narcotic to the regimen (e.g., acetaminophen and codeine). Severe pain relief necessitates the use of opiate analgesics. Narcotics should not be withheld because of the risk of inducing addiction. Oral agents should be used before parenteral narcotics are administered. Non-narcotic modulators of chronic pain such as selective serotonin reuptake inhibitors (e.g., paroxetine) or tricyclic antidepressants should be considered in difficult-to-manage patients.1,72 Tricyclic antidepressants are useful adjuncts, as they not only treat depression, but have a direct effect on pain and potentiate the effect of opioid narcotics.72 Referral to a dedicated pain clinic should be considered when available.


Pancreatic Enzymes 8 The use of pancreatic enzymes to relieve pain remains contro-

versial (see Table 39–7). Results from clinical trials are conflicting, especially when non–enteric-coated preparations were compared to enteric-coated enzyme products.7,69−72,74,75 The administration of non–enteric-coated pancreatic enzymes early in the course of the disease may afford pain relief by suppressing pancreatic enzyme secretion through a negative feedback mechanism involving proteases present in the duodenum. Effective enzyme therapy should reduce pancreatic stimulation, diminish intraductal pressure, and decrease pain. Possible reasons for failure of enzymes to relieve abdominal pain include insufficient concentrations of trypsin in the pancreatic enzyme preparation, a delayed release of trypsin from pHdependent dosage forms, and gastric acid inactivation or proteolytic destruction of trypsin.7,72,74,75 Suppression of gastric acid with an antisecretory drug is recommended, as it reduces the degradation of proteases in the stomach.7,69 Beneficial effects occur in a subset of individuals, primarily those with mild to moderate disease and in patients with a nonalcoholic etiology.7,9,68,72 CLINICAL CONTROVERSY Some clinicians believe that pancreatic enzyme supplementation should be used to relieve mild to moderate abdominal pain, while others believe that these agents are ineffective. A trial of pancreatic enzyme supplementation should be given before initiating treatment with narcotics.


Other Agents A number of other agents, including octreotide, allopurinol, and antioxidant therapy (e.g., organic selenium, vitamin E, vitamin C, or β-carotene), have been investigated for the purposes of relieving pain in chronic pancreatitis.7,9,68 There is insufficient evidence to support the use of these agents.

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GASTROINTESTINAL DISORDERS TABLE 39–7. Guidelines for the Pharmacologic Treatment of Chronic Pancreatitis Treatment of chronic pain (oral drug regimens) Non-narcotic r Acetaminophen: Dosage should be limited to 500 mg four times a day if patient drinks more than two alcoholic beverages per day; increased risk of hepatotoxicity, especially in chronic heavy alcohol use r Nonsteroidal anti-inflammatory drugs (NSAIDs): Standard dosage regimens of aspirin or traditional NSAIDs (e.g., ibuprofen); selective cyclooxygenase-2 (COX-2) inhibitors should be used in patients at risk for upper GI bleeding; use with caution in renal insufficiency r Tramadol: 50–100 mg every 4–6 hours not to exceed 400 mg/day; has narcotic-like effect; contraindicated in alcohol or hypnotic intoxication; drug interactions; expensive r Consider use of selective serotonin reuptake inhibitors (e.g., paroxetine) or tricyclic antidepressants in difficult-to-manage patients Narcotics r Codeine 30–60 mg every 6 h; hydrocodone 5–10 mg every 4–6 h; oxycodone 5–10 mg every 6 h; fentanyl patch 25–100 mcg/h; pentazocine 25–50 mg every 4–6 h; propoxyphene 65 mg every 4–6 h not to exceed 390 mg/day; methadone 2.5–10 mg every 4–6 h; morphine sulfate (extended-release) 30–60 mg every 8–12 h; hydromorphone 2–4 mg every 4–6 h r Risk of potentiation with alcohol; impaired respiration; constipation; hypotension r Dosing is usually based on providing continuous pain relief; consider combining narcotic with acetaminophen, NSAIDs, or selective COX-2 inhibitors; narcotic dependence is common; narcotic abuse is a concern in alcoholics; tolerance to narcotics may develop Pancreatic enzymes r Requires that high doses of proteases be delivered to the duodenum for relief of pain; non–enteric-coated pancreatic enzymes are recommended and should be taken with each meal and at night if needed; recommend name brands with proven efficacy and safety, as generic products have been associated with treatment failure; add H2 -receptor antagonist or proton pump inhibitor r Viokase-8 tablets or Ku-Zyme HP capsules: 6–8 with each meal (see Table 39–8); acid suppression adds to cost r May cause nausea, cramping, hyperuricemia; hypersensitivity to pork protein Treatment of maldigestion and steatorrhea Non–enteric-coated pancreatic enzymes r Viokase-8 tablets or Ku-Zyme HP capsules, 6–8 with each meal and at bedtime if needed (see Table 39–8) r May cause nausea, cramping, hyperuricemia; hypersensitivity to pork protein r Addition of antisecretory drug (H2 -receptor antagonist or proton pump inhibitor) may increase efficacy, but will also increase cost Enteric-coated pancreatic enzymes r Enteric-coated spheres, microspheres, and microtablets are available (see Table 39–8) r May cause nausea, cramping, hyperuricemia; hypersensitivity to pork protein r Fibrosing colonopathy has occurred in children using preparations that contain the methacrylic acid copolymer coating r Usually requires fewer capsules or tablets per meal; compliance issues r Does not usually require additional antisecretory agents; may be less expensive than non–enteric-coated plus H2 -receptor antagonist or proton pump inhibitor Antisecretory drugs r May improve enzyme treatment of abdominal pain or steatorrhea r Proton pump inhibitors may be more effective than H2 -receptor antagonists, but they are also more costly Compiled from Owyang,7 Toskes,9 Amann,69 Whitcomb et al,70 American Gastroenterological Association,71 Conwell and Zuccaro,72 Brown et al,74 Mossner,75 Greenberger,76 Keller and Layer,77 and Layer et al.78


TREATMENT OF MALABSORPTION Malabsorption requires treatment when steatorrhea is documented (>7 g of fat in the feces per 24 hours while on a diet of 100 g/day of fat) and persistent weight loss occurs despite efforts to correct it. The combination of pancreatic enzymes (lipase, amylase, and protease) and a reduction in dietary fat (to 5, where the enzymes are released.7,76 If an intragastric pH of 20,000 international units lipase per capsule) have led to their withdrawal from the market in the United States.7,69,82 Pancreatic enzymes contain nucleic acids, and when given in high therapeutic doses, they have been associated with hyperuricosuria, hyperuricemia, and kidney stones.7,69,70 Impaired folic acid absorption by oral pancreatic enzymes may lead to folic acid deficiency. Gastrointestinal side effects appear to be dose-related, but occur less frequently with the enteric-coated products. Sensitization and allergic reactions are uncommon but may occur in patients taking the powder.


Adjuncts to Enzyme Therapy The concurrent use of antisecretory drugs may improve the efficacy of pancreatic enzyme supplementation.7,76 The beneficial effects of an H2 -receptor antagonist or proton pump inhibitor result from

TABLE 39–8. Frequently Used Pancreatic Enzyme Preparations Enzyme Content (Units)a Product

Dosage Form

Lipase

Amylase

Protease

Creon-10 Creon-20 Ku-Zyme HP Lipram-CR10 Lipram-PN16 Lipram-CR20 Lipram-PN20 Lipram-UL12 Lipram-PN10 Lipram-UL18 Lipram-UL20 Pancrease Pancrease MT-4 Pancrease MT-10 Pancrease MT-16 Pancrease MT-20 Ultrase MT 12 Ultrase MT 18 Ultrase MT 20 Viokaseb Viokase 8 Viokase 16

ECMS ECMS C ECMS ECMS ECMS ECMS ECMS ECMS ECMS ECMS ECMS ECMT ECMT ECMT ECMT ECMT ECMT ECMT P UCT UCT

10,000 20,000 8000 10,000 16,000 20,000 20,000 12,000 10,000 18,000 20,000 4500 4000 10,000 16,000 20,000 12,000 18,000 20,000 16,800 8000 16,000

33,200 66,400 30,000 33,200 48,000 66,400 56,000 39,000 30,000 58,500 65,000 20,000 12,000 30,000 48,000 56,000 39,000 58,500 65,000 70,000 30,000 60,000

37,500 75,000 30,000 37,500 48,000 75,000 44,000 39,000 30,000 58,500 65,000 25,000 12,000 30,000 48,000 44,000 39,000 58,500 65,000 70,000 30,000 60,000

a All listed products contain pancrealipase. Pancrealipase contains not less than 24 USP units of lipase activity, not less than 100 USP units of amylase activity, and not less than 100 USP units of protease activity per milligram. b Units of 0.7 g of powder. C, powder encased in a cellulose capsule; ECS, enteric-coated sphere encased in a cellulose capsule; ECMS, entericcoated microspheres encased in a cellulose or gelatin capsule; ECMT, enteric-coated microtablets encased in a cellulose capsule; UCT, uncoated tablet; P, powder.

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both an increase in pH and a decrease in intragastric volume.7,84 These agents should maintain luminal gastric and duodenal pH above 4 and enhance lipase activity. Increased duodenal pH also prevents bile acid precipitation, increasing fatty acid solubility. Antacids appear to have little or no added effect in reducing steatorrhea.7 Symptomatic 10 patients whose steatorrhea is not corrected by enzyme replacement therapy and a reduction in dietary fat may benefit from the addition of an H2 -receptor antagonist. A proton pump inhibitor should be considered in patients who fail to benefit from the addition of an H2 -receptor antagonist. The additional cost of antisecretory therapy and the potential for adverse effects and drug interactions should be considered.


PHARMACOECONOMIC CONSIDERATIONS The pharmacoeconomic issues associated with the medical treatment of AP and CP have not been extensively examined. Aggressive medical and surgical care decreases mortality in AP, but the overall cost

EVALUATION OF THERAPEUTIC OUTCOMES ACUTE PANCREATITIS In patients with mild AP, pain control, fluid and electrolyte status, and nutrition should be assessed periodically, depending on the degree of abdominal pain and fluid loss. Patients with severe AP should be transferred to an intensive care unit for close monitoring of vital signs, prothrombin time, fluid and electrolyte status, white blood cell count, blood glucose, lactic dehydrogenase, aspartate aminotransferase, serum albumin, hematocrit, blood urea nitrogen, and serum creatinine. Continuous hemodynamic and arterial blood gas monitoring is essential. Serum lipase, amylase, and bilirubin require less frequent monitoring. The patient should be monitored for signs of infection, relief of abdominal pain, and adequate nutritional status. Therapeutic outcome depends on the severity of the acute attack, medical management (which is primarily supportive), and prevention or treatment of infection. Despite appropriate supportive therapy, deterioration of respiratory, renal, and cardiovascular function may lead to death.

CHRONIC PANCREATITIS The severity and frequency of abdominal pain should be assessed periodically in order to determine the efficacy of the patient’s pain control regimen. Most patients with abdominal pain can be adequately controlled with acetaminophen, NSAIDs, or selective COX-2 inhibitors. A trial of pancreatic enzymes and either an H2 -receptor antagonist or proton pump inhibitor may relieve pain in patients with mild to moderate disease. Patients with severe pain will require narcotics. In these patients, pain should be monitored daily and medications adjusted accordingly. Some patients will require endoscopic therapy or pancreatic surgery. The effectiveness of pancreatic enzyme supplementation in treating malabsorption is measured by improvement in body weight and stool consistency or frequency. The 72-hour stool test for fecal fat may be used when there is concern regarding the adequacy of treatment. Serum uric acid and folic acid concentrations should be monitored yearly in patients prone to hyperuricemia or folic acid deficiency. Blood glucose must be closely monitored in the diabetic patient.

effectiveness of a specific treatment is unknown. The relief of abdominal pain in AP and CP, as well as pancreatic enzyme supplementation in patients with CP, improves quality of life and nutritional status. Although the efficacy of octreotide in AP remains uncertain, its use in severe AP is reasonable and potentially cost effective. Antibiotic prophylaxis of targeted patients may reduce mortality and length of hospital stay, but pharmacoeconomic studies have not confirmed this suspicion. However, a reduction in the length of stay could offset the cost of antibiotic therapy. In some cases, medications that cost more may be more cost effective. This is particularly true with pancreatic enzymes and the microencapsulated enteric-coated dosage forms. These latter products may cost more per unit, but they offer greater patient acceptance and compliance when compared to uncoated tablets. In addition, when cost is based on the total number of tablets or capsules per day, rather than the cost of a single tablet or capsule, the high-potency preparations are usually similar in price to the uncoated products. The addition of an H2 -receptor antagonist or proton pump inhibitor may actually be cost effective for patients who are not adequately controlled on maximal enzyme therapy. Therapeutic outcome depends in part on the ability of the patient to discontinue alcohol and tobacco use and to maintain adequate nutrition. Pain control and pancreatic enzyme supplementation are important therapeutic measures that contribute to the patient’s quality of life. A small number of patients die from complications associated with an acute attack.

CONCLUSIONS Important advances have been made in recent years regarding our understanding of acute and chronic pancreatitis, especially as it relates to genetics, pathogenesis, and the natural history of the diseases. Although there has been a reduction in the mortality of patients with severe AP, controversy remains regarding the use of antibiotic prophylaxis. Patients with CP now benefit from improved strategies for managing pain and treating malabsorption. In the future, new and improved diagnostic techniques and medical treatments will replace many of the procedures and drugs we use today.

ABBREVIATIONS AP: acute pancreatitis ARDS: acute respiratory distress syndrome CCK: cholecystokinin COX-2: cyclooxygenase-2 CP: chronic pancreatitis ERCP: endoscopic retrograde cholangiopancreatography IMMC: interdigestive migrating motor complex NSAID: nonsteroidal anti-inflammatory drug Review Questions and other resources can be found at www.pharmacotherapyonline.com.

REFERENCES 1. Mitchell RMS, Byrne MF, Baillie J. Pancreatitis. Lancet 2003;361:1447– 1455. 2. Topazian M, Gorelick FS. Acute pancreatitis. In: Yamada T, Aplers DH, Kaplowitz N, et al, eds. Textbook of Gastroenterology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2003:2026–2061.

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CHAPTER 39 3. Bank S, Singh P, Pooran N, et al. Evaluation of factors that have reduced mortality from acute pancreatitis over the past 20 years. J Clin Gastroenterol 2002;35:50–60. 4. Grendell JH. Acute pancreatitis. Clin Perspect Gastroenterol 2000;3: 327–333. 5. Dervenis C, Johnson CD, Bassi C, et al. Diagnosis, objective assessment of severity, and management of acute pancreatitis. Int J Pancreatol 1999;25:195–220. 6. Banks PA. Practice guidelines in acute pancreatitis. Am J Gastroenterol 1997;92:377–386. 7. Owyang C. Chronic pancreatitis. In: Yamada T, Aplers DH, Kaplowitz N, et al, eds. Textbook of Gastroenterology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2003:2061–2090. 8. Etemad B, Whitcomb DC. Chronic pancreatitis: Diagnosis, classification and new genetic developments. Gastroenterology 2001;120:682–707. 9. Toskes PP. Update on diagnosis and management of chronic pancreatitis. Curr Gastroenterol Rep 1999;1:145–153. 10. Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med 1995;332:1482–1490. 11. Owyang C, Williams JA. Pancreatic secretion. In: Yamada T, Aplers DH, Kaplowitz N, et al, eds. Textbook of Gastroenterology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2003:340–366. 12. Cohen S, Bacon BR, Berline JA, et al. National Institutes of Health Stateof-the-Science Conference Statement: ERCP for diagnosis and therapy, January 14–16, 2002. Gastrointest Endosc 2002;56:803–809. 13. Eland IA, van Puijenbroek EP, Sturkenboom MJCM, et al. Drugassociated acute pancreatitis: Twenty-one years of spontaneous reporting in the Netherlands. Am J Gastroenterol 1999;94:2417–2422. 14. McArthur KE. Review article: Drug-induced pancreatitis. Aliment Pharmacol Ther 1996;10:23–38. 15. Eland IA, Rasch MC, Sturkenboom MJCM, et al. Acute pancreatitis attributed to the use of interferon alfa-2b. Gastroenterology 2000;119:230– 233. 16. Gershon T, Olshaker J. Acute pancreatitis following lisinopril rechallenge. Am J Emerg Med 1998;16:523–524. 17. Maringhini A, Termini A, Patti R, et al. Enalapril-associated acute pancreatitis: Recurrence after rechallenge. Am J Gastroenterol 1997;92:166– 167. 18. Izaeli S, Adamson PC, Blaney SM, et al. Acute pancreatitis after ifosfamide therapy. Cancer 1994;74:1627–1628. 19. Liviu L, Yair L, Yehuda S. Pancreatitis induced by clarithromycin. Ann Intern Med 1996;125:701 [Letter]. 20. Goffin E, Horsmans Y, Pirson Y, et al. Acute necrotic-hemorrhagic pancreatitis after famciclovir prescription. Transplantation 1995;59:1218–1219. 21. Hoff PM, Valero V, Holmes FA, et al. Paclitaxel-induced pancreatitis: A case report. J Natl Cancer Inst 1997;89:91–92 [Letter]. 22. Rodier JM, Pujade-Lauraine E, Batel-Copel L, et al. Granisetron-induced acute pancreatitis. J Cancer Res Clin Oncol 1996;122:132–133 [Letter]. 23. Balasch J, Martinez-Romain S, Carreras J, et al. Acute pancreatitis associated with danazol treatment for endometriosis. Hum Reprod 1994;9:1163– 1165. 24. Domingo P, Ferrer S, Kolle S, et al. Acute pancreatitis associated with sodium stibogluconate treatment in a patient with human immunodeficiency virus. Arch Intern Med 1996;156:1029–1032 [Letter]. 25. Torrus D, Massa B, Boix V, et al. Meglumine antimonate-induced pancreatitis. Am J Gastroenterol 1996;91:820–821 [Letter]. 26. Abdul-Ghaffar N, El-Sonbaty MR. Pancreatitis and rhabdomyolysis associated with lovastatin-gemfibrozil therapy. J Clin Gastroenterol 1995;21:340–341. 27. Stricker R, Man K, Bouvier D, et al. Pancreatorenal syndrome associated with combination antiretroviral therapy in HIV infection. Lancet 1997;349:1745–1746. 28. McDornald KB, Garbor BG, Perreault MM. Pancreatitis associated with simvastatin plus fenofibrate. Ann Pharmacother 2002;36:275–279. 29. Sammett D, Greben C, Sayeed-Shah U. Acute pancreatitis caused by penicillin. Dig Dis Sci 1998;43:1778–1783. 30. Goyal SB, Goyal R. Ketorolac tromethamine-induced acute pancreatitis. Arch Intern Med 1998;158:411 [Letter].

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31. Haviv YS, Sharkia M, Galun E, et al. Pancreatitis following hepatitis A vaccination. Eur J Med Res 2000;5:229–230. 32. Eland IA, Alvarez CH, Stricker BHCH, et al. The risk of acute pancreatitis associated with acid-suppressing drugs. Br J Clin Pharmacol 2000;49:473–478. 33. Birck R, Keim V, Fiedler F, vander Woude FJ, et al. Pancreatitis after losartan. Lancet 1998;351:1178 [Letter]. 34. Fisher AA, Bassett ML. Acute pancreatitis associated with angiotensin II receptor antagonists. Ann Pharmacother 2002;36:1883–1886. 35. Blomgren KB, Sundstrom A, Steineck G, et al. Obesity and treatment of diabetes with glyburide may both be risk factors for acute pancreatitis. Diabetes Care 2002;25:298–302. 36. Blomgren KB, Sundstr¨om A, Steineck G, et al. A Swedish case-control network for studies of drug-induced morbidity—acute pancreatitis. Eur J Clin Pharmacol 2002;58:275–283. 37. Mayer J, Rau B, Gansauge F, et al. Inflammatory mediators in human acute pancreatitis: Clinical and pathophysiological implications. Gut 2000;47:546–552. 38. Riche FD, Cholley BO, Laisne MJC, et al. Inflammatory cytokines, C reactive protein, and procalcitonin as early predictors of necrosis infection in acute necrotizing pancreatitis. Surgery 2003;133:257–262. 39. Somogyi L, Martin SP, Venkatesan T, et al. Recurrent acute pancreatitis: An algorithmic approach to identification and elimination of inciting factors. Gastroenterology 2001;120:708–717. 40. Abou-Assi S, Craig K, O’Keefe SJD, et al. Hypocaloric jejunal feeding is better than total parenteral nutrition in acute pancreatitis: Results of a randomized comparative study. Am J Gastroenterol 2002;97:2255–2262. 41. Scolapio J, Malhi-Chowla N, Ukleja A. Nutrition supplementation in patients with acute and chronic pancreatitis. Gastroenterol Clin North Am 1999;28:695–707. 42. Lobo DN, Memon MA, Allison SP, et al. Evolution of nutritional support in acute pancreatitis. Br J Surg 2000;87:695–707. 43. Kotani J, Usami M, Nomura H, et al. Enteral nutrition prevents bacterial translocation but does not improve survival during acute pancreatitis. Arch Surg 1999;134:287–292. ´ Gamal ME, et al. Randomized clinical trial of specific 44. Ol´ah A, Issekutz A, lactobacillus and fiber supplement to early enteral nutrition in patients with acute pancreatitis. Br J Surg 2002;89:1103–1107. 45. Isenhower HL, Mueller BA. Selection of narcotic analgesics for pain associated with pancreatitis. Am J Health-Syst Pharm 1998;55:480–486. 46. Yousaf M, McCallion K, Daimond T. Management of severe acute pancreatitis. Br J Surg 2003;90:407–420. 47. Norton ID, Clain JE. Optimizing outcomes in acute pancreatitis. Drugs 2001;61:1581–1591. 48. Ulrich CD. Medical management of acute pancreatitis: Strategies, reality, and potential. Curr Gastroenterol Rep 2000;2:115–119. 49. Brown A, Ballargeon JD, Hughes MD, et al. Can fluid resuscitation prevent pancreatic necrosis in severe acute pancreatitis? Pancreatology 2002;2:104–107. 50. Pezzilli R, Miglioli M. Multicentre comparative study of two schedules of gabexate mesilate in the treatment of acute pancreatitis. Dig Liver Dis 2001;33:49–77. 51. Holtz HG, Schmidt J, Ryschich EW, et al. Isovolemic hemodilution with dextran prevents contrast medium-induced impairment of pancreatic microcirculation in necrotizing pancreatitis of the rat. Am J Surg 1995;169:161–166. 52. Andriulli A, Leandro G, Clemente R, et al. Meta-analysis of somatostatin, octreotide and gabexate mesilate in the therapy of acute pancreatitis. Aliment Pharmacol Ther 1998;12:237–245. 53. Paran H, Mayo A, Paran D. Octreotide treatment in patients with severe acute pancreatitis. Dig Dis Sci 2000;45:2247–2251. 54. Karakoyunlar O, Sivrel E, Tanir N, et al. High-dose octreotide in the management of acute pancreatitis. Hepatogastroenterology 1999;46:1968– 1971. 55. Kramer KM, Levy H. Prophylactic antibiotics for severe AP: The beginning of an era. Pharmacotherapy 1999;19:592–602. 56. Sainio V, Kemppainen P, Poulallainen P, et al. Early antibiotic treatment in acute necrotizing pancreatitis. Lancet 1995;346:663–667.

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57. Pederzoli P, Bassi C, Vesentini S, et al. A randomized multicenter clinical trial of antibiotic prophylaxis with imipenem. Surg Gynecol Obstet 1993;176:480–483. 58. Delcenserie R, Yzet T, Ducroix JP. Prophylactic antibiotics in treatment of severe acute alcoholic pancreatitis. Pancreas 1996;13:198–201. 59. Golub R, Siddiai F, Pohl D. Role of antibiotics in acute pancreatitis: A meta-analysis. J Gastrointest Surg 1998;2:496–503 60. Sharma VK, Howden CW. Prophylactic antibiotic administration reduces sepsis and mortality in acute necrotizing pancreatitis: A meta-analysis. Pancreas 2001;22:1–4. 61. Bassi C, Falconi M, Talamini G, et al. Controlled clinical trial of pefloxacin versus imipenem in severe acute pancreatitis. Gastroenterology 1998;115:1513–1517. 62. Gloor B, Muller CA, Worni M, et al. Pancreatic infection in severe pancreatitis: The role of fungus and multiresistant organisms. Arch Surg 2001;136:592–596. 63. Howard TJ, Temple MB. Prophylactic antibiotics alter the bacteriology of infected necrosis in severe acute pancreatitis. J Am Coll Surg 2002:195:759–767. 64. Butturini G, Salvia R, Bettini M, et al. Infection prevention in necrotizing pancreatitis: An old challenge with new perspectives. J Hosp Infect 2001;49:4–8. 65. Shrikhande S, Friess H, Issenegger C. Fluconazole penetration into the pancreas. Antimicrob Agents Chemother 2000;44:2569–2571. 66. Poon RTP, Fan ST. Antisecretory agents for prevention of post-ERCP pancreatitis: Rationale for use and clinical results. J Pancreas 2003;4:233– 240. 67. Ammann RW, Muelihaupt B, Zurich Pancreatitis Study Group. The natural history of pain in alcoholic chronic pancreatitis. Gastroenterology 1999;116:1132–1140. 68. Warshaw A, Banks PA, Fernandez-del C. American Gastroenterological Association technical review: Treatment of pain in chronic pancreatitis. Gastroenterology 1998;115:765–776. 69. Amann ST. Chronic pancreatitis. Curr Treat Option Gastroenterol 1999;2:401–408. 70. Whitcomb D, Pfutzer RH, Slivka A. Alcoholic chronic pancreatitis. Curr Treat Option Gastroenterol 1999;2:273–282.

71. American Gastroenterological Association Medical Position Statement: Treatment of pain in chronic pancreatitis. Gastroenterology 1998;155:763–764. 72. Conwell DL, Zuccaro G. Pain management in chronic pancreatitis. Curr Treat Option Gastroenterol 1999;2:295–304. 73. Bhutani MS, Pasricha PJ. Neurolytic approaches for the treatment of pain in patients with chronic pancreatitis. Curr Treat Option Gastroenterol 2003;6:375–379. 74. Brown A, Hughes M, Tenner S, et al. Does pancreatic enzyme supplementation reduce pain in patients with chronic pancreatitis: A meta-analysis. Am J Gastroenterol 1997;92:2032–2035. 75. Mossner J. Palliation of pain in chronic pancreatitis: Use of enzymes. Surg Clin North Am 1999;79:861–872. 76. Greenberger NJ. Enzymatic therapy in patients with chronic pancreatitis. Gastroenterol Clin North Am 1999;28:687–693. 77. Keller J, Layer P. Pancreatic enzyme supplementation therapy. Curr Treat Option Gastroenterol 2003;6:369–374. 78. Layer P, Keller J, Lankich PG. Pancreatic enzyme replacement therapy. Curr Gastroenterol Rep 2001;3:101–108. 79. Apte MN, Keogh GW, Wilson JS. Chronic pancreatitis: Complications and management. J Clin Gastroenterol 1999;29:225–240. 80. Bruno MJ, Borm JJ, Hock FJ, et al. Gastric transit and pharmacodynamics of a two-millimeter enteric-coated pancreatin microsphere preparation in patients with chronic pancreatitis. Dig Dis Sci 1998;43:203– 213. 81. Halm U, Loser C, Lohr M, et al. A double-blind randomized, multicentre, crossover study to prove equivalence of pancreatin minimicrospheres versus microspheres in exocrine pancreatic insufficiency. Aliment Pharmacol Ther 1999;13:951–957. 82. Littlewood JM. Update on intestinal strictures. J R Soc Med 1999;92(Suppl 37):41–49. 83. Hendeles L, Hochhaus G, Kazerounian S. Generic and alternative brandname pharmaceutical equivalent: Select with caution. Am J Hosp Pharm 1993;50:323–329. 84. Bruno MJ, Rauws EAJ, Hoek FJ, et al. Comparative effects of adjuvant cimetidine and omeprazole during pancreatic enzyme replacement therapy. Dig Dis Sci 1994;39:988–992.

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40 VIRAL HEPATITIS Manjunath P. Pai, Renee-Claude Mercier, and Marsha A. Raebel

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Hepatitis A is transmitted via the fecal-oral route. Conditions in which transmission is more likely to occur include travel to countries with high rates of hepatitis A, poor conditions and hygiene, and overcrowded areas.

2 Hepatitis A causes an acute illness and does not lead to

6 Long-term therapy with lamivudine is associated with the

development of hepatitis B virus strains that are resistant to this agent. Although the impact of developing lamivudineresistant hepatitis B virus is not known, adefovir may be used to treat these resistant strains.

chronic liver disease. The infection can be divided into three stages: incubation, acute hepatitis, and convalescence. The disease is typically self-limited and rarely progresses to liver failure.

7 All infants should be immunized against hepatitis B. Older

3 Treatment of acute hepatitis A infection is primarily supportive, as pharmacologic treatment with antiviral agents is of no benefit.

ated primarily with illicit injection drug use in the United States.

4 Hepatitis B virus can cause both an acute and chronic illness and is more difficult to clear if acquired as an infant compared to acquisition as an adult. 5 The choice of first-line therapy for hepatitis B virus when comparing interferon-α2b and lamivudine is controversial. The duration of interferon-α2b therapy is finite (16 to 52 weeks) relative to lamivudine (52 weeks or longer) for chronic hepatitis B, but is associated with significant side effects.

Hepatitis is a major cause of morbidity and mortality in the United States. Viral hepatitis refers to the clinically important hepatotrophic viruses responsible for hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), delta hepatitis, and hepatitis E. Hepatitis G virus has also been described; however, its role in clinical illness is still not clear. Viral hepatitis has acute, fulminant, and chronic clinical forms, defined by duration or severity of infection. The clinical, biochemical, immunoserologic, and histologic features of viral hepatitis follow similar patterns regardless of the virus responsible for the patient’s illness. Hepatocellular response to injury and the resulting physical signs and symptoms are nonspecific. HAV is primarily responsible for acute hepatitis. It is most often linked to sporadic events of contaminated food in the United States and to international travel, and is usually a self-limited disease. HBV and HCV are primarily responsible for the development of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Immunomodulatory therapy and direct antiviral agents have been developed for both HBV and HCV. These therapeutic modalities require long courses of therapy and are associated with limited success. This chapter will focus on the pathophysiology, clinical course, and management of these three primary causes of viral hepatitis, namely HAV, HBV, and HCV.

children and adults in high-risk groups who have not been previously immunized should also receive the vaccine.

8 Hepatitis C is a significant public health problem associ-

9 No vaccines exist for the prevention of hepatitis C compared

to the individual and combined vaccines that are available for the prevention of hepatitis A and B.

10 The availability of pegylated versions of interferon has

allowed for less frequent dosing and better therapeutic response in chronic hepatitis C. However, therapeutic response of patients with chronic hepatitis C to combination pegylated interferon-α and ribavirin therapy is expected in less than half of treated patients with genotype 1.

HEPATITIS A VIRUS HAV has been associated with significant morbidity and occasional mortality for centuries as a known cause of acute hepatitis.1 Despite the availability of an effective vaccine against HAV, hepatitis A continues to be one of the most frequently reported vaccine-preventable diseases in the United States.2 Epidemiologic data in the United States from 1997 estimated that hepatitis A infections were responsible for 255 deaths, approximately 2.5 million days of symptomatic illness, 829,000 working days lost, and costs in the range of 330 to 580 million dollars.3

EPIDEMIOLOGY AND ETIOLOGY HAV causes both epidemics and sporadic infections. Both are related to overcrowded conditions and person-to-person spread or ingestion 1 of contaminated food or water. HAV is transmitted by the fecaloral route. The incidence of HAV correlates directly with poor sanitary conditions and hygienic practices.4 For international travelers, longer lengths of stay in a country with a high rate of hepatitis A also correlates with increased risk. In the United States, groups at increased risk of HAV, in addition to travelers, include men who have sex 737

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with men, injecting drug users, and persons working with nonhuman primates.2 HAV infection in the United States occurs primarily from personto-person transmission in communitywide outbreaks, in lower socioeconomic groups, and in sporadic common-source outbreaks (outbreaks in which all infected patients contract the infection from a single person or source).2 Children between the ages of 5 and 14 years are more likely to be involved in communitywide outbreaks, whereas common-source outbreaks primarily involve young adults. Both children and young adults can be infected from common-source outbreaks at day care centers.4 HAV infection in children is often asymptomatic or unrecognized. Therefore, children serve as an important source for transmitting the infection to others.2 Rarely, HAV is transmitted by transfusion of contaminated blood products collected while the donor is viremic with HAV.2 Cases of HAV associated with parenteral drug abuse are increasing.5 HAV are small, nonenveloped, single-stranded ribonucleic acid (RNA) viruses belonging to the Hepatovirus genus of the Picornaviridae. Four genotypes are known to infect humans. Most infections are caused by strains from either genotype I or III, although the genotypes do not appear to confer important biological differences.6

PATHOPHYSIOLOGY 2 HAV usually causes a self-limiting disease with a low case-

fatality rate. The disease is a systemic viral infection of up to (but not exceeding) 6 months in duration, producing inflammatory necrosis of the liver. The natural history of the infection is divided into three stages based on viral serologic markers: incubation, acute hepatitis, and convalescence. Incubation begins shortly after parenteral or oral inoculation with the virus. After the virus reaches the circulation, infective virions accumulate in hepatic sinusoids and are internalized by the hepatocytes. HAV replication occurs exclusively in the hepatocytes and gastrointestinal epithelial cells.6 Viral antigens are found in the hepatocyte cytoplasm during incubation. They are subsequently shed into bile and feces. The largest concentration of viral particles is found in stool specimens during the 1 to 2 weeks preceding clinical illness or elevation of liver enzymes. Infected persons are at peak infectivity at this time.2 Viral shedding declines as clinical symptoms appear. During the incubation stage, the host is asymptomatic. Acute hepatitis begins with a preicteric phase (before the onset of jaundice), which parallels initiation of the host immune response and occurs before significant liver cell injury. The preicteric phase is frequently associated with nonspecific influenza-like symptoms consisting of anorexia, nausea, fatigue, and malaise.6 Most patients with acute viral hepatitis develop only a few mild symptoms and minimal hepatocyte damage. This mild disease is called acute anicteric hepatitis. The minimal degree of liver cell damage is reflected by mild elevations of serum bilirubin, γ -globulin, and hepatic transaminase (alanine transaminase [ALT], aspartate transaminase [AST]) values to about twice normal. Subsets of patients experience enough hepatocyte destruction to produce significant liver dysfunction characterized by interruption of bilirubin metabolism and flow. This results in clinical jaundice and acute icteric hepatitis. Icteric hepatitis is generally accompanied by fever, right upper quadrant abdominal pain, nausea, vomiting, dark urine, acholic (light colored) stools, and worsening of systemic symptoms. Clinical symptoms are accompanied by elevations of the serum bilirubin, γ -globulin, and hepatic transaminases from 4 to 10 times above normal. Most patients with either acute anicteric or icteric hepatitis go through the convalescence stage

to complete recovery without developing complications or chronic sequelae. Liver injury is immune mediated with cytolytic T cells maintaining the primary role in cell destruction.6 Death of hepatocytes results in viral elimination and eventual resolution of the clinical illness. Viremia begins soon after infection and continues throughout the time liver enzymes are elevated.2 The host antibody response to HAV initially appears as the viral particles begin to disappear from stool. Like most host antibody responses, antibodies of the IgM class appear first and imply recent infection. IgM anti-HAV usually is detectable 5 to 10 days before symptoms appear. After 2 to 6 months, the IgM antibodies are replaced with IgG antibodies, which usually persist throughout life and confer immunity to HAV.2 Patients who receive immunoglobulin will have low titers of anti-HAV for several weeks after inoculation.2 Patients who receive hepatitis A vaccine will also have anti-HAV.2

CLINICAL PRESENTATION 2 Hepatitis A infection usually results in an acute, self-limited dis-

ease that rarely leads to fulminant hepatic failure. The clinical features of acute hepatitis A are summarized in Table 40–1. After an average incubation period of 28 days, with a range of 15 to 50 days, symptomatic individuals will experience an abrupt onset of anorexia, nausea, vomiting, malaise, fever, headache, and right upper quadrant abdominal pain.2 Patients with underlying liver disease such as chronic hepatitis C infection are more likely to develop fulminant hepatic failure.7 Clinical symptoms also vary with age. Children younger than 6 years old are usually asymptomatic or have a mild influenzalike illness without clinical jaundice.2 In contrast, more than 70% of infected adults and older children display the characteristic clinical syndrome of acute hepatitis with elevated hepatic transaminase levels and jaundice.2 The vast majority of people who become ill with HAV com2 pletely recover. HAV infection usually produces a self-limited illness that lasts less than 2 months, although 10% to 15% of patients exhibit a cholestatic illness with predominant elevations of alkaline phosphatase, γ -glutamyl transferase, and total bilirubin that continues or is relapsing for up to 6 months.2 Pruritus is often a major complaint

TABLE 40–1. Clinical Presentation of Acute Hepatitis A Signs and symptoms r The preicteric phase brings nonspecific influenza-like symptoms consisting of anorexia, nausea, fatigue, and malaise r Abrupt onset of anorexia, nausea, vomiting, malaise, fever, headache, and right upper quadrant abdominal pain with acute illness r Icteric hepatitis is generally accompanied by dark urine, acholic (light-colored) stools, and worsening of systemic symptoms r Pruritus is often a major complaint of icteric patients Physical examination r Icteric sclera, skin, and secretions r Mild weight loss of 2 to 5 kg r Hepatomegaly Laboratory tests r Positive serum IgM anti-HAV r Mild elevations of serum bilirubin, γ -globulin, and hepatic transaminase (alanine transaminase [ALT], and aspartate transaminase [AST]) values to about twice normal in acute anicteric disease r Elevations of alkaline phosphatase, γ -glutamyl transferase, and total bilirubin in patients with cholestatic illness

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of these patients.5 A relapse is rarely associated with extrahepatic manifestations such as cryoglobulinemia, arthritis, and vasculitis. No cases of a chronic carrier state or chronic hepatitis have been reported. The gold standard method of diagnosis of an acute HAV infection involves detection of serum IgM anti-HAV that becomes positive at the onset of symptoms. The antibody peaks during the early phase

VIRAL HEPATITIS 739

of convalescence and remains positive for 4 to 6 months after the onset of the disease. In addition to the presence of antibody, the diagnosis is based on the clinical suspicion, characteristic symptoms, and elevated aminotransferases and bilirubin. HAV infection cannot be differentiated from other types of viral hepatitis by clinical or epidemiologic features.2


TREATMENT: Hepatitis A Virus Infection
DESIRED OUTCOME The ultimate goal in treating acute viral hepatitis is to return the individual to the previous state of health. Intermediate goals while the individual is acutely symptomatic and infectious include decreasing morbidity and acute mortality, normalizing aminotransferases (to stop hepatic inflammation), stopping viral replication in the host, and ultimately eradicating the virus.


GENERAL APPROACH TO THERAPY Management of acute HAV infection is primarily supportive, as the disease is usually self-limited and the majority of patients infected with HAV will have full clinical and biochemical recovery within 12 weeks.6 General measures include a healthy diet, rest, maintaining fluid balance, and avoiding hepatotoxic drugs and alcohol. Special diets are of no benefit. Management includes laboratory tests (International Normalized Ratio and liver function tests) aimed at identifying the group of patients at risk of developing fulminant liver failure. Hospitalization is necessary only for those who have prolonged vomiting, coagulation defects, or fulminant hepatitis.


PHARMACOLOGIC THERAPY 3 Pharmacologic agents offer no clear benefit in the treatment

of patients infected with HAV. Corticosteroids have been used in patients with acute HAV when cholestatic hepatitis or fulminant hepatic failure is evident. However, controlled trials have failed to demonstrate any benefit and in some cases the use of corticosteroids may worsen clinical outcomes.8


FULMINANT HEPATITIS (ACUTE LIVER FAILURE) Liver injury that results in fulminant hepatic necrosis and acute liver failure is relatively rare. When it occurs, death results in days or weeks in nearly 80% of cases.9 Any potential hepatotoxic agent (e.g., acetaminophen) can be responsible, although viral hepatitis is the most common cause worldwide, especially HBV (1% of patients with acute hepatitis B develop fulminant hepatitis).9−11 Fulminant hepatitis caused by HAV occasionally occurs; acute liver failure caused by HCV is rare.9 Patients with fulminant hepatic necrosis typically develop signs and symptoms of viral hepatitis, and then rapidly develop evidence of hepatic failure. The clinical syndrome is usually a 1- to 3-week

course of hepatic failure and encephalopathy with coma developing within 8 weeks of the onset of acute hepatitis. Hyperexcitability, insomnia, somnolence, irritability, and impaired mental status are evidence of impending hepatic failure. Ominous signs include a rapid decrease in liver size, a rapid decline in aminotransferase levels, prolonged International Normalized Ratio or prothrombin time, and hypoglycemia. Manifestations of hepatic failure include metabolic encephalopathy, coma, coagulation defects, ascites, and edema. In fulminant liver failure, complications include gastrointestinal hemorrhage, sepsis, cerebral edema, renal failure, lactic acidosis, and disseminated coagulopathy, with death resulting from bleeding, cerebral edema, hypoglycemia, infection, and/or multisystem organ failure.9 Prompt referral for liver transplantation is the therapy of choice for most patients with fulminant hepatic failure.9 Transplantation should be considered in all cases in which the patient demonstrates progressive clinical deterioration (encephalopathy, hypoglycemia, metabolic acidosis, renal failure, and coagulation defects).11 Patients should be transferred at the first sign of altered mental status, because these patients often worsen very rapidly. One-year survival rates with liver transplantation for fulminant hepatitis are 50% to 80% (as compared to 17

Dose 720 ELISA unitsa 1440 ELISA units 25 Units 50 Units

Volume (mL)

Number Schedule Doses (months)b

0.5

2

0, 6–12

1

2

0, 6–12

0.5 1

2 2

0, 6–18 0, 6

a Havrix previously was also available as 360 ELISA units per dose. This formulation was administered as a three-dose schedule for persons 2 to 18 years of age. It is no longer available. b 0 months represents the timing of the initial dose; subsequent numbers represent months after the initial dose. From Centers for Disease Control.2

VIRAL HEPATITIS 741

endemic areas. Vaccination is cost effective for individuals who are likely to spend several or prolonged periods in highly endemic countries. On average, vaccination of the U.S. general public is unlikely to be cost-saving, as the cost per infection prevented can be several thousands of dollars.16,17 In contrast, vaccination programs targeted to patients at risk for developing hepatitis may be cost effective. For example, substitution of HBV vaccination programs in sexually transmitted disease clinics serving a million patients with a combined HAV/HBV vaccine was anticipated to prevent 2263 occult HAV infections and cost $13,397 per quality-adjusted life year (QALY) gained.18 Similarly, targeted vaccination of patients with chronic HCV with HAV vaccination has been deemed cost-effective.19

HEPATITIS B VIRUS Worldwide, over 400 million people are infected with some form of chronic HBV. HBV is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The economic consequences of infection with HBV are staggering. Primary prevention through universal vaccination of neonates and adolescents is likely to have the largest impact on curtailing this disease.20

EPIDEMIOLOGY HBV infection is a worldwide public health problem. The prevalence of HBV infection varies in different geographic areas of the world, with carrier rates ranging from 0.1% to 15%.20 A review of National Health and Nutrition Examination Survey (NHANES) II (1976–1980) and NHANES III (1988–1994) reported a 5.5% prevalence of HBV infection in the United States.21 Black participants had the highest prevalence (12.8%) compared to whites and Hispanics (3% to 5%).21 In highly endemic areas (China, Southeast Asia, the Middle East, and parts of Africa and South America), HBV spread is predominantly by mother-to-infant perinatal transmission and by child-to-child transmission. In highly endemic areas high rates of chronic viral carriage and virus-associated primary hepatocellular carcinoma are seen. In parts of the world in which the endemicity of HBV is relatively low (North America, Australia, Western Europe, and temperate South America), the chronic viral carriage rate is correspondingly low, mother-to-infant transmission is relatively uncommon, and HBV transmission occurs either through intimate contact or parenterally. High-risk groups in low endemic areas include intravenous drug abusers, multitransfused patients, health care providers, male homosexuals, heterosexual partners of HBV-infected people, and heterosexual partners of human immunodeficiency virus (HIV)– infected individuals.20 Transmission of HBV in the United States occurs predominantly through contact with infected blood products or body secretions (e.g., saliva, vaginal fluids, and semen). The routine practice of screening blood donors for hepatitis B surface antigen (HBsAg) has essentially eliminated HBV as a cause of posttransfusion hepatitis. However, products or concentrates of blood such as clotting factors can remain infective despite prescreening for HBsAg. Excluding cases resulting from clotting factor concentrates, most blood-borne HBV transmissions are a consequence of accidental inoculation by health care workers or the sharing of needles by intravenous drug abusers (percutaneous exposure).20 The chief obstacles to eradication of HBV include the carrier state and infections in utero, 4 neither of which is preventable. Individuals who acquire HBV as children (postnatally) have a very high rate of becoming chronic HBsAg carriers.32 A small percentage of these children develop complications such as cirrhosis or hepatocellular carcinoma within

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20 years of being infected.22 Unfortunately, for infants who acquire HBV in utero, progression to chronic liver disease occurs in about 90% of cases. Immunization of neonates and adolescents is now the current standard of care in the United States; however, only half of the world’s countries have such a policy in place.23

ETIOLOGY HBV is the smallest known deoxyribonucleic acid (DNA) virus, with roughly 3200 base pairs in its genome.24 It is an enveloped, doublestranded DNA virus belonging to the Hepadnaviridae family. This family of viruses replicates in the liver and cause hepatic dysfunction cycles that ultimately lead to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. A small spherical and tubular particle known as HBsAg can be found circulating in the bloodstream of infected patients. The viral core contains a single molecule of partially doublestranded DNA referred to as the HBV core antigen (HBcAg). A DNA polymerase viral peptide is also found in the core and is referred to as the HBV e antigen (HBeAg).24 Clearance of HBV is highly dependent on expression of HBeAg, which when expressed on the hepatocellular surface induces a potent immunologic response. A lack of HBeAg expression in certain precore mutants results in more aggressive hepatic disease which is resistant to interferon-α (IFN-α) therapy and a higher probability of graft failure after liver transplantation.25 In addition, HBV has been classified into seven genotypes (A through G) with geographic variance in distribution of these genotypes; specifically, genotype A, which is predominantly found in North America, compared to genotypes B and C, which are found in Southeast Asia. HBV genotype C has been associated with more active necroinflammation in the liver compared to genotype B. The role of other HBV genotypes on the natural history of HBV is not well characterized.26

PATHOPHYSIOLOGY HBV is not directly cytopathic; instead liver injury is immune related, and T lymphocytes are important for both the host cellular and humoral responses.27 Recovery from acute HBV infection depends on both B-cell and T-cell responses. B-cell–dependent antibodies are produced to presurface and surface antigens. Cytotoxic T lymphocyte response is mounted against multiple epitopes in the HBV envelope, nucleocapsid, and polymerase regions.27 Cytotoxic T lymphocyte–mediated lysis of infected hepatic cells occurs, resulting in liver injury. Immune clearance of virus is often accompanied by worsening liver disease, known as a flare. An extreme example of this is seen in fulminant hepatitis B, when there is often no evidence

of HBV replication when the patient presents—the virus has been rapidly and aggressively cleared by the infected individual’s immune system. Immune-mediated viral clearance can also occur through noncytolytic pathways via cytokine release.27 In contrast, development of chronic HBV is hypothesized to be a function of poor cytotoxic T-lymphocyte response to viral antigens. HBV is not considered a cytopathic virus; in certain circumstances, however, it can cause direct cytotoxic liver injury. Direct cytopathic liver injury can occur when the viral load is very high, as in the rare fibrosing cholestatic hepatitis.27 After the HBV enters the vascular compartment, it migrates to the liver, where primary replication occurs. The incubation period of HBV is 1 to 6 months—much longer than HAV.27 HBV replication occurs in liver cell nuclei, with HBsAg produced in the cell cytoplasm and expressed on the cell surface. These particles are also found circulating in the plasma of patients with acute HBV, the chronic carrier state, and chronic HBV infection.27 In acute HBV infection, serologic markers proceed in sequence from the development of HBsAg followed by HBeAg (30 to 60 days prior to onset of clinical symptoms) through to the appearance of anti-HBs in late convalescence (Table 40–4).20 Antibody to HBsAg (anti-HBs) is initially detected as the concentration of HBsAg in plasma wanes (but is probably present much earlier than detected by standard serologic assays). The presence of anti-HBs without HBsAg indicates protective immunity (see Table 40–4).20 Other antigen markers of HBV infection include pre-Surface1 and pre-Surface2 for the envelope, and the functional X protein. These markers are not routinely used clinically. Anti-HBc, the antibody directed against HbcAg, is first detected shortly after the onset of acute cellular injury (see Table 40–4). Anti-HBc is initially of the IgM class and signifies acute HBV infection. IgG-class anti-HBc antibodies become detectable several months following the acute HBV infection and persist along with HBs antibody for life. Anti-HBc is detectable in essentially all patients who have been exposed to HBV.20 The presence of plasma anti-HBc IgG antibodies signifies prior infection, but it is not protective (see Table 40–4).20,28 HBeAg is a protein subunit of the viral core detected in plasma immediately prior to or at the onset of hepatocyte injury and correlates with a high degree of infectivity. In contrast, the presence of antigen against HBe (anti-HBe) correlates with a very low degree of infectivity and portends complete recovery. Anti-HBe becomes detectable either immediately after the peak of liver injury or in early convalescence, and can persist for years. HBV may also play an indirect role in the malignant transformation of hepatocytes through mechanisms related to expression of viral surface markers with oncogenic potential or through integration of viral DNA into the cell.28

TABLE 40–4. Interpretation of the Laboratory Profile in Hepatitis B Virus (HBV) Infection Pattern Not infected/early incubation Early acute HBV infection Acute HBV infection Chronic HBV infectiona Resolved infection “Window” period following acute HBV infection

Is Patient Infectious? HBsAg No Yes Yes Yes No No

− + + + − −

HBeAg

Anti-HBc Total

Anti-HBs

Anti-HBe

− − + +/− − −

− − + + + +

− − − − + −

− − − − + +

a Patient should be evaluated for complications of chronic infection such as cirrhosis and hepatocellular carcinoma. anti-HBc, antibody to HbcAg; anti-Hbe, antibody to HbeAg; anti-HBs, antibody to HbsAg; HBcAg, hepatitis B core antigen; HbeAg, hepatitis B e antigen; HBsAg: hepatitis B surface antigen. From Lee.10

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CLINICAL PRESENTATION ACUTE HEPATITIS B The clinical course of HBV infection and the associated clinical features cannot be differentiated from other types of viral hepatitis based on symptoms. The duration of incubation is highly dependent on age and can vary between 6 and 24 weeks. Infants do not develop any symptoms and children between the ages of 1 and 5 years are asymptomatic in 85% to 95% of the cases.29 Symptomatic infections vary in severity and include fever, anorexia, nausea, vomiting, jaundice, dark urine, clay-colored or pale stools, and abdominal pain. Extrahepatic manifestations of HBV infection rarely occur and may include skin rash, arthralgias, and arthritis. Hepatic failure occurs rarely, with a case fatality rate of 0.4%.30 Acute HBV infection is diagnosed by the presence of anti-HBc IgM (see Table 40–4). There are periods during the course of acute HBV infection when specific serologic markers are absent; the lack of such markers complicates diagnosis. These “window” periods can be seen in the early incubation phase when HBsAg and HBeAg are not detectable despite the presence of ongoing viral replication, and early in convalescence when these two antigens are cleared prior to the appearance of anti-HBs antibody. Markers of HBV replication (HBV DNA and DNA polymerase) are sensitive indicators, and are occasionally obtained when a patient is suspected to be in the serologic window period. Low levels of HBV DNA can be detected in peripheral mononuclear cells and livers of patients several years after recovery from acute HBV. These data indicate that HBV is not eradicated in these patients and can be reactivated when their immune systems are suppressed.29

CHRONIC HEPATITIS B The presence of HBsAg in serum for at least 6 months or the presence of HBsAg and the absence of anti-HBc IgM meets the definition of chronic HBV infection. In addition, the presence of HBV DNA greater than 105 copies/mL and persistent or intermittent elevation in AST/ALT levels meet the diagnostic criteria for HBV.30 Risks associated with development of chronic HBV include the presence of 4 renal failure, diabetes, or HIV.31 The probability of developing chronic HBV is inversely proportional to age; infants have a 90% risk while adolescents and adults have ∼10% risk. Patients who develop chronic HBV are subsequently predisposed to developing chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). The clinical presentation of chronic HBV is summarized in Table 40–5. Progression from chronic HBV to HCC is also age dependent, with prospective studies indicating a 25% risk in patients who acquire the disease as infants, compared to a 15% risk if contracted as

VIRAL HEPATITIS 743

TABLE 40–5. Clinical Presentation of Chronic Hepatitis Ba Signs and symptoms r Easy fatigability, anxiety, anorexia, and malaise r Ascites, jaundice, variceal bleeding, and hepatic encephalopathy can manifest with liver decompensation r Hepatic encephalopathy is associated with hyperexcitability, impaired mentation, confusion, obtundation, and eventually coma r Vomiting and seizures Physical examination r Icteric sclera, skin, and secretions r Decreased bowel sounds, increased abdominal girth, and detectable fluid wave r Asterixis r Spider angiomata Laboratory tests r Presence of hepatitis B surface antigen for at least 6 months r Intermittent elevations of hepatic transaminase (alanine transaminase [ALT] and aspartate transaminase [AST]) and hepatitis B virus DNA greater than 105 copies/mL r Liver biopsies for pathologic classification as chronic persistent hepatitis, chronic active hepatitis, or cirrhosis a Chronic hepatitis B can be present even without all the signs, symptoms, and physical examination findings listed being apparent.

an adolescent.29 In addition, very high HBV DNA levels, normal ALT, and the presence of HBeAg characterize chronic HBV acquired through perinatal transmission. This immune-tolerant phase can last for 10 to 30 years, allowing for individuals with perinatal acquisition to be infectious in their adulthood and perpetuate vertical transmission of the disease. In contrast, children and adults who acquire chronic HBV infection present in the immune-clearance phase, which is marked by clearance of HBeAg, in 70% of cases within 10 years. Most patients who seroconvert remain HBeAg-negative and anti-HBe–positive with normal ALT and low HBV DNA, and are considered to be in an “inactive carrier state.”29 Liver biopsies performed in patients with chronic HBV infection are classified as chronic persistent hepatitis, chronic active hepatitis, and cirrhosis.33 Histologic results do not correlate with symptoms and often patients are asymptomatic until the development of cirrhosis.34 Cirrhosis is manifested by interlacing strands of fibrous tissue with nodules of regenerating cells resulting in a characteristic small and knobby-appearing liver. This form of injury is irreversible and can be exacerbated by heavy alcohol consumption and concomitant infection with HCV or HIV.35 Hepatic decompensation as a result of cirrhosis includes ascites, jaundice, variceal bleeding, and hepatic encephalopathy. The 5-year risk of decompensation after the development of cirrhosis is estimated to be 20%.26


TREATMENT: Hepatitis B Virus Infection
DESIRED OUTCOME No specific therapy is available for the management of acute HBV infection. Development of fulminant hepatitis secondary to acute HBV is rare and is managed with supportive care (see section on fulminant hepatitis). The long-term complications of chronic HBV include development of cirrhosis, liver failure, and HCC. The key goal of therapy for chronic HBV is to eradicate or permanently suppress HBV. The short-term objective is to limit hepatic inflammation and to reduce

the risk of fibrosis and/or decompensation. The longitudinal goal is to prevent transaminase flares and the development of long-term complications, as well as to prolong survival. Loss of HBeAg, either spontaneously or with pharmacologic therapy, is independently associated with improved survival in patients with chronic HBV. Thus HBeAg loss and development of anti-HBeAg is a critical outcome measure in patients with chronic HBV. In addition, durability of specific pharmacologic therapy for maintenance of HBeAg seroconversion is also important. Therapeutic strategies include the use of immunomodulators such as α-interferons and nucleoside analogs. Prevention of HBV

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resistance to nucleoside analogs during therapy is vital for adequate management of these patients.


GENERAL APPROACH TO TREATMENT Acquisition of HBV within the first 5 years of life is associated with a higher risk for development of cirrhosis.26 Consequently, early treatment of infants and children should be attempted, given that clearance of HBsAg rarely occurs spontaneously in this group. Spontaneous clearance of HBeAg occurs at a rate of approximately 10% per year in older groups.36 Individuals with long-standing disease with hepatic inflammation are likely to be poor responders to therapy and require the most intensive management. Numerous pharmacologic agents with varying modes of action are in clinical development. Three agents are currently approved for use in the United States by the Food and Drug Administration and include interferon-α2b (IFN-α2b), lamivudine, and adefovir dipivoxil.37 No drug therapy is recommended for patients with normal ALT values because this group responds poorly to therapy. Instead quarterly to biannual follow-up of these patients for HCC surveillance and ALT assessment should be considered. Patients with persistent ALT levels greater than twice the upper limit of normal should be considered for treatment. Patients with rising ALT levels, specifically rising to greater than five times the upper limit of normal, are considered to be having an exacerbation. Lamivudine therapy should be used for exacerbations because it has a rapid onset of effect. In contrast, IFN-α2b onset of action may not be rapid enough to prevent hepatic decompensation.38 5 Therapeutic choice between lamivudine and interferon is more controversial for patients who are HBeAg-positive with ALT levels two to five times the upper limit of normal. Notably, the relative risk of relapse after HBeAg seroconversion with lamivudine therapy is about four times higher than with an α-interferon–containing regimen.39 The decision to treat individuals is ultimately a function of disease severity, history of flares, hepatic function, drug cost, sideeffect profile, and patient choice. The long-term effects of IFN-α2b are better known than those of lamivudine. In addition, extending the duration of lamivudine therapy with the intent to improve response risks development of resistant HBV mutations. The availability of adefovir dipivoxil is promising as rescue therapy after lamivudine because it is active against both wild-type and select mutants of HBV. However, well-controlled comparative trails of lamivudine to adefovir dipivoxil are not available. The role of combination therapy has yielded conflicting results and requires further evaluation.38,40


NONPHARMACOLOGIC THERAPY About 75% of the 400 million people with chronic HBV live in Asia. Herbal medication use is a common therapeutic modality in many parts of the world and has been studied extensively in China. A meta-analysis of over 500 papers, including randomized controlled trials, concluded that existing studies were of poor quality, limiting the definitive interpretation of results.41 However, the meta-analysis did identify that bufotoxin and kurorinone were associated with increased seroconversion of HBeAg and clearance of HBV DNA. Further evaluation of these active components as a possible therapeutic alternative is warranted, but they are not currently being recommended for routine use.


PHARMACOLOGIC THERAPY Patients considered for treatment are those who are HBsAg-positive for greater than 6 months with persistent elevations in serum aminotransferases, detectable markers of viral replication (HBeAg and HBV DNA) in serum, and signs of chronic hepatitis on liver biopsy. Although symptomatic patients are more apt to seek medical attention and to have these irregularities discovered, symptoms alone are not a basis for treatment. To be treated with IFN-α, patients should not have decompensated liver disease or any specific contraindications to the therapy being considered. Current strategies to eradicate HBV include the use of antiviral agents that alter viral replication or immunomodulatory agents that modify the host immune response. IFN-α2b (Intron A) was approved by the FDA for use in chronic HBV in 1992. IFN-α2b monotherapy 5 now is used only in selected subgroups of patients with HBV. Lamivudine (Epivir-HBV) was approved for use in chronic HBV in 1998, and has broader indications for use, but questions remain regarding optimal duration of use and management of resistant viruses. 6 Adefovir dipivoxil (Hepsera) was approved for use in chronic HBV, including lamivudine-resistant HBV, in 2002. End points of therapy for HBV include disappearance of HBV DNA and elimination of HBeAg (virologic response), resolution of elevated aminotransferases (biochemical response), and improvement of liver histology.38 HBeAg seroconversion, an even stricter marker of viral response, denotes the loss of both HBeAg and HBV DNA and the appearance of anti-HBe. Loss of HBsAg can occur even years after completion of therapy.


FIRST-LINE THERAPY The American Association for the Study of Liver Diseases (AASLD) has published its guidelines for the management of chronic HBV.32 In addition, the Asian Pacific Association for the Study of the Liver (APASL) has updated a consensus statement on the management of 5 chronic HBV.38 The choice of first-line therapy between IFN-α2b and lamivudine is dependent on the categorization of specific patient populations by HBeAg positivity and ALT level. As stated earlier, factors such as disease severity, history of flares, hepatic function, drug cost, side-effect profile, and patient choice ultimately drive drug selection. In patients with chronic HBV who are HBeAg-positive and have intermittent or persistent elevation of ALT, either interferon or lamivudine may be used as first-line therapy. Lamivudine should be selected in patients at risk for decompensation given its rapidity of onset. A meta-analysis of 15 randomized controlled trials demonstrated that 33% of patients had loss of HBeAg with 12 to 24 weeks of therapy with IFN-α2b compared to 12% in controls.42 Pretreatment ALT levels of greater than 100 international units per liter and low HBV DNA levels (2 x ULN

Liver biopsy

HBeAg positive

HBeAg negative

Liver biopsy & HBV DNA

Necroinflammation

No

Yes Treatment if: HBV DNA > 105 copies/mL, or moderate inflammation

Recheck ALT every 3 to 6 months Decompensated liver disease or contraindication to interferon-α

No

Interferon- α2b

or

Yes

Lamivudine

Failure Breakthrough with YMDD mutant and increase in ALT

Lamivudine

If HBeAg seroconverts, continue for 3 to 6 months. If no seroconversion then treat long term

Continue lamivudine and consider adefovir

cannot be used in patients with decompensated cirrhosis. Lamivudine is better tolerated but does not sustain a durable response and may be affected by resistant HBV mutants. Specific recommendations from the AASLD and APASL are summarized as follows and apply to both adults and children (Fig. 40–1). 1. Patients with HBeAg-positive chronic HBV: ALT >2 times the upper limit of normal (ULN) or moderate to severe hepatitis on biopsy: Treatment may be initiated with either lamivudine or interferon-α ALT >2 times ULN: Treatment with lamivudine or interferon-α should be limited to patients with significant necroinflammation on liver biopsy. Patients should have their ALT assessed every 3 to 6 months.

FIGURE 40–1. Treatment algorithm for the management of patients with chronic hepatitis B virus infection. ALT, alanine transaminase; HBeAg, hepatitis B e antigen; ULN, upper limit of normal.

2. Patients with HBeAg-negative chronic HBV: Only patients with ALT >2 times ULN, HBV DNA >105 copies/mL, or moderate to severe hepatitis on biopsy should be considered for treatment with lamivudine or interferon-α. 3. Patients who fail to respond to a course of interferon-α and have ALT >2 times ULN, HBV DNA >105 copies/mL, or moderate to severe hepatitis on biopsy may be treated with a course of lamivudine. 4. Patients with decompensated cirrhosis: Interferon-α should not be used and lamivudine may be considered in these patients. 5. Patients in an inactive HBsAg carrier state: No treatment is indicated.

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ALTERNATIVE DRUG TREATMENTS Adefovir dipivoxil is the prodrug of adefovir, a nucleotide analog active against HBV. In vitro and preliminary clinical evidence demonstrate that adefovir is effective in suppressing HBV replication, 6 including lamivudine-resistant mutants. Two randomized doubleblind placebo-controlled trials were conducted in both HBeAgpositive and HBeAg-negative patients with approximately 50% of cases with ALT levels greater than 2 times ULN.46,47 Loss of HBeAg was noted in 24% of patients receiving adefovir dipivoxil 10 mg daily compared to 11% in the placebo group at week 48.47 A similar loss was noted with adefovir dipivoxil 30 mg daily; however, the higher dose was associated with an 8% incidence of reversible nephrotoxicity (≥0.5 mg/dL increase in serum creatinine). Given that HBeAg loss cannot be assessed in HBeAg-negative patients with chronic HBV, other endpoints such as HBV DNA reduction, normalization of ALT, and changes in liver biopsy inflammatory scores were assessed. Improvement in histologic liver abnormalities were noted in twice as many adefovir dipivoxil–treated patients compared to those on placebo.46 Undetectable HBV DNA levels were noted in 51% of patients on adefovir dipivoxil compared to none in the placebo arm. ALT normalization was also significantly higher in the adefovir dipivoxil group. No development of resistance to adefovir was noted in these trials. Comparative trials of adefovir dipivoxil to lamivudine have not been conducted to ascertain the placement of this agent. Famciclovir, an oral prodrug of penciclovir, is an effective agent for suppression of HBV, but is associated with a low rate of HBeAg clearance compared to lamivudine. Its use is limited by the need for thrice-daily administration, cross-resistance with lamivudine, and low efficacy.48 Combination therapy with lamivudine or thymosinα 1 is associated with improved HBeAg seroconversion compared to famciclovir alone.49 Thymosin-α 1 is an immunomodulatory agent that enhances the activity of T-helper1 cells. A meta-analysis of studies evaluating thymosin-α 1 indicated that it has limited activity during therapy, but induces a virologic response 12 months after the end of therapy.50 More data are necessary to evaluate the role of thymosinα 1 . Prednisone administration as a tapering course prior to antiviral therapy has been found to be beneficial in small subset of patients.51 However, patients with underlying cirrhosis are at an increased risk for fatal exacerbations when prednisone priming is given, and its use is not recommended in these patients. Other antiviral agents that have shown promising results in clinical trials include emtricitabine, entecavir, and clevudine.38 In addition, therapeutic vaccines against specific HBV epitopes and proinflammatory cytokines are being evaluated.52


SPECIAL POPULATIONS In contrast to IFN-α2b with its significant adverse side-effect profile, almost all patients are candidates for lamivudine therapy. Patient groups in which lamivudine has shown benefit include various transplant patients, those with decompensated cirrhosis, and patients with HBV mutants with mutations in the precore region of the viral genome who present as HBeAg-negative and HBV DNA-positive. Patients with normal aminotransferase levels should not be treated. Monitoring of this group, with treatment if disease progresses, is more advantageous than treatment, because many of these patients will not have progression of liver disease, while therapy is associated with cost and adverse event risk. Whereas the use of IFN-α2b is discouraged in patients with decompensated cirrhosis, an open trial of 35 such patients with lamivudine demonstrated significant benefit in laboratory and clinical

markers in the 23 patients who were maintained on therapy for greater than 6 months. HBV DNA was undetectable in all patients after 6 months and adverse effects were minimal.53 Lamivudine also showed no decrease in its activity in patients who had active replication, but were HBeAg-negative. After a year of treatment, 65% became HBV DNA–negative and had normal transaminases. Patients coinfected with HIV may not respond as well to IFN-α2b because HIV-associated immunosuppression can block the antiviral actions of IFN-α2b. These patients can be considered for therapy if their disease is relatively well controlled.54 Only a small proportion of cases of HBV infection in the United States are in children. The efficacy of IFN-α2b in children seems comparable to that in adults and those with elevated ALT levels at initiation of therapy are more likely to respond. A comparative trial of IFN-α2b 5 million units/m2 versus 10 million inits/m2 three times weekly for 6 months showed greater HBeAg clearance with the higher dose (53% vs. 7%).55 Children tolerate IFN-α2b therapy better than adults. Although some schemes of induction therapy dosing of IFN-α2b have been successful in patients who had not responded to previous IFN-α2b therapy, a course of lamivudine should be tried first before trying increased IFN-α2b doses.56 There are insufficient data to clarify management of pregnant patients, immunosuppressed patients, and patients coinfected with HCV.


DRUG CLASS INFORMATION
Interferons Interferon-α was first demonstrated to have benefits in patients with chronic HBV in the early 1970s. Development of recombinant technology and eventual availability of commercial forms of IFN-α have led to several randomized clinical trials in various countries. For a more detailed review of currently available interferon formulations including their pharmacology and disposition, please refer to the HCV section on interferons. IFN-α2b is currently the only interferon approved by the FDA for management of chronic HBV. As compared to a placebo response of 12% to 17%, 33% to 37% of patients respond to IFN-α2b therapy by losing HBeAg and HBV DNA.42 Even though most of these patients will maintain a long-term response, the low overall response rates combined with the adverse effects and need for subcutaneous dosing make IFN-α2b a less-than-ideal agent. Pretreatment predictors of response to IFN-α2b include low viral load (HBV DNA 100). For this subset of chronic HBV patients, an IFN-α2b regimen is a rational option, although these same parameters predict response for lamivudine, an alternative agent. Resolution of HBV viremia with IFN-α2b is associated with a transient exacerbation of the hepatitis, marked by a rise in serum ALT levels during the second or third month of therapy. Although IFN-α2b may have direct antiviral effects, this flare is related to immunomodulatory effects resulting in an increased host response (Fig. 40–2). In patients who respond to interferon, HBV DNA levels decrease within days of starting therapy. After 8 to 12 weeks, ALT levels increase, and the patient loses HBV DNA and HBeAg. ALT levels then normalize, and the patient develops anti-HBe.29 Without the flare, loss of viral replication rarely occurs. Patients infected with precore HBV mutants that prevent HBeAg expression (HBeAg-negative and HBV DNA– positive) are less likely to respond to IFN-α therapy and have a higher rate of relapse upon discontinuation.37 About 10% of the responders to IFN-α therapy also clear HBsAg in the first year, and although

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HBsAg HBeAg

+ +

+ +

+ +

+ +/−

+ +/− − − − −

Interferon-α

HBV DNA Anti-HBe

Serum ALT

Anti-HBs

Normal ALT

Months

−1

0

1

2

3

4

5

6

12

24

FIGURE 40–2. Typical sustained response to IFN-γ in a patient with chronic hepatitis B. ALT, alanine transaminase; Anti-HBe, antibody to hepatitis B e antigen; Anti-HBs, antibody to hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen.

biochemical and histologic responses also occur, they are more frequent in the group responding virologically. Long-term follow-up of patients treated with IFN-α has shown that response is sustained in about 90% of patients at least 5 years after therapy, and that a distinct survival benefit is present in those who have a virologic response. IFN-α2b should be administered by subcutaneous injection as 5 million units daily or 10 million units thrice weekly in adults. In children, thrice-weekly subcutaneous injections of 6 million units/m2 to a maximum of 10 million units per dose is recommended. Patients with HBV who are HBeAg-positive should be treated for 16 weeks, while HBeAg-negative patients should be treated for 12 months.26 5 Administration of interferon is associated with significant side effects, which diminish with continued treatment. Flu-like symptoms such as fevers, chills, and myalgias should be expected during the first month of therapy, typically several hours after administration. Consequently administration of IFN-α2b at bedtime along with a nonsteroidal anti-inflammatory agent improves tolerability. Pegylated formulations of interferon (see discussion in HCV section) are likely to be more tolerable but have not been studied sufficiently in patients with HBV. Additional adverse events associated with longterm IFN-α therapy include cytopenia, alopecia, thyroid dysfunction, and depression. Depression is a very common complication of IFN-α therapy, especially during the last third to fourth month of therapy. A high index for suspicion for the mental well being of patients should be maintained, as suicides have been linked to IFN-α therapy.57


Lamivudine Lamivudine (Epivir-HBV, 3TC) is a nucleoside analog that competitively inhibits viral reverse transcriptase and terminates proviral DNA chain extension. Because it does not affect host response, it suppresses viral replication but does not directly eliminate the virus from the hepatocytes. Its efficacy is also not associated with, or dependent upon, the flare response seen with interferon. Like IFN-α2b though, lamivudine demonstrates higher response rates in patients with elevated transaminases (ALT >100) and lower viral loads.58

VIRAL HEPATITIS 747

Two double-blind randomized controlled trials in adults compared lamivudine 100 mg by mouth daily for 52 weeks versus placebo in previously untreated patients.43,44 The results are comparable except that one trial in Asia had a higher biochemical response in both treatment and placebo groups.44 Both trials demonstrated significant histologic, virologic, and biochemical responses with lamivudine. Lamivudine also prevented histologic worsening or the development of hepatic fibrosis. The results of the Asian trial are especially impressive because it was previously thought that this was a difficult population to treat because of acquisition of disease at an early age.44 Long-term outcomes are not proven, but the results of these trials are encouraging. Of note, the 32% rate of HBeAg loss in the American trial is similar to the response demonstrated with IFN-α2b. Upon discontinuation of lamivudine HBV DNA tends to rebound, but to levels less than the original baseline. Virologic responses were maintained in about 75% of lamivudine-treated patients 5 16 weeks posttherapy. Treatment beyond 1 year increases the rate of HBeAg loss and slows the rate and extent of HBV DNA return. However, extending the duration of therapy would be associated with a possible increase in adverse effects, increased cost, and increased development of resistance to lamivudine. But a recent pilot study evaluating a 3-year lamivudine regimen in 16 patients noted histologic improvement despite development of lamivudine-resistant mutants and virologic breakthrough.59 Mutations in regions of reverse transcriptase, primarily the YMDD locus, confer resistance against lamivudine. These mutations occur after about 6 months of lamivudine therapy, are usually accompanied by increases in ALT and HBV DNA, and are more common in patients with elevated baseline viral loads. In the two lamivudine trials, the incidence of these mutations was 14% and 32%, respectively, after 1 year of therapy.43,44 It is thought that the mutant viruses are relatively less harmful because they are not able to replicate as effectively, but the mutants are replaced by wild-type virus upon treatment discontinuation. Despite the development of resistance, with continued lamivudine therapy the ALT and HBV DNA often remain below baseline levels and some patients may still convert from a HBeAgpositive state. In the foregoing studies, one reported no association between treatment and transaminase level changes, whereas the other reported posttreatment levels greater than three times baseline in 25% of the treatment group, compared to 8% in the placebo group. A different cohort of 55 patients had much a higher mutation rate (58% after 2 years of lamivudine therapy), with 13 patients (24%) experiencing an ALT spike over 10 times the normal range, and 3 patients (5%) demonstrating hepatic decompensation during the flare.60,61 Lamivudine has a much less toxic adverse effect profile than IFN-α2b, with serious side effects occurring at rates similar to those of placebo.58 The most commonly reported are fatigue, nausea and vomiting, headache, cough, and diarrhea. It is administered as a tablet or oral suspension at a dose of 100 mg orally once daily. Lamivudine is well absorbed and has renal elimination, requiring dosage adjustment if the creatinine clearance is 30 kg/m2 had a 77% lower chance of response to therapy compared to overweight and normal-weight patients.97 The exact mechanism of this interaction between weight and effect is not known. However, the natural progression of disease may be faster in obese patients and may be related to nonalcoholic steatohepatitis.98,99


DRUG CLASS INFORMATION
Interferons Three FDA approved IFN-α preparations are currently available in the United States and include IFN-α2a (Roferon-A), IFN-α2b (Intron A), and IFN alfacon-1 (Infergen). IFN-α2a and IFN-α2b are naturally occurring cytokines that have been manufactured using human recombinant techniques in Escherichia coli.100 In contrast, IFN alfacon-1 is a non–naturally occurring type 1 interferon also produced using human recombinant techniques, but it has a tenfold higher affinity for cell surface receptors.100 Despite this theoretical higher activity, IFN alfacon-1 has not been found to be superior to IFN-α2b. The mechanism of action of these interferons includes activation of tyrosine kinases that upregulate production of several gene products like 2 -5 oligoadenylate synthetase, β 2 -microglobulin, neopterin, and p68 kinases. These gene products are responsible for the immunomodulatory, antiviral, and antiproliferative properties of these agents. All of these products have to be administered subcutaneously three times a week. The dosage of 3 to 5 million units of IFN-α2a and IFN-α2b corresponds to 9- to 15-mcg doses of IFN alfacon-1. The expected rate of SVR response of these products is less than 20% when monotherapy is employed for 24 weeks. Flu-like symptoms such as headache, fatigue, and chills occur in more than two thirds of patients. Psychiatric adverse events such as nervousness and depression and hematologic toxicities such as neutropenia occur in almost a third of patients.101


Pegylated Interferons Peginterferon-α2a (Pegasys) and peginterferon-α2b (PEG-Intron) are FDA approved for use as monotherapy and in combination with ribavirin for the treatment of chronic HCV in patients with compensated liver disease who are interferon-treatment–na¨ıve. Their mechanism of action is similar to that of IFN-α, but they offer the advantage of higher and sustained concentrations compared to their nonpegylated versions.93 The size and branching of the polyethylene glycol structure affects tissue distribution and elimination of the parent compound. The polyethylene glycol moiety with peginterferon-α2a is

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TABLE 40–10. Side Effects of Interferon-α Early (in First 2 Weeks of Therapy) Fever Chills Myalgias Fatigue Malaise Nausea Sleep disturbance Abdominal pain

Hematologic

Neuropsychiatric

Autoimmune

Neutropenia Thrombocytopenia Anemia

Irritability Mood lability Depression Tearfulness Delirium Paresthesias Seizures Psychosis

Development of autoantibodies Hepatitis Thyroid dysfunction Thyroiditis Arthropathy Type I diabetes mellitus Exacerbation of psoriasis or lichen planus Exacerbation of other autoimmune phenomena

Diarrhea Headache Appetite changes

Miscellaneous Chronic fatigue Infections Increased sleep requirement Anorexia Weight loss Myalgias Low-grade fevers Decreased libido Alopecia Hypertriglyceridemia Irritability Anxiety Depression Attention span deficits

Absolute contraindications to use of interferon include current or past psychosis or severe depression, neutropenia or thrombocytopenia, organ transplant (except liver), symptomatic heart disease, decompensated cirrhosis, and uncontrolled seizures. Relative contraindications to interferon include uncontrolled diabetes and autoimmune disorders.

approximately twice the size of that of peginterferon-α2b. Consequently the elimination half-life of peginterferon-α2a and peginterferon-α2b are 80 and 40 hours, respectively. This extension in half-life is in stark contrast to the nonpegylated interferons, which have a half-life of ∼5 hours. Peginterferon-α2a should be administered as a 180-mcg dose subcutaneously once weekly for 48 weeks. In contrast, peginterferon-α2b follows a weight-based dosing strategy of 1.5 mcg/kg subcutaneously for 1 year. Other pharmaceutical differences include a requirement for reconstitution of lyophilized peginterferon-α2b prior to administration, and a requirement for refrigeration for storage of peginterferon-α2a. In addition, peginterferon-α2a contains benzyl alcohol and so its use is contraindicated in neonates and infants. The adverse event profile of both agents is comparable to their respective nonpegylated versions. A summary of the incidence of specific adverse events is displayed in Table 40–10. Interferons can significantly decrease the clearance of theophylline, resulting in an increased area under the plasma concentration-versustime curve. Caution should be used when α-interferons are initiated in patients on theophylline, as they are likely to require dosage reductions based on therapeutic drug monitoring.101

PHARMACOECONOMIC CONSIDERATIONS Ten to thirty percent of patients progress to cirrhosis after 30 years. Most individuals with chronic HCV in the United States are between the ages of 30 and 49 years and have yet to manifest sequelae of the disease. As a result, the impact of HCV on future health care costs is anticipated to be high. Unfortunately, clinical decisions to treat individual patients are confounded by the inconsistent progression and a lack of ability to predict clinical deterioration. Therapy with pegylated interferons and ribavirin can be very expensive and associated with serious adverse events. Consequently, assessing the cost, benefits, and cost-effectiveness of the various therapies is vital. The cost of medications based on average wholesale prices with the use of a pegylated interferon plus ribavirin is approximately $30,000 for a 48-week course of therapy.63 The cost of using nonpegylated interferon plus ribavirin is approximately $15,000 to $20,000.63


Ribavirin Ribavirin is a synthetic nucleoside antagonist that is administered orally in combination with α-interferons. Ribavirin has limited utility as monotherapy and should be administered twice daily with food when used in combination with α-interferons. Ribavirin is currently available in two 200-mg oral formulations, as a capsule (Rebetol) and as a tablet (Copegus). When ribavirin is used with peginterferon-α2a for patients with HCV genotype 1, it is dosed as 400 mg orally every morning and 600 mg orally every evening in patients up to 75 kg, and 600 mg orally twice daily for patients weighing more than 75 kg. For patients with genotypes 2 and 3 ribavirin is administered 400 mg orally twice daily when administered with peginterferonα2b or peginterferon-α2a. Hemolytic anemia is a common complication of ribavirin therapy. Dosage reductions of ribavirin are recommended for changes in hemoglobin values when used in combination with peginterferon-α2a. In general, the combination of ribavirin with α-interferons is associated with numerous adverse events to multiple organ systems, and these should be discussed with patients prior to initiation of therapy.101

Assuming conservatively that 10% of all chronic hepatitis C patients (2.7 million) were eligible for therapy in the United States, with 70% of patients having HCV genotype 1, the estimated cost for the pharmaceuticals alone would be approximately $4 billion. However, the cost of not treating HCV could lead to future costs associated with hospitalizations related to ascites, cirrhosis, variceal hemorrhage, HCC, and liver transplantation. A recent pharmacoeconomic analysis to examine the clinical benefits and cost-effectiveness of newer treatments for chronic HCV infection evaluated the incremental cost-effectiveness of using peginterferon-α2b plus ribavirin compared to IFN-α2b plus ribavirin, and monotherapy regimens of both interferons.102 The incremental cost per quality-adjusted life year (QALY) saved for combination therapy with peginterferon-α2b compared to standard therapy was $36,000 and $55,000 for men and women with HCV genotype 1, respectively. A QALY is defined as a patient’s desire for a year of life at

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a diminished state of health compared with life at an optimal state of health. The use of the QALY as a measure helps create a uniform set of values that can be applied to cost-effectiveness data from heterogeneous patient groups. Interpretation of data defining cost per QALY is further hampered by a lack of a standard benchmark to define when a therapeutic regimen should or should not be used. Historically, a cost-effectiveness threshold of ≤$50,000 has been used to define a cost-effective regimen, but this remains controversial when applied clinically. The QALY gains ranged from 0.6 months with IFN-α2b monotherapy to 6 months with combination peginterferon-α2b and ribavirin therapy in men. The key points of contention when evaluating any pharmacoeconomic analysis are the basic underlying assumptions. A lack of clear understanding of the natural course of chronic HCV, including the probability of progression, impairs such studies. For the time being, patient selection on the basis of predictors of response coupled with informed patient decision making regarding benefits and risks is appropriate. CLINICAL CONTROVERSIES Clinicians argue that a noninvasive dynamic measure of hepatic fibrosis is necessary given that the probability of progression of chronic HCV is unclear. Others argue that the development of such tests will still not predict when to initiate therapy. The role of long-term continuous therapy with peginterferon alone or in combination with ribavirin is unknown. Some clinicians believe that long-term combination therapy may improve clinical outcomes in select nonresponders..

EVALUATION OF THERAPEUTIC OUTCOMES To carry out the plans outlined above requires that viral genotyping be performed at baseline, with a viral load being assessed if the patient has HCV genotype 1. Before treatment, all patients should have a viral genotype performed, have thyroid function assessed, and women should have a negative pregnancy test. Liver biopsy is a useful test to evaluate the stage of fibrosis and may aid with the decision of when to initiate or defer therapy. The value of a pretreatment liver biopsy in patients with HCV genotypes 2 and 3 is limited given that antiviral therapy may lead to a favorable response in up to 80% of patients.90 During treatment, a complete blood count with platelets should be performed weekly for the first 4 weeks and monthly thereafter. Thyroid tests should be checked every 3 to 6 months during treatment and 6 months after.101 HCV RNA should be evaluated at baseline and 12 weeks of combination therapy, and additionally depending on the intended duration. This is because early virologic response, defined as a minimum two log10 reduction in the viral load in the first 12 weeks of therapy, is predictive of SVR in patients with HCV genotype 1. Consequently, patients without an early virologic response should have their treatment discontinued to reduce cost and prevent unnecessary adverse events.90 Aminotransferase and qualitative HCV RNA should be performed at the end of therapy and 6 and 18 months after the cessation of therapy. Follow-up biopsy is not indicated. In patients with established or suspected cirrhosis, screening for HCC with abdominal ultrasound and serum α-fetoprotein is recommended.90 However, neither the time frame nor cost-effectiveness of such screening has been defined. For patients not started on therapy because of mild histologic disease or normal ALT, liver biopsy should be repeated in 4 to 5 years and ALT at 6-month intervals, respectively.

The side effects of α-interferons occur frequently enough that the patient should be informed about them before treatment begins (see Table 40–10). Many side effects are dose related. The most common and predictable effects are influenza-like and can be counteracted by premedication with a single dose of acetaminophen around the time of injection. Severity decreases with subsequent injections and usually abates in 1 to 2 weeks.101 Later common adverse effects are fatigue, malaise, and cognitive changes. Because α-interferon therapy can exacerbate autoimmune disorders, it is important to exclude autoimmune diagnoses before initiating therapy. Thrombocytopenia and granulocytopenia are more common in patients with cirrhosis and hypersplenism. The psychiatric complications are especially severe in those with severe liver disease, occur in up to 20% of patients, and are the most common dose-limiting side effects. Therapy should be discontinued if serious complications occur. The dose of α-interferon must be reduced in 10% to 40% of patients. Treatment must be discontinued because of adverse effects in 5% to 10% of patients. For many patients, reassurance that the side effects are therapy related, not severe, and will disappear when therapy is stopped is sufficient. It is always important to reassure both patient and family, especially when psychiatric side effects are evident. These points are critical given that patient adherence is crucial to the ultimate success of HCV treatment.101 Ongoing monitoring of α-interferon toxicity includes weekly complete blood counts during the first 2 weeks of therapy and monthly thereafter. Patients should be asked about level of performance, mood changes, ability to concentrate, and symptoms. The dose of α-interferon should be decreased by 50% if any of the following develop: fatigue that interferes with the daily routine, serious mood changes, daily nausea with occasional vomiting, granulocytopenia (2 mg/dL), an increase in serum creatinine of more than 1.0 mg/dL over a 24- to 48-hour period indicates the presence of acute renal failure. Table 41–6 lists several equations that are commonly used to estimate CLcr in patients with acute renal failure.105−107 However, a rigorous evaluation of the accuracy and precision of each of these proposed methods is lacking, in part due to the absence of measured creatinine clearance and inability to accurately measure GFR in the acute care setting. The equation proposed by Jelliffe is a revised dynamic model of creatinine kinetics based on theoretical estimates of creatinine production and adjusted for age and changes in serum creatinine. However, its ability to predict changes in drug clearance (and dose adjustments) has not been evaluated. In the acute setting, factors previously discussed that may alter the serum creatinine concentration must be evaluated to avoid misinterpretation. It is ultimately most important to recognize that renal function in patients with acute renal failure is generally markedly lower than one would estimate using steady-state methods. CLINICAL CONTROVERSY

Other Special Populations Davis and Chandler100 confirmed the accuracy of the CG equation to predict CLcr in trauma patients with stable kidney function, and Thakur and colleagues41 demonstrated its successful utility in 42 paraplegic subjects. Renal transplant recipients are frequently monitored for renal function, as numerous complications may occur during the life of the allograft. Goerdt and associates101 assessed the bias and precision with which several nomographic methods predicted GFR (iohexol clearance) in 127 transplant patients with stable kidney function. The CG method performed poorly, overestimating iohexol clearance. This is expected, as iohexol clearance provides a true measure of GFR, whereas the CG CLcr estimate is falsely high because of the tubular secretion of creatinine. Schuck and coworkers102 compared the CG method with CL sinistrin, an accurate measure of GFR. The clearance of sinistrin was significantly overestimated by the CG method. These investigators noted significant variability in CG estimates of GFR and concluded that it was an unreliable predictor of

Serum creatinine values can fluctuate widely in patients with unstable renal function. Although some practitioners advocate use of the Cockcroft-Gault equation using the highest of the two serum creatinine values, most recommend calculation of CLcr using either the Brater or Jelliffe equations. Inappropriate use of the Cockcroft-Gault equation can significantly overestimate the value of CLcr when compared to equations that are designed to account for changes in serum creatinine in patients with unstable renal function. Table 41–7 illustrates the variability in the CLcr values when three different equations are used to estimate CLcr in patients with decreasing or improving renal function.

Kidney Function in Children Kidney function in the neonate is difficult to assess because of difficulty in urine and blood collection, the frequent presence of a

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TABLE 41–6. Equations for the Estimation of Creatinine Clearance in Adults with Unstable Renal Function Equations Reference 105

Jelliffe

Units mL/min per 1.73 m

Males E ss = wta [29.3 − 0.203 (age)] ss = E ss [1.035 − 0.0337 (S )] Ecorr cr [4wt a (Scr2 − Scr1 )] ss E = Ecorr − t day

2

CLcr =

E 14.4(Scr )

Chiou et al106

mL/min

Vd = 0.6 L (wta ) 2 [28 − 0.2 (age)] CLcr = 14.4(Scr1 + Scr2 ) 2[Vd (Scr1 − Scr2 )] − [CrClNR × wta ] + (Scr1 + Scr2 ) t min

Brater107

mL/min per 70 kg

CLcr =

[293 − 2.03 (age)] × [1.035 − 0.01685 (Scr1 + Scr2 )] (Scr1 + Scr2 ) 49 (Scr1 − Scr2 ) + (Scr1 + Scr2 )t day

Females E ss = wta [25.1 − 0.175 (age)] ss = E ss [1.035 − 0.0337 (Scr)] Ecorr a ss − [4wt (Scr2 − Scr1 )] E = Ecorr t day CLcr =

E 14.4(Scr )

Vd = 0.6 L (wta ) 2 wta [22.4 − 0.16 (age)] CLcr = 14.4 (Scr1 + Scr2 ) 2[Vd (Scr1 − Scr2 )] − [CrClNR × wta ] + (Scr1 + Scr2 ) t min CLcr = Male value × 0.86

ideal body weight (IBW) if weight >30% above IBW. CLcr , creatinine clearance; CrClNR , nonrenal clearance of creatinine = 0.048 mL/min per kg; E, creatinine excretion; Ess , steady-state creatinine excretion; Ess corr , corrected steady-state creatinine excretion; t day, time in days between Scr1 and Scr2 ; t min, time in minutes between Scr1 and Scr2 ; Scr1 , first serum creatinine value; Scr2 , second serum creatinine value; Vd , volume of distribution. a Use

TABLE 41–7. Estimation of Creatinine Clearance in Patients with Acute Renal Failure A patient with worsening renal function: JR is a 50-year-old male (70 kg, BSA 1.73m2 ), admitted to the ICU following an automobile accident. His renal function was normal prior to admission; however, his serum creatinine has increased from 0.6 mg/dL to 3 mg/dL in the past 24 hours.

Authors 1. Jelliffe105

CLcr 21.9 mL/min per 1.73m2

2. Brater107

19.1 mL/min

3. Cockcroft-Gault80

29.2 mL/min

Assumptions Ess = 1341.2 mg/day Ess corr = 1241 mg/day Scr = 1.8 mg/dL Scr1 = 0.6 mg/dL Scr2 = 3 mg/dL t = 1 day Wt = 70 kg Scr1 = 0.6 mg/dL Scr2 = 3 mg/dL t = 1 day Scr = 3 mg/dL Wt = 70 kg

A patient with improving renal function: JR has been in the ICU for 1 week, and his status is improving. His serum creatinine has decreased from 3.0 mg/dL to 1.0 mg/dL in the past 24 hours.

Authors 1. Jelliffe105

CLcr 64.5 mL/min per 1.73m2

2. Brater107

78.7 mL/min

3. Cockcroft-Gault80

87.5 mL/min

Assumptions Ess = 1341.2 mg/day Ess corr = 1297.7 mg/day Scr = 2 mg/dL Scr1 = 3 mg/dL Scr2 = 1 mg/dL t = 1 day Wt = 70 kg Scr1 = 3 mg/dL Scr2 = 1 mg/dL t = 1 day Scr = 1 mg/dL Wt = 70 kg

BSA, body surface area; CLcr , creatinine clearance; Ess , steady-state creatinine excretion; Ess corr , corrected steady-state creatinine excretion; t, time between Scr1 and Scr2 ; Scr1 , first serum creatinine level; Scr2 , second serum creatinine level; Wt, weight.

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non–steady-state serum creatinine, and disparity between development of glomerular and tubular function. Preterm infants demonstrate significantly reduced GFR prior to 34 weeks, which rapidly increases and becomes similar to that of term infants within the first week of life.108 Evaluation of GFR in preterm infants on day 3 of life, using an inulin infusion, failed to identify a relationship between patient weight and GFR. However, gestational age, which ranged from 23.4 to 36.9 weeks (mean 30.2 weeks), correlated with both GFR and the reciprocal of serum creatinine. The inulin clearance increased from 0.67 to 0.85 mL/min in those with gestational age 300 mg/day) should begin to receive pharmacotherapy. For children, microalbuminuria is considered present if albumin excretion exceeds 0.36 mg/kg per day, and overt albuminuria has been defined as an excretion rate that exceeds 4 mg/kg per day. The urinary albumin:creatinine ratio is also an accurate predictor of 24-hour proteinuria, a marker of renal disease. Guidelines for monitoring indicate that a urine albumin:creatinine ratio of >30 mg/g places the patient at increased risk of developing diabetic nephropathy and is an indication for the initiation of pharmacotherapeutic intervention.30 Microalbuminuria has also been suggested as a risk factor for renal dysfunction among patients with essential hypertension.125

MEASUREMENT OF RENAL PLASMA AND BLOOD FLOW

0.8

Therapeutic intervention

0.6 0.4 0.2 0

QUANTIFICATION OF RENAL FUNCTION

0

1

2

3

4

5

6

7

8

9

10

Time (mo)

FIGURE 41–3. Linear relationship between 1/serum creatinine concentration and creatinine clearance (A) and 1/serum creatinine concentration as a function of time in a hypothetical patient with progressive renal impairment (B). The arrow indicates a change in the rate of progression, which may be related to a therapeutic intervention.

steady-state conditions, the formation rate of creatinine equals the elimination rate (R), and CLcr is inversely related to Scr as: Scr = R/CLcr The reciprocal relationship between Scr and CLcr is then expressed as: 1/Scr = 1/R × CLcr

9 As renal function declines, the reciprocal of the serum creatinine

concentration decreases as a linear function of the CLcr , and the slope of the relationship is the reciprocal of the elimination rate of creatinine (Fig. 41–3A). Clinicians can use the reciprocal serum creatinine plotted as a function of time as a prognostic tool to predict when dialysis may be needed (when 1/Scr ∼0.1), or as a marker for evaluating the success of therapeutic interventions to alter the rate of decline in renal function (Fig. 41–3B). Several factors, such as changes in

Measurement of renal plasma and blood flow is usually reserved for research settings to evaluate hemodynamic changes related to disease or drug therapy. The kidneys receive approximately 20% of cardiac output and representative values of renal blood flow in men and women of about 1200 ± 250 and 1000 ± 180 mL/min per 1.73 m2 have been reported, respectively.126 Renal plasma flow (RPF) can be estimated to be 60% of renal blood flow if it is assumed that the average hematocrit is 40%. PAH is an organic anion that has been used extensively for the quantitation of renal plasma flow. PAH is approximately 17% bound to plasma proteins and is eliminated extensively by active tubular secretion. Because PAH elimination is active, saturation of the transport processes have historically been anticipated, at concentrations of PAH in plasma above 10 to 20 mg/L.44 Recently, Dowling and associates127 used a sequential infusion technique and only observed concentration-dependent renal clearance of PAH at concentrations above 100 mg/dL. Furthermore, PAH is also metabolized, possibly within the kidney, to N-acetyl-PAH, and the analytical method must be able to differentiate the parent compound from the metabolite if one desires to obtain an accurate assessment of RPF.63 Prescott and coworkers128 noted that the renal clearance of PAH alone decreases at low plasma concentrations, while the clearance of the acetyl metabolite increases. Further studies are necessary to evaluate the mechanisms and significance of these findings. The extraction ratio (ER) for PAH is 70% to 90% at plasma concentrations of 10 to 20 mg/L, hence the term “effective” renal plasma flow (ERPF) has been used when the clearance of PAH is not corrected for the extraction ratio or if it is assumed to be 1.2 Normal values for ERPF are about 650 ± 160 mL/min for men and 600 ± 150 mL/min for women.126 Children will reach normalized adult values by 3 years of age, and ERPF will begin to decline as a function of age after 30 years, reaching

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about one-half of its peak value by 90 years of age. The method for calculation of ERPF is based on the relationship between organ clearance, ER, and flow: ERPF = renal PAH CL = RPF × ER Effective renal blood flow (ERBF) can be estimated from ERPF by assuming the extraction ratio is 1 and correcting for the red blood cell volume of the blood (Hct, hematocrit): ERBF = ERPF/(1 − Hct) ERPF can also be measured using the radioisotopes 131 I-orthoiodohippurate or 99m Tc-mercaptoacetyltriglycine.129 One important advantage of this method is its ability to measure ERPF in total or for each kidney independently, as well as its ability to produce renal images. Russell and Dubovsky,130 using a single-injection technique, compared clearance methods with and without urine collection and showed similar results with each method.

QUANTITATIVE AND SEMIQUANTITATIVE ASSESSMENT OF TUBULAR FUNCTION Although GFR is perhaps the best overall indicator of renal function, it may not be reflective of tubular function; either secretory capacity or cellular function.131 Tubular secretory function can be assessed by measuring PAH transport as the prototype marker of the organic anion secretory system. N-1-Methylnicotinamide (NMN) and tetraethylammonium (TEA) are prototype compounds secreted by the cationic transport system and may be used as markers of cationic secretory capacity.2,132 Studies with NMN suggested its use to assess the effects of selected renal diseases on drug handling by the kidneys.133 Dowling and colleagues127 explored the utility of famotidine as a marker for cationic transport, but were unable to demonstrate saturation, perhaps due to contribution from other secretory pathways such as p-glycoprotein. It should be recognized that these transport systems are not necessarily mutually exclusive. Indeed, probenecid, which is secreted by the anionic pathway, inhibits the secretion of cationic compounds. Quantitative measures of tubular transport capacity are currently limited primarily to the research setting. Other measures of tubular function are less specific and are regarded primarily as indices of damage within the nephron.134 Schentag and Plaut131 demonstrated a delay in the increase of serum creatinine following aminoglycoside toxicity when compared to markers for tubular damage such as the low-molecular-weight protein β 2 -microglobulin (11.8 kDa) and urinary enzymes. The rise in β 2 -microglobulin is related to an early functional defect in the proximal tubular cell. This is followed by a rise in the excretion of enzymes released as a result of structural damage to the cells, and finally, by the formation and excretion of cellular casts. Other low-molecular-weight proteins used as markers of tubular function include retinol-binding protein (21 kDa) and protein HC (also known as α 1 -microglobulin, 27 kDa).134 These proteins are normally freely filtered at the glomerulus and then completely reabsorbed by the proximal tubule. Increases in their excretion are thus suggestive of tubular dysfunction but are not diagnostic, as an increased production rate or GFR of less than 30 mL/min may lead to increased excretion. In both cases, the maximal reabsorptive capacity may be exceeded, leading to net excretion of the protein. Retinol-binding protein and protein HC are elevated with tubular damage and may be more appropriate markers than β 2 microglobulin. Numerous urinary enzymes such as N-acetylglucosaminidase (NAG), alanine aminopeptidase (AAP), alkaline phosphatase (AP),

γ -glutamyltransferase (GGT), pyruvate kinase, glutathione transferase, lysozyme, and pancreatic ribonuclease have been used as diagnostic markers for renal disease. Jung and associates135 compared the ability of five enzymes (NAG, AAP, AP, GGT, and lysozyme) to detect early rejection episodes in kidney transplant patients. Only NAG and AAP were early predictors of rejection. NAG is an enzyme contained within the lysosome of the tubular cell and is released when the lysosome is damaged, whereas AAP is an enzyme of the brush border. Both markers were increased approximately 2 days earlier than serum creatinine in patients with transplant rejection.

QUALITATIVE DIAGNOSTIC PROCEDURES RADIOLOGIC STUDIES 10 Further evaluation of the etiology of kidney disease can be ac-

complished using several qualitative diagnostic techniques, including radiography, ultrasound, magnetic resonance imaging (MRI), and biopsy. The standard x-ray of the kidneys, ureters, and bladder (KUB) is useful for a gross estimate of kidney size and to detect the presence of calcifications.69 Although an easy test to perform, the useful information achieved is minimal, and more detailed evaluations are often necessary. The intravenous urogram (IVU; formerly known as intravenous pyelogram, or IVP) involves the use of a contrast agent to facilitate visualization of the urinary collecting system. It is primarily used in the assessment of structural changes that may be associated with nonglomerular hematuria, pyuria, or flank pain, resulting from recurrent urinary tract infections, obstruction, or stone formation.69 For patients with insufficient renal filtration, retrograde administration of dye into the ureters may be performed to facilitate visualization of the collecting system. Furthermore, local administration may avoid systemic exposure and associated adverse reactions (see Chap. 46). Contrast agents are also employed during renal angiography for the assessment of renovascular disease. As a test for the diagnosis of renovascular hypertension, the captopril (ACE inhibitor) test is a useful adjunct. Under conditions of unilateral renal artery stenosis, the affected kidney produces large quantities of angiotensin II, which vasoconstricts the efferent arteriole to maintain GFR. The administration of an ACE inhibitor results in reduced uptake of the contrast agent because perfusion of the affected kidney decreases. This occurs as a result of decreased efferent arteriolar vasoconstriction. For patients with bilateral disease, a decrease in uptake is observed in both kidneys.136 Computed tomography (CT) is a cross-sectional anatomic imaging procedure based on x-ray data. The procedure is frequently performed with contrast to enhance imaging. Spiral, or helical, CT, a more recent technique, provides visual threedimensional reconstruction of tissues. CT is performed as a test for the evaluation of obstructive uropathy, malignancy, and infections of the kidney.

RENAL ULTRASOUND Ultrasound uses sound waves to generate a two-dimensional image. The echogenicity of the kidney is compared with that of an adjacent organ—liver on the right and spleen on the left—with an increased echogenicity indicating an abnormal finding. Ultrasonography can distinguish the renal pyramids, medulla, and cortex, and abnormalities in structure, such as occurs with obstruction. Renal ultrasound is also used as a guide for site localization during percutaneous kidney biopsy.

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MAGNETIC RESONANCE IMAGING The MRI is based on aligning hydrogen nuclei in the body with the use of a powerful magnet and applying radiofrequency pulses. The signals emitted by the hydrogen nuclei during realignment on repeated pulses allows for generation of the tissue image. Realignment times can also be altered with the use of contrast agents (e.g., gadolinium or gadopentetate), leading to increased signal intensity and improved imaging. MRI is useful for the assessment of obstruction, malignancy, and renovascular lesions. The relative advantages and limitations of these procedures are discussed in more detail in several recent reviews.69,137,138

BIOPSY Renal biopsy is used in several conditions to facilitate diagnosis when clinical, laboratory, and imaging findings prove inconclusive. Proteinuria and hematuria are both associated with renal parenchymal disease. When less-invasive studies are unsuccessful in differentiating the cause and the possible causes have different therapeutic approaches, biopsy may be indicated. Functional status of the kidney is not assessed with biopsy, and severity of disease and progression is best measured using the quantitative tests discussed above. Contraindications to renal biopsy include a solitary kidney, severe hypertension, bleeding disorder, severe anemia, cystic kidney, and hydronephrosis, among others. Complications resulting from biopsy primarily include hematuria, which may last for several days, and perirenal hematoma.25

QUANTIFICATION OF RENAL FUNCTION

777

ER: extraction ratio ERBF: effective renal blood flow ERPF: effective renal plasma flow ESRD: end-stage renal disease GFR: glomerular filtration rate GGT: γ -glutamyltransferase HPLC: high-performance liquid chromatography IBW: ideal body weight IVU: intravenous urogram KUB: kidneys, ureters, and bladder (radiograph) MDRD: Modification of Diet in Renal Disease (study) MRP: multidrug resistance protein NAG: N-acetylglucosaminidase NKF K/DOQI: National Kidney Foundation Kidney Disease Outcomes Quality Initiative NMN: N-1-methylnicotinamide PAH: p-aminohippurate Pcr : creatinine production rate Plcr : plasma creatinine level P-gp: P-glycoprotein RBF: renal blood flow RPF: renal plasma flow Scr : serum creatinine concentration SNGFR: single nephron glomerular filtration rate SUN: serum urea nitrogen (concentration) TEA: tetraethylammonium Review Questions and other resources can be found at www.pharmacotherapyonline.com.

CONCLUSION REFERENCES The prevalence of kidney disease has increased dramatically over the past decade, indicating a need for early classification and monitoring of renal function in CKD patients. Renal function can be evaluated in clinical settings using estimated or measured creatinine clearance, estimated GFR, and measurement of urinary protein excretion. Accurate measurement of GFR using exogenous administration of inulin, iothalamate, or radioisotope techniques such as 99m Tc-DTPA is required in research settings to assess drug therapy outcomes and progression of disease. Use of qualitative assessments of renal function, such as x-ray, CT, MRI, sonography, and biopsy, can help to determine the underlying cause of kidney disease. The clinical pharmacist can have an important role in the care of CKD patients, including renal function assessment, dose individualization, drug therapy monitoring, and evaluation of therapeutic outcomes.

ABBREVIATIONS AAP: alanine aminopeptidase ABW: actual body weight ACE: angiotensin-converting enzyme Alb: serum albumin concentration AP: alkaline phosphatase CG: Cockcroft-Gault (method of calculating CLcr ) CKD: chronic kidney disease CL: clearance CLcr : creatinine clearance DTPA: diethylenetriamine pentaacetic acid EDTA: ethylenediaminetetraacetic acid EPO: erythropoietin

1. Campens D, Buntinx F. Selecting the best renal function tests. Int J Technol Assess Health Care 1997;13:343–356. 2. Sica DA, Schoolwerth AC. Renal handling of organic anions and cations: Excretion of uric acid. In: Brenner BM, ed. Brenner and Rector’s The Kidney, 6th ed. Philadelphia, WB Saunders, 2000:680–700. 3. Hsyu PH, Gisclon LG, Hui AC, Giacomini KM. Interactions of organic anions with the organic cation transporter in renal brush-border membrane vesicles. Am J Physiol 1988;254:F56–F61. 4. Bendayan R. Renal drug transport: A review. Pharmacotherapy 1996;16: 971–985. 5. Sikic BI. Pharmacologic approaches to reversing multidrug resistance. Semin Hematol 1997;34:40–47. 6. Hori R, Okumura K, Kamiya A, et al. Ampicillin and cephalexin in renal insufficiency. Clin Pharmacol Ther 1983;34:792–798. 7. Hori R, Okumura K, Nihira H. A new dosing regimen in renal insufficiency: Application to cephalexin. Clin Pharmacol Ther 1985;38:290– 295. 8. Maiza A, Daley-Yates PT. The clearance of drugs in different types of renal disease. Ren Fail 1988;11:67 (Abstract). 9. Lin JH, Lin T. Renal handling of drugs in renal failure. I. Differential effects of uranyl nitrate- and glycerol-induced acute renal failure on renal excretion of TEAB and PAH in rats. J Pharmacol Exp Ther 1988; 246:896–901. 10. Gloff CA, Benet LZ. Differential effects of the degree of renal damage on p-aminohippuric acid and inulin clearances in rats. J Pharmacokinet Biopharm 1989;17:169–177. 11. Bricker NS. On the meaning of the intact nephron hypothesis. Am J Med 1969;46:1–11. 12. Bosch JP. Renal reserve. A functional view of glomerular filtration rate. Semin Nephrol 1995;15:381–385. 13. Gaspari F, Perico N, Remuzzi G. Measurement of glomerular filtration rate. Kidney Int Suppl 1997;63:S151–S154.

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14. Walser M. Assessing renal function from creatinine measurements in adults with chronic renal failure. Am J Kidney Dis 1998;32:23–31. 15. Rahn KH, Heidenreich S, Bruckner D. How to assess glomerular filtration and damage in humans. J Hypertens 1999;17:309–317. 16. Levin A, Singer J, Thompson CR, et al. Prevalent left ventricular hypertrophy in the predialysis population: Identifying opportunities for intervention. Am J Kidney Dis 1996;27:347–354. 17. Lacombe C, Mayeux P. The molecular biology of erythropoietin. Nephrol Dial Transplant 1999;14(Suppl 2):22–28. 18. Alvestrand A. Carbohydrate and insulin metabolism in renal failure. Kidney Int Suppl 1997;62:S48–S52. 19. Martin KJ, Olgaard K, Coburn JW, et al. Diagnosis, assessment, and treatment of bone turnover abnormalities in renal osteodystrophy. Am J Kidney Dis 2004;43:558–565. 20. Nolin TD, Frye RF, Matzke GR. Hepatic drug metabolism and transport in the presence of kidney disease. Am J Kidney Dis 2003;42:906–925. 21. Dowling TC, Briglia AE, Fink JC, et al. Characterization of hepatic cytochrome P450 3A (CYP3A) activity in ESRD patients. Clin Pharmacol Ther 2003;73:427–434. 22. Meffin PJ, Zilm DM, Veenendaal JR. Reduced clofibric acid clearance in renal dysfunction is due to a futile cycle. J Pharmacol Exp Ther 1983;227: 732–738. 23. Verbeeck RK, Wallace SM, Loewen GR. Reduced elimination of ketoprofen in the elderly is not necessarily due to impairment of glucuronidation. Br J Clin Pharmacol 1984;17:783–784. 24. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Ann Intern Med 2003;139:137–147. 25. Kasiske BL, Keane WF. Laboratory assessment of renal disease: Clearance, urinalysis, and renal biopsy. In: Brenner BM, ed. Brenner and Rector’s The Kidney, 6th ed. Philadelphia, WB Saunders, 2000:1129– 1170. 26. Goldstein DE, Little RR. Monitoring glycemia in diabetes. Short-term assessment. Endocrinol Metab Clin North Am 1997;26:475–486. 27. Pugia MJ, Lott JA, Clark LW, et al. Comparison of urine dipsticks with quantitative methods for microalbuminuria. Eur J Clin Chem Clin Biochem 1997;35:693–700. 28. Newman DJ, Pugia MJ, Lott JA, et al. Urinary protein and albumin excretion corrected by creatinine and specific gravity. Clin Chim Acta 2000; 294:139–155. 29. Parsons M, Newman DJ, Pugia M, et al. Performance of a reagent strip device for quantitation of the urine albumin:creatinine ratio in a point of care setting. Clin Nephrol 1999;51:220–227. 30. Keane WF, Eknoyan G. Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): A position paper of the National Kidney Foundation. Am J Kidney Dis 1999;33:1004–1010. 31. Ruggenenti P, Gaspari F, Perna A, Remuzzi G. Cross-sectional longitudinal study of spot morning urine protein:creatinine ratio, 24-hour urine protein excretion rate, glomerular filtration rate, and end stage renal failure in chronic renal disease in patients without diabetes. BMJ 1998;316:504–509. 32. Rose BD, Renneke HG. Renal Pathophysiology—The Essentials. Baltimore, Williams & Wilkins, 1994. 33. Jones CA, McQuillan GM, Kusek JW, et al. Serum creatinine levels in the U.S. population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 1998;32:992–999. 34. Bauer JH, Brooks CS, Burch RN. Clinical appraisal of creatinine clearance as a measurement of glomerular filtration rate. Am J Kidney Dis 1982;2:337–346. 35. Green AJE, Halloran SP, Mould GP, et al. Interference by newer cephalosporins in current methods for measuring creatinine. Clin Chem 1990;36:2139–2140. 36. Massoomi F, Matthews HG III, Destache CJ. Effect of seven fluoroquinolones on the determination of serum creatinine by the picric acid and enzymatic methods. Ann Pharmacother 1993;27:586–588. 37. Young DS, ed. Effects of Drugs on Clinical Laboratory Tests, 4th ed. Washington, American Association of Clinical Chemistry (AACC) Press, 1995:3.190–3.211.

38. Daly TM, Kempe KC, Scott MG, et al. “Bouncing” creatinine levels. N Engl J Med 1996;334:1749–1750 (Letter). 39. van den Berg JG, Koopman MG, Arisz L. Ranitidine has no influence on tubular creatinine secretion. Nephron 1996;74:705–708. 40. Mayersohn M, Conrad KA, Achari R. The influence of a cooked meat meal on creatinine plasma concentration and creatinine clearance. Br J Clin Pharmacol 1983;15:227–230. 41. Thakur V, Reisin E, Solomonow M, et al. Accuracy of formula-derived creatinine clearance in paraplegic subjects. Clin Nephrol 1997;47:237– 242. 42. Poortsmans JR, Francaux M. Long-term oral creatine supplementation does not impair renal function in healthy athletes. Med Sci Sports Exerc 1999;31:1108–1110. 43. Robinson TM, Sewell DA, Casey A, et al. Dietary creatine supplementation does not affect some haematological indices, or indices of muscle damage and renal function. Br J Sports Med 2000;34:284–288. 44. Edmunds JW, Jayapalan S, DiMarco NM, et al. Creatine supplementation increases renal disease progression in Han:SPRD-cy rats. Am J Kidney Dis 2001;37:73–78. 45. Coll E, Botey A, Alvarez L, et al. Serum cystatin C as a new marker for noninvasive estimation of glomerular filtration rate and as a marker for early renal impairment. Am J Kidney Dis 2000;36:29–34. 46. Price CP, Finney H. Developments in the assessment of glomerular filtration rate. Clin Chim Acta 2000;297:55–66. 47. Randers E, Erlandsen EJ. Serum cystatin C as an endogenous marker of the renal function—A review. Clin Chem Lab Med 1999;37: 389–395. 48. Keevil BG, Kilpatrick ES, Nichols SP, Maylor PW. Biological variation of cystatin C: Implications for the assessment of glomerular filtration rate. Clin Chem 1998;44:1535–1539. 49. Page MK, B¨ukki B, Luppa P, Neumeier D. Clinical value of cystatin C determination. Clin Chim Acta 2000;297:67–72. 50. Bokenkamp A, Domanetzki M, Zinck R, et al. Cystatin C serum concentrations underestimate glomerular filtration rate in renal transplant recipients. Clin Chem 1999;45:1866–1868. 51. Akbas SH, Yavuz A, Tuncer M, et al. Serum cystatin C as an index of renal function in kidney transplant patients. Transplant Proc 2004;36:99–101. 52. Br¨andle E, Sieberth HG, Hautman RE. Effect of chronic dietary protein intake on the renal function in healthy subjects. Eur J Clin Nutr 1996; 50:734–740. 53. Knight EL, Stampfer MJ, Hankinson SE, et al. The impact of protein intake on renal function decline in women with normal renal function or mild renal insufficiency. Ann Intern Med 2003;138:460–467. 54. Brenner BM, Lawler EV, Mackenzie HS. The hyperfiltration theory: A paradigm shift in nephrology. Kidney Int 1996;49:1774–1777. 55. Woods LL. Intrarenal mechanisms of renal reserve. Semin Nephrol 1995; 15:386–395. 56. Dowling TC, Frye RF, Fraley DS, Matzke GR. Comparison of iothalamate clearance methods for measuring GFR. Pharmacotherapy 1999; 19:943–950. 57. Florijn KW, Barendregt JNM, Lentjes EGWM, et al. Glomerular filtration rate measurement by “single-shot” injection of inulin. Kidney Int 1994;46:252–259. 58. Soper CPR, Bending MR, Barron JL. An automated enzymatic inulin assay, capable of full sinistrin hydrolysis. Eur J Clin Chem Clin Biochem 1995;33:497–501. 59. Dall’Amico R, Montini G, Pisanello L, et al. Determination of inulin in plasma and urine by reverse-phase high-performance liquid chromatography. J Chromatogr B Biomed Appl 1995;672:155–159. 60. Buclin T, Pech`ere-Bertschi A, S´aechaud R, et al. Sinistrin clearance for determination of glomerular filtration rate: A reappraisal of various approaches using a new analytical method. J Clin Pharmacol 1997;37: 679–692. 61. Ruiz R, Cordova MA, Sierra M, et al. Automated sinistrin measurement. Clin Biochem 1997;30:501–504. 62. Agarwal R. Ambulatory GFR measurement with cold iothalamate in adults with chronic kidney disease. Am J Kidney Dis 2003;41: 752–759.

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CHAPTER 41 63. Dowling TC, Frye RF, Zemaitis MA. Simultaneous determination of p-aminohippuric acid, acetyl-p-aminohippuric acid and iothalamate in human plasma and urine by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1998;716:305–313. 64. Dowling TC, Frye RF, Fraley DS, Matzke GR. Comparison of iothalamate clearance methods for measuring GFR. Pharmacotherapy 1999; 19:943–950. 65. Frennby B, Sterner G, Alm´an T, et al. The use of iohexol clearance to determine GFR in patients with severe chronic renal failure—A comparison between different clearance techniques. Clin Nephrol 1995;43:35–46. 66. Rocco MV, Buckalew VM Jr, Moore LC, Shihabi ZK. Measurement of glomerular filtration rate using nonradioactive iohexol: Comparison of two one-compartment models. Am J Nephrol 1996;16:138–143. 67. Lundqvist S, Hietala S-O, Groth S, Sjdin J-G. Evaluation of single sample clearance calculations in 903 patients. A comparison of multiple and single sample techniques. Acta Radiol 1997;38:68–72. 68. Lundqvist S, Holmberg G, Jakobsson G, et al. Assessment of possible nephrotoxicity from iohexol in patients with normal and impaired renal function. Acta Radiol 1998;39:362–367. 69. Hricak H, Meux M, Reddy GP. Radiologic assessment of the kidney. In: Brenner BM, ed. Brenner and Rector’s The Kidney, 6th ed. Philadelphia, WB Saunders, 2000:1171–1200. 70. Frennby B, Alm´en T, Lilja B, et al. Determination of the relative glomerular filtration rate of each kidney in man. Acta Radiol 1995;36: 410–417. 71. Morton K, Pisani DE, Whiting JH Jr, et al. Determination of glomerular filtration rate using technitium-99m-DTPA with differing degrees of renal function. J Nucl Med Technol 1997;25:110–114. 72. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med 1999;130:461–470. 73. Rodrigo E, Fernandez-Fresnedo G, Ruiz JC, et al. Assessment of glomerular filtration rate in transplant recipients with severe renal insufficiency by Nankivell, Modification of Diet in Renal Disease (MDRD), and Cockroft-Gault equations. Transplant Proc 2003;35:1671–1672. 74. Vervoort G, Willems HL, Wetzels JF. Assessment of glomerular filtration rate in healthy subjects and normoalbuminuric diabetic patients: Validity of a new (MDRD) prediction equation. Nephrol Dial Transplant 2002;17:1909–1913. 75. Rule AD, Gussak HM, Pond GR, et al. Measured and estimated GFR in healthy potential kidney donors. Am J Kidney Dis 2004;43:112–119. 76. Skluzacek PA, Szewc RG, Nolan CR, et al. Prediction of GFR in liver transplant candidates. Am J Kidney Dis 2003;42:1169–1176. 77. Gonwa TA, Jennings L, Mai ML, et al. Estimation of glomerular filtration rates before and after orthotopic liver transplantation: Evaluation of current equations. Liver Transpl 2004;10:301–309. 78. Beddhu S, Samore MH, Roberts MS, et al. Creatinine production, nutrition, and glomerular filtration rate estimation. J Am Soc Nephrol 2003; 14:1000–1005. 79. Lemann J, Bidani AK, Bain RP, et al. Use of the serum creatinine to estimate glomerular filtration rate in health and early diabetic nephropathy. Am J Kidney Dis 1990;16:236–243. 80. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. 81. Shemesh O, Golbetz H, Kriss JP, et al. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int 1985;28:830–838. 82. Roubenoff R, Drew H, Moyer M, et al. Oral cimetidine improves the accuracy and precision of creatinine clearance in lupus nephritis. Ann Intern Med 1990;113:501–506. 83. Zaltzman JS, Whiteside C, Cattran D, et al. Accurate measurement of impaired glomerular filtration using single-dose oral cimetidine. Am J Kidney Dis 1996;27:504–511. 84. Van Acker BAC, Koomen GCM, Koopman MG, et al. Creatinine clearance during cimetidine administration for measurement of glomerular filtration rate. Lancet 1992;340:1326–1329. 85. Spinler SA, Nawarskas JJ, Boyce EG, et al. Predictive performance of ten equations for estimating creatinine clearance in cardiac patients. Iohexol Cooperative Study Group. Ann Pharmacother 1998;32:1275–1283.

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86. Salazar DE, Corcoran GB. Predicting creatinine clearance and renal drug clearance in obese patients from estimated fat-free body mass. Am J Med 1988;84:1053–1060. 87. Luke DR, Halstenson CE, Opsahl JA, et al. Validity of creatinine clearance estimates in the assessment of renal function. Clin Pharmacol Ther 1990;48:503–508. 88. Mawer CE, Knowles BR, Lucas SB, et al. Computer-assisted prescribing of kanamycin for patients with renal insufficiency. Lancet 1972;1:12–15. 89. Jelliffe RW. Estimation of creatinine clearance when urine cannot be collected. Lancet 1971;1:975–976. 90. Jelliffe RW. Creatinine clearance: Bedside estimate. Ann Intern Med 1973;79:604–605. 91. Hull JH, Hak LJ, Koch GC, et al. Influence of range of renal function and liver disease on predictability of creatinine clearance. Clin Pharmacol Ther 1981;29:516–521. 92. Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from adjusted serum creatinine. Nephron 1992;62:249–256. 93. Coresh J, Toto RD, Kirk KA, et al. Creatinine clearance as a measure of GFR in screens for the African-American study of kidney disease. Am J Kidney Dis 1998;32:32–42. 94. Goldwasser P, Aboul-Magd A, Maru M. Race and creatinine excretion in chronic renal insufficiency. Am J Kidney Dis 1997;30:16–22. 95. Ixkes MCJ, Koopman MG, van Acker BAC, et al. Cimetidine improves GFR-estimation by the Cockcroft-Gault formula. Clin Nephrol 1997; 47:229–236. 96. Orlando R, Floreani M, Padrini R, Palatini P. Evaluation of measured and calculated creatinine clearances as glomerular filtration markers in different stages of liver cirrhosis. Clin Nephrol 1999;51:341–347. 97. Lam NP, Sperelakis R, Kuk J, et al. Rapid estimation of creatinine clearances in patients with liver dysfunction. Dig Dis Sci 1999;44:1222–1227. 98. Caregaro L, Menon F, Angeli P, et al. Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis. Arch Intern Med 1994;154:201–205. 99. DeSanto NG, Anastasio P, Loguercio C, et al. Creatinine clearance: An inadequate marker of renal filtration in patients with early posthepatitic cirrhosis (Child A) without fluid retention and muscle wasting. Nephron 1995;70:421–424. 100. Davis GA, Chandler MHH. Comparison of creatinine clearance estimation methods in patients with trauma. Am J Health Syst Pharm 1996;53: 1028–1032. 101. Goerdt PJ, Heim-Duthoy KL, Macres M, Swan SK. Predictive performance of renal function equations in renal allografts. Br J Clin Pharmacol 1997;44:261–265. 102. Schuck O, Teplan V, Vitko S, et al. Predicting glomerular function from adjusted serum creatinine in renal transplant patients. Int J Clin Pharmacol Ther 1997;35:33–37. 103. Huang E, Hewitt R, Shelton M, Morse GD. Comparison of measured and estimated creatinine clearance in patients with advanced HIV disease. Pharmcotherapy 1996;16:222–229. 104. Quadri KHM, Bernardini J, Greenberg A, et al. Assessment of renal function during pregnancy using a random urine protein to creatinine ratio and Cockcroft-Gault formula. Am J Kidney Dis 1994;24: 416–420. 105. Jelliffe RW. Estimation of creatinine clearance in patients with unstable renal function, without a urine specimen. Am J Nephrol 2002;22: 320–324. 106. Chiou WL, Hsu FH. A new simple rapid method to monitor renal function based on pharmacokinetic considerations of endogenous creatinine. Res Commun Chem Pathol Pharmacol 1975;10:315–330. 107. Brater DC. Drug Use in Renal Disease. Balgowlah, Australia, ADIS Health Science Press, 1983:22–56. 108. Arant BS Jr. Developmental patterns of renal functional maturation compared in the human neonate. J Pediatr 1978;92:705–712. 109. van den Anker, de Groot R, Broerse HM, et al. Assessment of glomerular filtration rate in preterm infants by serum creatinine: Comparison with inulin clearance. Pediatrics 1995;96:1156–1158. 110. Sertel H, Scopes J. Rates of creatinine clearance in babies less than one week of age. Arch Dis Child 1973;48:717–720.

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111. Bajaj G, Alexander SR, Browne R, et al. 125 Iodine-iothalamate clearance in children. A simple method to measure glomerular filtration. Pediatr Nephrol 1996;10:25–28. 112. Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 1987;34:571–590. 113. Al-Harbi N, Lireman D. Comparison of three different methods of estimating the glomerular filtration rate in children after renal transplantation. Am J Nephrol 1997;17:68–71. 114. Fong J, Johnston S, Valentino T, Notterman D. Length/serum creatinine ratio does not predict measured creatinine clearance in critically ill children. Clin Pharmacol Ther 1995;58:192–197. 115. Pierrat A, Gravier E, Saunders C, et al. Predicting GFR in children and adults: a comparison of the Cockcroft-Gault, Schwartz, and modification of diet in renal disease formulas. Kidney Int 2003;64:1425–1436. 116. Lindeman RD, Tobin J, Shrock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985;33: 278–281. 117. Lindeman RD. Assessment of renal function in the old. Clin Lab Med 1993;13:269–277. 118. Fliser D, Ritz E, Franek E. Renal reserve in the elderly. Semin Nephrol 1995;15:463–467. 119. Smythe M, Hoffman J, Kizy K, et al. Estimating creatinine clearance in elderly patients with low serum creatinine concentrations. Am J Hosp Pharm 1994;51:198–204. 120. O’Connell MB, Wong MO, Bannick-Mohrland SD, et al. Accuracy of 2- and 8-hour urine collections for measuring creatinine clearance in the hospitalized elderly. Pharmacother 1993;13:135–142. 121. Agodoa L, Eknoyan G, Ingelfinger J, et al. Assessment of structure and function in progressive renal disease. Kidney Int Suppl 1997;63: S144–S150. 122. Rossing P, Astrup A-S, Smidt UM, et al. Monitoring kidney function in diabetic nephropathy. Diabetologia 1994;37:708–712. 123. Valensi P, Assayag M, Busby M, et al. Microalbuminuria in obese patients with or without hypertension. Int J Obes Relat Metab Disord 1996; 20:574–579. 124. Berrut G, Bouhanick B, Fabbri P, et al. Microalbuminuria as a predictor of a drop in glomerular filtration rate in subjects with non-insulindependent diabetes mellitus and hypertension. Clin Nephrol 1997;48: 92–97.

125. Mimran A, Ribstein J, DuCailar G. Is microalbuminuria a marker of early intrarenal vascular dysfunction in essential hypertension? Hypertension 1994;23:1018–1021. 126. Dworkin LD, Sun AM, Brenner BM. The renal circulations. In: Brenner BM, ed. Brenner and Rector’s The Kidney, 6th ed. Philadelphia, WB Saunders, 2000:277–318. 127. Dowling TC, Frye RF, Fraley DS, Matzke GR. Characterization of tubular functional capacity in humans using para-aminohippurate and famotidine. Kidney Int 2001;59:295–303. 128. Prescott LF, Freestone S, McAuslane JAN. The concentration-dependent disposition of intravenous p-aminohippurate in subjects with normal and impaired renal function. Br J Clin Pharmacol 1993;35:20–29. 129. Taylor A, Manatunga A, Morton K, et al. Multicenter trial validation of a camera-based method to measure Tc-99m mercaptoacetyltriglycine, or Tc-99m MAG3, clearance. Radiology 1997;204:47–54. 130. Russell CD, Dubovsky EV. Comparison of single-injection multisample renal clearance methods with and without urine collection. J Nucl Med 1995;36:603–606. 131. Schentag JJ, Plaut ME. Patterns of urinary β2-microglobulin excretion by patients treated with aminoglycosides. Kidney Int 1980;17:654–661. 132. Nassseri K, Daley-Yates PT. A comparison of N-1-methylnicotinamide clearance with 5 other markers of renal function in models of acute and chronic renal failure. Toxicol Lett 1990;53:243–245. 133. Maiza A, Daley-Yates PT. Estimation of the renal clearance of drugs using endogenous N-1-methylnicotinamide. Toxicol Lett 1990;53: 231–235. 134. Jung K. Urinary enzymes and low-molecular-weight proteins as markers of tubular dysfunction. Kidney Int Suppl 1994;47:S29–S33. 135. Jung K, Diego J, Strobelt V, et al. Diagnostic significance of some urinary enzymes for detecting acute rejection crises in renal transplant recipients: Alanine aminopeptidase, alkaline phosphatase, gamma-glutamyl transferase, N-acetyl-beta-glucosaminidase, and lysozyme. Clin Chem 1986; 32:1807–1811. 136. Taylor A, Nally JV. Clinical applications of renal scintigraphy. Am J Roentgenol 1995;164:31–41. 137. Mindell HJ, Fairbank JT. Renal imaging techniques. In: Greenberg A, ed. Primer on Kidney Diseases, 2nd ed. San Diego, Academic Press, 1998:47–53. 138. Lerman LO, Rodriguez-Porcel M, Romero JC. The development of x-ray imaging to study renal function. Kidney Int 1999;55:400–416.

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42 ACUTE RENAL FAILURE Bruce A. Mueller

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Identify acute renal failure (ARF) early and eliminate its cause to avoid the spread of damage.

2 Prevention is key; little can be done for established acute renal failure.

3 In situations in which development of ARF is likely, pa-

tients should receive therapy to prevent occurrence or reduce its severity. These situations include: diabetes mellitus, chronic kidney disease, the elderly, radiocontrast dye administration, and ICU patients. Some preventive thera-

The development of acute renal failure (ARF) presents a difficult challenge to the clinician. It has widely varying causes, and unlike other cases of organ failure such as neurologic or cardiovascular failure, the onset of ARF is often silent. In the ambulatory setting, patients may not notice ARF symptoms for days or weeks. Clinical and laboratory markers of its presence can be subtle and are often overlooked. Despite its often insidious presentation, ARF can be one of the most serious consequences that can occur, especially in a hospitalized patient. Renal replacement therapies (RRTs) like hemodialysis, peritoneal dialysis, and other related treatments have been available for decades, but have not resulted in dramatic improvements in patient outcomes. RRT can help patient management by normalizing blood electrolyte values, augmenting waste product removal, and maintaining fluid balance. Despite the supportive care that RRT offers, development of ARF is frequently a catastrophic event.

DEFINITION OF ARF A unifying definition of ARF does not exist. Clinicians disagree about when to make the diagnosis and published epidemiologic studies use different definitions in nearly every study.1 Nonetheless, most use some combination of absolute serum creatinine value and a change in serum creatinine value or daily urine output as criteria for making the diagnosis.2,3 In general, these studies typically view ARF as being a condition in which a previously normal serum creatinine rises by 0.5 mg/dL, or an absolute increase in serum creatinine of >1 mg/dL in a patient with previous chronic kidney disease (CKD). Clinicians must recognize that serum creatinine, while simple to measure, is not a very sensitive laboratory test. For example, a patient with an acute event that reduces the glomerular filtration rate (GFR) to zero will have no immediate change in serum creatinine. Depending on the creatinine generation rate and fluid status of the patient,

pies include: glucose control, sodium loading, and use of L-carnitine.

4 Avoid nephrotoxins as much as possible. 5 Once the cause of ARF is identified and is eliminated,

supportive therapy is the only remaining option, as we cannot hasten recovery of established ARF. Supportive therapies include: renal replacement therapies, nutritional support, avoidance of nephrotoxins, and aggressive fluid management.

it may take days before serum creatinine values meet the threshold of a rise of 0.5 mg/dL. This may delay recognizing that ARF has occurred.4

ARF CLASSIFICATION In the clinical setting, ARF is classified in a variety of ways. Classifying ARF by daily urine output can be useful. Anuria is defined as a urine output of 450 mL of urine per day. This simplistic approach actually is quite useful in determining prognosis. Hospitalized anuric or oliguric patients have significantly higher mortality rates than similar ARF patients with nonoliguria.5 Surviving oliguric ARF patients are also less likely to ever fully recover their renal function compared to nonoliguric patients.6 Clinically, the nonoliguric patient is easier to manage than the oliguric patient because of reduced concerns about fluid overload. Consequently, knowledge of something as simple as the amount of urine produced per day can yield important information for the clinician.

EPIDEMIOLOGY ARF is a common condition in the general population, with an annual incidence of approximately 200 cases per million population per year.2 The incidence rate is higher in hospitalized patients, 5% of whom may require RRT (Table 42–1).7 The highest incidence of ARF is in hospitalized patients in the intensive care unit. Depending on the definition used, ARF develops in 2% to 25% of patients in intensive care units.8−10 781

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TABLE 42–1. Incidence and Outcomes of Acute Renal Failure (ARF) Relative to Where It Occurs Community-Acquired

Hospital-Acquired

ICU-Acquired

Incidence Cause Overall survival rate Worsened outcome if:

Low (65 years than those not developing ARF.8,14−15 Few factors that clinicians can control are associated with ARF development. However, one of these factors that may be under control of prescribers is that of nephrotoxin exposure to the patient. For example, higher cumulative doses of intravenous contrast dye are directly related to the risk of developing ARF in patients receiving cardiac catheterization.14 This risk can be ameliorated by avoidance of nephrotoxins in patients at high risk of ARF development, or by dosing unavoidable nephrotoxins like aminoglycosides in ways documented to reduce ARF development.16 Additionally, clinicians can exert tighter control of serum glucose using insulin, and by doing so can reduce the rate of ARF development.17 One series reported that 5% of all patients admitted to an intensive care unit will require some RRT due to ARF.10 The mortality rate for these patients is remarkably higher than ICU patients not requiring RRT, even when severity of illness and other factors are controlled for (63% vs. 15%).10 The cause for this increase in mortality rates due to ARF does not appear to be solely related to the absence of renal function. Patients admitted to the ICU with CKD have significantly lower mortality rates than patients who are admitted to the ICU with ARF or who develop ARF in the ICU.18

OUTCOMES The development of ARF is one of the most serious events that can happen to a hospitalized patient, regardless of the reason for hospitalization. In patients admitted for cardiac surgery, the mortality risk is seven- to eightfold higher if the patient develops ARF.19 Patients who develop ARF following administration of intravenous radiocontrast dye and requiring dialysis have twice the mortality rate of similar patients receiving radiocontrast dye who do not experience an increase in their serum creatinine values.13 The outcome of a patient with ARF predominantly depends on the cause of the condition. In general, higher mortality rates are seen in conditions that result in hypoxia to the kidney causing acute tubular necrosis (ATN; 60%) or cortical necrosis (100%) compared to the lower mortality associated with autoimmune ARF causes like glomerulonephritis (9% to 25%), vasculitis (45%), or interstitial nephritis (13%).2 Similarly, postrenal causes like obstructive ARF tend to have lower mortality rates (27%), ostensibly because these obstructions can be surgically repaired before permanent damage can be done to the kidney. Other patient factors influence ARF outcomes. Understandably, those patients with higher severity of illness have higher mortality rates than those who do not.18 Critically ill patients with ARF due to sepsis have mortality rates that are significantly higher than those of patients who develop ARF for other reasons (74% vs. 45%).20

ETIOLOGY The classification of ARF into broad categories based on the precipitating factors facilitates the diagnosis and management of patients presenting with this disorder (Table 42–2). Traditionally, the causes of ARF have been categorized into prerenal azotemia (resulting from decreased renal perfusion), acute intrinsic renal failure (resulting from structural damage to the kidney), and postrenal obstruction (obstruction of urine flow from the kidney out of the body). The addition of the category “functional ARF” aids in the understanding of the pathophysiology of ARF. This category is the result of hemodynamic changes at the level of the glomerulus without decreased perfusion of the kidney or structural damage to it. The cause of ARF strongly influences patient outcome.2 Kidneys that are not perfused with blood for prolonged periods will develop

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TABLE 42–2. Classification of Acute Renal Failure Category Prerenal renal failure

Classification of Acute Renal Failure Systemic hypoperfusion

Isolated renal hypoperfusion

Functional acute renal failure

Acute intrinsic renal failure

Vascular

Glomerular

Acute tubular necrosis

Acute interstitial nephritis

Postrenal renal failure (obstruction)

Bladder outlet obstruction Ureteral (bilateral or unilateral with solitary functioning kidney) Renal pelvis or tubules

cortical necrosis and this condition is uniformly fatal. In contrast, ARF due to postrenal causes like obstruction have much lower mortality rates.2 Consequently, rapid diagnosis of the etiology of ARF is essential so that renal perfusion can be corrected and other causes of ARF eliminated.

Differential Diagnosis Intravascular volume depletion Dehydration Hemorrhage CHF Liver disease Nephrotic syndrome Overdiuresis Bilateral renal artery stenosis (unilateral renal artery stenosis in solitary kidney) Emboli Cholesterol Thrombotic Medications Cyclosporine ACEIs NSAIDs Hypercalcemia Hepatorenal syndrome Vasculitis Polyarteritis nodosa Thrombotic thrombocytopenic purpura Hemolytic uremic syndrome Emboli Cholesterol Thrombotic Systemic lupus erythematosus Poststreptococcal glomerulonephritis Antiglomerular basement membrane disease Ischemic Hypotension Vasoconstriction Exogenous toxins Contrast dye Heavy metals Drugs (amphotericin B, aminoglycosides, etc.) Endogenous toxins Myoglobin Hemoglobin Drugs Penicillins Ciprofloxacin Sulfonamides Infection Streptococcal Prostatic hypertrophy Improperly placed bladder catheter Cervical cancer Retroperitoneal fibrosis Crystal deposition Oxalate Indinavir Sulfonamides Acyclovir Tumor lysis syndrome

PRERENAL AZOTEMIA Prerenal ARF results from hypoperfusion of the renal parenchyma, with or without systemic arterial hypotension. Renal hypoperfusion with systemic arterial hypotension may be caused by a decline in

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intravascular volume (e.g., hemorrhage or dehydration) or a decline in effective blood volume (i.e., the blood volume perceived by the arterial baroreceptors). Examples of disease states in which there is a decline in effective blood volume without a decrease in intravascular volume include congestive heart failure (CHF) and liver failure. Because the kidney is initially undamaged, the urinalysis will be normal. Eventually, the fractional excretion of sodium will be low, reflecting an increase in the concentrations of the sodium-retentive hormones renin, angiotensin, and aldosterone. Urinary solutes will be concentrated as a result of the increased circulating levels of antidiuretic hormone that is released in response to the diminished arterial blood pressure. Renal hypoperfusion without systemic hypotension most commonly results from bilateral renal artery occlusion, or unilateral occlusion in a patient with a single functioning kidney. In these conditions, the sodium-retentive hormones are activated by the decline in renal parenchymal perfusion. However, systemic arterial blood pressure is usually elevated, leading to an inhibition of antidiuretic hormone release. Consequently, the urinary indices will reflect enhanced sodium reabsorption (i.e., a low fractional excretion of sodium), but the urinary solutes may not be maximally concentrated.

FUNCTIONAL ACUTE RENAL FAILURE Functional ARF refers to those entities that result in a decline in glomerular ultrafiltrate production secondary to a reduced glomerular hydrostatic pressure without damage to the kidney itself. The decline in glomerular hydrostatic pressure is a direct consequence of changes in glomerular afferent (vasoconstriction) and efferent (vasodilation) arteriolar circumference. These clinical conditions most commonly occur in individuals who have reduced effective blood volume (e.g., CHF, cirrhosis, severe pulmonary disease, or hypoalbuminemia) or renovascular disease (e.g., renal artery stenosis), and cannot compensate for changes in afferent or efferent arteriolar tone. Examples of disorders that result in afferent arteriolar vasoconstriction (and an increase in afferent arteriolar resistance) include hypercalcemia and the administration of certain medications (e.g., Cyclosporine and NSAIDs). A decrease in efferent arteriolar resistance usually results from the administration of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor antagonist. With correction of the underlying pathologic process or discontinuation of the responsible medication, renal function rapidly returns to baseline. The hepatorenal syndrome is included in this classification scheme since the kidney itself is not damaged and there is intense afferent arteriolar vasoconstriction leading to a decline in glomerular filtration. In all the above conditions, the urinalysis is no different from its baseline state and the urinary indices suggest prerenal azotemia. This syndrome of functional ARF is very common in individuals with CHF who receive an ACEI in an attempt to improve left ventricular function. The decline in efferent arteriolar resistance resulting from the inhibition of angiotensin II occurs rapidly. Therefore, if the dose of the ACEI is increased too rapidly, there will be a decline in glomerular ultrafiltrate production with a concomitant rise in the serum creatinine, leading to functional ARF. If the increase in the serum creatinine is not too severe (usually 3 g urinary protein per 24-hour collection period) and hemoglobinuria. Microscopic analysis of the urinary sediment frequently shows numerous red blood cells (RBCs) and RBC casts, the latter being considered diagnostic for glomerulonephritis. In the early stages of the illness, the fractional excretion of sodium is less than 1 because tubular function is still intact. However, as renal failure becomes more established, the fractional excretion of sodium may increase. The renal tubules are susceptible to a variety of insults. The tubules contained within the medulla of the kidney are particularly at risk from ischemic injury, as this portion of the kidney is very metabolically active, and thus has a high oxygen requirement. Severe hypotension or the administration of vasoconstricting drugs preferentially affects the tubules more than any other portion of the kidney. In addition, exogenous toxic substances (e.g., contrast agents, heavy metals, and pharmacologic agents such as aminoglycosides, amphotericin B, and foscarnet) and endogenous toxins (e.g., myoglobin, hemoglobin, and uric acid) may cause tubular injury. Once tubular cells die, they slough off into the tubular lumen, forming casts causing increased tubular pressures and reduced glomerular filtration.21 Regardless of the etiology, tubular injury leads to a loss of urine concentrating ability, defective distal sodium reabsorption, and a reduction in the GFR. The etiology of acute intrinsic renal failure secondary to tubular injury (referred to as acute tubular necrosis or ischemic ARF) is usually discernible by reviewing the patient’s history and medication list. The urinalysis suggests tubular injury by the presence of coarse “dirty brown” casts. RBCs and RBC casts are only rarely seen. The urinary indices suggest intrinsic renal dysfunction (i.e., high fractional excretion of sodium, urine osmolality equal to plasma osmolality, and a low urine creatinine:serum creatinine ratio). 1 The therapeutic approach for the management of ATN secondary to ischemia of the kidneys is changing. Historically, clinicians viewed ischemic ARF as a one-time event that resulted in tubular death. During this time the patient should be supported until renal function recovers. The new model for ischemic ARF is much like that used in treatment of myocardial infarction and stroke. Now, in addition to an initiation phase, when the patient experiences a hypoxic insult, an extension phase has been hypothesized.22 Similar to what is postulated to occur during a myocardial infarction, in the kidney continued hypoxia after the original ischemic event results in an inflammatory response that further damages the kidney. More renal tubular epithelial cells are damaged and die, particularly in the corticomedullary junction. Cytokine release further increases the inflammation. Renal perfusion becomes less organized, as renal vasodilation and vasoconstriction are not occurring efficiently, and the area of injury grows. All of this occurs in the first 24 hours after the initial insult.22 New therapies will address the development of ATN and stop the extension phase as early as possible by blocking the pathways that cause inflammation after the initial insult.23

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The interstitium of the kidney is also susceptible to injury from a variety of causes. Although acute interstitial nephritis is most commonly caused by medications (see Chap. 46), infections (e.g., streptococcal, leptospirosis, hantavirus, and human immunodeficiency virus), selected autoimmune disorders (systemic lupus erythematosus or mixed connective tissue disease) also may produce a similar syndrome. The presence of white blood cells (WBCs), WBC casts, and coarse granular casts in the urine all suggest interstitial inflammation. The presence of eosinophilia and eosinophiluria also strongly suggest the presence of an interstitial nephritis. Occasionally low to moderate proteinuria can be seen on urinalysis.

POSTRENAL OBSTRUCTION ARF resulting from obstruction may occur at any level within the urinary system from renal tubule to urethra. However, to cause ARF, the obstructing process must involve both kidneys, or one kidney in a patient with a single functioning kidney. Bladder outlet obstruction is the most common cause of obstructive uropathy. Crystal deposition within the tubules (e.g., secondary to uric acid, oxalate, acyclovir, sulfonamide, indinavir, or methotrexate), and ureteral obstruction (e.g., secondary to shed renal papilla or calculi) are infrequent causes of obstructive ARF. Crystal-induced ARF is often seen in patients who have severe volume contraction or who are receiving large doses of a drug with relatively low solubility. In these cases, patients do not have sufficient urine volume to keep the crystals from coming out of solution in the urine.24 The onset of acute anuria in the absence of a catastrophic event should suggest acute urinary tract obstruction. However, the development of ARF in a hospitalized patient admitted with normal renal function is rarely secondary to obstruction unless an indwelling urinary catheter has been misplaced. When the obstructing process (e.g., prostatic hypertrophy or cervical cancer) is gradual and incomplete, the patient may present with complaints of decreased force of the urinary stream and polyuria.

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ondary to diffuse arterial lesions within the kidney, such as that which occurs with hemolytic uremia syndrome, denotes a poor chance for salvage of renal function.

GLOMERULI The glomerulus consists of an enlargement of the proximal end of the renal tubule to incorporate a vascular tuft connecting the afferent and efferent arterioles (Fig. 42–1). The production of glomerular ultrafiltrate is predominantly dependent on the transcapillary hydrostatic pressure (dictated by the afferent and efferent arteriolar resistance) and the glomerular surface area. Afferent arteriolar tone is determined primarily by the local levels of angiotensin II (which induces vasoconstriction) and prostaglandins (which induce vasodilation). Efferent arteriolar tone is predominantly determined by the local concentration of angiotensin II. Pathophysiologic processes and medications that result in alterations of the afferent and efferent arteriolar tone (i.e., systemic hypotension, hypercalcemia, or use of ACEIs, angiotensin II receptor blockers, or NSAIDs) reduce glomerular ultrafiltrate production as a result of a decrease in glomerular hydrostatic pressure. Under these conditions, the serum creatinine will rise, the urine sediment will be normal, and the urine indices will suggest prerenal azotemia. However, the urinary solutes may or may not be maximally concentrated, depending on the circulating level of antidiuretic hormone that is necessary to maximally concentrate the urine. Damage to the glomerular capillary tuft (e.g., acute glomerulonephritis) results in a decline in the production of glomerular ultrafiltrate as a result of a decrease in glomerular capillary surface area. Under these conditions the serum creatinine rises and the urinalysis is significant for hematuria and proteinuria because of the increased permeability of the damaged glomerular capillaries. Proteinuria exceeding 3 g/day is often referred to as nephrotic range proteinuria. Prolonged heavy proteinuria secondary to glomerular damage may result in the nephrotic syndrome.

PATHOPHYSIOLOGY Mesangium

Bowman's capsule

A basic knowledge of renal function facilitates the understanding of how ARF manifests itself clinically. The most logical approach to understanding renal function is to divide the kidney into its four basic component parts: the vasculature, the glomeruli, the tubules, and the interstitium surrounding the other three component parts.

Bowman's space

A II

RENAL VASCULATURE The kidney is a highly vascular organ with blood vessels ranging from the very large (renal arteries) to the very small capillaries providing blood to each individual glomerulus. Obstruction of the renal artery will result in an increase in serum creatinine, hematuria, and proteinuria, but obstruction of smaller vessels will only cause infarction of the downstream parenchyma. If this area is small, no change in serum creatinine will occur. Smaller vessels may be obstructed with cholesterol emboli, vascular lesions, or platelet plugs, all of which will present as isolated decreased perfusion of the glomeruli. The serum creatinine frequently is increased since the lesions are usually diffuse. However, the urinalysis most commonly will be normal since the kidney itself is not ischemic and the glomeruli are not involved. The urinary indices suggest prerenal azotemia (i.e., a low urine sodium concentration and a low fractional excretion of sodium) in the absence of systemic hypotension or a decrease in effective blood volume. The urine volume may or may not be diminished. However, the onset of oliguria sec-

Formation of ultrafiltrate

Glomerular basement membrane

PG

A II

Afferent arteriole

Autonomic nerves

Formation of ultrafiltrate

Efferent arteriole Autonomic nerves

To proximal tubule

FIGURE 42–1. The formation of glomerular ultrafiltrate is dependent on the surface area of the glomerular capillaries, their permeability, and the net hydrostatic pressure across the capillary wall. As the glomerular capillary surface area increases secondary to mesangial cell relaxation, the formation of glomerular ultrafiltrate is increased. An increase or decrease in glomerular hydrostatic pressure results in either an increase or decrease in glomerular ultrafiltrate production. Afferent arteriolar vasoconstriction (which is primarily mediated by angiotensin II) or vasodilation (primarily mediated by prostaglandins) can result in a decrease or increase, respectively, in hydrostatic pressure across the capillary. Efferent arteriolar vasoconstriction (primarily mediated by angiotensin II) results in an increase in glomerular hydrostatic pressure. Under conditions in which renal blood flow is diminished, the kidney maintains glomerular ultrafiltration by vasodilating the afferent and vasoconstricting the efferent arterioles. Medications that may interfere with these processes might result in an abrupt decline in glomerular filtration.

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RENAL TUBULES Under normal conditions, approximately 180 L of glomerular ultrafiltrate are produced per day, the vast majority of which must be reabsorbed by the renal tubules to maintain homeostasis. Clinically, the renal tubule can be divided into three major sections: the proximal tubule, Henle’s loop, and the distal nephron, which includes the distal tubule, the cortical collecting tubule, and the medullary collecting ducts. In the proximal tubule, approximately 60% to 70% of the filtered load of water and solute is isovolemically reabsorbed, as is the vast majority of filtered amino acids, glucose, and bicarbonate. In addition to its other functions, Henle’s loop is responsible for a significant portion of the total reabsorption of potassium, calcium, and magnesium, as well as for generating the osmotic gradient within the kidney that is necessary for the concentration of urinary solutes. Damage to this portion of the nephron results in wasting of potassium and magnesium by the kidney and an inability of the kidney to concentrate the urine. The medullary portions of Henle’s loop are very sensitive to ischemia secondary to hypoperfusion. Consequently, in severe prerenal azotemia with renal hypoperfusion, there may be a loss of urinary concentrating ability despite the continued presence of a low urinary sodium concentration and a low fractional excretion of sodium. Major functions of the distal nephron include the regeneration of bicarbonate, the excretion of acid (hydrogen ion), the secretion of potassium, and the reabsorption of water. Damage to this portion of the nephron may present as significant acidemia and either hypoor hyperkalemia, depending on the mechanism of injury. For example, amphotericin B produces small pores in the luminal membrane of distal tubular cells. These pores allow small molecules such as potassium to leak out; the molecules are then wasted in the urine. Consequently, amphotericin B nephrotoxicity is characterized by hypokalemia secondary to renal potassium wasting. ATN is associated with urinary sediment characterized by the presence of tubular cells, coarse granular casts, and rarely, RBC casts.

INTERSTITIUM The interstitium of the kidney provides the structural support for the kidney and serves to provide the environment in which concentrating gradients can be established. In addition, the interstitium of the kidney plays a major role in urinary ammonia handling. To facilitate the regeneration of bicarbonate and the excretion of acid by the distal nephron, the kidney utilizes ammonia as a urinary buffer. When the interstitium of the kidney is damaged (e.g., in acute allergic interstitial nephritis), the concentrating gradient within the kidney may be dissipated and ammonia handling disrupted. Consequently, patients presenting with acute interstitial nephritis frequently are unable to concentrate the urinary solutes. The urinalysis may show mild proteinuria and hematuria. However, the striking finding on microscopic examination of the sediment is the presence of numerous WBCs and WBC casts. Rapid diagnosis is essential in the treatment of ARF in order to prevent extension of renal damage. The cause of most cases of ARF can be diagnosed from relatively few laboratory tests in conjunction with a good history and physical exam.

chronic. A past medical history of renal disease or chronic conditions such as poorly controlled hypertension or diabetes mellitus, previous laboratory data documenting the presence of proteinuria or an elevated serum creatinine, and the finding of bilateral small kidneys on renal ultrasonography all suggest the presence of severe and chronic kidney disease. For patients who do not have the above findings, their renal failure should be considered acute until proven otherwise. In these individuals, a careful review of their recent medications, including nonprescription, complementary, and alternative medications is mandatory. Special attention should be focused on diuretics, NSAIDs, antihypertensives, and any recent additions or changes in the patient’s medications. The patient’s recent history can usually provide an indication of when the onset of renal dysfunction began. Frequently, patients may notice a change in their voiding habits with an increase in urinary frequency or nocturia, both suggesting a urinary concentrating defect. A decrease in the force of the urinary stream may suggest an obstruction. The presence of cola-colored urine, indicating the presence of blood in the urine, is common in acute glomerulonephritis. If the accompanying proteinuria is severe, the patient may note excessive foaming of the urine in the toilet. The onset of bilateral flank pain may suggest swelling of the kidneys secondary to either acute glomerulonephritis or acute interstitial nephritis. The onset of severe headaches may suggest the development of hypertension as a result of ARF. A recent increase in the patient’s weight or complaints of tight-fitting rings secondary to salt and water retention also may be helpful in defining the onset of renal failure. For patients who develop ARF while hospitalized, a review of the laboratory data is usually sufficient to define the onset of ARF. However, significant renal injury can occur prior to an increase in the serum creatinine. Consequently, clinicians must pay careful attention to subtle changes in the patient’s weight, blood pressure, and urine output if they are to diagnose the onset of ARF. In addition to its prognostic significance, changes in urine output may be helpful in diagnosing the type of renal dysfunction that is present. Acute anuria is secondary to either complete urinary obstruction or a catastrophic event (e.g., shock, HUS, or acute cortical necrosis). Initial presentation with oliguria suggests prerenal azotemia, functional ARF, or acute intrinsic renal failure. Nonoliguric renal failure usually results from acute intrinsic renal failure or incomplete urinary obstruction. CLINICAL PRESENTATION OF ACUTE RENAL FAILURE GENERAL Outpatients often are not in acute distress; hospitalized patients may develop ARF after a catastrophic event SYMPTOMS Outpatient: Change in urinary habits, weight gain, or flank pain Inpatient: Typically ARF is noticed by clinicians before it is noticed by the patient

HISTORY

SIGNS Patient may have edema; urine may be colored or foamy. Vital signs may indicate orthostatic hypotension in volumedepleted patients

The diagnostic approach to the patient with ARF differs depending on the clinical setting in which the kidneys fail. For patients who present to the outpatient clinic or hospital with an elevated serum creatinine, the first objective is to determine if the renal failure is acute or

LABORATORY TESTS Urine and blood chemistries may determine prerenal cause complete blood cell count (CBC) and differential rules out infectious causes

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Urine microscopy may reveal casts, WBCs, RBCs, and eosinophils OTHER DIAGNOSTIC TESTS Renal ultrasound or cystoscopy may be needed to rule out obstruction; renal biopsy reserved for difficult diagnoses

PHYSICAL EXAMINATION A physical examination, including assessment of the patient’s volume and hemodynamic status, is the next step in evaluating individuals with ARF. Common physical findings in patients with ARF are listed in Table 42–3. The physical exam should be thorough, as clues regarding etiology can come from anywhere from the patient’s head (eye exam) to toe (evidence of dependent edema).

LABORATORY TESTS AND INTERPRETATION Chapter 41 describes the use of serum creatinine as a determinant of renal function. As stated earlier, many clinicians do not agree on the definition of ARF based on specific changes in serum creatinine

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values. The difficulty of using serum creatinine as a diagnostic laboratory test for hospitalized patients with ischemic ARF is that it is too insensitive to rapid changes in glomerular filtration rates. An abrupt cessation in glomerular filtration will not yield an immediate measurable change in serum creatinine. Reasons for this include: creatinine generation is relatively slow, lab tests are not very sensitive to small changes, and because fluid retention in renal failure dilutes the retained serum creatinine.4 By the time serum creatinine elevates enough to be noticed, the extension phase of ischemic ARF is complete.22 “Correction” of serum creatinine values for hypervolemic patients with ARF has been suggested for earlier detection of ARF in at-risk patients.4 Selected blood tests in addition to blood urea nitrogen (BUN) and serum creatinine can have value in the management of the patient with ARF. For example, infectious causes of ARF can be ruled out using a CBC with differential. Serum electrolyte values are likely to be abnormal, and particular attention should be paid to serum potassium and phosphorus values, which can be elevated and cause life-threatening conditions. Given the limited usefulness of solely using blood markers like creatinine or BUN to diagnose ARF, urinalysis should be performed. Urinalysis is an essential battery of tests when the clinician is attempting to determine the cause of renal failure. The finding of a high urinary

TABLE 42–3. Physical Examination Findings in Acute Renal Failure Physical Examination Finding Vital signs Orthostatic hypotension Febrile Skin Tenting Rash Petechiae

Splinter hemorrhages Janeway lesions Osler’s nodes Edema HEENT Hollenhorst plaque Roth spots Heart S3 heart sound New murmur (particularly diastolic murmurs) Lung Rales Abdomen Renal artery bruit Ascites Bladder distention Genitourinary Prostatic enlargement Gynecologic Abnormal bimanual examination

Possible Diagnosis

Category of Acute Renal Failure

Volume depletion Sepsis

Prerenal azotemia Acute intrinsic

Volume depletion Hypersensitivity reaction Thrombotic thrombocytopenic purpura Hemolytic uremic syndrome Sepsis Endocarditis

Prerenal azotemia Acute interstitial nephritis Acute intrinsic renal failure—vasculitis Acute intrinsic Intrinsic renal failure—glomerulonephritis

Total body volume overload

Suggests prerenal azotemia unlikely

Cholesterol emboli Endocarditis

Acute intrinsic renal failure—vascular Acute intrinsic renal failure—acute glomerulonephritis

Congestive heart failure Endocarditis

Prerenal azotemia Acute intrinsic renal failure—acute glomerulonephritis

Pulmonary edema with volume overload or left ventricular dysfunction

Suggests prerenal azotemia unlikely

Renal artery stenosis Liver failure or right heart failure Bladder outlet obstruction

Prerenal azotemia Prerenal azotemia Hepatorenal syndrome Postobstruction renal failure

Prostatic hypertrophy or cancer

Postobstruction renal failure

Possible bilateral ureteral obstruction or cervical cancer

Postobstruction renal failure

CHF, congestive heart failure; HEENT, head, eyes, ears, nose, and throat.

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TABLE 42–4. Diagnostic Parameters for Differentiating Causes of Acute Renal Failure Laboratory Test

Prerenal Azotemia

Acute Intrinsic Renal Failure

Postrenal Obstruction

Urine sediment

Normal

Cellular debris

Urinary RBC Urinary WBC Urine sodium FENa (%) Urine/serum osmolality Urine/serum creatinine BUN/SCr

None None 40 >2 40 Variable 40:1

500 mOsm/L) suggests stimulation of antidiuretic hormone and intact tubular function. These findings are consistent with prerenal azotemia. Diuretic use limits the utility of the fractional excretion of sodium calculation by increasing natriuresis, even in hypovolemic patients.

DIAGNOSTIC PROCEDURES Renal ultrasound is rarely helpful in determining the cause of ARF in a hospitalized patient who previously had normal renal function; however, for the outpatient who presents with renal failure, the renal ultrasound is instrumental in determining whether the renal failure is acute or chronic and whether or not obstruction is present. A plain film radiograph of the abdomen may be useful in documenting the presence of two kidneys and in checking for renal stones. If the possibility of renal artery obstruction exists, a radioisotope scan or renal angiography may be required. Intravenous pyelography is rarely used in the diagnostic work-up of ARF. Cystoscopy with retrograde pyelography may be helpful if the possibility of obstruction exists. If insertion of a urinary catheter into the patient’s bladder after the patient has voided does not yield a large volume of urine (>500 mL), then one can usually exclude postrenal obstruction as the cause of ARF. If a large volume of urine remains after the patient has voided, or if the patient is unable to void, urinary catheter placement into the bladder may result in alleviation of symptoms if the obstruction is somewhere between the bladder to the urethral opening. If the etiology of the ARF is unclear despite a careful history, physical examination, and appropriate diagnostic tests, percutaneous renal biopsy may be indicated. Renal biopsy is associated with some risk (primarily bleeding) and should only be performed in those few patients who meet criteria for biopsy. However, in cases in whom the cause of ARF is not evident, renal biopsies are useful in determining the cause in more than 90% of patients.25


PREVENTION AND TREATMENT: Acute Renal Failure
DESIRED OUTCOME 2 Given the dismal outcomes of patients with ARF, prevention is

critical. In many cases, the risk of ARF development is known and is predictable. For example, when patients with risk factors for ARF development are scheduled to receive radiocontrast dye or sur-

gery that will stop blood flow to the kidneys, the clinician knows that ARF may develop. In these cases preventive measures must be taken. Fortunately many therapeutic maneuvers have been identified that can reduce the risk of ARF development in these situations. Consequently the goals of treatment are (1) to prevent ARF, but if ARF develops, (2) avoid or minimize further renal insults that would delay recovery, and (3) provide supportive measures until kidney function returns.

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GENERAL APPROACH TO TREATMENT

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NONPHARMACOLOGIC

The general approach to the treatment of established ARF is dependent on the setting in which it develops. In the community setting, the first goal is to remove the causative agent (drugs or nephrotoxins) if possible. If the cause is immune-related, as may be the case with interstitial nephritis or glomerulonephritis, a rapid diagnosis must be made to begin appropriate immunologic therapy (usually corticosteroids). In the hospital setting, nephrotoxic agents should be discontinued and prerenal causes must be ruled out. Renal perfusion should be optimized to stop extension of any ischemic processes. This typically means a fluid challenge with close watch of the patient’s vital signs and urine output. Care must be taken not to fluid overload a patient with absent kidney function. Once renal failure is established and the cause is known, supportive care is all that can be provided. Renal replacement therapy is provided to maintain fluid and electrolyte balance while removing accumulating waste products. All further insults to the kidney must be prevented so the slow process of renal recovery can begin. In the case of ATN, this typically occurs within 10 to 14 days. Longer courses of ARF can occur if the kidney is exposed to repeated insults.

In situations in which administration of a nephrotoxin cannot be avoided, such as when radiocontrast dye is to be administered, nonpharmacologic therapies can be employed to prevent ARF. The key to nonpharmacologic ARF prevention is the elimination of the patient’s risk factors to the degree that is possible. The best-studied examples of this are the interventions used to maximize renal perfusion when radiocontrast dye is administered. Adequate hydration and sodium loading prior to radiocontrast dye administration have been shown to be beneficial therapies. A trial comparing infusions of 0.9% NaCl or 5% dextrose with 0.45% NaCl administered prior to radiocontrast dye infusion conclusively demonstrated that the normal saline was superior in preventing ARF.26 The intravenous solution infusion rate used in this study was 1 mL/kg per hour beginning the morning that the radiocontrast dye was going to be given, and all subjects were encouraged to drink fluids liberally as well. The benefits of 0.9% NaCl infusions have been found in similar studies,27 suggesting this regimen should be used in all at-risk patients who can tolerate the sodium and fluid load.


Preventive Dialysis


PREVENTION OF ARF 3 The therapies used to prevent ARF are much different than those

used to treat established ARF; consequently preventive therapies will be reviewed first and treatment options will follow. Given the dismal outcome of patients with ARF, numerous regimens have been tried to prevent the development of ARF in patients who will be receiving known nephrotoxins. Typically, these interventions are made prior to administration of nephrotoxins like radiocontrast dye, or prior to surgical procedures that will restrict blood flow to the kidneys for extended periods. Because the timing of the renal insult is known, this setting is ideal for conducting clinical studies into ARF prevention. Unfortunately the list of interventions that do not prevent ARF in this setting is longer than the list of those that do. Table 42–5 lists some of the interventions that have been studied to prevent ARF.

A novel approach to reducing the incidence of nephrotoxicity associated with radiocontrast dye administration is to provide RRT prophylactically to patients at high risk. Hemofiltration provided prior to and 24 hours after dye administration resulted in significantly reduced mortality rates and a reduced need for dialysis.28 In contrast, the use of hemodialysis within an hour of contrast dye infusion did not yield an improvement in nephrotoxicity rates, possibly because the toxicity due to dye occurs within minutes of its administration.29


PHARMACOLOGIC 4 One of the simplest ways to prevent acute nephrotoxicity is to avoid the use of nephrotoxic agents when possible. If

TABLE 42–5. Evidence of Benefit of Prophylactic Therapies for the Prevention of Acute Renal Failure Due to Nephrotoxin Exposure Intervention Hydration (sodium loading)

Mannitol Loop diuretics Dopamine Calcium channel blockers

Theophylline Acetylcysteine Fenoldopam Insulin (to maintain serum glucose of 80–110 mg/dL)

Evidence for Prevention of Nephrotoxicity Y

N N N +/−

Y Y N Y

Situations in Which Intervention Documented to be Effective Prior to amphotericin or contrast dye administration; tumor lysis syndrome prevention

Recipient should receive drug prior to transplantation and when kidney is stored in solution containing drug. Not useful for preventing contrast dye nephropathy. Prior to contrast dye administration Prior to contrast dye administration Critically ill patients

Y, some evidence exists for benefit; +/−, evidence equivocal; N, evidence suggests no benefit.

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nephrotoxic agents cannot be avoided, there may be ways to administer them in a manner that reduces their nephrotoxic potential. A good example of this is the use of amphotericin B to treat fungal infections. Amphotericin is a highly nephrotoxic agent, causing ARF in approximately 30% of patients who receive it.30 However, there are many infections for which no good alternative treatment exists. The nephrotoxic potential of amphotericin B deoxycholate can be reduced significantly simply by slowing the infusion rate from a standard 4-hour infusion to a slower 24-hour infusion of the same dose.31 In a patient with risk factors for the development of ARF, liposomal forms of amphotericin B can be used. These liposomal formulations are more expensive, but cause a lower incidence of kidney damage.32 Given the dismal outcome of established ARF, many drugs have been investigated for its prevention. Surprisingly, many of these interventions have been found to be of no benefit. Low doses of dopamine (≤2 mcg/kg per minute) increase renal blood flow and might be expected to increase GFR. Theoretically, this might be considered beneficial, as an enhanced GFR might flush nephrotoxins from the tubules, minimizing their toxicity. Furthermore, loop diuretics may decrease tubular oxygen consumption by reducing solute reabsorption.33 Despite these theoretical suggestions that loop diuretics and dopamine might be useful in ARF prevention, controlled studies do not support these theories. In a blinded and randomized trial conducted in patients undergoing cardiac surgery, dopamine 2 mcg/kg per minute, furosemide 0.5 mcg/kg per minute, and a 0.9% NaCl placebo given at initiation of surgery were compared to determine whether any of the these interventions would be beneficial.34 Postoperative increases in serum creatinine occurred significantly more often in the furosemide-treated subjects than in the other two groups. Dopamine afforded no benefit compared to the sodium chloride infusion, and therefore should not be used routinely in this manner. The use of diuretics to prevent nephrotoxicity may actually result in intravascular depletion, a prerenal state, and an exacerbation of ARF. A trial of forced diuresis, in which mannitol, furosemide, and/or dopamine were given, and resultant urinary losses were replaced with intravenous solutions found that diuretic use resulted in little benefit compared to IV solutions given alone.35 Interestingly, these investigators noted that patients that were unable to produce much urine despite diuretic administration were more likely to develop ARF than patients who did respond to diuretics. While this unresponsiveness to diuretics might simply be an indication of preexisting kidney damage, similar reports have linked diuretic unresponsiveness to increased mortality rates in critically ill patients with ARF.6 CLINICAL CONTROVERSIES Despite the fact that most studies do not show improved patient outcomes with its use, low-dose dopamine continues to be commonly used. The risks associated with dopamine use (extravasation and the potential for significant dosing errors) suggest that it should usually be avoided. Giving low-dose dopamine infusions (≤2 mcg/kg per minute) for the prevention of ARF is a surprisingly common practice given the paucity of data to support its use. While most studies do report an increase in urine output when low-dose dopamine is administered, almost none report that this practice yields a benefit to the patient. A meta-analysis of all low-dose dopamine studies conducted from 1966 to 2000 concluded that low-dose dopamine does not prevent ARF and its use could not be justified.36


Fenoldopam Fenoldopam is a selective dopamine-1 receptor agonist that has been investigated for its ability to prevent radiocontrast dye nephropathy. Originally approved for use as an intravenous antihypertensive agent, fenoldopam reduces systemic blood pressure while preserving renal blood flow, it appears to have salutary properties for the prevention of drug-induced nephrotoxicity. A large, multicenter, randomized, placebo-controlled trial of fenoldopam use to prevent radiocontrast dye nephropathy in patients with CKD found that fenoldopam provided no benefit.37 The disappointing results of this trial and that of the dopamine studies suggest that dopaminergic manipulation of the kidney is not likely to work as a preventive measure for nephrotoxicity (see Chap. 46).


Acetylcysteine Pretreatment with oral acetylcysteine, (also called n-acetylcysteine), 600 mg twice daily on the day before and the day of radiocontrast dye administration has been documented to lower the rate of ARF in patients with pre-existing CKD.38−39 The mechanism for acetylcysteine’s ability to reduce the incidence of radiocontrast dye nephrotoxicity is not fully elucidated, but likely is due to its antioxidant effects. Given the consistent findings of its efficacy and its relatively low cost, acetylcysteine should be given to all patients at risk for radiocontrast dye nephrotoxicity. Many other drugs have been investigated for the prevention of ARF, with varying degrees of success.33 A few of these agents bear mentioning. Theophylline 200 mg infused 30 minutes before contrast dye administration resulted in a fivefold decrease in nephropathy compared to a placebo infusion in high-risk patients.40 Despite this finding and for reasons that are unclear, most centers typically do not use this intervention to prevent contrast dye nephropathy. Calcium antagonists have shown promise in reducing ATN in kidneys that are transplanted,41 but their utility is limited in other clinical settings due to their hypotensive effects.


Glycemic Control Perhaps the most promising agent for the prevention of hospitalacquired ARF is a very old drug, but its use in the prevention of ARF is a very new finding. Van den Berghe and associates randomized patients in a surgical ICU to receive standard control (1 mL/kg/h within 1 h? Yes

No Furosemide 400 mg

Furosemide 80 mg IV q 6−8 h or 10 mg/h IV

Urine output >1 mL/kg/h within 2 h? Yes

No Furosemide 400 mg IV + chlorothiazide 500 mg

Titrate furosemide dose to maintain urine output of >1 mL/kg/h

Urine output >1 mL/kg/h within 2 h? Furosemide 40 mg/h IV as long as urine output >1 mL/kg/h until euvolemic

FIGURE 42–2. Suggested treatment algorithm for ICUacquired oliguric acute renal failure resulting from acute tubular necrosis.

Yes Continue chlorothiazide 500 mg q 12h and:

No Consider renal replacement therapy if: • pulmonary edema • hyperkalemia • acidosis • azotemia

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with diuretics instead of more invasive RRTs, despite the previously mentioned finding that diuretic use may be associated with a worse outcome.6 The most effective drugs in causing diuresis in the ARF setting are mannitol and the loop diuretics. These two therapies have distinct advantages and disadvantages. Mannitol, which works as an osmotic diuretic, can only be given parenterally. A typical starting dose is mannitol (20%) 12.5 to 25 g infused intravenously over 3 to 5 minutes. It has little nonrenal clearance, so when given to anuric or oliguric patients, mannitol will remain in the patient, potentially causing a hyperosmolar state. Additionally mannitol may cause ARF itself, so its use in ARF must be monitored carefully by measuring urine output and serum electrolytes and osmolality.59 Due to these limitations of mannitol, some have recommended that it be reserved for its nondiuretic uses, like management of cerebral edema.60 CLINICAL CONTROVERSIES In edematous patients, occasionally a clinician will suggest infusing albumin to provide intravascular oncotic pressure to mobilize fluid back into the intravascular space, and then administering loop diuretics to remove this fluid. Studies on the merits and costs of this combination have had mixed results. Furosemide, bumetanide, torsemide, and ethacrynic acid are the most frequently used loop diuretics in patients with ARF. Ethacrynic acid is reserved for patients who are allergic to sulfa compounds. Furosemide is the most commonly used loop diuretic because of its lower cost, availability in oral and parenteral forms, and good safety and efficacy profiles. A disadvantage with furosemide is its variable oral bioavailability in many patients. Consequently, initial furosemide doses (usually 40 to 80 mg) are usually administered intravenously to assess whether the patient will respond. Torsemide and bumetanide have better oral bioavailability than furosemide. Torsemide has a longer duration of activity than the other loop diuretics which allows for less frequent administration but also may make it more difficult to titrate the dose. Loop diuretics should all work equally well in a given patient provided that they are administered in equipotent doses parenterally so that bioavailability issues are obviated. In a patient who is unresponsive to aggressive loop diuretic dosing, switching to another loop diuretic is unlikely to be beneficial. In the outpatient setting, torsemide may be preferred because it can be administered

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once daily, and because of its relatively better oral bioavailability than furosemide.


Diuretic Resistance Inability to respond to administered diuretics is common in ARF and is associated with a poor patient outcome.6 An effective technique to overcome diuretic resistance is to give loop diuretics via continuous infusions instead of intermittent boluses. Less natriuresis occurs when equal doses of loop diuretics are given as a bolus instead of as a continuous infusion. Furthermore, adverse reactions from loop diuretics (myalgias and hearing loss) occur less frequently in patients receiving continuous infusion compared to those receiving intermittent boluses, ostensibly because lower serum concentrations are attained. However, these adverse effects still may occur with continuous infusion loop diuretics and should be monitored.61 The finding that the continuous infusions of loop diuretics have efficacy that is at least as good as intermittent bolus dosing, with fewer adverse effects, appears to be consistent for all agents, including furosemide,62 bumetanide,63 and torsemide.64 When continuous loop diuretic infusion is used, an initial loading dose is given (equivalent to furosemide 40 to 80 mg) prior to the initiation of the continuous infusion at a dose of 10 to 20 mg/hour of furosemide or its equivalent. Patients with low creatinine clearances have much lower rates of diuretic secretion into the tubular fluid; consequently, higher doses are generally used in patients with renal insufficiency.60 Diuretic resistance may occur simply because excessive sodium intake overrides the ability of the diuretics to eliminate sodium. Other reasons exist for diuretic resistance in this population. Patients with ATN have a reduced number of functioning nephrons on which the diuretic may exert its action. Other clinical states like glomerulonephritis are associated with heavy proteinuria. Intraluminal loop diuretics cannot exert their effect in the loop of Henle because they are extensively bound to the protein present in the urine. Still other patients may have reduced bioavailability of oral furosemide. Possible therapeutic options to counteract each form of diuretic resistance are presented in Table 42–7. Combination therapy of loop diuretics plus a diuretic from a different pharmacologic class can be an effective tool in the setting of ARF.65 Loop diuretics increase the delivery of sodium chloride to the distal convoluted tubule and collecting duct. With time, these areas of the nephron compensate for the activity of the loop diuretic and increase sodium and chloride resorption. Diuretics that work at the

TABLE 42–7. Common Causes of Diuretic Resistance in Patients with Acute Renal Failure and the Measures Used to Counteract Them Causes of Diuretic Resistance Excessive sodium intake (sources may be dietary, IV fluids, and drugs) Inadequate diuretic dose or inappropriate regimen Reduced oral bioavailability (usually furosemide) Nephrotic syndrome (loop diuretic protein binding in tubule lumen) Reduced renal blood flow Drugs (NSAIDs ACEIs, vasodilators) Hypotension Intravascular depletion Increased sodium resorption Nephron adaptation to chronic diuretic therapy NSAID use Congestive heart failure Cirrhosis Acute tubular necrosis

Potential Therapeutic Solutions Remove sodium from nutritional sources and medications Increase dose, use continuous infusion or combination therapy Use parenteral therapy; switch to oral torsemide or bumetanide Increase dose, switch diuretics, use combination therapy Discontinue these drugs if possible Intravascular volume expansion and/or vasopressors Intravascular volume expansion Combination diuretic therapy, sodium restriction Discontinue NSAID Treat the CHF, increase diuretic dose, switch to better absorbed loop diuretic High-volume paracentesis Higher dose of diuretic, diuretic combination therapy, add low-dose dopamine

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distal convoluted tubule (thiazides) or the collecting duct (amiloride, triamterene, and spironolactone) may have a synergistic effect when administered with loop diuretics by blocking the compensatory increase in sodium and chloride resorption. The combination of loop diuretics and usual doses of thiazide diuretics may be effective in renal disease despite the accumulation of endogenous organic acids in renal disease that blocks the transport of loop diuretics into the lumen. If oral thiazides cannot be given to the patient, chlorothiazide can be administered parenterally. Several drug combinations with loop diuretics have been investigated, including the addition of one or more of the following: theophylline, acetazolamide, spironolactone, thiazides, or metolazone.65 Of these combinations, metolazone is used most frequently with furosemide. Metolazone, unlike other thiazides, produces effective diuresis at a GFR below 20 mL/minute. This combination of metolazone and a loop diuretic has been used successfully in the management of fluid overload in patients with CHF, cirrhosis, and nephrotic syndrome. Additionally, this combination has been found to be efficacious in pediatric patients as well as adults.66 The combination of mannitol plus intravenous loop diuretics is used by some practitioners,67 but no convincing evidence of the superiority of this combination regimen to conventional dosing of either diuretic alone exists.


NUTRITIONAL INTERVENTIONS While most drug therapy has yet to show benefit in patients with ARF, certain nutritional interventions may be useful. Pre-existing nutrition status has been shown to be a strong predictor of outcomes in patients with ARF.15 The use of enteral nutrition in patients with ARF in ICUs has been associated with an improvement in outcomes.10 Parenteral nutrition did not show the same benefit and some have questioned whether parenteral nutrition should ever be used in this population.68 The most common interventions that must be made when treating patients with ARF involve fluid and electrolyte management. Most patients with ARF are fluid overloaded, and fluids must be restricted. This means maximally concentrated drug infusions and nutrition solutions. So-called “keep vein open” or maintenance intravenous infusions should be halted unless the patient is euvolemic or is receiving renal replacement solution that is able to maintain fluid balance. The most common electrolyte disorder in ARF is hyperkalemia. Life-threatening cardiac arrhythmias may occur from hyperkalemia, so potassium restriction is essential. The treatment of hyperkalemia is discussed in Chap. 50. Typically no potassium should be added to parenteral solutions unless hypokalemia is documented. Patients receiving enteral nutrition should be limited to a 3-g potassium diet. Serum potassium concentrations should be monitored daily, even in patients receiving RRT. Some centers add no potassium to their CRRT solutions and hypokalemia can result with prolonged therapy. Sodium restriction is also a necessary intervention. A diet with 3 g of sodium per day is usually a reasonable place to start. Ingestion of too much sodium is a common reason diuretic therapy fails. Clinicians should be vigilant about sources of sodium. For example, 1 L of 0.9% NaCl yields 154 mEq of sodium, or 3.5 g. Sodium is usually restricted even in patients who are receiving RRT. In continuous and intermittent RRTs there usually is no worry about hyponatremia developing because these therapies will incorporate isonatremic (135 to 140 mEq/L of sodium) solutions as dialysate or ultrafiltrate replacement solutions. Serum sodium concentrations should be monitored daily. Other electrolytes that require monitoring include magnesium and phosphorus. Both are eliminated by the kidneys and are not removed efficiently by dialysis. Typically their dietary intake is re-

stricted, but in patients receiving prolonged renal replacement, deficiency states can occur, particularly in pediatric patients due to their reduced body stores. Hypophosphatemia can also occur in these critically ill patients as a result of the refeeding syndrome, in which nutritional supplementation is instituted after the patient goes a long period of time without being fed. Nonetheless, in initial ARF, hyperphosphatemia is more likely. Patients who also have significant tissue destruction (trauma, rhabdomyolysis, tumor lysis syndrome, or sepsis) may have significant phosphorus released from the destroyed tissue. Treatment of the hyperphosphatemic state can include RRT; however, for patients not receiving these therapies, oral phosphatebinding antacids or sevelamer can be administered (see Chap. 44). In hyperphosphatemic patients, calcium-containing antacids are often avoided to prevent precipitation of calcium phosphate in the soft tissues. A common guideline is to maintain the calcium-phosphate product 7.6) symptomatic metabolic alkalosis. In general, this management is reserved for patients who are unresponsive to conventional fluid and electrolyte management or who are unable to tolerate the requisite volume load because of decompensated congestive heart failure or advanced renal failure.39,42 Alternatively, hemodialysis using a low-bicarbonate dialysate may be used for the rapid correction of metabolic acidosis.

Sodium chloride–responsive disorders usually result from volume depletion and chloride loss, which may accompany severe vomiting, prolonged nasogastric suction, and diuretic therapy. Initially therapy is directed at expanding intravascular volume and replenishing chloride stores. Sodium and potassium chloride–containing solutions should be administered to patients who can tolerate the volume load.40,42 Patients with metabolic alkalosis who are volume overloaded or intolerant to volume administration because of congestive heart failure may benefit from the carbonic anhydrase inhibitor acetazolamide. This agent inhibits the action of carbonic anhydrase, thereby inhibiting renal bicarbonate reabsorption. Unfortunately, it also increases the renal losses of potassium and phosphate. Administration of acetazolamide (250 to 375 mg once or twice daily) may promote a sufficient bicarbonate diuresis and return the pH toward normal. However, because the clinical effectiveness of the drug declines as the HCO− 3

HYDROCHLORIC ACID Hydrochloric acid is usually infused intravenously via a large central vein as a 0.1 to 0.25 N HCl solution in either 5% dextrose or normal saline, although sterile water has also been used. Extemporaneously prepared solutions can be made by adding 100 to 250 mEq of HCl

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through a 0.22-mm filter into a glass container of saline or dextrose. Hydrochloric acid may also be added to parenteral nutrient solutions and administered via a central line without serious degradation of proteins.45 The rate of infusion should be 100 to 125 mL/h (10 to 25 mEq/h), with frequent monitoring of arterial blood gases. To prevent overcorrection, the infusion should be stopped when the arterial pH falls to 7.50.40 The dose of hydrochloric acid may be based on an estimate of the total body chloride deficit:28 Dose HCl (in mEqs) = [0.2 L/kg×BW (in kilograms)]

approved for this purpose.28 Like ammonium chloride, arginine must undergo metabolism by the liver to produce hydrogen ions, with a conversion of 100 g to 475 mEq of H+ . Unlike ammonium chloride, arginine combines with ammonia in the body to synthesize urea; thus it may be used in patients with relative hepatic insufficiency. Patients with renal insufficiency should not receive arginine monohydrochloride because it may significantly elevate BUN and is associated with severe hyperkalemia.28,30 The increase in potassium is caused by arginine-induced shifts of potassium from the intracellular to the extracellular space.

× [103 − observed serum chloride] where the estimated chloride space is 0.2 times the body weight and the average serum chloride is 103 mEq/L. Alternatively, the dose may be calculated based on the estimated base deficit:42 Dose HCl (in mEqs) = [0.5 L/kg × BW (in kilograms)] − × (desired [HCO− 3 ] − observed [HCO3 ])

CLINICAL CONTROVERSY At present, there are no comparative data that address the relative accuracy of these two formulas for determining the dose of hydrochloric acid. The dose of hydrochloric acid is usually infused intravenously over 12 to 24 hours.49 A severe transient respiratory acidosis may occur if the hydrochloric acid is infused too quickly because of the slower reduction of the elevated bicarbonate concentration in the cerebrospinal fluid than in the extracellular fluid. Improvement is usually seen within 24 hours of initiating therapy. Arterial blood gases and serum electrolytes should be drawn every 4 to 8 hours to evaluate and adjust therapy.

AMMONIUM CHLORIDE Ammonium chloride has a limited role in the treatment of metabolic alkalosis. The liver converts ammonium chloride to urea and free hydrochloric acid:28 − 2NH4 Cl + 2HCO− 3 → CO(NH2 )2 + CO2 + 3H2 O + 2Cl

The dose of ammonium chloride can be calculated on the basis of the chloride deficit using the same method as for HCl, using the conversion of 20 g ammonium chloride providing 374 mEq of H+ . However, only half of the calculated dose of ammonium chloride should be administered so as to avoid ammonia toxicity. Ammonium chloride is available as a 26.75% solution containing 100 mEq in 20 mL, which should be further diluted prior to administration. A dilute solution may be prepared by adding 100 mEq of ammonium chloride to 500 mL of normal saline and infusing the solution at a rate of no more than 1 mEq/min. Improvement in metabolic status is usually seen within 24 hours. CNS toxicity, marked by confusion, irritability, seizures, and coma, has been associated with more rapid rates of administration. Ammonium chloride must be administered cautiously to patients with renal or hepatic impairment. In patients with hepatic dysfunction, impaired conversion of ammonia to urea may result in increased ammonia levels and worsened encephalopathy. In patients with renal failure, the increased urea synthesis may exacerbate uremic symptoms.28

SODIUM CHLORIDE-RESISTANT DISORDERS 12 Management of these disorders usually consists of treatment of

the underlying cause of the mineralocorticoid excess. Patients who are taking corticosteroids may require a dosage reduction or may need to be switched to a corticosteroid with less mineralocorticoid activity. Patients with an endogenous source of excess mineralocorticoid activity may require surgery or the administration of spironolactone, amiloride, or triamterene.39,42,46 Spironolactone is a competitive antagonist of the mineralocorticoid receptor. Amiloride and triamterene are potassium-sparing diuretics that inhibit the epithelial sodium channel in the distal convoluted tubule and collecting duct. All three agents inhibit aldosteronestimulated sodium reabsorption in the collecting duct. In addition, spironolactone directly inhibits aldosterone-stimulation of the hydrogen ion secretory pump. Thus most patients with mineralocorticoid excess, including Bartter’s and Gitelman’s syndromes, respond to therapy with these agents.39,40,46 Liddle’s syndrome, which is a form of pseudohyperaldosteronism caused by overactivity of the epithelial sodium channel, is not responsive to spironolactone, but may be treated with either amiloride or triamterene. Although experience is limited, some patients with Bartter’s and Gitelman’s syndromes may respond to nonsteroidal anti-inflammatory agents or angiotensinconverting enzyme inhibitors.47,48 Finally, aggressive potassium repletion may correct the alkalosis in those who have not responded to the approaches outlined above.

RESPIRATORY ACID-BASE DISORDERS As with the metabolic acid-base disturbances, there are two cardinal respiratory acid-base disturbances: respiratory acidosis and respiratory alkalosis. These disorders are generated by a primary alteration in carbon dioxide excretion, which changes the concentration of carbon dioxide, and therefore the carbonic acid concentration in body fluids. A primary reduction in PaCO2 causes a rise in pH (respiratory alkalosis), and a primary increase in PaCO2 causes a decrease in pH (respiratory acidosis). Unlike the metabolic disturbances, for which respiratory compensation is rapid, metabolic compensation for the respiratory disturbances is slow. Hence these disturbances can be further divided into acute disorders, with a duration of minutes to hours that is too short for metabolic compensation to have occurred, and chronic disorders, that have been present long enough for metabolic compensation to be complete.

RESPIRATORY ALKALOSIS ARGININE MONOHYDROCHLORIDE Arginine monohydrochloride at a dose of 10 g/h given intravenously has been used to treat metabolic alkalosis, although it was never FDA-

Respiratory alkalosis is characterized by a primary decrease in PaCO2 that leads to an elevation in pH. The PaCO2 falls when the excretion of CO2 by the lungs exceeds the metabolic production of CO2 . It is the

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CHAPTER 51 TABLE 51–9. Causes of Respiratory Alkalosis Central stimulation of respiration Anxiety Pain Fever Brain tumors, vascular accidents Head trauma Pregnancy Progesterone Catecholamines, theophylline, nicotine Salicylates Peripheral stimulation of respiration Pulmonary emboli Congestive heart failure Altitude Asthma Pulmonary shunts Hypotension Pneumonia “Stiff lungs” without hypoxemia Multiple mechanisms Hepatic cirrhosis Gram-negative sepsis Mechanical or voluntary hyperventilation

most frequently encountered acid-base disorder, occurring physiologically in normal pregnancy and in persons living at high altitudes.49 Respiratory alkalosis also occurs frequently among hospitalized patients (Table 51–9).

PATHOPHYSIOLOGY A decrease in PaCO2 occurs when ventilatory excretion exceeds metabolic production. Because endogenous production of CO2 is relatively constant, negative CO2 balance is primarily caused by an increase in ventilatory excretion of CO2 (hyperventilation). The metabolic production of CO2 , however, may be increased during periods of stress or with excess carbohydrate administration (e.g., parenteral nutrition). Hyperventilation may develop from an increase in neurochemical stimulation via either central or peripheral mechanisms, or be the result of voluntary or mechanical (iatrogenic) hyperventilation. A decrease in PaCO2 may occur in patients with cardiogenic, hypovolemic, or septic shock because oxygen delivery to the carotid and aortic chemoreceptors is reduced. This relative deficit in PaO2 stimulates an increase in ventilation. The hyperventilation in sepsis is also mediated via a central mechanism. Hyperventilation-induced respiratory alkalosis with an elevation in cardiac index and hypotension without peripheral vasoconstriction may therefore be an early sign of sepsis.

CLINICAL PRESENTATION Although most patients are asymptomatic, respiratory alkalosis may cause adverse neuromuscular, cardiovascular, and gastrointestinal effects.49 During periods of decreased PaCO2 , there is a decrease in cerebral blood flow, which may be responsible for symptoms of light-headedness, confusion, decreased intellectual functioning, syncope, and seizures. Nausea and vomiting may occur, probably as a result of cerebral hypoxia. In severe respiratory alkalosis, cardiac arrhythmias may occur, due to sensitization of the myocardium to the

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arrhythmogenic effects of circulating catecholamines.2 Acute respiratory alkalosis has no effect on blood pressure or cardiac output in awake individuals. Anesthetized patients, however, may experience a decrease in both cardiac output and blood pressure, possibly owing to the lack of a tachycardic response.50 CLINICAL PRESENTATION OF RESPIRATORY ALKALOSIS GENERAL The patient is usually asymptomatic if the condition is chronic and mild. SYMPTOMS The patient may complain of light-headedness, confusion, muscle cramps and tetany, and decreased intellectual functioning. Nausea and vomiting may occur, probably as a result of cerebral hypoxia. SIGNS In severe respiratory alkalosis pH >7.60 Syncope and seizures Cardiac arrhythmias Hyperventilation LABORATORY TESTS Serum chloride concentration is usually slightly increased. Serum ionized calcium, potassium, and phosphorus concentration may be decreased. The concentration of serum electrolytes may also be altered secondary to the development of respiratory alkalosis. The serum chloride concentration is usually slightly increased, and serum potassium concentration may be slightly decreased. Clinically significant hypokalemia can be a consequence of extreme respiratory alkalosis, although the effect is usually very small or negligible.2,50 Serum phosphorus concentration may decrease by as much as 1.5 to 2.0 mg/dL because of the shift of inorganic phosphate into cells. Reductions in the blood ionized calcium concentration may be partially responsible for symptoms such as muscle cramps and tetany. Approximately 50% of calcium is bound to albumin, and an increase in pH results in an increase in binding.49

COMPENSATION The initial response of the body to acute respiratory alkalosis is chemical buffering. Hydrogen ions are released from the body’s buffers— intracellular proteins, phosphates, and hemoglobin—and titrates down the serum bicarbonate concentration. This process occurs within minutes. Acutely, the bicarbonate concentration can be decreased by a maximum of 3 mEq/L for each 10–mm Hg decrease in PaCO2 17 (see Table 51–4). When only the physicochemical buffering has occurred, the disturbance is referred to as acute respiratory alkalosis. Metabolic compensation occurs when respiratory alkalosis persists for more than 6 to 12 hours. In response to the alkalemia, proximal tubular bicarbonate reabsorption is inhibited and the serum bicarbonate concentration falls. Renal compensation is usually complete within 1 to 2 days. The renal bicarbonaturia, as well as decreased NH4 + and titratable acid excretion, are direct effects of the reduced PaCO2 and pH on renal reabsorption of chloride and bicarbonate.2 The

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acuity of the respiratory alkalosis can be assessed on the basis of the degree of renal compensation (see Table 51–4). In fully compensated respiratory alkalosis, the bicarbonate concentration falls by 4 mEq/L below 24 for each 10–mm Hg drop in PaCO2 . For example, a sustained

decrease in PaCO2 of 20 mm Hg will lower serum bicarbonate from 24 to 14 mEq/L with a resultant pH of 7.46. Bicarbonate concentrations differing from those anticipated using the preceding guidelines suggest a mixed acid-base disorder (refer to Fig. 51–4).


TREATMENT: Respiratory Alkalosis Because most patients with respiratory alkalosis, especially chronic cases, have few or no symptoms and pH alterations are usually mild (pH not exceeding 7.50), treatment is often not required.42 The first consideration in the treatment of acute respiratory alkalosis with pH >7.50 is the identification and correction of the underlying cause. Relief of pain, correction of hypovolemia with intravenous fluids, treatment of fever or infection, treatment of salicylate overdose, and other direct measures may prove effective. A rebreathing device, such as a paper bag, may be useful in controlling hyperventilation in patients with the anxiety/hyperventilation syndrome.49 Oxygen therapy should be initiated in patients with severe hypoxemia. Patients with life-threatening alkalosis (pH >7.60) and complications such as arrhythmia or seizures may require mechanical ventilation with sedation and/or paralysis to control hyperventilation. Simple respiratory alkalosis rarely requires such aggressive therapy, but it may be necessary for patients with mixed respiratory and metabolic alkalosis.

Respiratory alkalosis in patients receiving mechanical ventilation is usually iatrogenic. It may often be corrected by decreasing the minute ventilation (i.e., the number of mechanical breaths per minute times the volume delivered), although other measures can also be employed. The use of a capnograph and spirometer in the breathing circuit enables a more precise adjustment of the ventilator settings. Another method of treating respiratory alkalosis is to increase the amount of dead space in the ventilator circuit by placing a known length of tubing between the artificial airway and the “Y” piece of the ventilator. This results in “rebreathing” of expired gas, and therefore an increase in the inspired carbon dioxide concentration, which should increase the carbon dioxide tension of the patient, correcting the respiratory alkalosis. In patients breathing more rapidly than the ventilator settings, sedation with or without paralysis may be beneficial.

RESPIRATORY ACIDOSIS

The degree to which cardiac contractility and heart rate are altered depends on the severity of the acidosis and the rapidity with which it develops. Modest acute hypercapnia (PaCO2 of 50 to 55 mm Hg) stimulates a stress-like response, with elevated catecholamines and corticosteroid hormone levels, and can result in increased cardiac output and pulmonary artery pressure.51 As the severity increases, cardiac output declines and vascular resistance decreases. Refractory hypotension may be present in some patients.2

PATHOPHYSIOLOGY Respiratory acidosis, a primary retention of carbon dioxide that lowers the pH, results from a failure of the lungs to excrete carbon dioxide normally. This may be the result of neuromuscular diseases that inhibit central control of ventilation or neuromuscular function, intrinsic airway or parenchymal pulmonary disease, or interruption in pulmonary perfusion (Table 51–10). Acute respiratory acidosis with hypoxemia, hypercarbia, and acidosis is life-threatening. Those disorders that produce an increase in PaCO2 and hypoxemia to a degree compatible with life (e.g., chronic obstructive pulmonary disease), with or without oxygen therapy, may result in chronic respiratory acidosis (Table 51–11). These patients can function normally without noticeable neurologic defects with PaCO2 concentrations in the range of 90 to 100 mm Hg (normal, 40 mm Hg), provided adequate oxygenation is maintained.50

CLINICAL PRESENTATION Respiratory acidosis may produce neuromuscular symptoms, including altered mental status, abnormal behavior, seizures, stupor, and coma. Hypercapnia may mimic stroke or CNS tumors by producing headache, papilledema, focal paresis, and abnormal reflexes. Carbon dioxide acts as a vasodilator in the brain, thus causing an increase in cerebral blood flow.2 This increase in cerebral blood flow is thought to be partially responsible for the CNS symptoms. The CNS response to hypercapnia is extremely variable between patients and is also influenced by the acuity of presentation. Chronic hypercapnia blunts the usual respiratory stimulus resulting from increased PaCO2 . In patients with severe chronic respiratory acidosis, hypoxemia rather than hypercapnia provides the primary ventilatory stimulus.50

TABLE 51–10. Causes of Acute Respiratory Acidosis Perfusion abnormalities Massive pulmonary embolism Cardiac arrest Airway and pulmonary abnormalities Severe pulmonary edema Severe pneumonia Smoke inhalation Pneumothorax Severe bronchospasm Acute respiratory distress syndrome Airway obstruction: foreign body, laryngeal edema Aspiration of vomitus Neuromuscular abnormalities Trauma, stroke Narcotic or sedative overdose Brain stem or cervical cord injury Guillain-Barr´e syndrome Myasthenia gravis Status epilepticus Mechanical ventilator Ventilator malfunction Inadequate frequency or tidal volume settings Large dead space Total parenteral nutrition (increased CO2 production)

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CLINICAL PRESENTATION OF RESPIRATORY ACIDOSIS GENERAL The patient is usually symptomatic. SYMPTOMS The patient may complain of confusion or difficulty thinking and headache. SIGNS In severe respiratory acidosis: Cardiac: Increased cardiac output if moderate, that decreases if severe. Refractory hypotension may be present in some patients. CNS: Abnormal behavior, seizures, stupor, and coma. Papilledema, focal paresis, and abnormal reflexes may also be present. LABORATORY TESTS Serum potassium concentration may be modestly increased. Hypercapnia may be moderate (PaCO2 of 50 to 55 mm Hg) to severe (PaCO2 of >80 mm Hg). Hypoxia (PaO2 is 80 mm Hg) and/or life-threatening hypoxia is present (PaO2 100) of generalized tonic-clonic (GTC) seizures who have multiple episodes of status epilepticus may be at risk for eventual cognitive declines. In addition, there appears to be a positive correlation between the early initiation of appropriate AED therapy and the ability to control seizure activity. The failure to control seizures seems to lead to an increase in seizure activity and also to the occurrence of other seizure types. Therefore, appropriate therapy should be initiated early after the diagnosis of epilepsy.

CLINICAL PRESENTATION The International League Against Epilepsy (ILAE) has proposed two major schemes for the classification of seizures and epilepsies: the International Classification of Epileptic Seizures and the International Classification of the Epilepsies and Epilepsy Syndromes.5,6 The International Classification of Epileptic Seizures (Table 54–1) combines the clinical description with certain electrophysiologic findings in order to classify epileptic seizures. Seizures are divided into two main pathophysiologic groups—partial seizures and generalized seizures—by EEG recordings and clinical symptomatology. Partial (focal) seizures begin in one hemisphere of the brain and—unless they become secondarily generalized—result in an asymmetric motor manifestation. Partial seizures manifest as alterations in motor functions, sensory or somatosensory symptoms, or automatisms. Partial seizures with no loss of consciousness are classified as simple partial. In some cases, patients will describe somatosensory symptoms as a “warning” prior to the development of a GTC seizure.

TABLE 54–1. International Classification of Epileptic Seizures I. Partial seizures (seizures begin locally) A. Simple (without impairment of consciousness) 1. With motor symptoms 2. With special sensory or somatosensory symptoms 3. With psychic symptoms B. Complex (with impairment of consciousness) 1. Simple partial onset followed by impairment of consciousness—with or without automatisms 2. Impaired consciousness at onset—with or without automatisms C. Secondarily generalized (partial onset evolving to generalized tonic-clonic seizures) II. Generalized seizures (bilaterally symmetrical and without local onset) A. Absence B. Myoclonic C. Clonic D. Tonic E. Tonic-clonic F. Atonic G. Infantile spasms III. Unclassified seizures IV. Status epilepticus Ref. 5, 6.

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CHAPTER 54

These warnings are in fact simple partial seizures and frequently are termed auras. Partial seizures with an alteration of consciousness are described as complex partial. With complex partial seizures, the patient may have automatisms, periods of memory loss, or aberrations of behavior.1 Some patients with complex partial epilepsy have been mistakenly diagnosed as having psychotic episodes. Complex partial seizures also may progress to GTC seizures. Patients with complex partial seizures typically are amnestic to these events. Generalized seizures have clinical manifestations that indicate involvement of both hemispheres. Motor manifestations are bilateral, and there is a loss of consciousness. Generalized seizures may be further subdivided by EEG and clinical manifestations. A partial seizure that becomes generalized is referred to as a secondarily generalized seizure. Generalized absence seizures are manifested by a sudden onset, interruption of ongoing activities, a blank stare, and possibly a brief upward rotation of the eyes. They generally occur in young children through adolescence. It is important to differentiate absence seizures from complex partial seizures. GTC seizures are what many people think of as epilepsy. The seizure results in a sudden sharp tonic contraction of muscles followed by a period of rigidity and clonic movements. During the seizure, the patient may cry or moan, lose sphincter control, bite the tongue, or develop cyanosis. After the seizure, the patient may have altered conciousness, drowsiness, or confusion for a variable period of time (postictal period) and frequently goes into a deep sleep. Tonic and clonic seizures may occur separately. Brief shocklike muscular contractions of the face, trunk, and extremities are known as myoclonic jerks. They may be isolated events or rapidly repetitive. A sudden loss of muscle tone is known as an atonic seizure. This may be described as a head drop, the dropping of a limb, or a slumping to the ground. These patients often wear protective headware to prevent trauma. The International Classification of Epilepsies and Epilepsy Syndromes adds components such as age of onset, intellectual development, findings on neurologic examination, and results of neuroimaging studies to define epilepsy syndromes more fully. Syndromes can include one or many different seizure types (e.g., Lennox Gastaut syndrome). The syndromic approach includes seizure type(s) and possible etiologic classifications (e.g., idiopathic, symptomatic, or unknown). Idiopathic describes syndromes that are presumably genetic but also those in which no underlying etiology is documented or suspected. A family history of seizures is commonly present, and neurologic function is essentially normal except for the occurrence of seizures. Symptomatic cases involve evidence of brain damage or a known underlying cause. A cryptogenic syndrome is assumed to be symptomatic of an underlying condition that cannot be documented. Unknown or undetermined is used when no cause can be identified. This syndromic classification is more important for prognostic determinations than for a classification based simply on seizure type. The syndrome classification scheme requires more information and,

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in return, provides a more powerful tool for comprehensive clinical management. A patient’s epilepsy is classified based on seizure type (i.e., generalized versus partial) and syndromic type (i.e., idiopathic, symptomatic, or cryptogenic). C L I N I C A L P R E S E N TAT I O N O F E P I L E P S Y GENERAL In most cases, the health care provider will not be in a position to witness a seizure. Many patients (particularly those with complex partial or generalized tonic-clonic seizures) are amnestic to the actual seizure event. Obtaining an adequate history and description of the ictal event (including time course) from a third party (e.g., significant other, family member, or witness) is critically important. SYMPTOMS Symptoms of a specific seizure will depend on seizure type. While seizures can vary between patients, they tend to be stereotyped within an individual.

r Complex partial seizures may include somatosensory or focal motor features.

r Complex partial seizures are associated with altered conciousness.

r Absence seizures may appear relatively bland, with only very brief (seconds) periods of altered conciousness.

r Generalized tonic-clonic seizures are major convulsive episodes and are always associated with a loss of conciousness. SIGNS Interictally (between seizure episodes), there are typically no objective, pathognomonic signs of epilepsy. LABORATORY TESTS There are currently no diagnostic laboratory tests for epilepsy. In some cases, particularly following generalized tonic-clonic (or perhaps complex partial) seizures, serum prolactin levels may be transiently elevated. Laboratory tests may be done to rule out treatable causes of seizures (e.g., hypoglycemia, altered electrolyted concentrations, infections, etc.) that do not represent epilepsy. OTHER DIAGNOSTIC TESTS

r EEG is very useful in the diagnosis of various seizure disorders.

r The EEG may be normal in some patients who still have the clinical diagnosis of epilepsy.

r While MRI is very useful (especially imaging of the temporal lobes), CT scan typically is not helpful except in the initial evaluation for a brain tumor or cerebral bleeding.


TREATMENT: Epilepsy
DESIRED OUTCOME The ultimate goal of treatment for epilepsy is no seizures and no side effects with an optimal quality of life. The best quality of life is associated with a seizure-free state.7 Often, however, a balance between efficacy and side effects must be reached because with the

older AEDs used as monotherapy, fewer than 50% of patients become seizure-free. Because therapy is continued for many years (often a lifetime), chronic side effects must be considered. If the patient is overly sedated or develops other significant side effects, some seizure control may have to be sacrificed to improve functioning. The patient should be

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involved in deciding what balance between frequency of seizures and the occurrence of side effects is most appropriate. The newer AEDs offer alternatives for balancing seizure frequency and drug side effects. Providing optimal quality of life goes beyond balancing seizures and side effects. It involves assessing all the concerns of a patient with epilepsy. For example, patients with epilepsy are concerned about driving, their future, forming relationships, safety, social isolation, social stigma, and so on. It is also important to recognize that patients with epilepsy may have other neuropsychiatric comorbidities such as depression, anxiety, and sleep disturbances.8−10 Clinicians should be aware of these potential problems and consider therapy where appropriate.


GENERAL APPROACH TO TREATMENT 1 The general approach to treatment involves identification of

goals, assessment of seizure type and frequency, development of a care plan, and a follow-up evaluation. During the assessment phase, it is critical to establish an accurate diagnosis of the seizure type and classification. This diagnostic step will help to determine the 2 appropriate initial AEDs. Patient-specific treatment goals must be identified, and these may change over time. In all patients, the goal should be “no seizures, no side effects, and an optimal quality of life.” It must be recognized that this may not be possible in a significant minority of patients. Despite appropriate AED treatment, approximately 30% to 35% of patients will be refractory to treatment. In this setting, seizure freedom may not be obtained, and more obtainable outcomes should be established (e.g., decrease in the number of seizures and minimized drug adverse effects). Identification of specific goals will help in the development of the short- and long-term treatment 3 plans. Patient characteristics such as age, medical condition, ability to comply with a prescribed regimen, and insurance coverage also should be explored because these may influence AED choices or help to explain a lack of response or unexpected adverse effects. Once the assessment is complete, the advantages and disadvantages of appropriate AEDs are compared. For patients with new-onset seizures, the choice is whether to use drug therapy and, if so, which one. For a patient with long-standing epilepsy, adequacy of the current medication regimen must be evaluated. An AED should not be considered ineffective unless the patient has experienced unacceptable adverse effects with continued seizures. 4 If a decision is made to start AED therapy, monotherapy is preferred, and about 50% to 70% of all patients with epilepsy can be maintained on one drug.11,12 However, many of these patients are not seizure-free. The percentage of patients who are seizure-free on one drug varies by seizure type. The prognosis for 12-month seizure freedom is best for those who have only GTC seizures (48% to 55%), worst for those who have only complex partial seizures (23% to 26%), and intermediate for those with mixed seizure types (25% to 32%).12 Drugs may be combined in an attempt to help the patient become seizure-free. Combining AEDs with different mechanisms of action may be advantageous, although this approach is as yet unproven.13 Approximately 65% of patients can be expected to be maintained on one AED and be considered well controlled, although not neces5 sarily seizure-free. Of the 35% of patients with unsatisfactory control, 10% will be well controlled with a two-drug treatment. Of the remaining 25%, 20% will continue to have unsatisfactory control despite multiple drug treatment. It has been suggested recently that there may be a genetic predisposition to epilepsy that is refractory to drug therapy. Some of these patients will become surgical can-

didates. For some patients, an implantable device such as the vagal nerve stimulator may be an additional nonpharmacologic option. Once the care plan is established, a prescription is generated for a specific AED. Usually this includes a dose-titration schedule. At this point, patient education and assurance of patient understanding of the plan are essential. Detailed directions regarding titration, what to do in the event of a treatment-emergent side effect, and what to do if a seizure occurs must be provided to patients. Documentation of the assessment, care plan, and educational process is essential. Providing the patient with a seizure and side-effect diary will assist in the followup and evaluation phase. At the follow-up stage of treatment (which can be done in the hospital, clinic, or pharmacy or by phone), the treatment goals must be reviewed. If the goal has been achieved, new goals should be identified. For example, if the GTC seizures are now controlled, the goal may be to control partial seizures. If a patient fails to respond to the first AEDs, trials with other AEDs should be attempted. Completion of the evaluation often requires a reassessment of the patient and development of a new care plan. The assessment at this point should evaluate compliance, efficacy, and safety of the initial treatment. Medication noncompliance may be the single most common reason for treatment failure. It is estimated that up to 60% of patients with epilepsy are noncompliant.14 The rate of noncompliance is increased by the complexity of the drug regimen and by doses taken three and four times a day. Noncompliance is not influenced by age, sex, psychomotor development, seizure type, or seizure frequency.14 CLINICAL CONTROVERSY Epilepsy is a clinical diagnosis defined by recurrent seizures. Controversy surrounds the most appropriate time to initiate AED therapy. Many clinicians do not initiate treatment until a second unprovoked seizure has occurred. Some clinicians start AED treatment after the first seizure, whereas others may initiate prophylactic treatment following a CNS insult thought likely to cause epilepsy eventually (e.g. stroke or head trauma). Appropriate treatment decisions may vary depending on individual patient clinical characteristics and circumstances. Drug treatment may not be indicated in patients whose seizures have minimal impact on their lives or those who have had only a single seizure. If a patient presents after a single isolated seizure, one of three treatment decisions can be made: treat, possibly treat, or do not treat. These decisions are based on the probability of the patient having a second seizure (Table 54–2). For patients with no risk factors, the probability of a second seizure is less than 10% in the first year and approximately 24% by the end of 2 years. If risk factors are present, this recurrence rate can increase dramatically and can be as high as 80% after 5 years.1 Are these rates high enough to warrant AED therapy? This decision often depends on patient-specific factors such as epilepsy syndrome, seizure etiology, presence of an neuroanatomic defect, and the EEG. Clearly, the patient’s lifestyle and preferences are of paramount importance. Patients who have had two or more seizures generally should be started on AEDs.


WHEN TO STOP ANTIEPILEPTIC DRUGS 6 The AEDs used initially to control seizures may not need to be

given for a lifetime. Polypharmacy may be reduced, and some patients can discontinue AEDs altogether. In reducing polypharmacy,

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CHAPTER 54 TABLE 54–2. Recurrence Risk for Patients Experiencing One Unprovoked Seizure Type of Patient Adults with single unproved seizure No CNS insult Influence of family history Sibling with seizure No sibling with seizures EEG patterns GSW on EEG Normal EEG Occurrence of previous seizure Due to an illness or childhood febrile seizure Remote symptomatic with Todd’s paresis Status epilepticus at onset Prior acute seizure Idiopathic

Ist-Yr Risk (%)

5th-Yr Risk (%)

10

34 29

29 7

46 27

15 9 10

58 26 39

26 41 37 60 10

48 75 56 80 29

CNS = central nervous system; EEG = electroencephalogram; GSW = generalized spikes and waves.

the drug considered less appropriate for the seizure type (or the agent deemed most responsible for adverse effects) should be discontinued first. In some cases, decreasing the number of AEDs a patient is receiving can decrease side effects and increase cognitive abilities.15 This improvement in cognition may be small, especially if the patient is on a drug that primarily affects psychomotor speed with less effect on higher-order cognitive functioning. 6 Factors favoring successful withdrawal of AEDs include a seizure-free period of 2 to 4 years, complete seizure control within 1 year of onset, an onset of seizures after age 2 but before age 35, and a normal neurologic examination and EEG. Factors associated with a poor prognosis in discontinuing AEDs, despite a seizurefree interval, include a history of a high frequency of seizures, repeated episodes of status epilepticus, a combination of seizure types, and development of abnormal mental functioning. Children who have irregular generalized spike and wave activity in EEG recordings prior to discontinuation of treatment may have a higher relapse rate (67%) compared with children without epileptiform activity (33%) or children with other types of epileptiform activity (33%) in their last EEG recordings before discontinuation. A 2-year seizure-free period is suggested for absence and rolandic epilepsy, whereas a 4-year seizurefree period is suggested for simple partial, complex partial, and absence associated with tonic-clonic convulsions. AED withdrawal generally is not suggested for patients with juvenile myoclonic epilepsy, absence with clonic-tonic-clonic seizures, or clonic-tonic-clonic seizures. The American Academy of Neurology has issued guidelines for discontinuing AEDs in seizure-free patients (Table 54–3). When the factors likely to be associated with successful withdrawal are present, the relapse rate is expected to be less than 32% for children and 39% for adults. If the decision is made to attempt AED withdrawal, this should be done gradually. This may be particularly true for patients with profound developmental disabilities. Some patients will have a recurrence of seizures as the AEDs are withdrawn. Sudden withdrawal is associated with the precipitation of status epilepticus. Withdrawal seizures are of particular concern for agents such as benzodiazepines and barbiturates. Seizure relapse has been reported to be more common if the AEDs are withdrawn over 1 to 3 months than over 6 months.

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TABLE 54–3. American Academy of Neurology Guideline for Discontinuing AEDs in Seizure-Free Patients After assessing the risks and benefits to both patient and society from a recurrent seizure, the discontinuance of antiepileptic drugs may be considered by the physician and informed patient or parent/guardian if the patient meets the following profile: r Seizure-free 2 to 5 years on AEDs (mean, 3.5 years) r Single type of partial seizure (simple partial, complex partial, or secondary generalized tonic-clonic seizure) or single type of primary generalized tonic-clonic seizures r Normal neurologic examination/normal IQ r EEG normalized with treatment

The risk of seizure relapse has been estimated at 10% to 70%. A meta-analysis determined that the relapse rate was 25% after 1 year and 29% after 2 years. Withdrawal doubles the risk of seizure recurrence for the first 1 to 2 years but does not modify the long-term prognosis of a person’s epilepsy. If seizures recur after AED withdrawal, AEDs should be restarted. Ninety percent of patients will regain at least another 2-year remission. In addition to seizure relapse, the withdrawal of AEDs has been associated with the emergence of anxiety and depression.15 CLINICAL CONTROVERSY It is not entirely clear which patients with epilepsy will require lifelong treatment. While many clinicians feel that AED therapy is lifelong, others would argue that certain patients with idiopathic epilepsy and a normal neurologic examination and EEG may be candidates for AED withdrawal following a prolonged period of seizure freedom (e.g., >2 to 3 years). Most of the data supporting discontinuing AEDs have been obtained from children. Some adults will be reticent to discontinue AED therapy even if the clinician is in favor of it because of the fear of having a seizure and the consequences (e.g., loss of driver’s license) that it would entail. The patient must be a willing participant in a therapeutic plan to discontinue an AED. The patient should agree to the plan to reduce or withdraw AED therapy. There may be a significant psychosocial benefit to the patient from AED withdrawal. Withdrawal may need to be scheduled at the convenience of the patient. A follow-up of 5 years is suggested for any patient withdrawn from AED therapy.


NONPHARMACOLOGIC THERAPY Nonpharmacologic therapy for epilepsy includes diet, surgery, and vagal nerve stimulation (VNS), which is implantation of a vagal nerve stimulator. A vagal nerve stimulator is an implanted medical device approved for use in epilepsy. The NCP system (NeuroCybernetic prosthesis) is indicated for use as an adjunctive therapy in reducing the frequency of seizures in adults and adolescents older than 12 years of age with partial-onset seizures that are refractory to AEDs. The device consists of an implantable, programmable pulse generator connected to a helical lead. The generator is implanted in a subcutaneous infraclavicular pocket and is powered by a lithium battery. The lead is attached to the left vagus nerve and delivers a biphasic current to the

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TABLE 54–4. Drugs of Choice for Specific-Seizure Disorders Seizure Type Partial seizures

Generalized seizures Absence Myoclonic Tonic-clonic

First-Line Drugs

Alternative Drugs

Carbamazepine Phenytoin Lamotrigine Valproic acid Oxcarbazepine

Gabapentin Topiramate Levetiracetam Zonisamide Tiagabine Primidone, phenobarbital Felbamate

Valproic acid, ethosuximide Valproic acid, clonazepam

Lamotrigine, levetiracetam Lamotrigine, topiramate, felbamate, zonisamide, levetiracetam Lamotrigine, topiramate, phenobarbital, primidone, oxcarbazepine, levetiracetam

Phenytoin, carbamazepine, valproic acid

nerve that can be programmed to different parameters by the physician through the skin. In addition, the patient can use a magnet placed over the generator to activate the generator during a seizure or aura. The mechanisms of antiseizure actions of VNS are unknown, but recent studies have indicated that VNS acutely causes widespread bilateral cortical and subcortical alterations in blood flow, suggesting that it affects synaptic activity in humans.16 The VNS device is relatively safe. The most common side effect associated with stimulation is hoarseness, voice alteration, increased cough, pharyngitis, dyspnea, dyspepsia, and nausea. Serious adverse effects reported include infection, nerve paralysis, hyesthesia, facial paresis, left vocal chord paralysis, left facial paralysis, left recurrent laryngeal nerve injury, urinary retention, and low-grade fever. Over all the VNS studies, the percentage of patients who achieved a 50% or greater reduction in their seizure frequency (responders) ranged from 23% to 50%. Surgery is the most widespread and most useful nonpharmacologic therapy.17 The use of surgery for intractable epilepsy that significantly interferes with patients’ lives and functioning is increasing in both adult and pediatric patients. The success rate is reported to be between 80% and 90% in properly selected patients. A National Institutes of Health Consensus Conference identified three absolute requirements for surgery. They are an absolute diagnosis of epilepsy, failure on an adequate trial of drug therapy, and definition of the electroclinical syndrome. A focus in the temporal lobe has the best chance for a positive outcome; however, extratemporal foci may be excised successfully in more than 75% of patients. The procedure is not without risk. Learning and memory are most susceptible to impairment postoperatively, and general intellectual abilities are also affected in a small number of patients. Surgery may be particularly useful in children with intractable epilepsy. Patients may still need to receive AED therapy for a period of time following successful epilepsy surgery in order to prevent seizure recurrence.18 The ketogenic diet was devised in the 1920s.19 It is high in fat and low in carbohydrates and protein and thus leads to acidosis and ketosis. Protein and calorie intake are set at levels that will meet requirements for growth. Most of the calories are provided in the form of heavy cream and butter. No sugar is allowed. Vitamins and minerals are supplemented. Medium-chain triglycerides may be substituted for the dietary fats. Fluids are also controlled. It requires strict control and parent compliance. Although some centers find this useful for refractory patients, others have found that it is poorly tolerated by patients. Long-term effects are unknown.


PHARMACOLOGIC THERAPY Optimal management of epilepsy therefore requires that AED treatment be individualized. Specifically, different patient groups (e.g., children, women of child-bearing potential, and the elderly) may be better suited to one AED versus another by virtue not only of seizure type but also of succeptability or relative risk for certain adverse effects. These issues will be highlighted further below. 7 Selection and optimization of AED therapy require not only an understanding of drug mechanism(s) of action and spectrum of clinical activity but also an appreciation of pharmacokinetic variability as well as patterns of drug-related adverse effects. An AED must demonstrate efficacy for the specific seizure type being treated. The drug treatments of first choice depend on the type of epilepsy, as well as on the interface between drug-specific adverse effects and patient preferences (Table 54–4). Ultimately, AED effectiveness is the result of the interaction of each of these factors. A suggested algorithm for a general approach to the treatment of epilepsy is shown in Fig. 54–1. The mechanism of action of most AEDs can be categorized as either affecting ion channels, augmenting inhibitory neurotransmission, or modulating excitatory neurotransmission. The ion channels affected include the sodium and calcium channels. Augmentation in inhibitory neurotransmission includes increasing CNS concentrations of GABA, whereas efforts to decrease excitatory neurotransmission are primarily focused on decreasing (or antagonizing) glutatmate and aspartate neurotransmission. AEDs that are effective against GTC and partial seizures probably reduce sustained repetitive firing of action potentials by delaying recovery of sodium channels from activation. Drugs that reduce corticothalmic T-type calcium currents are effective against generalized absence seizures. Myoclonic seizures respond to drugs that enhance GABAA receptor inhibition.20 In addition to mechanism of action, awareness of pharmacokinetic properties (Table 54–5), adverse effects (Table 54–6), and drug-drug interactions (Tables 54–7 and 54–8) can aid in the optimization of AED therapy. Pharmacokinetic interactions are a common complicating factor in AED selection. Interactions can occur in any of the pharmacokinetic processes: absorption, distribution, or elimination. Caution should be used when AEDs are added to or withdrawn from a drug regimen. Adverse effects of AEDs can be divided into acute and chronic (see Table 54–6). Acute effects can be dose/serum concentration– related or idiosyncratic. Concentration-dependent effects are common and troublesome but not usually life-threatening. Neurotoxic

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FIGURE 54–1. Algorithm for the treatment of epilepsy.

adverse effects are encountered commonly and can include sedation, dizziness, blurred or double vision, difficulty with concentration, and ataxia. In many cases these effects can be alleviated by decreasing drug dose. Most idiosyncratic reactions owing to an allergic reaction are mild, but they can be more serious if the hypersensitivity involves one or more organ systems. Other idiosyncratic side effects including hepatitis or blood dyscrasias are serious but rare. Acute organ failure, if it is going to occur, generally occurs within the first 6 months of AED therapy. Unfortunately, screening laboratory evaluations of blood and urine typically are not helpful in predicting or detecting the early stage of severe reactions and generally are not recommended in asymptomatic patients. Laboratory assessment including white blood cell counts and liver function tests may be reasonable if the patient reports an unexplained illness (e.g., lethargy, vomiting, fever, or rash).21 It is important to recognize that adverse effects can occur despite serum concentrations being within the proposed therapeutic range.22 Another potential long-term adverse effect of AED treatment is osteomalacia and osteoporosis.23 The bone disorders associated with AED use consist of a heterogeneous group of disorders. These include findings ranging from asymptomatic high-turnover disease,

with findings of normal bone mineral density, to markedly decreased bone mineral density sufficient to warrent the diagnosis of osteoporosis. While the etiology of these osteopathies is still uncertain, it has been hypothesized that certain drugs, including phenytoin, phenobarbital, and perhaps carbamazepine and valproic acid, may interfere with vitamin D metabolism. Whether the newer AEDs are associated with these effects is as yet unknown. Common laboratory findings in these patients include elevated bone-specific alkaline phosphatase concentration and decreased serum calcium and 25-OH vitamin D concentrations. Patients receiving these drugs at the least should receive supplemental vitamin D and calcium. The comparative effects of AEDs on cognition have been difficult to evaluate because of differences or inconsistencies in study design, included seizure types, control for serum drug concentrations, and the neuropsychological tests used. In general, there are not large differences between the older drugs,24,25 although the barbiturates phenobarbital and primidone appear to cause more cognitive impairment than other commonly used AEDs. Phenytoin, particularly when serum concentrations are above the commonly accepted therapeutic range, may have a greater effect on motor function and speed. Among the older AEDs, valproic acid may cause less impairment of cognition.

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TABLE 54–5. Antiepileptic Drug Pharmacokinetic Data AED

11/2 (h)a

Carbamazepine

12 M; 5–14 Co

Ethosuximide

A 60 C 30 16–22 5–40d 25.4 M 7–10 3–13

Felbamate Gabapentinb Lamotrigine Levetiracetam Oxcarbazepine Phenobarbital Phenytoin Primidone Tiagabine Topiramate Valproic acid Zonisamide

Time to Steady State (days)

Unchanged (%)

VD (1/kg)

Clinically Important Metabolite

Protein Binding (%)

21–28 for completion of auto-induction 6–12

1.8 mcg/dL) should be used. An alternative assay that may prove useful in the future is measurement of salivary cortisol. In the overnight DST, 1 mg of dexamethasone is administered at 11:00 P.M. The following morning at 8:00 A.M. plasma cortisol is obtained for analysis. The Cushing’s syndrome patient will not exhibit a suppressed cortisol concentration via the negative-feedback loop, and the morning cortisol concentration will be elevated above 5 mcg/dL, or as low as 1.8 mcg/dL.5,18 The overnight DST is useful only as a screening tool for Cushing’s syndrome, because of a high sensitivity, but a rather low specificity. Phenytoin, rifampin, phenobarbital, and other drugs that induce liver enzymes may cause an increase in the clearance rate of the dexamethasone, causing decreased levels leading to a false-positive suppression test.7 Plasma dexamethasone measured at the conclusion of this test can clarify results clouded by differences

ADRENAL GLAND DISORDERS

in metabolism from these drug interactions, individual variability, or patient noncompliance. The first test used to determine the etiology of Cushing’s syndrome is the plasma ACTH test. Plasma ACTH concentrations can be measured via RIA or IRMA.7,16 In the ACTH-dependent Cushing’s syndromes, ACTH may be normal or elevated. Very high levels of ACTH favor ectopic production. ACTH values are low in ACTH-independent (adrenal) Cushing’s syndrome. ACTH levels may appear artificially low in some ectopic ACTH-producing tumors because ACTH can be secreted as an active prohormone that is not detected by the assay. The high-dose DST operates under the same principle as the low-dose test.5,7 The high-dose test has its main application in differentiating the Cushing’s disease patient from the patient with another form of hypercortisolism. The Cushing’s disease patient will generally demonstrate a 50% reduction in urinary steroids over baseline, whereas the others will generally not suppress. The high-dose test is based on the principle that patients with Cushing’s syndrome not caused by adrenal tumors or ectopic ACTH production will suppress their hypothalamic-pituitary axis in the presence of glucocorticoids, but it takes much higher-than-normal doses. An overnight high-dose DST has been developed, whereby the patient has a baseline serum cortisol drawn at 8:00 A.M. and dexamethasone 8 mg is taken at 11:00 P.M. The next morning, at 8:00 A.M., another serum cortisol is drawn.7,16 The high-dose test is most useful when the low-dose test and other diagnostic studies have confirmed the diagnosis of Cushing’s syndrome. The high-dose DST has been studied in combination with ACTH and metapyrone testing, and results in better specificity than either test alone. Abnormal adrenal anatomy is effectively identified using highresolution CT scanning and perhaps MRI. Nodules as small as 1 to 1.5 cm on the adrenal cortex are easily identified by CT. With the use of thin-section scanning, nodules as small as 3 to 5 mm can be visualized.7,19,20

DIFFERENTIAL DIAGNOSIS Although the diagnosis of Cushing’s disease is not a difficult one, at times the clinician will need to differentiate it from syndromes that mimic Cushing’s. Pseudo-Cushing’s syndrome refers to a group of diseases that can mimic Cushing’s disease. Patients with obesity, chronic alcoholism, depression, and acute illness of any type can cloud the diagnosis of Cushing’s disease. Depressed patients, though mimicking the urinary steroid abnormalities of Cushing’s disease, will not resemble a cushingoid patient in appearance. The chronic alcoholic will have his laboratory panel returned to baseline after he or she stops drinking. The obese patient often will have normal cortisol concentrations on both serum and urinary screening.

TABLE 74–3. Summary of Tests Used to Diagnose Cushing’s Syndrome Test Plasma Cortisol (mcg/dL, A.M./P.M.) After low-dose DST After high-dose DST ACTH (pg/mL) Urine Cortisol (mcg/24 h)

1395

Normal

Hyperplasia

Adenoma

Carcinoma

170/80 ↓ ↓ 10–80

↑/↑↑ ↔ ↓/↔ ↑↑

↑↑/↑↑ ↔ ↔ ↓

↑↑↑/↑↑↑ ↔ ↔ ↓

20–90

↑↑

↑↑

↑↑↑

ACTH, adrenocorticotropic hormone; DST, dexamethasone suppression test.

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Iatrogenic Cushing’s syndrome, induced by pharmacologic agents, often is indistinguishable from Cushing’s disease. This syndrome can occur from administration of oral, inhaled, intranasal, and topical glucocorticoids, as well as progestins such as medroxyprogesterone

acetate and megestrol acetate.21–24 A careful history and serum determination in a basal state can aid the clinician in making the diagnosis. If exogenous glucocorticoids are being taken, plasma cortisol levels may increase, while corticosterone levels remain low.7,25


TREATMENT: Cushing’s Syndrome 3 If left untreated, Cushing’s syndrome is associated with a high

percentage of morbidity and mortality owing to associated disorders such as diabetes mellitus, cardiovascular disease, and electrolyte abnormalities. These disorders limit the survival of the Cushing’s disease patient to 4 to 5 years following initial diagnosis. The desired outcomes of treatment are to limit the morbidity and mortality and return the patient to a normal functional state by removing the source of hypercortisolism without causing any pituitary or adrenal deficiencies. 4 Once the etiology of the disease is identified, the treatment of choice for both ACTH-dependent and ACTH-independent Cushing’s syndrome is surgical resection of any offending tumors.22 However, several pharmacologic secondary treatment plans are available, depending on the etiology of the disease (Table 74–4).4,5,26


PHARMACOLOGIC THERAPY of Cushing’s syndrome (dosing can be found 5 Pharmacotherapy 27,28

in Table 74–4) can be divided into four categories based on the anatomic site of action of the agent: (1) steroidogenic inhibitors; (2) adrenolytic agents; (3) neuromodulators of ACTH release; and (4) glucocorticoid-receptor blocking agents.26,29,30 Steroidogenic inhibition may be accomplished with the following agents: metyrapone, aminoglutethimide, and ketoconazole. Either metyrapone or aminoglutethimide used alone has limited efficacy, with relapse occurring after discontinuation of therapy. Neither agent should be used after successful surgery. Their use should be restricted to the refractory patient who is not a surgical candidate. Combination therapy with these agents appears more effective than single-agent therapy and may cause fewer side effects.

Metyrapone inhibits 11-hydroxylase activity, resulting in inhibition of cortisol synthesis. Initially, patients may demonstrate an increase in plasma ACTH concentrations because of a sudden drop in cortisol. Metyrapone is biologically active following oral administration. Nausea, vomiting, vertigo, headache, dizziness, abdominal discomfort, and allergic rash have been reported following administration.26−30 Initially, aminoglutethimide was used to treat refractory forms of epilepsy, but it was later discovered to be a potent inhibitor of cortisol synthesis. Aminoglutethimide inhibits the conversion of cholesterol to pregnenolone early in the cortisol pathway.26,30,31 Plasma cortisol concentrations are reduced by up to 50% following aminoglutethimide therapy. Side effects include severe sedation, nausea, ataxia, and skin rashes.26,31 Most of these reactions are dose-dependent and limit the use of aminoglutethimide in most patients. Aminoglutethimide may decrease the anticoagulant effect of warfarin. As aminoglutethimide can induce the metabolism of exogenous glucocorticoids, careful titration is required with steroid replacement. Alone, aminoglutethimide is indicated for short-term use in inoperable Cushing’s disease with ectopic ACTH syndrome as the suspected underlying etiology. Aminoglutethimide may be used in combination with metyrapone. Smaller doses of both drugs can be used, thereby minimizing the toxicity associated with either agent. The combination therapy appears effective for various etiologies of Cushing’s disease and is useful in the inoperable patient. The imidazole derivative antifungal ketoconazole26,29,30 is highly effective in lowering cortisol in Cushing’s disease, resulting in normal corticosteroid values in 84% of patients, with an additional 11% of patients reporting improvement. Patients can be maintained successfully for months to years on ketoconazole therapy. In addition to lowering serum cortisol levels, ketoconazole can cause gynecomastia

TABLE 74–4. Possible Treatment Plans in Cushing’s Syndrome Based on Etiology Treatment Dosing Etiology

Nondrug

Generic (Brand) Drug Name

Initial

Usual

Ectopic ACTH syndrome

Surgery, chemotherapy, irradiation

Metyrapone (Metopirone) 250-mg tabs Aminoglutethimide (Cytadren) 250-mg tabs

1–6 g/day, divided every 4–6 h 1 g/day, divided every 6 h

Pituitarydependent

Surgery, irradiation

Cyproheptadine 2 mg/5 mL syrup or 4-mg tabs Mitotane (Lysodren) 500-mg tabs

1–1.5 g/day, divided every 4–6 h 0.5–1 g/day, divided two to four times a day for 2 weeks 4 mg twice a day

Adrenal adenoma Adrenal carcinoma

Surgery, postoperative replacement Surgery

ACTH, adrenocorticotropic hormone.

Metyrapone Ketoconazole (Nizoral) 200-mg tabs

24–32 mg/day, divided four times a day 1–6 g/day, increased by 1– 9–10 g/day, divided three to 2 g/day every 3–7 days four times a day See above See above 200 mg once or twice a day 600–800 mg/day, divided twice a day

Mitotane

See above

See above

Max 6 g/day 2 g/day

32 mg/day 16 g/day See above 1200 mg/day

See above

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and lower plasma testosterone values. All of these effects are attributed to its inhibition of a variety of cytochrome P450 enzymes, including 11-hydroxylase and 17-hydroxylase.27 The most common adverse effects are reversible elevation of hepatic transaminases, gynecomastia, and gastrointestinal upset.27 The adrenolytic agent mitotane is a cytotoxic drug that structurally resembles the insecticide dichlorodiphenyltrichloroethane (DDT). Mitotane inhibits the 11-hydroxylation of 11-desoxycortisol and 11-desoxycorticosterone in the cortex. The net result is a reduced synthesis of cortisol and corticosterone. It decreases the cortisol secretion rate, plasma cortisol concentrations, urinary free cortisol, and plasma concentrations of the 17-substituted steroids.27 This drug appears to selectively inhibit adrenocortical function without causing cellular destruction. Degeneration of cells within the zona fasciculata and reticularis occurs with resultant atrophy of the adrenal cortex. The zona glomerulosa is minimally affected during acute therapy, but can become damaged following long-term treatment.26,27,30 Because mitotane can severely reduce cortisol production, the patient should be hospitalized before initiating therapy. Mitotane should be continued as long as clinical benefits occur. Cortisol secretion rate, plasma cortisol concentration, urinary free cortisol, and urinary steroid production should be monitored to assess response to mitotane. If necessary, steroid replacement therapy can be given. Nausea and diarrhea are common adverse effects that occur at doses greater than 2 g/day and may be avoided by gradually increasing the dose and/or administering the agent with food. Approximately 80% of mitotane-treated patients develop lethargy and somnolence, and other central nervous system adverse drug reactions occur in approximately 40% of patients. Furthermore, significant but reversible hypercholesterolemia can result from mitotane use. Neuromodulatory agents include cyproheptadine, bromocriptine, valproic acid, ritanserin, and octreotide. None of the neuromodulatory agents has demonstrated consistent clinical efficacy in the treatment of Cushing’s disease. The existence of a bromocriptineresponsive subset of patients remains controversial.26,30 Cyproheptadine can decrease ACTH secretion in the Cushing’s disease patient. Morning plasma cortisol concentrations, as well as 24-hour urinary cortisol (free) concentrations should be monitored. Side effects are minor and include sedation and hyperphagia. Cyproheptadine should be reserved for nonsurgical candidates who fail more conventional therapy. Because the response rate is no more than 30%, patients should be followed closely for relapses. Glucocorticoid receptor antagonism may be accomplished via RU-486 (mifepristone). RU-486 is a progesterone- and glucocorticoid-receptor antagonist that inhibits dexamethasone suppression and raises endogenous cortisol and ACTH values in normal subjects.26,32 Limited clinical experience in Cushing’s suggests that RU-486 is highly effective in reversing the manifestation of hypercortisolism. Because of its novel site of action as a receptor antagonist leading to higher cortisol and ACTH levels, the diagnosis of treatmentinduced glucocorticoid insufficiency must rest on clinical signs only. The efficacy and long-term effects of RU-486 remain to be determined. Spironolactone has been used for its competitive antagonism of aldosterone in the treatment of Cushing’s syndrome. Spironolactone can provide symptomatic relief of the hypertension and hypokalemia often seen in Cushing’s syndrome. Close monitoring of 24-hour urinary free cortisol levels and serum cortisol levels are essential to monitor for adrenal insufficiency. Steroid secretion should be monitored with all of these drugs and steroid replacement given as needed. Whatever the choice, pharmacologic therapy in pituitary-dependent disease is mainly centered

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around patient stabilization prior to surgery or in patients waiting for potential response to other therapies.


NONPHARMACOLOGIC THERAPY
SURGERY During the last decade, the treatment of choice for Cushing’s disease has been transsphenoidal resection of the pituitary microadenoma.4,5,33 The advantages to this procedure include preservation of pituitary function, low complication rate, and high clinical improvement rate. The overall cure rate of histologically proven tumors approaches 90%. Bilateral adrenalectomy surgery had been the mainstay of therapy for years. It is used now only in patients for whom transsphenoidal surgery and pituitary irradiation have failed or cannot be used.5 Bilateral adrenalectomy rapidly reverses hypercortisolism. However, patients may develop Nelson’s syndrome, which involves sella turcica enlargement and hyperpigmentation, caused by postoperative hypothalamic stimulation. Therefore if bilateral adrenalectomy is used it should be accompanied by some form of hypothalamic inhibition, such as cyproheptadine. Irradiation (4000 to 5000 rads) of the pituitary has provided clinical improvement in approximately 50% of patients. Improvement is usually not seen until 6 to 12 months after therapy and can create pituitary-dependent hormone deficiencies. Most clinicians will reserve pituitary irradiation for the patient with a mild case of Cushing’s disease or as an adjunct to another therapy.34


Adrenal Adenoma Surgical resection of benign adrenal adenoma is associated with relatively few side effects and a high cure rate (95%). The contralateral gland in the patient with adrenal adenoma is usually atrophic, therefore steroid replacement is needed both perioperatively and postoperatively. Table 74–5 outlines an approach to steroid replacement for three separate routes of hydrocortisone. Therapy should be continued for 6 to 12 months following surgery. Before replacement therapy is discontinued, recovery of the adrenal axis may be assessed by administering ACTH and measuring cortisol response at 30 and 60 minutes. Cortisol levels should exceed 18 mcg/dL before discontinuance of the exogenous steroids.4


Adrenal Carcinoma Unlike the benign adenoma patient, patients with adrenal carcinoma have an unpredictable and unfavorable outcome with surgical resection.5 Often the complete tumor cannot be excised, leaving the patients with some degree of symptomatology and extra-adrenal involvement. Irradiation can be used if metastases are discovered. In the patient with adrenal carcinoma who is not a surgical candidate, the focus of treatment is on palliative pharmacologic intervention (e.g., mitotane). Mitotane appears to be the drug of choice in inoperable functional and nonfunctional adrenal carcinoma. Tumor regression is seen in approximately 35% to 50% of patients, with most regression occurring between the second and fourth month of therapy. Seventy-five percent of patients will exhibit a 30% fall in urinary steroids, with 50% of patients showing an improved clinical response after 5 months of

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TABLE 74–5. Alternative Steroid Replacement Regimens in the Adrenal Adenoma Patient Hydrocortisone Dose (mg) Time Operation day Postoperative day 1 Postoperative day 2 Postoperative day 3 Postoperative day 4 Postoperative day 5 Postoperative day 7 Postoperative days 8–10 Postoperative days 11–20 Postoperative days 21+

IV

IM

300 200 150 100

50 before surgery and 50 after surgery 50 every 12 h 50 every 12 h 50 every 12 h 50 every 12 h 25 every 12 h

PO

25 every 6 h 25 every 6 ha 25 every 6 h 25 every 8 h 25 every 12 h 20 at 8 A.M. 10 at 4 P.M.

a Add fludrocortisone 0.05–2 mg orally once daily starting on postoperative day 5. Adjust dose based on blood pressure, body weight, and serum electrolytes.

treatment. Patient survival appears prolonged, although no adequate clinical trials are available to support this assumption. Metyrapone, aminoglutethimide, and ketoconazole may be given to attempt control of steroid hypersecretion. 5-Fluorouracil has also been used in combination therapy.


Ectopic ACTH Syndrome In the ectopic ACTH syndrome multiple sites of tumors exist, and locating the ectopic site is essential but often difficult.

Therefore only approximately 10% of patients are cured following surgery, and the remaining 90% receive postoperative medication. Pharmacologic management with metyrapone is effective and remains the agent of choice in the ectopic ACTH syndrome.35 Aminoglutethimide and ketoconazole are alternative agents.4,35,36 Mitotane has been tried in patients with ectopic ACTH syndrome; however, its side-effect profile generally limits its use. RU-486 and the somatostatin analog octreotide have been reported to reduce the clinical signs of the ectopic ACTH syndrome.30,35 Further evaluation of these agents is needed.

HYPERALDOSTERONISM Excess aldosterone is categorized as either primary or secondary hyperaldosteronism.37−48

PRIMARY ALDOSTERONISM Etiology Primary aldosteronism implies that the physiologic abnormality is within the adrenal cortex. The most common causes include a solitary adrenal adenoma (60%) or idiopathic adrenocortical hyperplasia (35% bilateral and 5% unilateral). Other rare causes include adrenal cortex carcinoma, primary adrenocortical hyperplasia, reninresponsive adrenocortical adenoma, and genetic mutations, such as in glucocorticoid-suppressible hyperaldosteronism.39,40,42

Clinical Presentation The incidence of primary aldosteronism is disputed, with estimates ranging from approximately 0.5% to 9.5% of all hypertensive patients.39,49 The disease is more common in women aged 30 to 50 years. Signs and symptoms may include arterial hypertension, muscle weakness, fatigue, and headache, though many patients are asymptomatic.

Diagnosis The absolute diagnosis is relatively easy based on clinical findings and pertinent laboratory findings. However, as in Cushing’s disease, the discovery of the underlying etiology is mandatory to ensure proper treatment. Table 74–6 lists the various abnormalities that must be ruled out when suspicion of hyperaldosteronism is high.

CLINICAL PRESENTATION: PRIMARY HYPERALDOSTERONISM SYMPTOMS Patients may complain of muscle weakness, fatigue, paresthesias, and headache. SIGNS

r r r r r

Hypertension Reduced glucose tolerance is seen in 25% of patients. Metabolic alkalosis Tetany/paralysis Polydipsia/nocturnal polyuria

LABORATORY TESTS A serum potassium concentration of less than 3.5 mEq/L with a concurrent urinary potassium content greater than 30 mEq per 24 hours is suggestive of primary aldosteronism. Common laboratory findings include hypokalemia (80% to 90%), suppressed renin activity, elevated plasma aldosterone concentrations, hypernatremia (>142 mEq/L), hypomagnesemia, and elevated bicarbonate concentration (>31 mEq/L). OTHER DIAGNOSTIC TESTS A plasma-aldosterone-to-plasma-renin-activity ratio (PA:PRA) greater than 25 is indicative of primary hyperaldosteronism. A serum potassium concentration of less than 3.5 mEq/L with a concurrent urinary potassium content greater than 30 mEq per

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TABLE 74–6. Differential Diagnosis of Primary Aldosteronism Disease

Plasma Renin Concentration

Plasma Aldosterone Concentration

Primary aldosteronism Edematous disorders Malignant hypertension Congenital adrenal hyperplasia Cushing’s syndrome Liddle’s syndrome Bartter’s syndrome Licorice ingestion Low-renin essential hypertension

Low High High Low Low to normal Low High Low Low

High High High Low Low to normal Low High Low Low to normal

24 hours is suggestive of primary aldosteronism.36 Normokalemia does not exclude the diagnosis of primary aldosteronism. Between 7% and 38% of patients with primary aldosteronism will have serum potassium concentrations greater than 3.6 mEq/L. The diagnosis of primary aldosteronism can be made with a plasma-aldosteroneto-plasma-renin-activity ratio (PA:PRA). Hirohara and colleagues44 found a PA:PRA greater than 32% to be 100% sensitive and 61% specific in patients with aldosterone-producing adenomas. However, lower cutoffs of 20 and 25 ng/dL per ng/mL have been proposed to search for primary hyperaldosteronism.44−46 Differentiating between an aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) is imperative to formulate a proper treatment plan. A majority of the adenomas are singular and small, less than 1 cm. The left adrenal gland is affected at a higher rate than the right. Patients with APA generally have more severe hypertension, more profound hypokalemia, and higher plasma and urinary aldosterone levels compared to patients with BAH. CT scanning can usually detect most adenomas, though nonfunctional adenomas may occasionally cause confusion. The underlying abnormality in BAH remains a mystery, but some investigators believe that a hormone factor stimulates the zona glomerulosa, resulting in increased sensitivity to angiotensin II.34 In contrast to APA patients, patients with BAH are able to maintain control of the renin-angiotensin system, with little effect following doses of ACTH.

Therapeutic Management 6 BAH-Dependent Hyperaldosteronism. Spironolactone, the drug of choice in BAH-dependent hyperaldosteronism, competitively inhibits aldosterone biosynthesis within the adrenal gland, making it extremely useful in overstimulated BAH patients.40,41 It is available in oral form, with most patients responding to doses of 25 to 400 mg/day. The clinician should wait 4 to 8 weeks before reassessing the patient for urinary electrolytes and blood pressure control. Adverse effects of spironolactone include gastrointestinal discomfort, impotence, gynecomastia, and menstrual irregularities. Additionally, because salicylates increase the renal secretion of canrenone, the active metabolite, patients should be advised to avoid concomitant therapy with salicylates. Because spironolactone blocks testosterone biosynthesis, it often is not used in men. The drug of choice in men and patients intolerant of spironolactone is amiloride.37,39 The usual dose is 5 mg twice a day up to 30 mg/day if necessary. More recently, eplerenone, a new aldosterone antagonist with high affinity for the aldosterone receptor and low affinity for androgen and progesterone receptors, was approved for the treatment of hypertension. It appears to be more beneficial than spironolactone due

Blood Pressure High Normal High High High High Low to normal High High

to its limited progestational and antiandrogenic side effects. However, its role in the management of hyperaldosteronism has not been established.37,41 Second-line therapy is often required to control the blood pressure of patients with BAH. Agents useful as second-line choices include the calcium channel blockers, angiotensin-converting enzyme inhibitors, and low-dose diuretics such as hydrochlorothiazide.38,40,41

Therapeutic Management APA-Dependent Hyperaldosteronism. The treatment of choice for APA-dependent aldosteronism remains laparoscopic resection of the adenoma.50 If no primary lesion is found, resection of one and a half of the adrenal glands may be attempted, followed by supplemental spironolactone therapy. However, a recent retrospective analysis of patients with aldosterone-producing adenomas who chose medical management instead of surgical resection, revealed medical management to be efficacious in this population and should be considered as an alternative in patients in whom surgery is contraindicated.51 Summary The diagnosis of primary aldosteronism is made through the observation of elevated blood pressure, low serum potassium, high urinary potassium, elevated serum and urinary aldosterone, and an elevated PA:PRA (Fig. 74–5). Differentiating between the various etiologies is mandatory. Patients with adrenal adenomas can be distinguished from patients with hyperplasia by CT scan. Treatment depends on the etiology with surgical resection, well accepted as the treatment of choice in adenomas, and spironolactone or amiloride plus second-line agents in patients with hyperplasia.

SECONDARY ALDOSTERONISM Secondary hyperaldosteronism results from stimulation of the zona glomerulosa by an extra-adrenal factor, usually the renin-angiotensin system. Excessive potassium intake can create a physiologic increase in aldosterone, as can oral contraceptive use, pregnancy (10 times normal by the third trimester), and menses. Congestive heart failure, cirrhosis, renal artery stenosis, and Bartter’s syndrome also can lead to elevated aldosterone concentrations. Treatment of secondary aldosteronism is dictated by etiology. Control or correction of the extra-adrenal stimulation of aldosterone secretion should resolve the disorder. Medical therapy with spironolactone is the mainstay of treatment until an exact etiology can be located.

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ENDOCRINOLOGIC DISORDERS TABLE 74–7. Etiologies of Primary and Secondary Adrenal Insufficiency Primary Insufficiency

Mineralocorticoid excess states

Primary mineralocorticoid excess syndromes

Adenoma Bilateral idiopathic hyperplasia No lateralizing findings Idiopathic hyperplasia

Slow onset Acquired immunodeficiency syndrome Adrenomyeloneuropathy Amyloidosis Autoimmune adrenalitisa Bilateral adrenalectomy Congenital adrenal hypoplasia Hemochromatosis Isolated glucocorticoid deficiency Metastatic neoplasia Systemic fungal infection Tuberculosisb Fast onset Adrenal thrombosis, hemorrhage, or necrosis

FIGURE 74–5. Algorithm for the diagnosis of primary aldosteronism. a b

Secondary Insufficiency Craniopharyngioma Cure of Cushing’s syndrome Empty sella syndrome Tumors of the third ventricle Histiocytosis Hypothalamic tumors Hypopituitarism Long-term corticosteroid administration Lymphocytic hypophysitis Pituitary surgery, radiation, or tumor Sarcoidosis Postpartum pituitary necrosis Necrotic or bleeding pituitary macroadenoma Head trauma, lesions of the pituitary stalk Pituitary or adrenal surgery for Cushing’s syndrome

Accounts for approximately 70% of cases. Accounts for approximately 20% of cases.

HYPOFUNCTION OF THE ADRENAL GLAND 7 Primary adrenal insufficiency, or Addison’s disease, involves

the destruction of all regions of the adrenal cortex. Deficiencies arise in cortisol, aldosterone, and the various androgens. Approximately 40% to 53% of patients with idiopathic primary adrenal insufficiency present with one or more clinical disorders involving multiple endocrine organs. The organs involved can include ovary, thyroid, pancreas, and parathyroid gland. This polyglandular failure syndrome is associated with the idiopathic etiology only and has not been seen with adrenal insufficiency associated with tuberculosis or other invasive diseases. 8 Secondary insufficiency most commonly results from exogenous steroid use, leading to suppression of the hypothalamicpituitary-adrenal (HPA)-axis and decreased release of ACTH, resulting in impaired androgen and cortisol production. This has been reported from oral, inhaled, intranasal, and topical glucocorticoid administration.52−54 Other drugs reported to induce secondary adrenal insufficiency include rifampin, ketoconazole, phenytoin, phenobarbital, mirtazapine, and progestins such as medroxyprogesterone acetate and megestrol acetate.55−57 Chronic suppression also can result in atrophy of the anterior pituitary and hypothalamus, impairing recovery of function if the exogenous steroid is reduced. Secondary disease classically presents with normal concentrations of mineralocorticoids. Approximately 90% of the adrenal cortex must be destroyed before adrenal insufficiency symptoms will occur.58 Specific etiologies for both primary and secondary insufficiency are listed in Table 74–7. Adrenal hemorrhage can result from multiple etiologies including traumatic shock, coagulopathies, ischemic disorders, and other situations of severe stress, but septicemia is the most common. Symptoms include truncal pain, fever, shaking, chills, hypotension preceding shock, anorexia, headache, vertigo, vomiting, rash, psychiatric symptoms, abdominal rigidity or rebound, and death in 6 to 48 hours if not treated. The most common organisms found on autopsy are

Streptococcus pneumoniae, Staphylococcus spp., and Haemophilus influenzae.53

ADDISON’S DISEASE Distinguishing Addison’s disease from secondary insufficiency is difficult; however, the following guidelines may be helpful: 1. Hyperpigmentation usually is not seen in secondary adrenal insufficiency because of low amounts of melanocyte-stimulating hormone. Low amounts of melanocyte-stimulating hormone are present owing to a deficient pituitary secretion of ACTH and β-lipotropin, all of which are synthesized together in a common precursor peptide, pro-opiomelanocortin (POMC). 2. Aldosterone secretion usually is preserved in secondary insufficiency. 3. Weight loss, dehydration, hyponatremia, hyperkalemia, and elevated blood urea nitrogen are common in Addison’s disease. 4. Addison’s disease will have an abnormal response to the rapid ACTH-stimulation test. Plasma ACTH levels are usually 400 to 2000 pg/mL in primary insufficiency, versus normal to low (0 to 50 pg/mL; see Table 74–3) in secondary insufficiency. A normal cosyntropin-stimulation test does not rule out secondary adrenal insufficiency. The short cosyntropin-stimulation test can be used to assess patients suspected of hypocortisolism. Patients are given 250 mcg of synthetic ACTH intravenously or intramuscularly, with serum cortisol levels drawn at baseline and 30 to 60 minutes after the injection. An increase to a cortisol level ≥18 mcg/dL (500 mmol/L) rules out

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adrenal insufficiency.59 While this test remains the most commonly used method, in some patients with secondary adrenal insufficiency or mild primary adrenal insufficiency, this test will be normal. This result may be owing to the high dose of corticotropin given. Thus some suggest that higher cutoff values (≥22 to 25 mcg/dL) should be used.60 Alternatively, studies have demonstrated that equivalent results can be seen using 1 mcg of cosyntropin. The normal response is an increase to a cortisol level ≥18 mcg/dL 30 minutes after the injection. Other tests include the insulin hypoglycemia test, the metyrapone test, and the corticotropin-releasing hormone stimulation test.59,61,62 Cortisol levels greater than 18 to 20 mcg/dL 30 minutes after a cosyntropin-stimulation test are not useful in patients who are acutely ill.63 Severe infection, trauma, burns, illnesses, or surgery can increase cortisol production by as much as a factor of six, making the recognition of adrenal insufficiency in this population extremely difficult. In the critically ill, a random cortisol level below 15 mcg/dL is indicative of adrenal insufficiency, while a level greater than 34 mcg/dL suggests that adrenal insufficiency is unlikely.63 For patients who fall between these two values, a poor response to corticotropin (less than 9 mcg/dL increase in plasma cortisol from baseline at 30 or 60 minutes) indicates the possibility of adrenal insufficiency and a need for corticosteroid supplementation.63 Treatment of Addison’s disease must include adequate patient education, so that the patient is aware of treatment complications, expected outcome, missed doses, and drug side effects. The agents of choice are prednisone, hydrocortisone, and cortisone, administered twice daily with the treatment objective being the establishment of the lowest effective dose while mimicking the normal diurnal adrenal rhythm.59 Usually a twice-daily dosing schedule is adequate with the dose depending on the agent used. Recent studies64,65 indicate that the daily cortisol production varies between 5 and 10 mg/m2 . Hence, the 12- to 15-mg/m2 per day rule for cortisol supplementation, which is roughly equivalent to 15 to 25 mg of hydrocortisone or 25 to 37.5 mg of cortisone acetate daily. A morning dose of cortisone (20 mg), hydrocortisone (15 mg), or prednisone (2.5 mg) followed by an evening dose of the same agent at 33% to 50% of the morning dose is usually sufficient to duplicate the normal circadian rhythm of cortisol production. To replace the mineralocorticoid loss, fludrocortisone acetate can be used. A dose of 0.05 to 0.2 mg by mouth once a day is adequate. If parenteral therapy is needed, 2 to 5 mg of deoxycorticosterone trimethylacetate in oil intramuscularly every 3 to 4 weeks can be used. The main reason for adding the mineralocorticoid is to minimize the development of hyperkalemia. Adverse effects must be monitored closely. Symptoms include gastric upset, edema, hypertension, hypokalemia, insomnia, excitability, and diabetes mellitus. In addition, patient weight, blood pressure, and electrocardiogram should be monitored regularly.61 Most adrenal crises occur secondary to glucocorticoid dose reduction or lack of stress-related dose adjustments. It is recommended that patients receiving corticosteroid-replacement therapy add 5 to 10 mg hydrocortisone to their normal daily regimen shortly before strenuous activities such as hiking.61 Likewise, during times of severe physical stress such as febrile illnesses or after accidents, patients should be instructed to double their daily dose until recovery.66 The end point of therapy is difficult to assess in most patients, but a reduction in excess pigmentation is a good clinical marker. The development of features of Cushing’s syndrome indicates excessive replacement. Treatment of secondary adrenal insufficiency is identical to primary disease treatment with the exception that mineralocorticoid replacement usually is not necessary. Patient education still should be stressed with emphasis placed on establishing an alternate-day regimen.

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ACUTE ADRENAL INSUFFICIENCY Adrenal crisis, or Addisonian crisis, is characterized by an acute adrenocortical insufficiency. Adrenal crisis represents a true endocrine emergency. Anything that increases adrenal requirements dramatically can precipitate an adrenal crisis. Stressful situations, surgery, infection, and trauma all are potential triggering events, especially in the patient with some underlying adrenal or pituitary insufficiency. The most common cause of adrenal crisis is hypothalamic-pituitaryadrenal (HPA)-axis suppression brought on by chronic use of exogenous glucocorticoids and abrupt withdrawal. Treatment of adrenal crisis involves the administration of parenteral glucocorticoids. Hydrocortisone is the agent of choice owing to its combined mineralocorticoid and glucocorticoid activity. Hydrocortisone is started at 100 mg intravenously through rapid infusion, and followed by a continuous infusion or intermittent bolus of 100 to 200 mg every 24 hours. Intravenous administration is continued for 24 to 48 hours, at which time if the patient is stable, oral hydrocortisone may be started at a dose of 50 mg every 8 hours for another 48 hours. Following oral maintenance therapy, a hydrocortisone taper is initiated until the dosage is 30 to 50 mg/day in divided doses. Fluid replacement often is required and may be accomplished with 5% dextrose and isotonic saline (D5 NS) at a rate to support blood pressure. If hyperkalemia is present after the hydrocortisone maintenance phase, additional mineralocorticoid usually is required. Fludrocortisone acetate in a dose of 0.1 mg by mouth daily is the agent of choice. Patients with adrenal insufficiency should be instructed to carry a card or wear a bracelet or necklace, such as MedicAlert, that contains information about their condition. Patients should also have easy access to injectable hydrocortisone or glucocorticoid suppositories in case of an emergency or during times of physical stress, such as febrile illness or injury.61 CLINICAL PRESENTATION: ADRENAL INSUFFICIENCY SYMPTOMS

r Patients commonly complain of weakness, weight loss, gastrointestinal symptoms, craving for salt, headaches, memory impairment, depression, and postural dizziness. r Early symptoms of acute adrenal insufficiency also include myalgias, malaise, and anorexia. As the situation progresses, vomiting, fever, hypotension, and shock will develop. SIGNS

r r r r r r

Increased pigmentation Hypotension (postural) Fever Decreased body hair Vitiligo Features of hypopituitarism (amenorrhea and cold intolerance)

LABORATORY TESTS The short cosyntropin stimulation test can be used to assess patients suspected of hypercortisolism. OTHER DIAGNOSTIC TESTS Other tests include the insulin hypoglycemia test, the metyrapone test, and the corticotropin-releasing hormone stimulation test.

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HYPOALDOSTERONISM Hypoaldosteronism is rare and usually is associated with low renin status, diabetes, complete heart block, or severe postural hypotension, or it may occur postoperatively following tumor removal.2 Hypoaldosteronism may be part of a larger adrenal insufficiency or be the only defect the patient has. In nonselective hypoaldosteronism, the etiology of the low aldosterone is most likely generalized adrenocortical insufficiency (see Addison’s disease). In selective hypoaldosteronism, the etiology is usually a specific defect in the stimulation of adrenal aldosterone secretion (21-hydroxylase deficiency being most common) or a defect in peripheral aldosterone action (decreased aldosterone receptors). Laboratory analysis reveals low serum sodium and high serum potassium concentrations. Patients often will present with hyperchloremic metabolic acidosis. Because the deficiency is in the mineralocorticoid, replacement with fludrocortisone in a dose of 0.1 to 0.3 mg is usually effective. Patients should be followed for blood pressure response as well as electrolyte status.

ADRENAL VIRILISM 9 Virilism, excessive secretion of androgens from the adrenal

gland, is more commonly seen in females, with hirsutism being the dominant feature. Women who present with hirsutism also may have voice deepening, increased muscle mass, menstrual abnormalities, clitoral enlargement, redistribution of body fat and loss of female body contour, breast atrophy, and hair recession and crown balding.69 Though virilism may be easy to diagnose based on clinical symptoms, making the diagnosis on a biochemical basis is difficult. The most common etiology of virilism involves one of many possible congenital enzyme defects. Depending on the enzyme deficiency, accumulation of a variety of androgens, notably testosterone, can develop. Treatment of virilism centers around suppression of the pituitaryadrenal axis with exogenous glucocorticoids. Choice of steroids is variable. In adults, the usual steroids used are dexamethasone (0.25 to 0.5 mg), prednisone (2.5 to 5 mg), or hydrocortisone (10 to 20 mg).69 Antiandrogen use may allow lower steroid doses to be used.

CONGENITAL ADRENAL HYPERPLASIA Because many enzyme systems are needed to complete the complex cholesterol-to-cortisol pathway, enzyme deficiencies may lead to disruptions of the normal cascade of events (see Fig. 74–2). This group of enzyme disorders is known as congenital adrenal hyperplasia, mainly because of the resultant chronic adrenal gland stimulation that occurs following enzyme deficiency.67,68 The most frequent is steroid 21hydroxylase deficiency, accounting for more than 90% of cases. Any enzyme deficiency is capable of affecting any one or all three of the steroid pathways. Therefore treatment should be focused on replacement of the deficient hormone, as well as cessation of the chronic stimulation causing the hyperplasia. In Table 74–8, six of the most common enzyme deficiencies are briefly outlined.

HIRSUTISM Hirsutism (hypertrichosis) is defined as more hair than is cosmetically acceptable. The majority of cases occur in women with some degree of excess androgen production, though certain drugs also may induce hirsutism. Examples of such drugs include minoxidil, phenytoin, cyclosporine, methyldopa, danazol, metoclopramide, phenothiazines, reserpine, and diazoxide. Androgen excess can be derived from either the ovaries or the adrenal glands, with a small fraction coming from pituitary disorders. Ovarian excess is typically associated with obesity and menstrual abnormalities. In the patient with hirsutism, congenital adrenal hyperplasia, adrenal tumors, and ovarian tumors should be ruled out.69,70

TABLE 74–8. Congenital Adrenal Hyperplasia (CAH) Enzyme Deficiency (Disorder) 20-Hydroxylase (nonvirilizing CAH) 17-Hydroxylase (nonvirilizing CAH) 21-Hydroxylase (virilizing CAH)

11-Hydroxylase (virilizing CAH)

Symptoms Enlarged female genitalia and adrenal gland (due to cholesterol) Hypertension usually present Pubertal irregularities (acne, early pubic hair, voice lowering, and increased muscularity); mature normally with replacement Hypertension secondary to high deoxycortisol and virilism from androgen excess; mistaken for Cushing’s, but no glucose intolerance

3-Hydroxysteroid dehydrogenase (mixed CAH)

Both cortisol and aldosterone deficiencies

18-Hydroxysteroid dehydrogenase (corticosterone methyloxidase deficiency)

Hypotension

Lab Tests

Comments

All steroids are low in blood and urine

Poor prognosis for infants

Low concentrations of cortisol and estrogens High progesterone, renin, 17-hydroxyprogesterone and ACTH; low cortisol, sodium, and aldosterone

Mineralocorticoid replacement not necessary Most common form of CAH (90% of total), incidence of 1/10,000; monitor growth velocity, bone age, renin, and 17-hydroxyprogesterone Second most common form of CAH (9% of total), incidence of 1/100,000; final step in biosynthesis of corticosterone and cortisol; found only in adrenal cortex Defect affects both adrenals and gonads

Low plasma cortisone and aldosterone; high ACTH and MSH concentrations

Decreased aldosterone, cortisol, estrogens, and androgens; increased pregnenolone and cholesterol Restricted to zona glomerulosa; sole aldosterone defect; hyponatremia, hyperkalemia, increased renin

Mineralocorticoid replacement without glucocorticoid replacement

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TABLE 74–9. Relative Potencies of Glucocorticoids

Glucocorticoid

AntiInflammatory Potency

Equivalent Potency (mg)

Approximate Half-Life (min)

SodiumRetaining Potency

Cortisone Hydrocortisone Prednisone Prednisolone Triamcinolone Methylprednisolone Betamethasone Dexamethasone

0.8 1 3.5 4 5 5 25 30

25 20 5 5 4 4 0.6 0.75

30 90 60 200 300 180 100–300 100–300

2 2 1 1 0 0 0 0

Cosmetic approaches are generally tried first, with laser photothermodestruction offering the greatest long-term success. Only when cosmetic surgery is ineffective should suppressive therapy be used. Glucocorticoids, such as dexamethasone, can be used if the androgen source is adrenal, but may induce cushingoid symptoms even in doses of 0.5 mg/day. Oral contraceptives can be used in patients who require contraception concurrently. If oral contraceptives are used, a progestin with low androgen activity (norethynodrel or ethynodiol diacetate) should be employed. Gonadotropin-releasing hormone may be an effective adjunct to oral contraceptives if the source of androgen is ovarian. Antiandrogens are often added to the more specific therapies. The most common include spironolactone, flutamide, and finasteride, although none of these is approved by the Food and Drug Administration for the treatment of hirsutism. It can take 4 months for the antiandrogens to alleviate the hirsutism, and duration of therapy is unclear.69,70 CLINICAL CONTROVERSY Some clinicians believe that the usual starting doses for glucocorticoid supplementation are high and unnecessarily increase a patient’s risk for adverse outcomes such as osteoporosis.

PRINCIPLES OF GLUCOCORTICOID ADMINISTRATION Originally, the term glucocorticoid was given to these agents to describe their glucose-regulating properties. However, carbohydrate metabolism is only one of a multitude of effects that steroids can exhibit. The activity produced is a function of the receptor activated (glucocorticoid versus mineralocorticoid) as well as the agent and dose prescribed. The mechanism of glucocorticoids is complex and not fully known. The glucocorticoid enters the cell through passive diffusion and binds to its specific receptor. There are between 5000 and 100,000 receptors per cell. Steroids exhibit various binding affinities to the vast number of receptors in almost every tissue and therefore elicit a wide variety of biologic effects. After binding to the receptor, there is a structural change that occurs in the receptor, known as activation. After activation, the receptor-steroid complex binds to deoxyribonucleic acid sites in the cell called glucocorticoid regulatory elements (GREs). This binding to the GREs stimulates or inhibits transcription of nearby genes. The pharmacokinetics of the glucocorticoids varies with the agent given and the route of administration. In general, most steroids

given by the oral route are well absorbed. Water-soluble agents are more rapidly absorbed following intramuscular injection than are lipid-soluble agents. Intravenous administration is recommended when a quick onset of action is needed. A summary of the steroids is provided in Table 74–9. In addition to systemic steroids causing iatrogenic Cushing’s syndrome, they also can lead to increased susceptibility to infection, osteoporosis, sodium retention with resultant edema, hypokalemia, hypomagnesemia, cataracts, peptic ulcer disease, seizures, and generalized suppression of the HPA-axis. Long-term complications tend to be insidious and less likely to respond to steroid withdrawal. Suppression of the HPA-axis is a major concern whenever systemic steroids are tapered or withdrawn. Single doses of glucocorticoids can prevent the axis from responding to major stressors for several hours. In general, the longer the steroid is administered and the higher the dose used, the more suppression of the axis occurs. However, the possibility of suppression occurs any time the patient is exposed to supraphysiologic doses of a steroid.62,71 Symptoms of steroid withdrawal resemble those seen in a patient with adrenocortical deficiency. A variety of recommendations for steroid tapering are available.62,72,73 In general, patients who have been on long-term steroid therapy will need to be gradually withdrawn toward physiologic doses over months. On average, the normal adult produces approximately 20 to 30 mg of cortisol per day with the peak concentration occurring around 8:00 A.M. As the steroid or steroid-equivalent dose approaches the 20- to 30-mg level, the taper should be slowed and the patient checked for axis function. The primary mode to test HPA integrity is the ACTH test, either high- or low-dose. A normal ACTH test would indicate that daily steroid maintenance therapy is not needed. More recently, the use of exogenous human CRH was found to be nearly as useful in the assessment of pituitary-adrenal function.74 Caution should be used to prevent disease exacerbation during the steroid taper to prevent the need for rebolusing the patient with another course of high-dose steroids. The dilemma of prolonged steroid administration is sometimes lessened by the use of an alternate-day therapy (ADT) regimen.72,73 ADT theoretically minimizes the hypothalamic-pituitary suppression as well as some of the adverse effects seen with once-daily therapy. This can be especially important in the treatment of the child and young adult, in whom growth suppression is a major concern. ADT is not recommended for initial management, but rather in the management of the stabilized patient who needs long-term therapy. The patient will be exposed to “on” and “off” days, with the “on” day dose gradually increased with concurrent reduction in the “off” day dose over a period of 14 days. By the fourteenth day, the patient will be consuming medication only on the “on” day. It should be noted that not all patients will have

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TABLE 74–10. Factors in Successful Glucocorticoid Therapy Monitoring

Counseling

Recognizing complications

Glucose concentrations (serum and urine) Electrolytes (serum and urine) Ophthalmologic exams Stool tests for occult blood loss Growth and development (children and adolescents) Take with food to minimize gastrointestinal discomfort Never discontinue medication on your own; check with your physician; gradual dose reduction is usually necessary Carry or wear medical identification indicating that you are on long-term glucocorticoid therapy Dosage increases may be necessary at times of increased stress (surgery or emergency treatments) Be aware of potential side effects (i.e., visual disturbances, bruising, and delayed wound healing) What to do if you miss a dose: If your dosing schedule is Every other day: Take as soon as possible if remembered that morning. If not remembered until later, skip that day. Take the next morning, then skip the following day. Every day: Take as soon as possible, but skip if almost time for the next dose. Never double doses. Early in therapy and essentially unavoidable: insomnia, enhanced appetite, weight gain Common in patients with underlying risk factors: hypertension, diabetes mellitus, peptic ulcer disease Long-term intense treatment: cushingoid habitus, hypothalamic-pituitary-adrenal suppression, impaired wound healing Delayed and insidious: cataracts, atherosclerosis Rare and unpredictable: psychosis, glaucoma, pancreatitis

From United States Pharmacopeial Convention75 and Barlow.76

equivalent disease control on ADT, and it should be avoided in certain indications.73

EVALUATION OF THERAPEUTIC OUTCOMES Successful glucocorticoid therapy involves counseling the patient, monitoring the patient, and recognizing complications of therapy (Table 74–10). The risk:benefit ratio of glucocorticoid administration should always be considered, especially with concurrent disease states such as hypertension, diabetes mellitus, peptic ulcer disease, and uncontrolled systemic infections.

D5 NS: 5% dextrose and isotonic saline DDT: dichlorodiphenyltrichloroethane DST: dexamethasone suppression test GRE: glucocorticoid regulatory element HPA: hypothalamic-pituitary-adrenal IRMA: immunoradiometric assay MRI: magnetic resonance imaging PA:PRA: plasma-aldosterone-to-plasma-renin-activity ratio RIA: radioimmunoassay RU-486: mifepristone Review Questions and other resources can be found at www.pharmacotherapyonline.com.

CLINICAL CONTROVERSY Some clinicians believe that twice-daily administration of glucocorticoids in patients with adrenal insufficiency is not as effective as three-times daily. If a twice-daily regimen is used, the second dose should be administered 6 to 8 hours after the first.

ABBREVIATIONS ACTH: adrenocorticotropic hormone ADT: alternate-day therapy APA: aldosterone-producing adenoma BAH: bilateraladrenalhyperplasia CBG: corticosteroid-binding globulin CRH: corticotropin-releasing hormone CT: computed tomography

REFERENCES 1. Conn JW. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med 1955;45:6–17. 2. Orth DN, Kovacs WJ. The adrenal cortex. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR eds. Williams’ Textbook of Endocrinology. Philadelphia, Saunders, 1998:517–664. 3. Albright F. Cushing syndrome. Harvey Lect 1942–1943;38:123–186. 4. Boscaro M, Barzon L, Sonino N. The diagnosis of Cushing’s syndrome: atypical presentations and laboratory shortcomings. Arch Intern Med 2000;160:3045–3053. 5. Orth DN. Cushing’s syndrome. N Engl J Med 1995;332:791–803. 6. Williams GH, Duly RG. Diseases of the adrenal cortex. In: Isselbacher KJ, Braunwald E, Wilson JD et al, eds. Harrison’s Principles of Internal Medicine, 13th ed. New York, McGraw-Hill, 1994:1953–1976. 7. Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis and differential diagnosis of Cushing’s syndrome and Pseudo-Cushing’s states. Endocr Rev 1998;19:647–672.

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33. Semple PL, Vance ML, Findling J, Laws ER. Transsphenoidal surgery for Cushing’s disease: outcome in patients with a normal magnetic resonance imaging scan. Neurosurgery 2000;46:553–558. 34. Estrada J, Boronat M, Mielgo M, et al. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. N Engl J Med 1997;336:172–177. 35. Comi RJ, Gorden P. Long-term medical treatment of ectopic ACTH syndrome. South Med J 1998;91:1014–1018. 36. Berwaerts JJ, Verhelst JA, Verhaert GC, et al. Corticotropin-dependent Cushing’s syndrome in older people: Presentation of five cases and therapeutical use of ketoconazole. J Am Geriatr Soc 1998;46:880–884. 37. Young WF Jr. Primary aldosteronism: management issues. Ann N Y Acad Sci 2002;970:61–76. 38. Corry DB, Tuck ML. Secondary aldosteronism. Endocrinol Metab Clin North Am 1995;24:511–529. 39. Stewart PM. Mineralocorticoid hypertension. Lancet 1999;353: 1341–1347. 40. Ganguly A. Primary aldosteronism. N Engl J Med 1998;339:1828–1834. 41. Blumenfeld JD, Vaughan ED Jr. Diagnosis and treatment of primary aldosteronism. World J Urol 1999;17:15–21. 42. Fardella CE, Mosso L. Primary aldosteronism. Clin Lab 2002;48: 181–190. 43. Wheeler MH, Harris DA. Diagnosis and management of primary aldosteronism. World J Surg 2003;27:627–631. 44. Hirohara D, Nomura K, Okamoto T, et al. Performance of the basal aldosterone to renin ratio and of the renin stimulation test by furosemide and upright posture in screening for aldosterone-producing adenoma in low renin hypertensives. J Clin Endocrinol Metab 2001;86:4292–4298. 45. Loh KC, Koay ES, Khaw MC, et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab 2000;85:2854–2859. 46. Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: Prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab 2000;85:1863–1867. 47. Torpy DJ, Stratakis CA, Chrousos GP. Hyper- and hypoaldosteronism. Vitam Horm 1999;57:177–216. 48. Young WF. Primary aldosteronism: A common and curable form of hypertension. Cardiol Rev 1999;7:207–214. 49. Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: Prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab 2000;85:1863–1867. 50. Gagner M, Pomp A, Heniford BT, et al. Laparoscopic adrenalectomy: lessons learned from 100 consecutive procedures. Ann Surg 1997; 226:238–246. 51. Ghose RP, Hall PM, Bravo EL. Medical management of aldosteroneproducing adenomas. Ann Intern Med 1999;131:105–108. 52. Levin C, Maibach HI. Topical corticosteroid-induced adrenocortical insufficiency: Clinical implications. Am J Clin Dermatol 2002;3:141–147. 53. Bello CE, Garrett SD. Therapeutic issues in oral glucocorticoid use. Lippincotts Prim Care Pract 1999;3:333–341. 54. Sizonenko PC. Effects of inhaled or nasal glucocorticosteroids on adrenal function and growth. J Pediatr Endocrinol Metab 2002;15:5–26. 55. Goodman A, Cagliero E. Megestrol-induced clinical adrenal insufficiency. Eur J Gynaecol Oncol 2000;21:117–118. 56. Schule C, Baghai T, Bidlingmaier M, et al. Endocrinological effects of mirtazapine in healthy volunteers. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:1253–1261. 57. Werbel SS, Ober KP. Acute adrenal insufficiency. Endocrinol Metab Clin North Am 1993;22:303–328. 58. Carey RM. The changing clinical spectrum of adrenal insufficiency. Ann Intern Med 1997;127:1103–1105. 59. Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med 2003;139:194–204. 60. Oelkers W. The role of high- and low-dose corticotropin tests in the diagnosis of secondary adrenal insufficiency. Eur J Endocrinol 1998;139:567– 570. 61. Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003;361:1881–1893.

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62. Krasner AS. Glucocorticoid-induced adrenal insufficiency. JAMA 1999; 282:671–676. 63. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003;348:727–734. 64. Brandon DD, Isabelle LM, Samuels MH, et al. Cortisol production rate measurement by stable isotope dilution using gas chromatographynegative ion chemical ionization mass spectrometry. Steroids 1999;64: 372–378. 65. Kraan GP, Dullaart RP, Pratt JJ, et al. The daily cortisol production reinvestigated in healthy men. The serum and urinary cortisol production rates are not significantly different. J Clin Endocrinol Metab 1998;83:1247–1252. 66. Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insufficiency. JAMA 2002;287:236–240. 67. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med 2003;349:776–788. 68. Deaton MA, Glorioso JE, McLean DB. Congenital adrenal hyperplasia: Not really a zebra. Am Fam Phys 1999;59:1190–1196. 69. Rittmaster RS. Hirsutism. Lancet 1997;349:191–195.

70. Bergfeld WF. Hirsutism in women: Effective therapy that is safe for longterm use. Postgrad Med 2000;107:93–104. 71. Henzen C, Suter A, Lerch E, et al. Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment. Lancet 2000; 355:542–545. 72. Kountz DS, Clark CL. Safely withdrawing patients from chronic glucocorticoid therapy. Am Fam Physician 1997;55:521–552. 73. Baxter JD. Advances in glucocorticoid therapy. Adv Intern Med 2000; 45:317–349. 74. Choi CH, Tiu SC, Shek CC, et al. Use of the low-dose corticotropin stimulation test for the diagnosis of secondary adrenocortical insufficiency. Hong Kong Med J 2002;8:427–434. 75. United States Pharmacopeial Convention Inc. USPDI: Advice for the patient: Drug Information in Lay Language, Vol. II, 19th ed. Taunton, MA, Rand-McNally 1999:612–616. 76. Barlow JE. Complications of therapy. In: Boumpas DT, moderator. Glucocorticoid therapy for immune mediated diseases: Basic and clinical correlates. Ann Intern Med 1993;119:1198–1208.

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75 PITUITARY GLAND DISORDERS Amy Heck Sheehan, Jack A. Yanovski, and Karim Anton Calis

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Pharmacologic therapy for acromegaly should be consid-

ered when surgery and irradiation are contraindicated, when rapid control of symptoms is needed, or when other treatments have failed to normalize growth hormone (GH) and insulin-like growth factor-I (IGF-I) concentrations.

2 Dopamine agonists provide advantages of oral dosing and reduced cost when compared to somatostatin analogs and pegvisomant. However, dopamine agonists effectively normalize IGF-I concentrations in only 10% of patients. 3 Octreotide therapy should be initiated using the short-

acting subcutaneous formulation. Patients who have been maintained on subcutaneous octreotide for at least 2 weeks, and have shown response to therapy, may be converted to the long-acting depot form of octreotide.

4 Blood glucose concentrations should be monitored fre-

deficient (GHD) short stature. Prompt diagnosis of GHD and initiation of replacement therapy with recombinant GH is crucial for optimizing final adult heights.

7 All GH products are generally considered to be equally efficacious. The recommended dose for treatment of GHD short stature in children is 0.3 mg/kg per week.

8 Pharmacologic agents that antagonize dopamine or in-

crease the release of prolactin can induce hyperprolactinemia. Discontinuation of the offending medication and initiation of an appropriate therapeutic alternative usually normalizes serum prolactin concentrations.

9 Cabergoline appears to be more effective than bromocriptine for the medical management of prolactinomas and offers the advantage of less-frequent dosing and decreased adverse events.

quently in the early stages of octreotide therapy in all acromegalic patients.

10 Patients receiving cabergoline who plan to become preg-

5 Pegvisomant appears to be the most effective agent for normalizing IGF-I concentrations. However, further study is needed to determine the long-term safety and efficacy of this agent for the treatment of acromegaly.

11 Pharmacologic treatment of panhypopituitarism consists

6 Recombinant GH is currently considered the mainstay of

nant should discontinue the medication at least 1 month before planned conception. of glucocorticoids, thyroid-hormone preparations, sex steroids, and recombinant growth hormone, where appropriate, as lifelong replacement therapy.

therapy for the treatment of children with growth-hormone-

In the 1950s Geoffrey Harris and his colleagues uncovered the physiologic importance of pituitary hormones and proposed the theory of neurohormonal regulation of the pituitary by the hypothalamus.1 Today the pituitary gland is recognized for its essential role in body homeostasis, and for this reason it is often referred to as the “master gland.” The hypothalamus and the pituitary gland are closely connected, and together they provide a means of communication between the brain and many of the body’s endocrine organs. The hypothalamus uses nervous input and metabolic signals from the body to control the secretion of pituitary hormones that regulate growth, thyroid function, adrenal activity, reproduction, lactation, and fluid balance.

ANATOMY AND PHYSIOLOGY The hypothalamus (Fig. 75–1) is a small region at the base of the brain that receives autonomic nervous input from different areas of the body to regulate limbic functions, food and water intake, body

temperature, cardiovascular function, respiratory function, and diurnal rhythms. In addition, the hypothalamus controls the release of hormones from the anterior and posterior regions of the pituitary gland. Neurons in the hypothalamus produce vasopressin and oxytocin and make many hormone-releasing factors that stimulate or inhibit the release of trophic hormones. At the base of the hypothalamus, a projection known as the median eminence is rich with nerve axons and blood vessels and provides both chemical and physical connections between the hypothalamus and the pituitary gland. The pituitary gland, also referred to as the hypophysis, is located at the base of the brain in a cavity of the sphenoid bone known as the sella turcica. The pituitary is separated from the brain by an extension of the dura mater known as the diaphragma sella. The pituitary is a very small gland, weighing between 0.4 and 1 g in adults. It is divided into two distinct regions, the anterior lobe, or adenohypophysis, and the posterior lobe, or the neurohypophysis (see Fig. 75–1). The posterior pituitary gland secretes two major hormones, oxytocin and vasopressin (antidiuretic hormone) (Table 75–1). Oxytocin 1407

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Hypothalamus

Median eminence Optic chiasm

Dura

Superior hypophyseal artery

Diaphragma sella

Posterior pituitary

Hypothalamichypophyseal portal vessels

Anterior pituitary

Sphenoid sinus

FIGURE 75–1. Pituitary gland.

release from the posterior pituitary causes contraction of the smooth muscles in the breast during lactation and also plays a role in uterine contraction during parturition. Vasopressin is essential for proper fluid balance and acts on the renal collecting ducts to conserve water. Oxytocin and vasopressin are synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. The posterior pituitary gland contains the terminal nerve endings of these two nuclei as well as specialized secretory granules that release hormones in response to appropriate signals. Loss of anterior pituitary function does not necessarily affect the release of vasopressin or oxytocin, because these hormones are actually synthesized in the hypothalamus. Unlike the posterior pituitary, the release of anterior pituitary hormones is not regulated by direct nervous stimulation, but rather is controlled by specific hypothalamic releasing and inhibitory hormones. The median eminence of the hypothalamus contains a large number of capillaries that converge to form a network of veins known as the hypothalamic-hypophysial portal circulation. Inhibiting and releasing hormones synthesized in the neurons of the hypothalamus reach the anterior pituitary via the hypothalamic-hypophysial portal vessels to control release of anterior pituitary hormones. Although there is a direct arterial blood supply to the anterior pituitary lobe, the hypothalamic-hypophysial portal vessels provide the primary blood supply (see Fig. 75–1). In contrast to the posterior pituitary, the anterior pituitary lobe is extremely vascular and has the highest rate of blood flow of all body organs. The specialized secretory cells of the anterior pituitary lobe secrete six major polypeptide hormones (see Table 75–1). These include growth hormone (GH) or somatotropin, adrenocorticotropic hormone (ACTH) or corticotropin, thyroid-stimulating hormone (TSH) or thyrotropin, prolactin, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The release of these hormones is regulated primarily by hypothalamic releasing and inhibiting hormones. Thyrotropin-releasing hormone (TRH) stimulates anterior pituitary release of TSH and prolactin, corticotropin-releasing hormone (CRH) stimulates anterior pituitary release of ACTH, growth hormonereleasing hormone (GHRH) stimulates anterior pituitary release of GH, and gonadotropin-releasing hormone (GnRH) stimulates anterior pituitary release of LH and FSH. Hypothalamic release of somatostatin inhibits release of growth hormone, and hypothalamic release

of dopamine (prolactin-inhibitory hormone) inhibits the secretion of prolactin. Prolactin differs from the other anterior lobe hormones in that an inhibiting factor, rather than a stimulating factor, is primarily responsible for controlling its secretion. In the absence of hypothalamic input, an excess of prolactin is produced, whereas a deficiency state of other anterior pituitary hormones results. Physiologic regulation and action of anterior and posterior pituitary hormones are summarized in Table 75–1.2−4 Destruction of the pituitary gland may result in secondary hypothyroidism, hypogonadism, adrenal insufficiency, growth hormone deficiency, and hypoprolactinemia. The formation of certain types of pituitary tumors may result in pituitary hormone excess. Pituitary tumors may also physically compress the pituitary and prevent the release of the trophic hypothalamic factors that regulate pituitary hormones. In this chapter, the pathophysiology and role of pharmacotherapy in the treatment of acromegaly, short stature, hyperprolactinemia, and panhypopituitarism will be discussed.

GROWTH HORMONE Growth hormone has direct anti-insulin effects on lipid and carbohydrate metabolism. GH decreases utilization of glucose by peripheral tissues, increases lipolysis, and increases muscle mass. GH also stimulates gluconeogenesis in hepatocytes, impairs tissue glucose uptake, decreases insulin-receptor sensitivity, and impairs postreceptor insulin action. The growth-promoting effects of GH are largely mediated by insulin-like growth factors (IGFs) also known as somatomedins. GH stimulates the formation of IGF-I in the liver, as well as in other peripheral tissues. This anabolic peptide acts as a direct stimulator of cell proliferation and growth. There are two types of insulin-like growth factors, IGF-I and IGF-II. IGF-I regulates growth to some extent before, and largely after, birth. In contrast, IGF-II is thought to primarily regulate growth in utero.5 Growth hormone is secreted by the anterior pituitary in a pulsatile fashion with several short bursts that occur mostly at night. Because of the short half-life of growth hormone in the plasma (approximately 30 minutes), measurements of circulating GH concentrations throughout the waking hours are usually very low or undetectable. Daytime GH pulses are most likely to occur after meals, following exercise, or during periods of stress. The greatest amount of GH secretion occurs during the night within the first 1 to 2 hours of slow-wave sleep (stages III or IV). Secretion of growth hormone is lowest during infancy, increases slightly during childhood, reaches its peak during adolescence, and then begins to gradually decline during the middle-age years.3

GROWTH HORMONE EXCESS Acromegaly is a pathologic condition characterized by excessive production of growth hormone. This is a rare disorder that affects approximately 50 to 70 adults per million.6 Gigantism, which is even more rare than acromegaly, is the excess secretion of growth hormone prior to epiphyseal closure in children.7 Patients diagnosed with acromegaly are reported to have a two- to threefold increase in mortality, usually related to cardiovascular, respiratory, or neoplastic disease.8−10 Most patients are middle-aged at the time of diagnosis, and this disorder does not appear to affect one gender to a greater extent than the other. The most common cause of excess GH secretion in acromegaly, accounting for approximately 98% of all cases, is a growth hormone-secreting pituitary adenoma.8 Rarely, acromegaly may be caused by ectopic GH-secreting adenomas, GH cell hyperplasia, excess growth hormone-releasing hormone secretion, or as one of the manifestations of the multiple endocrine neoplasia

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TABLE 75–1. Pituitary Hormones Hormone Anterior pituitary hormones Growth hormone (GH)

Stimulation

Inhibition

Physiologic Effects

Physiologic GH-releasing hormone Ghrelin ADH GABA Norepinephrine Dopamine Serotonin Estrogen Sleep Stress Exercise Pharmacologic α-Adrenergic agonists (e.g., clonidine) β-Adrenergic antagonists (e.g., propranolol) Dopamine agonists (e.g., bromocriptine) GABA agonists (e.g., muscimol)

Physiologic Somatostatin Elevated IGF-I Growth hormone Progesterone Glucocorticoids Postprandial hyperglycemia Elevated free fatty acids

Physiologic TRH VIP Estrogen Serotonin Histamine Endogenous opioids Pregnancy and nursing Pharmacologic Dopamine antagonists (e.g., phenothiazines, haloperidol, methyldopa) Opiates Estrogens H2 -antagonists (e.g., cimetidine) MAO inhibitors

Physiologic Dopamine GABA

Adrenocorticotropic hormone (ACTH)

CRH

Elevated cortisol

Glucocorticoid effects Pigmentation

Thyroid-stimulating hormone (TSH)

TRH Estrogens Norepinephrine Serotonin

Thyroxine Triiodothyronine Somatostatin Glucocorticoids Dopamine

Iodine uptake and thyroid hormone synthesis

Luteinizing hormone (LH)

Physiologic GnRH Pharmacologic Clomiphene

Estradiol Testosterone Fasting

Ovulation Maintains corpus luteum

Estradiol Inhibin Fasting

Ovarian follicle development Stimulates estradiol and progesterone

Hypervolemia Hypoosmolality

Acts on renal collecting ducts to prevent diuresis

Prolactin

Follicle-stimulating hormone (FSH)

Posterior pituitary hormones Vasopressin (antidiuretic hormone; ADH) Oxytocin

Physiologic GnRH Menopause Ovarian disorders Pharmacologic Clomiphene Hyperosmolality Volume depletion Parturition Suckling

Stimulates IGF-I production IGF-I and GH promote growth in all body tissues

Pharmacologic Dopamine antagonists (e.g., phenothiazines) α-Adrenergic antagonists (e.g., phentolamine) β-Adrenergic agonists (e.g., isoproterenol) Serotonin antagonists (e.g., methysergide)

Lactation

Pharmacologic Dopamine agonists (e.g., levodopa, bromocriptine, pergolide, cabergoline)

Uterine contraction Milk ejection

CRH, corticotropin-releasing hormone; GABA, γ -aminobutyric acid; GnRH, gonadotropin-releasing hormone; IGF-I, insulin-like growth factor; MAO, monoamine oxidase; TRH, thyrotropin-releasing hormone; VIP, vasoactive intestinal peptide. From Amar et al,2 Cuttler,3 and Molitch.4

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TABLE 75–2. Clinical Presentation of Acromegaly General The patient will experience slow development of soft-tissue overgrowth affecting many body systems. Signs and symptoms may gradually progress over 10 to 15 years. Symptoms The patient may complain of symptoms related to local effects of the growth hormone (GH)-secreting tumor such as headache and visual disturbances. Other symptoms related to elevated GH and insulin-like growth factor-I (IGF-I) concentrations include excessive sweating, neuropathies, joint pain, and paresthesias. Signs The patient may exhibit coarsening of facial features, increased hand volume, increased ring size, increased shoe size, an enlarged tongue, and various dermatologic conditions. Laboratory tests The patient’s GH concentration will be greater than 1 mcg/L following an oral glucose tolerance test (OGTT) and IGF-I serum concentrations will be elevated. Glucose intolerance may be present in up to 50% of patients. Additional clinical sequelae r Cardiovascular diseases such as hypertension, coronary heart disease, cardiomyopathy, and left ventricular hypertrophy are common in patients with acromegaly. r Osteoarthritis and joint damage develops in up to 90% of acromegalic patients. r Respiratory disorders and sleep apnea occur in up to 60% of acromegalic patients. r Type 2 diabetes develops in approximately 25% of acromegalic patients. r Patients with acromegaly may also have an increased risk for the development of esophageal, colon, and stomach cancer. From Ben-Shlomo et al,8 Molitch,9 Melmed,10 Fatti et al,11 Vitale et al,12 and Webb et al.13

syndrome type 1, the McCune-Albright syndrome, or the Carney complex, all very rare hypersecretory endocrinopathies.8 The clinical signs and symptoms of acromegaly develop gradually over an extended period of time. In fact, because of the subtle and slowly developing changes in physical appearance that GH excess causes, most patients are not definitively diagnosed with acromegaly until 10 to 15 years after the presumed onset of excessive growthhormone secretion.9 Excessive secretion of GH and IGF-I adversely affects several organ systems. Almost all acromegalic patients will present with physical signs and symptoms of soft-tissue overgrowth. Table 75–2 summarizes the classic clinical presentation of patients with acromegaly.8−13 Some patients with acromegaly may present with few of these classic signs and symptoms, making recognition of this disease extremely difficult. The diagnosis of acromegaly is based on a combination of diagnostic tests and clinical signs and symptoms. Random measures of plasma GH levels are not usually dependable because of the pulsatile pattern of release. The oral glucose tolerance test (OGTT) is commonly used as an important diagnostic tool. Postprandial hyperglycemia inhibits the secretion of growth hormone for at least 1 to

2 hours. Therefore an oral glucose load would be expected to suppress growth-hormone concentrations. However, patients with acromegaly continue to secrete growth hormone during the OGTT, and GH concentrations remain elevated after oral glucose loads of 50 to 100 g in 80% of acromegalics.14 Since GH stimulates the production of IGF-I, serum IGF-I concentrations can also be measured to aid in the diagnosis of acromegaly. Circulating IGF-I is cleared from the body at a much slower rate than GH, and measurements can be collected at any time of the day to identify patients with GH excess.14 Current criteria for the diagnosis of acromegaly include failure of GH suppression below 1 mcg/L following an OGTT in the presence of elevated IGF-I serum concentrations.14 With the development of more sensitive GH and IGF-I assays, the cut-off value for diagnosis of acromegaly will likely decrease in the future. Insulin-like growth factor-I-binding-protein-3 (IGFBP-3) can also be measured because it is positively regulated by GH and binds to circulating IGF-I with high affinity. This test may be useful in monitoring response to therapy.8 Computed tomography and magnetic resonance imaging of the pituitary are important diagnostic tests to confirm the presence of a pituitary adenoma.9,14


TREATMENT: Acromegaly The primary treatment goals for patients diagnosed with acromegaly are to reduce GH and IGF-I concentrations, improve the clinical signs and symptoms of the disease, and decrease mortality.15−17 Many clinicians define cure of acromegaly as suppression of GH concentrations to lower than 1 mcg/L after a standard OGTT in the presence of normal IGF-I serum concentrations.15−18 The treatment of choice for acromegaly is transsphenoidal surgical resection of the growthhormone secreting adenoma.15,17,18 Postsurgical cure rates have been reported to range from 50% to 90%, depending on the type of adenoma and the expertise of the neurosurgeon.8,17,18 Complications of transsphenoidal surgery are relatively infrequent and include cerebrospinal fluid leak, meningitis, arachnoiditis, diabetes insipidus, and pituitary failure.8 For patients who are poor surgical candidates, those

who have failed surgical interventions, or others who refuse surgical treatment, radiation therapy may be considered. Radiation, however, may take several years to relieve the symptoms of acromegaly. Because neither radiation therapy nor surgery will cure all patients with acromegaly, adjuvant drug therapy is often needed to control symptoms.15,17,18


PHARMACOLOGIC THERAPY 1 Drug therapy should be considered for acromegalic patients in whom surgery and irradiation are contraindicated, when rapid

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control of symptoms is indicated, or when other treatments have failed to normalize GH and IGF-I concentrations. Pharmacologic treatment options include dopamine agonists, somatostatin analogs, and the GH receptor antagonist, pegvisomant. Dopamine agonists such as bromocriptine, pergolide, or cabergoline are effective in a small subset of patients and provide the advantages of oral dosing and reduced cost. Somatostatin analogs are more effective than dopamine agonists, reducing GH concentrations and normalizing IGF-I in approximately 50% to 60% of patients. Pegvisomant is a newly approved GH receptor antagonist that is highly effective, normalizing IGF-I concentrations in up to 97% of patients. However, additional long-term data are needed to establish safety and efficacy of pegvisomant in the management of acromegaly.


DOPAMINE AGONISTS 2 In normal healthy adults, dopamine agonists cause an increase

in growth hormone production. However, when these agents are given to patients with acromegaly, there is a paradoxical decrease in GH production.Most clinical experience with the use of dopamine agonists in acromegaly is with bromocriptine. Other agents such as pergolide, cabergoline, and lisuride have also been used. Bromocriptine is a semisynthetic ergot alkaloid that acts as a dopamine-receptor agonist. Most trials assessing the efficacy of bromocriptine in the treatment of acromegaly were conducted in the 1970s and early 1980s. It was determined from these studies that certain subsets of acromegalic patients have a favorable response to drug therapy with bromocriptine. These patients include individuals with high circulating concentrations of prolactin and patients who experience GH suppression following a single dose of 2.5 mg of bromocriptine, known as a bromocriptine challenge.19 A review evaluating 34 studies concluded that therapy with bromocriptine was effective in suppressing mean serum GH levels to less than 5 mcg/L in approximately 20% of patients.20 Only 10% of patients experience normalization of IGF-I concentrations with bromocriptine therapy, but over 50% of patients treated with bromocriptine experience improvement in acromegalic symptoms.15,21 Bromocriptine is commercially available in the United States as 2.5-mg oral tablets and 5-mg oral capsules. In acromegalic patients, significant reductions in growth hormone concentrations are observed within 1 to 2 hours of oral dosing. This effect persists for at least 4 to 5 hours. An overall clinical response in acromegalic patients typically occurs following 4 to 8 weeks of continuous bromocriptine therapy. For the treatment of acromegaly, bromocriptine is initiated at a dose of 1.25 mg at bedtime and is increased by 1.25-mg increments every 3 to 4 days as needed.14,19,20 Doses as high as 80 mg per day have been used for the treatment of acromegaly, but clinical studies have shown that dosages greater than 20 or 30 mg daily do not offer additional benefits in the suppression of GH.18,20,21 When used for the treatment of acromegaly, the duration of action of bromocriptine is shorter than for the treatment of hyperprolactinemia. Therefore the total daily dose of bromocriptine should be divided into three or four doses.18,19,21 The most common adverse effects of bromocriptine therapy include central nervous system symptoms such as headache, lightheadedness, dizziness, nervousness, and fatigue. Gastrointestinal effects such as nausea, abdominal pain, or diarrhea also are very common. Some patients may need to take bromocriptine with food to decrease the incidence of adverse gastrointestinal effects. Most adverse effects are seen early in the course of therapy and tend to decrease with continued treatment.18,21 Bromocriptine may cause thickening of bronchial secretions and nasal congestion. There have been rare cases of psychiatric disturbances, pleural diseases, and an erythromelalgic syndrome

PITUITARY GLAND DISORDERS

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(painful paroxysmal dilation of the blood vessels in the skin of the feet and lower extremities) reported with the use of bromocriptine. These conditions appear to be associated with higher doses and prolonged duration of therapy.20,21 Bromocriptine generally should be discontinued if a woman becomes pregnant while taking the drug. Surveillance of women who took bromocriptine throughout pregnancy do not suggest that bromocriptine is associated with an increased risk of birth defects.21 If a woman becomes pregnant while taking bromocriptine, the risks and benefits of therapy should be fully considered. In most cases, the benefits of successful therapy outweigh the risks, and bromocriptine therapy should be continued if it is effective in improving symptoms and reducing the elevated GH concentrations. Other dopamine agonists that have been used to treat acromegaly include pergolide, cabergoline, lisuride, and quinagolide. Cabergoline may be especially useful in patients with pituitary tumors that secrete both prolactin and growth hormone.21,22 Quinagolide, a dopamine agonist available in Europe, has been shown to be more effective than both bromocriptine and cabergoline in normalizing GH and IGF-I values in acromegalic patients.19 Because of the potential cost advantages and convenience of oral administration, dopamine agonists are often considered for the treatment of acromegaly prior to initiation of somatostatin analogs. However, the recent development of longacting somatostatin analogs has made these agents more attractive for first-line treatment of acromegaly.


SOMATOSTATIN ANALOGS Octreotide is a long-acting somatostatin analog that is approximately 40 times more potent in inhibiting GH secretion than endogenous somatostatin.23,24 It also suppresses the LH response to GnRH; decreases splanchnic blood flow; and inhibits the secretion of insulin, vasoactive intestinal peptide (VIP), gastrin, secretin, motilin, serotonin, and pancreatic polypeptide. Lanreotide is another somatostatin analog, currently not available in the United States, which is a slow-release depot formulation administered twice monthly.23 Octreotide (Sandostatin) injection is commercially available in the United States for subcutaneous or intravenous administration. A long-acting intramuscular formulation of octreotide (Sandostatin LAR) is also available for monthly administration. In addition to the treatment of acromegaly, octreotide has many other therapeutic uses, including the treatment of carcinoid tumors, vasoactive intestinal peptide tumors (VIPomas), gastrointestinal fistulas, variceal bleeding, diarrheal states, and irritable bowel syndrome. The efficacy of octreotide for the treatment of acromegaly has been determined by two major multicenter trials.25,26 These studies determined that drug therapy with octreotide suppresses mean serum GH concentrations to less than 5 mcg/L and normalizes serum IGF-I concentrations in 50% to 60% of acromegalic patients. Octreotide is also beneficial in reducing the clinical signs and symptoms of acromegaly. In a 6-month multicenter trial, 70% of patients experienced significant relief of headaches.26 In some patients, relief of headache symptoms occurred within minutes of octreotide administration. In addition, middle-finger circumference was reduced significantly, and 50% to 75% of the patients experienced improvement in symptoms of excessive perspiration, fatigue, joint pain, and cystic acne. A 2-year follow-up of 103 patients treated with octreotide showed that octreotide therapy is safe and effective for long-term use in acromegalic patients.27 Several small studies have shown that octreotide improves the cardiovascular manifestations of acromegaly; it decreased left-ventricular mass, decreased heart rate, and increased exercise capacity.28−30 Octreotide also improves oxygen desaturation,

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sleep quality, and subjective symptoms of sleepiness in acromegalic patients suffering from sleep apnea.31 Data from two major multicenter trials indicate that pituitary tumor growth is halted during octreotide treatment, and a small number of patients experience tumor regression.25,26 A more recent study determined that the growth of pituitary tumors during octreotide therapy is suppressed by approximately 83%.32 The pharmacodynamic effects of long-acting octreotide are similar to those of subcutaneously administered octreotide. Single monthly doses of long-acting octreotide have been shown to be at least as effective as daily doses of 300 or 600 mcg of subcutaneous octreotide administered in divided doses three times daily in normalizing IGF-I levels and maintaining suppression of mean serum GH concentrations.33 A large multicenter trial evaluating the efficacy of long-acting octreotide in acromegalic patients who had previously responded to subcutaneously administered octreotide reported suppression of GH concentrations to below 5 mcg/L in 94% of patients and normalization of IGF-I in 66% of patients following 1 year of therapy.34 Response to long-term therapy with octreotide is related to the presence and increased quantity of functioning somatostatin receptors located in the pituitary adenoma.26,27 Identification of patients who will most likely respond to octreotide, prior to the initiation of therapy, is important when considering the high cost of this medication and the inconvenience of subcutaneous or intramuscular drug administration. Suppression of serum GH concentrations after a single 50-mcg dose of octreotide has been used to predict a favorable long-term response (GH concentrations 50 g) require an open surgical procedure (open prostatectomy), which can be performed retro- or suprapubically. This necessitates hospitalization for at least a few days, anesthesia, and a longer recuperation time. Adverse effects of open prostatectomy include bleeding, urinary and soft tissue infection, retrograde ejaculation in 77% of patients, erectile dysfunction in 16% to 33% of patients, and urinary incontinence in 2% of patients. The reoperation rate is 3% to 5% at 10 years.56 Prostatectomy is ineffective for relieving irritative voiding symptoms of BPH because prostatectomy does not affect the detrusor muscle of the bladder.59 These patients may respond to oral anticholinergic agents (e.g., oxybutynin or L-hyoscyamine), which improve bladder compliance and decrease detrusor muscle irritability, as discussed in Chap. 83. A new trend in surgical treatment is use of less invasive or minimally invasive outpatient surgical procedures to remove excessive prostate tissue.6 These procedures use an energy source, (e.g., heat, cold, or laser) to eliminate excessive prostate tissue, characteristically are short (lasting minutes), have a lower potential to produce adverse effects, are less expensive than continuous drug therapy lasting years, and may be particularly useful in debilitated patients. One significant disadvantage of all minimally invasive surgical procedures is that many patients may require retreatment after an initial improvement in symptoms.60 Of the procedures available, only transurethral incision of the prostate (TUIP) has been thoroughly evaluated. This procedure is ideal for patients with moderate or severe BPH symptoms who have an enlarged prostate gland less than 30 g in size. TUIP is as effective as TURP, but requires less operation time, causes less blood loss, and produces fewer adverse effects.61,62 TUIP involves making two to three incisions at the bladder neck to widen the opening. These incisions are made using an endoscopic resectoscope. Other minimally invasive surgical procedures include visual laser ablation of the prostate (VLAP), transurethral electrovaporization of the prostate (TUVP), transurethral needle ablation of the prostate (TUNA), and transurethral microwave thermotherapy of the prostate (TUMT).8,63


PHYTOTHERAPY 11 Although phytotherapy is widely used in Europe for the manage-

ment of BPH, the published data on herbal agents are largely inconclusive and conflicting. Studies often lack placebo controls, which are essential in assessing treatments for BPH because spontaneous regression of symptoms can occur. Furthermore, as these agents are

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marketed under the Dietary Supplements Health and Education Act, their efficacy, safety, and quality are not regulated by the FDA. For these reasons, herbal products—including saw palmetto berry

EVALUATION OF THERAPEUTIC OUTCOMES The primary therapeutic outcome of BPH therapy is restoration of adequate urinary flow without adverse effects. As a disease in which therapy is directed at those symptoms the patient finds most bothersome, assessment of outcomes likewise depends on how the patient perceives the effectiveness and acceptability of therapy. Use of a validated, standardized instrument, such as the AUA Symptom Index, for assessing patient quality of life is important in this process.2,9,12,13 In patients being treated with pharmacotherapy, objective measures of bladder emptying are also useful at an appropriate time after drug therapy begins (6 to 12 months for 5α-reductase inhibitors, 3 to 4 weeks after the start of α 1 -adrenergic antagonists). These include the uroflowmeter and PVR urine volume, as described in the section on diagnostic evaluation section in this chapter. Key laboratory tests to monitor on an ongoing basis are serum BUN and creatinine and urinalysis. Because this patient population is at high risk for prostate cancer, PSA should be measured and a digital rectal examination performed annually. For patients taking 5α-reductase inhibitors, PSA must be compared with baseline and 6-month responses, as described in the section on 5α-reductase inhibitor.

SUMMARY A ubiquitous disease of aging men, symptomatic BPH requires medical attention to preserve patient quality of life and avoid complications, many of which can be life-threatening in this patient population. In men who have no or minor symptoms, watchful waiting is the therapeutic option of choice, as BPH remains stable or even regresses in about one-half of these men. For those with moderate to severe symptoms but no complications, pharmacotherapy is indicated. An α 1 -adrenergic antagonist is the agent of first choice. Second-generation agents including terazosin, doxazosin, or alfuzosin are also useful. Terazosin and

TABLE 82–5. Comparison of 5α-Reductase Inhibitors and α-Adrenergic Antagonists 5α-Reductase Inhibitors Decreases prostate size Peak onset Efficacy

Frequency of dosing

Decreases prostate-specific antigen Sexual dysfunction Cardiovascular adverse effects

Yes 3–6 months ++ (in patients with enlarged prostates) Once a day

α-Adrenergic Antagonists No 1–6 weeks ++

(Serenoa repens),64−67 stinging nettle (Urtica dioica),68 and African plum (Pygeum africanum)69 —are not recommended for BPH.13 An excellent review on phytotherapy for BPH has been published.70

doxazosin cause more cardiovascular adverse effects than extendedrelease alfuzosin and tamsulosin. Whether extended-release alfuzosin is as well tolerated as tamsulosin in patients at risk of hypotension or hypotension-related morbidity remains to be elucidated. 5αReductase inhibitors are preferred drug treatment in patients with enlarged prostates, who are likely to poorly tolerate the hypotensive adverse effects of α 1 adrenergic antagonists (Table 82–5). However, 5α-reductase inhibitors have a slow onset of action. For patients who fail monotherapy, combination drug therapy could be attempted and such regimens have been found to be most effective in patients with enlarged prostates greater than 40 g. Alternatively, surgery is an option. In patients who have complications of BPH, surgery is required. Although it has more adverse complications than does pharmacotherapy or watchful waiting, transurethral resection of the prostate is considered the gold standard.

ACKNOWLEDGMENT Some portions of this chapter were adapted with permission from Lee M. Health issues in the elderly male. In: Pharmacotherapy Self-Assessment Program Module 6, Respiratory and Endocrinology, 3rd ed. Kansas City, MO, American College of Clinical Pharmacy, 1999:181–207.

ABBREVIATIONS AUA: American Urological Association BPH: benign prostatic hyperplasia BUN: blood urea nitrogen DHT: dihydrotestosterone LUTS: lower urinary tract symptoms PSA: prostate-specific antigen PVR: postvoid residual TUIP: transurethral incision of the prostate TUMT: transurethral microwave thermotherapy of the prostate TUNA: transurethral needle ablation of the prostate TURP: transurethral resection of the prostate TUVP: transurethral electrovaporization of the prostate VLAP: visual laser ablation of the prostate Review Questions and other resources can be found at www.pharmacotherapyonline.com.

REFERENCES

Yes

1–2 times a day, depending on the agent No

++ No

+ Yes

1. Glynn RJ, Campion EW, Bouchard GR, Silbert JE. The development of benign prostatic hyperplasia among volunteers in the normative aging study. Am J Epidemiol 1985;131:79–90. 2. Roehrborn CG. The Agency for Health Care Policy and Research Clinical guidelines for the diagnosis and treatment of BPH. Urol Clin North Am 1995;22:445–453. 3. Uzzo RG, Herzlinger D, Vaughan D. Prostate development: hormonal and cellular considerations. American Urological Association Update Series 1996;15:1.

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CHAPTER 82 4. Steers WD. 5α reductase activity in the prostate. Urology 2001;58(Suppl 1):17–24. 5. Walsh PC. The role of estrogen/androgen synergism in the pathogenesis of benign prostatic hyperplasia. J Urol 1988;139:826. 6. Tammela T. Benign prostatic hyperplasia: Practical treatment guidelines. Drugs Aging 1997;10:349–366. 7. Barry MJ. Epidemiology and natural history of benign prostatic hyperplasia. Urol Clin North Am 1990;17:495–507. 8. Thorpe A, Neal D. Benign prostatic hyperplasia. Lancet 2003;361: 1359–1367. 9. Girman C, Panser L, Chute C, et al. Natural history of prostatism: Urinary flow rates in a community-based study. J Urol 1993;150:887–892. 10. Marberger MJ, Andersen JT, Nickel JC, et al. Prostate volume and serum prostate specific antigen as predictors of acute urinary retention. Combined experience from three large multicenter national placebo-controlled trials. Eur Urol 2000;38:563–568. 11. Jacobsen SJ, Jacobson DJ, Girman CJ, et al. Treatment for benign prostatic hyperplasia among community dwelling men: The Olmsted County Study of urinary symptoms and health status. J Urol 1999;162:1301–1306. 12. U.S. Department of Health and Human Services Public Health Service Agency for Health Care Policy and Research. Clinical practice guideline number 8. Benign prostatic hyperplasia: Diagnosis and treatment. Rockville, MD, U.S. Department of Health and Human Services, 1994: 1–215. 13. American Urological Association Practice Guidelines Committee. AUA guidelines on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol 2003;170:530–547. 14. Desgrandchamps F. Importance of individual response in symptom score evaluation. Eur Urol 2001;40(Suppl 3):2–7. 15. Wasson JH, Reda DJ, Bruskewitz RC, et al, for the Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. N Engl J Med 1995;332:75–79. 16. Dutkiewics S. Efficacy and tolerability of drugs for treatment of benign prostatic hyperplasia. Int Urol Nephrol 2001;32:423–432. 17. Lepor H, Williford WO, Barry MJ, et al. The impact of medical therapy on bother due to symptoms, quality of life and global outcome, and factors predicting response. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. J Urol 1998;160:1358–1367. 18. Kirby RS, Roehrborn C, Boyle P, et al. Efficacy and tolerability of doxazosin and finasteride alone or in combination in treatment of symptomatic benign prostatic hyperplasia—the Prospective European Doxazosin Combination Therapy (PREDICT) Trial. Urology 2003;61:119–126. 19. Roehrborn CG, McConnell J, Bonilla J, et al. Serum prostate specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia—Proscar long term efficacy and safety study. J Urol 2000;163:13–20. 20. Lepor H, Williford WO, Barry MJ, et al, for the Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996;335:533–539. 21. Anonymous. Dutasteride (Avodart) for benign prostatic hyperplasia. Med Lett Drugs Ther 2002;44:109–110. 22. Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: Meta-analysis of randomized clinical trials. Urology 1996;48:398–405. 23. McConnell JD, Bruskewitz R, Walsh P, et al, for the Finasteride LongTerm Efficacy and Safety Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338:557–563. 24. Wasson JH. Finasteride to prevent morbidity from benign prostatic hyperplasia. N Engl J Med 1998;338:612–613. 25. Andersen JT, Nickel JC, Marshall VR, et al. Finasteride significantly reduces acute urinary retention and need for surgery in patients with symptomatic benign prostatic hyperplasia. Urology 1997;49:839–845. 26. Marberger MJ on behalf of the Prowess Study Group. Long-term effects of finasteride in patients with benign prostatic hyperplasia: A double-blind, placebo-controlled, multicenter study. Urology 1998;51:677–686.

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27. Rittmaster RS. Finasteride. N Engl J Med 1994;330:120–125. 28. Park KH, Kim SW, Kim KD, et al. Effects of androgens on the expression of nitric oxide synthase mRNA in rat corpus cavernosum. BJU Int 1999;83:327–333. 29. Rosen R, O’Leary M, Altwein J, et al. Ejaculatory disorders are frequent and bothersome in aging males with LUTS: A worldwide survey (MSAM7). J Urol 2003;169(Suppl 1):365 (abstract). 30. Pannek J, Marks LS, Pearson JD, et al. Influence of finasteride on free and total serum prostate specific antigen levels in men with benign prostatic hyperplasia. J Urol 1998;159:449–453. 31. Caine P, Perlberg S, Shapiro A. Phenoxybenzamine for benign prostatic obstruction. Urology 1981;17:542–546. 32. Lepor H for the Terazosin Research Group. Long-term efficacy and safety of terazosin in patients with benign prostatic hyperplasia. Urology 1995;45:406–413. 33. Schulman CC, Lock TMTW, Buzelin JM, and the European Tamsulosin Study Group. Tamsulosin: 3-Year follow-up of efficacy and safety in 516 patients with LUTS suggestive of BPO. J Urology 1998;159:256 (Abstract #983). 34. Lukacs B, Grange JC, Comet D, et al, for the BPH Group in General Practice. Three year prospective study of 3,228 clinical BPH patients treated with alfuzosin in general practice. Prostate Cancer Prostatic Dis 1998;5:276–283. 35. Roehrborn CG, Oesterling JE, Olson PJ, Padley RJ, for the HYCAT Investigator Group. Serial prostate-specific antigen measurements in men with clinically benign prostatic hyperplasia during a 12-month placebocontrolled study with terazosin. Urology 1997;50:556–561. 36. Djavan B, Marberger M. A meta analysis on the efficacy and tolerability of α 1 adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 1999;36: 1–13. 37. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2000;288:2981–2997. 38. vanKerrebroeck P, Jardin A, Laval KU, et al. Efficacy and safety of a new prolonged release formulation of alfuzosin 10 mg once daily versus alfuzosin 2.5 mg thrice daily and placebo in patients with symptoms of benign prostatic hyperplasia. Eur Urol 2000;37:306–313. 39. Mottet N, Bressolle F, Delmas V, et al. Prostatic tissue distribution of alfuzosin in patients with benign prostatic hyperplasia following repeated oral administration. Eur Urol 2003;44:101–105. 40. Roehrborn CG. Efficacy and safety of once daily alfuzosin in the treatment of lower urinary tract symptoms and clinical benign prostatic hyperplasia: A randomized, placebo-controlled trial. Urology 2001;58:953–959. 41. McKeage K, Plosker GL. Alfuzosin. Drugs 2002;62:633–653. 42. Roehrborn CG. Are all α-blockers created equal? An update. Urology 2002;59(Suppl 2A):3–6. 43. Roehrborn CG for the ALFUS Study Group. Efficacy and safety of once daily alfuzosin in the treatment of lower urinary tract symptoms and clinical benign prostatic hyperplasia: A randomized placebo-controlled trial. Urology 2001;58:953–959. 44. Chapple CR, Burt RP, Andersson PO, et al. α-1-Adrenoreceptor subtypes in the human prostate. Br J Urol 1994;74:585–589. 45. Chapple CR. Pharmacotherapy for benign prostatic hyperplasia—The potential for α1-adrenoceptor subtype-specific blockade. Br J Urol 1998;81(Suppl):34–47. 46. Chapple CR, Wyndaele JJ, Nordling J, et al, on behalf of the European Tamsulosin Study Group. Tamsulosin, the first prostate selective alpha1A-adrenoreceptor antagonist. Eur Urol 1996;29:155–167. 47. Lowe FC. Coadministration of tamsulosin and three antihypertensive agents in patients with benign prostatic hyperplasia: Pharmacodynamic effect. Clin Ther 1997;19:730–742. 48. Lee E, Lee C. Clinical comparison of selective and non-selective α1adrenoreceptor antagonists in benign prostatic hyperplasia: Studies on tamsulosin in a fixed dose and terazosin in increasing doses. Br J Urol 1997;80:606–611.

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49. Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of α1 adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 1999;36:1–13. 50. Fulton B, Wagstaff AJ, Sorkin EM. Doxazosin. Drugs 1995;49:295–320. 51. Wilde MI, McTavish D. Tamsulosin. Drugs 1996;52:883–898. 52. DeMey C, Michel MC, McEwen J, Moreland T. A double-blind comparison of terazosin and tamsulosin on their differential effects on ambulatory blood pressure and nocturnal orthostatic stress testing. Eur Urol 1998;33:481–488. 53. DeMey C. Cardiovascular effects of alpha-blockers used for the treatment of symptomatic BPH: Impact on safety and well being. Eur Urol 1998;34(Suppl 2):18–28. 54. Kaplan SA, D’Alisera PM. Tolerability of α-blockade with doxazosin as a therapeutic option for symptomatic benign prostatic hyperplasia in the elderly patient: A pooled analysis of seven double-blind, placebocontrolled studies. J Gerontol 1998;53A:M201–M206. 55. McConnell JD for the MTOPS Steering Committee. The long term effects of medical therapy on the progression of BPH: Results from the MTOPS trial. J Urol 2002;167:1042. 56. Roos NP, Ramsey EW. A population based study of prostatectomy: Outcomes associated with different surgical procedures. J Urol 1987;37: 1184–1187. 57. Mebust WK, Holtgrewe HL, Cockett AT, et al. Transurethral prostatectomy: Immediate and postoperative complications. A cooperative study of 13 participating institutions evaluating 3,885 patients. J Urol 1989;141:243–247. 58. Kassabian VS. Sexual function in patients treated for benign prostatic hyperplasia. Lancet 2003;361:60–62. 59. Kuo HC, Chang SC, Hsu T. Predictive factors for successful surgical outcome of benign prostatic hypertrophy. Eur Urol 1993;24:12–16.

60. Tanuguntla HS, Evans CP. Minimally invasive therapies for benign prostatic hyperplasia. World J Urol 2002;20:197–206. 61. Hellstrom P, Lukkarinen O, Kontturi M. Bladder neck incision or transurethral electroresection for the treatment of urinary obstruction caused by small prostate? A randomized urodynamic study. Scand J Urol Nephrol 1986;20:187–192. 62. Christensen MM, Aagaard J, Madsen PO. Transurethral resection versus transurethral incision of the prostate: A prospective randomized study. Urol Clin North Am 1990;17:621–630. 63. Blute ML, Larson T. Minimally invasive therapies for benign prostatic hyperplasia. Urology 2001;58(Suppl 6a):33–41. 64. Debruyne F, Koch G, Boyle P, et al. Comparison of phytotherapeutic agent (Permixon) with an α-blocker (tamsulosin) in the treatment of benign prostatic hyperplasia: A 1-year randomized international study. Eur Urol 2002;41:497–507. 65. Gerber GS, Kuznetsov D, Johnson BC, et al. Randomized double blind controlled trial of saw palmetto in men with lower urinary tract symptoms. Urology 2001;58:960–964. 66. Marks LS, Tyler VE. Saw palmetto extract: Newest (and oldest) treatment alternative for men with symptomatic benign prostatic hyperplasia. Urology 1999;53:457–461. 67. Wilt TJ, Ishani A, Stark G, et al. Saw palmetto extracts for treatment of benign prostatic hyperplasia. JAMA 1998;280:1604–1609. 68. Wagner H, Flachsbarth H, Vogel G. A new antiprostatic principal of stinging nettle (Urtica dioica) roots. Phytomedicine 1994;1:213–224. 69. Andro MC, Riffaud JP. Pygeum africanum extract for the treatment of patients with benign prostatic hyperplasia: A review of 25 years of published experience. Curr Ther Res 1995;56:796–817. 70. Lowe FC, Fagelman E. Phytotherapy in the treatment of benign prostatic hyperplasia: An update. Urology 1999;53:671–678.

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83 URINARY INCONTINENCE Eric S. Rovner, Jean Wyman, Thomas Lackner, and David Guay

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 In evaluating urinary incontinence, drug-induced or drugaggravated etiologies must be ruled out.

2 Accurate diagnosis and classification of urinary incontinence type is critical to the selection of appropriate pharmacotherapy.

3 Nonpharmacologic therapy is the cornerstone of manage-

ment of urinary incontinence, should be the first therapy initiated, and should be continued even if drug therapy must be initiated.

4 Anticholinergic/antispasmodic agents are the therapies of choice for bladder overactivity (urge incontinence).

Urinary incontinence (UI) is defined as the complaint of involuntary leakage of urine.1 It is frequently accompanied by other bothersome lower urinary tract symptoms such as urgency, increased daytime frequency, and nocturia. It is a common yet underdetected and underreported health problem that can significantly affect quality of life. Patients with UI may have depression as a result of the perceived lack of self-control, loss of independence, and lack of self-esteem, and they often curtail their activities for fear of an “accident.” It may also have serious medical and economic ramifications for untreated or undertreated patients, including perineal dermatitis, worsening of pressure ulcers, urinary tract infections, and falls. This chapter highlights the epidemiology, etiology, pathophysiology, and treatment of stress, urge, mixed, and overflow UI in men and women.

EPIDEMIOLOGY Determining the true prevalence of UI is difficult because of problems with definition, reporting bias, and other methodologic issues.2 Epidemiologic studies have not historically used a standard definition of the condition or a standard methodology for data recording, with some studies including “postvoid dribbling,” while other studies specify “urinary leakage causing a social or hygienic problem.” The number of people suffering with UI is certainly great, and the impact of this condition is substantial, crossing all racial, ethnic, and geographic boundaries. Compared with continent controls, patients with UI have an overall poorer quality of life.3 Several studies have objectively shown that UI is associated with reduced levels of social and personal activities, increased psychological distress, and overall

5 Duloxetine (when approved for treatment of urinary incontinence), α-adrenergic receptor agonists, and topical (vaginal) estrogens (alone or together) are the therapies of choice in urethral underactivity (stress incontinence).

6 Patient-specific treatment goals should be identified. They

are not static and may change over time. Choice of therapy may also be influenced by characteristics such as patient age, comorbidities, concurrent medications, and ability to adhere to the prescribed regimen. If therapeutic goals are not achieved with a given agent at optimal dosage, consider adding a second agent or switching to an alternative single agent.

decreased quality of life as measured by numerous indices.4,5 The condition can affect people of all age groups but the peak incidence of UI, at least in women, appears to occur around the age of menopause, with a slight decrease in the age group 55 to 60 years, and then a steadily increasing prevalence after age 65. One of the earliest comprehensive epidemiologic studies on UI was conducted by Diokno and colleagues using a standardized survey questionnaire.6 The Medical, Epidemiologic, and Social Aspects of Aging survey found that the prevalence of UI in noninstitutionalized women 60 years of age and older was approximately 38%. Almost one-third of those surveyed noted urine loss at least once weekly and 16% noted UI daily. A recent publication from a National Institutes of Health working group conference estimated the median level of UI prevalence to be approximately 20% to 30% during young adult life, with a broad peak around middle age (30% to 40% prevalence) which increases in the elderly (30% to 50% prevalence).7 In the United States, chronic UI is one of the most common reasons cited for institutionalization of the elderly, and the condition is frequently encountered in the nursing home setting.8 Little is known about the basic differences in clinical and epidemiologic characteristics of incontinence across racial or ethnic groups. Some studies report a higher incidence of UI overall in white populations9,10 as compared to African-Americans, but differences in access to health care as well as cultural attitudes and mores may contribute to these differences. Consistent across all studies in unselected, noninstitutionalized populations, is the fact that UI is at least half as common in men as in women.11,12 Overall, the prevalence of UI in men has been recently estimated to be about 9%.13 Unlike in women, the prevalence of UI in men increases with age across most studies, with the highest prevalence recorded in the oldest patient cohorts.13 1547

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ETIOLOGY AND PATHOPHYSIOLOGY ANATOMY The lower urinary tract consists of the bladder, urethra, urinary or urethral sphincter, and the surrounding musculofascial structures including connective tissue, nerves, and blood vessels. The urinary bladder is a hollow organ composed of smooth muscle and connective tissue located deep in the bony pelvis in men and women. The urethra is a hollow tube that acts as a conduit for urine flow out of the bladder. The interior surface of both the bladder and urethra is lined by an epithelial cell layer termed transitional epithelium, which is in constant contact with urine. Previously considered inert and inactive, transitional epithelium may actually play an active role in the pathophysiology of many lower urinary tract disorders, including interstitial cystitis and UI. The urinary or urethral sphincter is a combination of smooth and striated muscle within and surrounding the most proximal portion of the urethra adjacent to the bladder in both men and women. This is a functional but not anatomic sphincter that includes a portion of the bladder neck or outlet as well as the proximal urethra.

The bladder and urethra normally operate in unison during the bladder filling and storage phase, as well as the bladder emptying phase of the micturition cycle. The smooth and striated muscles of the bladder and urethra are organized during the micturition cycle by a number of reflexes coordinated at the pontine micturition center in the midbrain. Disturbances in the neural regulation of micturition at any level (brain, spinal cord, or pelvic nerves) often lead to characteristic changes in lower urinary tract function that may result in UI.

MECHANISMS OF URINARY INCONTINENCE Simply stated, UI may occur only as a result of abnormalities of the urethra (including the bladder outlet and urinary sphincter) or the bladder, or from a combination of abnormalities of both structures.15 Abnormalities may result in either overfunction or underfunction of the bladder and/or urethra with the resulting development of UI. While this simple classification scheme excludes extremely rare causes of UI such as congenital ectopic ureters and urinary fistulas, it is useful in gaining a working understanding of the condition.

Urethral Underactivity (Stress Urinary Incontinence) URINARY CONTINENCE To prevent incontinence during the bladder filling and storage phase of the micturition cycle, the urethra, or more accurately the urethral sphincter, must maintain adequate resistance to the flow of urine from the bladder at all times until voluntary voiding is initiated. Urethral resistance or closure is maintained to a large degree by the proximal (under involuntary control) and distal (under both voluntary and involuntary control) urinary sphincters, a combination of smooth and striated muscles within and external to the urethra. Variable contributions to urethral resistance may also come from the urethral mucosa, submucosal spongy tissue, and the overall length of the urethra. During bladder filling and storage, the bladder accommodates increasing volumes of urine flowing in from the upper urinary tract without a significant increase in bladder (intravesical) pressure. In addition, bladder or detrusor smooth muscle activity is normally suppressed during the filling phase by centrally mediated neural reflexes. Normal bladder emptying occurs with a decrease in urethral resistance concomitant with a volitional bladder contraction. The bladder contraction occurs in a coordinated fashion, resulting in a rise in intravesical pressure. The rise in intravesical pressure is ideally of adequate magnitude and duration to empty the bladder to completion. A concomitant decrease in urethral resistance and funneling of the bladder outlet results in opening of the functional urinary sphincters and urine flow into the urethra until the bladder is emptied completely. The primary motor input to the detrusor muscle of the bladder is along the pelvic nerves emanating from spinal cord segments S2 to S4 . Parasympathetic impulses travel to the bladder along the efferent fibers of the pelvic nerves. The impulses pass through ganglia situated in the bladder wall before reaching their target. Acetylcholine appears to be the primary neurotransmitter at the neuromuscular junction in the human lower urinary tract. Both volitional and involuntary contractions of the detrusor muscle are mediated by activation of postsynaptic muscarinic receptors by acetylcholine. Of the five known subtypes of muscarinic receptors, bladder smooth-muscle cholinergic receptors are mainly of the M2 variety. However, M3 receptors are responsible for both the emptying contraction of normal micturition, as well as involuntary bladder contractions that may result in UI.14 Thus most pharmacologic antimuscarinic therapy is primarily anti-M3 –based (see discussion below).

Some patients characteristically note UI during exertional activities such as exercise, running, lifting, coughing, and sneezing. This implies that the compromised urethral sphincter is no longer able to resist the flow of urine from the bladder during periods of physical activity. In essence, increases in intra-abdominal pressure during physical activity are transmitted to the bladder (an intra-abdominal organ), compressing it and forcing urine through the weakened sphincter. This type of UI is known as stress urinary incontinence (SUI). Although the exact etiology of urethral underactivity and SUI in the woman is incompletely understood, clearly identifiable risk factors include pregnancy, childbirth, menopause, cognitive impairment, obesity, and age.16,17 The prevalence of SUI in women appears to peak during or after the onset of menopause. This implies that hormonal factors are important in maintaining continence. In men, SUI is most commonly the result of prior lower urinary tract surgery or injury, with resulting compromise of the sphincter mechanism within and external to the urethra. Radical prostatectomy for treatment of adenocarcinoma of the prostate is probably the most common setting in which surgical manipulation leads to UI. Overall, SUI in the male is uncommon, and in the absence of prior prostate surgery, severe trauma, or neurologic illness, is extraordinarily rare. Transurethral resection of the prostate for benign prostatic hyperplasia (see Chap. 82) may also lead to SUI in men.

Bladder Overactivity (Urge Urinary Incontinence) Bladder overactivity—including bladder filling and urinary storage characterized by involuntary bladder contractions—is termed urge urinary incontinence (UUI). Symptoms of bladder overactivity occur because the detrusor muscle is overactive and contracts inappropriately during the filling phase. The symptoms caused by the overactive bladder are typically urinary frequency, urgency, and urge incontinence. Frequency is defined as emptying the bladder more often than eight times per day. Urgency is described as a sudden, strong desire to urinate. People suffering from bladder overactivity typically have to empty their bladders frequently, and when they experience a sensation of urgency, they may leak urine if they are unable to reach the toilet quickly or if the sensation of urgency is very strong. Many patients may also have associated nocturia (>2 micturitions per night) and/or nocturnal incontinence (enuresis).

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The amount of urine lost may be large, as the bladder may empty completely. Sleep may be disturbed, as the need to void may be experienced during the night. Nocturia and enuresis are often particularly disruptive. Most patients with overactive bladder and UUI have no identifiable underlying etiology. In fact, the most common cause of bladder overactivity and UUI is “idiopathic.” Clearly identifiable risk factors for UUI include normal aging, neurologic disease (including stroke, Parkinson’s disease, multiple sclerosis, and spinal cord injury), and bladder outlet obstruction (e.g., due to benign prostatic hyperplasia [BPH] or prostate cancer). The mechanism for bladder overactivity must be either neurogenic or myogenic. The neurogenic hypothesis ascribes the overactive bladder and UUI to disease-related changes within the central or peripheral nervous system.18 The myogenic hypothesis states that overactive bladder and UUI result from changes within the smooth muscle of the bladder wall itself.19 Precipitating factors such as bladder outlet obstruction can cause a partial denervation of smooth muscle, leading to a state of decreased responsiveness to activation of intrinsic nerves, but supersensitivity to contractile agonists and direct electrical activation.20 However, in practice, UUI is difficult to categorize as either neurogenic or myogenic in origin, as these etiologies often seem to be interconnected and complementary.

Urethral Overactivity and/or Bladder Underactivity (Overflow Incontinence) Overflow incontinence, the result of urethral overactivity and bladder underactivity, is an important but uncommon type of UI in both men and women. Overflow incontinence results when the bladder is filled to capacity at all times but is unable to empty, causing urine to leak from a distended bladder past a normal outlet and sphincter. In the setting of urethral overactivity, the resistance to the flow of urine during volitional voiding is increased, resulting in functional or anatomic obstruction and incomplete bladder emptying. Common causes of urethral overactivity in men include BPH and prostate cancer. In women, urethral overactivity is rare, but may result from cystocele formation, or surgical overcorrection (iatrogenic obstruction) following anti-SUI surgery. In both sexes, overflow UI may be associated with systemic neurologic dysfunction or diseases, such as spinal cord injury or multiple sclerosis. Bladder underactivity may also result in overflow incontinence. Under certain circumstances, the detrusor muscle of the bladder may become progressively weakened and eventually lose the ability to voluntarily contract. In the absence of adequate contractility, the bladder is unable to empty completely, and large volumes of residual urine

URINARY INCONTINENCE

are left after micturition. Both myogenic and neurogenic factors have been implicated in producing the impaired contractility seen in this condition. Clinically, overflow incontinence is most commonly seen in the setting of long-term chronic bladder outlet obstruction in the male such as that due to BPH or prostate cancer.

Mixed Incontinence and Other Types of Urinary Incontinence Various types of UI may coexist in the same patient. The combination of bladder overactivity and urethral underactivity is termed mixed incontinence. This is often a difficult diagnosis to make because of the often-confusing array of presenting symptoms. Bladder overactivity may also coexist with impaired bladder contractility. This is most common in the elderly and is termed detrusor hyperactivity with impaired contractility.21 Functional incontinence is not caused by bladder- or urethraspecific factors. Rather, in patients with conditions such as dementia or cognitive or mobility deficits, the UI is linked to the primary disease process more than any extrinsic or intrinsic deficit of the lower urinary tract. An example of functional incontinence occurs in the postoperative orthopedic surgery patient. Following extensive orthopedic reconstructions such as total hip arthroplasty, patients are often immobile secondary to pain or traction. Therefore the patient may be unable to access toileting facilities in a reasonable period of time and may become incontinent as a result. The treatment of this type of UI may involve only placing a urinal or commode at the bedside that allows for simplified access to toileting. Finally, many localized or systemic illnesses may also result in UI because of their effects on the lower urinary tract or the surrounding structures, including: r r r r r r r r r

Dementia/delirium Depression Urinary tract infection (cystitis) Postmenopausal atrophic urethritis or vaginitis Diabetes mellitus Neurologic disease (e.g., stroke, Parkinson’s disease, multiple sclerosis, or spinal cord injury) Pelvic malignancy Constipation Congenital malformations

1 Many commonly used medications may also precipitate or aggravate existing voiding dysfunction and UI (Table 83–1).

TABLE 83–1. Medications Influencing Lower Urinary Tract Function Medication Diuretics α-Receptor antagonists α-Receptor agonists Calcium channel blockers Narcotic analgesics Sedative hypnotics Antipsychotics Anticholinergics Antidepressants, tricyclic Alcohol Angiotensin-converting enzyme inhibitors (ACEIs)

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Effect Polyuria, frequency, urgency Urethral relaxation and stress urinary incontinence in women Urethral constriction and urinary retention in men Urinary retention Urinary retention from impaired contractility Functional incontinence caused by delirium, immobility Anticholinergic effects and urinary retention Urinary retention Anticholinergic effects, α-antagonist effects Polyuria, frequency, urgency, sedation, delirium Cough as a result of ACEIs may aggravate stress urinary incontinence by increasing intra-abdominal pressure

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CLINICAL PRESENTATION CLINICAL PRESENTATION OF URINARY INCONTINENCE RELATED TO URETHRAL UNDERACTIVITY GENERAL The patient usually notes UI during activities like exercise, running, lifting, coughing, or sneezing. Much more common in females (seen only in males with lower urinary tract surgery or injury compromising the sphincter). SYMPTOMS Urine leakage with physical activity (volume is proportional to activity level). No UI with physical inactivity, especially when supine (no nocturia). May develop urgency and frequency as a compensatory mechanism (or as a separate component of bladder overactivity). DIAGNOSTIC TESTS Observation of urethral meatus while patient coughs or strains.

CLINICAL PRESENTATION OF URINARY INCONTINENCE RELATED TO BLADDER OVERACTIVITY GENERAL Can have bladder overactivity and UI without urgency if sensory input from the lower urinary tract is absent. SYMPTOMS Urinary frequency (>8 micturitions/day), urgency with or without urge incontinence; nocturia (≥2 micturitions/night) and enuresis may be present as well. DIAGNOSTIC TESTS Urodynamic studies are the gold standard for diagnosis. Also urinalysis and urine culture should be negative (rule out urinary tract infection as cause of frequency).

CLINICAL PRESENTATION OF URINARY INCONTINENCE RELATED TO URETHRAL OVERACTIVITY AND/OR BLADDER UNDERACTIVITY GENERAL Important but rare type of UI in both sexes. Urethral overactivity usually due to prostatic enlargement (males) or cystocele formation or surgical overcorrection following antiurethral underactivity (stress incontinence) surgery (females). SYMPTOMS Lower abdominal fullness, hesitancy, straining to void, decreased force of stream, interrupted stream, sense of incomplete bladder emptying. May have urinary frequency and urgency, too. Abdominal pain if acute urinary retention is also present. SIGNS Increased postvoid residual urine volume.

DIAGNOSTIC TESTS Digital rectal exam or transrectal ultrasound to rule out prostatic enlargement. Renal function tests to rule out renal failure due to acute urinary retention.

2 UI may present in a number of ways, depending on the under-

lying pathophysiology. Generally, SUI is considered the most common type of UI and probably accounts for at least a portion of UI in more than half of all incontinent females. Some studies have found that mixed UI (SUI + UUI) represents the most common type of UI.6 However, the proportions of SUI versus UUI versus mixed UI vary considerably with age group and sex of patients studied, study methodology, and a variety of other factors. A complete medical history, including an assessment of symptoms and a physical examination, is essential in correctly classifying the type of incontinence and thereby assuring appropriate therapy.

URINE LEAKAGE UI represents a spectrum of severity in terms of both volume of leakage and degree of bother to the patient. To carefully consider the level of patient discomfort when discussing urine leakage, the clinician must probe during the patient interview to accurately determine the precise nature of the problem. The use of absorbent products such as panty liners, pads, or briefs is an obvious point to discuss, but the clinician must keep in mind that their use varies among patients. The number and type of pads may not relate to the amount or type of incontinence, as their use is a function of personal preference and hygiene. A high number of absorbent pads may be used every day by a patient with severe, high-volume UI, or alternatively, by a fastidiously hygienic patient with low-volume leakage who simply changes pads often to avoid a sense of wetness or odor. Nevertheless, a large number of pads that are described by the patient as “soaked” is indicative of high-volume urine loss. Regardless of the volume of urine loss, the desire to seek evaluation and therapy for UI in all patients is almost always elective and contingent on the degree of bother to the individual patient. As with use of absorbent products, patients differ in the amount of urine loss they will tolerate before considering the condition bothersome enough to seek assistance.

SYMPTOMS Under the best of circumstances, UI is difficult to categorize based on symptoms alone (Table 83–2).22 In a study of patients who appeared to have SUI based on symptoms and patient history, urodynamics showed that only 72% of patients had SUI as the sole cause of incontinence.23 Patients with urethral underactivity or SUI characteristically complain of urinary leakage with physical activity. Volume of leakage is proportional to the level of activity. They will often leak urine during periods of exercise, coughing, sneezing, lifting, or even when rising from a seated to a standing position. Patients with pure SUI will not have leakage when physically inactive, especially when they are supine. Often they will have little or no UI at night, will not awaken to void during the night (nocturia), will not wet the bed, and often do not even wear absorbent products at bedtime. Urinary urgency and frequency may be associated with SUI, either as a separate component caused by bladder overactivity (mixed incontinence), or as a

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TABLE 83–2. Differentiating Bladder Overactivity from Urethral Underactivity Bladder Overactivity

Symptoms Urgency (strong, sudden desire to void) Frequency with urgency Leaking during physical activity (e.g., coughing, sneezing, lifting) Amount of urinary leakage with each episode of incontinence Ability to reach the toilet in time following an urge to void Nocturnal incontinence (presence of wet pads or undergarments in bed) Nocturia (waking to pass urine at night) Adapted from Rovner et al.

Urethral Underactivity

Yes Yes No

Sometimes Rarely Yes

Large if present

Usually small

No or just barely Yes

Yes Rare

Usually

Seldom

22

compensatory mechanism wherein the patient with SUI learns to toilet frequently to avoid large-volume urine loss during physical activity. Typical symptoms of bladder overactivity include frequency, urgency, and urge incontinence. Nocturia and nocturnal incontinence are often present. Urine leakage is unpredictable and the volume loss may be large. Patients will often wear protection both day and night. Urinary frequency can be affected by a number of factors unrelated to bladder overactivity, including excessive fluid intake (polydipsia) and bladder hypersensitivity states such as interstitial cystitis and urinary tract infection, and these should be ruled out. In some patients, bladder overactivity may manifest as UI without awareness in the absence of a sense of urinary urgency or frequency. Urinary urgency, a sensation of impending micturition, requires intact sensory input from the lower urinary tract. In patients with spinal cord injury, sensory neuropathies, and other neurologic diseases, a diminished ability to perceive or process sensory input from the lower urinary tract may result in bladder overactivity and UI without urgency or urinary frequency. When the bladder contraction occurs without warning and sensation is absent, the condition is referred to as reflex incontinence. Patients with overflow incontinence may present with lower abdominal fullness as well as considerable obstructive urinary symptoms, including hesitancy, straining to void, decreased force of urinary stream, interrupted stream, and a vague sense of incomplete bladder emptying. These patients may also have a significant component of urinary frequency and urgency. In patients with acute urinary retention and overflow incontinence, lower abdominal pain may also be present. Although these symptoms are not specific for overflow incontinence, they may warrant further investigation including an assessment of postvoid residual urine volume.

SIGNS A presenting complaint of UI mandates a directed physical examination and a brief neurologic assessment. This should ideally include an abdominal examination to exclude a distended bladder, a neurologic assessment of the perineum and lower extremities, a pelvic exam in women (looking especially for evidence of prolapse or hormonal deficiency), and a genital and prostate examination in men. SUI can usually be objectively demonstrated by having the patient cough or strain during the examination and observing the urethral meatus for a sudden spurt of urine. In women, SUI may be associated with varying degrees of vaginal prolapse including cystourethrocele (bladder and urethral prolapse), enterocele (small bowel prolapse),

rectocele (rectal prolapse), and uterine prolapse. These conditions may have important implications for therapy. Perineal skin maceration, erythema, breakdown, and ulceration may be indicative of chronic, severe UI. Patients with chronic incontinence may also manifest fungal infections of the skin of the perineum and upper thighs. In both sexes, digital rectal examination provides an opportunity to check ambient rectal tone, the integrity of the sacral reflex arc (e.g., anal wink), as well as assess the patient’s ability to perform a voluntary pelvic floor muscle contraction (i.e., Kegel exercise), which may be an important factor in deciding on appropriate therapy. In men, a digital examination of the prostate assesses for the presence of prostate cancer, inflammation, and BPH. A targeted neurologic examination includes an assessment of reflexes, rectal tone, and sensory or motor deficits in the lower extremities, which might be indicative of systemic or localized neurologic disease. As noted previously, neurologic diseases have the potential to affect bladder and sphincter function and thus may have significant implications in the incontinent patient.

PRIOR MEDICAL OR SURGICAL ILLNESS UI may present in the setting of concurrent, seemingly unrelated illnesses. New-onset UI may be the initial manifestation of certain systemic illnesses such as diabetes mellitus, metastatic malignancies, multiple sclerosis, and other neurologic illnesses. Central nervous system disease, or injury above the level of the pons, generally results in symptoms of bladder overactivity and UUI. Spinal cord injury or disease may manifest as bladder overactivity and UUI or as overflow incontinence, depending on the spinal level and completeness of the injury or disease. Medications may have wide-ranging effects on lower urinary tract function (see Table 83–1). A thorough inquiry into the use of new medications in the setting of recent-onset UI may show a relationship. Acute UI manifest in the immediate postoperative setting may be secondary to a number of factors, including surgical manipulation and immobility, and to a number of medications, including analgesics. In the postoperative setting, acute urinary retention and overflow incontinence is commonly related to the administration of anesthetic agents and/or opioid analgesics in the perioperative period. These agents may have profound effects on bladder contractility that are completely reversible once the agents are metabolized and excreted. Prior surgery may have effects on lower urinary tract function. UI following prostate surgery in men is very suggestive of injury to the

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sphincter and resultant SUI. Pelvic surgery for benign and malignant conditions may result in denervation or injury to the lower urinary tract. This includes bowel surgery and gynecologic procedures. For example, new-onset total UI following gynecologic surgery for uterine fibroids suggests the possibility of intraoperative bladder injury and subsequent development of a postoperative vesicovaginal fistula. Radiation therapy to the pelvis for malignant disease (e.g., prostate cancer or cervical cancer) may result in injury to the bladder or urethra and subsequent UI. In women, UI may be related to several gynecologic factors, including childbirth, hormonal status, and prior gynecologic surgery. Pregnancy and childbirth, particularly vaginal delivery, are associ-

ated with SUI and pelvic prolapse. Significant SUI in the nulliparous woman is rather uncommon. UI that becomes progressive at or around menopause suggests a hormonal component that may potentially be responsive to estrogen or hormone replacement therapy. Finally, UI may present in the setting of other significant pelvic floor disorders, signs, and symptoms. Constipation, diarrhea, fecal incontinence, dyspareunia, sexual dysfunction, and pelvic pain may be related to UI. A history of gross hematuria in the setting of UI mandates further urologic investigation, including radiologic imaging of the upper urinary tract and cystoscopy. Acute dysuria with or without hematuria in the setting of UI suggests cystitis. A urinalysis and urine culture should be performed in these patients.


TREATMENT: Urinary Incontinence
NONPHARMACOLOGIC TREATMENT 3 Nonpharmacologic treatment of UI constitutes the chief form of

incontinence management at a primary care level. For patients in whom pharmacologic or surgical management is inappropriate or undesired, nondrug treatment is the only option. Examples of patients fulfilling these criteria include patients who are not medically fit for surgery or those who plan future pregnancies (as these may adversely affect long-term surgical outcomes); those with overflow incontinence whose condition is not amenable to surgery or drug therapy; those with comorbid conditions that place them at high risk for adverse effects from drug therapy; those who are delaying surgery or do not want to undergo surgery; and those with mild to moderate symptoms who do not want to take medication. For additional information on nonpharmacologic interventions for UI, readers are referred to comprehensive literature reviews and consensus opinions of treatment guidelines on nonpharmacologic interventions by multidisciplinary experts.24 Table 83–3 summarizes the basic nondrug approaches. Behavioral interventions are the first line of treatment for SUI, UUI, and mixed UI. These include lifestyle modifications, scheduling regimens, and pelvic floor muscle rehabilitation. Because the key to the success with any type of behavioral intervention is the motivation of the patient or caregiver, these individuals must be active participants in developing a treatment plan. Regular follow-up is needed to help motivate patients and caregivers, provide reassurance and support, and to monitor treatment outcomes.


PHARMACOLOGIC TREATMENT
URGE URINARY INCONTINENCE Pharmacotherapy is useful when UUI symptoms are not adequately controlled with nonpharmacologic therapies, particularly in patients with a low functional bladder capacity. In many cases, the combined use of pharmacotherapy with nonpharmacologic therapy produces a better response than either intervention alone. 4 Proven to be the most effective agents in suppressing premature detrusor contractions, enhancing bladder storage, and relieving UUI symptoms and complications, anticholinergic/antispasmodic drugs constitute the pharmacotherapy of first choice for UUI (Tables 83–4 and 83–5).25−44 Drugs with anticholinergic activity act by antagonizing muscarinic cholinergic receptors, through which efferent

parasympathetic nerve impulses evoke detrusor contraction. In addition, women with mixed UI or UUI plus urethritis or vaginitis may benefit from a topical or systemic estrogen (alone or in combination with an anticholinergic drug).


Immediate-Release Oxybutynin Even though a substantial proportion of patients may discontinue oxybutynin immediate-release (IR) therapy because of its nonurinary antimuscarinic effects, oxybutynin IR remains the drug of first choice for UUI and the gold standard against which other drugs are compared. In addition to these antimuscarinic effects (e.g., dry mouth, constipation, vision impairment, confusion, cognitive dysfunction, and tachycardia), oxybutynin IR is associated with orthostatic hypotension secondary to α-adrenergic receptor blockade, as well as sedation and weight gain from histamine H1 -receptor blockade.26,31,45−49 Furthermore, adverse effects jeopardize medication adherence and can prevent dose escalation to that needed for optimal benefit. Emerging evidence suggests that the high incidence of adverse effects, especially dry mouth, of oxybutynin IR, and to a lesser extent oxybutynin extended-release (XL) and oxybutynin transdermal system (TDS), may be largely due to the active metabolite, N-desethyloxybutynin (DEO). This metabolite is generated by extensive first-pass metabolism in the liver and upper gastrointestinal tract.50 Since many of the adverse effects seen with oxybutynin are felt to be related to the primary hepatic metabolite DEO, the lower DEO plasma concentrations seen with oxybutynin TDS and oxybutynin XL (which are due to reduced first-pass metabolism) compared to those of oxybutynin IR may explain their lesser propensity to cause dry mouth and other anticholinergic adverse effects. Another factor associated with the adverse effects of oxybutynin IR, especially in older patients, is the transient high peak serum oxybutynin plasma concentration and area under the plasma concentrationversus-time curve (AUC), which is twofold higher in elderly patients than in younger adults, after both single and multiple doses.51 Oxybutynin IR is best tolerated when the dose is gradually escalated from no more than 2.5 mg twice daily to start, to 2.5 mg three times daily after 1 month, then further increased in increments of 2.5 mg/day every 1 to 2 months until the desired response or the maximum recommended or tolerated dose is attained. The optimal response usually requires no more than 5 mg three times daily (see Table 83–4).26,52 Adverse effects of oxybutynin IR can sometimes be managed by a dose reduction if this does not significantly compromise drug efficacy. Dry mouth can be relieved by the use of sugarless hard

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TABLE 83–3. Nonpharmacologic Management of Urinary Incontinence Intervention

Description

Lifestyle modifications

Self-management strategies targeted toward reducing or eliminating risk factors that cause or exacerbate urinary incontinence

Smoking cessation for patients with cough-induced stress incontinence; weight reduction for obese patients with stress incontinence; good bowel hygiene for patients with constipation; caffeine reduction, selected dietary and fluid modifications for patients with urge incontinence (e.g., eliminate aspartame, spicy foods, citrus fruits, carbonated beverages)

Toileting on a fixed schedule whose interval does not change, typically every 2 hours during waking hours

Used for stress, urge, and mixed incontinence in patients with cognitive or physical impairments; also used in patients without impairments who have infrequent voiding patterns Used for stress, urge, and mixed incontinence in institutionalized or homebound patients with cognitive or physical impairments; may also be used in patients who have diuretic-induced incontinence Used for stress, urge, and mixed incontinence in institutionalized and homebound elderly populations

Scheduling regimens Timed voiding

Habit retraining

Scheduled toiletings with adjustments of voiding intervals (longer or shorter) based on patient’s voiding pattern

Patterned urge response A specialized type of habit training that involves the use of toileting (PURT) an electronic monitoring device to identify the timing of incontinent episodes Prompted voiding Scheduled toiletings that require prompts to void from a caregiver, typically every 2 hours; patient assisted in toileting only if response is positive; used in conjunction with operant conditioning techniques for rewarding patients for maintaining continence and appropriate toileting Bladder training Scheduled toiletings with progressive voiding intervals; includes teaching of urge control strategies using relaxation and distraction techniques, self-monitoring, and use of reinforcement techniques; sometimes combined with drug therapy Pelvic floor muscle rehabilitation Pelvic floor muscle Regular practice of pelvic floor muscle contractions; may exercises (e.g., involve use of pelvic floor muscle contraction for urge Kegel exercises) inhibition

Patient Characteristics

Used for stress, urge, and mixed incontinence in patients who are functionally able to use toilet or toilet substitute, able to feel urge sensation, and able to request toileting assistance appropriately; primarily used in institutional settings or in homebound patients with an available caregiver Used for stress, urge, and mixed incontinence in patients who are cognitively intact, able to toilet, and motivated to comply with training program

Used for stress, urge, and mixed incontinence in patients who can correctly contract their pelvic floor muscles without use of accessory muscles; requires a cognitively intact and highly motivated patient Vaginal weight training Active retention of increasing vaginal weights; typically Women with stress incontinence who are cognitively used in combination with pelvic floor muscle exercises intact, can correctly contract pelvic floor muscles, able to at least twice a day stand, and who have sufficient vaginal vault and introitus to retain cone and are highly motivated; contraindicated in patients with moderate to severe pelvic organ prolapse Biofeedback Use of electronic or mechanical instruments to display Used for stress, urge, and mixed incontinence in patients visual or auditory information about neuromuscular or who are able to understand analog or digital signals, bladder activity; used to teach correct pelvic floor who are motivated, and who have the capability to learn muscle contraction and/or urge inhibition voluntary control through observation Nonimplantable Application of electrical current to sacral and pudendal Used for stress, urge, and mixed incontinence in patients electrical stimulation afferent fibers through vaginal, anal, or surface who are highly motivated; contraindicated in patients electrodes; used to inhibit bladder overactivity and to with diminished sensory perception, moderate or severe improve awareness, contractility, and efficiency of pelvic pelvic organ prolapse; urinary retention, history of muscle contraction cardiac arrhythmia, or demand cardiac pacemaker Extracorporeal magnetic Pulsed magnetic stimulation to pelvic floor musculature Initially tested in women with stress incontinence; innervation causing depolarization of motor neurons, thus inducing contraindicated in patients with demand cardiac pelvic floor muscle contraction; stimulation is provided pacemakers, or with metallic joint replacements; may be through a specially designed chair that contains a device useful treatment option when other approaches fail or for producing a pulsing magnetic field (e.g., Neotonus, are not feasible Inc., Marietta, GA) Anti-incontinence devices Intravaginal support Pessaries and other intravaginal devices designed to Used for female stress incontinence; in postmenopausal device (pessaries and support the bladder neck, relieve minor pelvic organ women, estrogen replacement is typically prescribed to bladder neck support prolapse, and change pressure transmission to the prevent ulceration and breakdown of vaginal tissue; prostheses) urethra (e.g., Coloplast AS, Humelbaek, Denmark) requires good manual dexterity to manipulate device (continued)

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TABLE 83–3. (Continued ) Intervention External occlusive device

Intraurethral occlusive device (urethral plug)

Complex valved catheter (investigational)

Description

Patient Characteristics

Small, single-use device that covers the urethral meatus Used for female and male stress incontinence; used in which is removed for voiding in women (e.g., FemAssist, cognitively intact patients with good manual dexterity Apple Medical, Marlboro, MA; CapSure, Bard Urological, Covington, GA); a penile clamp (e.g., Cunningham clamp) is available for men Small, single-use device that is worn in the urethra to Used for female stress incontinence patients who are provide mechanical obstruction to prevent urine cognitively intact with good manual dexterity; leakage; removed for voiding (e.g., FemSoft Insert, contraindicated with primary urge incontinence, urinary Rochester Med. Corp., Stewartville, MN) tract infection, urethral stricture, and any anatomic or pathologic condition making catheter passage difficult Intraurethral occlusive device that has a unidirectional Female stress incontinence and overflow incontinence valve that can be opened to permit voiding and resealed; may be left indwelling over a longer period of time than intraurethral occlusive devices, but requires a clinician to insert and remove; several devices are currently undergoing testing

Supportive interventions Toileting substitutes Urinals, bedside commodes, elevated toilet seats and other environmental modifications Physical therapy Gait and/or strength training Absorbent products

External collection devices (men only) Catheters

Used for patients with mobility impairments that make it difficult to reach a toilet in a timely fashion

Variety of reusable and disposable pads and pant systems; some products contain a polymer that absorbs urine and wicks it away from the body Condom catheter with leg bag Disposable, intermittent catheters and indwelling urethral and suprapubic catheters

candy, gum, or a saliva substitute. Constipation can be minimized by increasing the intake of water, dietary fiber, physical activity such as walking, or laxative therapy. The need for multiple daily dosing of oxybutynin IR can further jeopardize adherence, especially in people who take multiple medications or those who are cognitively impaired.


Extended-Release Oral Oxybutynin Because of problems noted with oxybutynin IR, oxybutynin extendedrelease (XL) was developed. It can be considered an alternative for the first-line therapy of UUI (see Table 83–5). Oxybutynin XL (Ditropan XL) is an extended-release formulation of oxybutynin.53 Its extended-release system consists of an osmotically active bilayer core (comprising a drug layer and a push layer containing osmotically active components) surrounded by a semipermeable membrane. Throughout the gastrointestinal tract, water permeates through the rate-controlling membrane into the tablet core, causing the drug to go into suspension and the push layer to expand, pushing the suspended drug out through an orifice.31 Following oral administration, oxybutynin XL is completely absorbed, and neither the rate nor extent of absorption are significantly affected by administration with food. Unlike oxybutynin IR, oxybutynin XL delivers a controlled amount of oxybutynin chloride continuously throughout the gastrointestinal tract over a 24-hour time period, reducing first-pass metabolism by cytochrome P450 (CYP450) isoenzyme 3A4, which is

Used for frail elderly patients with mobility impairments that make it difficult to reach a toilet in a timely fashion Used for all types of incontinence

Used in men with urge, stress, and overflow incontinence and in those with functional impairments Used for overflow incontinence; also used in patients who are bed-bound or with significant mobility impairments and severe incontinence, those with terminal illness, and those with sacral pressure ulcers until healing occurs

present in higher concentrations in the upper portion of the small intestine than the lower gastrointestinal tract.53,54 This results in relative bioavailabilities of oxybutynin and its active N-desethyloxybutynin metabolite of 153% and 69%, respectively, for oxybutynin XL compared with oxybutynin IR.55 The greater ratio of parent drug to active metabolite after oxybutynin XL administration, and probably less importantly a lower peak plasma drug concentration, are believed to be the reasons for fewer dose- and concentration-dependent adverse effects and better patient tolerance with the XL preparation as compared to oxybutynin IR.56 The elimination of oxybutynin XL is not known to be altered in patients with renal or hepatic impairment or in geriatric patients (up to 78 years of age).53 The absence of an effect of advanced age on oxybutynin XL pharmacokinetics is unexpected since the clearance of oxybutynin IR is significantly lower in elderly individuals. Controlled studies have demonstrated that oxybutynin XL is significantly more effective than placebo and equally effective as oxybutynin IR in terms of reducing the mean number of UI episodes, restoring continence, decreasing the number of micturitions per day, and increasing urine volume voided per micturition (see Table 83–5).30,31,45−47,57−59 In short-term studies of up to 12 weeks’ duration, oxybutynin XL was better tolerated than oxybutynin IR, with approximately 7% of patients discontinuing treatment because of adverse effects (as compared to approximately 27% in those taking oxybutynin IR).26,31,45,46,52,53 The rate and severity of adverse effects did not differ significantly between elderly persons (65 years of age and older) and younger adults

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TABLE 83–4. Pharmacotherapeutic Options in Patients with Urinary Incontinence Type Overactive bladder

Drug Class Anticholinergic agents/antispasmodics

Tricyclic antidepressants (TCAs)

Topical estrogen (only in women with urethritis or vaginitis)

Drug Therapy (Usual Dose) Oxybutynin IR (2.5–5 mg two, three or four times a day), oxybutynin XL (5–30 mg daily), oxybutynin TDS (3.9 mg/day) (apply 1 patch twice weekly), tolterodine IR (1–2 mg twice a day), tolterodine LA (2–4 mg daily), trospium chloride 20 mg twice a day, solifenacin 5–10 mg daily, darifenacin 7.5–15 mg daily Imipramine, doxepin, nortriptyline, or desipramine (25–100 mg at bedtime) Conjugated estrogen 0.5 g vaginal cream three times per week for up to 8 months. Repeat course if symptom recurrence. Or use estradiol vaginal insert/ring [2 mg (1 ring)] and replace after 90 days if needed. 40–80 mg/day (1 or 2 doses)

Dual serotoninnorepinephrine reuptake inhibitors

Duloxetinea

Stress

α-Adrenergic agonists

Pseudoephedrine (15–60 mg three times a day) with food, water, or milk

Estrogen

See estrogens (above). Works best if urethritis or vaginitis are present.

Imipramine

25–100 mg at bedtime

Cholinomimetics

Bethanechol (25–50 mg three or four times a day) on an empty stomach

Overflow (atonic bladder)

Comments Anticholinergics are the first-line drug therapy (oxybutynin or tolterodine are preferred).

TCAs are generally reserved for patients with an additional indication (e.g., depression, neuralgia) Marginally effective. Few adverse effects with cream and vaginal insert

Once approved, will become first-line therapy. Most adverse events diminish with time so support patient during initial period of use Pseudoephedrine is first-line therapy for women with no contraindication (notably hypertension) (second-line once duloxetine is approved) Phenylpropanolamine was the preferred agent until its removal from the U.S. market in 2000. Considered a somewhat less-effective alternative to pseudoephedrine. Combined pseudoephedrine and estrogen is somewhat more effective than pseudoephedrine alone in postmenopausal women. Imipramine is an optional therapy when first-line therapy is inadequate. Avoid use if patient has asthma or heart disease. Short-term use only. Never give IV or IM because of life-threatening cardiovascular and severe gastrointestinal reactions.

IR, immediate-release; LA, long-acting; XL, extended-release, TDS, transdermal system. a Investigational. Doses provided are those best supported by clinical trials to date.

with the XL preparation. A 12-week study demonstrated the superiority of oxybutynin XL over tolterodine IR in reducing the mean number of weekly incontinent episodes and micturitions.39 In the OPERA trial, oxybutynin XL was comparable to tolterodine long-acting (LA) in decreasing the mean number of incontinence episodes, but was superior in reducing weekly micturition frequency and achieving total dryness.60 In another study that pooled results of two open-label studies, tolterodine LA was associated with significantly greater patient-perceived improvement in bladder control and fewer withdrawals due to adverse effects than oxybutynin XL.

However, the treatments were similar in patients’ or physicians’ perception of benefit over baseline and proportions of withdrawals due to lack of efficacy. However, the lack of blinding may have introduced patient and observer bias.61 Oxybutynin XL, available only in a tablet formulation, is administered once daily, with or without food, and should not be crushed or chewed (see Table 83–4). Like oxybutynin IR, the dosage does not require adjustment in patients of advanced age, or in patients with renal or hepatic impairment. However, treatment should still be initiated at the smallest recommended dosage in the elderly (5 mg once daily).32,53

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TABLE 83–5. Efficacy of First-Choice Drugs for Bladder Overactivity in Placebo-Controlled Trialsa

Drug

Decreased Incontinence Episodes

Restored Continence

Decreased Frequency of Micturitions

Increased Volume per Void

24–52 47 10–20 16–33 23

16–67 37 6–17 9 NR

−2 to −63 1 4–6 4–19 6

9–24 13 12–14 11–20 14

Oxybutynin IR Oxybutynin XL Oxybutynin TDS Tolterodine Tolterodine LA

a All values constitute mean or median drug effect (drug response minus placebo response in percent), predominantly using poled data from multiple independent studies. IR, immediate-release; LA, long-acting; NR, not reported; XL, extended-release; TDS, transdermal system.

The maximum benefit of oxybutynin XL may not be realized for up to 4 weeks after starting therapy or after dose escalation. No known clinically relevant drug-drug interactions with either oxybutynin XL or oxybutynin IR have been identified. However, other drugs with anticholinergic activity may increase overall anticholinergic effects (i.e., produce an additive or synergistic pharmacodynamic interaction), as would be expected.53 Another potential pharmacodynamic interaction involves the mutual antagonism of anticholinergic agents and cholinergic stimulants such as the acetylcholinesterase inhibitors used to treat dementia.


Extended-Release Transdermal Oxybutynin The oxybutynin transdermal system (Oxytrol), which delivers 3.9 mg per day, is applied twice weekly (every 3 or 4 days). Transdermal absorption of oxybutynin from this formulation bypasses first-pass hepatic and gut metabolism, resulting in similar oxybutynin but lower plasma N-desethyloxybutynin concentrations than after administration of an equivalent dose via the oral route.50,62 Similar findings have been noted for the active R-enantiomer of N-desethyloxybutynin.63 No dosage adjustment of the TDS product for advancing age is necessary.44 Oxybutynin TDS is superior to placebo in reducing incontinence episodes and number of micturitions and increasing the volume voided per micturition.43,44 It is also similar to oxybutynin IR in reducing the frequency of UUI episodes and improving patient-perceived urinary leakage.64 Oxybutynin TDS and tolterodine LA are significantly superior to placebo and similar to each other in reducing the frequency of UUI episodes, increasing the volume voided per micturition, attaining complete continence, and improving quality of life.43 The commonest adverse effects with the TDS formulation are pruritus (15%) and erythema (9%) at the application site. The events of dry mouth (11%), constipation (5%), dizziness (5%), and abnormal vision ( 17,000; heart > 3200). Median waiting time for a cadaveric kidney is over 3 years. For liver transplantation the median time to transplant is over 2 years, whereas for heart transplantation it is approximately 6 months. For both heart and liver transplantation, clinical status is an important factor affecting waiting times, with the sickest patients receiving priority for available organs. In order to increase the number of organs available for transplantation, several strategies have been employed. The use of living donors for renal transplantation represents almost half of all kidney transplants. Between 1998 and 2001, the number of living liver transplants increased over 700%. Efforts to expand the cadaveric donor pool include relaxation of age restrictions, development of better preservations solutions, use of “marginal” and non-heart beating donors, and the use of split livers. Procurement of donor hearts with longer ischemic times, those with borderline left ventricular function, and even those with mild coronary artery disease amenable to bypass grafting

IL-2. The adverse effects associated with sirolimus include thrombocytopenia, anemia, and hyperlipidemia. face of T cells. The effect on T cells and adverse effects depend on the receptor targets.

10 Long-term allograft and patient survival is limited by

chronic rejection, cardiovascular disease, and long-term immunosuppressive complications, such as malignancy.

have all been considered in an effort to increase the supply.2 The use of heart donors older than 45 years of age is associated with a higher risk for 1-year mortality, but this must be viewed in the context of the higher risk of death with longer time on the waiting list if only younger donors are used.1 Despite all these efforts, patients continue to die awaiting transplant. In 2001, over 6000 people died on transplant waiting lists. While renal dialysis may be used for an extended period of time to partially replace the function of the kidneys, such options are not readily available for all liver and heart transplant candidates. Hepatocyte transplantation and artifical liver support are areas of research as alternatives or bridges to liver transplantation.3 Left-ventricular assist devices (LVADs) are now used commonly as a bridge to transplantation for many heart transplant candidates. Patient and graft survival rates following transplantation have improved significantly over the past 30 years as a result of advances in pharmacotherapy, surgical techniques, organ preservation, and the postoperative management of patients. (Table 87–1). In this chapter the epidemiology of endstage kidney, liver and heart disease is presented, the pathophysiology of organ rejection is reviewed, the pharmacotherapeutic options for the generation of individualized immunosuppressive regimens are critiqued and the unique complications of these regimens along with the therapeutic challenges they present are discussed. 1613

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TABLE 87–1. Organ-Specific Waiting Times for Transplant and Patient and Graft Survival Rates

Organ Kidney Living donor Cadaveric donor Liver Living donor Cadaveric donor Heart

Median Waiting Time (days)

Patient Survival (%)

Graft Survival (%)

1 Year

5 Years

1 Year

5 Years

97.5 94.2

90.1 80.7

94.3 88.7

78.6 65.7

86.9 86.3 85.6

84.2 72.1 72

79.3 80.6 85.3

78.1 64.1 70.6

1,144a

412

141

a

Based on data from 1999; inadequate follow-up for 2002 data. From ref. 1.

EPIDEMIOLOGY AND ETIOLOGY KIDNEY The number of people diagnosed with end-stage kidney disease (ESKD) in 2002 exceeded 400,000. There were over 100,000 new cases of ESKD in 2002. The primary therapeutic options for these individuals are hemodialysis, peritoneal dialysis, and/or renal transplantation. Renal transplantation is the preferred long-term therapeutic option for most patients with ESKD because it provides patients with the greatest potential improvement in overall quality of life. Dialysis catheter–related infections, update peritoneal dialysis–associated peritonitis, and scheduled dialysis treatments are avoided, and dietary restrictions are fewer. While the analysis of quality of life is complex, patients generally report improved quality of life following transplantation as compared with patients on maintenance dialysis.4 The most commonly reported causes of ESKD, diabetes mellitus, hypertension, and glomerulonephritis account for about 80% of all kidney transplants (see Chap. 44).5 Patients with medical conditions such as unstable cardiac disease or recently diagnosed malignancy, for whom the risk of surgery or chronic immunosuppression would be greater than the risks associated with chronic dialysis, are excluded from consideration for transplantation.

LIVER Noncholestatic cirrhosis (hepatitis C, alcoholic cirrhosis, hepatitis B, cryptogenic cirrhosis, and autoimmune hepatitis) accounts for approximately 60% of liver transplant recipients (see Chap. 37).1 Other indications for liver transplantation include primary biliary cirrhosis, primary sclerosing cholangitis, acute hepatic failure, primary liver cancer, and inborn errors of metabolism such as α 1 -antitrypsin deficiency, Wilson’s disease, tyrosinemia, types I, III, and IV glycogen storage disease, type I hyperoxaluria, and hemophilia A and B. Pediatric liver transplantation has been performed primarily for biliary atresia and inborn errors of metabolism. Timing of the transplant is critical for correction of the metabolic disease in order to prevent irreversible damage to the end organ (e.g., central nervous system in ornithine transcarbamylase deficiency) or to prevent hepatocellular carcinoma (e.g., tyrosinemia). In an effort to better allocate the available livers, a system based on the MELD (Model for End-stage Liver Disease) score has been adapted by the United Network for Organ Sharing (UNOS). This score, based on serum creatinine concentration, total serum bilirubin concentration, international normalization ratio (INR), and etiology of cirrhosis, is useful in predicting mortality.

There are few absolute contraindications to liver transplantation. Patients should have a reasonable life expectancy after transplantation. While hepatitis B and C can recur in the transplanted liver, these are not absolute contraindications to liver transplantation.3,6 However, retransplant for hepatitis B or C is highly controversial.

HEART Heart failure affects an estimated 4.9 million Americans, and approximately 400,000 new case are diagnosed each year (see Chap. 14).7 Cardiac transplant candidates typically are patients with end-stage heart failure who have New York Heart Association (NYHA) class III or IV symptoms despite maximal medical management and have an expected 1-year mortality risk of 25% or greater without a transplant.8 Idiopathic cardiomyopathy and ischemic heart disease account for heart failure in almost 90% heart transplant recipients.1 Other less common etiologies include valvular disease (4%), retransplantation for graft atherosclerosis or dysfunction (2%), and congenital heart disease (1.5%). Absolute contraindications to orthotopic cardiac transplantation include the presence of an active infection (except in the case of an infected ventricular assist device, which is an indication for urgent transplantation) or the presence of other diseases (i.e., malignancy) that may limit survival and/or rehabilitation and severe, irreversible pulmonary hypertension.

SURGICAL PROCEDURES Kidney transplantation is generally performed by placing the allograft retroperitoneally in the right iliac fossa. The renal artery and vein are anastamosed to the external iliac artery and vein, respectively, and the donor ureter is connected directly to the bladder. If the donor kidney has not undergone prolonged ischemia, the production of urine immediately follows revascularization. For the most part, native kidneys are not removed.9 The transplanted liver, in contrast to kidney, is placed orthotopically; the recipient’s own liver must be removed. Liver transplant occurs in several phases: removal of recipient liver, donor graft revascularization, and biliary reconstruction. During the anhepatic phase, the patient is placed on venovenous bypass to preserve venous return from the kidney and lower extremities. Size may be a limiting factor in liver transplantation. Donor and recipient are usually matched for size (±20%) to prevent splinting of the diaphragm and pulmonary complications that would result from transplantation of an excessively large liver.10

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Heart transplantation is usually an orthotopic procedure. Leaving most of the atria and septum of the recipient, the patient is placed on cardiopulmonary bypass. The donor heart is implanted by anastamosis of the left atrium to the residual left atrial wall and joining the right atrial wall and septum. The main pulmonary artery is connected to the ascending aorta.11

PHYSIOLOGIC CONSEQUENCES OF TRANSPLANTATION Transplantation is truly lifesaving for heart and liver transplant recipients, whereas renal transplantation is associated with improved quality of life and survival when compared with dialysis.12 Most heart transplant patients return to NYHA functional class I following transplantation. In fact, 89.9% of patients consider themselves to have no limitations on activity at 1-year follow-up; however, not all have returned to work.13 The specific physiologic consequences of kidney, liver, and heart transplantation are discussed below.

KIDNEY TRANSPLANTATION The glomerular filtration rate (GFR) of a successfully transplanted kidney may be near normal almost immediately after transplantation. In some patients, however, the concentration of standard biochemical indicators of renal function, such as serum creatinine and blood urea nitrogen (BUN), may remain elevated for several days. Standard formulas used to predict drug dosing rely on a stable serum creatinine and may be inaccurate immediately following transplantation (see Chap. 41). Although the allograft is able to remove uremic toxins from the body, it may take several weeks for other physiologic complications of chronic renal failure, such as anemia, calcium and phosphate imbalance, and altered lipid profiles, to resolve. The renal production of erythropoietin and 1-hydroxylation of vitamin D may return toward normal early in the postoperative period. Because the onset of physiologic effects may be delayed, continuation of pretransplant calcitriol, calcium supplementation, and/or phosphate binders may be warranted in some patients. Primary nonfunction of a renal allograft or delayed graft function (DGF) is characterized by the need for dialysis in the first 7 postoperative days or the failure of the serum creatinine to fall below 4 mg/dL or by 30% of the pretransplant value. The incidence of DGF in primary cadaveric renal transplantation ranges from 8% to 50% and results in a slower return of the kidney’s excretory, metabolic, and synthetic functions. DGF is associated with prolonged hospital stays, higher costs, difficult management of immunosuppressive therapy, slower patient rehabilitation, and poor graft survival. Urinary complications such as ureteral obstruction, thrombosis, or leak or vascular complications, including arterial or venous stenosis or thrombosis, also may result in early graft dysfunction. The primary cause of DGF is acute tubular necrosis (ATN). The incidence of ATN increases when kidneys are harvested from donors following cardiac arrest, from donors who are hypotensive or on vasopressors, or from older donors. Prolonged periods of ischemia can increase the risk of ATN. The management of patients with ATN may be difficult (see Chap. 42). Cyclosporine and tacrolimus may be implicated in the prolongation of ATN, but a clear cause-and-effect relationship has not been established. Persistently elevated serum creatinine and BUN levels confound the perioperative management of renal transplant recipients.

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Among the differential diagnoses are acute rejection, ATN, and/or cyclosporine or tacrolimus toxicity (see Chap. 46). These processes are not mutually exclusive. Definitive diagnosis is made by renal biopsy. In the presence of an elevated serum creatinine level, clinicians may reduce the dose of cyclosporine or tacrolimus to minimize the potential for drug nephrotoxicity and hasten the recovery from ATN. This practice may result in subtherapeutic immunosuppressant concentrations and hasten the occurrence of acute rejection. DGF predisposes patients to acute rejection. Induction therapy (e.g., using antibody preparations) and delaying the initiation of cyclosporine or tacrolimus administration may be useful in this setting.

LIVER TRANSPLANTATION The physiologic consequences of liver transplantation are complex, involving changes in both metabolic and synthetic function. Postoperatively, the liver transplant recipient likely will have many fluid, electrolyte, and nutritional abnormalities. Biliary tract dysfunction may alter the absorption of fats and fat-soluble drugs.14 The poor absorption of the lipid-soluble drug cyclosporine improves after successful liver transplantation and reestablishment of bile flow. Vitamin E deficiency and its neurologic complications in liver failure patients are reversed after successful liver transplantation in pediatric patients. In stable adult liver transplant patients, the concentrations of retinol and tocopherol are similar to those seen in normal healthy subjects, indicating recovery of transplanted liver production and excretion of bile salts needed for fat-soluble vitamin absorption. The effects of liver metabolism on drug disposition and elimination are summarized in Table 87–2. Failure of the newly transplanted liver occurs in 10% to 15% of cases and can result from several different mechanisms. Early graft failure can result from preexisting disease in the donor, and even coagulation defects have been acquired through donor organs. The technical complexity of the operation can produce flaws in revascularization that also lead to graft nonfunction. Surgical complications occur in about 25% of cases and result in a doubling of the hospital expense for the patient.15 Portal vein thrombosis, hepatic artery thrombosis, and bile duct leaks are all technical problems that have been encountered. Ischemic injury to the donor liver through preservation is difficult to predict and can produce early graft dysfunction. Perioperative immune events rarely lead to the classic picture of hyperacute rejection in liver transplantation, but graft failure in the first 2 postoperative weeks still may indicate antibody-mediated graft destruction.

HEART TRANSPLANTATION The orthotopically transplanted heart is denervated and no longer responds to physiologic stimuli in a normal manner. Patients, for example, do not experience classic angina. In situations requiring an increased heart rate (e.g., exercise or hypotension), the denervated heart is unable to acutely increase heart rate but instead relies on increasing the stroke volume. Later in the course of exercise or hypotension, heart rate increases in response to circulating catecholamines. While the maximum exercise capacity of heart transplant recipients is below normal, most patients are able to resume normal lifestyles and reasonably vigorous activity levels. Partial reinnervation may occur over time, thereby facilitating more normal physiologic (e.g., presence of classic angina) and pharmacologic responses and better exercise capacity.16 In the acute postoperative phase (0–6 weeks), responses present in the normal heart are interrupted or blunted. In the acutely

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TABLE 87–2. Changes in Drug Disposition and Elimination Following Liver Transplantation Result Serum Proteins ↓ Albumin

↑ Alpha-acid glycoprotein Metabolism/Elimination Microsomes

Oxidation Conjugation Biliary dysfunction Renal elimination

Comment

↑ Free fraction of drugs usually bound to albumin

Lower free fraction of drugs-lidocaine

↑ CYP2E1 activity ↔ CYP2D6 ↓ P450 enzymes activity Stable Normalizes after transplant ↓ Absporption of lipophilic compounds ↑ CSA metabolites in blood Elimination of gentamicin, vancomycin, cephalosporins less than predicted by serum creatinine

Diazepam, salicylic acid binding greater in liver transplant than chronic liver disease due to endogenous binding inhibitors (up to 45 days posttransplant)

Increased drug metabolism (induction) Unaffected Decreased drug elimination (inhibition) Renal elimination of metabolites limited

CYP = cytochrome P450 liver enzyme system. From ref. 14.

denervated heart, changes in cardiac output (heart rate × stroke volume) largely depend on heart rate changes engendered by circulating catecholamines. The donor sinus node function may be impaired by preservation injury, direct surgical trauma at excision, the presence of long-acting antiarrhythmics (e.g., amiodarone) taken prior to transplant by the recipient, and a lack of “conditioning” responsiveness to catecholamines.16 Therefore, the transplanted heart generally requires chronotropic support with either milrinone or pacing in the early posttransplant period to maintain a heart rate of 90 to 110 beats per minute and satisfactory hemodynamics (i.e., blood pressure, urine output, and tissue perfusion). Approximately 10% to 20% of transplant patients will have persistent chronotropic incompetence requiring either cardiac pacing or pharmacologic manipulation of the heart with theophylline or terbutaline after hospital discharge; however, few patients who receive a pacemaker use it permanently. Anatomic variables may further compromise optimal hemodynamic function and complicate hemodynamic assessment of the patient. Right ventricular function frequently is impaired, presumably as a result of preservation injury and elevated pulmonary vascular resistance. A “restrictive” hemodynamic pattern may be present initially, but it usually improves over the 6 weeks following transplantation. Donor-recipient size mismatch may contribute to early posttransplantation hemodynamic abnormalities characterized by higher right and left ventricular end-diastolic pressures. Supraventricular arrhythmias in the early posttransplant period usually are transient and may result from overvigorous use of catecholamines or milrinone; later, they should raise suspicion for acute rejection. Myocardial depression frequently occurs and generally requires inotropic support with agents such as dobutamine, milrinone, and epinephrine. On occasion, intra- or postoperative administration of vasodilators, including nitric oxide, and inotropic agents may be necessary to treat right-sided failure in the transplant patient; milrinone and isoproterenol are the preferred inodilators in this setting. Persistent abnormalities of diastolic function are noted in the transplanted heart such that intracardiac pressures increase in an exaggerated fashion with response to exercise and/or volume infusion.16 These abnormalities of diastolic function are due, at least in part, to

denervation but also to acute rejection or to the scarring secondary to previously treated rejection episodes, hypertension, or cardiac allograft vasculopathy. Hypertension often occurs following surgery secondary to the elevated catecholamine levels and systemic vascular resistance associated with end-stage heart failure on a healthy heart. Systolic blood pressure is maintained at 110 to 120 mm Hg to enhance cardiac function. Initial treatment may include nitroprusside or nitroglycerin; hydralazine and amlodipine are used later. The pharmacologic implications of the physiologic consequences of the transplanted heart are summarized in Table 87–3.2

PATHOPHYSIOLOGY OF REJECTION GENERAL CONCEPTS Allograft rejection depends on activation of alloreactive T cells and antigen-presenting cells (APCs) such as B-lymphocytes, macrophages, and dendritic cells. Acute allograft rejection is caused primarily by the infiltration of T cells into the allograft, which triggers inflammatory and cytotoxic effects on the graft. Complex interactions between the allograft and cellular cytokines, cell-to-cell interactions, CD4+ and CD8+ T cells, and B cells ultimately lead to chronic rejection and graft loss if adequate immunosuppression is not maintained.17 The sequence of events that underlies graft rejection is recognition of the donor’s histocompatibility differences by the recipient’s immune system, recruitment of activated lymphocytes, initiation of immune effector mechanisms, and finally graft destruction. Class I and II antigens of the major histocompatibility complex (MHC) are important for histocompatibility in transplantation.17 Class I antigens are present on virtually all nucleated cells in the body, whereas the class II antigens are located primarily on B-lymphocytes, APCs, and vascular endothelium.17 T helper (TH) cells, specialized to direct the immune system, can only recognize foreign antigen in the presence of MHC type II. Cytotoxic T cells, specialized to destroy, can only recognize antigen in the presence of MHC type I antigens.

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TABLE 87–3. Effect of Denervation on Cardiac Pharmacology Drug

Effect

Mechanism Direct mycocardial effect Denervation

Quinidine Verapamil Nifedipine Hydralazine β-Blocker Adenosine

Normal inotropic effect Minimal effect on AV node No effect on AV node Increased contractility Increased chronotropy Normal increase in contractility; normal increase in chronotropy No vagolytic effect AV block No reflex tachycardia No reflex tachycardia Increased antagonist effect Negative chronotropic effect

Acetylcholine

Negative chronotropic effect

Hypersensitivity Effect on sinus node of denervated heart

Digitalis Atropine Adrenaline/ noradrenaline Isoproterenol

Comment

Denervation Denervation Hypersensitivity No neuronal uptake

Increased cardiac output mediated by increased heart rate

Denervation Direct effect Denervation Denervation Denervation Hypersensitivity Effect on sinus node of denervated heart

Impair HR response, use sparingly Life-threatening asystole (>0.5 min) may occur if used to treat supraventricular arrhythmia or stress testing

AV = atriovenous node. From ref. 2.

Lymphocytes are the only cells in the body that can recognize specific antigens and are central to allograft rejection. 1 T-cell activation is caused by interactions between T-cell receptors, the MHC, cellular adhesion molecues, and costimulatory molecules. Among the series of events is calcineurin activation, which ultimately promotes interleukin 2 (IL-2) proliferation. After initial T-cell activation, the process of clonal expansion and immunologic progression is mediated by cytokines. IL-2 is released from T cells and activates T-lymphocytes locally and in other regions of the

body. Undifferentiated T-helper cells can be induced to develop along two lines: TH1 cells secrete IL-2, interferon-γ , and IL-12 and favor cytotoxicity, while TH2 cells secrete IL-4, -5, -10, and 13, which stimulate B-cell and immunoglobulin development. A predominance of TH2 cells has been associated with tolerance (the ability of the body to recognize the transplanted allograft as “self ”) in some experiemental models. The complex nature of these cytokine interactions makes it very difficult to design drugs with exclusive actions (see Fig. 87–1). Allograft inflammation results from these processes

Daclizumab Basiliximab

IL2-R

CD4 T cell

Sirolimus G1 OKT3 CD3 APC

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MHC II

M

Cell cycle

TCR

De novo purine synthesis

NFAT G2

Cosignal

MMF Azathioprine

S

Cyclosporine Steroids

Calcineurin Tacrolimus

NFAT-P

IL2 GENE Promoter Transcription

IL2

Ca++

FIGURE 87–1. Stages of CD4 T-cell activation and cytokine production with identification of the sites of action of different immunosuppressive agents. Antigen-major histocompatibility complex (MHC) II molecule complexes are responsible for initiating the activation of CD4 T cells. These MHC-peptide complexes are recognized by the T-cell recognition complex (TCR). A costimulatory signal initiates signal transduction with activation of second messengers, one of which is calcineurin. Calcineurin removes phosphates from the nuclear factors (NFAT-P) allowing them to enter the nucleus. These nuclear factors specifically bind to an interleukin-2 (IL-2) promoter gene facilitating IL-2 gene transcription. Interaction of IL-2 with the IL-2 receptor (IL-2R) on the cell membrane surface induces cell proliferation and production of cytokines specific to the T cell. APC = antigen-producing cells; MMF = mycophenolate mofetil. (With permission from ref. 17.)

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acting through specific (T-cell interactions with APCs) and nonspecific immunologic mechanisms (natural killer cell chemotaxis, release of vasoactive substances). Rejection of the transplanted tissue can take place at any time following surgery and is classified clinically as hyperacute rejection, acute cellular rejection, humoral rejection or chronic rejection. Efforts are made to allocate well-matched (HLA-A, -B, -DR) kidneys to improve overall rejection and survival rates. However, the benefit of having no recipient donor mismatches may be negated by excessive cold ischemia time (>36 hours) and donor age older than 60 years. Because of greater organ availability and more restricted cold ischemia times for livers and hearts, HLA tissue matching is not performed routinely before transplantation. However, if the potential recipient is reactive against a panel of random donor antigens (i.e., patient has a positive panel reactive antibody [PRA] > 10% to 20%), then a negative T-cell crossmatch is required prior to transplantation. Transplanted organs must be matched for ABO blood group compatibility with the recipient. ABO mismatching will result in hyperacute rejection. Liver transplantation may be carried out in emergency situations across ABO blood groups, but survival is lower than for ABO compatible liver transplants.

produce tissue damage through a delayed hypersensitivity-like mechanism. These immunologic and inflammatory events lead to the nonspecific signs and symptoms of acute rejection: pain and tenderness, fever, and lethargy.

KIDNEY Acute rejection which may affect 20% of patients during the first 6 months following transplantation is evidenced by an abrupt rise in serum creatinine concentration of ≥30%. A specific histologic diagnosis can be obtained via biopsy of the allograft and often is used to guide therapy for rejection. A biopsy specimen with a diffuse infiltrate of lymphocytes is consistent with acute cellular rejection. After the diagnosis of rejection has been confirmed, the potential risks and benefits of specific antirejection therapies must be evaluated. Hypertension often worsens during an episode of rejection. Patients may experience edema and weight gain as a result of sodium and fluid retention. Symptomatic azotemia also may develop in severe cases. Appropriate adjustments in pharmacotherapy are warranted in the face of diminished renal function.

LIVER HYPERACUTE REJECTION Hyperacute rejection may occur when preformed donor-specific antibodies are present in the recipient at the time of the transplant and may be evident within minutes of the transplant procedure. Hyperacute rejection can be induced by immunoglobulin G (IgG) antibodies that bind to antigens on the vascular endothelium, such as class I MHC, ABO, and vascular endothelial cell antigens. Tissue damage can be mediated through antibody-dependent, cell-mediated cytotoxicity or through activation of the complement cascade. The ischemic damage to the microvasculature rapidly produces tissue necrosis. Hyperacute rejection has become uncommon in kidney and heart transplants because transplant donors are matched for ABO blood groups and crossmatch testing is done to determine the presence of donor-specific lymphocytotoxic antibodies. A positive crossmatch presents a serious risk for graft failure even if hyperacute rejection does not occur. A negative lymphocytotoxicity crossmatch does not entirely rule out the possibility of hyperacute rejection because nonMHC antigens on the vascular endothelium can serve as targets of donor-specific antibodies. Hyperacute rejection rarely occurs in patients receiving a liver transplant. The liver’s special status for transplantation is not fully understood, but the local release of cytokines may alter the immunologic reaction taking place in the liver. Early graft dysfunction is treated with supportive care and retransplantation if possible.

ACUTE CELLULAR REJECTION Acute rejection is most common in the first few months following transplantation but can occur at any time during the life of the allograft. Acute rejection generally is reversible, especially if treated. While most cases of acute rejection can be treated effectively, none of the currently available therapies prevents or changes the course of chronic rejection. Cellular rejection is mediated by alloreactive T-lymphocytes that appear in the circulation and infiltrate the allograft through the vascular endothelium. After the graft is infiltrated by lymphocytes, the cytotoxic cells can specifically kill allograft targets, whereas the local release of lymphokines will attract and stimulate macrophages to

The liver appears to be less immunogenic and more likely to promote immunologic tolerance than the other vascularized organs. An immunologic explanation for graft dysfunction becomes more probable as time passes in a patient with an initially functioning liver graft. Initial episodes of acute cellular rejection often occur between 6 days and 6 weeks post-transplantation but also can occur earlier or later. The clinical signs of acute cellular rejection include leukocytosis and a change in the color or quantity of bile. An increased serum bilirubin concentration and increases in hepatic enzymes are the most common biochemical parameters monitored and are sensitive markers of rejection. The liver biopsy is used as definitive evidence of the diagnosis of rejection, but response to antirejection medication also has been used in differentiating rejection from other causes of hepatic dysfunction in a liver transplant patient. Other reasons for graft dysfunction include defects in bile duct reconstruction, opportunistic infections, and toxicity from parenteral nutrition, sepsis, or drug-induced hepatotoxicity.

HEART Acute rejection is a major determinant of survival following cardiac transplantation and accounts for approximately 17% of all deaths.18 The incidence of rejection is substantially higher during the early months following transplantation, with 90% of all rejections occurring within the first 6 months. Because the incidence of acute rejection is highest during this time period, surveillance endomyocardial biopsies are performed at regularly scheduled intervals following transplantation. A typical schedule would be to perform weekly biopsies for the first postoperative month, biweekly biopsies for the next 2 months, monthly biopsies for the next 4 to 6 months, and bimonthly biopsies for the next 7 to 12 months. Biopsy frequency subsequently decreases to every 3 to 12 months. In addition, the severity of rejection tends to be greater when it occurs early in the postoperative period. Although a minority of patients (37%) remain rejection-free, most will experience at least one episode of rejection during the first year. Rejection of the cardiac allograft is not necessarily accompanied by overt clinical signs or symptoms. Nonspecific findings may include low-grade fever, malaise, and mild reduction in exercise capacity, whereas heart failure or atrial arrhythmias may reflect more severe rejection. The

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“gold standard” for detection of rejection is histologic confirmation using endomyocardial specimens obtained by transvenous biopsy of the right ventricle. Cardiac function is assessed by either echocardiography or measurement of right-sided heart and pulmonary wedge pressures and cardiac output by pulmonary artery catheterization at the time of each biopsy. The majority of rejection episodes are characterized histologically by lymphocytic infiltrates with or without myocyte degeneration. The treatment of rejection is based on a number of factors, including type, histologic grade, clinical symptoms, hemodynamic changes, noninvasive findings, and duration of time post-transplantation. Mild degrees of acute cellular rejection usually are not treated unless the patient is symptomatic, whereas the presence of moderate to severe rejection with or without necrosis mandates treatment.19

HUMORAL REJECTION Humoral rejection, sometimes referred to as vascular rejection, is an antibody-mediated process directed against HLA antigens present on the donor vascular endothelium. It can be characterized by capillary deposition of immunoglobulins (IgG), complement, and fibrinogen on immunofluorescence staining. Circulating immune complexes often precede humoral rejection. This form of rejection is less common than cellular rejection and generally occurs in the first 3 months after transplantation. It is associated with an increased fatality rate and appears to be more common when antilymphocyte antibodies are used for rejection prophylaxis. An increased risk of humoral rejection has been linked to females, recipients with elevated PRA, cytomegalovirus seropositivity, a positive crossmatch, and prior sensitization to OKT3.20 Strategies to reverse humoral rejection include plasmapheresis, often in combination with intravenous immunoglobulin (IVIG), high-dose intravenous glucocorticoids, antithymocyte globulin, cyclosphosphamide, rituximab, and mycophenolate mofetil.

CHRONIC REJECTION Chronic rejection is a major cause of late graft loss and is one of the most important problems that remains to be resolved. While chronic rejection simply may be a slow and indolent form of acute cellular rejection, the involvement of the humoral immune system and antibodies against the vascular endothelium appear to play a role. Persistent perivascular and interstitial inflammation is a common finding in kidney, liver, and heart transplantation. Owing to the complex interaction of multiple drugs and diseases over time, it is difficult to delineate the true nature of chronic rejection. For example, cytomegalovirus is associated with the development of chronic rejection in both liver and heart transplant recipients. Unlike acute rejection, chronic rejection is not reversible.

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KIDNEY Advances in the management of acute rejection, has increased the duration of functioning grafts from living and cadaveric donors by more than 70%.21 Chronic rejection remains the most common cause of graft loss in the late post-transplant period (>1 year). Although acute rejection is a strong predictor of chronic rejection, it is unclear why the reduction in the incidence of acute rejection associated with the widespread adoption of cyclosporine and tacrolimus has not had an impact on the incidence of chronic rejection. The current tendency to decrease doses of cyclosporine and tacrolimus in the face of “good” graft function without dynamic measurement of immunologic factors may lead to subclinical rejection. Hypertension, proteinuria, and a progressive decline in renal function represent the classic triad of chronic rejection. Manifestations of chronic rejection generally depend on the degree of renal insufficiency and hypoalbuminemia. Classic symptoms of uremia occur as end-stage kidney disease develops.

LIVER Chronic rejection of the liver is characterized by an obliterative arteriopathy and the loss of bile ducts, which has been referred to as the vanishing bile duct syndrome. These patients experience an asymptomatic rise in the canalicular liver enzymes (alkaline phosphatase and γ -glutamyl transpeptidase) and become jaundiced. These changes are considered the result of immunologic and ischemic injury and can be seen in patients who have not responded adequately to therapy for acute rejection.

HEART Chronic rejection is the leading cause of graft failure and death in heart transplant recipients.22 It manifests as a vasculopathy that is characterized by accelerated intimal thickening or development of atherosclerotic plaques, similar to those seen in the general population with coronary artery disease (CAD). Endothelial injury is the first step in the process, which can be caused by both cell-mediated and humoral responses to the transplanted allograft. Vasculopathy can affect both the arterial and venous vessels but is restricted to the transplanted allograft and rarely affects the recipient’s native vessels. Lipid abnormalities, immunosuppressants, and cytomegalovirus have been linked to the development of vasculopathy. Routine surveillance with coronary angiography, intravascular ultrasound, or other procedures can aid in the diagnosis of vasculopathy. HMG-CoA reductase inhibitors and angiotensin-converting enzyme inhibitors (ACEIs) have been used to decrease the incidence of vasculopathy.22 Percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) have been used in severe cases of vasculopathy; these procedures, however, are limited by significantly increased mortality compared with the general population.22


TREATMENT: Solid-Organ Rejection
DESIRED OUTCOME 2 Transplant immunosuppression must be balanced in terms of

graft and patient survival (the prevention of rejection versus the risk of adverse effects associated with therapy, including lifethreatening infection or malignancy). A multidrug approach is rational from the immunomechanistic viewpoint because the agents

may have overlapping and potentially synergistic mechanisms. Furthermore, multidrug immunosuppression may allow the use of lower doses of individual agents associated with different side-effect profiles to minimize the severity of expected adverse effects. The goals of immunosuppression vary depending on the time interval since transplantation. Immediately following surgery, the primary goal of therapy is to prevent hyperacute and acute rejection. The high doses of immunosuppressants required to achieve this goal may

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or tacrolimus) at the time of transplantation, the term is used more recently to define two perioperative immunosuppressive strategies: (1) the provision of a highly intense level of immunosuppression, either universally or on the basis of patient-specific risk factors such as age and race, or (2) the use of antibody therapy to provide enough immunosuppression to delay the administration of the nephrotoxic calcineurin inhibitors cyclosporine and tacrolimus. The rationale for delayed calcineurin inhibitor administration varies slightly depending on the type of transplant. In renal transplantation, the newly transplanted kidney is susceptible to nephrotoxic injury, whereas in liver and heart transplantation, the idea is to protect patients with preexisting renal insufficiency from further insults during the perioperatiave period. Additionally, cyclosporine and tacrolimus dosage adjustment to maintain target concentrations may be difficult in the perioperative period.

result in serious complications (e.g., nephrotoxicity, infection, thrombocytopenia, and drug-induced diabetes) if maintained long term. Rapid dosage reductions may minimize these effects.


GENERAL APPROACH TO TREATMENT
INDUCTION THERAPY Induction therapy involves the use of a high level of immunosuppression at the time of transplantation with or without the immediate introduction of cyclosporine or tacrolimus (see Fig. 87–2). While induction historically consisted of the use of polyclonal or monoclonal antibodies in addition to triple therapy of azathioprine, highdose corticosteroids, and a calcineurin inhibitor (e.g., cyclosporine

Induction therapy?

RATG

No induction therapy

IL-2RA

IV methlyprednisolone

Maintenance therapy Based on center-specific protocols. Usually consists of: CI (CSA or TAC ⫾ MMF or SRL ⫾ Steroids

FIGURE 87–2. Center-specific protocols may use RATG, an IL2RA, or no induction therapy. In any situation, patients receive IV methylprednisolone prior to, during, or immediately following the transplant operation. The patient will then begin the maintenance immunosuppressive regimen. The center-specific protocol will specify which calcineurin inhibitor (cyclosporine or tacrolimus) is used in combination with mycophenolate mofetil or sirolimus with or without steroids. Patients are then monitored for signs and symptoms of rejection. If rejection is suspected, a biopsy can be done for definitive diagnosis or the patient may be empirically treated for rejection. Empiric treatment generally involves administration of high-dose corticosteroids. If signs and symptoms of rejection are resolved with empiric therapy, the patient will continue to be monitored according to the center-specific protocol. If rejection is confirmed by biopsy, treatment may be based on the severity of rejection. High-dose corticosteroids are most frequently used for mild to moderate rejection. RATG can be used for moderate to severe rejections or steroid-resistant rejections. Severe rejection episodes that are not resolved with steroids or RATG are treated with OKT3. RATG = rabbit antithymocyte immunoglobulin; IL2RA = interleukin-2 receptor antagonist; CI = calcineurin inhibitor; CSA = cyclosporine; TAC = tacrolimus; MMF = mycophenolate mofetil; SRL = sirolimus; BUN =blood urea nitrogen; SCr = serum creatinine; LFTs = liver function tests; OKT3 = muromonab CD3.

Monitor patient (see Table 87–9)

Kidney or liver transplant

Heart transplant

Are there signs or symptoms of rejection? (↑BUN/SCr for kidney transplant; ↑LETs for liver transplant)

Biopsy

Rejection? Yes

No

No

Yes Empiric treatment Mild

Moderate to severe

Steroids

Steroids + RATG

Rejection resolved?

Rejection resolved?

Labs resolved?

Yes

No

Yes

No

No

OKT3

Yes

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CLINICAL CONTROVERSY Some clinicians use induction therapy with IL2RAs or RATG for all transplant recipients. Others reserve induction therapy for patients who are at a higher risk for rejections, such as those who have a high PRA, had previous transplants or multiple pregnancies, or are of non-Caucasian race.


ACUTE REJECTION The primary goal of acute rejection therapy is to minimize the intensity of the immune response and prevent irreversible injury to the allograft. The available options may include (1) increasing the doses of current immunosuppressive drugs such as cyclosporine or tacrolimus, (2) “pulse” steroids with subsequent dose taper, (3) addition of an additional immunosuppressant indefinitely, or (4) short-term treatment with antirejection therapy such as OKT3 or antithymocyte globulin. The treatment of acute rejection varies among transplant centers and by type of allograft, but most always begins with “pulse” steroid therapy for several days (oral or intravenous). Recent data in renal transplantation indicate, however, that African-Americans do not respond as well to glucocorticoids as non-African-Americans. Other therapies, such as antithymphocyte globulin, thus may be preferable for this patient population.23 If biopsy results are available, these findings also may guide therapy in favor of other approaches such as antilymphocyte preparations. Cytolytic agents generally are reserved for steroid-resistant rejection, signs of hemodynamic compromise (heart), or more severe rejections. For the treatment of acute allograft rejection, antithymocyte globulin is better tolerated than and preferred over OKT3. Other innovative forms of therapy for persistent or intractable rejection have been investigated, including mycophenolate mofetil, tacrolimus, low-dose methotrexate, sirolimus, total lymphoid irradiation, and photopheresis (e.g., immune-modulating therapy, which involves apheresis with isolation of peripheral blood leukocytes, treatment of the leukocytes ex vivo with 8-methoxypsoralen and ultraviolet light, and subsequent reinfusion into the patient).24,25 The dosages of other immunosuppressant drugs often are decreased while administering corticosteroids, OKT3, or antithymocyte globulin therapy. Prophylactic agents such as valganciclovir, nystatin, trimethoprim-sulfamethoxazole, H2 -receptor antagonists or protonpump inhibitors, and/or antacids may be used to minimize adverse effects associated with intensive immunosuppression.


MAINTENANCE THERAPY 3 The goal of maintenance immunosuppression is to prevent acute

and chronic rejection while minimizing drug-related toxicity. In the long-term management of the transplant patient, the doses of immunosuppressants are reduced gradually (over 6 to 12 months) in an effort to minimize adverse effects. Many institutions may withdraw specific immunosuppressives completely in select patients to reduce long-term toxicity as well as cost. It is important to recognize that while the goals of transplant immunosuppression are universal, protocols for immunosuppressive therapy vary widely among institutions. Maintenance therapy can involve numerous combinations of the various available immunosuppressive agents. Transplant organ and

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1621

type (cadaveric versus living-related), the degree of HLA mismatch, time post-transplant, post-transplant complications (including the number of acute rejections), previous immunosuppressive adverse reactions, compliance, and financial considerations are among the patient-specific factors considered in individualizing maintenance immunosuppression. Calcineurin inhibitors (CIs) generally are a central component in most maintenance regimens, although CI-free immunosuppression remains the “Holy Grail” of transplant immunology. Transplant patients may receive mono-, dual-, or triple-drug therapy during the maintenance phase. As patients progress through the posttransplant course, the risk of acute rejection decreases; accordingly, maintenance immunosuppression is tapered, and in some cases, certain agents may be discontinued. The changes seen with chronic rejection are not reversible with current immunosuppressive therapies. Some strategies for managing chronic rejection include increasing immunosuppression or changing immunosuppression to prevent further progression of chronic rejection. However, often this strategy provides little clinical benefit. Ideally, immunosuppression should be optimized to prevent acute rejection episodes to minimize the occurrence of chronic rejection.


CALCINEURIN INHIBITORS (CIs)
CYCLOSPORINE (CSA) 4 The introduction of CSA has improved the outcomes of trans-

plantation significantly. Patient and graft survival rates have improved secondary to a lower incidence of acute rejection episodes and severe infectious complications.26 Despite these improvements in survival, concerns regarding its long-term use include late rejection episodes, frequency of hypertension, drug cost, and quality of kidney function.


Pharmacology/Mechanism of Action CSA inhibits T-cell proliferation by inhibiting the production of IL-2 and other cytokines by T cells (see Fig. 87–1). CSA binds to cyclophilin, a cytoplasmic immunophilin. The CSA-cyclophilin complex inhibits the action of calcineurin, an enzyme that activates the nuclear factor of activated T cells (NF-AT), which is, in turn, responsible for the transcription of several key cytokines necessary for T-cell activity, including IL-2. IL-2 is a potent growth factor for T cells, responsible for activation and clonal expansion.


Pharmacokinetics CSA is highly lipophilic and depends on bile for intestinal absorption. Following oral administration, the absorption of CSA is incomplete and erratic, especially in liver recipients with T-tube diversion of bile. CSA is associated with clinically significant interpatient and intrapatient variability in pharmacokinetic parameters owing to unpredictable bioavailability, which averages 30% (range 3% to 60%). Bowel function and bile flow play a major role in intestinal absorption. Because of the significant variability in absorption, peak concentrations are reached within 2 to 6 hours of oral administration. CSA is distributed widely into tissues and body fluids, resulting in a large and variable volume of distribution. The mean terminal half-life with normal liver function is 19 hours.

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TABLE 87–4. Summary of Immunosuppressant Adverse Effects Adverse Effects

AZA

MMF

Steroids

Adrenal suppression

+

Cataracts/glaucoma

+

Hypertension

Tremor Gastrointestinal abnormalities

++ Nausea, vomiting

++ Diarrhea, nausea, abdominal pain

CSA

++

++

++

+

++ +

++ ++ Diarrhea, nausea, vomiting, anorexia ++

GI bleeding

Respiratory abnormalities Nephrotoxicity

Headache Hepatotoxicity

TAC

+

++

++

+

++

+

++

Hyperlipidemia

++

++

+

Glucose alterations

++

+

++

++ ++ +

++

Hirsutism

++

++

+

++

++

++

+

++ + ++

+

++

+

++

ATG

OKT3

+

+

++

+

Gingival hyperplasia

Hyperkalemia Hypokalemia Hypomagnesemia

IL2RA

+/++

Osteoporosis/aseptic necrosis Personality changes Weight gain Acne

Pruritis Thrombocytopenia Leukocytosis Leukopenia

SIR

++ ++

Management Taper doses slowly; administer every other day; patient identification card Annual eye examinations or as indicated Monitor blood pressure; sodium restriction and antihypertensive medications as needed Adjust dose as needed AZA: administer after meals; MMF: decrease or divide dose, administer with food; TAC/PRED: administer with food; ulcer prophylaxis TAC: pleural effusion, dyspnea OKT3: pulmonary edema Monitor serum creatinine/BUN; adjust dose and discontinue as needed Check drug concentration; adjust dose Monitor liver enzymes; AZA-associated toxicity is reversible and usually occurs within the first 6 months of therapy; adjust dose and discontinue as needed Dietary counseling; pharmacotherapy as needed Monitor glucose; adjust doses of hypoglycemics or immunosuppressants Annual bone examinations; weight bearing exercise Patient and family education Patient education; exercise Dose reduction; increased hygiene; topical agents (e.g. retinoic acid) Patient education; appropriate dental hygiene; consider TAC Patient education; consider TAC Treatment when appropriate Monitor platelets Monitor WBCs Monitor WBCs; dosedependent and reversible with AZA/MMF Monitor serum electrolytes

+ Monitor serum magnesium

++ indicates >10% risk; + indicates 440 mcg/L per hour have been shown to correlate with rejection.40 Peak concentrations measured 2 hours after an oral dose (C2 ) have been shown to have a better predictive value in terms of rejection compared with trough concentrations.39 Some transplant centers have adopted this strategy to manage CSA levels because of the convenience of a single blood sample. The suggested therapeutic range for C2 CSA levels is 1.5 to 2 mcg/mL for the first few months after transplant and 0.8 mcg/mL after 6 to 12 months.40,41


TACROLIMUS (TAC) TAC is a macrolide antibiotic with immunosuppressive activity via inhibition of calcineurin. It was thought originally that TAC may decrease the risk of chronic allograft rejection, but experience has demonstrated that this is not the case. However, it should be noted that up to this point, TAC traditionally has been used in high-risk patients. Today, TAC is used more commonly than CSA by most transplant centers in all transplant patients, regardless of risk category.


Pharmacology/Mechanism of Action TAC inhibits T-cell activity by inhibiting the production of IL-2 and other cytokines by T cells (See Fig. 87–1). TAC binds to a cytoplasmic immunophilin called FK-binding protein-12 (FKBP12). Like CSA, the TAC-FKBP12 complex inhibits calcineurin, ultimately inhibiting NF-AT and the transcription of cytokines necessary for T-cell activity, most notably IL-2.


Pharmacokinetics TAC is a highly lipophilic compound; however, it does not rely on bile for absorption. Following oral administration, the bioavailability of TAC ranges from 5% to 67%, with a mean of 29%.42 FKBP12 is found in high concentrations in red blood cells, which causes extensive binding of TAC to erythrocytes. TAC is also metabolized primarily by CYP 3A4, although other cytrochrome P450 enzymes have been reported.42 The elimination half-life of TAC is 8.7 hours. Increased metabolism in children results in a shorter half-life.


Efficacy Currently, TAC is approved for use in kidney and liver transplants. However, it has been studied extensively and is used widely in all types of solid-organ transplants. Studies comparing CSA with TAC

as primary immunosuppression demonstrate equal efficacy of the two agents in kidney, liver, and heart transplants. The potency and effectiveness of TAC have prompted studies to investigate withdrawal of corticosteroids or other concomitant immunosuppressants. A large randomized, controlled trial compared triple-drug therapy, consisting of TAC, corticosteroids, and mycophenolate mofetil, with early withdrawal of corticosteroids or mycophenolate in kidney transplant recipients. The results demonstrated equal efficacy in the three arms with no difference in acute rejection rates after 6 months of therapy.43 Furthermore, TAC has demonstrated equal efficacy to CSA, each in combination with azathioprine, with regard to corticosteroid withdrawal.44


Adverse Effects The adverse effects associated with TAC include neurologic toxicity, nephrotoxicity, and electrolyte disturbances such as hyperkalemia and hypomagnesemia42 (see Table 87–4). The incidence of post-transplant diabetes is approximately 8% to 10% but is often reversible when doses of TAC and/or steroids are reduced.45 As observed with CSA, most adverse effects related to TAC improve with dosage reduction or discontinuation. In comparison with CSA, TAC may be associated with increased occurrence of neurologic complications, including tremor, paresthesias, headache, and insomnia. On the contrary, TAC is associated with less hypercholesterolemia and hypertension.45−47 The occurrence of nephrotoxocity appears to be similar to CSA. TAC also has been reported to cause alopecia, which is usually self-limiting and reversible.


Drug-Drug and Drug-Food Interactions Because of their common metabolic pathways, CSA and TAC share the same drug interaction profile (see Table 87–6). CYP 3A4 inhibitors increase TAC concentrations, whereas CYP 3A4 inducers decrease blood levels. One distinct drug interaction with TAC that differs from CSA is an interaction with antacids. In vitro data suggest that drugs that increase the pH of the gastrointestinal tract, such as magnesium-, aluminum- or calcium-containing antacids, sodium bicarbonate, and magnesium oxide, can cause a pH-mediated degradation of TAC or physical adsorption to TAC in the gastrointestinal tract.48,49 Such compounds should be separated from TAC administration by at least 2 hours to prevent the physical interaction. Reversible myopathy has been reported with concomitant administration of TAC with HMG-CoA reductase inhibitors.50 TAC is also an inhibitor of CYP 3A4 but much weaker than CSA.51 The number of reported cases of myopathy with HMG-CoA reductase inhibitors in patients treated with TAC is fewer than with CSA. Nonetheless, patients should be monitored for clinical signs of myopathy when receiving HMG-CoA reductase inhibitors in combination with TAC. It is also important to maintain consistency with administration of TAC with regard to meals and food intake to minimize alterations in TAC absorption and pharmacokinetics. One study in healthy volunteers indicates that the Cmax , AUC, and tmax of TAC were significantly higher when administered after a 10-hour fast compared with either a high-fat or low-fat/high-carbohydrate meal. Administration of TAC with food decreased Cmax by 77% for the high-fat meal and 64.7% for the low-fat meal. AUC also was decreased by 33.5% and 26.1%, respectively, and tmax was increased 4.72- and 2.34-fold, respectively. The authors concluded that food reduces both the rate and extent of TAC absorption and that a high-fat meal may further delay gastric

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emptying, further reducing TAC concentrations.52 As with CSA, grapefruit juice also significantly increases TAC concentrations.


Dosing and Administration Initial intravenous TAC doses range from 0.05 to 0.1 mg/kg per day and are administered by continuous infusion. Oral doses range from 0.1 to 0.3 mg/kg per day given in two divided doses every 12 hours. TAC doses are then adjusted according to trough blood levels, clinical response, and adverse effects. A review of the role of TAC in renal transplantation suggests that target 12-hour whole-blood trough concentrations are 15 to 20 ng/mL (0 to 1 month after transplantation), 10 to 15 ng/mL (1 to 3 months after transplantation), and 5 to 12 ng/mL (>3 months after transplantation).44 Because TAC is highly bound to red blood cells, plasma levels are much lower than whole blood concentrations. Therapeutic plasma levels of TAC range from 0.5 to 2 ng/mL. Pediatric transplant patients clear the drug more rapidly and require doses two- to fourfold higher than adults on a milligram per kilogram basis to maintain equivalent therapeutic concentrations. A modified release formulation of TAC that will allow for once-daily administration is currently in phase III clinical trials.


CALCINEURIN INHIBITOR NEPHROTOXICITY 5 One of the most common side effects observed in all trans-

plant recipients receiving maintenance CSA or TAC therapy is nephrotoxicity. Two types of toxicity can occur. Acute nephrotoxicity frequently is seen early and is dose-dependent and reversible, but chronic nephropathy is more common. Clinical manifestations of CI nephrotoxicity include elevated serum creatinine and blood urea nitrogen levels, hyperkalemia, hyperuricemia, mild proteinuria, and a decreased fractional excretion of sodium. CI nephrotoxicity is recognized as the leading cause of renal dysfunction following nonrenal solid-organ transplant. One study looked at more than 69,000 liver, heart, lung, and intestinal transplant recipients and found a combined incidence of 16.5% of newly diagnosed chronic renal failure after a mean follow-up of 46 months. A total of 28.9% of these patients with chronic renal failure went on to develop ESRD, requiring dialysis or kidney transplant. Patients with no history of CI use had a lower relative risk of developing nephropathy compared with those who did receive CI. Furthermore, CSA was associated with a higher risk of developing nephropathy compared with TAC (RR 1.25, p < 0.001).53 The predominant mechanism for CI nephrotoxicity is renal vasoconstriction, primarily of the afferent arteriole, resulting in increased

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renal vascular resistance, decreased renal blood flow by up to 40%, reduced glomerular filtration rate by up to 30%, and increased proximal tubular sodium reabsorption with a reduction in urinary sodium and potassium excretion. A number of other mechanisms have been implicated, including changes in the renin-angiotensin-aldosterone system, prostaglandin synthesis, nitrous oxide production, sympathetic nervous system activation, and calcium handling.54 Measures to reduce CI nephrotoxicity include delaying administration immediately postoperatively in patients at high risk for nephrotoxicity (using alternative induction protocols including an IL-2 receptor antagonist or antilymphocyte globulin), monitoring CI trough blood levels and reducing the CI dosage if the vasoconstrictive effects are problematic, and avoiding other nephrotoxins (e.g., aminoglycosides, amphotericin B, and NSAIDs) when possible. When using these agents, drug concentrations of CI and those of the other drugs, if available, should be monitored closely. In addition, the concomitant administration of drugs known to elevate CI levels requires intentional dosage reductions to avoid unnecessary renal and other toxicity31 (see Table 87–6). Currently, no proven therapies consistently prevent or reverse the nephrotoxic effects of CSA; however, a number of agents have been studied, including prostaglandin analogues, pentoxyphylline, and fish oils.55 In kidney transplants, it is often difficult to differentiate CI nephrotoxicity from renal allograft rejection. Because the clinical features of acute renal allograft rejection and CI nephrotoxicity may overlap considerably, a renal biopsy continues to be the diagnostic “gold standard” (Table 87–7). However, differentiating between chronic renal allograft rejection and CI nephrotoxicity may be more difficult because, in addition to clinical signs and symptoms, biopsy findings also may be similar. CLINICAL CONTROVERSY Although CIs are the mainstay of immunosuppressive protocols, some clinicians attempt to use CI-sparing protocols to avoid the significant adverse effects associated with CIs. Others will delay the initiation of CIs to avoid the doserelated adverse effects associated with early use of CIs posttransplantation.


GLUCOCORTICOIDS 6 Corticosteroids have been used since the beginning of the mod-

ern transplantation era. Despite their many adverse events, they

TABLE 87–7. Differential Diagnosis of Acute Rejection and CSA or TAC Nephrotoxicity Acute Rejection History Clinical presentation

Laboratory Biopsy

Often 6 weeks postoperatively Afebrile Hypertension Graft nontender Good urine output Gradual rise in serum Cr (>0.15 mg/dL/day) Elevated CSA or TAC concentration Intersitial fibrosis, tubular atrophy, glomerular thrombosis, arterial inflammation

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continue to be a cornerstone of immunosuppression regimens in many transplant centers. The most commonly used corticosteroids in transplantation are methylprednisolone and prednisone.


PHARMACOLOGY/MECHANISM OF ACTION Corticosteroids block cytokine activation by binding to glucocorticoid response elements, thereby inhibiting IL-1, -2, -3, and -6, γ -interferon, and tumor necrosis factor α (TNF-α) synthesis (See Fig. 87–1). Additionally, steroids interfere with cell migration, recognition, and cytotoxic effector mechanisms.56


PHARMACOKINETICS Prednisone is converted to active prednisolone in the body and has multiple effects on the immune system. Prednisone is very well absorbed from the gastrointestinal (GI) tract and has a long biologic half-life, so it can be dosed once daily.


EFFICACY Animal models of transplantation in the 1950’s and 1960’s used steroids empirically in combination with azathioprine.57 Steroids subsequently became a part of the immunosuppressive regimens used in the first human transplants58 and continue to be used in immunosuppressive protocols today. The efficacy of steroids is irrefutable based on the decades of clinical experience. Systematic studies comparing steroid-free immunosuppressive agent combinations with conventional therapy are difficult to perform due to the hundreds of potential combinations that now exist. However, recent studies of steroid-free immunosuppressive agent combinations with newer, more specific immunosuppressants suggests that steroids may in the future have less of a role in maintenance immunosuppression.43,44

and organ function. As doses are tapered, it is preferable to administer steroids every other day and between 7 and 8 A.M. to mimic the body’s diurnal release of cortisol. Although conversion to alternate-day regimens or complete withdrawal of prednisone in patients with stable posttransplant courses has been used with success in some transplant centers, steroids often are continued for the entire life of the functional graft. Long-term steroid use and its associated deleterious effects are well recognized and particularly troublesome in transplant patients (see Table 87–4). The first-line therapy for the treatment of acute graft rejection is high-dose intravenous methylprednisolone (250 to 1000 mg) daily for 3 days or oral prednisone (200 mg). Doses of oral prednisone are then tapered over 5 days to 20 mg/day. Prednisone should be taken with food to minimize GI upset. The dose of prednisone varies with the transplant center’s protocol but usually is highest immediately following transplant and during treatment for acute rejection. It is becoming frequent practice to taper prednisone with the goal of discontinuation over a period of months. Corticosteroids never should be discontinued abruptly; tapering should be gradual because of suppression of the hypothalamic-pituitary-adrenal axis. Corticosteroids slow the growth rates in children, prompting clinicians to use alternate-day dosing or to withhold steroids until rejection occurs. Because of the many detrimental effects associated with chronic steroid therapy, dose minimization has been the goal of therapy. The availability of CSA, TAC, and mycophenolate mofetil has permitted complete withdrawal of corticosteroids in some patients. Steroid withdrawal protocols use either a rapid taper of steroids within days of the transplant or a slower taper, whereby patients are weaned gradually from steroids over months to years after transplant. Factors to consider when evaluating studies of these alternative strategies in transplant patients include patient selection criteria, timing and rapidity of withdrawal, and duration of follow-up.


ANTIPROLIFERATIVE AGENTS
MYCOPHENOLATE MOFETIL (MMF)


ADVERSE EFFECTS Adverse effects of prednisone that occur in more than 10% of patients include increased appetite, insomnia, indigestion (bitter taste), and mood changes. Side effects that occur less commonly but which are seen with high doses or prolonged therapy include cataracts, hyperglycemia, hirsutism, bruising, acne, sodium and water retention, hypertension, bone growth suppression, and ulcerative esophagitis (see Table 87–4).


DRUG-DRUG AND DRUG-FOOD INTERACTIONS Barbiturates, phenytoin, and rifampin induce hepatic metabolism of prednisone and thus decrease the effectiveness of prednisone. Prednisone decreases the effectiveness of vaccines and toxoids.56


DOSING AND ADMINISTRATION An intravenous corticosteroid, commonly high-dose methylprednisolone, is given during the perioperative period. The dose of methylprednisolone is tapered rapidly and discontinued within days and oral prednisone is initiated. Prednisone doses are tapered progressively over time depending on the type of additional immunosuppression

7 Mycophenolic acid (MPA) was first isolated from the Penicillin

glaucum mold. It was first studied as an antibiotic but later was found to have immunosuppressive properties. Mycophenolate mofetil (MMF) the morpholinoethyl ester of MPA appears to be a specific immunosuppressant for lymphocytes, resulting in fewer adverse effects than azathioprine, making it the preferred agent over azathioprine.


Pharmacology/Mechanism of Action MMF is rapidly and completely converted to MPA by first-pass metabolism. MPA exerts its immunosuppressive effect through noncompetitive binding to inosine monophosphate dehydrogenase (IMPDH). IMPDH is the key enzyme responsible for guanosine nucleotide synthesis via the de novo pathway. Inhibition of IMPDH results in decreased nucleotide synthesis and diminished DNA polymerase activity, ultimately reducing lymphocyte proliferation.59 The actions of MPA are more specific for T and B cells, which use only the de novo pathway for nucleotide synthesis (see Fig. 87–1). Other cells within the body have a salvage pathway by which they can synthesize nucleotides, making them less susceptible to the actions of MPA and thereby reducing, but not eliminating, the potential for the hematologic adverse effects seen with azathioprine, which affects both the de novo and salvage pathways. In addition to the decreasing

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lymphocyte proliferation, MPA also may downregulate activation of lymphocytes.60


Pharmacokinetics Following oral administration, bioavailability of MMF is 94%, and peak concentrations of MPA are reached within 1 hour. A total of 97% of MPA is bound to albumin in the blood. MPA is eliminated by the kidney and also undergoes glucuronidation in the liver to an inactive glucuronide metabolite (MPAG) that is excreted in the bile and urine. Enterohepatic cycling of MPAG can undergo deconjugation, thereby recirculating MPA into the bloodstream. The half-life of MPA is 18 hours.


Efficacy Currently, MMF is approved for use in kidney, liver, and heart transplants. A recent analysis of 5599 patients in the Joint International Society for Heart and Lung Transplantation (ISHLT) and UNOS Thoracic Registry showed a statistically significant survival advantage for MMF compared with azathioprine (1 year, 96% versus 93%; 3 years, 91% versus 86%).61 Efficacy has been demonstrated in combination with both CSA and TAC. MMF also has demonstrated efficacy in the treatment of acute rejection. Kidney transplant recipients converted to MMF after the first acute rejection episode had fewer subsequent rejections compared with those who continued with azathioprine after rejection treatment. The change in therapy was associated with no increase in adverse effects or malignancies and a trend toward better graft function and survival.62 Monotherapy with MMF can decrease the risk of nephrotoxicity associated with CIs. Clinical trials have evaluated the benefits of CI withdrawal from MMF-based immunosuppression in stable kidney and liver transplants. Withdrawal of CIs resulted in improved renal function and lower blood pressure, lipid, and uric acid levels. These benefits, however, were offset by an unacceptable increase in organ rejection in all the studies.63−65 Monotherapy with MMF generally is not used in clinical practice.


Adverse Effects Unlike CSA and TAC, MMF is not associated with nephrotoxicity, neurotoxicity, or hypertension. GI side effects such as nausea, vomiting, diarrhea, and abdominal pain, however, occur more frequently in MMF-treated patients compared with those receiving azathioprine or placebo66 (see Table 87–4). In addition, GI symptoms occur with similar frequency during intravenous and oral therapy. Clinically, however, dose reduction, dividing the total daily dose into three, administration with food, and upward titration from lower doses during initial therapy may alleviate some of these GI symptoms. MMF also has hematologic effects resulting in leukopenia and anemia, particularly with higher doses. Tissue-invasive cytomegalovirus (CMV) also was more common in MMF-treated patients,66 although this may be related to differenes in the use of CMV prophylaxis within the studies. Malignancy and post-transplant lymphoproliferative disease (PTLD) are of significant concern with greater amounts of immunosuppression. Longer follow-up of patients receiving MMF is required to characterize the lifelong risk of malignancy. Because peripheral intravenous MMF administration is associated with local edema and inflammation, central venous administration may be the preferred route.

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Drug-Drug and Drug-Food Interactions Food delays the absorption and decreases MPA Cmax by 25% but has no effect on MPA AUC. As a result, prescribing information indicates that MMF should be taken on an empty stomach; however, MMF is often given with food in clinical practice to minimize GI adverse effects. Administration with aluminum- and magnesium-containing antacids or cholestyramine, significantly decreases the AUC of MPA and should be avoided.59 It has been suggested that administration of iron may produce similar results, but this has not been tested. Acyclovir, commonly used in renal transplant recipients for the treatment and prevention of viral infections, competes with MPAG for renal tubular secretion. AUCs of both entities are increased with concomitant acyclovir and MMF administration.59 Single-dose intravenous ganciclovir in combination with MMF produced no change in the disposition of ganciclovir, MPA, or MPAG.67 Although no pharmacokinetic interaction in a single-dose study was demonstrated, there is potential for additive pharmacodynamic effects such as bone marrow suppression. Decreased MPA trough concentrations have been reported when MMF is administered with CSA compared with those achieved when MMF is given with TAC or sirolimus. This interaction is most likely due to CSA interference with the enterohepatic recycling of MPAG, which results in decreased MPA concentrations.68 To achieve equivalent MPA and MPAG concentrations, it is necessary to administer MMF 3 g/day with CSA compared with MMF 2 g/day with TAC.


Dosing and Administration MMF is currently available in both oral and intravenous formulations. Although intravenous administration of equal doses closely mimics oral administration, the two cannot be considered bioequivalent.69 Unlike other immunosuppressive agents, there is no compelling indication that MMF should be dosed in adult patients on a milligram per kilogram basis given the weak correlation between MPA AUC and body weight.59 The dose of MMF for optimizing immunosuppression and minimizing adverse effects is 2 g/day administered in two divided doses given every 12 hours. The dose of MMF in heart transplantation is 3 g/day in two divided doses to achieve the necessary higher levels of immunosuppression. Pediatric doses of MMF are approximately 40 mg/kg per day in two doses. The total daily dose may be separated into three or four dosing intervals if patients are unable to tolerate the GI side effects. With regard to therapeutic drug monitoring, plasma appears to be the most appropriate medium for measuring MPA. Better outcomes are associated with MPA AUC levels of greater than 42.8 mcg/mL per hour (by HPLC)70 although a reference range of 30 to 60 mcg/mL per hour has been proposed.71 However, the correlation between MPA AUC levels and adverse effects is low. Further studies are required to determine the best modality to monitor MPA levels (AUC versus trough concentrations), the acceptable targets for each, and the appropriate strategy to monitor MPA levels.70,71


MYCOPHENOLATE SODIUM Mycophenolate sodium is an enteric-coated formulation of the sodium salt of mycophenolic acid designed to reduce the GI side effects of MMF. This formulation allows for mycophenolic acid to be released directly in the small intestine for absorption rather than in the stomach. Because mycophenolic acid is the activated form of MMF, the actions

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are identical between the two. Likewise, the adverse effects are similar between the two, including the incidence of GI toxicity, despite the enteric coating. Clinical trials have demonstrated similary efficacy between MMF and mycophenolate sodium in kidney transplants both immediately following transplantation72 and in patients who were switched from MMF to mycophenolate sodium.73 Mycophenolate sodium 1.44 g/day is therapeutically equivalent to MMF 2 g/day.74


AZATHIOPRINE Azathioprine, a prodrug for 6-mercaptopurine, has been used as an immunosuppressant in combination with glucocorticoids since the earliest days of the modern transplantat era. It is associated with substantial toxicities, however, and its use has dramatically declined with the availability of newer, less toxic immunosuppressants.


Pharmacology/Mechanism of Action Azathioprine is an inactive compound that is converted rapidly to 6-mercaptopurine (6-MP) in the blood and is subsequently metabolized by three different enzymes. Xanthine oxidase (XO), found in the liver and GI tract, converts 6-MP to the inactive final end product, 6-thiouric acid. Thiopurine methyltransferase (TPMT), found in hematopoietic tissues and red blood cells, methylates 6-MP to an inactive product, 6-methylmercaptopurine. Finally, hypoxanthineguanine phophoribosyltransferase (HGPRT) is the first step responsible for converting 6-MP to 6-thioguanine nucleotides (TGNs), the active metabolites, which are incorporated into nucleic acids, ultimately disrupting both the salvage and de novo pathways of DNA, RNA, and protein synthesis. This process is toxic to the cell and renders the cell unable to proliferate (see Fig. 87–1). TGNs eventually are catabolized by XO and TPMT to inactive products.


Pharmacokinetics Oral bioavailability of azathioprine is approximately 40%. Metabolism of 6-MP is primarily by xanthine oxidase to inactive metabolites, which are excreted by the kidneys. The half-life of azathioprine, the parent compound, is very short, approximately 12 minutes. The half-life of 6-MP is longer, ranging from 0.7 to 3 hours. However, it is the activity of the TGNs that determines the pharmacodynamic half-life of the drug. The half-life of TGNs has been estimated to be 9 days once therapy has been stopped.75


Adverse Effects Dose-limiting adverse effects of azathioprine are often hematologic (see Table 87–4). Leukopenia, anemia, and thrombocytopenia can occur within the first few weeks of therapy and can be managed by dose reduction or discontinuation of azathioprine. Other common adverse effects include nausea and vomiting, which can be minimized by taking azathioprine with food. Alopecia, hepatotoxicity and pancreatitis are less common adverse effects of azathioprine; they generally are reversible on dose reduction or discontinuation.26


Drug-Drug and Drug-Food Interactions Allopurinol inhibits xanthine oxidase and can increase the bioavailability of azathioprine and 6-MP concentrations by as much as fourfold. The metabolic pathways shift to favor production of TGNs which

ultimately results in increased bone marrow suppression and pancytopenia. Doses of azathioprine should be reduced by 50% to 75% when allopurinol is added. Additional clinically significant drug interactions include other bone marrow–suppressing agents such as ganciclovir, sulfamethoxazole-trimethoprim, and sirolimus and other drugs that irritate the GI tract.


Dosing and Administration Initial doses of azathioprine are 3 to 5 mg/kg per day intravenously or orally. Individualization to maintain the white blood cell count between 3500 and 6000 cells/mm may be accomplished in some with doses as low as 0.25 mg/kg per day.3 Patients often are instructed to take azathioprine in the evening when initiating or titrating therapy to allow for dose adjustments based on morning determinations of their white blood cell count.


SIROLIMUS (SRL) 8 Sirolimus (SRL), also known as rapamycin, is another immuno-

suppressive macrolide antibiotic that is structurally similar to TAC. It represents the first in the newest class of immunosuppressants, with a unique mechanism of action. The potential of SRL to decrease the incidence of chronic rejection remains to be seen.


PHARMACOLOGY/MECHANISM OF ACTION The mechanism of action of SRL is distinct from CSA or TAC. SRL binds to FKBP12, but the resulting complex does not inhibit the activity of calcineurin. Whereas CSA and TAC inhibit cytokine production, SRL appears to inhibit the response to these cytokines. The SRL-FKBP12 complex binds to the mammalian target of rapamycin (mTOR) (see Fig. 1). IL-2 stimulates mTOR to activate kinases that ultimately advance the cell cycle from G1 to the S phase. Thus the SRL-FKBP12 complex inhibits T-cell proliferation by inhibiting the cellular response to IL-2 and progression of the cell cycle.76


PHARMACOKINETICS SRL is a lipophilic compound. Bioavailability after oral administration is low, only 15%, with peak concentrations being reached within 1 to 2 hours.76 SRL has a high volume of distribution, readily distributing into most tissues of the body. SRL binds extensively to erythrocytes because of the high FKBP12 concentration found in red blood cells (RBCs). Metabolism occurs primarily by CYP 3A4 both in the gut and in the liver. The half-life is reported to be 60 hours but can range up to 110 hours in patients with liver dysfunction.77


EFFICACY Currently, SRL is only approved for the prevention of rejection in kidney transplants in combination with corticosteroids and CSA or after withdrawal of CSA in patients with low to moderate immunologic risk. Two concurrent clinical trials evaluated the use of SRL in kidney transplants. All patients in both studies received CSA and steroids and were randomly assigned to one of three groups. The U.S. trial compared patients randomly assigned to receive SRL in a fixed dose of a 6-mg loading dose followed by 2 mg daily (I), a fixed dose of a

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15-mg loading dose followed by 5 mg daily (II), or azathioprine (III). The global trial used the same SRL administration arms (I and II) but compared patients with placebo (III). The results of both studies showed similar patient and graft survival in all groups at 12 months but lower rates of acute rejection in the SRL arms compared with azathioprine and placebo.78,79 Studies evaluating early CSA withdrawal in SRL-based immunosuppressive protocols enrolled patients 3 months after transplant who were receiving SRL, which was adjusted based on trough blood concentrations, who did not have a recent or severe rejection episode and adequate renal function. Patients were randomly assigned to continue triple-drug therapy with SRL (adjusted to trough concentrations of greater than 5 ng/mL), CSA, and steroids or to double-drug therapy with SRL (adjusted to trough concentrations of 20 to 30 ng/mL) and steroids. The results showed a low risk of acute rejection following CSA discontinuation (5.6%) and no difference in graft survival. Long-term follow-up (2 years) showed improved renal function and blood pressure without an increase in acute rejection or graft loss in patients who discontinued CSA.80 Currently, since the safety and efficacy of SRL has not been established in liver or lung transplants, it is recommended that its use be avoided in these populations immediately following transplant. In contrast, limited data on the use of SRL in heart transplantation indicate benefit in reversing acute rejection in patients who do not respond to antilymphocyte therapy.81 Furthermore, SRL may slow the progression of vasculopathy, which may have an impact on chronic rejection and long-term patient survival after heart transplantation.82 Use of SRL and TAC concomitantly was avoided in early studies because it was thought that the two would compete for FKBP12 receptor binding sites. However, clinical experience has demonstrated that this is not the case, and literature now substantiates the efficacy of SRL in combination with TAC.83,84 SRL has also demonstrated efficacy in combination with MMF in kidney transplants to avoid the use of CIs and decrease the risk of nephrotoxicity.85,86

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DRUG-DRUG AND DRUG-FOOD INTERACTIONS CYP 3A4 is the major metabolic pathway for SRL; thus the drug interactions mediated by induction or inhibition of the CYP 3A4 enzyme system are similar to those seen with CSA and TAC (see Table 87–6). Administration of the microemulsion formulation of CSA with SRL significantly increases the AUC and trough SRL levels. The same is not seen with the standard formulation of CSA. Conversely, CSA concentrations and AUC are also increased by SRL. The mechanism is proposed to be competitive binding to CYP 3A4 and p-glycoprotein.77 It is recommended that patients separate the dose of SRL and CSA by 4 hours to minimize the interaction.92 Concomitant administration of TAC does not affect SRL levels.93 As with CSA and TAC, grapefruit juice produces increases in SRL levels. Administration of SRL with a high-fat meal was associated with a delayed rate of absorption, decreased Cmax , and increased AUC, indicating an increase drug exposure, whereas the half-life remained unchanged.94 The clinical significance of this is unknown.


DOSING AND ADMINISTRATION A fixed SRL dosing regimen is approved for concomitant use with CSA that includes a loading dose of 6- or 15-mg followed by 2 or 5 mg daily, respectively. Therapeutic monitoring of SRL is advocated using whole blood concentrations measured by HPLC, which is specific for the parent compound to a target level of 10 to 15 ng/mL when used in combination with a CI or, 15 to 25 ng/mL, when used in regimens that include CSA withdrawal. When RIA is used, which measures the parent compound and metabolites, reference ranges of 15 to 20 ng/mL and 20 to 30 ng/mL should be used, respectively. CLINICAL CONTROVERSY


ADVERSE EFFECTS Myelosuppression associated with SRL appears to be dose-related. Thrombocytopenia is usually seen within the first 2 weeks of SRL therapy but generally improves with continued treatment. Leukopenia and anemia caused by SRL typically are transient.87 SRL levels greater than 15 ng/mL have been correlated with thrombocytopenia and leukopenia.88 Hypercholesterolemia and hypertriglyceridemia are quite common in patients receiving SRL. It is postulated that the mechanism of this adverse effect is related to an overproduction of lipoproteins or inhibition of lipoprotein lipase. Peak cholesterol and triglyceride levels are often seen within 3 months of starting SRL but usually decrease after 1 year of therapy and can be managed by reducing the dose, discontinuing SRL, or by starting therapy with a HMG-CoA reductase inhibitor or fibric acid derivative. One recent study suggests that the dyslipidemia associated with SRL is not a major risk factor for early cardiovascular complications following kidney transplant.89 Reports of delayed wound healing and wound dehiscence could be due to inhibition of smooth muscle proliferation and intimal thickening.90 Mouth ulcers also have been reported with SRL, more commonly with the oral solution. The cause may be a direct effect of the drug or secondary to activation of herpes simplex virus.91 Interstitial pneumonitis has been described in kidney, liver, and heart-lung transplant recipients that is reversible after discontinuing SRL.77 Other adverse effects reported with SRL include increased liver enzymes, hypertension, rash, acne, diarrhea, and arthralgia (see Table 87–4).

Routine therapeutic drug monitoring of SRL therapy is not recommended in patients who are receiving triple-drug therapy with CSA and steroids. However, many clinicians now feel that SRL drug levels should be monitored in all patients, although there is no accepted therapeutic range.


POLYCLONAL ANTIBODIES (ANTITHYMOCYTE GLOBULINS) globulins available in the 9 There are currently two antithymocyte ®

United States: ATG (ATGAM ), an equine polyclonal antibody, and RATG (Thymoglobulin® ), a rabbit polyclonal antibody. The rabbit preparation is less immunogenic and may have other advantages over the equine preparation. Both ATG and RATG are currently approved only for the treatment of rejection; however, the drugs are used often as induction therapy to prevent acute rejection.


PHARMACOLOGY/MECHANISM OF ACTION Because of their polyclonal antibody nature, both ATG and RATG exert their immunosuppressive effect by binding to a wide array of lymphocyte receptors, including CD2, CD3, CD4, CD8, CD25, and CD45, among others. Binding of ATG or RATG to the various

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receptors results in complement-mediated lysis and subsequent lymphocyte depletion. T cells are the major lymphocytic target for the compounds; however, other blood cell components are also affected, including B cells and other leukocytes (see Fig. 87–1). Damaged T cells are removed subsequently by the spleen, liver, and lungs.


PHARMACOKINETICS ATG is poorly distributed into lymphoid tissue and binds primarily to circulating lymphocytes, granulocytes, and platelets. The terminal half-life of ATG is 5.7 days. RATG has a volume of distribution of 0.12 L/kg. The terminal half-life in renal transplant recipients is significantly longer than ATG at 30 days.95 Peak plasma concentrations are reached after 5 to 7 days of ATG or RATG infusions. Antiequine antibodies can form in up to 78% of patients receiving ATG therapy. Similarly, antirabbit antibodies can form in up to 68% of patients receiving RATG therapy. The effects of preformed antibodies on the efficacy and safety of these preparations has not been studied adequately.


EFFICACY ATG and RATG are used most commonly for the treatment of acute allograft rejection or as induction therapy to prevent acute rejection. ATG is currently approved for both indications in kidney transplants. RATG, however, is approved only for the treatment of acute allograft rejection in kidney transplants. However, both drugs have been studied extensively for both indications. The efficacy of ATG and RATG induction therapy has been described in liver and heart transplant recipients. Use of RATG as part of quadruple therapy in liver transplant is associated with similar rates of patient and graft survival and acute rejection compared with dual therapy; however, a significant increase in the number of CMV infections was noted. The clinical usefulness of quadruple therapy is questionable in light of the increased cost.96 Quadruple-drug therapy results in similar rates of patient and graft survival and malignancy in heart transplants, but a significantly lower rate of acute rejection and infection episodes is seen at 1 year compared with triple-drug therapy.97

lins, including ATG and RATG, should not be administered within 2 months of receiving a live vaccine.


DOSING AND ADMINISTRATION ATG doses range from 10 to 30 mg/kg per day as a single dose for 7 to 14 days. RATG is a more potent compound and is administered at doses of 1 to 1.5 mg/kg per day as a single dose for 7 to 14 days for rejection or for 5 to 10 days for induction of immunosuppression. It is recommended that both ATG and RATG be administered centrally or through a high-flow vein with an in-line 0.22-micron filter over at least 4 hours to minimize phlebitis and thrombosis. However, literature supports peripheral administration of both agents.98,99


MONOCLONAL ANTIBODIES
INTERLEUKIN 2 RECEPTOR ANTAGONISTS (IL2RA) There are currently two available interleukin 2 receptor antagonists, basilixmab, a chimeric monoclonal antibody (25% murine), and daclizumab, a humanized monoclonal antibody (90% human, 10% murine). Daclizumab contains a greater proportion of human sequences, making it theoretically less immunogenic. The percentage of murine component determines the antibody’s affinity for the epitope. Therefore, the chimeric antibody basiliximab has a higher affinity than daclizumab.100


Pharmacology/Mechanism of Action Both basiliximab and daclizumab exert their immunosuppressive effect by specifically binding to the alpha chain (CD25) on the surface of activated T-lymphocytes (see Fig. 87–1). Binding of either basilixmab or daclizumab to the IL-2 receptor prevents IL-2-mediated activation and proliferation of T cells, a critical step in clonal expansion of T cells and the development of allograft rejection. Saturation of the IL-2 receptor occurs rapidly and confers immunosuppressive effect immediately.100


ADVERSE EFFECTS


Pharmacokinetics

Most adverse effects reported with ATG and RATG are related to the lack of specificity for T cells owing to their polyclonal nature. Doselimiting myelosuppression, including leukopenia, anemia, and thrombocytopenia, occurs frequently. Other adverse effects include anaphylaxis, hypotension, hypertension, tachycardia, dyspnea, urticaria, and rash (see Table 87–4). Serum sickness is seen more frequently with ATG than RATG. Nephrotoxicity has been reported but is rare in the absence of serum sickness. Infusion-related febrile reactions are most common with the first few doses and can be managed by premedicating the patient with acetaminophen, diphenhydramine, and steroids. Finally, as with any immunosuppressive agent, ATG and RATG are associated with an increased risk of infections, particularly viral infections, and malignancy.

Most of the pharmacokinetic data available for both basiliximab and daclizumab are in renal transplant patients. Caution must be used when extrapolating these data to non-renal-transplant recipients. Daclizumab has a small volume of distribution, approximately 5.3 L. The system clearance is highly variable and depends on body weight. The terminal half-life of daclizumab is about 20 days in renal transplant patients compared with 3 to 4 days in bone marrow transplant recipients. Specific data on the pharmacokinetics of daclizumab in liver transplant patients are lacking, but the half-life appears to be significantly lower compared with renal transplant recipients. It has been suggested that the increased elimination rate seen in liver transplant recipients may be due to significant intraoperative blood losses as well as loss via ascites. Therapeutic concentrations are 5 to 10 mg/L. Adjustments are not required on the basis of weight, race, gender, or degree of proteinuria. Basiliximab has a slightly higher volume of distribution, 8 L, and a shorter half-life, approximately 7 days. Additionally, the halflife of basiliximab appears to be lower in liver transplant recipients. Increased blood loss did not account for this difference in


DRUG-DRUG AND DRUG-FOOD INTERACTIONS Administration of ATG or RATG can interfere with the immune response to live vaccines, such as varicella vaccine. Immune globu-

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elimination, but losses via ascites accounted for about 20% of basiliximab elimination. It has been recommended that patients with volumes of ascites greater than 10 L receive an additional dose of basiliximab on postoperative day 8.101 While drug elimination is enhanced in liver transplants, receptor suppression with the two-dose regimen seems to be long lasting.102 Both basiliximab and daclizumab saturate CD25 in vivo at serum concentrations of 0.2 and 1 mg/L or greater, respectively.103


Efficacy Induction therapy with IL-2 receptor antagonists has been studied extensively in kidney, liver, and heart transplants.102−107 A metaanalysis of daclizumab and basiliximab in renal transplantation evaluated the result of eight randomized, controlled trials involving more than 1800 patients. IL-2 receptor antagonists reduced the risk of rejection significantly (odds ratio 0.51) in CSA-based regimens at 6 months. No increases in graft loss, infectious complications, malignancy, or death were noted.104 Review of the daclizumab trials continued to show less biopsy-proven rejection at 1 year, 28% versus 43% ( p < 0.0001) in the daclizumab (both double- and triple-therapy combined) and standard-therapy arms, respectively. No graft or patient survival advantage was found for daclizumab-treated patients, but the studies were not powered to detect this difference.103 A large multicenter, randomized trial of 381 liver transplant recipients compared basiliximab with CSA and steroids alone. The results showed a decrease in acute rejection in the basiliximab group regardless of hepatitis C virus (HCV) status, although only the HCVnegative cohort was statistically significant.102 Other investigators have reported higher rates of HCV recurrence in patients receiving daclizumab (54% versus 15%).103 The most effective IL-2 receptor antagonist regimens remain to be defined, particulary for those with HCV. In heart transplantation, induction with daclizumab produced favorable results with a lower incidence of acute rejection: 18% in the daclizumab-treated patients compared with 63% in the group receiving CSA, MMF, and prednisone with no induction therapy (P = 0.04). The time to occurrence of the first rejection episode also was significantly longer in the daclizumab-treated patients.106 There were no adverse reactions to daclizumab and no significant differences between the groups in the incidence of infection or cancer during follow-up. Data for basiliximab in heart transplant recipients are lacking. IL-2 receptor antagonists offer a reasonable addition to CI- or steroid-sparing protocols. In renal transplant recipients, 40% to 50% of patients receiving daclizumab with no initial CI required the eventual addition of CSA.103 Alternative protocols using low-dose CSA in conjunction with daclizumab, MMF, and steroids showed similar results to matched controls107 and lower rejection rates compared with OKT3 induction.100 Basiliximab has been used in combination with low-dose TAC in patients with early evidence of DGF. Similar rates of rejection and steroid-resistant rejection were seen in patients who received basiliximab (20 mg at the time of diagnosis of DGF and again 5 days later) in conjunction with lower TAC doses compared with patients without DGF who received standard TAC doses and no IL2RA induction.100

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ciated with no increased risk of infectious complications or malignancy when compared with standard immunosuppression. In contrast to polyclonal antibody preparations and OKT3, basiliximab and daclizumab have not been associated with infusion-related reactions. However, since the marketing of basiliximab, an increased number of hypersensitivity reactions have been reported. Of note, only one patient developed anti-idiotypic antibodies to the murine portion during clinical trials.100 The manufacturer of basiliximab reported an increase in mortality in a placebo-controlled trial, which was associated with an increase in severe infections.


Drug-Drug and Drug-Food Interactions Reports of increased CSA and TAC levels in patients receiving concomitant basiliximab have recently been published.109,110 Both authors hypothesized a potential interaction with the cytochrome P450. No drug interactions have been reported with daclizumab.


Dosing and Administration Basiliximab is administered as two 20-mg intravenous doses: intraoperatively and again on postoperative day 4. Basiliximab is compatible with both 0.9% sodium chloride and 5% dextrose and can be administered either centrally or peripherally over 20 to 30 minutes in a solution of 50 mL. This regimen results in saturation of the IL-2 receptor for 30 to 45 days. The daclizumab approved dosing regimen for renal transplantation is 1 mg/kg every 2 weeks from the time of transplant for a total of five doses. Daclizumab should be diluted in 50 mL sterile 0.9% sodium chloride and administered peripherally or centrally over 15 minutes. This regimen saturates the IL-2 receptors for approximately 90 to 120 days after renal transplantation.56,100 Alternative dosing regimens have been proposed for daclizumab in combination with TAC, MMF, and steroids: 1 mg/kg every 2 weeks for five doses or, daclizumab 2 mg/kg every 2 weeks for two doses. At 6 months, the probability of kidney or pancreas allograft rejection and patient survival was similar in the daclizumab groups. This is an important finding because the two-dose regimen may have considerable implications for posthospital adminstration.108 Eckhoff and colleagues111 compared liver transplant recipients at risk for renal dysfunction who recieved daclizumab 2 mg/kg on day 0 followed by daclizumab 1 mg/kg on day 5 with a group who received conventional immunosuppression without daclizumab. There were fewer rejection episodes in the daclizumab group, and graft and patient survival were similar.111


MUROMONAB-CD3 (OKT3)
Pharmacology/Mechanism of Action Muromonab-CD3 (OKT3) is a murine monoclonal antibody to the CD3 receptor on mature human T cells (see Fig. 87–1). Minutes following the administration of OKT3, T-cell concentrations decrease dramatically, as measured by CD3 levels. Cells reappear after a few days but bear no CD3 receptors. After cessation of OKT3 therapy, T-cell function normalizes in a week.112


Adverse Effects


Pharmacokinetics

Few adverse effects have been reported with basiliximab and daclizumab (see Table 87–4). In clinical trials, these drugs were asso-

OKT3 has a volume of distribution of 6.5 L and half-life of about 18 hours. Concentrations above 0.9 mcg/mL are considered

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therapeutic. OKT3 concentrations of 800 ng/mL or greater in combination with a CD3+ T cell counts of 12 months

Daily Daily

1–2 times per week 1–2 times per week

Every 1–2 weeks Every 1–2 weeks

Monthly Monthly

Every 1–2 months Every 1–2 months

Once Daily Daily Daily Once Once

Once 1–3 times per week 1–2 times per week 1–2 times per week Every 3 months Every 3 months

Monthly Every 1–2 weeks Every 1–2 weeks Every 1–2 weeks Every 3 months Every 3 months

Every 1–3 months Monthly Monthly Monthly Every 3 months Every 3 months

Every 1–3 months Every 1–2 months Every 1–2 months Every 1–2 months Every 3 months Every 3 months

Chemistries include sodium, potassium, chloride, CO2 content, magnesium, calcium, phosphorus and blood glucose. Liver function tests include total bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transpeptidase (GGTP), alkaline phosphatase. Complete blood count includes white blood cells (WBC), red blood cells (RBC), platelets and/or differential. Lipid panel includes total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride and/or very low-density lipoprotein (VLDL). SCr = serum creatinine; BUN = blood urea nitrogen; HbA1c = hemoglobin A1c.

CARDIOVASCULAR DISEASE Cardiovascular disease is a leading cause of morbidity and mortality in transplant patients.129 Preexisting cardiovascular disease, which is common in end-stage organ failure, is not reversed with transplantation. Additionally, hypertension, hyperlipidemia, and diabetes are common complications in transplant recipients and are independent risk factors that contribute significantly to cardiovascular disease. Chronic rejection has been linked to hypertension and hyperlipidemia.130,131

HYPERTENSION Corticosteroids, CSA, TAC, and impaired kidney graft function may cause post-transplant hypertension. The primary mechanism of CIassociated hypertension in heart transplant recipients may be related to the CI-induced stimulation of intact renal sympathetic nerves and the absence of reflex cardiac inhibition of the sympathetic nervous system, but a number of other mechanisms, including decreased prostacyclin and nitric oxide production, also have been proposed.54,132,133 In addition to the propensity to cause peripheral vasoconstriction, CIs promote sodium retention, resulting in extracellular fluid volume expansion. TAC appears to have less potential to induce hypertension following transplantation than CSA.134 Most classes of antihypertensive medications effectively reduce blood pressure in transplant patients (see Chap. 13).135 Calcium channel blockers traditionally have been the first-line agents to treat hypertension after transplantation.136 In addition to their ability to control blood pressure, calcium channel blockers may ameliorate the nephrotoxic effects of CSA, improve renal hemodynamics, decrease the incidence of delayed graft function and development of allograft atherosclerosis, and provide some immunosuppression. Calcium channel blockers, however, also may contribute to gingival hyperplasia that is often associated with CSA-based immunosuppression.130 CYP 3A4 interactions with CSA and TAC are of concern with this class of medications, particularly with diltiazem, verapamil, and nicardipine, and CSA or TAC concentrations must be monitored to ensure proper dosage adjustments. ACEIs and angiotensin II receptor blockers (ARBs) traditionally have been avoided in kidney transplant recipients because of the potential for hyperkalemia and decreased glomerular filtration rate. ACEIs and ARBs are now considered to be an equivalent alternative to calcium channel blockers for the treatment of hypertension in all transplant recipients. When ACEIs or ARBs are used in patients after transplantation, serum creatinine and potassium levels should be mon-

itored closely. If the increase in serum creatinine is greater than 30% within 1–2 weeks after initiating ACEIs or ARBs, the drug should be discontinued and other measures used to control blood pressure (see Chap. 46). CLINICAL CONTROVERSY Many clinicians avoid using ACEIs in kidney transplant recipients because of the potential to decrease the glomerular filtration rate by promoting efferent arteriole vasodilation in the presence of CI-induced afferent arteriole vasoconstriction. Emerging evidence suggests that this situation does not occur. ACEIs should be avoided in recipients with renal artery stenosis or discontinued in recipients who have an acute significant elevation in serum creatinine after ACEI initiation. Multiple antihypertensive agents usually are necessary to achieve the goal blood pressure in transplant recipients. Therefore, the addition of β-blockers, diuretics, or centrally acting antihypertensives usually is necessary. β-blockers generally are considered to be secondline therapy in solid-organ transplant recipients, because of the potential to worsen metabolic disturbances caused by immunosuppressants, such as hyperkalemia and dyslipidemia. CI-induced hypertension is often salt-sensitive, making it very responsive to diuretics. Centralacting agents (e.g., clonidine) are used often as adjunctive therapy in transplant recipients who are not able to achieve blood pressure control with calcium channel blockers or ACEIs.

HYPERLIPIDEMIA Hyperlipidemia may be exacerbated by corticosteroids, CIs, diuretics, and β-blockers.137 Corticosteroids promote insulin resistance and a decrease in lipoprotein lipase activity, as well as excessive triglyceride production. The mechanism of CI-induced hyperlipidemia is not well understood. CIs may decrease the activity of the lowdensity lipoprotein (LDL) receptor or lipoprotein lipase, altering LDL catabolism.131 TAC appears to have less potential to induce hyperlipidemia than CSA.44,45,138 Post-transplant hyperlipidemia is characterized by elevated LDL, very-low-density lipoprotein (VLDL), triglyceride apolipoprotein B, and lipoprotein(a) levels.131 It is controversial whether the management of hyperlipidemia in transplant recipients should be more aggressive than current guidelines for the general population established by the National Cholesterol Education Program (NCEP).139 Aggressive lipid lowering may not only

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TABLE 87–10. Special Pharmacotherapy Considerations in Transplant Recipients Problem

Pharmacotherapy

Infection Perioperative prophylaxis Pneumocystis carinii pneumonia prophylaxis Fungal Prophylaxis Treatment

Hyperkalemia

Hyperglycemia Diabetes pretransplant

Post-transplant diabetes

Donor culture results Penicillin allergy: vancomycin Bowel decontamination TMP/SMX 400/80 qd or tiw Pentamidine 300 mg inhaled q mo OR Dapsone 50–100 mg po qd Nystatin, clotrimazole Fluconazole, itraconazole, ketoconazole Amphotericin B

Restrict dietary intake; dialysis

Insulin Oral hypoglycemics

Metformin Insulin Oral hypoglycemics

Ulcer Prophylaxis

Hyperlipidemia

H2 -receptor antagonists Sucralfate

Proton pump inhibitors Diet HMG-CoA reductase inhibitors (“statins”) Gemfibrozil

Hypertension

Calcium channel blockers

ACE inhibitors; angiotensin II receptor antagonists

Osteoporosis

Malignancy Prevention

Treatment

Special Considerations

Oral calcium supplementation (1000–1500 mg/day) Oral vitamin D Calcifediol (1000 IU/day) Calcitriol (0.5 mcg/day) Hormone-replacement therapy Calcitonin or oral bisphophonates

Minimize immunosuppressant doses; avoid sun exposure (sun block, hats, clothing); routine self-examinations (skin, lymph nodes); yearly gynecologic/prostate exams Discontinue or minimize immunosuppressants Surgical, radiologic, or anti-neoplastic therapy

Sulfa allergy

Inhibit P450 3A4; monitor CSA and TAC levels; decrease doses Consider liposomal products; decrease or stop CSA or TAC to minimize nephrotoxicity Remember to adjust doses of renally eliminated drugs, e.g., acyclovir, ganciclovir, TMP-SMX May be exacerbated by CSA or TAC or ACEIs, acidosis or RI; fludrocortisone acetate 0.1 mg PO qd–bid for refractory hyperkalemia Glucocorticoids, TAC, and CSA also increase hypoglycemic requirements Insulin requirements will increase with improving renal function Avoid in those with RI Risk factors: Obesity, family history, African-American race, cadaveric kidney, TAC > CSA May resolve/improve as immunosuppressive doses decrease Adjust dose in those with RI Decreased TAC absorption If RI: Caution aluminum content No RI: Caution hypophosphatemia CSA > TAC; consider switch to TAC; discontinue or hold SRL CSA/TAC may increase “statin” levels; start at lowest dose Monitor for muscle cramps, CPK levels and LFTs Adjust dose in those with RI Caution with concomitant “statin” Diltiazem, verapamil inhibit CSA/TAC metabolism Dihydropyridines may potentiate CSA-gingival hyperplasia May exacerbate hyperkalemia Monitor K+ , Scr to assess for renal allograft vascular disease; may be useful in post-transplant erythrocytosis (HCT > 55%) If daily intake 3% Data lacking for bisphosphonates in patients with RI AZA particularly associated with skin cancers CSA/TAC may be associated with lymphoproliferative disorders (lymphomas) Do not abruptly withdraw corticosteroids

TMP-SMX = trimethoprim-sulfamethoxazole; CSA = cyclosporine; TAC = tacrolimus; ACEI = ACE inhibitor; RI = renal insufficiency; CMV = cytomegalovirus; SRL = sirolimus; CPK = creatinine phosphokinase enzymes; LFTs = liver function tests; K+ = potassium; Scr = serum creatinine; HCT = hematocrit.

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arrest the progress or prevent the complications of atherosclerosis but also may promote graft survival in the kidney and heart transplant population. With the use of lipid-lowering agents, potential interactions with immunosuppressive regimens must be considered. Dietary intervention, although safe, may be relatively ineffective for the treatment of hyperlipidemia in the transplant population. Along with dietary modification, dose reduction or withdrawal of CSA and/or steroids may assist in minimizing hyperlipidemia. For most patients, the combination of dietary intervention and an HMGCoA reductase inhibitor should be considered the treatment of choice. HMG-CoA reductase inhibitors are highly effective in the treatment of hyperlipidemia, especially increased LDL, in transplant patients. HMG-CoA reductase inhibitors as a class have been shown to have immunomodulatory effects on MHC expression and T-cell activation and have been shown to reduce cardiac allograft rejection.131,140 HMG-CoA reductase inhibitors should be used with caution in transplant recipients because of several reports of rhabdomyolysis when these agents are combined with CIs.35,50,140 Safety measures, including the use of low HMG-CoA reductase inhibitor doses and avoiding inappropriately high CSA or TAC concentrations. The concurrent use of medications known to increase the risk of myopathy (such as gemfibrozil) should be avoided.131 Patients should be informed of the signs and symptoms of rhabdomyolysis. Baseline and followup creatine phosphokinase (CPK) measurements (every 6 months) have been used to identify patients who develop subclinical rhabdomyolysis when cholesterol-lowering therapy is used. Pravastatin may be preferred as a result of its lower interactive potential with CIs because it is not metabolized by CYP 3A4. The potential for hepatotoxicity from HMG-CoA reductase inhibitors warrants close monitoring of liver function in all transplant recipients.137 Bile acid–binding resins may be used to lower cholesterol in transplant patients, but adequate doses are difficult to achieve without the development of GI adverse effects. Because the absorption of CSA is dependent on the presence of bile in the GI tract, patients should be instructed to separate dosing of bile acid–binding resins and CSA by at least 2 hours. Bile acid–binding resins also should be separated from other immunosuppressants by at least 2 hours to avoid physical adsorption in the GI tract. For transplant patients who have hypertriglyceridemia refractory to dietary intervention, fish oil and fibric acid derivatives are well-tolerated, effective alternatives (see Chap. 21). Fibric acid derivatives are most effective in lowering serum triglyceride concentrations.

POST-TRANSPLANT DIABETES MELLITUS (PTDM) Corticosteroids and CIs can impair glucose control in previously diabetic patients, as well as cause new-onset post-transplant diabetes mellitus (PTDM) in 4% to 20% of patients. Corticosteroids induce insulin resistance and impair peripheral glucose uptake, whereas CIs appear to inhibit insulin production.142 TAC seems to be more diabetogenic than CSA, although recent studies have failed to show a statistical difference.44 Other possible risk factors that have been identified for PTDM include ethnicity (African-American or Hispanic), age (>40 years), pretransplant diabetes status, family history, and weight.143 Patients with PTDM should be referred for nutritional counseling and advised on the merits of weight loss (if appropriate). There are, however, some special considerations in transplant patients. Up to 40% of patients with PTDM will require insulin therapy.142 In diabetic patients who can be managed with an oral hypoglycemic agent, glipizide, which is metabolized extensively by the liver, may be preferred over renally eliminated agents such as glyburide. Metformin should

be used with extreme caution because of the risk of accumulation and lactic acidosis in those with moderate renal impairment. Regardless of therapy, frequent blood glucose monitoring is imperative in the early postoperative phase both to improve glucose control and to identify those with PTDM. Changes in renal function secondary to CI nephrotoxicity or delayed graft function or acute rejection in kidney transplant recipients affects the elimination of many hypoglycemic agents, including insulin, and may result in hyper- or hypoglycemia. Patients and clinicians also should be aware that dose changes of immunosuppressant drugs also affect glycemic control. Tapering of immunosuppressive medications may result in reduced insulin requirements, whereas steroid pulses for the treatment of rejection may result in increased insulin requirements.

INFECTION Both the severity and incidence of infections and deaths due to infections have decreased dramatically since the introduction of CSA and the use of lower steroid dosages. Nonetheless, infection and rejection remain the most frequently encountered complications associated with immunosuppression in the first year after transplantation.144 The risk of infection is related directly to the overall level of immunosuppression and is greatest during the first 3 postoperative months, as well as following treatment of acute rejection episodes.145 Infectious complications following transplantation generally are classified according to the causative organism, site of infection, and time of appearance following surgery. Bacterial infections occur most frequently within the first month after transplantation and generally affect the urinary tract, wound, or vascular access sites. Viral infections are caused most commonly by herpes simplex (early transplant), herpes zoster (late post-transplant), or cytomegalovirus (CMV). Chapter 120 discusses the treatment of infection in the immunocompromised host. Special considerations of therapy in transplant patients for CMV, herpes, and Pneumocystis carinii infections are described in the following paragraphs. Cytomegalovirus (CMV) is the most important viral pathogen affecting transplant patients; 50% to 60% of patients have been infected with the virus. Following transplantation, patients may develop symptomatic primary or secondary CMV infections. A previously CMV-seronegative patient who receives an organ or blood product from a CMV-seropositive donor is considered to have primary CMV infection. A secondary infection is characterized by reactivation of the latent virus or reinfection in a previously seropositive patient. Patients with primary infections generally are more symptomatic than patients with secondary infections. The incidence and severity of CMV infections in transplant recipients are related to the intensity of immunosuppression required to prevent graft rejection. Patients treated on multiple occasions with high-dose steroids or patients receiving OKT3 or antilymphocyte preparations146 and patients with poor HLA matching, cadaveric allografts, and CMV-positive donor serology have more severe CMV disease. Transplant centers use different strategies for managing CMV, which often are based on the risk of CMV infection. Prophylactic strategies use oral or intravenous antiviral or immunoglobulin preparations to prevent the reactivation or emergence of CMV. Prophylaxis is used most often in high-risk patients (i.e., donor-recipient CMVserology mismatch or use of antilymphocyte preparations). Some centers routinely screen transplant recipients for CMV via blood tests (i.e., pp65 antigenemia, polymerase chain reaction [PCR]) and use preemptive therapy in patients who have a positive test. Treatment is given to all patients who have evidence of active CMV infection. Ganciclovir and valganciclovir have been used prophylactically and

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preemptively in transplant patients. Other treatment strategies include intravenous immunoglobulins (IVIGs) and CMV hyperimmune immunoglobulin (CMVIG). Ganciclovir and CMVIG are the mainstays for treatment of CMV infection. CMV has been linked to chronic rejection and cardiac allograft vasculopathy. CLINICAL CONTROVERSY Some clinicians will use CMV prophylaxis for all patients receiving transplants. Others will reserve prophylaxis for only those patients who are at a higher risk for CMV infection, such as those with donor-recipient CMV serology mismatch or recipients who have received induction therapy or rejection treatment with antithymocyte globulin. A third strategy is to preemptively treat patients who have laboratory evidence of CMV infection. Herpes simplex virus (HSV) infections in transplant patients are most commonly the result of reactivation of a previous infection. Symptomatic HSV infection usually presents as labial or oral lesions in the first 1 to 3 months after transplantation, but patients also may present with reactivation of varicella-zoster as “shingles.” Prophylactic therapy with low-dose oral acyclovir delays the development of HSV infections in patients following transplantation. The incidence of Pneumocystis carinii pneumonia (PCP) within the first year after transplantation is reported to be 3% to 5%.147 Low-dose trimethoprim-sulfamethoxazole (TMP-SMX 400 mg/ 80 mg three times weekly) is effective in the prevention of PCP infections. Alternative agents include aerosolized pentamidine (300 mg every month), dapsone, and atovaquone. The duration of PCP prophylaxis is unclear. The risk of infection caused by P. carinii is likely to decrease as immunosuppression is reduced; therefore, prophylaxis in patients requiring treatment for acute rejection may be appropriate.

MALIGNANCY Advances in immunosuppression have decreased the incidence of acute rejection and increased patient survival, thus increasing the patient’s lifetime exposure to immunosuppression. While the precise mechanism is unclear, post-transplant malignancy seems to be related to the overall level of immunosuppression, as evidenced by a difference in the rates of malignancy associated with quadruple versus triple versus dual immunosuppressant regimens. The risk of malignancy in transplant recipients is increased three- to fourfold over the general population. While the risk of lung, breast, colon, and prostate cancers does not appear to increased, a number of cancers that are uncommon in the general population often occur with a higher prevalence in transplant recipients: post-transplant lymphomas and lymphoproliferative disorders (PTLD), Kaposi’s sarcoma, renal carcinoma, in situ carcinomas of the uterine cervix, hepatobiliary tumors, and anogenital carcinomas. Skin cancers are the most common tumors, accounting for 38% of all malignancies. Factors that may predispose transplant recipients to skin cancers include copious sun exposure and therapy with azathioprine, possibly due to azathioprine’s metabolite, nitroimidazole, which causes significant photosensitivity.148 Azathioprine therapy is associated with a 2:1 predominance of squamous over basal cell carcinomas, whereas basal cell carcinoma occurs more frequently in the general population. Azathioprine-induced cutaneous squamous cell carcinoma is also associated with more metastatic disease and accounts for 6% of all deaths in comparison with less than 1% with CSA. Patients must be encouraged to use effective techniques to reduce sun exposure.148

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PTLD encompasses a broad spectrum of disorders ranging from benign polyclonal hyperplasias to malignant monoclonal lymphomas. Factors that predispose patients to PTLD include Epstein-Barr virus seronegativity at transplant and intense immunosuppression, particularly with OKT3 and antithymocyte globulin. Non-renal-transplant recipients are more likely to develop PTLD secondary to the heavy immunosuppression used to reverse rejection. Administration of ganciclovir or acyclovir preemptively during antilymphocyte therapy may decrease the risk of eventual PTLD. Treatment of life-threatening PTLD generally includes severe reduction or cessation of immunosuppression. Other options include systemic chemotherapy or rituximab.149 Post-transplant malignancies appear an average of 5 years after transplantation and increase with the length of follow-up. As many as 72% of patients surviving greater than 20 years may be affected. Malignancy accounts for 11.8% of deaths after cardiac transplantation and is the single most common cause of death in the sixth to the tenth posttransplant years.147

CONCLUSION Transplantation is a lifesaving therapy for several types of end-organ failure. Advances in the understanding of transplant immunology have produced an unprecedented number of choices in terms of immunosuppression. The increasing number of effective immunosuppressive medications and therapies offer clinicians diverse ways to prevent allograft rejection in a patient-specific manner. However, the vast array and efficacy of currently available immunosuppressive agents make it increasingly difficult to evaluate their long-term efficacy. Clinicians must be keenly aware of the adverse effects of immunosuppressive medications and their treatment in order to optimize the care of the transplanted patient.

ABBREVIATIONS 6-MP: 6-mercaptopurine ACE: angiotensin-converting enzyme ARB: angiotensin II receptor blocker ATG: antithymocyte globulin ATN: acute tubular necrosis AUC:area under the concentration curve AZA: azathioprine BUN: blood urea nitrogen CABG: coronary artery bypass grafting CAD: coronary artery disease CI: calcineurin inhibitor Cmax : peak concentration CMV: cytomegalovirus CPK: creatinine phosphokinase CSA: cyclosporine CYP: cytochome P450 liver enzyme system DGF: delayed graft function ESRD: end-stage renal disease FKBP: FK-binding protein GI: gastrointestinal HCT: hematocrit HLA: human leukocyte antigen HPLC: high-performance liquid chromatography HSV: herpes simplex virus IABP: intraaortic balloon pump

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IgG: immunoglobulin G IL-2: interleukin 2 IL2RA: interleukin 2 receptor antagonist IMPDH: inosine monophosphate dehydrogenase ISHLT: International Society of Heart and Lung Transplantation LDL: low-density lipoprotein LVAD: left ventricular assist device MELD: model for end-stage liver disease MHC: major histocompatibility complex MMF: mycophenolate mofetil MPA: mycophenolic acid MPAG: mycophenolic acid glucuronide mTOR: mammalian target of rapamycin NFAT: nuclear factor of activated T cells NYHA: New York Heart Association OKT3: muromonab-CD3 PCP: Pneumocystis carinii pneumonia PRA: panel of reactive antibodies PTCA: percutaneous transluminal coronary angioplasty PTDM: posttransplant diabetes mellitus PTLD: posttransplant lymphoproliferative disorder RBC: red blood cell RIA: radioimmunoassay SIR: sirolimus TAC: tacrolimus TGN: 6-thioguanine nucleotides tmax : time to peak concentration TMP-SMX: trimethoprim-sulfamethoxazole TNF: tumor necrosis factor TPMT: thiopurine methyltransferase UNOS: United Network for Organ Sharing VLDL: very-low-density lipoprotein WBC: white blood cells XO: xanthine oxidase Review Questions and other resources can be found at www.pharmacotherapyonline.com.

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80. Oberbauer R, Kreis H, Johnson RWG, et al. Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune maintenance regimen study. Transplantation 2003;76:364–370. 81. Ankersmit HJ, Roth G, Zuckermann A, et al. Rapamycin as rescue therapy in a patient supported by biventricular assist device to heart transplantation with consecutive ongoing rejection. Am J Transplant 2003;3: 231–234. 82. Mancini D, Pinney S, Burkhoff D, et al. Use of rapamycin slows progression of cardiac transplantation vasulopathy. Circulation 2003;108:48–53. 83. van Hooff JP, Squifflett JP, Wlodarczyk Z, et al. A prospective, randomized multicenter study of tacrolimus in combination with sirolimus in renal transplant receipients. Transplantation 2003;75:1934–1939. 84. Pham SM, Qi XS, Mallon SM, et al. Sirolimus and tacrolimus in clinical cardiac transplantation. Transplant Proc 2002;34:1839–1842. 85. Flechner SM, Goldfard D, Moldin C, et al. Kidney transplantation without calcineurin inhibitor drugs: A prospective, randomized trial of sirolimus versus cyclosporine. Transplantation 2002;74:1070–1076. 86. Kreis H, Cisterne JM, Land W, et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000;69:1252–1260. 87. Saunders RN, Metcalfe MS, Nicholson ML. Rapamycin in transplantation: A review of the evidence. Kidney Int 2001;59:3. 88. Kahan BD, Napoli KL, Kelly PA, et al. Therapeutic drug monitoring of sirolimus: Correlations with efficacy and toxicity. Clin Transplant 2000; 14:97–109. 89. Chueh SCJ, Kahan BD. Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporine-based immunosuppressive regimen: Incidence, risk factors, progression, and prognosis. Transplantation 2003;76:375–382. 90. Guilbeau JM. Delayed wound healing with sirolimus after liver transplant. Ann Pharmacother 2002;36:1391–1395. 91. van Gelder T, ter Meulen CG, Hen´e R, et al. Oral ulcers in kidney transplant recipients treated with sirolimus and mycophenolate mofetil. Transplantation 2003;75:788–791. 92. Kaplan B, Meier-Kriesche HU, Napoli KL, Kahan BD. The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. Clin Pharmacol Ther 1998;63:48. 93. McAlister VC, Mahalati K, Peltekian KM, et al. A clinical pharmacokinetic study of tacrolimus and sirolimus combination immunosuppression comparing simultaneous to separated administration. Ther Drug Monit 2002;23:346–350. 94. Zimmerman JJ, Ferron GM, Lim HK, Parker V. The effect of a highfat meal on the oral bioavailability of the immunosuppressant sirolimus (rapamycin). J Clin Pharmacol 1999;39:1155–1161. 95. Bunn D, Lea CK, Bevan DJ, et al. The pharmacokinetics of antithymocyte globulin (ATG) following intravenous infusion in man. Clin Nephrol 1996;45:29–32. 96. Neuhaus P, Klupp J, Langrehr JM, et al. Quadruple tacrolimus-based induction therapy including azathioprine and ALG does not significantly improve outcome after liver transplantation when compared with standard induction with tacrolimus and steroids: Results of a prospective, randomized trial. Transplantation 2000;69:2343–2353. 97. Carrier M, White M, Perrault LP, et al. A 10-year experience with intravenous Thymoglobuline in induction of immunosuppression following heart transplantation. J Heart Lung Transplant 1999;18:1218–1223. 98. Marvin MR, Drogan C, Sawinski D, et al. Administration of rabbit antithymocyte globulin (Thymoglobulin) in ambulatory renal-transplant patients. Transplantation 2003;75:488–489. 99. Rahman GF, Hardy MA, Cohen DJ. Administration of equine antithymocyte globulin via peripheral vein in renal transplant recipients. Transplantation 2000;69:1958–1960. 100. Cibrik DM, Kaplan B, Meier-Kriesche H. Role of anti-interleukin-2 receptor antibodies in kidney transplantation. BioDrugs 2001;15:655–666. 101. Kovarik J, Breidenbach T, Gerveau C, et al. Disposition and immunodynamics of basiliximab in liver allograft recipients. Clin Pharmacol Ther 1998;64:66–72.

102. Moser, MAJ. Options for induction immunosuppression in liver transplant recipients. Drugs 2002;62:995–1011. 103. Carswell CI, Plosker GL, Wagstaff AJ. Daclizumab: A review of its use in the management of organ transplantation. BioDrugs 2001;15:745–773. 104. Adu D, Cockwell P, Ives NJ, et al. Interleukin-2 receptor monoclonal antibodies in renal transplantation: Meta-analysis of randomized trials. Br Med J 2003;326:789–794. 105. Neuhaus P, Clavien PA, Kittur D, et al. Improved treatment response with basiliximab immunoprophylaxis after liver transplantation: Results from a double-blind randomized placebo-controlled trial. Liver Transpl 2002;8:132–142. 106. Beniaminovitz A, Itescu S, Letiz K, et al. Prevention of rejection in cardiac transplantation by blockade of the interleukin-2 receptor with a monoclonal antibody (see comments). N Engl J Med 2000;342: 613–619. 107. Leitz K, John R, Beniaminovitz A, et al. Interleukin-2 receptor blockade in cardiac transplanation: Influence of HLA-DR locus incompatibility on treatment efficacy. Transplantation 2003;75:781–787. 108. Stratta RJ, Alloway RR, Lo A, Hodge E. Two-dose daclizumab regimen in simultaneous kidney-pancreas transplant recipients: Primary endpoint analysis of a multicenter, randomized study. Transplanation 2003; 75:1260–1266. 109. Strehlau J, Pape L, Offner G, et al. Interleukin-2 receptor antibodyinduced alterations of ciclosporin dose requirements in paediatric transplant recipients. Lancet 2000;356:1327–1328. 110. Sifontis NM, Benedetti E, Vasquez EM. Clinically significant drug interaction between basiliximab and tacrolimus in renal transplant recipients. Transplant Proc 2002;34:1730–1732. 111. Eckhoff DE, McGuire G, Sellers M, et al. The safety and efficacy of a two-dose daclizumab (Zenapax) induction therapy in liver transplant recipients. Transplantation 2000;69:1867–1872. 112. Wilde MI, Goa KL. Muromonab-CD3: A reappraisal of it pharmacology and use as prophylaxis of solid organ transplant rejection. Drugs 1996;51:865–894. 113. Shield CF III, Jacobs RJ, Wyant S, Da A. A cost-effective analysis of OKT3 induction therapy in cadaveric kidney transplantation. Am J Kidney Dis 1996;27:855–864. 114. Calne R, Moffatt SD, Friend PJ, et al. Campath-IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplant 1999;68:1613. 115. Knechtle SJ, Pirsch JD, Becher BN, et al. Campath-1H induction plus rapamycin monotherapy in renal transplantation (abstract). Am J Transplant 2002;2:S459. 116. Tzakis AG, Kato T, Nishida S, et al. Preliminary experience with campath 1H (C1H) in intestinal and liver transplantation. Transplantation 2003;75:1227. 117. Reams BD, Davis RD, Curl J, Palmer SM. Treatment of refractory acute rejection in a lung transplant recipient with campath 1H. Transplanation 2002;74:903. 118. Marcos A, Eghtesad G, Fung JJ, et al. Use of alemtuzumab and tacrolimus monotherapy for cadaveric liver transplantation: With particular reference to Hepatitis C virus. Transplantation 2004;78:966–971. 119. Kahan BD, Wong RL, Carter C, et al. A phase I study of a 4-week course of SDZ-RAD (RAD) quiescent cyclosporine-prednisone-treated renal transplant recipients. Transplantation 1999;68:1100. 120. Kovarik JM, Kahan BD, Kaplan B, et al. Longitudinal assessment of everolimus in de novo renal transplant recipients over the first posttransplant year: Pharmacokinetics, exposure-response relationships, and influence on cyclosporine. Clin Pharmacol Ther 2001;69:48–56. 121. Nashan B. Early clinical experience with a novel rapamycin derivative. Ther Drug Monit 2002;24:53–58. 122. Kirchner GI, Meier-Wiedenbach I, Manns MP. Clinical pharmacokinetics of everolimus. Clin Pharmacokinet 2004;43:83–95. 123. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003;349:847–858. 124. Williams JW, Mital D, Chong A, et al. Experiences with leflunomide in solid organ transplantation. Transplantation 2002;73:358–366.

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CHAPTER 87 125. Hardinger KL, Wang CD, Schnitzler MA, et al. Prospective, pilot, openlabel, short-term study of conversion to leflunomide reverses chronic renal allograft dysfunction. Am J Transplant 2002;2:867–871. 126. Koshiba R, van Damme B, Rutgeerts O, et al. FTY720, an immunosuppressant that alters lymphocyte trafficking, abrogates chronic rejection in combination with cyclosporine A. Transplantation 2003;75:945–952. 127. Ferguson RM, Mulgaonkar S, Tedesco H, et al. High efficacy of FTY720 with reduced cyclosporine dose in preventing rejection in renal transplantation: 12-month preliminary results (abstract 624). Am J Transplant 2003;3(suppl 5):311. 128. Tedesco H, Kahan B, Maurad G, et al. FTY720 combined with Neoral and corticosteroids is effective and safe in prevention of acute rejection in renal allograft recipients (interim data) (abstract 429). Am J Transplant 2001;1(suppl 1):243. 129. Bostom AD, Brown RS, Chavers BM, et al. Prevention of post-transplant cardiovascular disease: Report and recommendations of an ad hoc group. Am J Transplant 2002;2:491–500. 130. Zhang R, Leslie B, Boudreaux P, et al. Hypertension after kidney transplantation: Impact, pathogenesis and therapy. Am J Med Sci 2003; 325:202–208. 131. Moore R, Hernandez D, Valantine H. Calcineurin inhibitors and posttransplant hyperlipidemias. Drug Saf 2001;24:755–766. 132. Textor SC, Taler SJ, Canzanello VJ, Schwartz L. Cyclosporine, blood pressure and atherosclerosis. Cardiol Rev 1997;5:141–151. 133. Ventura HO, Malik FS, Mehra MR, et al. Mechanisms of hypertension in cardiac transplantation and the role of cyclosporine. Curr Opin Cardiol 1997;12:375–381. 134. Taylor DO, Varr ML, Radovancevic B, et al. A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: Decreased hyperlipidemia and hypertension with tacrolimus. J Heart Lung Transplant 1999;18:336–345. 135. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003:289; 2560–2572.

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136. Tylicki L, Habicht A, Watchinger B, H¨orl WH. Treatment of hypertension in renal transplant recipients. Curr Opin Urol 2003;13:91–98. 137. Massy ZA, Kasiske BL. Post-transplant hyperlipidemia: Mechanisms and management. J Am Soc Nephrol 1996;7:971–977. 138. Vincenti F, et al. Tacrolimus (FK506) in kidney transplantation: Fiveyear survival results of the U.S. multicenter, randomized, comparative trial. Transplant Proc 2001;33:1019–1020. 139. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497. 140. Mach F. Statins as immunomodulators. Transplant Immunol 2002;9: 197–200. 141. Asberg A. Interactions between cyclosporin and lipid-lowering drugs: implications for organ transplant recipients. Drugs 2003;63:367– 378. 142. Jindal RM, Sidner RA, Milgrom ML. Post-transplant diabetes mellitus: The role of immmunosuppression. Drug Saf 1997;16:242–257. 143. Reisæter AV, Hartmann A. Risk factors and incidence of post-transplant diabetes mellitus. Transplant Proc 2001;33:8–18S. 144. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998;338:1741–1751. 145. Thaler SJ, Rubin RH. Opportunistic infections in the cardiac transplant patients. Curr Opin Cardiol 1996;11:191–203. 146. Hebart H, Kanz L, Jahn G, Einsel H. Management of cytomegalovirus infection after solid-organ or stem-cell transplantation. Drugs 1998;55: 59–72. 147. Higgins RM, Bloom SL, Hopkin JM, Morris PJ. The risks and benefits of low-dose cotrimoxazole prophylaxis for Pneumocystis pneumonia in renal transplantation. Transplantation 1989;47:558–560. 148. Penn I. Post-transplant malignancy: The role of immunosuppression. Drug Saf 2000;23:101–113. 149. Berney T, Delis S, Kato T, et al. Successful treatment of post-transplant lymphoproliferative disease with prolonged rituximab treatment in intestinal transplant recipients. Transplantation 2002;74:1000–1006.

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88 OSTEOPOROSIS AND OSTEOMALACIA Mary Beth O’Connell and Terry L. Seaton

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Women and men over age 50 should be assessed for fac-

tors that increase the risk of developing osteoporosis and related fractures. Patients with premature or severe osteoporosis should be evaluated for secondary causes of bone loss.

2 Bone density testing can establish the degree of bone health,

predict fracture risk, and influence prevention and treatment decisions. Portable equipment can be used as a preliminary screening method in the community to determine the need for further testing.

3 All people, regardless of age, should incorporate a healthy

6 Raloxifene is an alternative treatment option to prevent vertebral fractures, particularly in women who cannot tolerate or will not take bisphosphonates. It may also be useful for women who have a history of breast cancer or a significant risk for developing breast cancer (investigational).

7 Although estrogens increase bone mineral density and decrease fractures, they are no longer recommended for osteoporosis prevention because of toxicity concerns. When used to treat menopausal symptoms, they will have a positive bone effect.

lifestyle beginning at birth that emphasizes regular exercise, nutritious diet, and tobacco avoidance to prevent and treat osteoporosis.

8 Male osteoporosis is often secondary to specific diseases

4 To ensure adequate calcium intake, most Americans will

9 Patients chronically taking glucocorticoids need to be iden-

need supplementation with 500 mg of elemental calcium once or twice daily. Most elderly patients require vitamin D supplementation of 400 to 1000 units/day, from sources such as beverages, multivitamins, and combination calcium and vitamin D products.

5 Bisphosphonates are the cornerstone for osteoporosis treat-

ment. They are the drugs of choice because they prevent both nonvertebral (especially hip) and vertebral fractures.

Despite being an essentially preventable condition, osteoporosis remains a disturbingly common health problem. As such, the U.S. president declared 2002–2011 to be the “Decade of the Bone and Joint,” and the U.S. Surgeon General in 2004 released a report, “Bone Health and Osteoporosis.” This report has activities for patients and health professionals to use in promoting bone health and preventing complications of osteoporosis (www.hhs.gov/surgeongeneral/library/bonehealth/). Decreased bone mass, quality, and strength contribute to increased osteoporosis and fracture risk. Osteoporosis-related fractures commonly cause pain, kyphosis, disability, and death. Because a perfect bone formation therapy remains elusive, clinicians must actively promote a bone-healthy lifestyle beginning at birth in all people to prevent bone loss. Osteomalacia, or deficient bone mineralization, is less common but also leads to skeletal muscle weakness, fractures, and other complications. This chapter reviews bone physiology, pathophysiol-

and drugs and responds well to bisphosphonate therapy and lifestyle changes including diet.

tified and started on bisphosphonate therapy to prevent osteoporosis-related fractures.

10 Osteomalacia, although less common than osteoporosis,

can be insidious and coexist with osteoporosis. A serum 25-hydroxyvitamin D concentration should be obtained in anyone with decreased oral vitamin D intake, limited or no sun exposure, or unexplained muscle weakness or pain.

ogy, and assessment, and offers nonpharmacologic and pharmacologic prevention and treatment strategies for these skeletal diseases.

OSTEOPOROSIS EPIDEMIOLOGY The exact prevalence is unknown, but experts estimate that nearly half of Americans aged 50 years or older, or approximately 44 million people, have low bone mass. This number is expected to rise to over 60 million people during the next 15 years. The incidence varies widely among subpopulations and depends on many risk factors, the skeletal site measured, and the radiologic technology used. In the late 1990s, based on peripheral bone mineral density (BMD) measurements, 40% of postmenopausal women had osteopenia and 7% had osteoporosis.1 1645

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When World Health Organization BMD classifications are applied to central BMD (femoral neck) data from the third National Health and Nutrition Examination Survey (NHANES III, conducted from 1988 to 1994), the respective osteopenia and osteoporosis prevalences among American subgroups are as follows:2 r r r r r

Non-Hispanic white women: 52% and 20% Mexican-American women: 49% and 10% Non-Hispanic black women: 35% and 5% Men of all races: 47% and 6%, using the mean young male BMD Men of all races: 33% and 4%, using the mean young female BMD

Osteoporosis increases with age. Osteoporosis prevalences are even higher for nursing home residents. Hundreds of thousands of fractures occur each year in the United States. The lifetime risk of a white woman experiencing a fracture is approximately 50%.3 Fracture risk increases with age and lower BMD.

ETIOLOGY AND RISK FACTORS 1 Many modifiable and nonmodifiable factors are associated with

an increased risk of developing osteoporosis and related bone fractures (Table 88–1).3−8 The magnitude and significance of these risk factors varies by gender, ethnicity, age, and the duration of risk factor presence. After accounting for confounders, the four strongest factors that predict fracture risk are low BMD, prior fragility fracture, age, and family history of osteoporosis.7 The largest trial, the Study of Osteoporotic Fractures, revealed that women with five or more risk factors were at increased risk of hip fracture compared to women with two or fewer risk factors.9 While the existence of multiple risk factors incurs greater fracture risk, the absence of risk factors does not necessarily eliminate fracture risk.

PHYSIOLOGY BONE FUNCTION AND COMPOSITION The skeleton provides structural support, protects vital organs and the hematopoietic system, and maintains homeostasis of calcium and other ions. The two types of bone, trabecular (cancellous) and cortical (compact) bone, occur in varying amounts at different anatomic sites: r r r r

Distal radius: 75% cortical and 25% trabecular Lumbar spine: 34% cortical and 66% trabecular Femoral neck: 75% cortical and 25% trabecular Trochanter: 50% cortical and 50% trabecular.10

Trabecular bone is a meshwork of struts giving it a large surface area that is in close contact with the bone marrow cavity for bone turnover and metabolic activity. Cortical bone is formed in layers and is highly calcified (about 80% to 90%). Because of these different structures and environments, trabecular bone is more metabolically active and cortical bone is more structurally strong and protective. Bone comprises minerals (50% to 70%), an organic matrix (20% to 40%), water (5% to 10%), and lipids (3 months) Anticonvulsants (phenytoin, phenobarbital) Heparin Parenteral nutrition Thyroid supplements Aluminum Medroxyprogesterone (acetate contraceptive implant) Lithium Immunosuppressants Diuretics (loop) Cancer chemotherapy Gonadotropin-releasing hormone agonists Prior fall or fear of falling Impaired senses (vision or hearing) Physical disabilities (deconditioning/decreased strength, ambulation difficulties) Environmental (obstacles, lack of handrails, poor lighting, slippery floors) Orthostatic hypotension Visual impairment Environmental obstacles and hazards Cognitive impairment Medications Antidepressants (tricyclic agents or selective serotonin reuptake inhibitors) Benzodiazepines (especially long-acting) Diuretics (any) Hypotensive agents (any)

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Phosphate

Ca2+ Mg2+ Na+ Osteoblast

Integrin molecules

Osteoclast

Osteoid deposition

H+

Proteases

Mineralization phase Quiescence

Formation

Reversal

Resorption

F2

ME

las he t Ru dgeh SO n×2 og X

bla sts

F

MR

m

yo

cy te

s

FIGURE 88–1. Steps in bone remodeling: resorption, reversal, formation, and quiescence. See text for details.

Chondrocyte

ian Mesenychmal Stem cell

Adipocyte Leptin Run×2 PPARγ

C/EBPs PPARγ

Ind

Pre-osteoblast

Lining Cell

Osteoblast

SF

BMP TGFβ PTH, PTHrP Wnt, LRP5 GH, FGF IGF, Indian hedgehog Vitamin D Transcription factors Run×2, CBFAI, Osterix

FosB Fral Osterix Run×2

MC

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Osteocyte Receptors: PTH, PG, E, D, integrins, cytokines, P, A Influences: E,TGF-β, BMP Expresses: cytokines, IGFBP, PG leptin, osteocalcin, collagen, CSF-1 OPG

−

RANKL

+

RANK

Osteoclast

Myeloid cell

1KK/NF-κB TRAF 6 Monocyte or MCSF Preosteoclast C-fms transcription Macrophage c-fos factors PDGF MCSF RANKL JNK ERK Src

Receptors: IL-1, IL-4, cfms PGE2, TGFβ, INFγ 2, calcitonin Expresses: TRAP, cathepsin K, αVβ3, H+

FIGURE 88–2. Differentiation and feedback control of osteoblasts and osteoclasts. αVβ3, integrin; A, androgen; BMP, bone morphogenetic proteins; C/EBP, IGFBP, insulin-like growth factor binding protein; CCAAT-enhancer binding protein; cfms, transcription factor; CSF, colony-stimulating factor; cFOS, activator protein; D, vitamin D; E, estrogen; ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; fos B, regulatory protein; Fral, regulatory protein; GH, growth hormone; H+ , hydrogen ion; IGF, insulin-like growth factor; CBFAI, transcription factor; IKK, inhibitor of NF-κB kinase; IL, interleukins; INF, interferon; JNK, c-Jun N-terminal kinase; LRP, Wnt co-receptor; MCSF, macrophage colony-stimulating factor; MRF, myogenic regulatory factors; MEF, myocyte-enhancer factor; NF-κB, nuclear factor κB; OPG, osteoprotegerin; osterix, transcription factor; P, progestin; PDGF; platelet-derived growth factor; PG, prostaglandin; PPAR, peroxisome proliferator-activated receptor; PTH, parathyroid hormone; PTHrP, PTHrelated peptide; RANK, receptor activator of nuclear factor κB; RANKL, receptor activator of nuclear factor κB ligand; Runx2, rnt-related transcription factor 2; Src, tyrosine kinase; SOX, transcription factor; TGF, transforming growth factor; TNF, tumor necrosis factor; TRAF6, TNF receptor associated factor 6; TRAP, tartrate-resistant acid phosphatase; Wnt, protein.

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CHAPTER 88

Serum Calcium and Phosphate Regulation and Vitamin D Metabolism Vitamin D and PTH maintain calcium homeostasis (Fig. 88–3).10,13,14 The sun (ultraviolet B, 290 to 315 nm) converts 7-dehydrocholesterol in the skin to vitamin D3 . Sunscreens inhibit vitamin D skin production. In northern climates, during the winter months the angle of the sun limits the ability to create vitamin D. Significant seasonal variations lead to fluctuations in 25(OH) vitamin D concentrations. Nadirs occur in February and March and peaks occur in August.15,16 Although a few foods naturally contain vitamin D3 (e.g., cholecalciferol from fish oils) or vitamin D2 (e.g., ergocalciferol from plants), most dietary intake is from foods fortified with vitamin D (Table 88–2). Because both vitamin D3 and D2 work similarly in the body, they are referred to here as vitamin D. Vitamin D undergoes hepatic conversion to 25(OH) vitamin D (calcidiol) via D-25hydroxylase (cytochrome P450 27A1). PTH stimulates renal conversion of 25-hydroxyvitamin D to the active form, 1α-25-dihydroxyvitamin D (calcitriol), via 25(OH)D-1α-hydroxylase (cytochrome P450 27B1). Decreased serum calcium concentrations lead to increased serum PTH concentrations, which lead to elevated calcitriol concentrations (see Fig. 88–3). Calcitriol promotes intestinal calcium absorption, and calcitriol and PTH work together to release calcium from bone to restore homeostasis. Polymorphisms with the intestinal vitamin D receptor (BsmI, ApaI, TaqI, and FokI) have been inconsistently

DIET

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D3

D3 D2 VITAMIN D

25-OH-D 1,25(OH)2 D

1,25(OH)2 D

PTH

Ca Pi

Ca

Pi

Blood Ca+ + , Pi Resorption

FIGURE 88–3. Effects of vitamin D and parathyroid hormone on calcium balance. See text for details. PTH, parathyroid hormone, Ca, calcium, Pi, phosphorus.

associated with low bone density.17 Vitamin D receptors are found in many tissues, such as bone, intestine, brain, heart, stomach, pancreas, lymphocytes, skin, and gonads.14 Serum phosphorus is less tightly regulated than serum calcium. Excess ingested phosphorus is absorbed and adjusted by the kidney.

TABLE 88–2. Dietary Sources of Calcium and Vitamin Da Food

Serving Size

Calcium Content (mg)

Vitamin D Content (units)

Milk Powdered nonfat milk Ice cream Yogurt, fortified American cheese Cheddar cheese Cottage cheese Swiss cheese Parmesan cheese Cheese pizza Macaroni and cheese Slim Fast Orange juice, fortified Soymilk, fortified Bread, fortified Cereals, fortified Sardines with bones Salmon with bones Catfish Halibut Tuna Almonds Bok choy Broccoli Collards Cornbread Egg, medium Figs, dried Kale Orange Soybeans Spinach Tofu Turnip greens

1 cup 1 teaspoon 1 cup 1 cup 1 oz 1 oz 1/2 cup 1 oz 1 tablespoonful 1 slice 1 cup 11 oz 1 cup 1 cup 1 slice 1 cup 3 oz 3 oz 3 oz 3 oz 4 oz 1 oz 1/2 cup 1 cup 1/2 cup 1 slice 1 5 medium 1/2 cup 1 1 cup 1/2 cup 4 oz 1/2 cup

300 50 200 240–415 150 211 100 250 70 150 360 400 350 80–300 100 100–250 370 170–210

100

80 125 130–160 180 85 55 125 95 52 130 110 140 125

60

140 100 100 60 230 310 570 680 260

25

a To calculate calcium content, multiply precentage on package by 1000. To calculate vitamin D content, multiply percentage on package by 400.

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PTH also controls the kidney “set point” and decreases renal phosphorus reabsorption.

PATHOPHYSIOLOGY OF OSTEOPOROSIS Osteoporosis is “characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk.”3 Bone loss results when resorption exceeds formation. The World Health Organization classifies bone mass based on T-score (number of standard deviations from the mean compared to bone mass of average young women). Normal bone mass is defined as a T-score greater than –1, osteopenia as a Tscore of –1 to –2.5, and osteoporosis as a T-score of less than –2.5.3,7 In addition to low BMD, high bone turnover, poor bone strength, and impaired bone architecture result in the bone’s increased susceptibility to fracture. Severe osteoporosis is defined as a history of a fragility fracture plus a T-score 7.5 mg prednisone/ day for >3 months) or FDA-approved osteoporosis therapy. Knowledge of low BMD can encourage prevention and lead to positive lifestyle changes.

BIOCHEMICAL AND BIOPSY EVALUATION A complete blood count, chemistry panel (with calcium corrected for albumin), erythrocyte sedimentation rate, PTH concentration, and 24-hour urine for calcium and creatinine are occasionally ordered to determine secondary causes.4 Measurement of 25(OH) vitamin D is becoming more common. Measurement of TSH, free T4 (thyroxine) and free T3 (triiodothyronine) can be used to rule out hyperthyroidism from endogenous disease or thyroid replacements. In the past, biochemical markers have been considered as research tools only.7,10 Now that increased bone turnover independently predicts fracture risk and more automated and precise assays exist, these tests may become more common for drug selection and monitoring.10 Response to drug therapy can be measured more quickly than bone density measurements, 1 to 3 months vs. 6 to 12 months,

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respectively.4,10 A decrease of bone resorption tests of at least 20% is considered a positive response. Until assay variability is further improved, these tests should not be used for diagnosis. Commonly used markers of bone resorption include urine and serum C-terminal or N-terminal telopeptides and urine deoxypyridinoline, and of bone

formation include bone-specific alkaline phosphatase and osteocalcin. When possible, these tests should be performed at similar times due to circadian rhythms. Bone biopsy is rarely useful for osteoporosis, but can be used to identify other conditions such as osteomalacia.


PREVENTION AND TREATMENT: Osteoporosis
DESIRED OUTCOMES

to restore independence and quality of life, and prevent subsequent fractures or death.

The goal from birth to around 20 to 30 years of age is to achieve the highest peak bone mass as possible. Beyond this age, the goals are to maintain BMD and minimize age-related and postmenopausal bone loss. In women and men with osteopenia, prevention of osteoporosis is the goal. For a variety of reasons, osteoporosis prevention is not always possible. For those at significant risk of developing an osteoporosisrelated fracture, the aims are to increase bone mineral density, prevent further bone loss, and to prevent falls and fractures and their associated sequelae. For those who experience an osteoporosis-related fracture, the goals are to achieve adequate pain control, maximize rehabilitation


GENERAL APPROACH TO TREATMENT A bone-healthy lifestyle beginning at birth is advocated for all people throughout life. Calcium and vitamin D supplements are used for everyone when diet is insufficient. Treatment of osteopenia remains controversial (see clinical controversy below). Prescription medications, with bisphosphonates being the drugs of choice, are used for treating patients with a T-score of –2.5 or lower. Figure 88–4

All people throughout life • • • • •

Proper nutrition (minerals and electrolytes, vitamins, protein, carbohydrates) Calcium and vitamin D supplementation if needed to achieve adequate intakes Optimal physical activity (weight-bearing, muscle strengthening, balance) Healthy social habits (nonsmoking, minimal alcohol and caffeine) Fall and trauma prevention (environment, disability aids)

Consider treating without measuring BMD

Population appropriate for BMD testing • All women ≥ 65 years of age • Women aged 60–64 years, with increased risk for osteoporotic fractures • Men at high risk

• Men and women with increased risk plus a fragility fracture • Men and women taking chronic systemic glucocorticoids

Hip osteoporosis T-score < −2.5

Treat with bisphosphonate

Bisphosphonate intolerant

Treatment Options • Parenteral bisphosphonate • Teriparatide • Raloxifene • Calcitonin

Normal BMD T-score > −1

Z-score < −2.0

Spine osteoporosis only T-score < −2.5

Workup for secondary osteoporosis • PTH • TSH • 25-OH vitamin D • CBC • Chemistry panel • Condition-specific tests

Treatment options • Bisphosphonate • Raloxifene • Calcitonin

Osteopenia T-score of −1 to −2.5

Monitor DXA every 1–5 years. Data supporting treatment with medication are inconclusive

Treat underlying cause if present

FIGURE 88–4. Bone health therapeutic algorithm. BMD, bone mineral density; CBC, complete blood count; DXA, dual-energy x-ray absorptiometry; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone.

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provides an osteoporosis management algorithm that incorporates both nonpharmacologic and pharmacologic approaches.

OSTEOPOROSIS AND OSTEOMALACIA

TABLE 88–4. Daily Calcium and Vitamin D Requirements

CLINICAL CONTROVERSY Not all clinicians believe that women and men with osteopenia, especially premenopausal women, should receive osteoporosis prevention beyond instituting bone-healthy lifestyle and calcium and vitamin D supplementation. Although some statistically significant findings exist, the absolute clinical value of treatment is very small. Women with osteopenia have a 1.8-fold greater risk for developing a fracture than women with normal BMD, but the absolute risk difference is very low (0.86 fractures/100 person-years with normal BMD vs. 1.55 fractures/100 person-years with osteopenia).1 The FOSIT study investigators report reduced fracture risk in 1 year with alendronate in patients with either osteopenia or osteoporosis, but in a trial that was only designed to assess BMD change.130 Furthermore, the patients with osteopenia were not analyzed separately. Reanalysis of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial72 found that postmenopausal women with osteopenia had a 75% reduction in new clinical vertebral fractures compared with the placebo group (16 vs. 4 new fractures, respectively).131 Because long-term data on treating osteopenia in younger premenopausal, perimenopausal, or postmenopausal women or men with osteoporosis prescription medications are not known, the benefit-risk profile for early or lifelong use is also not known. Until clinical data are sufficiently collected, an adequate guideline cannot be established and a pharmacoeconomic analysis cannot be conducted.


NONPHARMACOLOGIC PREVENTION AND TREATMENT
DIET CHANGES 3 For all individuals, a well-balanced diet with adequate calcium

and vitamin D is essential for healthy bones (see Table 88–2). Dairy products account for most dietary calcium intake. Americans, especially seniors and those with lactose intolerance, ingest insufficient dietary calcium. Serum calcium does not reflect dietary intake because calcium homeostasis is tightly controlled. A practical approach is to count calcium contributions from certain key foods: milk, yogurt, cheese, ice cream, cottage cheese, and fortified orange juice or soy products. Most vitamin D comes from sun-induced skin conversion, except in northern climates or people with minimal to no sun exposure. Besides fatty fish, few unfortified foods contain substantial amounts of vitamin D (see Table 88–2). In the United States, milk and orange juice are fortified with 400 units/quart of vitamin D; however, quantities are quite variable and the process is not well regulated. If adequate intakes26 (Table 88–4) cannot be achieved with food, calcium and vitamin D supplements are needed (Table 88–5). Many observational studies have found an association between high caffeine intake and decreased BMD. This finding, however, could be a surrogate marker for decreased calcium-containing beverage and food intake.27 Although 2 to 5 cups of caffeine produce small increases in calcium excretion (about 4 to 5 mg calcium per cup of coffee), the effect can be offset with adequate calcium intake. Phosphorus is part of bone hydroxyapatite [3Ca3 (PO4 )2 (OH)2 ]. Normally the body has sufficient phosphorus and bone resorption is not required. Insufficient intake (e.g., carbonated beverages replacing milk) or increased phosphorous-bound calcium complexes (e.g.,

1653

Infant Birth to 6 months 6 months–1 year Children 1–3 years 4–8 years 9–13 years Adolescents 14–18 years Adults 19–50 years 51–70 years ≥71 years

Adequate Calcium Intake (mg)

Adequate Vitamin D Intake (units)

210 270

200 200

500 800 1300

200 200 200

1300

200

1000 1200 1200

200 400 600

Adapted from Institute of Medicine Dietary Reference Intakes.26

calcium ingested with food) can produce hypophosphatemia and a corresponding rise in PTH.28 A growing concern now exists for approximately 10% to 15% of seniors who are hypophosphatemic, and also during teriparatide administration, when the need for phosphorus is large. Drinking some milk or orange juice, eating some meals without supplemental calcium, or occasionally using a calcium phosphate supplement may help. Phosphorus supplementation is not routinely recommended. Magnesium is found in bone and is required for enzymatic reactions. Fruits and vegetables contain magnesium and may be important for healthy bone.29 No data currently exist to support supplementation. Vitamin A can increase production and action of osteoclasts and impair osteoblasts. Excessive vitamin A intake (≥1.5 to 2 mg/day) from foods or supplements has been associated with decreased BMD and increased fracture risk in women30 and men.31 Patients should be educated to avoid consuming excessive amounts of vitamin A. Vitamin C positively influences collagen production, and increases osteoblast formation and osteoclast formation and survival. Some, but not all, observational studies showed that vitamin C supplementation (1000 mg or more) was associated with higher BMD than that of nonusers.32 Again, it is premature to suggest routine supplementation. Vitamin K is required for γ -carboxylation of osteocalcin before incorporation into bone matrix.33 Low-vitamin-K diets are associated with high amounts of uncarboxylated osteocalcin, lower BMD, and higher hip fracture rates. Early research suggests added vitamin K, especially when combined with other antiresorptive agents, has a positive effect on bone health. Currently, however, supplements are not recommended. Although warfarin decreases clotting factor production by antagonizing vitamin K, it alone probably does not cause bone loss. Protein intake can increase IGF-1, low-protein diets can increase PTH, and high-protein diets can increase urinary calcium excretion.34 Many observational studies reported higher BMD with higher protein intakes; however, most observational studies also found low protein intake to be associated with a lower fracture rate.35 Moderate protein intake is recommended.


SOCIAL HABIT CHANGES 3 Smoking cessation and minimal alcohol use should be advo-

cated. Smoking causes bone loss and increases hip fracture risk by several mechanisms. Smoking is associated with early menopause,

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TABLE 88–5. Calcium and Vitamin D Product Selectiona Productb Calcium carbonate (40%) Trade and generic products Generic suspension Titralac Liquid Titralac Chewable Titralac Extra Strength Tums Chewable Tums E-X Tums Ultra Other chewable brands Mylanta Soothing Lozenges Cal Carb-HD powder Calcium carbonate with vitamin D Generic + vitamin D Calcilyte + vitamin Dd Calel-D + vitamin D Caltrate + vitamin D Os-Cal + vitamin D Viactiv chewsc Caltrate 600 pluse Olay Vitamins Essential Bone Health Formulationf Calcium citrate (24%) Generic Citracal Citracal Liquitabd Citracal + vitamin D Calcium phosphate tribasic (39%) Posture Posture-D Dical-D chewable wafers + vitamin D Multivitamin (D 3 ) Vitamin A (5000 units) Cod liver oil (D 3 ) 5 mL: vitamin A (4000 units), Gel caps: vitamin A (1250–2500 units) Ergocalciferol (D 2 ) Drops (per mL) Tablets

Calcium (mg)

Vitamin D (units)

200–600 500/5 mL 400/5 mL 168 300 200 300 500 168–500 240 2.4 g/7-g packet 600 500 500 600 500 500 600

125 200 200 200 125 100 200

600

200

240 200 500 316

200

600 600 232 40

125 200 400 500 130–270

8000 50,000

a Only calcium products with 500–600 mg per tablet or with an alternative dosage form (i.e., chewable, liquid, or dissolvable tablet) are listed. b Many products beginning to add magnesium, boron, zinc, copper, and manganese, and adding “Plus” or “Ultra” to name. c Also contains vitamin K. d Tablet for solution. e Also contains magnesium, zinc, copper, boron, and manganese. f Also contains phosphorus and magnesium.

decreased body weight, enhanced estrogen metabolism, increased PTH concentrations, and decreased vitamin D concentrations. Excessive alcohol use has been associated with low BMD and subsequent fracture in some, but not all, studies. The effects are greater with chronic heavy drinking early in life. Malnutrition associated with alcoholism could also play a role. Alcohol use also may increase the risk of falls.


EXERCISE 3 Bones adapt to handle the workload to which they are sub-

jected. Long-term exercise (likely many years) during youth increases peak BMD. Physical activity, especially aerobics, weight

bearing, and resistance exercise and walking, preserves BMD in postmenopausal women.36 Continued activity appears necessary to maintain benefit. Exercise also enhances calcium and estrogen therapy.37 In addition to the positive bone effects, physical activity likely reduces fracture risk by reducing falls (from improved balance, posture, flexibility, range of motion, muscle strength, and endurance). Physical activity, as tolerated, should be encouraged for all patients with osteoporosis. Before starting an exercise program for an elderly patient or one with severe osteoporosis, a medical examination is recommended. Referral to a physical therapist may be helpful. Excessive exercise in a premenstrual woman, however, can lead to amenorrhea and estrogen deficiency with consequent bone loss and increased fracture risk.38

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FALL PREVENTION Exercises to improve muscle strength, gait, balance, and flexibility should be employed whenever possible. Tai chi also reduces fall risk.39 The need for ambulation-assistive devices (canes and walkers) and assistance with transferring from various positions or for toileting should be assessed. Vision should be assessed and corrected when necessary. The living environment should be evaluated and modified to minimize falls. Loose rugs and extension cords should be eliminated, grab bars mounted in the bathroom, handrails installed on stairs, nonskid tape placed in bathtubs, and adequate lighting ensured. Although the use of hip protectors decreases fractures from falls, most patients do not like to wear them. Medications should be reviewed and those that may cause falls should be eliminated when possible. Examples include psychotropics, sedative-hypnotics, antidepressants, antihypertensives, and diuretics. Sedative-hypnotic use should be limited or discontinued. When benzodiazepines must be used, shorter-acting ones are recommended, but are still not risk-free. Other drugs altering balance and lowering blood pressure and blood glucose changes should be carefully monitored. Patients should be warned about medications that contribute to orthostasis and should be warned about abrupt postural changes.


PHARMACOLOGIC PREVENTION AND TREATMENT

OSTEOPOROSIS AND OSTEOMALACIA

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fragility fracture and the initiation of therapy for those with osteopenia (T-score 15 years One 10-mg tablet daily Children 6–14 years One 5-mg chewable tablet daily Children 2–5 years One 4-mg chewable tablet or oral granule packet daily a The timing of drug administration can be individualized. If the patient has combined asthma and seasonal allergic rhinitis, the dose should be given in the evening.

studies published to date show them to be no more effective than peripherally selective antihistamines, and less effective than intranasal steroids.49 The recent development of monoclonal antibodies directed against the binding site of IgE points to a potentially exciting new way to treat allergic respiratory diseases. Omalizumab, a recombinant humanized anti-IgE monoclonal antibody, is the first to show efficacy in allergic rhinitis.50 The actual mechanism of how this agent is thought to work is quite complex.51 Anti-IgE antibodies bind to the site on the IgE molecule that recognizes the IgE receptor, thereby preventing the IgE molecule from binding to mast cells or basophils. The half-life of IgE antibodies on the mast cell surface is about 6 weeks, and as the antibodies turn over they become available for binding to anti-IgE antibodies. Therefore, by giving repeated doses of omalizumab, the number of IgE antibodies on the mast cell surface can be significantly reduced over time. These new IgE molecules are not eliminated, but remain in circulation as small immune complexes. IgE receptor numbers on basophils and mast cells may be decreased as a result of downregulation. Because of the expensive nature of this therapy, omalizumab’s role has not been defined. Some promising results have been described when it is used in combination with immunotherapy.52 CLINICAL CONTROVERSY Omalizumab may offer significant long-term benefits to allergic rhinitis patients, but it may prove to be too expensive to gain widespread acceptance. As mentioned earlier in this chapter, microbial exposure in the early years of life could help prevent allergic disease by developing a non-atopic immune response.6 This concept was further studied by administering Lactobacillus rhamnosus prenatally to mothers who had at least one first-degree relative or partner with atopic disease (eczema, allergic rhinitis, or asthma) and postnatally for 6 months to their infants.53 CLINICAL CONTROVERSY Recent evidence shows that probiotics might be useful in preventing the onset of allergic disease, but more research needs to be conducted before use of these products is recommended.

steroids. The most recent detailed review estimated expenditures of $3.4 billion annually in the United States, with the majority of this cost attributed to prescription medications and outpatient visits.54 Of prescribed medications, 51% were peripherally selective antihistamines, 25% intranasal steroids, and 5% were older antihistamines. A

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total of 58% of patients received one or more agents. The mean prescription medication expenditure was $103 per patient for those on Medicaid, $155 with private insurance, and $69 for patients with no insurance. These figures do not include expenditures for nonprescription medications. With various brands and generic equivalents of nonprescription nonsedating products being heavily marketed to consumers, one would guess that usage of these agents would greatly increase. How this will affect the prescription market is unknown. Direct-to-consumer advertising for prescription-only allergic rhinitis treatment options has also increased significantly. Indirect costs related to missed school or work days and loss of productivity may approach the amount for the direct costs.55 The most cost-effective choice of treatment for allergic rhinitis is an individualized decision. Seasonal allergic rhinitis patients who see improvement and can tolerate nonprescription and/or generic antihistamines will experience the least impact on out-of-pocket medical and drug expenses. If these are not effective, the economic picture becomes more complicated. Choices should follow the logical path based on symptoms, tolerance, and efficacy, as described earlier in this chapter.

EVALUATION OF THERAPEUTIC OUTCOMES With allergic rhinitis, the major outcomes issues include the effect of the disease on a patient’s life, the efficacy and tolerability of treatment, and patient satisfaction. Consideration must be given to how the condition is affecting the patient’s job or school performance, family and social interactions, and other aspects of quality of life. The drug therapy should prevent or minimize symptoms with minimal or no adverse effects. The patient should not have difficulty obtaining needed medication for financial or other reasons. Patients should be questioned about their satisfaction with the management of their allergic rhinitis. The management should result in minimal disruption to their lives. Both the Medical Outcomes Study 36-Item Short Form Health Survey and the Rhinoconjunctivitis Quality of Life Questionnaire have been used to evaluate outcomes of treatment for seasonal and perennial allergic rhinitis.56−58 These tools go beyond measuring improvement in symptoms and include such items as sleep quality, nonallergic symptoms (e.g., fatigue, poor concentration, and others), emotions, and participation in a variety of activities. How well each of the current treatment modalities performs and how they compare in improving patient outcomes remain to be determined. Clinicians caring for allergic rhinitis patients should develop a comprehensive pharmaceutical care plan that addresses several areas. Discuss and agree on therapeutic end points for allergic rhinitis, including the patient’s acceptable level of symptom relief, onset of symptom relief expectations, and seasonal starts and stops. Discuss adverse drug reaction self-monitoring and prevention based on treatment selection. Assess patient attitude toward adherence to and persistence with oral, ocular, intranasal, or immunologic therapies. Ensure proper matching of treatment to symptoms and intervene with the prescriber if necessary. Conduct seasonal or annual review with patient. The therapeutic goal for all patients with allergic rhinitis is to minimize or prevent symptoms. Evaluation of success is accomplished primarily through the discussions with the patient, in whom both relief of symptoms and tolerance of drug therapy must be discussed.

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ABBREVIATIONS HEPA: high-efficiency particulate air (filter) IgE: immunoglobulin E LT: leukotriene RAST: radioallergosorbent test Review Questions and other resources can be found at www.pharmacotherapyonline.com.

REFERENCES 1. McCrory DC, Williams JW, Dolor RJ, et al. Management of Allergic Rhinitis in the Working-Age Population. Evidence Report/Technology Assessment No. 67. Prepared by Duke Evidence-based Practice Center under Contract No. 290-97-0014. Agency for Healthcare Research and Quality, January 2003. 2. Spector SL. Supplement: New insights into allergic rhinitis: Quality of life, associated airway diseases, and antihistamine potency. Overview of comorbid associations of allergic rhinitis. J Allergy Clin Immunol 1997; 99:S773–780. 3. The American Academy of Allergy, Asthma, and Immunology Inc. The Allergy Report. Available at http://www.aaaai.org/ar/. Accessed October 31, 2003. 4. Marshall PS, O’Hara C, Steinberg P. Effects of seasonal allergic rhinitis on fatigue levels and mood. Psychosom Med 2002;64:684–691. 5. Sauder A, Kovacs M. Anxiety symptoms in allergic patients: Identification and risk factors. Psychosom Med 2003;65:816–823. 6. Riedler J, Braun-Fahrlander C, Eder W, et al. Exposure to farming early in life and development of asthma and allergy: A cross-sectional survey. Lancet 2001;358:1129–1133. 7. Crimi P, Boidi M, Minale P, et al. Differences in prevalence of allergic sensitization in urban and rural school children. Ann Allergy Asthma Immunnol 1999;83:252–256. 8. Skoner DP. Allergic rhinitis: Definition, epidemiology, pathophysiology, detection, and diagnosis. J Allergy Clin Immunol 2001;8:S2–S8. 9. Wilson SJ, Shute JK, Holgate ST, et al. Localization of interleukin (IL)4 but not 5 to human mast cell secretory granules by immunoelectron microscopy. Clin Exp Allergy 2000;30:493–500. 10. Riccio AAM, Tosco MA, Cosentino C, et al. Cytokine pattern in allergic and non-allergic chronic rhinosinusitis in asthmatic children. Clin Exp Allergy 2002;32:422–426. 11. Wood-Baker R, Lau L, Howarth PH. Histamine and the nasal vasculature: the influence of H1 and H2-histamine receptor antagonism. Clin Otolaryngol 1996;21:348–352. 12. Howarth PH. Mediators of nasal blockage in allergic rhinitis. Allergy 1997;52(40 Suppl):12–18. 13. Howarth PH. Leukotrienes in rhinitis. Am J Resp Crit Care Med 2000; 161(2 Pt 2):S133–136. 14. Clark RR, Baroody FM. What drives the symptoms of allergic rhinitis? J Respir Dis 1998;19:S6–15. 15. Gerth van Wijk R. Perennial allergic rhinitis and nasal hyperreactivity. Am J Rhinol 1998;12:33–35. 16. Klaewsongkram J, Ruxrungtham K, Wannakrairot P, et al. Eosinophil count in nasal mucosa is more suitable than the number of ICAM-1positive nasal epithelial cells to evaluate the severity of house dust mitesensitive allergic rhinitis: A clinical correlation study. Int Arch Allergy Immunol 2003;132:68–75. 17. Braunstahl GJ, Fokkens WJ, Overbeek SE, et al. Mucosal and systemic inflammatory changes in allergic rhinitis and asthma: A comparison between upper and lower airways. Clin Exp Allergy 2003;33:579–587. 18. Lasley MV, Shapiro GG. Testing for allergy. Pediatr Rev 2000;21:39–43. 19. Li JT. Allergy testing. Am Fam Physician 2002;66:621–626. 20. Trask G, Shapiro G, Shapiro P. The effects of perennial allergic rhinitis on dental and skeletal development: A comparison of sibling pairs. Am J Orthod Dentofacial Orthop 1987;92:286–293.

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21. Shapiro G, Shapiro P. Nasal airway obstruction and facial development. Clin Rev Allergy 1984;2:225–236. 22. Verdiani P, Di CS, Baronti A. Different prevalence and degree of nonspecific bronchial hyperreactivity between seasonal and perennial rhinitis. J Allergy Clin Immunol 1990;86:576–582. 23. Ferguson BJ. Allergic rhinitis: Recognizing signs, symptoms and triggering allergens. Postgrad Med 1997;101:110–116. 24. Rosenwasser LJ. Treatment of allergic rhinitis. Am J Med 2002;113: 17S–24S. 25. Sporik S, Holgate S, Platts-Mills T. Exposure to house dust mite allergen and the development of asthma in childhood: A prospective study. N Engl J Med 1990;323:502. 26. Reisman R, Mauriello P, Davis G, et al. A double-blind study of the effectiveness of a high efficiency particulate air (HEPA) filter in the treatment of patients with perennial allergic rhinitis and asthma. J Allergy Clin Immunol 1990;85:1050–1057. 27. Casale TB, Blaiss MS, Gelfand E, et al. First do no harm: Managing antihistamine impairment in patients with allergic rhinitis. J Allergy Clin Immunol 2003;111:S835–842. 28. Sansgiry SS, Shringarpure GS. Springtime confusion: Are consumers getting the right information on how to treat seasonal allergies? J Allergy Clin Immunol 2003;112:627–628. 29. Bender BG, Berning S, Dudden R, et al. Sedation and performance impairment of diphenhydramine and second-generation antihistamines: A meta-analysis. J Allergy Clin Immunol 2003;111:770–776. 30. Richardson GS, Roehrs TA, Rosenthal L, et al. Tolerance to daytime sedative effects of H1 antihistamines. J Clin Psychopharmacol 2002;22: 511–515. 31. Simons FE, Silas P, Portnoy JM, et al. Safety of cetirizine in infants 6 to 11 months of age: A randomized, double-blind, placebo-controlled study. J Allergy Clin Immunol 2003;111:1244–1248. 32. 2003 Survey Pharmacist Survey of OTC Products. Pharmacy Today 2003 (October Supplement):22–26. 33. Berger WE, White MV. Efficacy of azelastine nasal spray in patients with an unsatisfactory response to loratadine. Ann Allergy Immunol 2003; 91:205–211. 34. Astelin product information. Wallace Laboratories, Cranbury, NJ, 1997. 35. Empey DE, Young GA, Letley E, et al. Dose response study of the nasal decongestant and cardiovascular effects of pseudoephedrine. Br J Clin Pharmacol 1980;9:351–358. 36. Drew CDM, Knight GT, Hughes DTD, et al. Comparison of the effects of D-(−)-ephedrine and L-(+)-pseudoephedrine on the cardiovascular and respiratory systems in man. Br J Clin Pharmacol 1978;6:221–225. 37. Cantu C, Arauz A, Murilla-Bonilla LM, et al. Stroke associated with sympathomimetics contained in over-the-counter cough and cold drugs. Stroke 2003;34:1667–1673. 38. Drug interaction facts. In: Tatro DS, ed. Facts and Comparisons. St. Louis, Facts and Comparisons, 1999:679. 39. Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral H1 receptor antagonists in allergic disease: Systematic review of randomized controlled trials. Br Med J 1998;317:1624–1629.

40. Quintiliani R. Hypersensitivity and adverse reactions associated with the use of newer intranasal corticosteroids for allergic rhinitis. Curr Ther Res 1996;57:478–488. 41. Mehle ME. Are nasal steroids safe? Curr Opin Otolaryngol Head Neck Surg 2003;11:201–205. 42. Adams RJ, Fuhlbrigge AL, Finkelstein JA, Weiss ST. Intranasal steroids and the risk of emergency department visits for asthma. J Allergy Clin Immunol 2002;109:636–642. 43. Noon L. Prophylactic inoculation against hay fever. Lancet 1911;1: 1572–1573. 44. Frew AJ. Immunotherapy of allergic disease. J Allergy Clin Immunol 2003;111:S712–S719. 45. Moller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002;109:251–256. 46. Durham SR, Walker SM, Varga EM, et al. Long term clinical efficacy of grass pollen immunotherapy. N Engl J Med 1999;341:468–475. 47. Schoenwetter WF. Safe allergen immunotherapy. Postgrad Med 1996; 100:123–135. 48. Meltzer EO, Malmstrom K, Lu S, et al. Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: A randomized placebo controlled clinical trial. J Allergy Clin Immunol 2000;105:917–922. 49. Casale TB, Condemi J, LaForce C, et al. Effect of omalizumab on symptoms of seasonal allergic rhinitis. JAMA 2001;286:2956–2967. 50. Nathan RA. Pharmacotherapy of allergic rhinitis: A critical review of leukotriene receptor antagonists compared with other treatments. Ann Allergy Asthma Immunol 2003:90:182–190. 51. Frew AJ. Anti-IgE and asthma. J Allergy Asthma Immunol 2003;91: 117–118. 52. Kuehr J, Brauburger J, Zielen S, et al. Efficacy of combination treatment with anti-IgE plus immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis. J Allergy Clin Immunol 2002;109: 274–280. 53. Kalliomaki M, Salminen S, Arvilommi H, et al. Probiotics in primary prevention of atopic disease: A randomized placebo-controlled trial. Lancet 2001;357:1076–1079. 54. Law AW, Reed SD, Sundy JS, Schulman KA. Direct costs of allergic rhinitis in the United States: Estimates from the 1996 medical expenditure survey. J Allergy Clin Immunol 2003;111:296–300. 55. Rossoff LJ, Stempel DA, Alam R, et al. The health and economic impact of allergic rhinitis. Am J Manage Care 1997;3:S8–S18. 56. Bousquet J, Duchateau J, Pignat JC, et al. Improvement of quality of life by treatment with cetirizine in patients with perennial allergic rhinitis as determined by a French version of the SF-36 questionnaire. J Allergy Clin Immunol 1996;98:309–316. 57. Meltzer EO, Nathan RA, Selner JC, Storms W. Quality of life and rhinitic symptoms: Results of a nationwide survey with the SF-36 and RQLQ questionnaires. J Allergy Clin Immunol 1997;99:S815–S819. 58. Harvey RP, Comer C, Sanders B, et al. Model for outcomes assessment of antihistamine use for seasonal allergic rhinitis. J Allergy Clin Immunol 1996;97:1233–1241.

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PLATE 1. Macules are circumscribed, flat lesions of any shape or size that differ from surrounding skin because of their color. A. Macules may be the result of hyperpigmentation (A), hypopigmentation, dermal pigmentation (B), vascular abnormalities, capillary dilatation (erythema) (C ), or purpura (D). B. The clinical appearance of a drug reaction that has produced an eruption consisting of multiple, well-defined red macules of varying size that blanch upon pressure (diascopy) and are thus due to inflammatory vasodilation. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 14.)

C.

A.

PLATE 2. Papules are small, solid, elevated lesions that are less than 1 cm in diameter. The major portion of a papule projects above the plane of the surrounding skin. A. Papules may result, for example, from metabolic deposits in the dermis (A), from localized dermal cellular infiltrates (B), and from localized hyperplasia of cellular elements in the dermis and epidermis (C ). Papules with scaling are referred to as papulosquamous lesions, as in psoriasis (see Chap. 96). B. Clinical examples of papules. C. Two welldefined and dome-shaped papules of firm consistency and brownish color, which are dermal melanocytic nevi; multiple, well defined, and coalescing papules of varying size are seen. Their violaceous color, glistening surface, and flat tops are characteristic of lichen planus. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 15.)

B.

1

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B.

PLATE 3. A. Plaque is a mesa-like elevation that occupies a relatively large surface area in comparison with its height above the skin surface. B. Well-defined, reddish, scaling plaques can coalesce to cover large areas of the back and buttocks, with some regression in the center as is common in psoriasis (see Chap. 96). C. Lichenification, a thickening of the skin and accentuation of skin, can result from repeated rubbing. It develops frequently in patients with atopy, and also occurs in eczematous dermatitis or other conditions associated with pruritus. Lesions of lichenification are not as well defined as most plaques and often show signs of scratching, such as in excoriations and crusts. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 16.)

C.

2

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A.

C.

PLATE 4. Nodules are palpable, solid, round or ellipsoidal lesions. Depth of involvement and/or substantive palpability rather than diameter differentiates a nodule from a papule. A. Nodules may be located in the epidermis (B) or extend into the dermis or subcutaneous tissue (A). B. This photograph shows a well-defined, firm nodule with a smooth and glistening surface through which telangiectasia (dilated capillaries) can be seen; there is central crusting indicating tissue breakdown and thus incipient ulceration (nodular basal cell carcinoma). C. Multiple nodules of varying size can be seen (melanoma metastases). (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 17.)

B.

3

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C.

A.

PLATE 5. A. Wheals are rounded or flat-topped papules or plaques that are characteristically evanescent, disappearing within hours. An eruption consisting of wheals is termed urticaria and usually itches. B. Wheals may be tiny papules 3 to 4 mm in diameter, as in cholinergic urticaria. C. Alternatively, wheals may present as large, coalescing plaques, as in allergic reactions to penicillin, other drugs, or alimentary allergens. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 18.)

B.

4

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B. PLATE 6. Vesicles and bullae are the technical terms for blisters. Vesicles are circumscribed lesions that contain fluid, while bullae are vesicles that are larger than 0.5 cm in diameter. A. Subcorneal vesicles (A) result from fluid accumulation just below the stratum corneum, while spongiotic vesicles (B) result from intercellular edema. B. Multiple translucent subcorneal vesicles are extremely fragile, collapse easily, and thus lead to crusting (arrows). These lesions are staphylococcal impetigo. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 18.)

PLATE 7. Acute dermatitis caused by poison ivy. Note the linear arrangement of lesions typical of phytodermatitis acquired by inadvertent contact with the plant. The severe vesiculobullous reaction is typical for urushiol, an oily poisonous irritant found in plants of the genus Toxicodendron. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 1167.)

5

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PLATE 9. Seborrheic dermatitis with involvement of the nasolabial folds, cheeks, eyebrows, and nose. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 1199.)

A.

B. PLATE 8. A. This patient has allergic chronic dermatitis involving the dorsal aspects of the hands and the distal forearms, but with minimal involvement of the palms. In this case, contact dermatitis is secondary to use of thiuram present in rubber gloves, prescribed for treatment of an irritant hand dermatitis. B. This patient, a florist, has allergic contact dermatitis due to exposure to tuliposide A, the allergen in Peruvian lilies (Alstroemeria spp.). Note the more prominent involvement of the palms of the dominant hand. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 1169.)

PLATE 10. Seborrheic dermatitis of the upper back. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 1200.)

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PLATE 12. Severe solar damage of the face revealing telangiectasias as well as actinic keratoses at different stages in development, including the flat, pink macules and hyperkeratotic papules. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 722.)

PLATE 11. This patient exhibits a striking amiodarone-induced, slate-gray pigmentation of the face. The blue color (ceruloderma) is caused by deposition in the dermis of a brown pigment, which is contained in macrophages and endothelial cells. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 876.)

PLATE 13. This case of squamous cell carcinoma must be differentiated in diagnosis from chondrodermatitis nodularis helicis, which unlike the carcinoma, is painful. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed., New York, McGraw-Hill, 2003, p 738.)

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A.

A.

B.

PLATE 15. These two superficial spreading melanomas illustrate the ABCDs of melanoma. A, asymmetry: The lesions are not symmetrical and often have irregular borders. B, border: Note the highly irregular, uneven, and notched border. C, color: The color is variegated with different shades of brown, black, and tan. D, diameter: The diameter is usually (but not always) more than 6 mm in melanomas. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 925.)

B.

PLATE 14. A. Basal cell carcinoma, nodular type. B. An ulcerated nodular basal cell carcinoma. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 749.)

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94 DERMATOLOGIC DRUG REACTIONS, SELF-TREATABLE SKIN DISORDERS, AND SKIN CANCER Nina H. Cheigh

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com. As the largest organ of the body, the skin, also known as the integumentary system, is the site of a vast number of pathologic conditions. Patients present with insults to and infections of the skin in a variety of primary care settings, ranging from community pharmacies to emergency departments, requesting evaluation of and advice about skin lesions. In a survey of patients about the sources of advice they use for skin conditions, pharmacists ranked second, just behind physicians. Interestingly, the advice sought seemed to depend on the nature of the condition, in that patients sought more pharmacist advice on conditions such as dermatitis, psoriasis, skin cancer, and acne.1 To properly assess a patient, pharmacists and other primary care providers must not only understand clinical presentations of common skin disorders, but they must also be able to quickly identify patients that may need referral for further evaluation by a physician. In this chapter skin disorders that are self-treatable and dermatologic reactions to medications are presented from a primary care perspective of a pharmacist or other health professional who commonly recommends nonprescription therapies, or refers patients to prescribers or physician specialists. Skin infections are mentioned here, but covered in detail in Chap. 108, on skin and soft tissue infections.

SKIN STRUCTURE AND FUNCTION The skin has many important functions. Its three layers—the epidermis, dermis, and hypodermis (subcutaneous tissue)—provide a barrier, prevent dehydration, protect from external injury or microorganisms, maintain body temperature, and even express emotions through dilation or constriction of blood vessels. The dermal layer contains most of the structural components of skin, such as mast cells, fibroblasts, collagen, elastic fibers, sweat glands, sebaceous glands, pigment-producing melanin cells, and vasculature. The hair and nails are considered appendages of the skin. Hair, comprising keratinized epithelial cells, is protein bound and grows in cycles. Scalp hair grows at a rate of approximately 35 mm/day, but this can be affected by various medications and hormones. The nails, also comprised of keratinized cells, have different anatomic components. The nail plate is the main part of the nail, and is highly adherent to the

nail bed, which grows underneath. Generally, toenails tend to grow at a much slower rate than fingernails. Several factors affect the growth of the nails, including genetics, age, and weather.2

PATIENT ASSESSMENT Before a treat-or-refer recommendation can be made, the pharmacist or other health professional must make a reasoned assessment of the problem and make a presumptive diagnosis (or at least rule out some of the many skin disorders). Several factors affect this decision, including patient age and hormonal status, patient complaint and history, and lesion assessment.

AGE AND HORMONAL STATUS A primary factor to consider in evaluation is the age of the patient. Changes in the anatomy and physiology of skin and its appendages relate closely to patient age, and for women hormonal status also affects the evaluation.

GERIATRIC CONSIDERATIONS In addition to wrinkling and dryness, expected age-related skin changes include an increase in uneven pigmentation and thinning of the protective layers, thus predisposing the skin to external injuries. Langerhans cells are reduced by 50% in number, reducing natural immunity to skin cancers. The vascularity of the skin declines, and thus older patients tend to look pale (pallor), feel cold to the touch, and have an increased predisposition to develop certain conditions such as psoriasis, seborrhea, pemphigoid, and candidiasis. Changes in the skin appendages can also occur in the elderly, such as thinning and graying of the hair on the scalp. Women can develop facial hair due to the reduction of estrogen levels. The thickness of the nails is reduced, and nails change in color.

PEDIATRIC CONSIDERATIONS Certain dermatologic conditions, such as atopic dermatitis, are most likely to occur in children. Also, the rate and amount of absorption 1741

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of medications through the skin is higher in children. Infants may not be able to safely metabolize or excrete medications because of immaturity of their hepatic and renal systems. They also have immature sebaceous gland activity, and thus present frequently with seborrheic dermatitis of the scalp, also known as “cradle cap.” In adolescence, hair appears in new places: the face in boys, and the pubic and other areas in both boys and girls. Sweating and sebaceous gland activity is greater, thus resulting in increased body odor and skin conditions such as acne (see Chap. 96).

r

HORMONE-RELATED CONSIDERATIONS Variations in progesterone and estrogen can result in dermatologic disorders as women go through changes and events of their lives. Menopausal women tend to develop brown hyperpigmentation, or melasma. Women who are on hormone replacement therapy or oral contraceptives also develop these nonspecific brown discolorations on their skin. Pregnant women develop many changes, including hyperpigmentation of the areola and genitalia. These women can also develop melasma, otherwise commonly known as the “mask of pregnancy.” Most pregnant women develop stretch marks, or striae gravidarum, around the abdomen, thighs, breasts, and buttocks. They can also develop disorders such as pruritic urticarial papules and plaques of pregnancy (PUPPPS). Women who are pregnant also typically notice changes in their hair, as it becomes thinner or thicker, or straighter or curlier.

PATIENT HISTORY In addition to clues offered by patient age and special conditions such pregnancy, several key questions can provide insights into the patient’s skin disorder or injury. Getting an accurate history and other information from the patient is critical for ensuring optimal treatment and avoiding undue complications.

THE INTERVIEW When interviewing the patient, the health care professional should make careful notes of the interaction. Questions that are helpful in assessment include: r

r

Are you having other symptoms, such as difficulty breathing, fever, or nausea and vomiting? When patients present with a rash or skin lesion, the first consideration should be for any potential anaphylaxis or angioedema. Many medications can be responsible for these reactions, and these must be ruled out. If a patient has a severe reaction with difficulty breathing, the patient may require immediate or even emergent referral to an emergency care facility to obtain proper care. Epinephrine, intravenous corticosteroids, or oral prednisone may be needed immediately. Where did the problem first appear? Where are you affected? Did it spread? Asking where the skin lesions are is important, as it is likely that the entire skin surface is not visible to the health care professional, and the source of the infection may be concealed. For example, although the arms and legs can demonstrate a rash, it would be pertinent to determine if the trunk is also affected, indicating a more systemic cause, as

r

r

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opposed to an unaffected trunk, which would likely indicate a nonsystemic cause. If they are not visible, what do the lesions took like? The patient can be asked whether the lesion is painful or itchy, and can thus can be assessed for any infection requiring immediate treatment. For example, if the area is oozing, erythematous, and warm to the touch, it is most likely infected. Alternatively, if the lesion is not painful and no other symptoms are present, other conditions are likely present. If appropriate, the lesions can be assessed by the clinician for color, texture, size, and temperature. Also, it is important to note any asymmetry (e.g., the lesion is present on only one side of the body). How long have the lesions been present? Some patients present after having had a skin condition for quite sometime without seeking any advice. This information is also helpful if the lesions appeared soon after the start of a certain suspected medication. Have the lesions changed in size, shape, color, or consistency? This question is important in determining any changes that might have occurred with the condition. Most importantly, this question enables evaluation of the patient’s melanoma risk. Typically, any skin lesion that changes in these elements should be further examined by a physician. What do you think the problem may be? Many patients have some idea as to what the source of their problem may be, so it is helpful to ask this question, and get their opinions and observations. Obtain a general medical and allergy history. After questioning the patient, the clinician or other health care professional may be able to rule out recently started drugs or new diseases as causes of the patient’s reaction.

LESION ASSESSMENT If appropriate and acceptable to the patient, the health professional should make a quick visual assessment of the skin lesions. The skin surface should be closely examined, preferably in natural light. As proper diagnosis is based on pattern recognition, the pharmacist or other health professional must understand and demonstrate competence in assessing the lesions (Figs. 94–1 through 94–6, Plates 1 through 6).3 In addition, when referral is needed, the clinician or other health care professional should describe lesions to dermatologists or other physicians in a consistent manner.

SITE DISTRIBUTION AND ARRANGEMENT Note the area involved (e.g., face, trunk, arms, or legs) and the number of lesions present (single or multiple). The arrangement of the lesions is also helpful, such as stating that the lesions are linear (in a line), grouped, annular (ring-shaped), or serpiginous (resembling a snake). Symmetry or asymmetry should be noted; in skin cancer, lesions are typically asymmetrical.

SURFACE TEXTURE Unless the lesions are oozing or appear to be infectious (see Fig. 94– 6B), they should be palpated with caution. Palpation helps the health care professional determine whether the lesion is smooth or rough, firm or soft, or scaly or crusting.

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BORDER Poorly circumscribed lesions are those for which it is hard to tell where the normal skin begins and ends (see Fig. 94–5B), while welldefined lesions have clearer demarcations between healthy skin and lesions (see Fig. 94–5B).

LESIONS AND SKIN COLOR Lesions should be examined for variations from the patient’s predominant skin color. Increased pigmentation (brownish color), loss of pigmentation, redness (erythema), pallor, cyanosis, and yellowing should be noted. Color can be very indicative when underlying systemic diseases are involved. For example, anemia and reduced blood flow can result in decreased skin redness. Cyanosis can indicate reduced cardiac blood flow or lung disease. Jaundice can suggest liver disease.

OTHER FEATURES An assessment of the nails, hair, and mucous membranes should also be performed as needed and appropriate. Once the health care professional identifies the specific questions to ask and can provide a reasonable description of the lesion, referral or appropriate therapies can be recommended. As there are hundreds of varieties of dermatologic disorders, here we will focus on common conditions most frequently encountered by the pharmacist and other primary care professionals, with an emphasis on skin disorders that are often treated with nonprescription medications, and on drug-induced skin disorders. Infectious skin conditions are covered in detail in Chap. 108, on skin and soft tissue infections.

A

ALLERGIC, IRRITANT, AND INFECTION-RELATED SKIN DISORDERS DERMATITIS

B FIGURE 94–1. Macules are circumscribed, flat lesions of any shape or size that differ from surrounding skin because of their color. A. Macules may be the result of hyperpigmentation (A), hypopigmentation, dermal pigmentation (B), vascular abnormalities, capillary dilatation (erythema) (C ), or purpura (D). B. The clinical appearance of a drug reaction that has produced an eruption consisting of multiple, well-defined red macules of varying size that blanch upon pressure (diascopy) and are thus due to inflammatory vasodilation. See Plate 1. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 14.)

TYPE OF LESIONS The size of lesions should be measured. Typically, lesions are described as being less than or greater than 0.5 cm in diameter. A macule (see Fig 94–1A) or a papule (see Fig. 94–2A) is typically 1 cm or less in diameter, while the term patch is sometimes used for larger flat macules (see Fig. 94–1B).

The word dermatitis is a general term denoting an inflammatory erythematous rash. Many types of dermatitis have been described, with the most common being atopic dermatitis (see Chap. 97 for a complete discussion) and contact dermatitis. Although atopic dermatitis can occur at any age, it is most common in infants and children, and thus age can be a critical identifier in distinguishing between atopic and contact dermatitis. Atopic dermatitis is also frequently associated with elevated IgE levels and family history of atopic disease, such as dermatitis, allergic rhinitis, and asthma.4

CONTACT DERMATITIS Contact dermatitis is an acute (Fig. 94–7, Plate 7) or chronic (Fig. 94–8, Plate 8) inflammatory skin condition that results from contact of an inciting factor with the skin. Typically, contact dermatitis can be further divided into two major subgroups, allergic or irritant, depending on whether the cause is an antigen (allergen), or irritant, such as an organic substance. In allergies, the antigenic substance triggers the Langerhans cells, and their immunologic responses produce the allergic skin reaction, sometimes several days later. Irritant contact dermatitis is more likely to be the result of a reaction within a few hours of exposure. Although symptoms of either type of contact dermatitis (erythematous vesicles with pruritus) are generally similar, the allergic type can result in more serious erosions or oozing pustules. Common offending agents for contact dermatitis are listed in Table 94–1.5

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A

C

B

FIGURE 94–2. Papules are small, solid, elevated lesions that are less than 1 cm in diameter. The major portion of a papule projects above the plane of the surrounding skin. A. Papules may result, for example, from metabolic deposits in the dermis (A), from localized dermal cellular infiltrates (B), and from localized hyperplasia of cellular elements in the dermis and epidermis (C ). Papules with scaling are referred to as papulosquamous lesions, as in psoriasis (see Chap. 96). B. Clinical examples of papules. C. Two well-defined and dome-shaped papules of firm consistency and brownish color, which are dermal melanocytic nevi; multiple, well defined, and coalescing papules of varying size are seen. Their violaceous color, glistening surface, and flat tops are characteristic of lichen planus. See Plate 2. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 15.)

TABLE 94–1. Common Allergens Producing Contact Dermatitis Among People in the United States. Fragrance Flavorings Rubber Metals Adhesives Glues Plastics

Formaldehyde Lanolin (wool) Neomycin sulfate Nickel Paraben mix Thimerosal

When patients present with symptoms of contact dermatitis, pharmacists and other primary care providers should initially ask key questions about exposure to potentially offending substances. Initial treatment of contact dermatitis should always focus on identification and removal of the offending agent. When this is not possible, the patient should be advised to avoid exposure to those agents considered most likely to be responsible. The second goal of treatment is the relief of symptoms. Products that relieve itching, rehydrate the skin, and decrease weeping of the lesions will provide some immediate relief. The dosage form of topical preparations is determined by the stage of inflammation. In the acute stage, wet dressings are preferred because ointments and creams further irritate the tissue. Astringents such as aluminum acetate, Burow solution, or witch hazel decrease

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A

B

C

FIGURE 94–3. A. Plaque is a mesa-like elevation that occupies a relatively large surface area in comparison with its height above the skin surface. B. Well-defined, reddish, scaling plaques can coalesce to cover large areas of the back and buttocks, with some regression in the center as is common in psoriasis (see Chap. 96). C. Lichenification, a thickening of the skin and accentuation of skin, can result from repeated rubbing. It develops frequently in patients with atopy, and also occurs in eczematous dermatitis or other conditions associated with pruritus. Lesions of lichenification are not as well defined as most plaques and often show signs of scratching, such as in excoriations and crusts. See Plate 3. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 16.)

weeping from lesions, “dry out” the skin, and provide relief from itching. These agents are applied as wet dressings and should not be used for more than 7 days. For chronic dermatitis, lubricants, emollients, or moisturizers should be applied after bathing. Soap-free (or mild) cleansers and products containing colloidal oatmeal also contribute to alleviating itch and soothing the skin. If the patient’s reaction does not subside within a few days, or further spread occurs, the patient should be referred for specialist follow-up and for prescription therapy with stronger topical corticosteroids and possibly oral corticosteroid therapy.

SEBORRHEIC DERMATITIS The prevalence of seborrheic dermatitis peaks during infancy, and then again during the fourth to seventh decades of life, affecting 3% to 5% of adults in the United States. In infants, seborrheic dermatitis is commonly referred to as “cradle cap.” Typically, this condition occurs around the areas of skin rich in sebaceous follicles, such as the face (Fig. 94–9, Plate 9), ears, scalp, and upper trunk (Fig. 94–10, Plate 10), although it is not classified as a disease of the sebaceous glands per se.6 Therapy of seborrheic dermatitis has four major goals: to loosen and remove scales, prevent yeast colonization, control any secondary

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C

A

B

FIGURE 94–4. Nodules are palpable, solid, round or ellipsoidal lesions. Depth of involvement and/or substantive palpability rather than diameter differentiates a nodule from a papule. A. Nodules may be located in the epidermis (B) or extend into the dermis or subcutaneous tissue (A). B. This photograph shows a well-defined, firm nodule with a smooth and glistening surface through which telangiectasia (dilated capillaries) can be seen; there is central crusting indicating tissue breakdown and thus incipient ulceration (nodular basal cell carcinoma). C. Multiple nodules of varying size can be seen (melanoma metastases). See Plate 4. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 17.)

infections, and reduce itching and erythema. Interestingly, the disease typically seems to improve with warmer weather and worsens when the air is colder. Many topical agents are used to manage seborrheic dermatitis. Depending on what area of the body is affected, the pharmacist or other health professional can assist in selection of proper vehicles (i.e., solutions or shampoos for the scalp). Ingredients such as selenium sulfide, salicylic acid, and coal tar can help soften and remove the scales. Seborrheic dermatitis responds very quickly to low-potency topical corticosteroid preparations, but judicious use is important to avoid long-term adverse effects. Topical ketoconazole 2% can also be used to help control the yeast colonization.7

patches, erosion of skin, vesicles, and ulcerations, can be seen in adults who wear diapers for incontinence. This reaction is a type of contact dermatitis, as it results from direct fecal and moisture contact with the skin in an occlusive environment. Treatment of diaper dermatitis includes frequent diaper changes and keeping the area dry. Lukewarm water and mild soap can be used to cleanse the area thoroughly, which should then be allowed to dry. Occlusive agents—such as zinc oxide, titanium dioxide, petrolatum, or any combination of these—should be generously applied to the area before the diaper is applied.

DRUG-INDUCED SKIN DISORDERS DIAPER DERMATITIS Diaper dermatitis, or diaper rash, is an acute, inflammatory dermatitis of the buttocks and genital and perineal region. Commonly seen in infants in diapers, this condition, which results in erythematous

Approximately 2% to 3% of hospitalized patients experience an adverse cutaneous drug reaction, with a higher incidence in older individuals. Almost every commonly used drug has been implicated in producing local and/or systemic drug reactions (Table 94–2).

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TABLE 94–2. Types of Drug-Induced Skin Eruptions Clinical Presentation

Pattern and Distribution of Skin Lesions

Mucous Membrane Involvement

Implicated Drugs

Treatment Supportivea

Erythema multiforme

Target lesions, limbs

Absent

Stevens-Johnson syndrome

Atypical targets, widespread

Present

Anticonvulsants (including lamotrigine), sulfonamide antibiotics, allopurinol, NSAIDs, dapsone As above

Toxic epidermal necrolysis Pseudoporphyria

Present

As above

Absent

Tetracycline, furosemide, naproxen

Supportivea

Linger lgA disease

Epidermal necrosis with skin detachment Skin fragility, blister formation in photodistribution Bullous dermatosis

Present or absent

Supportivea

Pemphigus

Flaccid bullae, chest

Present or absent

Bullous pemphigoid

Tense Bullae, widespread

Present or absent

Vancomycin, lithium, diclofenac, piroxicam, amiodarone Penicillamine, captopril, piroxicam, penicillin, rifampin Furosemide, penicillamine, penicillins, sulfasalazine, captopril

Intravenous immunoglobulins, cyclosporine Supportivea

Supportivea Supportivea

a Supportive care includes administration of systemic glucocorticoids until all symptoms of active disease disappear. NSAIDs, nonsteroidal anti-inflammatory drugs. Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 1335.

Typically, these reactions are unpredictable, ranging from mild, selflimiting episodes, to more severe, life-threatening ones. Some reactions are nonallergic, but drug-induced skin reactions tend to be immunologic in origin and relate to hypersensitivity. Pharmacists and other primary care providers should develop an organized and thorough approach to evaluation of patients with potential drug-induced skin disorders. This process begins with a comprehensive drug history, including episodes of previous drug allergies, and is based on an understanding of the mechanisms involved in drug reactions.

CUTANEOUS DRUG REACTIONS Maculopapular eruptions are the most common manifestation of druginduced skin reactions. Lesions tend to resemble those of measles, often involving the trunk or pressure areas, and are frequently symmetrical. These eruptions are classified as either early, appearing within a few hours to 3 days after ingestion of the drug, or late, appearing up to 9 days after the exposure. Most reactions disappear within a few days after discontinuing the agent, and thus symptomatic control of the affected area is the primary intervention. Topical corticosteroids and oral antihistamines can relieve pruritus. In severe eruptions, a short course of systemic corticosteroids may be warranted. A fixed-drug reaction, typically presenting as an erythematous or hyperpigmented round or oval lesion, usually ranges from a few millimeters to 20 cm in diameter.8 Although the lesion can appear anywhere, the oral mucosa or genitalia are the most common sites. If the patient takes the agent again, the drug reaction tends to recur within 30 minutes to 8 hours after rechallenge, in the exact same location, and this is highly indicative of the fixed-drug reaction (lesions may also occur in other locations).9 The pathogenesis of fixed-drug reactions is not well understood.

Treatment of fixed-drug reactions involves removal of the offending agent. Rechallenge should be avoided when possible. Other therapeutic measures include the use of corticosteroids, antihistamines to relieve itching, and perhaps cool water compresses on the affected area.9 Sun-induced drug eruptions tend to appear similar to a sunburn, and present with erythema, papules, edema, and sometimes vesicle formation. They also appear in areas that tend to be most exposed to sunlight, such as the ears, nose, cheeks, forearms, and hands. Photosensitivity is subdivided into phototoxicity, which is defined as a nonimmunologic reaction, and a photoallergic reaction, which involves an immunologic mechanism and is far less common.10 Common medications associated with photosensitivity reactions include fluoroquinolones, nonsteroidal anti-inflammatory drugs, phenothiazines, antihistamines, estrogens, progestins, sulfonamides, sulfonylureas, thiazide diuretics, and tricyclic antidepressants.2 Typically, patients can achieve symptom resolution by discontinuing the medication. Patients with photosensitivity reactions should be treated much the same as burn victims would be; management of the “burn” is of primary importance. Some patients benefit from topical corticosteroids and oral antihistamines, but these are relatively ineffective. Systemic corticosteroids, typically oral prednisone at 1 mg/kg per day tapered over 3 weeks, is more effective for these patients. Pharmacists and other health care professionals should encourage the proper use of sunscreen, and recommend a protective product that protects against ultraviolet A and B rays.11

HYPERPIGMENTATION Many medications can cause changes in skin color. These can be caused by the medication, or may be due to disturbances in melanin production or formation. Depending on the medication, the site of hyperpigmentation can vary. For example, patients receiving

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A

C

B FIGURE 94–5. A. Wheals are rounded or flat-topped papules or plaques that are characteristically evanescent, disappearing within hours. An eruption consisting of wheals is termed urticaria and usually itches. B. Wheals may be tiny papules 3 to 4 mm in diameter, as in cholinergic urticaria. C. Alternatively, wheals may present as large, coalescing plaques, as in allergic reactions to penicillin, other drugs, or alimentary allergens. See Plate 5. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 18.)

anticonvulsants such as phenytoin, phenobarbital, and carbamazepine report a brown patchy lesion in sun-exposed areas.8 Patients who receive anticonvulsant therapy for more than 1 year are at a 10% risk of developing some form of hyperpigmentation related to the medication.12 Women on oral contraceptives frequently report melasma, or brown, irregularly-shaped macules on the cheeks, forehead, or upper lip. Hormonal changes in estrogen and progesterone as well as sun exposure may cause the increase in melanin deposition.13 Other medications commonly associated with skin hyperpigmentation

include antimalarial agents, phenothiazines, tetracyclines,14 and amiodarone (Fig. 94–11, Plate 11).15 Patients with drug-induced hyperpigmentation can use skin bleaching creams and/or cosmetic agents that help to even out skin tone. Many such products have been marketed. Hydroquinone or kojic acid are most commonly found in cosmetic agents to aid in bleaching the darkened area of skin. Many times these agents are formulated in conjunction with such agents as α-hydroxy acids, which help to slowly slough off the outermost layer of skin. These patients using bleaching

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A

FIGURE 94–7. Acute dermatitis caused by poison ivy. Note the linear arrangement of lesions typical of phytodermatitis acquired by inadvertent contact with the plant. The severe vesiculobullous reaction is typical for urushiol, an oily poisonous irritant found in plants of the genus Toxicodendron. See Plate 7. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 1167.)

B FIGURE 94–6. Vesicles and bullae are the technical terms for blisters. Vesicles are circumscribed lesions that contain fluid, while bullae are vesicles that are larger than 0.5 cm in diameter. A. Subcorneal vesicles (A) result from fluid accumulation just below the stratum corneum, while spongiotic vesicles (B) result from intercellular edema. B. Multiple translucent subcorneal vesicles are extremely fragile, collapse easily, and thus lead to crusting (arrows). These lesions are staphylococcal impetigo. See Plate 6. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 18.)

creams absolutely must use sunscreen, as areas being treated with these creams tend to be even more sun-sensitive.

SKIN CANCERS Actinic keratoses (AKs) are abnormal keratinocytes that develop in response to prolonged exposure to ultraviolet radiation. These lesions can develop into squamous cell or basal cell carcinomas, and the

presence of suspicious lesions is one of the top reasons that patients seek medical attention for dermatologic disorders. AK usually presents as a small (2 to 6 mm), erythematous papule that feels flat, rough, or scaly when palpated (Fig. 94–12, Plate 12). It tends to be found in chronically sun-exposed areas, such as the top of the hands, head, neck, and forearms. Typically, patients with AKs are elderly and have fair skin, light-colored eyes, freckles, and a history of significant sun exposure and tend to sunburn easily. Because AKs are likely caused by ultraviolet radiation, sun-preventive measures, particularly in childhood, are of utmost importance.16 Most commonly, AKs are treated with liquid nitrogen, which will remove the lesion. Another frequently used therapy is topical 5-fluorouracil. Patients who are prescribed topical 5-fluorouracil should be properly counseled, as significant erythema, erosion, crusting, and even ulceration normally occur during treatment. Squamous cell carcinoma (SCC) is a cutaneous malignancy with estimates of approximately 200,000 cases in the United States in 2001. SCC seems to be more common in advanced age, and twice as common in men as in women. Because of their susceptibility to the negative effects of long-term sun exposure, patients of Celtic ancestry and those with blue or green eyes, red hair, and fair complexion are at the greatest risk of developing SCC.17 Other risk factors include precursor lesions such as AKs, long-term immunosuppression, and ultraviolet radiation. SCC can appear in many areas, but mainly occurs

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A

FIGURE 94–9. Seborrheic dermatitis with involvement of the nasolabial folds, cheeks, eyebrows, and nose. See Plate 9. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 1199.)

B FIGURE 94–8. A. This patient has allergic chronic dermatitis involving the dorsal aspects of the hands and the distal forearms, but with minimal involvement of the palms. In this case, contact dermatitis is secondary to use of thiuram present in rubber gloves, prescribed for treatment of an irritant hand dermatitis. B. This patient, a florist, has allergic contact dermatitis due to exposure to tuliposide A, the allergen in Peruvian lilies (Alstroemeria spp.). Note the more prominent involvement of the palms of the dominant hand. See Plate 8. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 1169.)

in sun-exposed areas such as the head, neck, and dorsal aspect of the hands. Most SCCs appear as a firm, flesh-colored, or erythematous papule or plaque (Fig. 94–13, Plate 13). Some resemble an ulcer. Treatment for SCC is determined by the tumor’s risk for metastasis, but commonly involves some form of surgical excision. Basal cell carcinoma (BCC) is the most common cancer in humans, with an estimated 900,000 cases per year in the United States.17

FIGURE 94–10. Seborrheic dermatitis of the upper back. See Plate 10. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 1200.)

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FIGURE 94–11. This patient exhibits a striking amiodarone-induced, slate-gray pigmentation of the face. The blue color (ceruloderma) is caused by deposition in the dermis of a brown pigment, which is contained in macrophages and endothelial cells. See Plate 11. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 876.)

FIGURE 94–12. Severe solar damage of the face revealing telangiectasias as well as actinic keratoses at different stages in development, including the flat, pink macules and hyperkeratotic papules. See Plate 12. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 722.)

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FIGURE 94–13. This case of squamous cell carcinoma must be differentiated in diagnosis from chondrodermatitis nodularis helicis, which unlike the carcinoma, is painful. See Plate 13. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed., New York, McGraw-Hill, 2003, p 738.)

BCCs can occur anywhere on the body, but they appear most commonly on the head and neck, usually as a nodular, pigmented lesion (Fig. 94–14, Plate 14). Treatment varies depending on the histology of the lesion, but frequently requires Mohs micrographic surgery, surgical excision, and possible use of topical agents. Topical imiquimod is approved by the Food and Drug Administration for treating BCC of areas other than the face, and this agent resulted in some clearances in a phase II study.18 Topical 5-fluorouracil has also been used, but needs further evaluation to warrant routine use. The risk of malignant melanoma is increasing, with a prediction that prevalence could reach 1 in 50 by 2010.19 Most frequently, melanoma occurs on the back and extremities of white males and females, while in Asians and blacks, it tends to appear on mucous membranes and soles and palms. Risk factors include skin type, sun exposure and response to the sun (i.e., ability to tan), family history, and change in the appearance of moles. The presence of any nonhealing lesion should raise the suspicion of skin cancer. In addition to assessing these risk factors, pharmacists can play a key role in examining the questionable lesion(s) and by assessing the lesion’s asymmetry, border, color, diameter, and history, as when a mole changed and led to the appearance of the lesion (Fig. 94–15, Plate 15). Patients who fit these criteria should be further evaluated by a dermatologist.

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A

A

B FIGURE 94–15. These two superficial spreading melanomas illustrate the ABCDs of melanoma. A, asymmetry: The lesions are not symmetrical and often have irregular borders. B, border: Note the highly irregular, uneven, and notched border. C, color: The color is variegated with different shades of brown, black, and tan. D, diameter: The diameter is usually (but not always) more than 6 mm in melanomas. See Plate 15. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 925.)

B

FIGURE 94–14. A. Basal cell carcinoma, nodular type. B. An ulcerated nodular basal cell carcinoma. See Plate 14. (Reprinted with permission from Freedberg IM, et al, eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003, p 749.)

ABBREVIATIONS AK: actinic keratosis BCC: basal cell carcinoma PUPPPS: pruritic urticarial papules and plaques of pregnancy SCC: squamous cell carcinoma Review Questions and other resources can be found at www.pharmacotherapyonline.com.

REFERENCES 1. Kilkenny M, Stathakis V, Jolley D, et al. Maryborough skin health survey: Prevalence and sources of advice for skin conditions. Austral J Dermatol 1998;39:235–237.

2. DeSimone II EM. Skin, hair and nails. In: Jones RM, Rospond RM, eds. Patient Assessment in Pharmacy Practice. Baltimore, Lippincott Williams & Wilkins, 2003:102–128. 3. Ashton RE. Teaching non-dermatologists to examine the skin: a review of the literature and some recommendations. Br J Dermatol 1995;132: 221–225. 4. Leung DYM, Eichenfield LF, Boguniewicz M. Atopic dermatitis (atopic eczema). In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003:1180–1194. 5. Belsito DV. Allergic contact dermatitis. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Dermatology in General Medicine, 6th ed. New York, McGraw-Hill, 2003:1164–1180. 6. Burton JL, Pye PJ. Seborrhea is not a feature of seborrheic dermatitis. Br Med J 1983;286:1169. 7. Katsambas A, et al. A double-blind trial of treatment of seborrheic dermatitis with 2% ketoconazole cream compared with 1% hydrocortisone cream. Br J Dermatol 1989;353:121. 8. Bruinsma W. A Guide to Drug Eruptions, 6th ed. Oosthuizen, Netherlands, DeZwaluw, 1995. 9. Korkij W, Soltani K. Fixed drug eruption. Arch Dermatol 1984;120: 520–524.

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10. Gamis-Jones S. Dermatologic side effects of psychopharmacologic agents. Dermatol Clin 1996;14:503–507. 11. Mammen L, Schmidt CP. Photosensitivity reactions: a case report involving NSAIDS. Am Fam Physician 1995;52:575–578. 12. Moller R. Pigmentary disturbances due to drugs. Acta Derm Venereol (Stockh) 1966;46:423–431. 13. Jelinek JE. Cutaneous side effects of oral contraceptives. Arch Dermatol 1970;101:181–186. 14. Granstein RD, Sober AJ. Drug and heavy metal-induced hyperpigmentation. J Am Acad Dermatol 1981;5:1–18.

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15. Trimble JW, Mendelson DS, Fetter BF, et al. Cutaneous pigmentation secondary to amiodarone therapy. Arch Dermatol 1983;119:914–918. 16. Salasche S. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 200;42:S4. 17. Miller DI, Weinstock MA. Nomnelanoma skin cancer in the United States: incidence. J Am Acad Dermatol 1994;30:774. 18. Marks R, et al. Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial. J Am Acad Dermatol 2001;44:807. 19. Rigel DS. Melanoma update: 2001. Skin Cancer Found J 2001;19:13.

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95 ACNE VULGARIS Dennis P. West, Lee E. West, Maria Letizia Musumeci, and Giuseppe Micali

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 In the United States, acne vulgaris is the most common skin disorder, affecting 40 to 50 million people.

2 Four primary factors are identified as being involved in the

5 Most therapeutic interventions function primarily to prevent the formation of new acne lesions and have minimal impact on existing lesions.

formation of acne lesions: increased sebum production, sloughing of keratinocytes, bacterial growth, and inflammation.

6 Because most treatments for acne reduce or prevent new

3 Acne vulgaris is a disease of the pilosebaceous unit (i.e., the sebaceous glands and adjacent hair follicle).

or with topical antimicrobials, salicylic acid, or azelaic acid. Moderate acne may be managed with topical retinoids in combination with oral antibiotics, and if indicated, benzoyl peroxide. Severe acne is often managed with oral isotretinoin.

4 Several types of lesions present at the same time in var-

ious stages of development, including noninflammatory and inflammatory lesions, scars, and residual hyperpigmentation.

eruptions, they may take up to 8 weeks for visible results.

7 Mild acne usually is managed with topical retinoids alone

8 Minocycline has more adverse effects than the other tetracyclines.

Acne is a common, chronic inflammatory disorder of the pilosebaceous unit in which a microcomedo develops as the initial condition. The most common form of acne is acne vulgaris. Other variants of acne are neonatal acne, adult acne, acne cosmetica, and acne mechanica. These descriptors refer to age of onset or causative factors. Localization of acne vulgaris on the facial area, especially in an adolescent population, significantly impacts self-esteem. Although acne is self-limiting, it can persist for years and can result in disfigurement and scarring.1 Acne may also be associated with anxiety, depression, and higher-than-average unemployment rates.2 As the emotional impact of acne is not always easy to assess clinically,3,4 it is important for the health care professional to educate patients on causes of acne, discussing treatment regimens, and counseling on proper medication use.

EPIDEMIOLOGY 1 In the United States, acne vulgaris is the most common3

skin disorder, affecting between 40 and 50 million people. Acne vulgaris affects approximately 80% of the population between the age of 12 and 25 years,5 with no gender, race, or ethnicity prevalence.3,6 Acne age of onset varies, but usually begins at puberty. A form of acne called adult acne may first occur after the mid-20s,7 affecting females more than males, and with lesions generally distributed in the lower facial area around the mouth, chin, and jaw line.8

ETIOLOGY 2 Four primary factors are identified as being involved in the for-

mation of acne lesions: increased sebum production, sloughing of keratinocytes, bacterial growth, and inflammation.9−11

INCREASED SEBUM PRODUCTION Androgen stimulation is enhanced at puberty and sebaceous glands actively produce sebum. Testosterone, the predominant androgen, and its metabolites along with androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate, are all increased in acne and apparently capable of enhancing sebaceous gland activity. Anatomic sites for acne tend to be more metabolically active in converting androgens to dihydrotestosterone. Androgenic activity drives sebum production in the sebaceous glands; however, most acne patients do not have an endocrine abnormality. Acne-affected pilosebaceous units apparently have a hyperresponsiveness to circulating androgens.9 Increased sebum production per se is not necessarily responsible for acne, but may rather be viewed as an underlying factor.

SLOUGHING OF KERATINOCYTES A primary factor in the development of acne is the process of follicular keratinization. Sloughing of keratinocytes within the hair follicle is a normal process, but in acne, follicular keratinization more readily involves keratinocyte clumping and subsequent plugging of 1755

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the hair follicle pore. Increased sloughing of keratinocytes correlates with comedo formation and may be related to influences such as local cytokine modulation, a decrease in sebaceous linoleic acid, and androgen stimulation.9,12 Abnormal follicular keratinization may be a primary event, or may be a secondary response to irritation or other factors.

Androgen stimulation

BACTERIAL GROWTH AND COLONIZATION

Sebum + Follicular keratinocytes

The mix of “trapped” keratinocytes and sebum provide an environment for the normally-occurring bacteria Propionibacterium acnes to flourish.13 Although P. acnes, a partial anaerobe, resides in the follicle as normal flora, it triggers immune responses such that titers of antibodies to P. acnes are higher in patients with severe acne than in non-acne control subjects.

Sebaceous gland Follicular wall Inflammatory lesion P. acnes Follicular microcomedone

Follicular wall

Closed comedone (blackhead) Open comedone (whitehead)

FIGURE 95–1. Principal influences in formation of acne lesions.

INFLAMMATION AND IMMUNE RESPONSE Inflammation may be a consequence of increased sebum production, keratinocyte sloughing, and bacterial growth. Also, P. acnes may trigger inflammatory acne lesions by producing biologically active mediators and promoting proinflammatory cytokine release.14−16

PATHOPHYSIOLOGY 3 Acne vulgaris is a disease of the pilosebaceous unit (i.e., the

sebaceous gland and adjacent hair follicle). Sebaceous glands, predominant on the face, chest, and upper back, respond to androgen stimulation. These glands provide sebum to the follicular canal and eventually to the skin surface through the follicular opening (the pore). Follicular canal contents include keratinocytes, Propionibacterium acnes (P. acnes), and free fatty acids. Formation of the primary lesion, the comedo, may be thought of as a plugging of the pilosebaceous follicle. In acne, the follicular canal widens and an increase in cell production may be seen. Sebum mixes with excess loose cells in the follicular canal to form a keratinous plug. The resulting lesion appears as a “blackhead,” or open comedo. The brown or black color is not a result of dirt accumulation, but that of melanin (pigment). Inflammation or trauma to the follicle may lead to formation of a “whitehead,” or closed comedo. If the follicular wall is damaged or ruptured, the contents of the follicle may extrude into dermis and present clinically as a pustule. Closed comedones are of clinical importance since they may become larger, inflammatory lesions secondary to local P. acnes activity (Fig. 95–1).9 Acne lesions may take months to heal completely, and fibrosis associated with healing may lead to permanent scarring.17

4

C L I N I C A L P R E S E N TAT I O N O F A C N E VULGARIS

Acne lesions typically occur on the face, back, upper chest, and shoulder area. Severity of the disease varies from a mild comedonal form to severe inflammatory necrotic acne.18 Acne vulgaris is described as mild, moderate, or severe, depending on the type and severity of lesions present. See Table 95–1 for descriptions of mild, moderate, and severe acne. SYMPTOMS Generally, the diagnosis of acne vulgaris consists of findings that include a mixture of lesions of acne (e.g., comedones,

pustules, papules, nodules, and cysts) on the face, back, or chest. Although there is no precise definition for acne, many practitioners consider the presence of 5 to 10 comedones to be diagnostic. SIGNS There may be more than one morphologic type of lesion present (see Table 95–1), in various stages of development, including noninflammatory and inflammatory lesions, scars, and residual hyperpigmentation.18 NONINFLAMMATORY LESIONS An open comedo or blackhead is a plug of sebum, keratinocytes, and microorganisms blocking a dilated hair follicle opening, whereas a closed comedone or whitehead is a similar plug blocking a closed hair follicle opening to the surface of the skin. INFLAMMATORY LESIONS

r A papule is a well-defined, elevated, palpable, distinct area of skin generally less than 1 cm in diameter involving the epidermis and/or dermis. Papules may not have a change in skin color, but are always raised and may have variable textures. r A pustule is an elevated, distinct, superficial cavity filled with purulent fluid, typically surrounding a hair follicle. r A nodule is an elevated, firm, distinct, palpable, round or oval lesion up to 1 cm in diameter which occurs in the dermis and/or hypodermis. SCARS Permanent scars may occur as a result of inflammatory acne lesions. RESIDUAL HYPERPIGMENTATION Inflammatory acne lesions may trigger noticeable hyperpigmentation that may persist weeks to months after resolution of the lesion.1 LABORATORY TESTS There are no laboratory tests to diagnose acne vulgaris. Diagnosis is based on clinical signs. Other dermatologic conditions, such as folliculitis, acne rosacea, and other various acneiform disorders, sometimes may be confused with acne vulgaris.19

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TABLE 95–1. Predominance of Acne Lesion Type by Acne Severity Typical Frequency of Lesion Type Acne Severity Mild Moderate Severe

Closed Comedones

Open Comedones

Few to numerous

Few to numerous

Possible

Few to numerous

Few to numerous

Few to numerous

Few to numerous

Predominant Lesions Noninflammatory lesions (open and closed comedones) Inflammatory papules and pustules with some noninflammatory lesions Inflammatory lesions and scarring with some noninflammatory lesions

Papules

Pustules

Nodules

Scarring

Possible

None

None

Numerous

Numerous

Few

Possible

Extensive

Extensive

Extensive

Extensive


TREATMENT: Acne Vulgaris 5 Most therapeutic interventions function primarily to prevent the

formation of new acne lesions and have minimal impact on existing lesions. Among the factors that may affect acne are genetics, climate, diet, environment, stress, and physical activity. Stress seems to aggravate, but not induce, acne.20 In response to stress, immunoreactive nerve fibers may stimulate sebaceous gland activity and provoke inflammatory reactions via mast cells.21 The ingestion of iodine may exacerbate acne or induce acneiform lesions.10 Dietary factors in acne are controversial.

Initial treatment is aimed at reducing lesion count and will vary in duration from a few months to a few years, depending on severity and response to treatment. Once control is achieved, chronic indefinite treatment may be required. Therapy with both topical and systemic antibiotics should be for the minimum duration necessary to achieve control of acne, in order to minimize the likelihood of resistance.9,26,27 Topical treatment forms include creams, lotions, solutions, gels, and disposable wipes. Responses to different formulations may be dependent on skin type and individual preferences: r

CLINICAL CONTROVERSY An observational study has concluded that the incidence of acne in Western and non-Western societies is greatly different and suggests that it is not due to genetic influence alone, but most likely occurs due to differences in diet. These authors felt that a non-westernized diet, representing a substantially low glycemic index, influenced a dramatically lower incidence of acne.22 It is disputed whether this conclusion is accurate, since acne is influenced by multiple factors and there are no data to support an effect of glycemic index on acne.23,24 Whether proven or not, some clinicians feel that diet is a factor in skin conditions, including acne, and needs to be further addressed.25

r r

Oily to normal skin types may tolerate gels, solutions, and lotions. Normal skin may tolerate gels, solutions, lotions, and creams. Normal to dry skin may tolerate lotions and creams.

Ointments are not typically included in topical acne therapy due to their occlusive nature and possible induction of acne cosmetica. Systemic treatment is required in patients with moderate to severe acne, especially when acne scarring is a possibility.28 Antibiotics such as tetracyclines and macrolides are the agents of choice for papulopustular acne. In severe papulopustular and nodulocystic/conglobate acne, oral isotretinoin is the treatment of choice. Hormonal therapy represents an alternative effective regimen in female patients.

NONPHARMACOLOGIC THERAPY
GENERAL APPROACH TO TREATMENT 18 6 Severity, lesion types, scarring, and skin discoloration, as well

as previous treatment history, helps to determine a treatment approach to acne vulgaris (see Table 95–1).9,11,26,27 Most treatments reduce or prevent new eruptions and may take up to 8 weeks to produce visible results. During the first few weeks of therapy, acne may appear to worsen as existing acne lesions may resolve more rapidly. Patients must understand the need to continue therapy for optimal outcome. 7 Patient education with emphasis on goals, realistic expectations, and dangers of overtreatment is important to optimize therapeutic outcomes. Treatment regimens are targeted to types of lesions and acne severity.9,18 Mild acne usually is managed with topical retinoids alone or with topical antimicrobials, salicylic acid, or azelaic acid. Moderate acne may be managed with topical retinoids in combination with oral antibiotics, and if indicated, benzoyl peroxide.27 Severe acne is often managed with oral isotretinoin.

Scrubbing the skin with abrasive scrubs or excessive face washing does not necessarily open or cleanse pores. Follicular plugging originates too deeply to be affected by superficial epidermal scrubbing, which often leads to skin irritation. Since surface cleansing with soap and water primarily affects sebum and bacteria on the surface of the skin and has minimal impact within the follicle, cleansing has a relatively small impact on the treatment of acne. To avoid skin irritation and dryness during some acne therapies, it is important to use gentle, nondrying cleansing agents.

PHARMACOLOGIC THERAPY Recently, worldwide consensus statements regarding management and treatment of acne have been widely distributed to improve and optimize outcomes. See Table 95–2 for highlights of consensus statements from The Global Alliance to Improve Outcomes in Acne.9 Figure 95–2 provides acne treatment algorithms based on acne severity. See Table 95–3 for the action spectra of selected acne treatments.

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TABLE 95–2. Treatment Guidelines for Acne Vulgaris Therapy Topical retinoids

Hormonal therapy

Oral isotretinoin

Combination therapy

Recommendations r r r r r

Should be primary treatment for most forms of acne vulgaris Use early for best results Should be applied to the entire affected area Combine with antimicrobial therapy when inflammatory lesions are present Essential part of maintenance therapy Excellent choice for women who also need oral contraceptives for gynecologic reasons r Use early in female patients with moderate to severe acne or with symptoms of seborrhea, acne, hirsutism, or alopecia r Useful as part of combination therapy in women with or without endocrine abnormalities r Sometimes used in women with late-onset acne Indications: r Severe nodulocystic acne r Severe acne variants r Inflammatory acne with scarring, after conventional therapy has failed r Moderate to severe acne, especially frequently relapsing cases r Acne with severe psychological distress Typical dose: r 0.5–1.0 mg/kg daily in two divided doses, with cumulative dose of 120–150 mg/kg per treatment course (4–6 months) r A lower dose ( 0.1 g/mL) organisms are encountered; streptomycin is used but may be more toxic. m Second-generation cephalosporins—IV: cefuroxime; PO: cefaclor, cefditoren, cefprozil, cefuroxime axetil, and loracarbef. n Third-generation cephalosporins—PO: cefdinir, cefixime, cefetamet, cefpodoxime proxetil, and ceftibuten. o Reserve for serious infection. p Aminoglycosides: gentamicin, tobramycin, and amikacin; use per sensitivities. q Cefoxitin, cefotetan. r IV/PO: ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. s Reserve for serious infection when less toxic drugs are not effective. t Generally reserved for patients with hypersensitivity reactions to penicillin. b

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105 CENTRAL NERVOUS SYSTEM INFECTIONS Elizabeth D. Hermsen and John C. Rotschafer

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 The three most likely pathogens of bacterial meningitis in the United States are Streptococcus pneumoniae, Neisseria meningitidis, and Hemophilus influenzae, although routine vaccination may cause a change in the epidemiology in the years to come.

2 In cases of meningitis, initial findings can include (a) presenting signs and symptoms: fever, headache, nuchal rigidity, Brudzinski’s or Kernig’s sign, and altered mental status, and (b) abnormal cerebrospinal fluid (CSF) chemistries: elevated white blood cell (WBC) count (>100 cells/mm3 ), elevated protein (>50 mg/dL), and decreased glucose levels (6 years

Pneumococcus, Mycoplasma pneumoniae, adenovirus

1–3 months

Ampicillin-sulbactam, cephalosporinb carbapenemc Ribavirin for RSV Macrolide-azalide,d trimethoprim-sulfamethoxazole Ribavirin Semisynthetic penicilline or cephalosporinf Amoxicillin or cephalosporinf Ampicillin-sulbactam, amoxicillin-clavulanate Ribavirin for RSV Macrolide/azalided cephalosporin,f amoxicillin-clavulanate

CMV = cytomegalovirus; RSV = respiratory syncytial virus. a See section on treatment of bacterial pneumonia. b Third-generation cephalosporin: ceftriaxone, cefotaxime, cefepime. Note that cephalosporins are not active against Listeria. c Carbapenem: imipenem-cilastatin, meropenem. d Macrolide/azalide: erythromycin, clarithromycin-azithromycin. e Semisynthetic penicillin: nafcillin, oxacillin. f Second-generation cephalosporin: cefuroxime, cefprozil. See text for details regarding ribavirin treatment for RSV infection.

bacteriologic cure. For concentration-dependent antimicrobials (e.g., aminoglycosides and fluoroquinolones), a peak drug concentration to pathogen MIC ratio of greater than 8 to 10 or the ratio of the pathogen MIC to antibiotic area under the curve (AUC) of greater than 25 to 40 for gram-positive pathogens and greater than 100 for gram-negative pathogens correlates with bacteriologic cure. An understanding and application of these inherent drug characteristics would appear to be of the utmost importance for the selection of an optimal therapeutic regimen. Thus, whenever possible, identification of the causative pathogen and expected/defined antibiotic activity

(i.e., MIC) is of paramount importance to the selection/design of the optimal antibiotic regimen.


COMMUNITY-ACQUIRED PNEUMONIA For community-acquired pneumonia, the bacterial causes are relatively constant, even across geographic areas and patient populations. Unfortunately, pathogen resistance to standard antimicrobials is increasing (e.g., penicillin-resistant pneumococci), necessitating

TABLE 106–11. Antibiotic Doses for the Treatment of Bacterial Pneumonia Daily Antibiotic dose Antibiotic Class Macrolide Azalide Tetracyclinea Penicillin

Extended-spectrum cephalosporins Fluoroquinolones

Aminoglycosides

Antibiotic Clarithromycin Erythromycin Azithromycin Tetracycline HCL Oxytetracycline Ampicillin Amoxicillin/amoxicillin-clavulanateb Piperacillin-tazobactam Ampicillin-sulbactam Ceftriaxone Ceftazidime Cefepime Gatifloxacinc Levofloxacin Ciprofloxacin Gentamicin Tobramycin

Pediatric (mg/kg/day) 15 30–50 10 mg/kg × 1 day, then 5 mg/kg/day × 4 days 25–50 15–25 100–200 40–90 200–300 100–200 50–75 150 100–150 10–20 10–15 20–30 7.5 7.5

Adult (total dose/day) 0.5–1 g 1–2 g 500 mg day 1, then 250 mg/day × 4 days 1–2 g 0.25–0.3 g 2–6 g 0.75–1 g 12 g 4–8 g 1–2 g 2–6 g 2–4 g 0.4 g 0.5–0.75 g 0.5–1.5 g 3–6 mg/kg 3–6 mg/kg

Note: Doses may be increased for more severe disease and may require modification in patients with organ dysfunction. a Tetracyclines are rarely used in pediatric patients, particularly in those younger than 8 years of age because of tetracycline-induced permanent tooth discoloration. b Higher dose amoxicillin, amoxicillin-clavulanate (e.g., 90 mg/kg/day) is used for penicillin resistant S. pneumoniae. c Fluoroquinolones are avoided in pediatric patients because of the potential for cartilage damage; however, their use in pediatrics is emerging. Doses shown are extrapolated from adults and will require further study.

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CHAPTER 106 TABLE 106–12. Guidelines for the Empirical Treatment of Community-Acquired Pneumonia Clinical Setting Outpatients Inpatients, general medical ward

Inpatients, intensive care unit

Empirical Therapy Macrolide/azalide, doxycycline, or fluoroquinolone Extended-spectrum cephalosporin + macrolide/azalide or β-lactam/β-lactamase inhibitor + macrolide/azalide or fluoroquinolone Extended-spectrum cephalosporin or β-lactam/β-lactamase inhibitor + fluoroquinolone or macrolide/azalide

careful attention by the clinician to local and regional bacterial susceptibility patterns.83 Thus, whenever possible, initial therapy should be based on presumed antibacterial susceptibility and consist of older, less-expensive agents, with newer and more expensive antibiotics reserved for unresponsive illness or special circumstances. The indiscriminate use of recently introduced agents increases health care costs and, in some instances (such as with the widespread use of fluoroquinolones), induces resistance among a significant percentage of community-acquired organisms.84,85 It must be emphasized, however, that the rapidly evolving epidemiology of bacterial resistance, including the increasing emergence of penicillin-resistant pneumococcus in many areas of the United States and Europe,86 forces the clinician to be vigilant and knowledgeable about antibiotic sensitivity patterns in each community. The indiscriminate use of antimicrobials for the treatment of pneumonia has contributed to the problem of antimicrobial resistance, underscoring the need for defining the optimal antibiotic regimen for each patient.82,83 9 Recommended empirical therapy differs among outpatients, hospitalized patients, and hospitalized patients admitted to an intensive care unit82 (Table 106–12). Additionally, antimicrobial therapy should be initiated in hospitalized patients with acute pneumonia within 8 hours of admission because an increase in mortality has been demonstrated when therapy was delayed beyond 8 hours of admission.


NOSOCOMIAL PNEUMONIA 10 Antibiotic selection within the hospital environment demands

greater care because of constant changes in antibiotic resistance patterns in vitro and in vivo. Ironically, some β-lactam antibiotics, which were developed to treat multiple-antibiotic–resistant hospitalacquired organisms, can themselves induce broad-spectrum bacterial β-lactamases and thereby lead to even greater problems with resistance.86 These facts underscore the importance of regularly documenting the epidemiology of pathogens and infectious diseases within a specific practice or institution. As a result, an antimicrobial agent for a specific infectious disease favored in one practice site may not be the most desirable selection in another despite similarities in size and patient profile. Strict and careful control and, possibly, rotation of empirical antibiotics in the hospital environment may help to limit the emergence of resistant organisms. Newer antibiotics developed to treat resistant, hospital-acquired pathogens are, however, costly; therefore, their use must be moderated to some extent in an era where capitated hospital costs and mandated budget cuts will not tolerate careless antibiotic use.

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SEVERE ACUTE RESPIRATORY SYNDROME The treatment of SARS involves primarily supportive care and procedures to prevent transmission to others.77 Owing to the uncertainty associated with the diagnosis of SARS, empirical therapy with broadspectrum antibiotics should be employed. To date, fluoroquinolones or macrolides typically have been used. Although its efficacy is unproven, patients also have been treated with ribavirin. Owing to the potential benefit of corticosteroids in the presence of progressive pulmonary disease, methylprednisolone also has been used in doses ranging from 80 to 500 mg/day.


FLUOROQUINOLONE ANTIBIOTICS The in vitro spectrum of antibacterial activity of systemically absorbed fluoroquinolone antibiotics, such as ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin, suggests that these drugs have an important role in the treatment of bacterial infections of the lower respiratory tract. Numerous clinical studies describe the efficacy of these drugs for the treatment of purulent bronchitis, acute exacerbations of chronic bronchitis, pneumonia, and cystic fibrosis.87 The widespread use of earlier analogues (ciprofloxacin) by primary care physicians has led, however, to pathogen resistance and treatment failures, including, perhaps most important, isolates of S. pneumonia. Although newer fluoroquinolones are more active against common respiratory tract pathogens than older agents, this experience renders it difficult to recommend their indiscriminate use for routine community-acquired pneumonia. Nevertheless, these drugs may be effective alternative agents for the treatment of community-acquired pneumonia or in the initial treatment of nosocomial pneumonia for hospitalized patients and patients residing in extended-care facilities. The availability of newer analogues with broad spectra of antibacterial activity, including S. pneumoniae (e.g., gatifloxacin), further enhances the desirability of a fluoroquinolone as a first-line agent, expanding the therapeutic armamentarium for both community-acquired and nosocomially acquired pneumonia. At present, fluoroquinolone use in pediatrics remains restricted and limited because of possible fluoroquinolone-induced destructive lesions of growing cartilage primarily of the weight-bearing joints. These fluoroquinolone-associated arthritic lesions were determined in animals following large doses, but have not been reflected in the human experience. The need for fluoroquinolones for the treatment of selected infections arising in pediatric patients continues, and their continued safety in these patients has served as the foundation for ongoing controlled clinical efficacy and safety trials in pediatric patients.


MACROLIDE-AZALIDE ANTIBIOTICS Among the more recently introduced classes of oral antibiotics, the newer macrolide-azalide antibiotics (clarithromycin-azithromycin) possess excellent activity against most S. pneumoniae and Mycoplasma and appear to offer viable alternatives to erythromycin, particularly in patients who are intolerant of erythromycin analogues (e.g., gastrointestinal upset) and, with azithromycin, in patients who are taking medications that may result in a clinically significant drug-drug interaction (e.g., erythromycin with carbamazepine or theophylline).40 Azithromycin offers the added advantage of once-daily dosing and short-course therapy because of the drug’s extensive tissue distribution characteristics and prolonged elimination half-life.40

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PREVENTION Prevention of some cases of pneumonia is possible through the use of vaccines and medications against selected infectious agents. Polyvalent polysaccharide vaccines are available for two of the leading causes of bacterial pneumonia, pneumococcus and H. influenzae type b. Inactivated influenza virus vaccines formulated annually to contain antigens representative of expected prevalent strains are widely available and generally well tolerated. Recently, a newly developed cold-adapted live influenza virus vaccine available as a nasal spray (Flumist) was approved.88 Immunization is recommended for individuals likely to experience serious complications from influenza infection, such as patients with underlying heart or lung disease or chronic renal disease and the elderly. For a detailed description of the use of these vaccines, see Chap. 122. Although they should not replace active immunization, the tricyclic amines amantadine hydrochloride and rimantadine hydrochloride may be administered for prevention and treatment of influenza A infection.89 When therapy is initiated to healthy individuals within 48 hours of the onset of symptoms, both drugs have been proved to decrease the severity and shorten the course of illness by approximately 1 day. The recommended dose for each drug is 5 mg/kg per day in one or two doses not to exceed 150 mg/day in children 1 to 9 years of age and 200 mg/day in two divided doses in patients 9 years of age or older. Additionally, the discovery of the importance of neuraminidase to the viability of the influenza A and B virus has led to the development of the most effective drugs available for the prevention and treatment of influenza disease. Oseltamivir and zanamivir are the first of a new class of neuraminidase inhibitors. Zanamivir is available for aerosol administration, leading to some concern over aerosolization in patients with disease-induced hyperactive airways, whereas oseltamivir is available for oral administration. Both agents are effective in preventing disease, particularly if therapy is begun within 30 hours of symptom onset or exposure (e.g., epidemics) and for treatment in febrile individuals.90,91

EVALUATION OF THERAPEUTIC OUTCOMES After therapy has been instituted, appropriate clinical parameters should be monitored to ensure efficacy and safety of the therapeutic regimen. In patients with bacterial infections of the upper or lower respiratory tract, the time to resolution of initial presenting symptoms and the lack of appearance of new associated symptomatology is important to determine. In patients with community-acquired pneumonia or pneumonia from any source of mild to moderate clinical severity, the time to resolution of cough, decreasing sputum production, and fever, as well as other constitutional symptoms of malaise, nausea, vomiting, and lethargy, should be noted. If the patient requires supplemental oxygen therapy, the amount and need also should be assessed regularly. A gradual and persistent improvement in the resolution of these symptoms and therapies should be observed. Initial resolution should be observed within the first 2 days, progressing to complete resolution within 5 to 7 days, but usually in no more than 10 days. In patients with nosocomial pneumonia or substantial underlying diseases or both, additional parameters can be followed, including the magnitude and character of the peripheral blood WBC count, chest radiograph, and blood gas determinations. Similar to patients with less severe disease, some resolution of symptoms should be observed within 2 days of instituting antibiotic therapy. If within 2 days of starting seemingly appropriate antibiotic therapy no resolution of symptoms is observed, or if the patient’s clinical status is

deteriorating, the appropriateness of initial antibiotic therapy should be critically reassessed. The patient should be evaluated carefully for deterioration in underlying concurrent disease(s). Additionally, the caregiver should consider the possibility of changing the initial antibiotic therapy to expand antimicrobial coverage not included in the original regimen (e.g., Mycoplasma, Legionella, and anaerobes). Furthermore, the possible need for antifungal therapy (amphotericin B) should be considered. Some resolution of symptoms should be observed within 2 days of starting proper antibiotic therapy, with complete resolution expected within 10 to 14 days.

ABBREVIATIONS AUC: area under the curve COPD: chronic obstructive pulmonary disease ELISA: enzyme-linked immunosorbent assay MIC: minimum inhibitory concentration PCR: polymerase chain reaction RSV: respiratory syncytial virus RSVIG: repiratory syncytial virus immune globulin SARS: severe acute respiratory syndrome Review Questions and other resources can be found at www.pharmacotherapyonline.com.

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CHAPTER 106 15. Rodriguez WJ. Management strategies for respiratory syncytial virus infections in infants. J Pediatr 1999;135(suppl 2):S45–50. 16. Adcock PM, Stout GG, Hauck MA, Marshall GS. Effect of rapid viral diagnosis on the management of children hospitalized with lower respiratory tract infection. Pediatr Infect Dis J 1997;16:842–846. 17. Black S. Epidemiology of pertussis. Pediatr Infect Dis J 1997;16(suppl 4):S85–89. 18. Visentin M, Salmona M, Tacconi MT. Reye’s and Reye-like syndromes: Drug-related diseases? Drug Metab Rev 1995;27:517–539. 19. Katcher ML. Cold, cough, and allergy medications: Uses and abuses. Pediatr Rev 1996;17:12–17. 20. MacKay DN. Treatment of acute bronchitis in adults without underlying lung disease. J Gen Intern Med 1996;11:557–562. 21. O’Brien KL, Dowell SF, Schwartz B, et al. Cough illness/bronchitis: Principles of judicious use of antimicrobial agents. Pediatrics 1998;101: 178–181. 22. Nicholson KG. Use of antivirals in influenza in the elderly: Prophylaxis and therapy. Gerontology 1996;42:280–289. 23. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: A randomized, controlled trial. JAMA 2000;283:1016–1024. 24. Monto AS, Webster A, Keene O. Randomized, placebo-controlled studies of inhaled zanamivir in the treatment of influenza A and B: Pooled efficacy analysis. J Antimicrob Chemother 1999;44(suppl B):23–29. 25. Adams SG, Anzueto A. Antibiotic therapy in acute exacerbations of chronic bronchitis. Semin Respir Infect 2000;15:234–247. 26. American Thoracic Society. Standards for the diagnosis and care of patients with chronic bronchitis. Am J Respir Crit Care Med 1995; 152(suppl):S78–122. 27. Grossman RF. Acute exacerbations of chronic bronchitis. Hosp Pract 1997;132:85–94. 28. Godfrey S. Bronchiolitis and asthma in infancy and early childhood. Thorax 1996;51(suppl 2):S60–64. 29. Wilson R, Wilson CB. Defining subsets of patients with chronic bronchitis. Chest 1997;112:303S–309. 30. Anzueto A, Jubran M, Ohan JA, et al. Effects of aerosolized surfactant in patients with stable bronchitis: A prospective, randomized, controlled trial. JAMA 1997;278:957–960. 31. Wilson R, Tillotson G, Ball P. Clinical studies in chronic bronchitis: A need for better definition and classification of severity. J Antimicrob Chemother 1996;37:205–208. 32. Saint S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic obstructive pulmonary disease exacerbations: A meta-analysis. JAMA 1995;273:957– 960. 33. Russo RL, D’Aprile MD. Role of antimicrobial therapy in acute exacerbations of chronic obstructive pulmonary disease. Ann Pharmacother 2001;35:576–581. 34. Ball P. Epidemiology and treatment of chronic bronchitis and its exacerbations. Chest 1995;108:43S–52. 35. Wilson R. Outcome predictors in bronchitis. Chest 1995;108(suppl): 53S–57. 36. Lund BC, Ernst EJ, Klepser ME. Strategies in the treatment of penicillin-resistant Streptococcus pneumoniae. Am J Health Syst Pharm 1998;55:1987–1994. 37. Harwell JI, Brown RB. The drug-resistant pneumococcus: Clinical relevance, therapy, and prevention. Chest 2000;117:530–541. 38. Campbell GD, Silberman R. Drug-resistant Streptococcus pneumoniae. Clin Infect Dis 1998;26:1188–1195. 39. Balter MS, La Forge J, Low DE, et al. Canadian guidelines for the management of acute exacerbations of chronic bronchitis. Can Respir J 2003;10(suppl B):3B–32. 40. Reed MD, Blumer JL. Azithromycin: A critical review of the first azilide antibiotic and its role in pediatric practice. Pediatr Infect Dis J 1997;16:1069–1083. 41. Klassen TP. Recent advances in the treatment of bronchiolitis and laryngitis. Pediatr Clin North Am 1997;44:249–261. 42. Klassen TP, Sutcliffe T, Watters LK, et al. Dexamethasone in salbutamol-

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treated inpatients with acute bronchiolitis: A randomized, controlled study. J Pediatr 1997;130:191–196. Muller NL, Miller RR. Diseases of the bronchioles: CT and histopathologic findings. Radiology 1995;196:3–12. Ottolini MG, Hemming VG. Prevention and treatment recommendations for respiratory syncytial virus infection. Drugs 1997;54:867–884. McCarthy CA, Hall CB. Recent approaches to the management and prevention of respiratory syncytial virus infection. Curr Clin Top Infect Dis 1998;18:1–18. Englund JA, Piedra PA, Ahn YM, et al. High-dose, short-duration ribavirin aerosol therapy compared with standard ribavirin therapy in children with suspected respiratory syncytial virus infection. J Pediatr 1994; 125:635–641. Darville T, Yamauchi T. Respiratory syncytial virus. Pediatr Rev 1998; 19:55–61. Committee on Infectious Diseases. Reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections. Pediatrics 1996;97:137–140. Committee on Infectious Diseases. 1997 Redbook: Report of the Committee on Infectious Diseases, 24th ed. Elk Grove Village, IL, American Academy of Pediatrics, 1997:445. Meert KL, Sarnaik AP, Gelmini MJ, et al. Aerosolized ribavirin in mechanically ventilated children with respiratory syncytial virus lower respiratory tract disease: A prospective, double-blind, randomized trial. Crit Care Med 1994;22:566–572. The Prevent Study Group. Reduction of respiratory syncytial virus hospitalizations among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics 1997;99:93–99. The Impact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102:531–537. Cunha BA. Community-acquired pneumonia: Diagnostic and therapeutic approach. Med Clin North Am 2001;85:43–77. Mandell LA. Community-acquired pneumonia: Etiology, epidemiology and treatment. Chest 1995;108(suppl):35S–42. Cunha BA. Nosocomial pneumonia: Diagnostic and therapeutic considerations. Med Clin North Am 2001;85:79–114. Baker CJ, Edwards MS. Group B streptococcal infections. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant, 4th ed. Philadelphia, Saunders, 1995:980–1054. American Thoracic Society. Hospital-acquired pneumonia in adults: Diagnosis, assessment of severity, initial antimicrobial therapy, and preventative strategies. Am J Respir Crit Care Med 1996;153:1711–1725. Beringer PM. New approaches to optimizing antimicrobial therapy in patients with cystic fibrosis. Curr Opin Pulm Med 1999;5:371–377. Stout JE, Yu VL. Legionellosis. N Engl J Med 1997;337:682–687. Bartlett JG. Anaerobic bacterial infections of the lung and pleural space. Clin Infect Dis 1993;16(suppl 4):S248–255. Martin G, Lazarus A. Epidemiology and diagnosis of tuberculosis. Postgrad Med 2000;108:42–54. McCray E, Weinbaum CM, Braden CR, et al. The epidemiology of tuberculosis in the United States. Clin Chest Med 1997;18:99–113. Telzak EE. Tuberculosis and human immunodeficiency virus infection. Med Clin North Am 1997;81:345–360. Plouffe J. Importance of typical pathogens of community acquired pneumonia. Clin Infect Dis 2000;31(suppl 2):S35–39. File TM, Tan JS, Plouffe JF. The role of atypical pathogens: Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila in respiratory infection. Infect Dis Clin North Am 1998;12:569–592. Ashley EA, Johnson MA, Lipman MC. Human immunodeficiency virus and respiratory infection. Curr Opin Pulm Med 2000;6:240–245. Schneider RF, Rosen MJ. Pulmonary complications of HIV infection. Curr Opin Pulm Med 1997;3:151–158. Noskin GA, Glassroth J. Bacterial pneumonia associated with HIV-1 infection. Clin Chest Med 1996;17:713–723.

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69. Pizzo PA. Management of fever in patients with cancer and treatmentinduced neutropenia. N Engl J Med 1993;328:1323–1332. 70. Hughes WT, Armstrong D, Bodey GP, et al. 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis 1997;25:551–573. 71. Whimbey E, Goodrich J, Bodey GP. Pneumonia in cancer patients. Cancer Treat Rep 1995;79:185–210. 72. Mayhall CG. Ventilator-associated pneumonia or not? Contemporary diagnosis. Emerg Infect Dis 2001;7:200–204. 73. ASCO Ad Hoc Colony-Stimulating Factor Guidelines Expert Panel. Update of recommendations for the use of hematopoietic colonystimulating factors: Evidence-based clinical practice guidelines. J Clin Oncol 1996;14:1957–1960. 74. Gallego M, Valles J, Rello J. New perspectives in the diagnosis of nosocomial pneumonia. Curr Opin Pulm Med 1997;3:116–119. 75. Young PJ, Ridley SA. Ventilator-associated pneumonia: Diagnosis and prevention. Anaesthesia 1999;54:1183–1197. 76. Estes RJ, Meduri GU. The pathogenesis of ventilator-associated pneumonia: I. Mechanisms of bacterial transcolonization and airway inoculation. Intensive Care Med 1995;21:365–383. 77. Sampathkumar P, Temesgen Z, Smith TF, Thompson RL. SARS: Epidemiology, clinical presentation, management, and infection control measures. May Clin Proc 2003;78:882–890. 78. Amsden GW, Duran JM. Interpretation of antibacterial susceptibility reports: In vitro clinical breakpoints. Drugs 2001;61:163–166. 79. Honeybourne D. Antibiotic penetration in the respiratory tract and implications. Curr Opin Pulm Med 1997;3:170–174. 80. Bodem CR, Lampton LM, Miller DP, et al. Endobronchial pH: Relevance to aminoglycoside activity in gram-negative bacillary pneumonia. Am Rev Resp Dis 1983;127:39–41.

81. Smaldone GC, Palmer LB. Aerosolized antibiotics: Current and future. Respir Care 2000;45:667–675. 82. Barlett JG, Dowell SF, Mandell LA, et al. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis 2000;31:347–382. 83. Heffelfinger JD, Dowell SF, Jorgensen JH. Management of communityacquired pneumonia in the era of pneumococcal resistance: A report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group. Arch Intern Med 2000;160:1399–1408. 84. Jacoby GA. Prevalence and resistance mechanisms of common bacterial respiratory pathogens. Clin Infect Dis 1994;18:951–957. 85. Collignon P, Turnidge JD. Antibiotic resistance in Streptococcus pneumoniae. Med J Aust 2000;173(suppl):S58–64. 86. Shlaes DM, Gerding DN, John JF, et al. Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: Guidelines for the prevention of antimicrobial resistance in hospitals. Clin Infect Dis 1997;25:584–599. 87. Aminimanizani A, Beringer P, Jelliffe R. Comparative pharmacokinetics and pharmacodynamics of the newer fluoroquinolone antibacterials. Clin Pharmacokinet 2001;40:169–187. 88. Gruber WC. The role of live influenza vaccines in children. Vaccine 2002;20(suppl 2):S66–73. 89. Committee on Infectious Diseases, American Academy of Pediatrics. Reduction of the influenza burden in children. Pediatrics 2002;110: 1246–1252. 90. Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors. Lancet 2000;355:827–835. 91. McNicholl IR, McNicholl JJ. Neuraminidase inhibitors: Zanamivir and oseltamivir. Ann Pharmacother 2001;35:57–70.

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107 UPPER RESPIRATORY TRACT INFECTIONS Yasmin Khaliq, Sarah Forgie, and George Zhanel

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Most nonspecific upper respiratory tract infections have a

viral, not bacterial, etiology and tend to resolve spontaneously.

2 Each time antibiotics are administered for an upper respiratory tract infection, the recipient is at increased risk of selection and carriage of resistant organisms that can be passed to others. This can lead to future antibiotic failure.

3 Amoxicillin is the drug of choice for acute otitis media. For patients who are suspected of having infection or who are at high risk for infection with drug-resistant Streptococcus pneumoniae, high-dose amoxicillin should be administered.

4 Vaccination against influenza and pneumococcus may decrease the risk of acute otitis media, especially in those with recurrent episodes.

5 Viral and bacterial sinusitis are difficult to differentiate because their clinical presentations are similar. Viral infections, however, tend to resolve by 7 to 10 days. Persistence of symptoms beyond this time likely indicates a bacterial infection.

antibiotics, the advantages of amoxicillin include proven efficacy and safety, a relatively narrow spectrum that minimizes emergence of resistance, good tolerability, and low cost.

7 Group A β-hemolytic Streptococcus (S. pyogenes) is the

most common bacterial cause of pharyngitis, and despite representing a small percentage of causes of pharyngitis, it is the only commonly occurring form of acute pharyngitis for which antimicrobial therapy is indicated.

8 Antimicrobial treatment of pharyngitis should be limited

to those who have clinical and epidemiologic features of group A streptococcal pharyngitis with a positive laboratory test. Penicillin is first-line treatment. Amoxicillin can be used for children because of its better taste.

9 The evidence that treatment of group A streptococcal

pharyngitis prevents rheumatic fever comes solely from studies using depot intramuscular penicillin. Penicillin administered by other routes has been assumed to be equally efficacious. The ability of other antibiotics to eradicate group A Streptococcus has led to extrapolation that these agents also will prevent rheumatic fever.

6 Amoxicillin is first-line treatment for acute bacterial sinusitis. Since there is no difference in clinical outcome among

Upper respiratory tract infections include otitis media, sinusitis, pharyngitis, laryngitis (croup), rhinitis, and epiglottitis. These infections are responsible for the majority of antibiotics prescribed in ambulatory practice in the United States.1 In 1998, the estimated cost of otitis media was $3 to $4 billion in the United States and $600 million in Canada.2 1 Most nonspecific upper respiratory tract infections have 3,4a viral, not bacterial, etiology and tend to resolve spontaneously. Strategies for limiting unnecessary antibiotic use have been developed1,3,5 in an effort to address the problem of increased bacterial resistance that is associated with antibiotic use. This is particularly important for Streptococcus pneumoniae, the leading bacterial cause of meningitis, pneumonia, otitis media, and sinusitis.1 In Canada, an average of 15 deaths per year due to S. pneumoniae are reported in children younger than 5 years of age.6 This chapter will focus primarily on otitis media, pharyngitis, and sinusitis because these infectious entities are frequently bacterial in origin, and apprpriate antibiotic treatment can minimize morbidity and potentially prevent complications.

OTITIS MEDIA Otitis media is inflammation of the middle ear. The diagnosis of acute otitis media includes signs and symptoms of infection of the middle ear, such as otalgia, fever, and irritability, as well as the presence of fluid in the middle ear.7−11 In otitis media with effusion, middle ear fluid is present, but signs and symptoms of infection are absent. Otitis media is most common in infants and children, 75% of whom have had at least one episode by the age of 1 year.12 About 20% of otitis cases occur in adults, particularly in those with a history of these infections as a child.13 Table 107–1 lists the risk factors for otitis media. Risk factors for otitis media owing to resistant pathogens include (1) daycare attendance, (2) prior antibiotic exposure, and (3) age younger than 2 years.14

PATHOPHYSIOLOGY Acute otitis media usually follows a viral upper respiratory tract infection that causes Eustachian tube dysfunction and mucosal swelling in 1963

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TABLE 107–1. Risk Factors for Otitis Media Winter season/outbreaks of respiratory syncytial or influenza virus Attendance of day care centers Lack of breastfeeding in infants Native American or Inuit origin Early age of first diagnosis Nasopharyngeal colonization with middle ear pathogens Genetic predisposition Siblings in the home Lower socioeconomic status Exposure to tobacco smoke Use of a pacifier Male gender Immunodeficiency Allergy Urban population From refs. 11, 12, and 14.

the middle ear.12,14 Bacteria and viruses that colonize the nasopharynx thus enter the middle ear and are not cleared properly by the mucociliary system.7 In the presence of effusion, the bacteria proliferate and cause infection.7,14 Children tend to be more susceptible to otitis media than adults because the anatomy of their Eustachian tube is shorter and more horizontal, facilitating bacterial entry into the middle ear.14

tis media, non–β-lactam antibiotic treatment is mostly considered when penicillin-allergic patients are treated or when treatment failure occurs. S. pneumoniae resistance to amoxicillin with or without clavulanate is reported to range from 1% to 14%.17,18 The secondgeneration cephalosporins that were most active were cefuroxime and cefprozil, followed by cefixime and cefaclor, with resistance rates of 6% to 12% in Canada and about 25% to 50% in the United States. The approximate rates of resistance for individual classes are clarithromyin (8% to 26%), trimethoprim-sulfamethoxazole (16% to 30%), doxycycline (4%), and levofloxacin (1%). β-Lactamase–producing H. influenzae and M. catarrhalis are found in 23% to 35% and up to 100% of infected patients, respectively.17,19 It is important to note that susceptibilities vary by geographic region, particularly for H. Influenzae.20 While these organisms tend to cause infection that is more likely to resolve spontaneously as compared with S. pneumoniae, they are still pathogens that must be accounted for, particularly in treatment failures. 2 Bacterial resistance increases with antibiotic usage such that it is difficult to achieve an appropriate balance between antibiotic prescribing and minimizing resistance. Each time antibiotics are administered, the recipient is at increased risk of selection and carriage of resistant organisms that can be passed to others. This can lead to future antibiotic failure. Without antibiotic therapy, however, acute otitis media secondary to S. pneumoniae is less likely to resolve spontaneously than that from other causes. S. pneumoniae is increasingly resistant to penicillin, and penicillin-resistant S. pneumoniae is more likely to be resistant to multiple antibiotics.15,16,18

MICROBIOLOGY S. pneumoniae is the most common bacterial cause of acute otitis media, with an incidence of 20% to 35%.6,8,15 Nontypeable Haemophilus influenzae and Moraxella catarrhalis are each responsible for 20% to 30% and 20% of cases, respectively. Bacterial organisms that have been associated less frequently with otitis media include Staphylococcus aureus, S. pyogenes, and gram-negative bacilli such as Pseudomonas aeruginosa.14 In 20% to 30% of cases, no bacterial pathogen is found, and in up to 44%, a viral etiology is found with or without concomitant bacteria.7

CLINICAL PRESENTATION AND DIAGNOSIS Acute otitis media presents as an acute onset of signs and symptoms of middle ear infection such as otalgia, irritability, and tugging on the ear, following cold symptoms of runny nose, nasal congestion, or cough (Table 107–2). Resolution of the symptoms of acute otitis media occurs over 1 week. Pain and fever tend to resolve after 2 to 3 days, with most children becoming asymptomatic at 7 days. Over a period of 1 week, changes in the eardrum normalize, and the pus becomes serous

BACTERIAL RESISTANCE Bacterial resistance to antimicrobial therapy for acute otitis media is of growing concern, particularly in view of the increasing levels of drug resistant S. pneumoniae. Data from the United States (1999–2000) indicate that 8.3% to 34.2% of all S. pneumoniae isolates are penicillin-nonsusceptible (minimum inhibitory cincentration [MIC] = 0.12–1 mcg/mL), that 12.2% to 21.5% are highly penicillin-resistant (MIC ≥ 2 mcg/mL), and that these rates are highly variable based on regional differences.16,17 Canadian data from isolates collected between 1997 and 2002 indicate that 20.2% of S. pneumoniae isolates are penicillin-nonsusceptible.18 High-level penicillin resistance increased from 2.4% to 13.8% from 1999 to 2002, and multidrug resistance was reported at 8.8% in 2002. Multidrug resistance in the United States is reported as 12.2% to 22.4% of S. pneumoniae isolates.16,17 Multidrug resistance is defined as concomitant resistance to at least three diferent antibiotic classes. Antibiotic resistance rates with other β-lactams (penicillins other than penicillin, as well as cephalosporins), macrolides (azithromycin and clarithromycin), clindamycin, trimethoprim-sulfamethoxazole, tetracyclines, and fluoroquinolones also must be considered. In oti-

TABLE 107–2. Clinical Presentation of Acute Otitis Media General The acute onset of signs and symptoms of middle ear infection following cold symptoms of runny nose, nasal congestion, or cough Signs and Symptoms Pain that can be severe (more than 75% of patients) Children may be irritable, tug on the involved ear, and have difficulty sleeping Fever is present in less than 25% of patients and, when present, is more often in younger children Examination shows a discolored, thickened, bulging eardrum Pneumatic otoscopy or tympanometry demonstrates an immobile eardrum; 50% of cases are bilateral Draining middle ear fluid occurs (less than 3% of patients) that usually reveals a bacterial etiology Laboratory Tests Gram stain, culture, and sensitivities of draining fluid or aspirated fluid if tympanocentesis is performed From ref. 7.

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fluid. Air-fluid levels are apparent behind the eardrum, at which the stage is now referred to as otitis media with effusion. This does not represent ongoing infection, nor are additional antibiotics required.12 Otitis media with effusion also can occur de novo and is thought to be a result of respiratory viruses. Otitis media with effusion usually occurs in spring or autumn, not winter, and may be a result of allergens or viruses common at these times. It also differs from acute otitis media in that pain is not present, nor a bulging eardrum. Effusions resolve slowly. At 3 months, 90% have disappeared.10,12 Younger children or those with a history of recurrent infections have

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a further delay in resolution.7,12,21 Because of symptoms of viral upper respiratory tract infection (the “common cold”), antibiotics frequently are prescribed for otitis media with effusion but are not needed if duration is less than 3 months.8 Limiting antibiotic use to documented acute otitis media would save up to $8 million annually in the United States.8,20 Unfortunately the longer the time spent with otitis media with effusion, the higher is the likelihood of poor linguistic performance.22,23 Complications of otitis media are infrequent but include mastoiditis, bacteremia, meningitis, and auditory sequelae.


TREATMENT: Acute Otitis Media
DESIRED OUTCOME The goals of treatment of acute otitis media are the reduction in signs and symptoms, eradication of the infection, and prevention of complications. Avoidance of unnecessary antibiotic prescribing is another goal in view of the increasing problem of S. pneumoniae resistance.


GENERAL APPROACH TO TREATMENT 8 The management of acute otitis media is not without controversy. For example, a systematic review of studies demonstrated that antimicrobial therapy provides resolution of symptoms in about 95% of patients, whereas about 80% of placebo-treated patients also have a resolution of symptoms.21,24 Although only a small benefit has been found, antimicrobial treatment is still considered an appropriate management strategy.15 However, the choices of which patient should receive antimicrobials, which antimicrobial regimen, and at what point antibiotics should be given after diagnosis require further evaluation. Generally, otitis media is treated empirically without laboratory tests.


NONPHARMACOLOGIC THERAPY Acetaminophen or a nonsteroidal anti-inflammatory agent such as ibuprofen can be used to relieve pain and malaise in acute otitis media. Decongestants, antihistamines, topical corticosteroids, and expectorants have not been proved effective for acute otitis media.10,26 Side effects associated with these treatments also may be unpleasant. Surgical insertion of tympanostomy tubes (T-tubes) is an effective method for the prevention of recurrent otitis media. These small tubes are placed through the inferior portion of the tympanic membrane under general anesthesia and aerate the middle ear. Children with recurrent otitis who have more than three episodes in 6 months or four or more episodes (one of which is recent) in a year should be considered for T-tube placement. If these children have moderate to severe nasal obstruction in addition to recurrent otitis, adenoidectomy may be of benefit. Tonsillectomy, however, is not indicated for the treatment of otitis media. Although T-tube insertion is effective for many, some children may require subsequent surgeries. Repeat T-tube placement with adenoidectomy (regardless of adenoid size) should be considered if the child continues to have episodes of acute otitis media after extrusion of the original T-tubes.


PHARMACOLOGIC THERAPY
ANTIMICROBIAL THERAPY Acute otitis media must be distinguished from otitis media with effusion. Antimicrobials are indicated only in the former unless the effusion persists beyond 3 months in otitis media with effusion. Middle ear effusion in acute otitis media tends to continue after antimicrobial therapy is completed but does not require retreatment. Studies have not demonstrated any one antimicrobial agent to be superior in the treatment of acute uncomplicated otitis media.21 Amoxicillin is considered the drug of choice regardless of the prevalence of drug resistant S. pneumoniae.6,15 Amoxicillin has the best pharmacodynamic profile (time above the minimum inhibitory concentration [MIC90 ] in the middle ear fluid for more than 40% of the dosing interval) against drug-resistant S. pneumoniae of all available oral agents, it has a long record of safety, it possesses a narrow spectrum, and it is inexpensive.20 Its excellent efficacy against S. pneumoniae outweighs the issue of β-lactamase–producing H. influenzae and M. catarrhalis, against which amoxicillin may not be effective. This is so because H. influenzae and M. catarrhalis are both more likely to lead to a spontaneous resolution of the infection compared with S. pneumoniae. 3 Amoxicillin is the drug of choice for acute otitis media. Highdose amoxicillin (80–90 mg/kg per day) is recommended if drug-resistant S. pneumoniae is suspected or a patient is at high risk for a resistant infection. Treatment recommendations for acute otitis media are found in Table 107–3. Patients who have received a course of antibiotics within the last 3 months are considered high risk. Higher middle ear fluid concentrations of amoxicillin as a result of higher dosing should overcome drug-resistant S. pneumoniae even with its increased MIC.27 Some clinicians have expressed concerns, however, about the increased risk of adverse effects and patient noncompliance associated with high-dose amoxicillin. If treatment failure occurs with amoxicillin, an agent should be chosen with activity against β-lactamase–producing H. influenzae and M. catarrhalis, as well as drug-resistant S. pneumoniae.14,20 Examples include amoxicillin-clavulanate, cefuroxime, and intramuscular ceftriaxone. Second-generation cephalosporins, while β-lactamase– stable, are expensive, have an increased incidence of side effects, and may increase selective pressure for resistant bacteria. They also are less effective against drug-resistant S. pneumoniae. Consideration also must be given to the fact that most cephalosporins do not achieve adequate middle ear fluid concentrations against drug-resistant S. pneumoniae for the desired duration over the dosing interval. Oral cephalosporins that may be tried include cefuroxime (as advocated by the Centers for Disease Control and Prevention [CDC]

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TABLE 107–3. Acute Otitis Media Treatment Recommendationsa,b Antibiotic Therapy in Prior Month No

Day 0 Amoxicillin usual dose 40–45 mg/kg/day Amoxicillin high dose 80–90 mg/kg/day (high-risk patients)

Yes

Amoxicillin high dose 80–90 mg/kg/day Amoxicillin-clavulanate high dosed Amoxicillin component 80–90 mg/kg/ day Clavulanate component 6.4 mg/kg/day Cefuroxime axetil Suspension: 30 mg/kg/day divided twice daily (max: 1 g) Tablets: 250 mg twice daily

Clinically Defined Treatment Failure Day 3 Amoxicillin-clavulanate high dosed Amoxicillin component 80–90 mg/kg/day clavulanate component 6.4 mg/kg/day Cefuroxime axetil Suspension: 30 mg/kg/day divided twice daily (max: 1 g) Tablets: 250 mg twice daily Intramuscular ceftriaxone 1 g (50 mg/kg) daily for 3 days Intramuscular ceftriaxone 1 g (50 mg/kg) daily for 3 days Clindamycinc 10–30 mg/kg/day divided every 6–8 hours (max: 1.8 g/day) Tympanocentesis

Clinically Defined Treatment Failure Days 10 to 28 Same as day 3

Amoxicillin-clavulanate high dosed Amoxicillin component 80–90 mg/kg/ day Clavulanate component 6.4 mg/kg/day Cefuroxime axetil Suspension: 30 mg/kg/day divided twice daily (max: 1 g) Tablets: 250 mg twice daily Intramuscular ceftriaxone 1 g (50 mg/kg) daily for 3 days Tympanocentesis

a

These recommendations are made by a group convened by the Centers for Disease Control. The recommended duration of treatment for oral therapy is 7 to 10 days. Clindamycin is only recommended in cases of documented S. pneumoniae. It is not effective against H. influenzae or M. catarrhalis. d Higher doses of clavulanate produce a significant increase in diarrhea. From refs. 8 and 15. b c

guidelines), as well as cefprozil or cefpodoxime.11,15 Intramuscular ceftriaxone is the only agent other than amoxicillin that achieves middle ear fluid concentrations above the MIC for more than 40% of the dosing interval.20 While single doses have been used, daily doses for 3 days are recommended to optimize clinical outcomes.14,15 Ceftriaxone should be reserved for severe and unresponsive infections or for patients in whom oral medication is inappropriate because of vomiting, diarrhea, or possible nonadherence. Ceftriaxone is an expensive agent, and the intramuscular injections generally are not appealing to young patients. Tympanocentesis also can be considered for treatment failure. It has a therapeutic effect of relieving pain and pressure and can be used to collect fluid to identify the causative agent. This procedure, however, is not frequently performed in practice.9,14 CLINICAL CONTROVERSY It is not clear when antibiotics should be prescribed for acute otitis media—at the onset of signs and symptoms or after 48 to 72 hours to allow assessment for a spontaneous resolution. In general, the North American approach is to institute empirical treatment immediately. In some European countries such as the Netherlands, the practice is not to initiate treatment initially, but rather to treat a child 6 months to 2 years of age only if he or she does not improve by 24 hours or an older child by 72 hours.

Patients with penicillin allergy can be treated with several alternative antibiotics. Some clinicians feel that the incidence of

cross-reaction is sufficiently low that use of a cephalosporin is warranted in patients who have not experienced immediate pencillin hypersensitivity reactions. Others prefer to use a macrolide such as azithromycin or clarithromycin, erythromycin-sulfisoxazole, trimethoprim-sulfamethoxazole, or if S. pneumoniae is documented, clindamycin as alternative agents. However, the incidence of resistance is much higher with these agents,9,14 and of these agents, only clindamycin is recommended by the CDC guidelines.15


DELAYED ANTIMICROBIAL THERAPY It is difficult to identify who will benefit from antimicrobial therapy. With or without treatment, about 60% of children who have acute otitis media are symptom-free within 24 hours. In almost 40% of the remaining children, antibiotic use reduces the duration of symptoms by about 1 day.28,29 A trial of 315 children (6 months to 10 years of age) compared immediate antibiotic treatment with a 72-hour delay in treatment that was to be given only if the child had not improved. Symptoms continued for 1 extra day in 10% to 20% of the delayed-therapy group, but 10% fewer also experienced diarrhea. At 3 days, there was no difference in symptoms. In the delayed-therapy group, only 24% of children eventually received antibiotics, and 77% of parents reported being satisfied with this approach.30 Delayed treatment decreases antibiotic use by 31% (and associated side effects) and minimizes bacterial resistance to rates as low as 30% to 50% of that in countries that do not delay antimicrobial therapy.31,32 Some clinicians feel that delayed treatment is not

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advisable in children younger than 2 years of age, those with recent antimicrobial exposure, or when underlying conditions exist because these patients are at increased risk of susceptibility to invasive disease and resistant bacerial infections.11 If delayed therapy is tried, use of appropriate pain medication, such as oral ibuprofen or acetaminophen, should be advised. If a child 6 months to 2 years of age does not improve by 24 hours or an older child by 72 hours, antibiotic treatment should be initiated.31 In addition to the desire for immediate symptom improvement, prevention of mastoiditis and meningitis has been suggested as a reason to prescribe immediate antibiotic treatment for acute otitis media. The rates of mastoiditis in the Netherlands, Norway, and Denmark (all countries in which delayed therapy has been adopted) and those in Canada, the United States, Australia, and the United Kingdom were compared.32 The delay of antibiotic use resulted in an increase from about 2 to 4 cases of mastoiditis per 100,000 children per year, accompanied by about 1600 fewer children per 100,000 experiencing antibiotic side effects. Of note, in the Netherlands, only 1.1% of infections caused by S. pneumoniae are penicillinresistant.

EVALUATION OF THERAPEUTIC OUTCOMES Treatment failure is a lack of clinical improvement after 3 days in the signs and symptoms of infection, including pain, fever, and redness/bulging of the tympanic membrane. Early reevaluation of the eardrum when signs and symptoms are improving can be misleading because effusions persist. A concern that requires evaluation after otitis infections is hearing loss resulting from persistent middle ear effusions. Examination of an asymptomatic child may be delayed until 3 months after the infection began, at which time the continued presence of fluid should prompt a hearing evaluation.10

ANTIBIOTIC PROPHYLAXIS OF RECURRENT INFECTIONS Recurrent otitis media is defined as at least three episodes in 6 months or at least four episodes in 12 months. Recurrent infections are of concern because patients younger than 3 years of age are at high risk for hearing loss and language and learning disabilities.11 Data from studies generally do not favor prophylaxis. A meta-analysis demonstrated that prophylaxis against these infections leads to a reduction of 0.11 episodes per month.35 This translates into one infection prevented each time one child is treated for 9 months. Prophylaxis is even less effective in those with effusion. Amoxicillin 20 mg/kg per day and sulfisoxazole 75 mg/kg per day have been evaluated. Success with sulfizoxazole generally is thought to be better because it results in less carriage of resistant organisms; however, side effects are much worse (i.e., rash, mouth sores, and potential for blood dyscrasias). Of further concern is antibiotic resistance as a result of continued use of these antibiotics. For this reason, treatment can be delayed until the onset of symptoms of an upper respiratory tract infection (viral symptoms). Another approach is to limit antibiotic prophylaxis duration to 6 months and during the winter months.11 T-tube placement, adenoidectomy, and tonsillectomy may be of value in children with recurrent treatment failure.

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SHORT COURSES OF THERAPY 33 2 A meta-analysis of 32 trials reported no difference in effect

(cure rates) after short (1 in 1 million). However, the risk remains. Outbreaks have been reported in the United States as recently as the late 1980s and early 1990s. Furthermore, acute rheumatic fever is widespread in developing countries (e.g., it is estimated that there are 50,000 cases of acute rheumatic fever per year in India).

Antimicrobial therapy reduces the median duration of illness from 17 to 9 to 11 days.50 A patient with persistence or worsening of symptoms 72 hours after initiating antimicrobial therapy may be considered a treatment failure.45 Referral to a specialist should be considered in patients who have not responded to first- or second-line therapy, those with recurrent and chronic disease, and patients at risk for complications. Surgery may be considered in more complicated patients.

PHARYNGITIS Pharyngitis is an acute infection of the oropharynx or nasopharynx.61 It results in 1% to 2% of all outpatient visits.62 While viral causes are most common, group A β-hemolytic Streptococcus, or S. pyogenes, is the primary bacterial cause and is the focus of this section.61,63 In the pediatric population, group A Streptococcus, or “strep throat,” causes 15% to 30% of cases of pharyngitis. In adults, it is the cause of 5% to 15% of all symptomatic episodes of pharyngitis.61−64

MICROBIOLOGY 6 Viruses cause most of the cases of acute pharyngitis. Specific

etiologic agents include rhinovirus (20%), coronavirus (≥5%), adenovirus (5%), influenza virus (2%), parainfluenza virus (2%), and Epstein-Barr virus (>1%).61,63 A bacterial etiology for acute pharyngitis is far less likely. Out of all the bacterial causes, group A Streptococcus is the most common (15% to 30% of persons of all ages with pharyngitis52 ), and it is the the only commonly occurring form of acute pharyngitis for which antimicrobial therapy is indicated 52,61 Other less common causes of acute pharyngitis include groups C and G Streptococcus, Corynebacterium diphtheriae, Neisseria gonorrhoeae, M. pneumoniae, Arcanobacterium haemolyticum, Yersinia enterocolitica, and Chlamydia pneumoniae. Treatment options for these organisms will not be addressed in this chapter.61,63

PATHOPHYSIOLOGY The mechanism by which group A Streptococcus causes pharyngitis is not well defined.52 Asymptomatic pharyngeal carriers of the organism may have an alteration in host immunity (e.g., a breach in the pharyngeal mucosa) and the bacteria of the oropharynx, allowing colonization to become infection. Pathogenic factors associated wtih the organism itself also may play a role. These include the antiphagocytic M protein, erythrogenic toxins, hemolysins, streptokinase, and proteinase. Group A streptococcal pharyngitis is difficult to differentiate from viral pharyngitis based on history and clinical findings. However,

TABLE 107–7. Clinical Presentation and Diagnosis of Group A Streptococcal Pharyngitis General A sore throat of sudden onset that is mostly self-limited Fever and constitutional symptoms resolving in about 3 to 5 days Clinical signs and symptoms are similar for viral causes as well as nonstreptococcal bacterial causes Signs and Symptoms Sore throat Pain on swallowing Fever Headache, nausea, vomiting, and abdominal pain (especially children) Erythema/inflammation of the tonsils and pharynx with or without patchy exudates Enlarged, tender lymph nodes Red swollen uvula, petechiae on the soft palate, and a scarlatiniform rash Several symptoms that are not suggestive of group A Streptococcus are cough, conjunctivitis, coryza, and diarrhea Laboratory Tests Throat swab and culture or rapid antigen detection testing From refs. 52, 61–65, 67, and 68.

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DIAGNOSIS For a patient presenting with pharyngitis, the most important clinical decision that needs to be made is whether the pharyngitis is caused by group A Streptococcus. Diagnosis is essential because it it directs management. Clinical scoring systems such as the Centor criteria69 have been advocated for diagnosis in adults to overcome the lack of sensitivity and specificity of clinician judgment and to avoid laboratory testing of all patients.62,64 These criteria include history of fever, tonsillar exudates, absence of cough, and presence of enlarged lymph nodes. However, there is concern that use of these criteria will lead to overprescribing because they give physicians the option of a “no test” strategy, where prescriptions can be written based purely on the clinical criteria.61,63 Guidelines from the Infectious Disease Society of America, the American Academy of Pediatrics, and the American Heart Association suggest that testing be done in all patients with signs and symptoms. Only those with a positive test for group A Streptococcus require antibiotic treatment.61,65,70 A combined approach would take into account the prevalence of group A streptococcal disease (which differs by age group and geography) and history of a close contact of a well-documented case, along with clinical criteria, to aid in assessing a patient’s risk of the disease. If the diagnosis cannot be excluded at this point,

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laboratory testing is recommended to confirm or exclude group A Streptococcus as the cause of pharyngitis. It is important to note that laboratory testing should not be used without consideration of clinical criteria. This is so because a positive test does not necessarily indicate disease. A positive test may indicate carriage (but not active infection) with group A Streptococcus. The incidence of carriage in children is 5% to 20% and is considerably lower in adults.52,65 There are several options to test for group A streptococcal pharyngitis. A throat swab can be sent for culture or used for rapid antigen-detection testing (RADT). RADT is more practical in that it gives results quickly, it can be done at the bedside, and it is less expensive than culture. Cultures are the “gold standard” and have a 90% sensitivity but require 24 to 48 hours for results.63 Cultures are recommended for children, adolescents, parents, and schoolteachers with negative RADT tests (which have a sensitivity below 80%), as well as in situations of outbreak or to monitor resistance.64,65,67 Delaying therapy while awaiting test results does not affect the risk of complications (although some argue that symptomatic benefit is postponed), and patients must be educated as to the value of waiting. Newer RADT tests use optical immunoassay and chemiluminescent DNA probes, but the cost of such tests may be prohibitive, and results of individual tests should be compared with cultures to validate their sensitivity in practice.65


TREATMENT: Pharyngitis
DESIRED OUTCOME


PHARMACOLOGIC THERAPY
ANTIMICROBIAL THERAPY

The goals of treatment of pharyngitis are to improve clinical signs and symptoms, minimize adverse drug reactions, prevent transmission to close contacts, and prevent acute rheumatic fever and suppurative complications, such as peritonsillar abscess, cervical lymphadenitis, and mastoiditis.61,62


GENERAL APPROACH TO TREATMENT Antimicrobial therapy should be limited to those who have clinical and epidemiologic features of group A streptococcal pharyngitis with a positive laboratory test.


NONPHARMACOLOGIC THERAPY Since pain is often the primary reason for visiting a physician, emphasis on analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) to aid in pain relief is strongly recommended.71 However, acetaminophen is a better option because there is some concern that NSAIDs may increase the risk for necrotizing fasciitis/toxic shock syndrome. Toxic shock syndrome has been linked to GAS pharyngitis. Either systemic or topical analgesics can be used, as well as antipyretics and other supportive care, including rest, fluids, lozenges, and saltwater gargles. Symptoms may resolve 1 to 2 days sooner with such interventions.62−64

Antimicrobial therapy decreases the duration of signs and symptoms by 1 to 2 days.62,72 Therapy also decreases the severity of symptoms when initiated within 2 to 3 days of onset in patients with proven group A Streptococcus. Microbiological eradication will occur in 48 to 72 hours, which aids in decreasing transmission.62 7 Antimicrobial treatment should be limited to those who have clinical and epidemiologic features of group A streptococcal pharyngitis with a positive laboratory test. Penicillin is the drug of choice in the treatment of group A streptococcal pharyngitis61,62 (Table 107–8). It has the narrowest spectrum of activity, and it is effective, safe, and inexpensive. The only controlled studies that have demonstrated that antimicrobial therapy prevents rheumatic fever were done with procaine penicillin, which was later replaced with benzathine penicillin.73,74 8 The evidence that treatment of group A streptococcal pharyngitis prevents rheumatic fever comes solely from studies using depot intramuscular penicillin. Penicillin given by other routes has been assumed to be equally efficacious. The ability of other antibiotics to eradicate group A Streptococcus has led to extrapolation that these agents also will prevent rheumatic fever.64 Amoxicillin can be used in children because the suspension has a better taste than that of penicillin.61,66 Gastrointestinal side effects and rash, however, are more common. In patients allergic to penicillin, a macrolide such as erythromycin or a first-generation cephalosporin such as cephalexin (if the reaction is non–IgE-mediated hypersensitivity with hives or anaphylaxis) can be used.61 Newer macrolides such as azithromycin and clarithromycin are equally effective as erythromycin and cause fewer gastrointestinal adverse effects.

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TABLE 107–8. Dosing Guidelines for Pharyngitis Drug

Adult Dosage

Penicillin VK

Pediatric Dosage

250 three times daily or four times daily or 500 mg twice daily 1.2 million units intramuscularly

Penicillin benzathine Penicillin G procaine and benzathine mixture Amoxicillin Erythromycin Estolate

50 mg/kg/day divided in 3 doses

10 days

0.6 million units for under 27 kg (50,000 units/kg) 1.2 million units (benzathine 0.9 million units, procaine 0.3 million units)

One dose

500 mg three times daily

40–50 mg/kg/day divided in 3 doses

10 days 10 days

20–40 mg/kg/day divided two to four times daily (max: 1 g/day) 1 g daily divided two to four times daily (adolescents, adults) 40 mg/kg/day divided two to four times daily (max: 1 g/day) 250–500 mg PO four times daily

Same as adults

Not recommended in adolescents and adults

Stearate Ethylsuccinate Cephalexin

Duration

One dose

— Same as adults 25–50 mg/kg/day divided in 4 doses

10 days

From refs. 61, 63, 65, and 79.

Second-generation cephalosporins, such as cefuroxime and cefprozil, or third-generation cephalosporins, such as cefpodoxime and cefdinir, which are β-lactamase–stable, have been advocated for clinical failures with penicillin. In cases of documented macrolide resistance (owinng to low-level macrolide resistance—erythromycin MIC 1–8 mcg/mL—caused by expression of the mefA/E gene leading to efflux of macrolide out of the bacterial cell), clindamycin is an alternative. The new ketolides such as telithromycin also may have a role to play, especially in regions with a high prevalence of macrolide-resistant strains. If patients are unable to take oral medications, intramuscular benzathine penicillin can be given, although it is painful and is no longer available in Canada.61 Amoxicillin-clavulanate or clindamycin may be considered for recurrent episodes to maximize bacterial eradication in potential carriers and to counter copathogens that produce β-lactamases.61,65,67 Tables 107–8 and 107–9 outline dosing for acute and recurrent episodes of pharyngitis. To date, no resistance of group A Streptococcus to penicillin has been reported in clinical isolates.61,62,65,75 Macrolide resistance is low (>5%) and is not widespread.75,76 However, there have been reports of an outbreak of macrolide-resistant group A streptococcal pharyngitis in the United States. The concern is that if macrolide use continues to increase, macrolide resistance rates also will increase.77,78 Therefore, use of newer macrolides as first-line therapy is discouraged in febrile patients with upper respiratory tract infections. Group A Streptococcus resistance rates to tetracyclines and sulfonamides are high; therefore, use of these agents is no longer recommended.61

CLINICAL CONTROVERSY The duration of therapy for group A streptococcal pharyngitis is 10 days to maximize bacterial eradication.61 Shortcourse therapy has been advocated to help overcome compliance issues that lead to bacteriologic failure.80 A 6-day course of amoxicillin shows promising results, as well as other recent studies with newer broad-spectrum agents (e.g., azithromycin, cefuroxime, cefprozil, cefdinir, cefixime, cefpodoxime, and telithromycin) that have demonstrated durations of 5 days to be effective. However, confounding factors from these studies, such as lack of strict entry criteria or differentiation between new or failed infections, limit the widespread application of short antibiotic courses at this time.61 Furthermore, newer agents are more expensive and may be more likely to lead to resistance in light of their broad spectra of activity.63 CLINICAL CONTROVERSY Once-daily amoxicillin given at a dose of 750 mg is as effective as penicillin 250 mg three times daily (duration 10 days each) in children aged 4 to 18 years with group A streptococcal pharyngitis.81 This dosing regimen has not yet been endorsed by expert panels but may gain support in the future if the results are reproducible.61,62,64

TABLE 107–9. Antibiotics and Dosing for Recurrent Episodes of Pharyngitis Drug

Adult Dosage

Clindamycin

600 mg orally divided in 2–4 doses

Amoxicillin-clavulanate Penicillin benzathine

500 mg twice daily 1.2 million units intramuscularly for one dose As above 20 mg/kg/day orally in 2 divided doses × last 4 days of treatment with penicillin

Penicillin benzathine with rifampin

From refs. 61, 63, 65, and 79.

Pediatric Dosage 20 mg/kg/day in 3 divided doses (max: 1.8 g/day) 40 mg/kg/day in 3 divided doses 0.6 million units for under 27 kg (50,000 units/kg) As above Rifampin dose same as adults

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Overprescribing is a large concern that requires consideration. Antibiotics are prescribed in 73% of patients who visit their physician with a complaint of sore throat.82 This is well above the incidence of group A Streptococcus. For those who receive antibiotics, 68% of prescriptions are described as being nonrecommended treat-

ments, e.g., extended-spectrum macrolides (e.g., azithromycin and clarithromycin) or fluoroquinolones (e.g., ciprofloxacin, gatifloxacin, levofloxacin, and moxifloxacin). Cost and resistance are factors that should discourage this practice.

EVALUATION OF THERAPEUTIC OUTCOMES/CONTACT CASES

10. American Academy of Pediatrics. Managing otitis media with effusion: Practice guideline. Pediatrics 1994;94:5. 11. Bitnum A, Allen UD. Medical therapy of otitis media: Use, abuse, efficacy, and morbidity. J Otolaryngol 1998;27(suppl 2):26–35. 12. Faden H, Duffy L, Boeve M. Otitis media: Back to the basics. Pediatr Infect Dis J 1998;17:1103–1113. 13. Culpepper L, Froom J, Grob P, et al. Acute otitis media in adults: A report from the International Primary Care Network. J Am Board Fam Pract 1993;6:333–339. 14. Hoberman S, Marchant CD, Kaplan SL, et al. Treatment of acute otitis media consensus recommendations. Clin Pediatr 2002;41:373–390. 15. Dowell SF, Butler JC, Giebink GS, et al. Acute otitis media: Management and surveillance in an era of pneumococcal resistance. A report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J 1999;18:1–9. 16. Doern GV, Heilmann KP, Huynh HK, et al. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the United States during 1999–2000, including a comparison of resistance rates since 1994–1995. Antimicrob Agents Chemother 2001;45:1721– 1729. 17. Thornsberry C, Sahm DF, Kelly LJ, et al. Regional trends in antimicrobial resistance among clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States: Results from the TRUST surveillance program, 1999–2000. Clin Infect Dis 2002;34(suppl 1):S4–16. 18. Zhanel GG, Palatnick L, Nichol KA, et al. Five year incidence of antimicrobial resistance in respiratory tract isolates of Streptococcus pneumoniae: Results of the Canadian Respiratory Organism Susceptibility Study (CROSS), 1997–2002. Antimicrob Agents Chemother 2003;47: 1867–1874. 19. Zhanel GG, Palatnick L, Nichol KA, et al. Five year incidence of antimicrobial resistance in respiratory tract isolates of Haemophilus influenzae and Moraxella catarrhalis: Results of the Canadian Respiratory Organism Susceptibility Study (CROSS), 1997–2002. Antimicrob Agents Chemother 2003;47:1875–1881. 20. McCracken GH. Prescribing antimicrobial agents for treatment of acute otitis media. Pediatr Infect Dis J 1999;18:1141–1146. 21. Rosenfeld RM, Vertrees JE, Carr J, et al. Clinical efficacy of antimicrobial drugs for acute otitis media: Metaanalysis of 5400 children from thirtythree randomized trials. J Pediatr 1994;124:355–367. 22. Teele DW, Klein JO, Chase C, et al. Otitis media in infancy and intellectual ability, school achievement, speech, and language at age 7 years. J Infect Dis 1990;162:685–694. 23. Luotonen M, Uhari M, Aitola L, et al. Recurrent otitis media during infancy and linguistic skills at the age of nine years. Pediatr Infect Dis J 1996;15:854–858. 24. Takata GS, Chan LS, Morphew T, et al. Evidence assessment of the accuracy of methods of diagnosing middle ear effusion in children with otitis media with effusiom. Pediatrics 2003;112:1379–1387. 25. American Academy of Pediatrics. Policy statement: Reduction of the influenza burden in children. Pediatrics 2002;110:1246–1252. 26. Flynn CA, Griffin G, Tudiver F. Decongestants and antihistamines for acute otitis media in children. Cochrane Database Syst Rev 2002; D001727. 27. Seikel K, Shelton S, McCracken G. Middle ear fluid concentrations of amoxicillin after large dosages in children with acute otitis media. Pediatr Infect Dis J 1997;16:710–711. 28. Del Mar CB, Glasziou P, Hayem M. Are antibiotics indicated as intial treatment for children with acute otitis media? A meta analysis. Br Med J 1997;314:1526.

Most cases of pharyngitis are self-limited; however, antimicrobial therapy will hasten resolution when given early to proven cases of group A Streptococcus.52,61 Fever generally resolves by 3 to 5 days and most other acute symptoms by 1 week.52 Tonsils and lymph nodes may take a few weeks to return to baseline. Children should be kept home from day care or school until afebrile and for the first 24 hours after antimicrobial treatment is initiated, after which time transmission is unlikely.64−66 Follow-up testing generally is not necessary for index cases or in asymptomatic contacts of the index patient.61,63,65 Symptomatic contacts may be treated without cultures.66 In epidemics or in cases of severe infection, follow-up testing may be prudent. The incidence of invasive group A streptococcal infection in household contacts is rare, and routine chemoprophylaxis is not recommended by the CDC,83 although testing is advocated and guides management.61,65 Twenty-five percent of household contacts are carriers, but treatment would only be required in persons with signs and symptoms of disease or contacts of severe or resistant disease.61

ABBREVIATIONS MIC: minimal inhibitory concentration MIC90 : minimal inhibitory concentration for 90% of isolates RADT: rapid antigen-detection testing Review Questions and other resources can be found at www.pharmacotherapyonline.com.

REFERENCES 1. Snow V, Mottur-Pilson C, Gonzales R, for the American College of Physicians-American Society of Internal Medicine. Principles of appropriate antibiotic use for treatment of nonspecific upper respiratory tract infections in adults. Ann Intern Med 2001;134:487–489. 2. Elden LM, Coyte PC. Socioeconomic impact of otitis media in north America. J Otolaryngol 1998;27(suppl 2):9–16. 3. Gonzales R, Bartlett JG, Besser RE, et al. Principles of appropriate antibiotic use for treatment of nonspecific upper respiratory tract infections in adults: Background. Ann Intern Med 2001;134:490–494. 4. Turnidge J. Responsible prescribing for upper respiratory tract infections. Drugs 2001;61:2065–2077. 5. Gonzales R, Bartlett JG, Besser RE, et al. Principles of appropriate antibiotic use for treatment of acute respiratory tract infections in adults: Background, specific aims, and methods. Ann Intern Med 2001;134: 479–486. 6. Canadian Immunization Guide, 6th ed. Ottawa, Health Canada, 2002. 7. Hendley JO. Otitis media. New Engl J Med 2002;347:1169–1174. 8. Dowell SF, Marcy SM, Phillips WR, et al. Otitis media: Principles of judicious use of antimicrobial agents. Pediatrics 1998;101(suppl): 165–171. 9. Canadian Pediatric Society (CPS). Antibiotic management of acute otitis media. Pediatr Child Health 1998;3:265–267.

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29. Culpepper L, Froom J. Routine antimicrobial treatment of acute otitis media: Is it necessary? JAMA 1997;278:1643–1645. 30. Little P, Gould C, Williamson I, et al. Pragmatic randomised, controlled trial of two prescribing strategies for childhood acute otitis media. Br Med J. 2001;322:336–342. 31. Froom J, Culpepper L, Jacobs M, et al. Antimicrobials for acute otitis media? A review from the international primary care network. Br Med J 1997;315:98–102. 32. van Zuijlen DA, Schilder AG, van Balen FA. National differences in incidence of acute mastoiditis: Relationship to prescribing patterns of antibiotics for acute otitis media? Pediatr Infect Dis J 2001;20:140–144. 33. Korzyrskyj AL, Hildes-Ripstein E, Longstaffe SEA, et al. Treatment of acute otitis media with shortened courses of antibiotics: A meta-analysis. JAMA 1998;279:1736–1742. 34. Cohen R, Levy C, Boucherat M, et al. A multicentre, randomized, doubleblind trial of 5 versus 10 days of antibiotic therapy for acute otitis media in young children. J Pediatr 1998;133:634–639. 35. Williams RL, Chalmers TC, Stange KC, et al. Use of antibiotics in preventing recurrent otitis media and in treatinn otitis media wtih effusion: A meta-analytic attempt to resolve the brouhaha. JAMA 1993;270: 1344–1351. 36. Heikkinen T, Ruuskanen O, Waris M, et al. Influenza vaccination in the prevention of acute otitis media in children. Am J Dis Child 1991;145: 445–448. 37. Clements DA, Langdon L, Bland C, et al. Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care. Arch Pediatr Adolesc Med 1995;149:1113–1117. 38. Eskola J, Kilpi T, Palmu A, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001;344:403–409. 39. Fireman B, Black SB, Shinefield HR, et al. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J 2003;22:10–15. 40. Recommendations of the Advisory Committee on Immunization Practices (ACIP) Advisory Committee on Immunization Practices. Preventing pneumococcal disease among infants and young children. MMWR 2000;43(RR-09):1–38. 41. Vennhoven R, Bogaert D, Uiterwaal C, et al. Effect of conjugate penumococcal vaccine followed by polysaccharide penumococcal vaccine on recurrent acute otitis media: A randomised study. Lancet 2003;361: 2189–2195. 42. Hickner JM, Bartlett JG, Besser RE, et al. Principles of appropriate antibiotic use for acute rhinosinusitis in adults: Background. Ann Intern Med 2001;134:498–505. 43. O’Brien KL, Dowell SF, Schwartz B, et al. Acute sinusitis: Principles of judicious use of antimicrobial agents. Pediatrics 1998;101(suppl): 174–77. 44. Noyek A, Brodovsky D, Coyle S, et al. Classification, diagnosis and treatment of sinusitis: Evidence-based clinical practice guidelines. Can J Inf Dis 1998;9(suppl B):3–24B. 45. Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg Suppl 2000;123:S1–32. 46. Agency for Health Care Policy and Research. Diagnosis and Treatment of Acute Bacterial Rhinosinusitis: Summary—Evidence Report/ Technology Assessment, Number 9, March 1999. Rockville, MD, Agency for Health Care Policy and Research; available at www.ahrq.gov/ clinic/epcsums/sinussum.htm. 47. American Academy of Pediatrics. Clinical practice guidelines: Management of sinusitis. Pediatrics 2001;108:798–808. 48. Low DE, Desrosiers M, McSherry J, et al. A practical guide for the diagnosis and treatment of acute sinusitis. Can Med Assoc J 1997;156(suppl 6): S1–14. 49. Evans KL. Recognition and management of sinusitis. Drugs 1998;56: 59–71. 50. Lindbaek M, Hjortdahl P, Johnsen ULH. Randomised, double-blind, placebo-controlled trial of penicillin V and amoxycillin in treatment of acute sinus infections. Br Med J 1996;313:325–329. 51. Wald E. Microbiology of acute and chronic sinusitis. In: Lusk RP, ed. Pediatric Sinusitis. New York, Raven Press, 1992:43–47.

52. Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 4th ed. New York, Churchill-Livingstone, 2000. 53. Gwaltney JM. Acute community acquired bacterial sinusitis: To treat or not to treat. Can Respir J 1999;6(suppl A):46–50A. 54. Williams JW Jr, Aguilar CCCC, Cornell J, et al. Antibiotics for acute maxillary sinusitis. Cochrane Rev 2003;3. 55. van Buchem FL, Knottnerus JA, Schrijnemaekers VJJ, et al. Primary-carebased randomised, placebo-controlled trial of antibiotic treatment in acute maxillary sinusitis. Lancet 1997;349:683–687. 56. Piccirillo JF, Mager DE, Frisse ME, et al. Impact of first-line vs secondline antibiotics for the treatment of acute uncomplicated sinusitis. JAMA 2001;286:1849–1856. 57. de Bock GH, Dekker FW, Stolk J, et al. Antimicrobial treatment in acute maxillary sinusitis: A meta-analysis. J Clin Epidemiol 1997;50: 881–890. 58. Canadian Pharmacists Association. Compendium of Pharmaceutical Specialties. Ottawa, Canadian Pharmacists Association, 2003. 59. Gilbert DN, Moellering RC, Sande MA, eds. The Sanford Guide to Antimicrobial Therapy 2003. Hyde Park, NY, Antimicrobial Therapy, Inc., 2003. 60. Williams JW Jr, Holleman DR Jr, Samsa GP, et al. Randomized controlled trial of 3 vs 10 days of trimethoprim-sulfamethoxazole for acute maxillary sinusitis. JAMA 1995;273:1015–1021. 61. Bisno AL, Gerber MA, Gwaltney JM, et al. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis (IDSA guidelines). Clin Infect Dis 2002;35:113–125. 62. Snow V, Mottur-Pilson C, Cooper RJ, et al, for the American College of Physicians, American Society of Internal Medicine. Principles of appropriate antibiotic use for acute pharyngitis in adults. Clinical practice guideline, part I. Ann Intern Med 2001;134:506–508. 63. Bisno A. Acute pharyngitis. N Engl J Med 2001;344:205–211. 64. Cooper RJ, Hoffman JR, Bartlett JG, et al. Principles of appropriate antibiotic use for acute pharyngitis in adults: Background. Clinical practice guideline, part II (endorsed by the Center for Disease Control, American Academy of Family Physicians, and the American College of PhysiciansAmerican Society of Internal Medicine). Ann Intern Med 2001;134: 509–517. 65. American Academy of Pediatrics. Group A streptococcal infections. In: Pickering LK, ed. Red Book 2003: Report of the Committee on Infectious Diseases, 26th ed. Elk Grove Village, IL, American Academy of Pediatrics 2003:526–536. 66. Hayes CS, Williamson HW. Management of group A beta-hemolytic streptococcal pharyngitis. Am Fam Phys 2001;63:1557–1565. 67. Schwartz B, Marcy M, Phillips WR, et al. Pharyngitis: Principles of judicious use of antimicrobial agents. Pediatrics 1998;101;171–174. 68. Summary of notifiable diseases, United States, 1998. MMWR 1998; 47:1. 69. Centor RM,Witherspoon JM, Dalton HP, et al. The diagnosis of strep throat in adults in the emergency room. Med Decision Making 1981;1: 239–246. 70. Dajani A, Taubert K, Ferrieri P, et al. Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: A statement for health professionals. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, the American Heart Association. Pediatrics 1995;96:758–764. 71. Dickinson JA. Acute pharyngitis (letter). N Engl J Med 2001;344: 1479–1480. 72. Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat. Cochrane Rev 2003;2. 73. Chamovitz R, Catanzaro FJ, Stetson CA, et al. Prevention of rheumatic fever by treatment of previous streptococcal infections. N Engl J Med 1954;251:466–471. 74. Denny FW, Wannamaker LW, Brink WR, et al. Prevention of rheumatic fever. JAMA 1950;143:151–153. 75. Kaplan EL, Johnson DR, del Rosario MC, et al. Susceptibility of group A beta-hemolytic streptococci to thirteen antibiotics: Examination of 301 strains isolated in the United States between 1994 and 1997. Pediatr Infect Dis J 1999;18:1069–1072.

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CHAPTER 107 76. De Azavedo JCS, Yeung RH, Bast DJ, et al. Prevalence and mechanisms of macrolide resistance in clinical isolates of group A streptococci from Ontario, Canada. Antimicrob Agents Chemother 1999;43: 2144–147. 77. Martin JM, Green M, Barbadora KA, et al. Erythromycin-resistant group A streptococcus in schoolchildren in Pittsburgh. N Engl J Med 2002;346:1200–1206. 78. Seppala H, Klaukka T, Vuopio-Varkila J, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. N Engl J Med 1997;337:441–446. 79. Bacterial diseases. In: Beers MH, Berkow R., eds. The Merck Manual of Diagnosis and Therapy, 17th ed. Whitehouse Station, NJ, Merck & Co.,

80. 81. 82.

83.

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Inc., 1995–2003. Accessed on November 29th, 2003 at www.merck.com/ mrkshared/mmanual/section13/chapter157/157a.jsp. Guay DRP. Short-course antimicrobial therapy of respiratory tract infections. Drugs 2003;63:2169–2184. Feder HMJ, Gerber MA, Randolph MF, et al. Once daily therapy for streptococcal pharyngitis with amoxicillin. Pediatrics 1999;103:47–51. Linder JA, Stafford RS. Antibiotic treatment of adults with sore throat by community primary care physicians: A national survey, 1989–1999. JAMA 2001;286:1181–1186. Robinson KA, Rothcock G, Phan Q, et al. Risk for severe group A streptococcal disease among patients’ household contacts. Emerg Infect Dis 2003;9; found at www.medscape.com/viewarticle/45281˙print.

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108 SKIN AND SOFT TISSUE INFECTIONS Susan L. Pendland, Douglas N. Fish, and Larry H. Danziger

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Folliculitis, furuncles (boils), and carbuncles begin around

hair follicles and are caused most often by Staphylococcus aureus. Folliculitis generally can be treated with local measures such as warm, moist compresses or topical antibiotics. Small furuncles usually are treated with warm, moist heat to promote drainage; large furuncles and carbuncles are treated most often with an antistaphylococcal antibiotic such as dicloxacillin. Lesions often drain spontaneously; if not, surgical incision may be necessary.

2 Erysipelas is a superficial skin infection with extensive lym-

phatic involvement that is caused by Streptococcus pyogenes and is treated with penicillin. Serious infections should be treated with intravenous antibiotics.

3 Impetigo, a superficial skin infection characterized by fluid-

filled vesicles that develop rapidly into pus-filled blisters that rupture to form golden-yellow crusts, is caused by S. aureus and/or S. pyogenes and occurs most commonly in children. Dicloxacillin is used commonly for treatment, although topical antibiotics such as mupirocin are also effective.

4 Lymphangitis is an infection of the subcutaneous lymphatic channels generally caused by S. pyogenes. Acute lymphangitis is characterized by the rapid development of fine red linear streaks extending from the initial infection site toward the regional lymph nodes, which are usually enlarged and tender. Penicillin is the drug of choice.

5 Cellulitis is an infection of the epidermis, dermis, and su-

perficial fascia. Lesions generally are hot, painful, and erythematous, with nonelevated, poorly defined margins. The most common causes of cellulitis are S. pyogenes and S. aureus. Treatment generally consists of a penicillinaseresistant penicillin for 7 to 10 days.

of superficial fascia and subcutaneous fat. Early and aggressive surgical d´ebridement is an essential part of therapy for treatment of necrotizing fasciitis.

7 Diabetic foot infections are managed with a comprehen-

sive treatment approach that includes both proper wound care and antimicrobial therapy. Antimicrobial regimens for diabetic foot infections should include broad-spectrum coverage of staphylococci, streptococci, enteric gram-negative bacilli, and anaerobes. Outpatient therapy with oral antimicrobials should be used whenever possible.

8 Prevention is the single most important aspect in the man-

agement of pressure sores. After a sore develops, successful local care includes a comprehensive approach consisting of relief of pressure, proper cleaning (d´ebridement), disinfection, and appropriate antimicrobial therapy if an infection is present. Good wound care is crucial to successful management.

9 All bite wounds (either animal or human) should be irrigated

thoroughly with large volumes of sterile normal saline, and the injured area should be immobilized and elevated. Infections developing within the first 24 hours after a dog or cat bite are caused most often by Pasteurella multocida and should be treated with penicillin or amoxicillin for 10 to 14 days. Infections developing more than 36 to 48 hours after an animal bite are most likely caused by staphylococci or streptococci and should be treated with an antistaphylococcal penicillin or cephalosporin.

10 While antimicrobial prophylaxis of dog or cat bites is not

6 Necrotizing fasciitis is a rare but life-threatening infection of

recommended routinely, patients with noninfected human bite injuries of the hand should be given prophylactic antimicrobial therapy with penicillin plus dicloxacillin for 3 to 5 days. Infected wounds of the hand, particularly clenched-fist injuries, should be treated with penicillin plus dicloxacillin or amoxicillin-clavulanate for 7 to 14 days.

The skin serves as a barrier between humans and their environment and therefore functions as a primary defense mechanism against infections. The skin consists of the epidermis, the dermis, and subcutaneous fat. The epidermis is the outermost, nonvascular layer of the skin. It varies in thickness from approximately 0.1 mm on most areas of the body to a maximum of 1.5 mm on the soles of the feet.

Although extremely thin, the epidermis is composed of several layers. The innermost layer consists of continuously dividing cells. The outer layers are renewed as cells are gradually pushed outward. As the cells approach the surface, they become flattened, lose their nuclei, and are filled with keratin. The outermost layer, the stratum corneum, is composed of flattened, cornified, nonnucleated cells. The

subcutaneous tissue that results in progressive destruction

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dermis is the layer of skin directly beneath the epidermis. It consists of connective tissue and contains blood vessels and lymphatics, sensory nerve endings, sweat and sebaceous glands, hair follicles, and smooth muscle fibers. Beneath the dermis is a layer of loose connective tissue containing primarily fat cells. This subcutaneous fat layer is of variable thickness over the body. Beneath the subcutaneous fat lies the fascia, which separates the skin from underlying muscle. It is generally divided into superficial fascia, which is located immediately beneath the skin, and deep fascia, which forms sheaths for muscles. Skin and soft tissue infections (SSTIs) may involve any or all layers of the skin, fascia, and muscle. They also may spread far from the initial site of infection and lead to more severe complications, such as endocarditis, Gram-negative sepsis, or streptococcal glomerulonephritis. The treatment of SSTIs at times may necessitate both medical and surgical management. This chapter presents details of the pathogenesis and management of some of the most common infections involving the skin and soft tissues. The first part of the chapter discusses a variety of SSTIs that range in severity from superficial to life-threatening. The remainder of the chapter discusses diabetic foot infections, pressure sores, and human and animal bites.

EPIDEMIOLOGY A number of classification schemes have been developed to describe SSTIs. Bacterial infections of the skin can be classified as primary or secondary (Table 108–1). Primary bacterial infections usually involve areas of previously healthy skin and typically are caused by a single pathogen. In contrast, secondary infections occur in areas of previously damaged skin and are frequently polymicrobic. SSTIs are also classified as complicated or uncomplicated. Infections are considered complicated when they involve deeper skin structures (e.g., fascia, muscle layers, etc), require significant surgical intervention, or occur in patients with compromised immune function (e.g., diabetes mellitus, human immunodeficiency virus [HIV] infection, etc).1

The classification system recently developed by Eron divides SSTIs into four classes based on severity of signs and symptoms, as well as the presence and stability of any comorbidities.2 The classification was used to develop an algorithm to help with admission and treatment decisions. Class 1 includes patients who are afebrile and otherwise healthy. These patients generally can be managed on an outpatient basis with topical or oral antimicrobials. Class 2 includes patients who are febrile and ill-appearing but have no unstable comorbid conditions.Some class 2 patients may be treated with oral antimicrobials, but most likely will require some parenteral therapy, either as an outpatient or with short-term hospitalization. Patients having a toxic appearance, at least one unstable comorbidity, or a limb-threatening infection are grouped into class 3. Class 4 includes patients with sepsis syndrome or other life-threatening infection, such as necrotizing fasciitis. Patients in classes 3 and 4 require hospitalization and parenteral antimicrobial therapy initially but may be candidates for oral or outpatient parenteral therapy once their condition has stabilized. Patients in class 4 also generally require some type of surgical intervention. SSTIs are among the most common infections seen in both community and hospital settings. However, data on the exact incidence of SSTIs are lacking. Most infections are believed to be mild and therefore treated in an outpatient setting, making it difficult to quantify community-acquired SSTIs. One description of office visits among health plan members listed cellulitis and impetigo as the primary diagnosis for 2.2% and 0.3% of patients, respectively.3 According to the most recent Healthcare Cost and Utilization Project Nationwide Inpatient Sample, SSTIs are the twenty-eighth most common diagnosis of patients in community hospitals.4 Approximately 0.1% of the adult population in the United States required hospitalization for SSTIs in 1995.2 While the exact incidence of SSTIs is unknown, the frequency of infection caused by invasive group A streptococci and drug-resistant gram-positive cocci have been increasing.1 Group A streptococci (Streptococcus pyogenes) are among the most common etiologic agents of SSTIs. While they may be found in many mild, superficial skin infections, they are also responsible for life-threatening cases of necrotizing fasciitis.1 A dramatic increase in necrotizing fasciitis due

TABLE 108–1. Bacterial Classification of Important Skin and Soft Tissue Infections Primary Infections Erysipelas Impetigo Lymphangitis Cellulitis Necrotizing fasciitis Type I Type II Secondary Infections Diabetic foot infections Pressure sores Bite wounds Animal Human Burn wounds

Group A streptococci Staphylococcus aureus, group A streptococci Group A streptococci; occasionally S. aureus Group A streptococci, S. aureus; occasionally other gram-positive cocci, gram-negative bacilli, and/or anaerobes Anaerobes (Bacteroides spp., Peptostreptococcus spp.) and facultative bacteria (streptococci, Enterobacteriaceae) Group A streptococci S. aureus, streptococci, Enterobacteriaceae, Bacteroides spp., Peptostreptococcus spp., Pseudomonas aeruginosa S. aureus, streptococci, Enterobacteriaceae, Bacteroides spp., Peptostreptococcus spp., Pseudomonas aeruginosa Pasteurella multocida, S. aureus, streptococci, Bacteroides spp. Eikenella corrodens, S. aureus, streptococci, Corynebacterium spp., Bacteroides spp., Peptostreptococcus spp. Pseudomonas aeruginosa, Enterobacteriaceae, S. aureus, streptococci

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CHAPTER 108 TABLE 108–2. Predominant Microorganisms of Normal Skin Bacteria Gram-positive Coagulase-negative staphylococci Micrococci (Micrococcus luteus) Corynebacterium species (diphtheroids) Propionibacterium species Gram-negative Actinetobacter species Fungi Malassezia species Candida species

to S. pyogenes is a major concern because of the high morbidity and mortality associated with these infections. Another worrisome trend is the increased in vitro resistance reported for many gram-positive bacteria.1 Of greatest concern is the increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA).5 Treatment choices for SSTIs have been further complicated by the increased incidence of macrolide-resistant strains of S. aureus and S. pyogenes.1

ETIOLOGY The majority of SSTIs are caused by gram-positive organisms and, less commonly, gram-negative bacteria present on the skin surface.1 Gram-positive bacteria (coagulase-negative staphylococci, diphtheroids) are the predominant flora of the skin, with gramnegative organisms (Escherichia coli and other Enterobacteriaceae) being relatively uncommon6 (Table 108–2). S. aureus, as well as a variety of gram-negative bacteria, can be found in moist intertriginous areas (e.g., axilla, groin, and toe webs) of the body. Acinetobacter species have been cultured from these moister areas in 25% of the population.6,7 S. aureus also inhabits the anterior nares of approximately 30% of healthy individuals.6 Colonization, whether transient or permanent, provides a nidus for infection should the integrity of the epidermis be compromised. S. aureus and S. pyogenes account for the majority of communityacquired SSTIs.1 Data from the most recent SENTRY Antimicrobial Surveillance Program showed S.aureus to also be the most common cause (45.9%) of nosocomial SSTIs.5 Also of note in this study was the 30% incidence of methicillin resistance among strains of S. aureus. Other common nosocomial pathogens included Pseudomonas aeruginosa (11%), enterococci (8%), and E. coli (7%).5

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hydrolyzed to form free fatty acids that strongly inhibit the growth of many bacteria and fungi.8 The conditions that may predispose a patient to the development of skin infections include (1) a high concentration of bacteria (>105 microorganisms), (2) excessive moisture of the skin, (3) inadequate blood supply, (4) availability of bacterial nutrients, and (5) damage to the corneal layer allowing for bacterial penetration.7,8 The majority of SSTIs result from the disruption of normal host defenses by processes such as skin puncture, abrasion, or underlying diseases (e.g., diabetes). The nature and severity of the infection depends on both the type of microorganism present and the site of inoculation.

FOLLICULITIS, FURUNCLES, AND CARBUNCLES 1 Folliculitis is inflammation of the hair follicle and can3 be caused

by physical injury, chemical irritation, or infection. Infection occurring at the base of the eyelid is referred to as a stye. Furuncles and carbuncles occur when a follicular infection extends from around the hair shaft to involve the deeper areas of the skin. A furuncle, commonly known as an abscess or boil, is a walled-off mass of purulent material arising from a hair follicle.3 The lesions are called carbuncles when they coalesce and extend to the subcutaneous tissue. This aggregate of infected hair follicles forms deep masses that generally open and drain through multiple sinus tracts.3 S. aureus is the most common cause of folliculitis, furuncles, and carbuncles. Inadequate chlorine levels in whirlpools, hot tubs, and swimming pools have been responsible for outbreaks of folliculitis caused by P. aeruginosa.9 C L I N I C A L P R E S E N TAT I O N FOLLICULITIS

r Pruritic, erythematous papules typically appear within 48 hours (range 6–72 hours) of exposure to large numbers of organisms. r Papules evolve into pustules that generally heal in several days. r Systemic signs such as fever and malaise are uncommon, although they have been reported in cases caused by P. aeruginosa. FURUNCLES

r Furuncles can occur anywhere on hairy skin but generally develop in areas subject to friction and perspiration.

r Furuncles are discrete lesions, whether occurring as singular or multiple nodules.

r The lesion starts as a firm, tender, red nodule that PATHOPHYSIOLOGY The skin and subcutaneous tissues normally are extremely resistant to infection but may become susceptible under certain conditions. Even when high concentrations of bacteria are applied topically or injected into the soft tissue, resulting infections are rare.8 Several host factors act together to confer protection against skin infections. The surface of the skin is relatively dry, has a pH of approximately 5.6, and therefore is not conducive to bacterial growth.6 Continuous renewal of the epidermal layer results in the shedding of keratocytes, as well as skin bacteria. In addition, sebaceous secretions are

becomes painful and fluctuant.

r Lesions often drain spontaneously. CARBUNCLES

r Carbuncles are broad, swollen, erythematous, deep, and painful follicular masses.

r Unlike folliculitis and furuncles, carbuncles are commonly associated with fever, chills, and malaise.

r Bacteremia with secondary spread to other tissues is common.

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TREATMENT: Folliculitis, Furuncles, and Carbuncles Treatment of folliculitis generally requires only local measures, such as warm saline compresses or topical therapy (e.g., clindamycin, erythromycin, mupirocin, or benzoyl peroxide).10 Topical agents generally are applied two to four times daily for 7 days. Small furuncles generally can be treated with moist heat, which promotes localization and drainage of pus.10 Large and/or multiple

EVALUATION OF THERAPEUTIC OUTCOMES Many follicular infections resolve spontaneously without medical or surgical intervention. Lesions may need to be incised if they do not respond to a few days of moist heat and over-the-counter topical agents. Following drainage, most lesions begin to heal within several days.

ERYSIPELAS 2 Erysipelas is an infection of the 11more superficial layers of the

skin and cutaneous lymphatics. The intense red color and burning pain associated with this skin infection led to the common name of St. Anthony’s fire. The infection is almost always caused by β-hemolytic streptococci, with the organisms gaining access via small breaks in the skin. While group A streptococci (S. pyogenes) are responsible for most infections, group G streptococci also have been implicated in a considerable number of infections.12,13 Infections are more common in infants, young children, the elderly, and patients with nephrotic syndrome.10 Erysipelas also commonly occurs in areas of preexisting lymphatic obstruction or edema.10 Diagnosis is made on the basis of the characteristic lesion. C L I N I C A L P R E S E N TAT I O N GENERAL

r The lower extremities are the most common sites for erysipelas.

furuncles and carbuncles generally are treated with a penicillinaseresistant penicillin (dicloxacillin 250 mg orally every 6 hours for 7 to 10 days). An alternative agent for penicillin-allergic patients is clindamycin (150–300 mg orally every 6 hours). Surgical incision is indicated for large and fluctuant lesions that do not drain spontaneously.10

SYMPTOMS

r Patients often experience flulike symptoms (fever, malaise) prior to the appearance of the lesion.

r The infected area is described as painful or as a burning pain. SIGNS

r The lesion is bright red and edematous, often with lymphatic streaking.

r Temperature is often mildly elevated. r The clinical presentation differs from cellulitis in that the lesion has clearly demarcated raised margins. LABORATORY TESTS

r Cultures should be considered. r The causative organism usually cannot be cultured from the surface skin but sometimes may be aspirated from the edge of the advancing lesion. OTHER DIAGNOSTIC TESTS

r A complete blood count is often performed because leukocytosis is common.

r C-reactive protein is also generally elevated.


TREATMENT: Erysipelas The goal of treatment of erysipelas is rapid eradication of the infection. Mild to moderate cases of erysipelas are treated with procaine penicillin G 600,000 units intramuscularly twice daily or penicillin VK 250–500 mg orally four times daily (in children 1–18 years of age, 25,000–90,000 units/kg per day divided into four doses) for 7 to 10 days.10,14,15 Penicillin-allergic patients can be treated with clindamycin 150–300 mg orally every 6 to 8 hours (in children, 10–30 mg/ kg per day in three to four divided doses). For more serious infections, the patient should be hospitalized, and aqueous penicillin G

EVALUATION OF THERAPEUTIC OUTCOMES Erysipelas generally responds quickly to appropriate antimicrobial therapy. Temperature and white blood count should return to normal within 48 to 72 hours. Erythema, edema, and pain also should resolve gradually.

2–8 million units daily should be administered intravenously.10,11 Marked improvement usually is seen within 48 hours, and the patient often may be switched to oral penicillin to complete the course of therapy. One randomized, double-blind, placebo-controlled study showed that the median time for cure, intravenous antibiotics, and hospital stay was reduced in patients receiving prednisolone in addition to antibiotics. Further studies are needed, however, before corticosteroids can be recommended for routine use.13

IMPETIGO 3 Impetigo is a superficial skin infection that is seen most com-

monly in children and is transmitted easily from person to person.16 The infection generally is classified as bullous or nonbullous

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based on clinical presentation.3 Impetigo is most common during hot, humid weather, which facilitates microbial colonization of the skin.10 Minor trauma, such as scratches or insect bites, then allows entry of organisms into the superficial layers of skin, and infection ensues.10 Impetigo is highly communicable and readily spreads through close contact, especially among siblings and children in day-care centers and schools.10,11 Most cases of impetigo were caused by S. pyogenes, but S. aureus either alone or in combination with S. pyogenes has emerged more recently as the principal cause of impetigo.16 The bullous form is caused by strains of S. aureus capable of producing exfoliative toxins.16 The bullous form most frequently affects neonates and accounts for approximately 10% of all cases of impetigo.10,16

SKIN AND SOFT TISSUE INFECTIONS

1981

SIGNS

r Nonbullous impetigo manifests initially as small, fluidfilled vesicles.

r These lesions rapidly develop into pus-filled blisters that rupture readily.

r Purulent discharge from the lesions dries to form golden-yellow crusts that are characteristic of impetigo. r In the bullous form of impetigo, the lesions begin as vesicles and turn into bullae containing clear yellow fluid. r Bullae soon rupture, forming thin, light brown crusts. r Regional lymph nodes may be enlarged.

C L I N I C A L P R E S E N TAT I O N LABORATORY TESTS

GENERAL

r Exposed skin, especially the face, is the most common site for impetigo.

r Cultures should be collected. r Crusted tops of lesions should be raised so that purulent material at the base of the lesion can be cultured.

r Cultures should not be collected from open, draining skin

SYMPTOMS

r Pruritus is common, and scratching of the lesions may

pustules because they may be colonized with staphylococci and other normal skin flora.

further spread infection through excoriation of the skin.

r Other systemic signs of infection are minimal. r Weakness, fever, and diarrhea sometimes are seen with bullous impetigo.

OTHER DIAGNOSTIC TESTS

r A complete blood count is often performed because leukocytosis is common.


TREATMENT: Impetigo Although impetigo may resolve spontaneously, antimicrobial treatment is indicated to relieve symptoms, prevent formation of new lesions, and prevent complications, such as cellulitis. Penicillinaseresistant penicillins (dicloxacillin 12.5 mg/kg orally daily in four divided doses for children) are preferred for treatment because of the increased incidence of infections caused by S. aureus. First-generation cephalosporins are also effective, although they are generally more expensive. Cephalexin (25–50 mg/kg orally daily in two divided doses for children) and cefadroxil (30 mg/kg orally daily in two divided doses for children) are used commonly. Penicillin, administered as either a single intramuscular dose of benzathine penicillin G (300,000–

600,000 units in children, 1.2 million units in adults) or as oral penicillin VK, is effective for infections caused by S. pyogenes. Penicillin-allergic patients can be treated with clindamycin (adults 150–300 mg orally every 6 to 8 hours; children 10–30 mg/kg per day in three to four divided doses). The duration of therapy is 7 to 10 days. Topical antibiotics, such as mupirocin and bacitracin, have been used to treat nonbullous impetigo. Mupirocin ointment (applied three times daily for 7 days) is as effective as erythromycin.17 With proper treatment, healing of skin lesions generally is rapid and occurs without residual scarring. Removal of crusts by soaking in soap and warm water also may be helpful in providing symptomatic relief.10,14

EVALUATION OF THERAPEUTIC OUTCOMES Clinical response should be seen within 7 days of initiating antimicrobial therapy for impetigo. Treatment failures could be due to noncompliance or antimicrobial resistance. A follow-up culture of exudates should be collected for culture and sensitivity, with treatment modified accordingly.16

C L I N I C A L P R E S E N TAT I O N GENERAL

r Lymphadenitis (acute or chronic inflammation of the lymph nodes) also may occur when microorganisms reach the lymph nodes and elicit an inflammatory response. SYMPTOMS

LYMPHANGITIS 4 Acute lymphangitis is an inflammation involving the subcuta-

neous lymphatic channels. Lymphangitis usually occurs secondary to puncture wounds, infected blisters, or other skin lesions. Most infections are caused by S. pyogenes.14,18

r Systemic manifestations of infection (i.e., fever, chills, malaise, and headache) often develop rapidly before any sign of infection is evident at the initial site of inoculation or even after the initial lesion has subsided. r Systemic symptoms often are more profound than would be expected based on examination of the cutaneous lesion.

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SIGNS

LABORATORY TESTS

r Identification of a peripheral lesion associated with

r Cultures of the affected lesions often yield negative results

proximal red linear streaks directed toward the regional lymph nodes is diagnostic of acute lymphangitis. r Lymph nodes usually are enlarged and tender. r Peripheral edema of the involved extremity often is present. r Thrombophlebitis and acute lymphangitis in the lower extremities may be confused because both are associated with red linear streaking and tender areas; however, in thrombophlebitis, no portal of entry is identifiable.

because the infection resides within the lymphatic channels. r Offending pathogens often can be identified by Gram stain of the initial lesion if done early in the course of the disease. OTHER DIAGNOSTIC TESTS

r A complete blood count frequently is performed because leukocytosis is common.


TREATMENT: Lymphangitis The goal of therapy for lymphangitis is rapid eradication of infection and prevention of further systemic complications. Penicillin is the antibiotic of choice. Because these infections are potentially serious and rapidly progressive, initial treatment should be with intravenous penicillin G. Parenteral treatment should be continued for 48 to 72 hours,

followed by oral penicillin VK for a total of 10 days.14,18,19 Nondrug therapy includes immobilization and elevation of the affected extremity and warm-water soaks every 2 to 4 hours.14 For penicillin-allergic patients, clindamycin may be used.

EVALUATION OF THERAPEUTIC OUTCOMES Lymphangitis usually responds rapidly to appropriate therapy; signs and symptoms often are decreased markedly or absent within 24 hours of starting antibiotics.

C L I N I C A L P R E S E N TAT I O N GENERAL

r There is usually a history of an antecedent wound from a minor trauma, abrasion, ulcer, or surgery.

r Because these infections occur often in patients with CELLULITIS 5 Cellulitis is an acute, infectious process that represents a more

serious type of SSTI. Cellulitis initially affects the epidermis and dermis and may spread subsequently within the superficial fascia. Cellulitis is considered a serious disease because of the propensity of the infection to spread through lymphatic tissue and to the bloodstream. S. pyogenes and S. aureus are the most frequent etiologic agents. However, a number of bacteria have been implicated in various types of cellulitis (see Table 108–1). The rising incidence of infections due to MRSA is a major concern in both the community and hospital settings. Injection drug users are predisposed to a number of infectious complications, including abscess formation and cellulitis at the site of injection.20 These SSTIs are located most frequently on the upper extremities and often are polymicrobic in nature.21 Infecting organisms are believed to originate from the skin and/or oropharynx, as well as from contaminated needles, syringes, and diluents.21 S. aureus and streptococci are the most common pathogenic organisms isolated from these infections. Anaerobic bacteria, especially oropharyngeal anaerobes, are also found commonly, particularly in polymicrobic infections.21 Acute cellulitis with mixed aerobic and anaerobic flora generally occurs in diabetics, where the skin is adjacent to some site of trauma, at sites of surgical incisions to the abdomen or perineum, or where host defenses have been otherwise compromised (vascular insufficiency). In older patients, cellulitis of the lower extremities also may be complicated by thrombophlebitis. Other complications of cellulitis include local abscess, osteomyelitis, and septic arthritis.14,15

alterations in host defense mechanisms, poor nutrition, or both, systemic findings such as hypotension, dehydration, and altered mental status are common. SYMPTOMS

r Patients often experience fever, chills, or malaise and complain that the affected area feels hot and painful. SIGNS

r Cellulitis is characterized by erythema and edema of the skin.

r Lesions, which may be extensive, are nonelevated and have poorly defined margins.

r Affected areas generally are warm to touch. r Inflammation generally is present with little or no necrosis or suppuration of soft tissue.

r Tender lymphadenopathy associated with lymphatic involvement is common. LABORATORY TESTS

r Cultures should be collected when possible. r A Gram stain of fluid obtained by injection and aspiration of 0.5 mL of saline (using a small 22-gauge needle) into the advancing edge of the lesion may aid the microbiologic diagnosis but often yields negative results. r Diagnosis usually is made on clinical grounds, i.e., the appearance of the lesion.

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OTHER DIAGNOSTIC TESTS

r A complete blood count frequently is performed because leukocytosis is common.

SKIN AND SOFT TISSUE INFECTIONS

1983

Bacteremia may be present in as many as 30therefore, blood cultures may be useful for diagnosis in some patients.


TREATMENT: Cellulitis The goal of therapy of acute bacterial cellulitis is rapid eradication of the infection and prevention of further complications. Antimicrobial therapy of bacterial cellulitis is directed against the type of bacteria either documented or suspected to be present based on the clinical presentation. Local care of cellulitis includes elevation and immobilization of the involved area to decrease swelling. Cool sterile saline dressings can decrease pain and can be followed later with moist heat to aid in localization of the cellulitis. Surgical intervention (incision and drainage) as a mode of therapy is rarely indicated in the treatment of cellulitis. Since staphylococcal and streptococcal cellulitis are indistinguishable clinically,11 administration of a semisynthetic penicillin (nafcillin or oxacillin) is recommended until a definitive diagnosis, by skin or blood cultures, can be made10,14,15 (Table 108–3). Mild to moderate infections not associated with systemic symptoms may be treated orally with dicloxacillin. If documented to be a mild cellulitis secondary to streptococci, oral penicillin VK or intramuscular procaine penicillin may be administered. More severe infections, either staphylococcal or streptococcal, should be treated initially with intravenous antibiotic regimens. Ceftriaxone 50–100 mg/kg as a single daily dose is efficacious in the treatment of cellulitis in pediatric patients.22 The usual duration of therapy for cellulitis is 7 to 10 days.10,14,15 In penicillin-allergic patients, oral or parenteral clindamycin may be used.1,2 Alternatively, a first-generation cephalosporin, such as cefazolin (1–2 g intravenously every 8 hours), may be used cautiously for patients who have not experienced immediate or anaphylactic penicillin reactions and are negative for a penicillin skin test. In mild cases in which an oral cephalosporin can be used, cefadroxil 500 mg twice daily or cephalexin 250–500 mg four times daily is recommended. Other oral cephalosporins, such as cefaclor, cefprozil, and cefpodoxime proxetil, are also effective in the treatment of cellulitis but are considerably more expensive.14 In severe cases in which cephalosporins cannot be used because of documented methicillin-resistant staphylococci or severe β-lactam allergies, vancomycin should be administered. Alternative agents for documented infections with resistant gram-positive bacteria such as MRSA and vancomycin-resistant enterococci (VRE) include linezolid, quinupristin-dalfopristin, and daptomycin.1,2,23−26 The excellent activity of these drugs against resistant gram-positive pathogens and significantly higher cost make them most appropriate for treatment of complicated or refractory infections or those caused by multidrug-resistant pathogens. The carbapenems (i.e., imipenem, meropenem, and ertapenem) and the β-lactamase inhibitor combination antibiotics (ampicillinsulbactam, ticarcillin–lavulanic acid, and piperacillin-tazobactam) also appear to be equivalent to standard therapies in adults.1,27−30 The greater cost of these newer agents without increased efficacy compared with other reliable regimens, however, makes them less desirable.

CLINICAL CONTROVERSY Oral fluoroquinolones have demonstrated efficacy similar to parenteral cephalosporins in the treatment of soft tissue infections caused by gram-positive organisms.1,31,32 Caution is warranted when treating SSTIs with ciprofloxacin owing to the unreliable activity of this agent against streptococci.1 Lower eradication rates of streptococci also have been reported with moxifloxacin when compared with cephalexin in the treatment of uncomplicated SSTIs.33 The newer fluoroquinolones (i.e., levofloxacin, gatifloxacin, and moxifloxacin) are all effective treatment for uncomplicated SSTIs, but their role in complicated infections has not been elucidated.1,33−35 The use of fluoroquinolones is of concern, however, because of increasing reports of resistance among both gram-positive and gram-negative bacteria.36 Sensitivity testing is recommended when a fluoroquinolone is to be used. Also, fluoroquinolones are not approved for use in children because of toxicity concerns. For cellulitis caused by gram-negative bacilli or a mixture of microorganisms, immediate antimicrobial chemotherapy, as determined by Gram stain, is essential (see Table 108–3). Surgical excision of necrotic tissue and drainage also may be appropriate. Gram-negative cellulitis may be treated appropriately with an aminoglycoside or firstor second-generation cephalosporin. If gram-positive aerobic bacteria are also present, penicillin G or a semisynthetic penicillin should be added to the regimen. Ceftazidime and the fluoroquinolones are effective in the treatment of cellulitis caused by both gram-negative and gram-positive bacteria.1,31 Since some infections may be polymicrobic in nature, antibiotic therapy may need to be broadened to include agents with good activity against anaerobic bacteria. Many different treatment regimens are possible depending on the bacteriology of the lesion (see Table 108–3). Usually an aminoglycoside combined with an antianaerobic cephalosporin, extended-spectrum penicillin, or clindamycin is used. Second- or third-generation cephalosporins have been suggested as single-agent therapy in certain instances.37,38 Monotherapy with a β-lactam plus β-lactamase inhibitor combination antibiotic or a carbapenem also may be appropriate in seriously ill patients. Therapy should be 10 to 14 days in duration. Because gram-negative and mixed aerobic-anaerobic cellulitis can progress quickly to serious tissue invasion, therapeutic intervention should be immediate. If treated early, a quick response can be seen. Unfortunately, because these infections often occur in patients with compromised immune defenses, they may still progress, even with therapeutic intervention. If the infectious process is secondary to a systemic cause (e.g., diabetes), the treatment course often is prolonged and may be associated with high morbidity and mortality. Infections in injection drug users generally are treated similarly to those in other types of patients.21 It is important that

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TABLE 108–3. Initial Treatment Regimens for Cellulitis Caused by Various Pathogens Antibiotic

Adult Dose and Route

Pediatric Dose and Route

Staphylococcal or Unknown Gram-Positive Infection Mild infection Dicloxacillin 0.25–0.5 g PO every 6 ha,b Moderate-severe infection Nafcillin or oxacillin 1–2 g IV every 4–6 ha,b Streptococcal (Documented) Mild infection

Moderate–severe infection Gram-Negative Bacilli Mild infection

Penicillin VK 0.5 g PO every 6 ha or procaine penicillin G 600,000 units IM every 8–12 ha Aqueous penicillin G 1–2 million units IV every 4–6 ha,c Cefaclor 0.5 g PO every 8 hd or cefuroxime axetil 0.5 g PO every 12 hd

Aminoglycosidee or IV cephalosporin (first- or second-generation depending on severity of infection or susceptibility pattern)d Polymicrobic Infection without Anaerobes Aminoglycosidee + penicillin G 1–2 million units every 4–6 h or a semisynthetic penicillin (nafcillin 1–2 g every 4–6 h) depending on isolation of staphylococci or streptococcib Moderate–severe infection

Polymicrobic Infection with Anaerobes Mild infection Amoxicillin/clavulanate 0.875 g PO every 12 h or A fluoroquinolone (ciprofloxacin 0.4 g PO every 12 h or levofloxacin 0.5–0.75 g PO every 24 h) plus clindamycin 0.3–0.6 g PO every 8 h or metronidazole 0.5 g PO every 8 h Moderate–severe infection Aminoglycosidee,f + clindamycin 0.6–0.9 g IV every 8 h or metronidazole 0.5 g IV every 8 h or Monotherapy with second- or third-generation cephalosporin (cefoxitin 1–2 g IV every 6 h or ceftizoxime 1–2 g IV every 8 h) or Monotherapy with imipenem 0.5 g IV every 6–8 h, meropenem 1 g IV every 8 h, or extendedspectrum penicillins with a β-lactamase inhibitor (piperacillin/tazobactam 4.5 g IV every 6 h)

Dicloxacillin 25–50 mg/kg/day PO in four divided dosesa,b Nafcillin or oxacillin 150–200 mg/kg/day (not to exceed 12 g/24 h) IV in four to six equally divided dosesa,b Penicillin VK 125–250 mg PO every 6–8 h, or procaine penicillin G 25,000–50,000 units/kg (not to exceed 600,000 units) IM every 8–12 ha Aqueous penicillin G 100,000–200,000 units/kg/day IV in four divided dosesa Cefaclor 20–40 mg/kg/day (not to exceed 1 g) PO in three divided doses or cefuroxime axetil 0.125–0.25 g (tablets) PO every 12 h Aminoglycosidee or intravenous cephalosporin (first- or second-generation depending on severity of infection or susceptibility pattern) Aminoglycosidee + penicillin G 100,000 to 200,000 units/kg/day IV in four divided doses or a semisynthetic penicillin (nafcillin 150–200 mg/kg/day [not to exceed 12 g/24 h] IV in four to six equally divided doses) depending on isolation of staphylococci or streptococcib Amoxicillin/clavulanic acid 20 mg/kg/day PO in three divided doses

Aminoglycosidee plus clindamycin 15 mg/kg/day IV in three divided doses or metronidazole 30–50 mg/kg/day IV in three divided doses

a

For penicillin-allergic patients, use clindamycin 150–300 mg orally every 6–8 h (pediatric dosing: 10–30 mg/kg/day in 3–4 divided doses). For methicillin-resistant staphylococci, use vancomycin 0.5–1 g every 6–12 h (pediatric dosing 40 mg/kg/day in divided doses) with dosage adjustments made for renal dysfunction. c For type II necrotizing fasciitis, use clindamycin 0.6–0.9 g IV every 8 h (in children, clindamycin 15 mg/kg/day IV in 3 divided doses) should be added. d For penicillin-allergic adults, use a fluoroquinolone (ciprofloxacin 0.5–0.75 g PO every 12 h or 0.4 g IV every 12 h; levofloxacin 0.5–0.75 g PO or IV every 24 h; gatifloxacin 0.4 g PO or IV every 24 h; or moxifloxacin 0.4 g PO or IV every 24 h). e Gentamicin or tobramycin, 2 mg/kg loading dose, then maintenance dose determined by serum concentrations. f A fluoroquinolone or aztreonam 1 g IV every 6 h may be used in place of the aminoglycoside in patients with severe renal dysfunction or other relative contraindications to aminoglycoside use. b

blood cultures be obtained because 25% to 35% of patients may be bacteremic.21,39 Also, patients should be assessed for the presence of abscesses; incision, drainage, and culture of these lesions are of extreme importance.10 Initial antimicrobial therapy while awaiting

EVALUATION OF THERAPEUTIC OUTCOMES If treated promptly with appropriate antibiotics, the majority of patients with cellulitis are cured rapidly. Culture and sensitivity results

culture results of abscesses should include coverage for anaerobic organisms, in addition to S. aureus and streptococci.21 In areas where MRSA is prevalent, treatment with vancomycin plus metronidazole is preferred.21

should be evaluated carefully both for the adequacy of culture material and the presence of resistant organisms. Additional high-quality samples for culture may be needed for microbiologic analysis. Failure

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to respond to therapy also may be indicative of an underlying local or systemic problem or a misdiagnosis.

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1985

C L I N I C A L P R E S E N TAT I O N GENERAL

NECROTIZING SOFT TISSUE INFECTIONS Necrotizing soft tissue infections consist of a group of highly lethal infections that require early and aggressive surgical d´ebridement in addition to appropriate antibiotics and intensive supportive care.40 A number of different descriptive terms have been used to classify necrotizing infections. These have been based on factors such as predisposing conditions, onset of symptoms, pain, skin appearance, etiologic agent, gas production, muscle involvement, and systemic toxicity. While many of the necrotizing soft tissue infections have been designated as unique infectious processes, they all share similar pathophysiologies, clinical features, and treatment approaches.40 The major clinical entities of necrotizing infections are necrotizing fasciitis and clostridial myonecrosis (gas gangrene).40 6 Necrotizing fasciitis is a rare but very severe infection of the subcutaneous tissue that may be caused by aerobic and/or anaerobic bacteria and results in progressive destruction of the superficial fascia and subcutaneous fat. It is generally characterized as one of two different types based on bacterial etiology. Type I necrotizing fasciitis generally occurs after trauma and surgery and involves a mixture of anaerobes (Bacteroides, Peptostreptococcus) and facultative bacteria (streptococci and members of Enterobacteriaceae) that act synergistically to cause destruction of fat and fascia. In type I infections, the skin may be spared, and the speed at which the infection spreads is somewhat slower than type II. Necrotizing fasciitis affecting the male genitalia has been termed Fournier’s gangrene. Type II necrotizing fasciitis is caused by virulent strains of S. pyogenes and is more commonly referred to as streptococcal gangrene. This type of infection has received considerable attention in recent years because of reports of “flesh-eating bacteria” by the lay press. Unlike previous reports of streptococcal gangrene that affected older individuals with underlying diseases, recent reports have occurred primarily in young, previously healthy adults following some type of minor trauma. It differs from the polymicrobial type I infections in its clinical presentation. Type II infections have rapidly extending necrosis of subcutaneous tissues and skin, gangrene, severe local pain, and systemic toxicity.11 Type II infections are also highly associated with an early onset of shock and organ failure and are present in approximately half the cases of streptococcal toxic shock-like syndrome.11 Clostridial myonecrosis is a necrotizing infection that involves the skeletal muscle. Gas production and muscle necrosis are prominent features of this infection, which readily explains why this infection is commonly referred to as gas gangrene.40 The infection advances rapidly, often over a matter of a few hours.40 Most infections occur after surgery or trauma, with Clostridium perfringens identified as the most common etiologic agent.

r These infections may occur in almost any anatomic location but most frequently involve the abdomen, the perineum, and the lower extremities. r Patients often have predisposing factors such as diabetes mellitus, local trauma or infection, or recent surgery. SYMPTOMS

r Systemic symptoms generally are marked (e.g., fever, chills, and leukocytosis) and may include shock and organ failure, especially in patients with type II infections. r In general, pain in the affected area and systemic toxicity are more pronounced than would be expected with cellulitis. SIGNS

r At the beginning of an infection, it may be difficult to differentiate between necrotizing fasciitis and cellulitis.

r Like cellulitis, the affected area is initially hot, swollen, and erythematous without sharp margins.

r The affected area is often shiny, exquisitely tender, and painful.

r Diffuse swelling of the area is followed by the appearance of bullae filled with clear fluid.

r The infectious process progresses rapidly, with the skin taking on a maroon or violaceous color after several days.

r Without appropriate intervention, the infection will evolve rapidly into a frank cutaneous gangrene, sometimes with myonecrosis (involvement of skin and muscle). r Because of the aggressive nature and high mortality (20% to 50%) associated with these infections, a rapid diagnosis is critical. LABORATORY TESTS

r Although computed tomography and magnetic resonance imaging studies can distinguish these infections, the best and most rapid diagnosis of necrotizing infections is obtained via surgical exploration. r Intraoperative samples should be collected for culture and sensitivity, as well as for histologic examination. r Unlike necrotizing fasciitis, clostridial myonecrosis shows little inflammation on histologic examination. OTHER DIAGNOSTIC TESTS

r Because marked systemic symptoms are seen commonly in necrotizing infections, blood samples should be collected for complete blood count and chemistry profile, as well as for bacterial culture.


TREATMENT: Necrotizing Soft Tissue Infections After the diagnosis is made, immediate and aggressive surgical d´ebridement of all necrotic tissue is essential.40 Broad-spectrum antibiotics should be administered, with coverage against streptococci, Enterobacteriaceae, and anaerobes. A number of antibiotic regimens have been used successfully to treat necrotizing soft tissue infections; these are generally similar to those used for severe polymicrobic cellulitis involving anaerobes (see Table 108–3). Other combina-

tion antibiotic regimens that may be used prior to obtaining bacteriologic data include ampicillin, gentamicin, and clindamycin (or metronidazole); ampicillin-sulbactam and gentamicin; or imipenem and metronidazole.10 Antibiotic therapy can be modified after Gram stain and culture reports are available. If a diagnosis of type II necrotizing fasciitis is established, the broad-spectrum empirical therapy should be

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replaced with the combination of penicillin and clindamycin.11 While S. pyogenes remains susceptible to penicillin, clindamycin has been shown experimentally to be more effective.11 A number of factors have been postulated to explain the higher efficacy of clindamycin. These include the mechanism of action (inhibition of protein synthesis), which is not affected by the size of the inoculum or the stage of

bacterial growth.11 In addition, clindamycin has immunomodulatory properties that may account for the higher efficacy.11 The combination of penicillin and clindamycin is also recommended for treatment of clostridial myonecrosis.40 In addition, hyperbaric oxygen is of some benefit for clostridial myonecrosis.40

EVALUATION OF THERAPEUTIC OUTCOMES

The optimum technique for obtaining culture material from ulcerated lesions is still debated.41 Routine swab cultures of ulcerative lesions are difficult to interpret because of organisms that colonize the surface of the wounds. Cultures of material from sinus tracts are also unreliable. The correlation between these superficial cultures and true deep cultures (via biopsy or needle aspiration of drainage or abscess fluid) is poor.43,47,48 Therefore, cultures and sensitivity tests should be done with specimens obtained from a deep culture whenever possible. Before the wound is cultured, it should be scrubbed vigorously with saline-moistened sterile gauze to remove any overlying necrotic debris.49 Cultures then can be obtained from the wound base, preferably from expressed pus.49 Specimens obtained from curettage of the base of the ulcer correlate best with results from deep-tissue or bone biopsies.49

Because of the high mortality associated with necrotizing infections, rapid and complete d´ebridement of all devitalized and necrotic tissue is essential. Surgical d´ebridement, coupled with appropriate antimicrobial therapy and typical supportive measures for management of shock and organ failure, should stabilize the patient. Vital signs and laboratory tests should be monitored carefully for signs of resolution of the infection. Change in antimicrobial therapy or additional surgical d´ebridement may be needed in patients who do not show signs of improvement.

DIABETIC FOOT INFECTIONS Three major types of foot infections are seen in diabetic patients: deep abscesses, cellulitis of the dorsum, and mal perforans ulcers.41 Most deep abscesses involve the central plantar space (arch) and are caused by minor penetrating trauma or by an extension of infection of a nail or web space of the toes. Skin infections of the dorsal area generally arise from infections in the toes that are related to routine care of the nails, nailbeds, and calluses of the toes. Mal perforans ulcer is a chronic ulcer of the sole of the foot. The ulcer develops on thickened, hardened calluses over the first or fifth metatarsal. Mal perforans ulcers are associated with neuropathy, which is responsible for the misalignment of the weight-bearing bones of the foot.41 Osteomyelitis is one of the most serious complications of foot problems in diabetic patients and may occur in 30% to 40% of infections.42−44

EPIDEMIOLOGY Disorders of the foot are among the most common complications of diabetes, accounting for as many as 20% of all hospitalizations in diabetic patients at an annual cost of $200 to $350 million.42,45 Approximately 25% of diabetic patients experience significant soft tissue infection at some time during the course of their lifetime. Approximately 55,000 lower extremity amputations, often sequelae of uncontrolled infection, are performed each year on diabetic patients; this represents 50% of all nontraumatic amputations in the United States.45 Between 10% and 20% of diabetics will undergo additional surgery or amputation of a second limb within 12 months of the initial amputation.46 By 5 years, this increases to 25% to 50%, with death reported in as much as two-thirds of patients.46

ETIOLOGY Diabetic foot infections begin with local bacterial invasion and typically involve a number of different bacterial pathogens.46 The infections are polymicrobic in nature, with an average of 4.1 to 5.8 isolates per culture47 (Table 108–4). Staphylococci (especially S. aureus) and streptococci are the most common pathogens, although gram-negative bacilli and/or anaerobes occur in approximately 50% of cases.48 Common gram-negative bacilli isolated include E. coli, Klebsiella spp., Proteus spp., and P. aeruginosa. Bacteroides fragilis and Peptostreptococcus spp. are among the most common anaerobes isolated.

PATHOPHYSIOLOGY Three key factors are involved in the development of diabetic foot problems: (1) neuropathy, (2) angiopathy and ischemia, and (3) immunologic defects. Any of these disorders can occur in isolation; however, they frequently occur together. Neuropathic changes to the autonomic nervous system as a consequence of diabetes may affect the motor nerve supply of small intrinsic muscles of the foot, resulting in muscular imbalance, abnormal stresses on tissues and bone, and repetitive injuries.50 Diminished sensory perception causes an absence of pain and unawareness of minor injuries and ulceration. Also, the sympathetic nerve supply may be damaged and can result in an absence of sweating; this leads to dry cracked skin, which can become secondarily infected.42

TABLE 108–4. Bacterial Isolates from Foot Infections in Diabetic Patients Organisms

Percentage of Isolates

Aerobes Gram-positive Staphylococcus aureus Streptococcus spp. Enterococcus spp. Coagulase-negative staphylococci Gram-negative Proteus spp. Enterobacter spp. Escherichia coli Klebsiella spp. Pseudomonas aeruginosa Other gram-negative bacilli Anaerobes Peptostreptococcus spp. Bacteroides fragilis group Other Bacteroides spp. Clostridium spp. Other anaerobes

69% 45% 13% 11% 8% 7% 24% 5% 3% 3% 2% 2% 7% 31% 13% 5% 4% 2% 7%

From Ref. 34 with permission.

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Atherosclerosis is more common, appears at a younger age, and progresses more rapidly in the diabetic than in the nondiabetic. Diabetics may have problems with both small vessels (microangiopathy) and large vessels (macroangiopathy) that can result in varying degrees of ischemia, ultimately leading to skin breakdown and infection. Diabetic patients typically have normal humoral immunity, normal levels of immunoglobulins, and normal antibody responses. Patients with diabetes, however, have impaired phagocytosis and intracellular microbicidal function as compared with nondiabetics; this may be related to angiopathy and low tissue levels of oxygen.42 These defects in cell-mediated immunity make patients with diabetes more susceptible to certain types of infection and impair the patients’ ability to heal wounds adequately.50 C L I N I C A L P R E S E N TAT I O N GENERAL

r Infections are often much more extensive than they appear initially.

SKIN AND SOFT TISSUE INFECTIONS

1987

SIGNS

r Clinical signs of infection in the diabetic foot may not be present secondary to the angiopathy and neuropathy.

r When present, lesions vary in size and clinical features (e.g., erythema, edema, warmth, presence of pus, draining sinuses, pain, and tenderness). r A foul-smelling odor suggests the presence of anaerobic organisms. r Temperature may be mildly elevated or normal. LABORATORY TESTS

r Specimens for culture and sensitivities should be collected.

r If possible, deep intraoperative samples should be obtained during surgical d´ebridement.

r Because of the complex microbiology of these infections, wounds must be cultured for both aerobic and anaerobic organisms.

SYMPTOMS

r Patients with peripheral neuropathy often do not experience pain but seek medical care for swelling or erythema in the foot.

OTHER DIAGNOSTIC TESTS

r The presence of osteomyelitis also must be assessed via radiograph, bone scan, or both, as appropriate.


TREATMENT: Diabetic Foot Infections 7 The goal of therapy of diabetic foot infections is preservation

of as much normal limb function as possible while preventing additional infectious complications. Up to 90% of these infections can be treated successfully with a comprehensive treatment approach that includes both wound care and antimicrobial therapy.43 After carefully assessing the extent of the lesion and obtaining necessary cultures, necrotic tissue must be thoroughly d´ebrided, with wound drainage and amputation as required. Wounds must be kept clean and dressings changed frequently (two to three times daily). Because of the relationship between hyperglycemia and immune system defects, glycemic control must be maximized to ensure optimal wound healing. In addition, the patient’s activities should be restricted initially to bed rest for leg elevation and control of edema, if present. Finally, appropriate antimicrobials must be initiated.42−45 However, the optimal antimicrobial therapy for diabetic foot infections has yet to be defined. The majority of mild, uncomplicated infections can be managed successfully on an outpatient basis with oral antimicrobials and good wound care. Many different agents have been studied, including cefaclor, cephalexin, fluoroquinolones, clindamycin, and amoxicillin– clavulanic acid; these agents provide clinical cure rates of 60% to 85% in published studies.44,48,50,51 However, significant failure rates and/or relapse rates have been reported with the use of oral agents. In addition, the development of resistance was problematic in some infections involving P. aeruginosa and staphylococci.52 Many clinicians consider amoxicillin–clavulanic acid to be the preferred agent because of its broad spectrum of activity, which includes staphylococci, streptococci, enterococci, and many Enterobacteriaceae and anaerobes.48 However, this agent does not have activity against P. aeruginosa. Fluoroquinolones, which provide coverage against P. aeruginosa, have been studied extensively as monotherapy, but they are perhaps most appropriately used in combination with metronidazole or clindamycin

to provide anaerobic activity.2 Oral antimicrobials should be used cautiously in serious infections, especially those complicated by osteomyelitis, extensive ulceration, areas of necrosis, or a combination of these. Initial therapy for patients requiring hospitalization for moderate to severe infections is similar to that for polymicrobic cellulitis with anaerobes (see Table 109–3). Monotherapy with broad-spectrum parenteral antimicrobials, along with appropriate medical or surgical management, or both, is often effective in treating these infections, including those in which osteomyelitis is present.53,54 Monotherapy is particularly attractive because of the potential advantages of convenience, cost, and avoidance of toxicities. Microbiologic and clinical cure rates ranging from 60% to 90% may be expected from any of these agents; selection of a specific regimen is determined primarily by cost. In penicillin-allergic patients, metronidazole or clindamycin plus either a fluoroquinolone, aztreonam, or possibly a thirdgeneration cephalosporin is appropriate.2,44,48,50 Vancomycin also is used frequently in severe infections because of its excellent activity against gram-positive pathogens. With the increased incidence of MRSA, linezolid, quinupristin-dalfopristin, and daptomycin are alternatives for treatment of these resistant organisms.1,2 Because these patients already may have some degree of diabetic nephropathy that may place them at higher risk of nephrotoxicity, strong recommendations have been made for the avoidance of aminoglycoside antibiotics unless no alternative agents are available.42 When an aminoglycoside is used, care must be taken to avoid further compromising renal function. All antibiotic regimes should be adjusted as necessary for renal dysfunction. Empirical therapy that is totally comprehensive in its coverage of all possible pathogens may not be necessary unless the infection is life-threatening.48,53,54 No differences were reported in the efficacy of ampicillin-sulbactam versus imipenem-cilastatin for

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treatment of limb-threatening diabetic foot infections despite the higher incidence of potential pathogens resistant to the ampicillinsulbactam regimen.53 Mild infections can be treated with oral agents and generally should be treated for at least 10 to 14 days, whereas more severe

infections dictate initial parenteral therapy and often require up to 21 days or more of antibiotic therapy. In cases of underlying osteomyelitis, treatment should continue for 6 to 12 weeks.42,44,48,50 After healing of the infection has occurred, a well-designed program for prevention of further infections should be instituted.

EVALUATION OF THERAPEUTIC OUTCOMES

EPIDEMIOLOGY

Therapy should be reevaluated carefully after 48 to 72 hours to assess favorable response. Change in therapy (or route of administration, if oral) should be considered if clinical improvement is not observed at this time. For optimal results, drug therapy should be appropriately modified according to information from deep tissue culture and the clinical condition of the patient. Infections in diabetic patients often require extended courses of therapy because of impaired host immunity and poor wound healing.

Pressure sores are seen most frequently in chronically debilitated persons, the elderly, and persons with serious spinal cord injury. Generally, patients who are at risk for pressure sores are elderly or chronically ill young patients who are immobilized either in bed or a wheelchair and who may have altered mental status and/or incontinence.

PRESSURE SORES The terms decubitus ulcer, bed sore, and pressure sore are used interchangeably. The decubitus ulcer and the bed sore are types of pressure sores. The term decubitus ulcer is derived from the Latin word decumbere, meaning “lying down.” Pressure sores, however, can develop regardless of a patient’s position. Numerous systems for classification of pressure sores have been described. The two most frequently used systems are those of Shea55 and the 1989 National Pressure Ulcer Advisory Panel.56 These classification systems define the various stages of progression through which a pressure sore may pass (Table 108–5). Complications of pressure sores are not uncommon and may be life-threatening. Infection is one of the most serious and most frequently encountered complications of pressure ulcers. Bacterial colonization must be differentiated from true bacterial infection. While most pressure sore wounds are colonized, the majority of these eventually heal.57 When the tissue is infected, there is bacterial invasion of previously healthy tissue. Without treatment, an initial small, localized area of ulceration can progress rapidly to 5 to 6 cm within days. The visible ulcer is just a small portion of the actual wound; up to 70% of the total wound is below the skin. A pressure-gradient phenomenon is created by which the wound takes on a conical nature; the smallest point is at the skin surface, and the largest portion of the defect is at the base of the ulcer (Fig. 108–1).

ETIOLOGY Similar to diabetic foot infections, a large variety of aerobic grampositive and gram-negative organisms, as well as anaerobes, frequently are isolated from wound cultures.58 Curettage of the ulcer base after d´ebridement provides more reliable culture information than does needle aspiration.57 Biopsy specimens give the most reliable data but may not be practical to obtain. Deep-tissue cultures from different sites may give different results. Cultures collected from pressure ulcers reveal polymicrobial growth. A culture collected by swab is likely to identify surface bacteria colonizing the wound rather than to diagnose the infection.59

PATHOPHYSIOLOGY Many factors are thought to predispose patients to the formation of pressure sores: paralysis, paresis, immobilization, malnutrition, anemia, infection, and advanced age. Four factors thought to be most critical to their formation are pressure, shearing forces, friction, and moisture; however, there is still debate as to the exact pathophysiology of pressure sore formation. Pressure is the essential element in the formation of pressure sores. The areas of highest pressure are generated most often over the bony prominences. Studies show that when the pressure is relieved intermittently within a 2-hour period, only minimal changes

PRESSURE

TABLE 108–5. Pressure Sore Classification48 Stage 1

Stage 2 Stage 3∗ Stage 4∗ ∗

Pressure sore is generally reversible, is limited to the epidermis, and resembles an abrasion. It is best described as an irregularly shaped area of soft tissue swelling with induration and heat. A stage 2 sore may also, be reversible; it extends through the dermis to the subcutaneous fat along with extensive undermining. In this instance, the sore or ulcer extends further into subcutaneous fat along with extensive undermining. The sore or ulcer is characterized by penetration into deep fascia involving both muscle and bone.

Stage 3 and 4 lesions are unlikely to resolve on their own and often require surgical intervention.

Bone

Muscle Subcutaneous fat Dermis

Surface

FIGURE 108–1. Distribution of forces involved with sore formation in a conical fashion.

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occur in soft tissue and skin structures.60 Therefore, both the degree of pressure and the length of time that the pressure is applied are important. Shearing forces are caused by the sliding of adjacent parallel surfaces of soft tissues in an unequal fashion. This situation can occur when the head of a bed is raised, causing the upper torso to slide downward, transmitting pressure to the sacrum and other areas. This effect results in occlusion or distortion of vessels, leading to compromise of the dermis. At the same time, sitting and gravity create shearing forces; the posterior sacral skin area can become fixed secondary to friction with the bed. The effects of friction and shearing forces combine, resulting in transmission of force to the deep portion of the superficial fascia and leading to further damage of soft tissue structures. Compounding the problems of shearing and friction forces are the macerating effects of excessive moisture in the local environment, resulting from incontinence and perspiration. This factor is of critical importance because when combined with the other forces, it increases the risk of pressure sore formation fivefold.61

SKIN AND SOFT TISSUE INFECTIONS

1989

Supine 1%

Occiput

< 1%

Scapula 1%

3%

Spinous processes

Elbow

23%

15%

Greater trochanter

7%

Lateral malleolus

Sacrum

24%

Ischial tuberosities

C L I N I C A L P R E S E N TAT I O N GENERAL

r Pressure sores can occur anywhere on the body. r However, more than 95% of all pressure sores are located on the lower part of the body (65% in the region of the pelvis and 3.4% on the lower extremities) (Fig. 108–2). r The most common sites on the lower portion of the body are the sacral and coccygeal areas, ischial tuberosities, and greater trochanter.

Lower leg

8%

Heel

FIGURE 108–2. Supine view of areas where pressure sore formation tends to occur.

SYMPTOMS

r Patients with pressure sores commonly have other medical problems that may mask the typical signs and symptoms of infection.

LABORATORY TESTS

r Cultures should be collected from either a biopsy or fluid obtained by needle aspiration.

SIGNS

OTHER DIAGNOSTIC TESTS

r Clinical infection is recognized by the presence of

r Clinicians also must be aware of the possibility of

surrounding redness, heat, and pain. r Purulent discharge, foul odor, and systemic signs (e.g., fever and leukocytosis) of infection may be present.

underlying osteomyelitis; therefore, magnetic resonance imaging or other radiographic procedures should be considered.


TREATMENT: Pressure Sores 8 Prevention is the single most important aspect in the manage-

ment of pressure sores. Prevention is far easier and less costly than the intensive care necessary for the healing and eventual closure of pressure sores. Of primary importance, then, is the ability to identify patients who are at high risk so that preventive measures may be instituted. The medical approach to the treatment of pressure sores depends on the stage of the disease. Medical management generally is indicated for lesions that are of moderate size and relatively shallow depth (stage 1 or 2 lesions) and are not located over a bony prominence. Depending on their location and severity, from 30% to 80% of these ulcers will heal without an operation. Surgical intervention is almost always necessary for ulcers that extend through superficial fascia or into bone (stage 3 and 4 lesions).

The goal of therapy is to clean and decontaminate the ulcer to promote wound healing by permitting the formation of healthy granulation tissue or to prepare the wound for an operative procedure. The main factors to be considered for successful topical therapy (local care) are (1) relief of pressure, (2) d´ebridement of necrotic tissue as needed, (3) wound cleansing, (4) dressing selection, and (5) prevention, diagnosis, and treatment of infection.62 Friction and shearing forces can be minimized with proper positioning. Skin care and prevention of soilage are important, with the intent being to keep the surface relatively free of moisture. Patients with problems of incontinence should be cleaned frequently, and efforts should be made to keep the involved areas dry. Natural sheepskin is believed to be useful in minimizing the effects of moisture, shearing forces, and friction. Relief of pressure is probably the

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single most important factor in preventing pressure sore formation. Relief for a period of only 5 minutes once every 2 hours is believed to give protection against pressure sore formation.60 The goals of d´ebridement and cleansing measures are removal of devitalized tissue and reduction of bacterial contamination, which can slow granulation time and, therefore, impede healing. D´ebridement can be accomplished by surgical, mechanical, or chemical means. Surgical d´ebridement rapidly removes necrotic material from the wound and is recommended for urgent situations (e.g., cellulitis and sepsis).62 Mechanical d´ebridement generally involves wet-to-dry dressing changes. Saline-soaked gauze is applied to the wound; after drying, the gauze is removed and with it any adherent necrotic tissue. Other effective mechanical therapies include hydrotherapy (use of the whirlpool [Hubbard tank] to remove necrotic tissue and debris), wound irrigation, and dextranomers (beads placed in the wound to absorb exudate and bacteria). Chemical d´ebridement includes enzymatic and autolytic agents. Enzymatic d´ebridement involves application of topical d´ebriding agents to remove devitalized tissue. This method is recommended for patients who cannot tolerate surgery or are in a long-term care or home setting. Autolytic d´ebridement involves the use of synthetic dressings that allow devitalized tissue to self-digest via enzymes present in wound fluids. Autolytic d´ebridement is contraindicated in the treatment of infected pressure sores.

EVALUATION OF THERAPEUTIC OUTCOMES With appropriate wound care and antimicrobial therapy, infected pressure sores can heal. A reduction in erythema, warmth, pain, and other signs and symptoms should be seen in 48 to 72 hours.

Pressure sore wounds should be cleaned with normal saline. Cleansing agents that are cytotoxic, such as povidone-iodine, iodophor, sodium hypochlorite solution, hydrogen peroxide, and acetic acid, should be avoided.62 Many of these agents impair healing. Many different types of dressings are available for pressure sores. Wound dressing materials should keep the wound moist, allow free exchange of air, act as a physical barrier to bacteria, and prevent physical damage. Controlled studies of the various types of wound dressings have shown no significant differences in healing outcomes.62 Occlusive dressings should be avoided if infection is present.59 If occlusive dressings are used, any infection should be controlled or the dressing frequency increased. Systemic treatment (see Table 108–3) of an infected pressure ulcer should be guided by results from appropriately collected cultures. Systemic antibiotics generally are reserved for treatment of bacteremia, sepsis, cellulitis, or osteomyelitis.59 However, a 2-week trial of topical antibiotics (silver sulfadiazine or triple antibiotic) is recommended for a clean ulcer that is not healing or is producing a moderate amount of exudate despite appropriate care.59 Other nonpharmacologic approaches to shortening the healing time have included the use of hyperbaric oxygenation, hydrotherapy, high-frequency/high-intensity sound waves, and electrotherapy.57,63 Electrical stimulation is the only adjunctive therapy that has been shown to be effective.57,63

Cat bites, with an estimated incidence of 5% to 15% of all animal bites, are the second most common cause of animal bite wounds in the United States.69 Bites and scratches occur most commonly on the upper extremities, with most injuries reported in women.64 Infection rates, estimated at 30% to 50%, are more than double those seen with dog bites.64,69

BITE WOUNDS Bite wounds have a substantial potential for infectious complications. If left untreated, complications such as soft tissue infection and osteomyelitis may occur, possibly requiring extensive d´ebridement or amputation. Approximately half the population in the United States will be bitten by either an animal or another human sometime during their lifetimes.64

ANIMAL BITES EPIDEMIOLOGY Dog bites account for approximately 80% of all animal bite wounds requiring medical attention. A survey of U.S. emergency departments reported an annual adjusted total of 333,687 visits from 1992 to 1994 for new dog bite–related injuries.65 Based on the data gathered in this study, approximately 914 new dog bite injuries are seen in emergency departments every day. Dog bites commonly occur in individuals younger than 20 years of age (52.2% of reported cases) who are most often male (57.8%). More than 70% of bites are to the extremities.64 Occasionally, facial bites may occur, and these are seen most often in children younger than 15 years of age and can be a lethal event via exsanguination. From 1979 through 1994, 279 deaths were the result of attacks by dogs.66 Patients at greatest risk of acquiring an infection after a bite have had a puncture wound (usually the hand), have not sought medical attention within 12 hours of the injury, and are older than 50 years of age.67,68

ETIOLOGY Infections from dog bite wounds are caused predominantly by organisms documented to be from the dog’s oral flora.68,70 Most infections are polymicrobial, with approximately five bacterial isolates per culture.71 Pasteurella species are the most frequent isolates. Other common aerobes include streptococci, staphylococci, Moraxella, and Neisseria. The most common anaerobes are Fusobacterium, Bacteroides, Porphyromonas, and Prevotella.71 Wound-site cultures in both infected and noninfected patients have similar bacteria present, with aerobic organisms isolated from 74% to 90% and anaerobic organisms isolated from 41% to 49%.71−73 Infections arising from cat bites or scratches are frequently (75%) caused by P. multocida, which has been isolated in the oropharynx of 50% to 70% of healthy cats.67 Mixed aerobic and anaerobic infections have been reported in 63% of cat bite wounds, whereas approximately one-third of cultures grow aerobes only.71 Both tularemia (Pasteurella tularensis) and rabies also have been transmitted by cat bites.67

PATHOPHYSIOLOGY The potential for infection from an animal bite is great owing to the pressure that can be exerted during the bite and the vast number of potential pathogens that make up the normal oral flora.70 Cats’ teeth are slender and extremely sharp. Their teeth easily penetrate into bones and joints, resulting in a higher incidence of septic arthritis

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and osteomyelitis.64 While a dog’s teeth may not be as sharp, they can exert a pressure of 200 to 450 lb/in2 and therefore result in a serious crush injury with much devitalized tissue.70 Known human pathogens such as S. aureus, P. multocida, and anaerobes are among the more than 64 species of bacteria that are harbored in the average dog mouth.70 In addition, the polymicrobic (aerobic and anaerobic) nature of animal bites provides a synergistic relationship, thus making an infection harder to eradicate.70 C L I N I C A L P R E S E N TAT I O N GENERAL

r Health care providers see two distinct groups of patients seeking medical attention for dog bites.

r The first group presents within 12 hours of the injury; these patients require general wound care, repair of tear wounds, or rabies and/or tetanus treatment. r The second group of patients presents more than 12 hours after the injury has occurred; these patients usually have clinical signs of infection and seek medical attention for infection-related complaints.

SKIN AND SOFT TISSUE INFECTIONS

1991

SIGNS

r Patients with infected dog bite wounds generally present with a localized cellulitis and pain at the site of injury.

r Cellulitis usually spreads proximally from the initial site of injury, and a gray malodorous discharge may be encountered. r If P. multocida is present, a rapidly progressing cellulitis is observed, with pain and swelling developing within 24 (70%) to 48 (90%) hours of initial injury. r Fever is uncommon. r Fewer than 20% of patients have a concomitant adenopathy or lymphangitis. LABORATORY TESTS

r Samples for bacterial cultures (aerobic and anaerobic) should be obtained.

r Wounds seen less than 8 hours or more than 24 hours after injury that show no signs of infection may not need to be cultured. OTHER DIAGNOSTIC TESTS

SYMPTOMS

r Patients seek medical care for infection-related complaints (i.e., pain, purulent discharge, and swelling).

r A roentgenogram of the affected part should be considered when infection is documented in proximity to a bone or joint.


TREATMENT: Dog and Cat Bites (see Table 108–3) Cultures obtained from early, noninfected bite wounds are not of great value in predicting the subsequent development of infection. Documentation of the mechanism of injury is important; if possible, an immunization history of the animal should be obtained. It is also important for the patient’s tetanus immune status to be determined. Wounds should be irrigated thoroughly with a copious volume (>150 mL) of sterile normal saline. Proper irrigation will reduce the bacterial count in the wound. Antibiotic or iodine solutions do not offer any advantage over saline and actually may increase tissue irritation. Several management techniques used in the treatment of bite wounds remain controversial; these include the extent and type of d´ebridement,74 the use of primary closure within 24 hours of the injury,73 and indications for the use of antibiotics. The role of prophylactic antimicrobial therapy for the early, noninfected bite wound remains controversial.64,75 Unfortunately, suggestions concerning the use of prophylactic antibiotics are based on minimal data because few clinical trials have been performed. Most reports are of retrospective studies or observations of complicated cases. A meta-analysis of eight randomized trials of dog-bite wounds evaluated the use of antibiotics for prophylaxis for the prevention of infectious complications.76 The overall occurrence of infectious complications ranged from 3.2% to 45.8%. All studies used oral antibiotics, with six of the eight using either penicillin or a penicillinaseresistant penicillin. Five of the eight studies documented a reduced risk of infection in patients receiving antimicrobial prophylaxis. Controlled studies have not shown benefits definitively with prophylactic antibiotics for noninfected bites. Because up to 20% of bite wounds may become infected, a 3- to 5-day course of antimicrobial therapy generally is recommended.64 This is especially important for patients at greater risk for infection (patients older than 50 years of age and those with puncture wounds and wounds to the hands, and

those who are immunocompromised).77,78 Treatment should be directed at the typical aerobic and anaerobic oral flora of dogs, as well as at potential pathogens from the skin flora of the bite victim. CLINICAL CONTROVERSY To date, there is no single, universally agreed on treatment regimen for bite wounds. Penicillin provides excellent coverage for P. multocida but not for S. aureus and most of the other staphylococci that are commonly isolated from bite wounds. Although penicillinase-resistant penicillins, first-generation cephalosporins, erythromycin, and clindamycin have excellent activity against staphylococci, these agents are not active against most strains of P. multocida. Antibiotic regimens suggested for empirical therapy of dog bite wounds include (1) a combination of a β-lactam antibiotic and a β-lactamase inhibitor, (2) a second-generation cephalosporin with anaerobic activity, or (3) penicillin in combination with a firstgeneration cephalosporin or clindamycin. Tetracyclines (e.g., doxycycline) and trimethoprim-sulfamethoxazole have activity against P. multocida and often are recommended as an alternative form of therapy for patients who are allergic to penicillins. However, tetracyclines should not be used in children and/or pregnant women; trimethoprim-sulfamethoxazole also should be avoided during pregnancy. Erythromycin may be considered an alternative in growing children or pregnant women. If erythromycin is selected, bacterial sensitivities should be obtained and clinical response monitored carefully because most strains of P. multocida are resistant. In addition to irrigation and antibiotics, when indicated, the injured area should be immobilized and elevated. Clinical

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failures due to edema have occurred despite appropriate antibiotic therapy.64 Therefore, it is important to stress to patients that the affected area should be elevated for several days or until edema has resolved. Infections developing within the first 24 hours of a bite are caused most often by P. multocida and should be treated with penicillin VK 500 mg orally four times daily (in children, 80,000–90,000 units/kg per day orally divided into four doses) or amoxicillin 500 mg orally three times daily (in children, 40 mg/kg per day orally divided into three doses). Tetracycline is an alternative for penicillin-allergic children and nonpregnant adults (500 mg orally four times daily; in children, 50 mg/kg per day orally divided into four doses).77 For severe infections, IV penicillin (1.2 million units every 4 to 6 hours) therapy should be started and followed by oral therapy when the signs of cellulitis have subsided. Treatment should be given for 10 to 14 days. For infections developing more than 36 to 48 hours after the bite, the risk of P. multocida being involved decreases dramatically. In these patients, staphylococci or streptococci are the most likely causative pathogens. Therapy in this instance includes a penicillinaseresistant penicillin (dicloxacillin 250–500 mg orally four times daily; in children, 25–50 mg/kg per day orally divided into four doses) or a cephalosporin (cefuroxime axetil 500 mg orally twice daily; in children, 20–30 mg/kg per day orally divided into two doses) and should be given for a full 10 to 14 days.77 The fluoroquinolones are highly active in vitro against Pasteurella and other common aerobic isolates found in these bite wounds. Some of the newer fluoroquinolones also have activity against anaerobes commonly isolated in these infections. However, clinical data on the use of fluoroquinolones with enhanced anaerobic

activity are lacking, and the role of these agents in the therapy of bite wounds has yet to be defined.79 Tetanus does not occur commonly after dog bites; however, it is a theoretical possibility. If the immunization history of a patient with anything other than a clean, minor wound is unknown, tetanusdiphtheria (TD) toxoids and tetanus immune globulin (TIg) should be administered.80 Patients with wounds that do not require immunization with TD toxoids are those who have had three or more immunization doses of TIg within the past 5 years. Patients who have received three or more doses of TIg within the last 10 years or patients who received two doses of TIg within the first 24 hours of injury do not require additional TIg therapy.80 Because the rabies virus can be transmitted via saliva, rabies may be a potential complication of a bite. When the symptoms of rabies develop after a bite, the prognosis for survival is poor. Roughly 3% of rabies cases documented in animals were in dogs (the most frequent vectors are skunks, raccoons, and bats). After a patient has been exposed to rabies, the treatment objectives consist of thorough irrigation of the wound, tetanus prophylaxis, antibiotic prophylaxis, if indicated, and immunization. Prompt, thorough irrigation of the wound with soap or iodine solution may reduce the development of rabies.69 Postexposure prophylaxis immunization consists of the administration of both passive antibody and vaccine. The only exceptions to antibody administration are patients who have been immunized previously and have the appropriate degree of documented rabies antibody titers. The management of cat bites is similar to that discussed for dog bites. Cat scratches typically involve the same organisms as bites and should be treated accordingly. Antibiotic therapy with penicillin is the mainstay, and therapy is as described for dog bites.

EVALUATION OF THERAPEUTIC OUTCOMES

most common isolates, followed by Staphylococcus spp. (predominately S. aureus).79 Eikenella corrodens is isolated from human bite wounds approximately 30% of the time.69,79 Anaerobic microorganisms have been isolated in approximately 40% of human bites and 55% of clenched-fist injuries.60 Common anaerobes recovered from human bite infections include Prevotella, Fusobacterium, Veillonella, and Peptostreptococcus species.79

Results of a Gram stain should be used to confirm the appropriateness of therapy. If signs and symptoms are not reduced within 24 hours, then surgical d´ebridment may be needed.

HUMAN BITES EPIDEMIOLOGY Human bites are the third most frequent type of bite. Infected human bites can occur as bites from the teeth or from blows to the mouth (clenched-fist injuries). Human bites generally are more serious than animal bites and carry a higher likelihood of infection than do most animal bites. Infectious complications occur in 10% to 50% of patients with human bites.69,81,82 Self-inflicted bites most commonly occur on the lips or around the fingernails (from sucking or biting the nails). Bites by others can occur to any part of the body, but most often involve the hands. Bites to the hand are most serious and become infected more frequently. The clenched-fist injury is a traumatic laceration caused by one person hitting another in the mouth and is a very serious bite wound. The areas most commonly affected by this injury are the third and fourth metacarpophalangeal joints.

ETIOLOGY Infections caused by these injuries are similar and are caused most often by the normal oral flora, which include both aerobic and anaerobic microorganisms. Streptococcus spp. (especially S. anginosus) are the

PATHOPHYSIOLOGY Human bites generally are more serious and more prone to infection than animal bites, particularly clenched-fist injuries.70 While the force of a punch may sever a tendon or nerve or break a bone, it most often causes a breach in the capsule of the metacarpophalangeal joint, leading to direct inoculation of bacteria into the joint or bone.64 When the hand is relaxed, the tendons carry bacteria into deeper spaces of the hand, resulting in more extensive infection.64 C L I N I C A L P R E S E N TAT I O N GENERAL

r Most clenched-fist injuries are already infected by the time patients seek medical care, and most require hospitalization. SYMPTOMS

r Patients with infected bites to the hand may develop a painful, throbbing, swollen extremity.

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r Wounds often have a purulent discharge, and the patient

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LABORATORY TESTS

r Samples for bacterial cultures (aerobic and anaerobic)

complains of a decreased range of motion.

should be collected as per animal bites.

r In severe infections, a peripheral leukocytosis of 15,000 to

SIGNS

r Signs of infection include erythema, swelling, and clear

30,000 cells/mm3 may be seen; therefore, the white blood count should be monitored for resolution of infection.

or pussy discharge.

r Adjacent lymph nodes may be enlarged. r In clenched-fist injuries, edema may limit the ability of

OTHER DIAGNOSTIC TESTS

r If damage to a bone or joint is suspected, radiographic

tendons to glide in their sheaths, thereby limiting a joint’s range of motion.

evaluation should be undertaken.


TREATMENT: Human Bites (see Table 108–4) 9 Management of bite wounds consists of aggressive irrigation,

surgical d´ebridement, and immobilization of the affected area. Primary closure for human bites generally is not recommended. Tetanus toxoid and antitoxin may be indicated. Transmission of viruses has been documented through human bites; therefore, information about the biter is important. Although the possibility of acquiring the human immunodeficiency virus (HIV) through bites is believed to be unlikely, the presence of the virus in the saliva makes disease transmission possible. If the biter is HIV-positive, the victim should have a baseline blood specimen drawn to determine preexposure HIV status and then be retested in 3 months and 6 months.82 The bite wound should be irrigated thoroughly and vigorously with a virucidal agent such as povidone-iodine.69 Bite victims exposed to blood-tainted saliva should be offered antiretroviral chemoprophylaxis. 10 Patients with noninfected hand bite injuries should be given prophylactic antibiotic therapy. Initial therapy should consist of a penicillinase-resistant penicillin (dicloxacillin 250–500 mg orally four times daily; in children, 25–50 mg/kg per day orally divided into four doses) in combination with penicillin VK 250–500 mg orally four times daily (in children, 40,000–90,000 units/kg per day orally divided into four doses). Prophylactic therapy should be given for

EVALUATION OF THERAPEUTIC OUTCOMES Results of a Gram stain should be used to confirm the appropriateness of therapy. Surgical d´ebridement may be necessary if signs and symptoms are not reduced within 24 hours.

ABBREVIATIONS HIV: human immunodeficiency virus MRSA: methicillin-resistant Staphylococcus aureus SSTI: skin and soft tissue infection TD: tetanus-diphtheria TIg: tetanus immune globulin VRE: vancomycin-resistant enterococci Review Questions and other resources can be found at www.pharmacotherapyonline.com.

REFERENCES 1. Fung HB, Chang JY, Kuczynski S. A practical guide to the treatment of complicated skin and soft tissue infections. Drugs 2003;63:1459–1480.

3 to 5 days as for dog bites.83 A first-generation cephalosporin or macrolide is not recommended because the sensitivity of these agents to E. corrodens is variable.84 For infected bite wounds, penicillin and a penicillinase-resistant penicillin or amoxicillin–clavulanic acid 875 mg/125 mg orally twice daily (40 mg/kg per day orally of the amoxicillin component divided into two doses) should be started empirically pending the culture results. Tetracyclines or a combination of clindamycin plus a fluoroquinolone or trimethoprim-sulfamethoxazole may be used as an alternative therapy for the penicillin-allergic patient. Hospitalization for minor wounds is not necessary if surgical repair of vital structures has not been performed. Patients suffering serious injuries or clenchedfist injuries should be started on intravenous antibiotics. Duration of therapy for infected bite injuries should be 7 to 14 days. Antibiotic therapy always should be used in clenched-fist injuries. Therapy should include penicillin (or ampicillin) plus a penicillinase-resistant penicillin until the final cultures are available. Therapeutic failures have been documented when either firstgeneration cephalosporins or penicillinase-resistant penicillins have been used alone, most likely because of their poor and variable activity against E. corrodens.85,86 Therapy should be continued from 7 to 14 days.83 2. Eron LJ, Lipsky BA, Low DE, et al. Managing skin and soft tissue infections: Expert panel recommendations on key decision points. J Antimicrob Chemother 2003;52(suppl. S1):i3–i17. 3. Stulberg DL, Penrod MA, Blatny RA. Common bacterial skin infections. Am Fam Phys 2002;66:119–124. 4. Elixhauser A, Steiner CA. Most Common Diagnoses and Procedures in U.S. Community Hospitals, 1996: Summary. HCUP Research Note. Rockville, MD, Agency for Health Care Policy and Research, 1996; available at http://www.ahrq.gov/data/hcup/commdx/commdx.htm. 5. Rennie RP, Jones RN, Mutnick AH, and the SENTRY Program Study Group (North America). Occurrence and antimicrobial susceptibility patterns of pathogens isolated from skin and soft tissue infections: report from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 2000). Diagn Microbiol Infect Dis 2003;45:287–293. 6. Granato PA. Pathogenic and indigenous microorganisms of humans. In: Murray PR, Baron EJ, Jorgensen JH, et al, eds. Manual of Clinical Microbiology, 8th ed. Washington, ASM Press, 2003:44–54. 7. Ducan WC, McBride ME, Knox JM. Experimental production of infection in humans. J Invest Dermatol 1970;54:319–323. 8. Yagupski P. Bacteriologic aspects of skin and soft tissue infections. Pediatr Ann 1993;22:217–224. 9. Centers for Disease Control and Prevention. Pseudomonas dermatitis/folliculitis associated with pools and hot tubs: Colorado and Maine, 1999–2000. MMWR 2000;49:1087–1091. 10. Swartz MN. Cellulitis and subcutaneous tissue infections. In: Mandell GL,

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11. 12.

13.

14. 15. 16. 17.

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23.

24.

25. 26.

27.

28.

29.

30.

31.

32.

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Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed. New York, Churchill-Livingstone, 2000:1037–1057. Bisno AL, Stevens DL. Streptococcal infections of skin and soft tissues. New Engl J Med 1996;334:240–245. Eriksson B, Jorup-Ronstrom C, Karkkonen K, et al. Erysipelas: Clinical and bacteriologic spectrum and serological aspects. Clin Infect Dis 1996;23:1091–1098. Bergkvist P, Sjobeck K. Antibiotic and prednisolone therapy of erysipelas: A randomized, double-blind, placebo-controlled study. Scand J Infect Dis 1997;29:377–382. Sadick NS. Current aspects of bacterial infections of the skin. Dermatol Clin 1997;15:341–349. Ben-Amitai D, Ashkenazi S. Common bacterial skin infections in childhood. Pediatr Ann 1993;22:225–233. Brown J, Shriner DL, Schwartz RA, Janniger CK. Impetico: An update. Int J Dermatol 2003;42:251–255. Britton JW, Fajardo JE, Krafte-Jacobs B. Comparison of mupirocin and erythromycin in the treatment of impetigo. J Pediatr 1990;117:827– 829. Swartz MN. Lymphadenitis and lymphangitis. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed. New York, Churchill-Livingstone, 2000:1066–1075. Bass JW. Treatment of skin and skin structure infections. Pediatr Infect Dis J 1992;11:152–155. Binswanger IA, Kral AH, Bluthenthal RN, et al. High prevalence of abscesses and cellulitis among community-recruited injection drug users in San Francisco. Clin Infect Dis 2000;30:579–581. Ebright JR, Pieper B. Skin and soft tissue infections in injection drug users. Infect Dis Clin North Am 2002;16:697–712. Dagan R, Moshe P, Watemberg N, et al. Outpatient treatment of serious community-acquired pediatric infections using once daily intramuscular ceftriaxone. Pediatr Infect Dis J 1987;6:1080–1084. Stevens DL, Herr D, Lampiris H, et al, and the Linezolid MRSA Study Group. Linezolid versus vancomycin for the treatment of methicillinresistant Staphylococcus aureus infections. Clin Infect Dis 2002;34: 1481–1490. Stevens DL, Smith LG, Bruss JB, et al. Randomized comparison of linezolid (PNU-100766) versus oxacillin-dicloxacillin for treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2000;44:3408–3413. Tedesco KL, Rybak MJ. Daptomycin. Pharmacotherapy 2004;24:41–57. Nichols RL, Graham DR, Barriere SL, et al. Treatment of hospitalized patients with complicated gram-positive skin and skin structure infections: Two randomized, multicentre studies of quinupristin/dalfopristin versus cefazolin, oxacillin or vancomycin. Synercid Skin and Skin Structure Infection Group. J Antimicrob Chemother 1999;44:263–273. Gould IM, Hudson M, Morris J, et al. Imipenem versus standard therapy in the treatment of serious soft tissue infection. Drugs Exp Clin Res 1988;14:555–558. Graham DR, Lucasti C, Malafaia O, et al. Ertapenem once daily versus piperacillin-tazobactam four times per day for treatment of complicated skin and skin-structure infections in adults: Results of a prospective, randomized, double-blind multicenter study. Clin Infect Dis 2002;34: 1460–1468. Kulhanjian J, Dunphy M, Hamstra S, et al. Randomized comparative study of ampicillin/sulbactam vs ceftriaxone for treatment of soft tissue and skeletal infections in children. Pediatr Infect Dis J 1989;8:605–610. Tan JS, Wishnow RM, Talan DA, et al. Treatment of hospitalized patients with complicated skin and skin structure infections: Double-blind, randomized, multicenter study of piperacillin-tazobactam versus ticarcillinclavulanate. Antimicrob Agents Chemother 1993;37:1580–1586. Gentry LO, Ramirez-Ronda CH, Rodriquez-Noriega E, et al. Oral ciprofloxacin vs parenteral cefotaxime in the treatment of difficult skin and skin structure infections. Arch Intern Med 1989;148:2579– 2583. Gentry LO. Therapy with newer oral β-lactam and quinolone agents for infections of the skin and skin structures: A review. Clin Infect Dis 1992; 14:285–297.

33. Parish LC, Routh HB, Miskin B, et al. Moxifloxacin versus cephalexin in the treatment of uncomplicated skin infections. Int J Clin Pract 2000;54:497–503. 34. Nichols RL, Smith JW, Gentry LO, et al. Multienter randomized study comparing levofloxacin and ciprofloxacin for uncomplicated skin and skin structure infections. South Med J 1997;90:1193–1200. 35. Tarshis GA, Miskin BM, Jones TM, et al. Once daily oral gatifloxacin verus oral levofloxacin in treatment of uncomplicated skin and soft tissue infections: Double-blind multicenter randomized study. Antimicrob Agents Chemother 2001;45:2358–2362. 36. Zervos MJ, Hershberger E, Nicolau DP, et al. Relationship between fluoroquinolone use and changes in susceptibility to fluoroquinolones of selected pathogens in 10 United States teaching hospitals, 1991–2000. Clin Infect Dis 2003;37:1643–1648. 37. LeFrock J, Blais F, Schell, et al. Cefoxitin in the treatment of diabetic patients with lower extremity infections. Infect Surg 1983;2:361–374. 38. Hughes C, Johnson C, Bamberger D, et al. Treatment and long-term follow-up of foot infections in patients with diabetes or ischemia: A randomized, prospective, double-blind comparison of cefoxitin and ceftizoxime. Clin Ther 1987;10(suppl A):36–49. 39. Crane L, Levine D, Aervos M, et al. Bacteremia in narcotic addicts at Detroit Medical Center: Microbiology, epidemiology, risk factors, and empiric therapy. Rev Infect Dis 1986;8:364–373. 40. Urschel JD. Necrotizing soft tissue infections. Postgrad Med J 1999;75: 645–649. 41. Gentry LO. Diagnosis and management of the diabetic foot ulcer. J Antimicrob Chemother 1993;32(suppl A):77–89. 42. Lipsky BA, Pecoraro RE, Wheat LJ. The diabetic foot: Soft tissue and bone infection. Infect Dis Clin North Am 1990;4:409–432. 43. Caputo GM, Cavanagh PR, Ulbrecht JS, et al. Assessment and management of foot disease in patients with diabetes. New Engl J Med 1994; 331:854–860. 44. Smith AJ, Daniels T, Bohnen JMA. Soft tissue infections and the diabetic foot. Am J Surg 1996;172(suppl 6A):7S–12S. 45. Levin ME. Foot lesions in patients with diabetes mellitus. Endocrinol Metab Clin North Am 1996;25:447–462. 46. Slovenkai MP. Foot problems in diabetes. Med Clin North Am 1998; 82:949–971. 47. Gerding DN. Foot infections in diabetic patients: The role of anaerobes. Clin Infect Dis 1995;20(suppl 2):S283–288. 48. Grayson ML. Diabetic foot infections: Antimicrobial therapy. Infect Dis Clin North Am 1995;9:143–161. 49. Shea KW. Antimicrobial therapy for diabetic foot infections. Postgrad Med 1999;106:85–94. 50. West NJ. Systemic antimicrobial treatment of foot infections in diabetic patients. Am J Health Syst Pharm 1995;52:1199–207. 51. Parish LC, Aten EM. Treatment of skin and skin structure infections: A comparative study of augmentin and cefaclor. Cutis 1984;34:567–570. 52. Eron LJ, Harvey L, Hixon DL, et al. Ciprofloxacin therapy of infections caused by Pseudomonas aeruginosa and other resistant bacteria. Antimicrob Agents Chemother 1985;28:308–310. 53. Grayson ML, Gibbons GW, Habershaw GM, et al. Use of ampicillinsulbactam versus imipenem-cilastatin in the treatment of limb-threatening foot infections in diabetic patients. Clin Infect Dis 1994;18:683–693. 54. Lipsky BA, Baker PD, Landon GC, et al. Antibiotic therapy for diabetic foot infections: Comparison of two parenteral-to-oral regimens. Clin Infect Dis 1997;24:643–648. 55. Shea JD. Pressure sores: Classification and management. Clin Orthop 1975;112:89–100. 56. National Pressure Ulcer Advisory Panel. Pressure ulcers: Incidence, economics, risk. Consensus Development Conference Statement. Decubitus 1989;2:24–29. 57. Kanj LF, Wilking SVB, Phillips TJ. Pressure ulcers. J Am Acad Dermatol 1998;38:517–536. 58. Gradon J, Adamsom C. Infections of pressure ulcers: Management and controversies. Infect Dis Clin Pract 1995;1:11–16. 59. Findlay D. Practical management of pressure ulcers. Am Fam Phys 1996; 54:1519–1528.

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CHAPTER 108 60. Goode PS, Allman RM. The prevention and management of pressure sores. Med Clin North Am 1989;73:1511–1524. 61. Reuler JB, Cooney TG. The pressure sore: Pathophysiology and principles of management. Ann Intern Med 1981;94:661–666. 62. Cervo FA, Cruz AC, Posillico JA. Pressure ulcers: Analysis of guidelines for treatment and management. Geriatrics 2000;55:55–60. 63. Cuddigan J, Frantz RA. Pressure ulcer research: Pressure ulcer treatment. A monograph from the National Pressure Ulcer Advisory Panel. Adv Wound Care 1998;2:294–300. 64. Goldstein E. Bite wounds and infection. Clin Infect Dis 1992;14:633–640. 65. Weiss HB, Friedman DI, Coben JH. Incidence of dog bite injuries treated in emergency departments. JAMA 1998;279:51–53. 66. Anonymous. Dog bite related fatalities—United States, 1995–1996. MMWR 1997;46:463–467. 67. Rest JG, Goldstein EJC. Management of human and animal bite wounds. Emerg Med Clin North Am 1985;3:117–126. 68. Goldstein EJC, Citron DM, Finegold SM. Role of anaerobic bacteria in bite wound infections. Rev Infect Dis 1984;6(suppl 1):S177–183. 69. Griego RD, Rosen T, Orengo IF, et al. Dog, cat, and human bites: A review. J Am Acad Dermatol 1995;33:1019–1029. 70. Brooks I. Microbiology and management of human and animal bite wound infections. Primary Care Clin Office Pract 2003;30:1–11. 71. Talan DA, Citron DM, Abrahamian FM, et al. Bacteriologic analysis of infected dog and cat bites. New Engl J Med 1999;340:85–92. 72. Wiggins ME, Akelamn E, Weiss AP. The management of dog bites and dog bite infections to the hand. Orthopedics 1994;17:617–623. 73. Goldstein EJC, Citron DM, Finegold SM. Dog bite wounds and infection: A prospective clinical study. Ann Emerg Med 1980;9:508–512. 74. Callaham ML. Treatment of common dog bites: Infection risk factors. J Am Coll Emerg Phys 1978;7:83–87.

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75. Elenbass RM, McNaoney WK, Robinson WA. Prophylactic oxacillin in dog bite wounds. Ann Emerg Med 1982;11:248–251. 76. Cummings P. Antibiotics to prevent infections in patients with dog bite wounds: A meta-analysis of randomized trials. Ann Emerg Med 1994;23:535–540. 77. Elliot DL, Tolle SW, Goldberg L, et al. Pet-associated illness. New Engl J Med 1985;313:985–995. 78. Goldstein E, Citron DM, Richwals GA. Lack of in vitro efficacy of oral forms of certain cephalosporins, erythromycin, and oxacillin against Pasteurella multocida. Antimicrob Agents Chemother 1988;32:213–215. 79. Talan DA, Abrahamian FM, Moran GJ, et al. Clinical presentation and bacteriologic analysis of infected human bites in patients presenting to emergency departments. Clin Infect Dis 2003;37:1481–1489. 80. Goldstein EJ, Reinhardt JF, Murray PM, et al. Outpatient therapy of bite wounds: Demographic data, bacteriology, and a prospective, randomized trial of amoxicillin–clavulanic acid versus penicillin (dicloxacillin). Int J Dermatol 1987;26:123–127. 81. Mann RJ, Hoffield TA, Farmer CB. Human bites of the hand: Twenty years of experience. J Hand Surg 1977;2:97–99. 82. Bunzli WF, Wright DH, Hoang AD, et al. Current management of human bites. Pharmacotherapy 1998;18:227–234. 83. Talan D. Infectious disease issues in the emergency department. Clin Infect Dis 1996;23:1–14. 84. Goldstein E, Gombert M, Agyare E. Susceptibility of Eikenella corrodens to newer beta-lactam antibiotics. Antimicrob Agents Chemother 1980; 18:832–833. 85. Goldstein E, Miller T, Citron D, et al. Infections following clenched-fist injury: A new perspective. J Hand Surg 1978;3:455–459. 86. Goldstein E, Barene M, Miller TA. Eikenella corrodens in hand infections. J Hand Surg 1983;8:563–566.

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109 INFECTIVE ENDOCARDITIS Michael A. Crouch and Angie Veverka

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Infective endocarditis (IE) is an uncommon infection usually occurring in persons with preexisting cardiac valvular abnormalities (e.g., prosthetic heart valves) or with other specific risk factors (e.g., intravenous drug abuse).

2 Three groups of organisms cause a majority of IE cases: streptococci (55% to 62% of cases), staphylococci (25% to 35%), and enterococci (5% to 18%). 3 The clinical presentation of IE is highly variable and nonspecific, although a fever and murmur usually are present. Classic peripheral manifestations (Osler nodes) may or may not occur. 4 The diagnosis of IE requires the integration of clinical, laboratory, and echocardiographic findings. The two major diagnostic criteria are bacteremia and echocardiographic changes (e.g., valvular vegetation).

5 Treatment of IE involves isolation of the infecting pathogen

and determination of antimicrobial susceptibilities, followed by high-dose, parenteral, bactericidal antibiotics for an extended period.

6 Surgical replacement of the infected heart valve is an

Endocarditis is an inflammation of the endocardium, the membrane lining the chambers of the heart and covering the cusps of the heart valves.1,2 More commonly, endocarditis refers to infection of the heart valves by various microorganisms. Although it typically affects native valves, it also may involve nonvalvular areas or implanted mechanical devices (e.g., mechanical heart valves). Bacteria primarily cause endocarditis, but fungi and other atypical microorganisms can lead to the disease; thus the more encompassing term infective endocarditis (IE) is preferred. Endocarditis is often referred to as acute or subacute depending on the pace and severity of the clinical presentation. The acute, fulminating form is associated with high fevers and systemic toxicity. Virulent bacteria, such as Staphylococcus aureus, frequently cause this syndrome, and if untreated, death occurs within a few days to weeks. On the other hand, subacute IE is more indolent and is caused by less invasive organisms, such as viridans streptococci, usually occurring in preexisting valvular heart disease. IE is best classified based on the etiologic organism, the anatomic site of infection, and pathogenic risk factors.2 Infection also may follow surgical insertion of a prosthetic heart valve, resulting in prosthetic valve endocarditis (PVE).3

important adjunct to endocarditis treatment in certain situations (e.g., patients with acute heart failure).

7 β-Lactam antibiotics, such as penicillin G, nafcillin,

and ampicillin, remain the drugs of choice for streptococcal, staphylococcal, and enterococcal endocarditis, respectively.

8 Aminoglycosides are essential to obtain a synergistic bac-

tericidal effect in the treatment of enterococcal endocarditis. Adjunctive aminoglycosides also may decrease the emergence of resistant organisms (e.g., prosthetic valve endocarditis caused by coagulase-negative staphylococci) and hasten the pace of clinical and microbiologic response (e.g., some streptococcal and staphylococcal infections).

9 Vancomycin is reserved for patients with immediate β-lactam allergies and the treatment of resistant organisms.

10 Antimicrobial prophylaxis is used as an attempt to prevent

IE in patients at high risk (such as persons with prosthetic heart valves) before a bacteremia-causing procedure (e.g., dental extraction).

EPIDEMIOLOGY AND ETIOLOGY IE is an uncommon but not rare infection affecting about 10,000 to 20,000 persons annually in the United States. The infection accounts for approximately 1 in every 1000 hospital admissions.1 Yet the incidence of IE may be increasing, and it is now the fourth leading cause of infectious disease syndromes that are life threatening, after urosepsis, pneumonia, and intraabdominal sepsis.4 The male-to-female ratio is 1.7:1. Overall, most cases occur in individuals older than 50 years of age, and it is uncommon in children.1,2 PVE accounts for 7% to 25% of cases of IE.5 As the population ages, and as valve replacement surgery becomes more common, the mean age of patients with IE increases. However, those with a history of intravenous drug abuse (IVDA), who tend to be younger males, are also at high risk of IE. Other conditions associated with a higher incidence of IE include diabetes, long-term hemodialysis, and poor dental hygeine. 1 Most persons with IE have risk factors, such as preexisting cardiac valvular abnormalities. Many types of structural heart disease result in turbulence of blood flow that increases the risk for IE. 1997

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TABLE 109–1. Etiologic Organisms in Infective Endocarditis Agent

Percentage of Cases

Streptococci Viridans streptococci Other streptococci Staphylococci Coagulase-positive Coagulase-negative Enterococci Gram-negative aerobic bacilli Fungi Miscellaneous bacteria Mixed infections “Culture negative”

55–62 30–40 15–25 20–35 10–27 1–3 5–18 1.5–13 2–4 38◦ C (100.4◦ F) Petechiae and splinter hemorrhages are excluded. None of the peripheral lesions are pathognomonic for IE Presence of rheumatoid factor, glomerulonephritis, Osler’s nodes, or Roth spots Positive blood cultures that do not meet the major criteria Serologic evidence of active infection; single isolates of coagulase-negative staphylococci, and organisms that very rarely cause IE are excluded from this category

Note: Cases are defined clinically as definite if they fulfill two major criteria, one major criterion plus three minor criteria, or five minor criteria; they are defined as possible if they fulfill one major and one minor criterion or three minor criteria. HACEK denotes Haemophilus species (H. parainfluenzae, H. aphrophilus, H. paraphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae). Adapted from ref. 15.

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recent diagnostic criteria (the Duke criteria) include major and minor variables14,15 (Table 109–3). Based on the number of major and minor criteria that are fulfilled, patients suspected of IE are divided into three separate categories: definite IE, possible IE, or IE rejected15 (see Table 109–3).

PROGNOSIS The outcome for endocarditis is improved with rapid diagnosis, appropriate treatment (i.e., antimicrobial therapy, surgery, or both), and prompt recognition of complications should they arise. Factors associated with increased mortality include (1) heart failure, (2) culturenegative endocarditis, (3) endocarditis caused by resistant organisms such as fungi or gram-negative bacteria, (4) left-sided endocarditis caused by S. aureus, and (5) prosthetic-valve endocarditis.1,16 The presence of heart failure has the greatest negative impact on the short-

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term prognosis.4 For native-valve IE, mortality rates range from 16% to 27%; lower rates occur with viridans streptococci (4% to 9%), and higher rates occur with left-sided IE caused by enterococci (15% to 20%) and staphylococci (25% to 47%). Even higher rates of mortality are seen with unusually encountered organisms (e.g., mortality greater than 50% for Pseudomonas aeruginosa). The mortality rate for right-side IE associated with IVDA is generally low (e.g., 10%).4 For those who relapse after treatment for IE, most will do so within the first 2 months after discontinuation of antimicrobials. Relapse rates for viridans streptococcus are generally low (2%), whereas relapse is more likely in those with enterococcal infection (8% to 20%) and PVE (10% to 15%).5 After appropriate treatment and recovery, the risk of morbidity and mortality following IE persist for years, although it declines gradually annually. Morbidity remains elevated because of a greater likelihood of recurrent IE, heart failure, and embolism or, if a valve is replaced, the risk of anticoagulation, valve thrombosis, or additional valve surgery.17


TREATMENT: Infective Endocarditis
DESIRED OUTCOMES The desired outcomes for treatment and prophylaxis of IE are to r r r r

r

Relieve the signs and symptoms of the disease. Decrease morbidity and mortality associated with the infection. Eradicate the causative organism with minimal drug exposure. Provide cost-effective antimicrobial therapy determined by the likely or identified pathogen, drug susceptibilities, hepatic and renal function, drug allergies, and anticipated drug toxicities. Prevent IE from occurring or recurring in high-risk patients with appropriate prophylactic antimicrobials.


GENERAL APPROACH TO TREATMENT 5 The most important approach in the treatment of IE is isolation

of the infecting pathogen and determination of antimicrobial susceptibilities, followed by high-dose, parenteral, bactericidal antibiotics for an extended period.1,2 Treatment usually is started in the hospital, but in selected patients it is often completed in the outpatient setting so long as defervescence has occurred and follow-up blood cultures show no growth. Large doses of parenteral antimicrobials usually are necessary to achieve bactericidal concentrations within vegetations. An extended duration of therapy is required, even for susceptible pathogens, because microorganisms are enclosed within valvular vegetations and fibrin deposits. These barriers impair host defenses and protect microbes from phagocytic cells. In addition, the high bacterial concentrations within vegetations may result in an inoculum effect that further resists killing (see Chap. 103 for additional discussion). Many bacteria are not actively dividing, further limiting the rate of bacterial death. For most patients, 4 to 6 weeks of therapy is required. Pharmacodynamic investigations in the IE animal model allow quantitation of bacterial densities within vegetations over time as a function of antibiotic concentration. These models empirically confirm many of the observed IE treatment principles.18,19 The antibiotic concentration in serum that is needed to kill bacteria within vegetations may be many times the minimal bactericidal concentration

(MBC) of the infecting pathogen depending on additional characteristics. The most effective antibiotics have a rapid and homogeneous distribution into the vegetation, kill bacteria rapidly, and are least susceptible to a large inoculum. Aminoglycosides have the most favorable characteristics, followed by β-lactams, and then glycopeptides.19


NONPHARMACOLOGIC THERAPY 6 Surgery is an important adjunct in the management of endocardi-

tis. In most surgical cases, valvectomy and valve replacement are performed to remove infected tissue and to restore hemodynamic function. Echocardiographic features that suggest the need for surgery include persistent vegetation or an increase in vegetation size after prolonged antibiotic treatment, valve dysfunction, or perivalvular extension (e.g., abscess).4 Surgery also may be considered in cases of PVE endocarditis caused by resistant organisms (e.g., fungi or gramnegative bacteria), or if there is persistent bacteremia or other evidence of failure despite appropriate antimicrobial therapy.3,21 The major indications for surgical intervention in the past have been heart failure in left-sided IE and persistent infection in right-sided IE.1


PHARMACOLOGIC THERAPY 7 Specific treatment recommendations from the American Heart

Association (AHA) provide guidance for the management of the more common causes of IE.22 These guidelines were last updated in 1995, with expected revision to be initiated in 2005. β-Lactam antibiotics, such as penicillin G, nafcillin, and ampicillin, remain the drugs of choice for streptococcal, staphylococcal, and enterococcal endocarditis, respectively. These recommendations are summarized in Tables 109–4 through 109–9 and are discussed in more detail in the following sections. Because these guidelines address only common causes of endocarditis, readers are referred to other references for more in-depth discussion of unusually encountered organisms.4

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TABLE 109–4. Suggested Regimens for Therapy of Native-Valve Endocarditis Due to Penicillin-Susceptible Viridans Streptococci and Streptococcus bovis (Minimum Inhibitory Concentration ≤0.1 mcg/mL)a Antibiotic

Dosage and Route

Duration (wks)

Aqueous crystalline penicillin G sodium

12–18 million units/24 h IV either continuously or in six equally divided doses

4

2 g once daily IV or IMb

4

12–18 million units/24 h IV either continuously or in six equally divided doses 1 mg/kg IM or IV every 8 h

2

2

When obtained 1 h after a 20–30 min IV infusion or IM injection, serum concentration of gentamicin of approximately 3 mcg/mL is desirable; trough concentration should be 65 years, renal impairment, or impairment of the eighth nerve. Other potentially nephrotoxic agents (e.g., nonsteroidal anti-inflammatory drugs) should be used cautiously in patients receiving gentamicin. d Vancomycin dosage should be reduced in patients with impaired renal function. Each dose of vancomycin should be infused over at least 1 h to reduce the risk of the histamine-release “red man” syndrome. IV = intravenous; IM = intramuscular. From Wilson WR, Karchmer AW, Dajani AS, et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, and staphylococci, and HACEK microorganisms. JAMA 1995;274:1706–1713, with permission. Copyright 1995–1997, American Medical Association. b

8 For some pathogens, such as enterococci, the use of synergis-

tic antimicrobial combinations (including an aminoglycoside) is essential to obtain a bactericidal effect. Combination antibiotics also may decrease the emergence of resistant organisms during treatment (e.g., PVE caused by coagulase-negative staphylococci) and hasten the pace of clinical and microbiologic response (e.g., some streptococcal and staphylococcal infections). Occasionally, combination treatment will result in a shorter treatment course.

CLINICAL CONTROVERSY The AHA guidelines recommend traditional aminoglycoside dosing whenever clinicians use these antibiotics. Extendedinterval dosing (once-daily administration) is an intriguing dosing strategy, but data only support this approach for the treatment of streptococcal IE, and it is not recommended routinely.

TABLE 109–5. Therapy for Native-Valve Endocarditis Due to Strains of Viridans Streptococci and Streptococcus bovis Relatively Resistant to Penicillin G (Minimum Inhibitory Concentration > 0.1 mcg/mL and < 0.5 mcg/mL)a Antibiotic

a

Dosage and Route

Duration (wks)

Aqueous crystalline penicillin G sodium

18 million units/24 h IV either continuously or in six equally divided doses

4

With gentamicin sulfateb

1 mg/kg IM or IV every 8 h

2

Vancomycin hydrochloridec

30 mg/kg per 24 h IV in two equally divided doses, not to exceed 2 g/24 h unless serum levels are monitored

4

Comments Cefazolin or other first-generation cephalosporins may be substituted for penicillin in patients whose penicillin hypersensitivity is not of the immediate type Vancomycin therapy is recommended for patients allergic to β-lactams

Dosages recommended are for patients with normal renal function. For specific dosing adjustment and issues concerning gentamicin, see Table 109–4 footnotes. c For specific dosing adjustment and issues concerning vancomycin, see Table 109–4 footnotes. IV = intravenous; IM = intramuscular. From Wilson WR, Karchmer AW, Dajani AS, et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, and staphylococci, and HACEK microorganisms. JAMA 1995;274:1706–1713, with permission. Copyright 1995–1997, American Medical Association. b

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TABLE 109–6. Therapy for Endocarditis Due to Staphylococcus in the Absence of Prosthetic Materiala Antibiotic Methicillin-Susceptible Staphylococci Regimens for non-β-lactam-allergic patients Nafcillin sodium or oxacillin sodium

Dosage and Route

Duration (wks)

2 g IV every 4 h

4–6

With optional addition of gentamicin sulfate† Regimens for β-lactam-allergic patients Cefazolin (or other first-generation cephalosporins in equivalent dosages)

1 mg/kg IM or IV every 8 h

With optional addition of gentamicinb Vancomycin hydrochloridec

1 mg/kg IM or IV every 8 h 30 mg/kg per 24 h IV in two equally divided doses, not to exceed 2g/24 h unless serum levels are monitored

Methicillin-Resistant Staphylococci Vancomycin hydrochloridec

Comments

Benefit of additional aminoglycosides has not been established

3–5 days

2 g IV every 8 h

4–6

3–5 days 4–6

30 mg/kg per 24 h IV in two equally divided doses, not to exceed 2 g/ 24 h unless serum levels are monitored

Cephalosporins should be avoided in patients with immediate type hypersensitivity to penicillin Recommended for patients allergic to penicillin

4–6

a For treatment of endocarditis due to penicillin-susceptible staphylococci (minimum inhibitory concentration ≤0.1 mcg/mL), aqueous crystalline penicillin G sodium (Table 109-4, first regimen) can be used for 4 to 6 wk instead of nafcillin or oxacillin. Shorter antibiotic courses have been effective in some drug addicts with right-sided endocarditis due to Staphylococcus aureus (see text). See text for comments on use of rifampin. b For specific dosing adjustment and issues concerning gentamicin, see Table 109–4 footnotes. c For specific dosing adjustment and issues concerning vancomycin, see Table 109–4 footnotes. IV = intravenous; IM = intramuscular. From Wilson WR, Karchmer AW, Dajani AS, et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, and staphylococci, and HACEK microorganisms. JAMA 1995;274:1706–1713, with permission. Copyright 1995–1997, American Medical Association.

Subsequent to the most recent publication of the AHA guidelines (1995), the British Society for Antimicrobial Chemotherapy (BSAC) has published treatment recommendations.23 Although derived separately, these recommendations are quite similar to those of the AHA with regard to organism-specific treatment. The only major difference in these two guidelines pertains to empirical treatment of endocarditis. After appropriate blood cultures are obtained, the BSAC guidelines suggest empirical therapy with penicillin plus gentamicin for most patients, but when staphylococcal infection is suspected, they

recommend vancomycin plus gentamicin. Although communityacquired staphylococcal infections rarely are methicillin-resistant, the BSAC guidelines recommend vancomycin for all suspected staphylococcal infections in an attempt to simplify recommendations, at least during the initial phase of treatment. While not specifically mentioned in the BSAC guidelines, a penicillinase-resistant penicillin (e.g., nafcillin) is a reasonable alternative to vancomycin during the short-term empirical treatment of community-acquired infection suspected to be staphylococci while identification and susceptibilities are obtained.

TABLE 109–7. Treatment of Staphylococcal Endocarditis in the Presence of a Prosthetic Valve or Other Prosthetic Materiala Antibiotic

Dosage and Route

Regimen for Methicillin-Resistant Staphylococci 30 mg/kg per 24 h IV in 2 or 4 equally Vancomycin hydrochlorideb divided doses, not to exceed 2 g/24 h unless serum levels are monitored With rifampinc 300 mg orally every 8 h 1 mg/kg IM or IV every 8 h And with gentamicin sulfated,e Regimen for Methicillin-Susceptible Staphylococci Nafcillin sodium or oxacillin 2 g IV every 4 h sodium With rifampinc 300 mg orally every 8 h 1 mg/kg IM or IV every 8 h And with gentamicin sulfated,e

a

Duration (wks)

Comments

≥6 ≥6 2

Rifampin increases the amount of warfarin sodium required for antithrombotic therapy.

≥6

First-generation cephalosporins or vancomycin should be used in patients allergic to β-lactam.

≥6 2

Cephalosporins should be avoided in patients with immediate-type hypersensitivity to penicillin or with methicillin-resistant staphylococci.

Dosages recommended are for patients with normal renal function. For specific dosing adjustment and issues concerning vancomycin, see Table 109–4 footnotes. c Rifampin plays a unique role in the eradication of staphylococcal infection involving prosthetic material (see text); combination therapy is essential to prevent emergence of rifampin resistance. d For specific dosing adjustment and issues concerning gentamicin, see Table 109–4 footnotes. e Use during initial 2 weeks. IV = intravenous; IM = intramuscular. From Wilson WR, Karchmer AW, Dajani AS, et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, and staphylococci, and HACEK microorganisms. JAMA 1995; 274:1706–1713, with permission. Copyright 1995–1997, American Medical Association. b

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TABLE 109–8. Standard Therapy for Endocarditis Due to Enterococcia Antibiotic Aqueous crystalline penicillin G sodium With gentamicin sulfateb Ampicillin sodium With gentamicin sulfateb Vancomycin hydrochloridec With gentamicin sulfateb

Dosage and Route

Duration (wks)

18–30 million units/24 h IV either continuously or in six equally divided doses 1 mg/kg IM or IV every 8 h

4–6

12 g/24 h IV either continuously or in six equally divided doses 1 mg/kg IM or IV every 8 h

4–6

30 mg/kg per 24 h IV in two equally divided doses, not to exceed 2 g/24 h unless serum levels are monitored 1 mg/kg IM or IV every 8 h

4–6

4–6

Comments Four-week therapy recommended for patients with symptoms 3 months in duration

4–6

4–6

Vancomycin therapy is recommended for patients allergic to β-lactams; cephalosporins are not acceptable alternatives for patients allergic to penicillin

a All enterococci causing endocarditis must be tested for antimicrobial susceptibility in order to select optimal therapy (see text). This table is for endocarditis due to gentamicin- or vancomycin-susceptible enterococci, viridans streptococci with a minimum inhibitory concentration of >0.5 mcg/mL, nutritionally variant viridans streptococci, or prosthetic valve endocarditis caused by viridans streptococci or Streptococcus bovis. Antibiotic dosages are for patients with normal renal function. b For specific dosing adjustment and issues concerning gentamicin, see Table 109–4 footnotes. c For specific dosing adjustment and issues concerning vancomycin, see Table 109–4 footnotes. IV = intravenous; IM = intramuscular. From Wilson WR, Karchmer AW, Dajani AS, et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, and staphylococci, and HACEK microorganisms. JAMA 1995; 274:1706–1713, with permission. Copyright 1995–1997, American Medical Association.


STREPTOCOCCAL ENDOCARDITIS Streptococci cause a majority of IE cases, with most isolates being viridans streptococci. Viridans streptococci refer to a large number of different species, such as S. mutans, S. sanguis, and S. mitis. These bacteria are common inhabitants of the human mouth and gingiva, and they are especially common causes of endocarditis involving native valves.1,24 During dental surgery and even when brushing the teeth, these organisms can cause a transient bacteremia. In susceptible individuals, this potentially can result in IE. Streptococcal endocarditis is usually subacute, and the response to medical treatment is good. S. bovis is not a viridans streptococcus, but it is included in this group because it is penicillin sensitive and requires the same treatment as viridans streptococci. S. bovis is a group D Streptococcus that resides in the gastrointestinal tract. IE caused by this organism is often associated with a gastrointestinal pathology, especially colon carcinoma. Endocarditis caused by S. pneumoniae, S. pyogenes, and groups B, C, and G streptococci are relatively uncommon, and their treatment is not well defined.1 Antimicrobial regimens for viridans streptococci are well studied, and in uncomplicated cases, response rates as high as 98% can be

expected. Viridans streptococci are penicillin-susceptible, although some are more susceptible than others. Most are exquisitely sensitive to penicillin G and have minimal inhibitory concentrations (MICs) of less than 0.1 mcg/mL.22,24 Approximately 10% to 20% are moderately susceptible (MIC 0.1–0.5 mcg/mL). This difference in in vitro susceptibility led to recommendations that the MIC be determined for all viridans streptococci and that the results be used to guide therapy. Some streptococci are deemed tolerant to the killing effects of penicillin, where the MBC exceeds the MIC by 32 times. A tolerant organism is inhibited but not killed by an antibiotic normally considered bactericidal.25 Bactericidal activity is required for successful treatment of IE; therefore, infections with a tolerant organism may relapse after treatment. Despite some animal studies of endocarditis suggesting that tolerant strains do not respond as readily to β-lactam therapy as nontolerant ones, this phenomenon is primarily a laboratory finding with little clinical significance.26 Treatment for tolerant strains is identical to that for nontolerant organisms, and measurement of the MBC is not recommended.22,23 An assortment of regimens can be used to treat uncomplicated endocarditis caused by fully susceptible viridans streptococci (see Table 109–4). Two single-drug regimens consist of either

TABLE 109–9. Therapy for Endocarditis Due to HACEK Microorganisms (Haemophilus parainfluenzae, Haemophilus aphrophilus, Actinobacillus actinomycetemocomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae)a Antibiotic

Duration (wks)

Ceftriaxone sodium

2 g once daily IV or IMb

4

Ampicillin sodiumc

12 g/24 h IV either continuously or in six equally divided doses 1 mg/kg IM or IV every 8 h

4

With gentamicin sulfated a

Dosage and Route

Comments Cefotaxime sodium or other third-generation cephalosporins may be substituted

4

Antibiotic dosages are for patients with normal renal function. Patients should be informed that IM injection of ceftriaxone is painful. Ampicillin should not be used if laboratory tests show β-lactamase production. d For specific dosing adjustment and issues concerning gentamicin, see Table 109–4 footnotes. IV = intravenous; IM = intramuscular. From Wilson WR, Karchmer AW, Dajani AS, et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, and staphylococci, and HACEK microorganisms. JAMA 1995; 274:1706–1713, with permission. Copyright 1995–1997, American Medical Association. b c

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high-dose parenteral penicillin G or ceftriaxone for 4 weeks. If a shorter course of therapy is desired, the guidelines suggest highdose parenteral penicillin G plus an aminoglycoside.22 When used in select patients, this combination is equally effective to 4 weeks of penicillin alone. Although streptomycin was listed in previous guidelines, gentamicin is the preferred aminoglycoside because serum drug concentrations are obtained easily, clinicians are more familiar with its use, and the few strains of streptococci resistant to the effects of streptomycin-penicillin remain susceptible to gentamicin-penicillin. Other aminoglycosides are not recommended. The decision of which regimen to use depends on the perceived risk versus benefit. For example, a 2-week course of gentamicin in an elderly patient with renal impairment may be associated with ototoxicity, worsening renal function, or both. Furthermore, the 2-week regimen is not recommended for patients with complications such as extracardiac foci. On the other hand, a 4-week course of penicillin alone generally entails greater expense, especially if the patient remains in the hospital. Monotherapy with once-daily ceftriaxone offers ease of administration, facilitates home health care treatment, and may be cost-effective.27 The BSAC guidelines suggest that all the following conditions be present to consider a 2-week treatment regimen for penicillinsensitive streptococcal endocarditis23,28 : r r r r r r

Penicillin-sensitive viridans streptococcus or S. bovis (penicillin MIC < 0.1 mcg/mL) No cardiovascular risk factors such as heart failure, aortic insufficiency, or conduction abnormalities No evidence of thromboembolic disease Native-valve infection No vegetation of greater than 5 mm diameter on echocardiogram Clinical response within 7 days (The temperature should return to normal, the patient should feel well, and the patient’s appetite should return to normal.)

9 When a patient has a history of an immediate-type hypersen-

sitivity to penicillin, vancomycin is the drug of choice for IE caused by viridans streptococci. When vancomycin is chosen, the addition of gentamicin is not recommended.22 First-generation and some third-generation cephalosporins (ceftriaxone) are alternatives in patients with a history of delayed penicillin reactions. Most patients who report a penicillin allergy have a negative penicillin skin test and consequently are at low risk of anaphylaxis.29 The published experience with penicillin is more extensive than with alternative regimens; therefore, a thorough allergy history must be obtained before a second-line therapy is administered. In patients with complicated infections (e.g., extracardiac foci) or when the streptococcus has an MIC of 0.1–0.5 mcg/mL, combination therapy with an aminoglycoside and penicillin (higher dose preferred) for the first 2 weeks, followed by penicillin alone for an additional 2 weeks, is recommended22 (see Table 109–5). Some viridans streptococci have biologic characteristics that complicate diagnosis and treatment. For example, a few bacteria have nutritional deficiencies that hinder growth in routine culture media.2 These organisms require special broth supplemented with pyridoxal hydrochloride or cysteine. For patients infected with nutritionally variant streptococc,i or when the Streptococcus has an MIC of more than 0.5 mcg/mL, treatment should follow the enterococcal endocarditis treatment guidelines22 (see Table 109–8). The rationale for combination therapy of penicillin-susceptible viridans streptococci is that enhanced activity against these organisms

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usually is observed when cell wall active agents are combined with aminoglycosides in vitro.22,26 Combined treatment results in quicker sterilization of vegetations in animal models of endocarditis and probably explains the high response rates observed in patients treated for a total of 2 weeks.22 The combined treatment, however, is not superior to penicillin alone. For IE caused by streptococci relatively resistant to penicillin (MIC of 0.1–0.5 mcg/mL), combination therapy for 2 weeks is recommended, followed by penicillin alone for 2 additional weeks.22,24 Some authors question the need for combination therapy for such relatively resistant streptococci, emphasizing that few human data suggest that patients with endocarditis caused by these organisms respond less well to penicillin alone.30 Whether or not extended-interval aminoglycoside dosing has a role in IE is controversial. This dosing approach, as compared with thrice-daily dosing, appears to have an equal and possibly greater efficacy in streptococcal endocarditis.31−34 One study specifically evaluated the combination of ceftriaxone (2 g daily) with gentamicin (3 mg/kg daily) for 2 weeks compared with ceftriaxone (2 g daily) alone for 4 weeks for penicillin-sensitive streptococci. Both regimens were safe and effective with similar clinical cure rates at 3 months following treatment.35


STAPHYLOCOCCAL ENDOCARDITIS Endocarditis caused by staphylococci is becoming more prevalent, mainly because of increased IVDA, more frequent use of peripheral and central venous catheters, and increased frequency of valve replacement surgery.36,37 Staphylococcus aureus is the most common organism causing IE among those with IVDA and persons with venous catheters. Coagulase-negative staphylococci (usually S. epidermidis) are prominent causes of PVE. Staphylococcal endocarditis is not a homogeneous disease; appropriate management requires consideration of several questions, such as, Is the organism methicillin resistant? Should combination therapy be used? Is the infection on a native or prosthetic valve? Does the patient have a history of IVDA? Is the infection on the left or right side of the heart? Another consideration in staphylococcal endocarditis is that some organisms may exhibit tolerance to antibiotics. However, similar to streptococci, the concern for tolerance among staphylococci should not affect antibiotic selection.22 Any patient who develops staphylococcal bacteremia is at risk for endocarditis. Many investigators have attempted to develop criteria that identify the bacteremic patient likely to have IE.37 In hospitalized patients with S. aureus bacteremia and an identified focus of infection, such as a vascular catheter, the risk of concomitant IE is low, and treatment of the bacteremia can be reduced to 2 weeks. This approach applies only if the patient does not have a prosthetic valve or additional clinical evidence for endocarditis.36,37 On the other hand, the following parameters predict higher risk of IE in patients with S. aureus bacteremia: (1) the absence of a primary site of infection, (2) community acquisition of infection, (3) metastatic signs of infection, and (4) valvular vegetations detected by echocardiography.1,4 The recommended therapy for patients with left-sided IE caused by methicillin-sensitive S. aureus (MSSA) is 4 to 6 weeks of nafcillin or oxacillin, often combined with a short course of gentamicin (see Table 109–6). From in vitro studies, the combination of an aminoglycoside and penicillinase-resistant penicillin or vancomycin enhances the activity of these drugs toward MSSA. In animal models of endocarditis, combinations of penicillin with an aminoglycoside eradicate organisms from vegetations more rapidly than penicillins

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alone.36 In human studies, the addition of an aminoglycoside to nafcillin for the first week of therapy hastens the resolution of fever and bacteremia, but it does not affect survival or relapse rates.38 Traditional thrice-daily dosing of aminoglycosides is recommended when administered for staphlococcal IE, albeit initial data have evaluated gentamicin given once a day.39 If a patient has a mild, delayed allergy to penicillin, firstgeneration cephalosporins (such as cefazolin) are effective alternatives, but they should be avoided in patients with a history of immediate-type hypersensitivity reactions to penicillins (see Table 109–6). The potential for a true immediate-type allergy should be assessed carefully, and a penicillin skin test should be conducted before giving antibiotic treatment to any patient claiming an allergy.40 9 In a patient with a positive skin test or a history of immediate hypersensitivity to penicillin, vancomycin is the agent of choice. Vancomycin, however, kills S. aureus slowly and is regarded as inferior to penicillinase-resistant penicillins for MSSA.37 Rifampin as an adjunctive therapy is controversial; however, this agent, added to vancomycin in refractory or complicated infections in patients with left-sided IE may result in dramatic patient improvement.36,37 Generally, antibiotic therapy should be continued for 4 to 6 weeks. Unfortunately, left-sided IE caused by S. aureus continues to have a poor prognosis, with a mortality rate of 25% to 47%.16,22 For reasons discussed in the following section, those with IE associated with IVDA have a more favorable response to therapy. During the past decade, greater numbers of staphylococci became resistant to penicillinase-resistant penicillins (e.g., methicillin). 9 Vancomycin is the drug of choice for these resistant organisms because most MRSAs and coagulase-negative staphylococci are susceptible to it (see Table 109–6). The presence or lack of a prosthetic heart valve in patients with a methicillin-resistant organism guides therapy and determines whether vancomycin should be used alone or, if a prosthetic valve is present, whether combination therapy is necessary3,22 (see Table 109–7).


Staphylococcus Endocarditis: Intravenous Drug Abuser Infective endocarditis in those with IVDA is frequently (60% to 70%) caused by S. aureus, although other organisms may be common in certain geographic locations.41 In this setting, the tricuspid valve is frequently infected, resulting in right-sided IE. Most patients have no history of valve abnormalities, are usually otherwise healthy, and have a good response to medical treatment. Nonetheless, surgery may be required. Standard treatment for MSSA endocarditis is 4 weeks of monotherapy with a penicillinase-resistant penicillin (see Table 109–6). In the intravenous drug abuser, however, the clinical response with right-sided MSSA endocarditis is usually excellent. Emerging data suggest that these patients may be treated effectively (clinical and microbiologic cure exceeding 90%) with a 2-week course of nafcillin or oxacillin plus an aminoglycoside.41−47 Short-course vancomycin, in place of nafcillin or oxacillin, appears to be ineffective.45 Another trial suggested that a 2-week regimen of a penicillinase-resistant penicillin alone, without the addition of an aminoglycoside, is as effective as combined therapy in MSSA tricuspid valve endocarditis.48 Although these data suggest that an aminoglycoside is unnecessary for short-course treatment in the intravenous drug abuser with rightsided IE, most clinicians are uncomfortable with monotherapy and choose combination treatment in this situation so long as there are

no reasons to avoid an aminoglycoside. Short-course therapy should not be used in left-sided endocarditis, and it is inappropriate in patients with underlying acquired immunodeficiency syndrome (AIDS) or substantial pulmonary complications, such as lung abscess from right-sided IE.22 An intriguing therapeutic approach for staphylococcal endocarditis in those with IVDA is oral treatment. Preliminary data have suggested that short-course intravenous treatment (primarily nafcillin, mean 16 days) followed by oral treatment (dicloxacillin or oxacillin, mean 26 days) might be effective for tricuspid valve MSSA endocarditis.49 The positive results of this trial can be explained by the duration of intravenous antibiotics (>2 weeks), which may be a sufficient treatment course in this patient population. Yet two other studies that predominantly used oral therapy (ciprofloxacin and rifampin) found this approach to be effective (cure rates exceeding 90%) in addicts with uncomplicated right-sided endocarditis caused by MSSA.50,51 At this time, concerns with resistance (e.g., ciprofloxacin) and limited published data preclude routine use of oral antibacterial regimens for the treatment of IE in the intravenous drug abuser. CLINICAL CONTROVERSY Oral antibiotics for the treatment of IE have been assessed primarily in those with IVDA. Although treating IE with oral antibiotics would decrease adverse events associated with prolonged use of intravenous catheters (e.g., infection, septic thrombus), the paucity of data preclude this being a routine treatment.


Staphylococcal Endocarditis: Prosthetic Valves PVE accounts for approximately 15% of all IE cases.52 An episode of PVE occurring within 2 months of surgery strongly suggests that the cause is staphylococci implanted during the procedure.3 Yet the risk of staphylococcal endocarditis remains elevated for up to 12 months after 9 valve replacement. Because this type of IE is typically a nosocomial infection, methicillin-resistant organisms are common, and vancomycin is the cornerstone of therapy. Combination antimicrobials are recommended because of the high morbidity and mortality associated with PVE and its refractoriness to therapy.3,22 Although the addition of rifampin to a penicillinase-resistant penicillin or vancomycin does not result in predictable bacterial synergism, rifampin may have unique activity against staphylococcal infection that involves prosthetic material, where its addition results in a higher microbiologic cure rate.2 Combination therapy also decreases the emergence of resistance to rifampin, which frequently occurs when it is used alone. For methicillin-resistant staphylococci (both MRSA and coagulasenegative staphylococci), vancomycin is recommended with rifampin for 6 weeks or more (see Table 109–7). An aminoglycoside is added for the first 2 weeks if the organism is aminoglycoside-susceptible. For MSSA, a penicillinase-resistant penicillin is administered in place of vancomycin. PVE responds poorly to medical treatment and has a higher mortality compared with native-valve endocarditis. Valve dehiscence and incompetence can result in acute heart failure, and surgery is often a component of treatment.3 After 12 months, the likely organism for PVE parallels that of native-valve endocarditis. As with native-valve endocarditis, antimicrobial therapy should be based on the identified organism and

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in vitro susceptibility. If an organism is identified other than staphylococci, the treatment regimen should be guided by susceptibilities and should be at least 6 weeks in duration.3,23 Additionally, a concomitant aminoglycoside is recommended if streptococci or enterococci are identified. Once-daily aminoglycoside regimens have not been evaluated in PVE and are not recommended.3 The use of anticoagulation is controversial in PVE. Those who require anticoagulation for prosthetic valves should continue the anticoagulant cautiously during endocarditis therapy, unless a contraindication to therapy exists.


ENTEROCOCCAL ENDOCARDITIS Enterococci are normal inhabitants of the human gastrointestinal tract and, occasionally, of the anterior urethra. These organisms are usually of low virulence but can become a pathogen in predisposed patients following genitourinary manipulations (older men) or obstetric procedures (younger women).2 Historically, enterococci were considered group D streptococci, but they have been reclassified into the genus Enterococcus (E. faecalis and E. faecium). E. faecalis is the most common clinical isolate (approximately 90%) of the two species. Enterococci cause 5% to 18% of endocarditis cases, but they are more resistant to therapy than staphylococci and streptococci. Enterococci are noteworthy for these reasons: (1) no single antibiotic is bactericidal, (2) MICs to penicillin are relatively high (1– 25 mcg/mL), (3) intrinsic resistance occurs to all cephalosporins and relative resistance occurs to aminoglycosides (e.g., “low level” aminoglycoside resistance), (4) combinations of a cell wall active agent such as a penicillin or vancomycin and an aminoglycoside are necessary for killing, and (5) resistance to all available drugs is increasing.1,22,53 Monotherapy with penicillin for IE caused by enterococci results in relapse rates of 50% to 80%. When used alone, penicillins are only bacteriostatic against enterococci, and combination therapy is always recommended for susceptible strains.53 The relapse rate following penicillin-gentamicin therapy for susceptible strains is less than 15%.13 The killing of enterococci by the bactericidal combination of an aminoglycoside and a penicillin is the best clinical example of antibiotic synergy. Because the aminoglycoside cannot penetrate the bacterial cell in the absence of the penicillin, enterococci usually will appear to be resistant to aminoglycosides by routine susceptibility testing (low-level resistance). However, in the presence of an agent that disrupts the cell wall such as penicillin, the aminoglycoside can gain entry, attach to bacterial ribosomes, and cause rapid cell death. An aminoglycoside-vancomycin combination is also synergistic against enterococci and is appropriate therapy for the penicillinallergic patient.54 Enterococcal endocarditis ordinarily requires 4 to 6 weeks of high-dose penicillin G or ampicillin plus an aminoglycoside for cure (see Table 109–8). Ampicillin has greater in vitro activity than penicillin G, although there are no clinical data to document differences in efficacy. A 6-week course is recommended for patients with symptoms lasting longer than 3 months, recurrent cases, and those with mitral valve involvement. Streptomycin has been the most extensively studied aminoglycoside, but gentamicin is presently favored. Other aminoglycosides cannot be substituted routinely. In the treatment of enterococcal endocarditis, relatively low serum concentrations of aminoglycosides appear adequate for successful therapy, such as a gentamicin peak concentration of approximately 3 mcg/mL.55 Even though the most recent treatment guidelines advocate this

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low-peak-concentration approach, it is debated as to whether this is suitable because it has not been well documented to be equally or more efficacious than higher-serum-concentration approaches.56 Treatment of enterococcal endocarditis does not have the high success rate seen with IE caused by viridans streptococci presumably because the organism is more resistant to killing. Although some data support the use of extended-interval aminoglycoside dosing for other types of endocarditis (i.e., streptococci), the data are more vague regarding this strategy in enterococcal IE.57 While some studies suggest that extended-interval aminoglycoside dosing and short-interval (traditional) dosing are clinically equivalent,58−60 discordant studies imply otherwise.61,62 The paucity of human data precludes routine use of extended-interval aminoglycoside dosing in this setting. Resistance among enterococci to penicillins and aminoglycosides is increasing.53 Enterococci that exhibit high-level resistance to streptomycin (MIC > 2000 mcg/mL) are not synergistically killed by penicillin and streptomycin because the aminoglycoside either no longer binds to the ribosome or is inactivated by an aminoglycosidemodifying enzyme, streptomycin adenylase. Because enterococci will appear resistant to aminoglycosides on routine susceptibility testing, the only way to distinguish high-level from low-level resistance is by performing special susceptibility tests using 500– 2000 mcg/mL of the aminoglycoside. High-level streptomycinresistant enterococci occur with a frequency of 40% to 50%, and high-level resistance to gentamicin is now found in 10% to 50% of isolates. Although most gentamicin-resistant enterococci are resistant to all aminoglycosides (including amikacin), 30% to 50% remain susceptible to streptomycin.53 High-level gentamicin resistance is mediated by a bifunctional aminoglycoside-modifying enzyme, 6 -acetyltransferase/2 -phosphotransferase, and most strains also possess streptomycin adenylase. These organisms do not commonly cause IE; data on appropriate therapy are sparse, and therapeutic options are few. Case reports indicate that some patients will respond to high doses of ampicillin, as observed in the early trials of penicillin monotherapy.63 In addition to isolates with high-level aminoglycoside resistance, β-lactamase-producing enterococci (especially E. faecium) have been reported.64 If these organisms are discovered, use of vancomycin or ampicillin-sulbactam should be considered. VRE are reported increasingly, primarily with E. faecium. Vancomycin resistance occurs when the bacterium replaces the normal vancomycin target with a peptidoglycan precursor that does not bind vancomycin.65 Combination therapies including teicoplanin, quinupristin-dalfopristin, or linezolid appear to be the most promising treatments.


LESS COMMON TYPES OF INFECTIVE ENDOCARDITIS
HACEK Group Gram-negative bacteria from the HACEK group (Hemophilus parainfluenzae, H. aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterum hominis, Eikenella corrodens, and Kingella kingae) are unusual causes of IE. Frequently, these types of IE present as subacute illnesses with large vegetations and emboli.66 These oropharyngeal organisms typically are slow growing and should be considered as possible causes of “culture negative” endocarditis. Ceftriaxone or high-dose ampicillin with gentamicin for 4 weeks is the recommended therapy, although ceftriaxone may be preferred22 (see Table 109–9). Valve replacement is required occasionally.

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Culture-Negative Endocarditis Sterile blood cultures are reported in up to 5% of patients with IE if strict diagnostic criteria are used.1,5,67 This type of IE may occur as a result of unidentified subacute right-sided IE, previous antibiotic therapy, slow-growing fastidious organisms, nonbacterial etiologies (e.g., fungi), and improperly collected blood cultures. When blood cultures from patients suspected of IE show no growth after 48 to 72 hours, the laboratory should be advised and cultures held for up to a month to detect growth of fastidious organisms. Clinicians should individualize therapy for culture-negative IE. In patients without a history of IVDA, culture-negative IE treatment usually will follow an approach that encompasses treatment for enterococci, the HACEK group, and nutritionally variant streptococci. Although controversial, one source recommends penicillin or ampicillin, an aminoglycoside (e.g., gentamicin), and ceftriaxone. In the intravenous drug abuser in whom staphylococci are suspected, a penicillinase-resistant penicillin or a cephalosporin with activity against staphylococci could be added to the preceding regimen.1 Therapy for PVE often includes at least vancomycin and gentamicin.5 Irrespective of the treatment chosen, extended antimicrobial therapy is required (e.g., 6 weeks), although the aminoglycoside may be removed after 2 weeks if clinical improvement is observed. The preceding empirical approaches to culture-negative IE highlight the need for proper collection and monitoring of blood cultures and an extensive medication history.


Other Atypical Microorganisms Endocarditis caused by organisms such as Coxiella burnetii; Brucella, Candida, and Aspergillus spp.; Legionella; and gram-negative bacilli (e.g., Pseudomonas) is relatively uncommon. Medical therapy for IE caused by these organisms is usually unsuccessful.5 Readers are referred elsewhere for an in-depth discussion regarding the management of unusually encountered organisms.4 Consultation with an infectious disease expert is warranted when these microorganisms are identified. Patients at higher risk of gram-negative bacilli IE include intravenous drug abusers and those with prosthetic heart valves. In addition to Pseudomonas spp., other gram-negative bacilli that have been implicated include Salmonella spp., Escherichia coli, Citrobacter spp., Klebsiella-Enterobacter spp., S. marcescens, Proteus spp., and Providencia spp.1 Generally, these infections have a poor prognosis, with mortality rates as high as 60% to 80%.16 Valve replacement is considered mandatory for left-sided pseudomonal IE.4 If medical management is implemented, large doses of a penicillin with activity

PHARMACOECONOMIC CONSIDERATIONS IE remains an uncommon disease, but the cost of treatment can be substantial. In the past, the long duration of hospitalization required to administer intravenous antimicrobials was the major expense. In selected cases, abbreviated, outpatient, and possibly in the future oral antimicrobial therapy may appreciably reduce the cost of care. Shorter-course antimicrobial regimens are advocated when possible. For instance, in exquisitely sensitive streptococcal endocarditis (MICs < 0.1 mcg/mL), a 2-week regimen of high-dose parenteral penicillin G in combination with an aminoglycoside is as effective as 4 weeks of penicillin alone.22,23 Uncomplicated right-sided MSSA endocarditis in the intravenous drug abuser also may be treated with

toward Pseudomonas (e.g., piperacillin 18 g/day) with an aminoglycoside are necessary for an extended period (e.g., 6 weeks).1,4 Higher doses of the aminoglycoside (e.g., 8 mg/kg per day) may improve the survival rates of Pseudomonas IE, especially when combined with surgery.66,68 All cases of Legionella IE have had an extended febrile course over months and high anti-Legionella antibody titers and have occurred in patients with prosthetic valves.4 When special media are used, blood cultures will reveal this organism. Prolonged parenteral therapy with either doxycycline or erythromycin, with prolonged oral therapy (e.g., 6 to 17 months), has elicited cure in some patients.4 Most patients require concomitant valve replacement. Fungi cause between 2% and 4% of endocarditis cases; most patients with fungal endocarditis have undergone recent cardiovascular surgery, are intravenous drug abusers, have received prolonged treatment with intravenous catheters or antibiotics, or are immunocompromised.1,2,69 Candida spp. and Aspergillus spp. are most commonly involved, and the mortality rate is high for these reasons: (1) large, bulky vegetations that often form, (2) systemic septic embolization that may occur, (3) the tendency for fungi to invade the myocardium, (4) poor penetration of vegetations by antifungals, (5) the low toxic:therapeutic ratio of agents such as amphotericin B, and (6) the lack of consistent fungicidal activity of available antifungal agents.1,70 When fungal IE is identified, the combined medicalsurgical approach is recommended. Because these infections occur infrequently, scant clinical data are available to make solid treatment recommendations; however, the use of antifungal agents alone has been globally unsuccessful. Amphotericin B is the mainstay pharmacologic approach with the possible addition of flucytosine. The usefulness of fluconazole and itraconazole remains unknown at this time, although high-dose itraconazole may be of worth in Aspergillus endocarditis, and fluconazole has had limited success in Candida IE. Coxiella burnetii (Q fever) just recently has been recovered from blood cultures, but infection is more likely to be identified via serologic tests. It is a common cause of IE in certain areas of the world where goat, cattle, and sheep farming are widespread. The most favorable therapy for Q fever is unknown but may include doxycycline with trimethoprim-sulfamethoxazole, rifampin, or fluoroquinalones.4 Brucella are facultative intracellular gram-negative bacilli. Humans are infected by this organism after ingesting infected unpasteurized milk or undercooked meat, inhalation of infectious aerosols, or contact with infected tissues. This type of IE is more common in veterinarians and livestock handlers. Cure requires valve replacement and antimicrobial agents including doxycycline with streptomycin or gentamicin or doxycycline with trimethoprim-sulfamethoxazole or rifampin for an extended period (8 weeks to months).4

a 2-week course. Treatment with nafcillin or oxacillin in combination with an aminoglycoside appears to be cost-effective. The initiation of outpatient parenteral antibiotics should be considered early in the treatment of IE, after the patient is stable clinically and responds favorably to initial antibiotics. Outpatient treatment has been demonstrated to be safe and effective in select situations.71 Patients considered for home therapy must be hemodynamically stable, compliant with therapy, have careful medical monitoring, understand the potential complications of the disease, and have immediate access to medical care. Advances in technology allow for the outpatient administration of complex antibiotic regimens that significantly reduce the cost of therapy. Simple regimens, such as single daily doses of ceftriaxone for streptococcal IE, are particularly attractive. Although

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endocarditis is common in those with a history of IVDA, and home health care would substantially reduce the cost of treatment, many clinicians are uncomfortable with outpatient intravenous therapy because central venous access is required. Sudden cardiac decompensation in an outpatient setting is also of concern.

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This test may be useful when the causative organisms are only moderately susceptible to antimicrobials, when less well-established regimens are used, or when response to therapy is suboptimal and dosage escalation is being considered.

SERUM DRUG CONCENTRATIONS EVALUATION OF THERAPEUTIC OUTCOMES The evaluation of patients treated for IE includes assessment of disease signs and symptoms, blood cultures, microbiologic tests, serum drug concentrations, and other tests that evaluate organ function.

SIGNS AND SYMPTOMS Fever usually subsides within 1 week of initiating therapy.1,2 Persistence of fever may indicate ineffective antimicrobial therapy, emboli, infections of intravascular catheters, or drug reactions. In some patients, low-grade fever may persist even with appropriate antimicrobial therapy. With defervescence, the patient should begin to feel better, and other symptoms, such as lethargy or weakness, should subside.

BLOOD CULTURES Blood cultures should be negative within a few days, although microbiologic response to vancomycin may be slower.1,2 If bacteria continue to be isolated from blood beyond the first few days of therapy, it may indicate that the antimicrobials are inactive against the pathogen or that the doses are not producing adequate concentrations at the site of infection. After the initiation of therapy, blood cultures should be rechecked until negative. During the remainder of therapy, frequent blood culturing is not necessary. Additional blood cultures should be rechecked after successful treatment (e.g., once or twice within the 8 weeks after treatment) to ensure cure.

MICROBIOLOGIC TESTS For all isolates from blood cultures, MICs should be determined; MBCs are no longer recommended.22,23 The agent currently being used should be tested, as well as alternatives that may be required if intolerance, allergy, or resistance occurs. Occasionally, it is useful to determine whether synergy exists for antimicrobial combinations, although synergistic regimens usually can be predicted from the literature. Methods for in vitro determinations of synergy are summarized in Chap. 103. Serum bactericidal titers (SBTs; also called Schlicter tests) have been used in the past in association with a number of infectious diseases.72,73 The SBT is the greatest dilution of a patient’s serum sample that is obtained while receiving antimicrobial treatment that kills greater than 99.9% of an inoculum of the infecting pathogen in vitro over 18 to 24 hours. In animal models of endocarditis, studies suggest that an SBT of 1:8 is predictive of response.18 In humans with endocarditis, however, the correlation with SBTs and outcome is not clear. One investigation found peak and trough SBT ratio of 1:64 or greater and 1:32 predicted cure, although a lower titer did not predict failure.74 Serum bactericidal titers of 1:32 are achieved easily for most streptococci causing endocarditis because the MBC is low relative to achievable concentrations of penicillin; however, for enterococci, methicillin-resistant staphylococci, and gram-negative bacilli, high SBTs may be difficult to achieve. At present, SBTs have little value in monitoring treatment of common types of IE and should not be recommended routinely.22,23

Of the agents used commonly for IE, measurement of serum drug concentrations is routinely available for aminoglycosides (except streptomycin) and vancomycin. Few data, however, support attaining any specific serum concentrations in patients with IE. In general, serum concentrations of the antimicrobial should exceed the MBC of the organisms, but in practice, this principle is usually not helpful in monitoring patients with endocarditis. Aminoglycoside concentrations rarely exceed the MBC for certain organisms, such as streptococci and enterococci, and concentrations have not been correlated with response, such as aminoglycosides and vancomycin for staphylococci.74,75 When aminoglycosides are administered for IE caused by grampositive cocci with a traditional thrice-daily regimen, peak serum concentrations are recommended to be on the low side of the traditional ranges (3 mcg/mL for gentamicin). If extended-interval dosing is used, which is not a standard practice at this time, the most appropriate method of monitoring has not been determined. When vancomycin is administered, the most recent treatment guidelines (1995) recommend serum drug monitoring.22 Although the guidelines recommend to obtain peak serum concentrations when using vancomycin, measuring peak concentrations has limited applicability. The primary goal of serum vancomycin monitoring clinically is to ensure that there are adequate trough concentrations when treating resistant organisms.

TABLE 109–10. Cardiac Conditions Associated with Endocarditis Endocarditis Prophylaxis Recommended High-risk category Prosthetic cardiac valves, including bioprosthetic and homograft valves Previous bacterial endocarditis Complex cyanotic congenital heart disease (e.g., single ventricle states, transposition of the great arteries, tetralogy of Fallot) Surgically constructed systemic pulmonary shunts or conduits Moderate-risk category Most other congenital cardiac malformations (other than above and below) Acquired valvular dysfunction (e.g., rheumatic heart disease) Hypertrophic cardiomyopathy Mitral valve prolapse with valvar regurgitation and/or thickened leaflets Endocarditis Prophylaxis Not Recommended Negligible-risk category (no greater risk than the general population) Isolated secundum atrial septal defect Surgical repair of atrial septal defect, ventricular septal defect, or patent ductus arteriosus (without residua beyond 6 mo) Previous coronary artery bypass graft surgery Mitral valve prolapse without valvar regurgitation Physiologic, functional, or innocent heart murmurs Previous Kawasaki disease without valvar dysfunction Previous rheumatic fever without valvar dysfunction Cardiac pacemakers (intravascular and epicardial) and implanted defibrillators From Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: Recommendations by the American Heart Association. JAMA 1997;277:1794– 1801, with permission. Copyright 1995–1997, American Medical Association.

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TABLE 109–11. Dental Procedures and Endocarditis Prophylaxis

TABLE 109–12. Other Procedures and Endocarditis Prophylaxis

Endocarditis Prophylaxis Recommendeda Dental extractions Periodontal procedures including surgery, scaling and root planing, probing, and recall maintenance Dental implant placement and reimplantation of avulsed teeth Endodontic (root canal) instrumentation or surgery only beyond the apex Subgingival placement of antibiotic fibers or strips Initial placement of orthodontic bands but not brackets Intraligamentary local anesthetic injections Prophylactic cleaning of teeth or implants where bleeding is anticipated Endocarditis Prophylaxis Not Recommended Restorative dentistryb (operative and prosthodontic) with or without retraction cordc Local anesthetic injections (nonintraligamentary) Intracanal endodontic treatment; after placement and buildup Placement of rubber dams Postoperative suture removal Placement of removable prosthodontic or orthodontic appliances Taking of oral impressions Fluoride treatments Taking of oral radiographs Orthodontic appliance adjustment Shedding of primary teeth

Endocarditis Prophylaxis Recommended Respiratory tract Tonsillectomy and/or adenoidectomy Surgical operations that involve respiratory mucosa Bronchoscopy with a rigid bronchoscope Gastrointestinal tracta Sclerotherapy for esophageal varices Esophageal stricture dilation Endoscopic retrograde cholangiography with biliary obstruction Biliary tract surgery Surgical operations that involve intestinal mucosa Genitourinary tract Prostatic surgery Cystoscopy Urethral dilation Endocarditis Prophylaxis Not Recommended Respiratory tract Endotracheal intubation Bronchoscopy with a flexible bronchoscope, with or without biopsyb Tympanostomy tube insertion Gastrointestinal tract Transesophageal echocardiographyb Endoscopy with or without gastrointestinal biopsyb Genitourinary tract Vaginal hysterectomyb Vaginal deliveryb Cesarean section In uninfected tissue Urethral catheterization Uterine dilation and curettage Therapeutic abortion Sterilization procedures Insertion or removal of intrauterine devices Other Cardiac catheterization, including balloon angioplasty Implanted cardiac pacemakers, implanted defibrillators, and coronary stents Incision or biopsy of surgically scrubbed skin Circumcision

a Prophylaxis is recommended for patients with high- and moderate-risk cardiac conditions. b This includes restoration of decayed teeth (filling cavities) and replacement of missing teeth. c Clinical judgment may indicate antibiotic use in selected circumstances that may create significant bleeding. From Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: Recommendations by the American Heart Association. JAMA 1997;277:1794– 1801, with permission. Copyright 1995–1997, American Medical Association.

PREVENTION 10 Antimicrobial prophylaxis is used as an attempt to prevent IE in

patients at high risk.76,77 The use of antimicrobials for this purpose requires consideration of (1) cardiac conditions associated with endocarditis, (2) procedures causing bacteremia, (3) organisms likely to cause endocarditis, and (4) pharmacokinetics, spectrum, cost, adverse effects, and ease of administration of available antimicrombial agents. The objective of prophylaxis is to diminish the likelihood of IE in high-risk individuals (Table 109–10) who are undergoing procedures that cause transient bacteremia (Tables 109–11 and 109–12). Although there are no prospective, controlled human trials demonstrating that prophylaxis in high-risk individuals protects against the development of endocarditis during bacteremia-induced procedures, animal studies suggest possible benefit.78 Most causes of IE, however, appear not to be secondary to an invasive procedure. Bacteremia as a consequence of daily activities in fact may be the major culprit, and the value of antibiotic prophylaxis before bacteremia-causing procedures has been questioned.79 Retrospective human studies, though, support that a reduction of endocarditis occurs in selected patients following dental surgery where prophylaxis is employed.80 The common practice of using antimicrobal therapy in this setting remains controversial. The mechanism of a beneficial effect in humans is unclear, but antibiotics may decrease the number of bacteria at the surgical site, kill bacteria after they are introduced into the blood, and prevent adhesion of bacteria to the valve. Studies have found that prophylaxis

a Prophylaxis is recommended for high-risk patients; optional for medium-risk patients. b Prophylaxis is optional for high-risk patients. From Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: Recommendations by the American Heart Association. JAMA 1997;277:1794– 1801, with permission. Copyright 1995–1997, American Medical Association.

does not reduce the frequency of bacteremia immediately following tooth extraction as compared with a control group, suggesting that a reduction in adhesion or effects after the bacteria adhere to the endocardium are more likely mechanisms.81,82 Other studies have further questioned the benefit of antibiotic prophylaxis.83 CLINICAL CONTROVERSY The common practice of administering antibiotics to high-risk individuals before a bacteremia-causing procedure is controversial. Despite limited data supporting this approach and the fact that 100% compliance with AHA preventative guidelines would have only a modest benefit, the use of single-dose antibiotics for the prevention of endocarditis remains a standard of care.

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TABLE 109–13. Prophylactic Regimens for Dental, Oral, Respiratory Tract, or Esophageal Procedures Situation

Regimena

Agent

Standard general prophylaxis Unable to take oral medications

Amoxicillin Ampicillin

Allergic to penicillin

Clindamycin or Cephalexinb or cefadroxilb or Azithromycin or chlarithromycin Clidamycin or Cefazolinb

Allergic to penicillin and unable to take oral medications

Adults: 2 g; children: 50 mg/kg orally 1 h before procedure Adults: 2 g intramuscularly (IM) or intravenously (IV); children: 50 mg/kg IM or IV within 30 min before procedure Adults: 600 mg; children: 20 mg/kg orally 1 h before procedure Adults: 2 g; children: 50 mg/kg orally 1 h before procedure

Adults: 500 mg; children: 15 mg/kg orally 1 h before procedure Adults: 600 mg; children: 20 mg/kg IV within 30 min before procedure Adults 1 g; children: 25 mg/kg IM or IV within 30 min before procedure

a

Total children’s dose should not exceed adult dose. Cephalosporins should not be used in individuals with immediate-type hypersensitivity reaction (urticaria, angioedema, or anaphylaxis) to penicillins. From Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: Recommendations by the American Heart Association. JAMA 1997;277:1974–1801, with permission. Copyright 1995–1997, American Medical Association. b

PATIENTS AT RISK Patients with certain cardiac lesions, particularly those with prosthetic heart valves or a history of bacterial endocarditis, are at high risk for developing IE (see Table 109–10). Nevertheless, only 15% to 25% of patients who develop IE are in a definable high-risk category.76 Few cases of IE are preventable with antibiotic prophylaxis, even with 100% effectiveness.84 The concern of antibiotic resistance also questions the routine use of antimicrobials in this setting. Despite the low probability that IE will develop, prophylaxis is recommended for some dental, respiratory, gastrointestinal, and genitourinary pro-

cedures (see Tables 109–11 and Tables 109–12) because of the significant morbidity associated with the disease. Patients undergoing valve implant surgery are at a much greater risk for IE than are those patients undergoing dental surgery.

PROCEDURES CAUSING BACTEREMIA Bacteremia accompanies many everyday events, such as brushing the teeth and chewing, although certain medical and surgical procedures are more likely to cause a transient bacteremia (see Tables 109–11 and

TABLE 109–14. Prophylactic Regimens for Genitourinary Gastrointestinal (Excluding Esophageal) Procedures Situation

Agenta

High-risk patients

Ampicillin plus gentamicin

High-risk patients allergic to ampicillin/amoxicillin

Vancomycin plus gentamicin

Moderate-risk patients

Amoxicillin or ampicillin

Moderate-risk patients allergic Vancomycin to ampicillin/amoxicillin

a

Regimenb Adults: Ampicillin 2 g intramuscularly (IM) or intravenously (IV) plus gentamicin 1.5 mg/kg (not to exceed 120 mg) within 30 min of starting the procedure; 6 h later, ampicillin 1 g IM/IV or amoxicillin 1 g orally. Children: Ampicillin 50 mg/kg IM or IV (not to exceed 2 g) plus gentamicin 1.5 mg/kg within 30 min of starting the procedure; 6 h later, ampicillin 25 mg/kg IM/IV or amoxicillin 25 mg/kg orally. Adults: Vancomycin 1 g IV over 1–2 h plus gentamicin 1.5 mg/kg IV/IM (not to exceed 120 mg); complete injection/infusion within 30 min of starting the procedure. Children: Vancomycin 20 mg/kg IV over 1–2 h plus gentamicin 1.5 mg/kg IV/IM; complete injection/infusion within 30 min of starting the procedure. Adults: Amoxicillin 2 g orally 1 h before procedure, or ampicillin 2 g IM/IV within 30 min of starting the procedure. Children: Amoxicillin 50 mg/kg orally 1 h before procedure, or ampicillin 50 mg/kg IM/IV within 30 min of starting the procedure. Adults: Vancomycin 1 g IV over 1–2 h; complete infusion within 30 min of starting the procedure. Children: Vancomycin 20 mg/kg IV over 1–2 h; complete infusion within 30 min of starting the procedure.

Total children’s dose should not exceed adult dose. No second dose of vancomycin or gentamicin is recommended. From Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: Recommendations by the American Heart Association. JAMA 1997;277:1794–1801, with permission. Copyright 1995–1997, American Medical Association. b

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109–12). Antibiotic prophylaxis is recommended in patients at risk undergoing a bacteremia-causing procedure. For dental procedures of the gums and oral structures that cause bleeding, viridans streptococci frequently cause bacteremia, whereas instrumentation and surgery of the gastrointestinal and genitourinary tracts more often result in enterococcal bacteremia.1

ANTIBIOTIC REGIMENS The AHA routinely publishes guidelines regarding the prevention of IE, with the most recent revision occurring in 1997.78 A single 2-g dose of amoxicillin is recommended for adult patients at risk, given 1 hour before undergoing procedures associated with bacteremia (see Table 109–13). Because the duration of antimicrobial prophylaxis appears to be relatively short, these guidelines do not advocate a second oral dose of amoxicillin, which was recommended previously. Alternative prophylaxis regimens for patients allergic to penicillins or those unable to take oral medications and regimens for genitourinary and gastrointestinal procedures are provided (Tables 109–13 and 109–14). One report highlights the need to educate physicians and patients regarding these guidelines because overuse of IE prophylaxis occurs in low-risk patients, and underuse is common in moderate-risk patients.85

ABBREVIATIONS AHA: American Heart Association BSAC: British Society for Antimicrobial Chemotherapy IE: infective endocarditis IVDA: intravenous drug abuse MBC: minimal bactericidal concentration MIC: minimal inhibitor concentration MRSA: methicillin-resistant S. aureus MSSA: methicillin-sensitive S. aureus NBTE: nonbacterial thrombotic endocarditis PVE: prosthetic valve endocarditis SBT: serum bactericidal titers TEE: transesophageal echocardiogram TTE: transthoracic echocardiogram Review Questions and other resources can be found at www.pharmacotherapyonline.com.

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51.

52.

streptococcal endocarditis. Antimicrob Agents Chemother 1993;37: 207–212. Gavalda J, Pahissa A, Almirante B, et al. Effect of gentamicin dosing interval on therapy of viridans streptococcal experimental endocarditis with gentamicin plus penicillin. Antimicrob Agents Chemother 1995;39: 2098–2103. Francioli P, Ruch W, Stamboulian D, et al. Treatment of streptococcal endocarditis with a single daily dose of ceftriaxone and netilmicin for 14 days: A prospective multicenter study. Clin Infect Dis 1995;21: 1406–1410. Sexton DJ, Tenenbaum MJ, Wilson WR, et al. Ceftriaxone once daily for 4 weeks compared to ceftriaxone plus gentamicin once daily for 2 weeks for treatment of penicillin-susceptible streptococcal endocarditis. Clin Infect Dis 1998;27:1470–1474. Karchmer A. Staphylococcal endocarditis. In: Kaye D, ed. Infectious Endocarditis, 2d ed. New York, Raven Press, 1992:225–249. Petti CA, Fowler VG. Staphylococcus aureus bacteremia and endocarditis. Cardiol Clin 2003;21:219–233. Korzeniowski O, Sande MA. The National Collaborative Endocarditis Study Group: Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts. Ann Intern Med 1982;97:496–503. Gavalda J, Lopez P, Martin T, et al. Efficacy of ceftriaxone and gentamicin given once a day using human-like pharmacokinetics in treatment of experimental staphylococcal endocarditis. Antimicrob Agents Chemother 2002;46:378–384. Dodek P, Phillip P. Questionable history of immediate-type hypersensitivity to penicillin in staphylococcal endocarditis: Treatment based on skin test results versus empirical alternative treatment—A decision analysis. Clin Infect Dis 1999;29:1251–1256. Miro JM, del Rio A, Mestres CA. Infective endocarditis and cardiac surgery in intravenous drug abusers and HIV-1 infected patients. Cardiol Clin 2003;21:167–184. Chambers HF. Short-course combination and oral therapies of Staphylococcus aureus endocarditis. Med Clin North Am 1993;7:69–80. DiNubile MJ. Abbreviated therapy for right-sided Staphylococcus aureus endocarditis in injection drug users: The time has come? Eur J Clin Microbiol Infect Dis 1994;13:533–534. DiNubile MJ. Short-course antibiotic therapy for right-sided Staphylococcus aureus endocarditis in injection drug users. Ann Intern Med 1994; 121:873–876. Chambers HF, Miller T, Newman MD. Right-sided endocarditis in intravenous drug abusers: Two-week combination therapy. Ann Intern Med 1988;109:619–624. Espinosa FJ, Valdes M, Martin-Luengo M, et al. Right sided endocarditis caused by Staphylococcus aureus in parenteral drug addicts: Evaluation of a combined therapeutic scheme for 2 weeks versus conventional treatment. Enferm Infec Microbiol Clin 1993;11:235–240. Torres-Tortosa M, de Cueto M, Vergara A, et al. Prospective evaluation of a two-week course of intravenous antibiotics in intravenous drug addicts with infective endocarditis. Eur J Clin Microbiol Infect Dis 1994;13: 559–564. Ribera E, Gomez-Jimenez J, Cortes E, et al. Effectiveness of cloxacillin with and without gentamicin in short-term therapy for right-sided Staphylococcus aureus endocarditis: A randomized, controlled trial. Ann Intern Med 1996;125:969–974. Parker RH, Fossieck BE. Intravenous followed by oral antimicrobial therapy for staphylococcal endocarditis. Ann Intern Med 1980;93: 832–834. Dworkin RJ, Lee BL, Sande MA, Chambers HF. Treatment of rightsided Staphylococcus aureus endocarditis in intravenous drug abusers with ciprofloxacin and rifampin. Lancet 1989;2:1071–1073. Heldman AW, Hartert TV, Ray SC, et al. Oral antibiotic treatment of rightsided staphylococcal endocarditis in injection drug users: Prospective, randomized comparison with parenteral therapy. Am J Med 1996;101: 68–76. Berlin JA, Abrutyn E, Strom BL, et al. Incidence of infective endocarditis in the Delaware Valley, 1988–1990. Am J Cardiol 1995;76:933–936.

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53. Eliopolis GM. Enterococcal endocarditis. In: Kaye D, ed. Infective Endocarditis, 2d ed. New York, Raven Press, 1992:209–223. 54. Murray BE. The life and times of the enterococcus. Clin Microbiol Rev 1990;3:46–65. 55. Wilson WR, Wilkowske CJ, Wright AJ, et al. Treatment of streptomycinsusceptible and streptomycin resistant enterococcal endocarditis. Ann Intern Med 1984;100:816–823. 56. Eliopolis GM. Aminoglycoside resistant enterococcal endocarditis. Infect Dis Clin North Am 1993;7:117–133. 57. Tam VH, Preston SL, Briceland LL. Once-daily aminoglycosides in the treatment of gram-positive endocarditis. Ann Pharmacother 1999;33: 600–606. 58. Houlihan HH, Stokes DP, Rybak MJ. Pharmacodynamics of vancomycin and ampicillin alone and in combination with gentamicin once daily or thrice daily against Enterococcus faecalis in an in vitro infection model. J Antimicrob Chemother 2000;46:79–86. 59. Gavalda J, Cardona PJ, Almirante B, et al. Treatment of experimental endocarditis due to Enterococcus faecalis using profiles of ampicillin in human serum. Antimicrob Agents Chemother 1996;40: 173–178. 60. Schwank S, Blaser J. Once versus thrice-daily netilmicin combined with amoxicillin, penicillin, or vancomycin against Enterococcus faecalis in a pharmacodynamic in vitro model. Antimicrob Agents Chemother 1996; 40:2258–2261. 61. Fantin B, Carbon C. Importance of the aminoglycoside dosing regimen in the penicillin-netilmicin combination for treatment of Enterococcus faecalis–induced experimental endocarditis. Antimicrob Agents Chemother 1990;34:2387–2391. 62. Marangos MN, Nicolau DP, Quintiliani R, Nightingale CH. Influence of gentamicin dosing interval on the efficacy of penicillin-containing regimens in experimental Enterococcus faecalis endocarditis. J Antimicrob Chemother 1997;39:519–522. 63. Lipman ML, Silva J. Endocarditis due to Streptococcus faecalis with highlevel resistance to gentamicin. Rev Infect Dis 1989;11:325–328. 64. Wells VD, Wong ES, Murray BE, et al. Infections due to beta-lactamaseproducing, high-level gentamicin-resistant Enterococcus faecalis. Ann Intern Med 1992;116:285–292. 65. Tailor SA, Bailey EM, Rybak MJ. Enterococcus: An emerging pathogen. Ann Pharmacother 1993;27:1231–1242. 66. Hessen MT, Abrutyn E. Gram-negative bacterial endocarditis. In: Kaye D, ed. Infective Endocarditis, 2d ed. New York, Raven Press, 1992: 251–264. 67. Tunkel AR, Kaye D. Endocarditis with negative blood cultures. N Engl J Med 1992;326:1215–1217. 68. Reyes MP, Lerner AM. Current problems in the treatment of infective endocarditis due to Pseudomonas aeruginosa. Rev Infect Dis 1983;5: 314–321. 69. Moyer DV, Edwards JE. Fungal endocarditis. In: Kaye D, ed. Infective Endocarditis, 2d ed. New York, Raven Press, 1992:299–312. 70. Pierrotti LC, Baddour LM. Fungal endocarditis, 1995–2000. Chest 2002; 122:302–310. 71. Rehm SJ. Outpatient intravenous antibiotic therapy for endocarditis. Infect Dis Clin North Am 1998;12:879–901. 72. Santoro J, Ingerman M. Response to therapy: Relapse and reinfections. In: Kaye D, ed. Infective Endocarditis, 2d ed. New York, Raven Press, 1992:423–433. 73. Levinson ME. In vitro assays. In: Kaye D, ed. Infective Endocarditis, 2d ed. New York, Raven Press, 1992:151–167. 74. Weinstein MP, Stratton CW, Ackley A, et al. Multicenter collaborative evaluation of a standardized serum bactericidal test as a prognostic indicator in infective endocarditis. Am J Med 1985;78:262–269. 75. McCormack JP, Jewesson PJ. A critical reevaluation of the “therapeutic range” of aminoglycosides. Clin Infect Dis 1992;14:320–339. 76. Durack DT. Prophylaxis of infective endocarditis. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed. New York, Churchill-Livingstone, 2000:917–925. 77. Durack DT. Prevention of infective endocarditis. N Engl J Med 1995; 332:38–44.

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78. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: Recommendations by the American Heart Association. JAMA 1997; 277:1794–1801. 79. Roberts GJ. Dentist are innocent! “Everyday” bacteremia is real culprit: A review and assessment of the evidence that dental surgical procedures are a principal cause of bacterial endocarditis. Pediatr Cardiol 1999;20: 317–325. 80. Greenman RL, Bisno AL. Prevention of bacterial endocarditis. In: Kaye D, ed. Infective Endocarditis, 2d ed. New York, Raven Press, 1992:465–481. 81. Hall G, Hedstrom SA, Heimdahl A, Nord CE. Prophylactic administration of penicillins for endocarditis does not reduce the incidence of postextraction bacteremia. Clin Infect Dis 1993;17:188–194.

82. Van der Meer JT, Van Wijk W, Thompson J, et al. Efficacy of antibiotic prophylaxis for prevention of native-valve endocarditis. Lancet 1992; 339:135–139. 83. Strom BL, Abrutym E, Berlin JA, et al. Risk factors for infective endocarditis: oral hygiene and nondental exposures. Circulation 2000;102: 2842–2848. 84. Strom BL, Abrutyne E, Berlin JA, et al. Dental and cardiac risk factors for infective endocarditis: A population-based, case-control study. Ann Intern Med 1998;129:761–769. 85. Seto TB, Kwiat D, Taira DA, et al. Physicians’ recommendations to patients for use of antibiotic prophylaxis to prevent endocarditis. JAMA 2000;284:68–71.

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110 TUBERCULOSIS Charles A. Peloquin

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Tuberculosis (TB) is the most prevalent communicable infectious disease on earth and remains out of control in many developing nations. These nations require medical and financial assistance from developed nations in order to control the spread of TB globally.

2 In the United States, TB disproportionately affects ethnic minorities as compared with whites, reflecting greater ongoing transmission in ethnic minority communities. Additional TB surveillance and preventive treatment are required within these communities.

3 Coinfection with human immunodeficiency virus (HIV) and

TB accelerates the progression of both diseases, thus requiring rapid diagnosis and treatment of both diseases.

4 Mycobacteria are slow growing organisms; in the labora-

tory, they require special stains, special growth media, and long periods of incubation to isolate and identify.

5 TB can produce atypical signs and symptoms in infants,

1 Tuberculosis (TB) remains a leading infectious killer globally.

TB is caused by Mycobacterium tuberculosis, which can produce either a silent, latent infection or a progressive, active disease.1 Left untreated or improperly treated, TB causes progressive tissue destruction and eventually death. Because of renewed public health efforts, TB rates in the United States continue to decline. In contrast, TB remains out of control in many developing countries—to the point that one-third of the world’s population currently is infected.1 Estimates suggest that 1 person dies of TB in India each minute (Times of India, August 29, 2003). Given increasing drug resistance, it is critical that a major effort be made to control TB before the most effective drugs are lost permanently. M. tuberculosis preferentially infects humans, and the closely related M. bovis causes a similar disease in cattle and other livestock. Although uncommon today, humans frequently developed TB by drinking milk contaminated with M. bovis—a threat that spurred the development of pasteurization. Today, airborne M. tuberculosis is the main threat to humans. Evidence of TB has been found in ancient human remains, and ancient texts describe it.1−3 TB commonly was known as “consumption” because of the pronounced weight loss that it caused.1 Other common names included “wasting disease” and the “white plague.” As the term plague implies, TB had a profound impact on human

the elderly, and immunocompromised hosts, and it can progress rapidly in these patients.

6 Latent TB infection (LTBI) can lead to reactivation disease years after the primary infection occurred.

7 The patient suspected of having active TB disease must be isolated until the diagnosis is confirmed and he or she is no longer contagious. Often, isolation takes place in specialized “negative pressure” hospital rooms to prevent the spread of TB.

8 Isoniazid and rifampin are the two most important TB drugs; organisms resistant to both these drugs (multidrug-resistant TB [MDR-TB]) are much more difficult to treat.

9 Never add a single drug to a failing regimen! 10 Directly observed treatment (DOT) should be used when-

ever possible to reduce treatment failures and the selection of drug-resistant isolates.

history, most notably in Europe. (Note: The “black plague,” or bubonic plague, is a separate disease caused by Yersinia pestis.) TB rates generally have risen with increasing urbanization and overcrowding because it is easier for an airborne disease to spread when people are packed closely together.3 Hence TB became a significant pathogen in Europe during the Middle Ages and peaked during the Industrial Revolution, when it caused about 25% of all deaths in Europe and in the United States.1−3 This dire threat led to the rise of public health departments and to procedures such as the isolation of infected patients. Thus TB was directly responsible for many of the health care practices that we take for granted today. Unfortunately, in developing nations, some of these practices are not widely available, and TB continues to rage unabated.

EPIDEMIOLOGY Globally, roughly 2 billion people are infected by M. tuberculosis, and roughly 2 to 3 million people die from active TB each year despite the fact that it is curable.1,2,4 In the United States, about 13 million people are latently infected with M. tuberculosis, meaning that they are not currently sick but that they could fall ill with TB at any time. The United States had over 15,000 new cases of active 2015

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28,000

Cases

24,000 20,000 16,000 12,000 1983

1987

1991

1995

1999

2003

Year

FIGURE 110–1. Reported TB cases in the United States, 1982–2003.

TB in 2002 and about 1500 deaths.5 (For detailed data analysis, visit the Centers for Disease Control and Prevention (CDC) Web site at www.cdc.gov/nchstp/tb.) The annual incidence of TB in the United States declined by about 5% per year from 1953 to 19836 (Fig. 110–1). In 1984, this decline slowed, and then the incidence of TB rose from 1988 to 1992, reaching 10.5 cases per 100,000 population. Since 1992, more effective infection control practices and treatment protocols have reduced TB rates to 5.2 per 100,000 population as of 2002.5 Despite this good news, the eradication of TB from the United States will remain very difficult. One reason is that we continue to import new cases from countries where TB remains out of control.4,5

whites and Asians compared with younger people from these groups. This reflects reactivation of latent infection acquired many years earlier when TB was very common. Older blacks and Hispanics also have more TB than younger folks, but the differences by age are not as pronounced.6 This reflects a greater amount of recent transmission among younger blacks and Hispanics compared with younger whites and Asians. Until the age of 15, TB rates are similar for males and females, but after that, the male predominance increases with each decade of life.6

COINFECTION WITH HUMAN IMMUNODEFICIENCY VIRUS (HIV) for active TB, especially 3 HIV is the most important risk factor 2,4,6,7

among people 25 to 44 years of age. TB and HIV seem to act synergistically within patients and across populations, making each disease worse than it might otherwise be. Roughly 10% of U.S. TB patients are coinfected with HIV, and roughly 20% of TB patients ages 25 to 44 years are coinfected.5,6 HIV coinfection may not increase the risk of acquiring M. tuberculosis infection, but it does increase the likelihood of progression to active disease.1,7 Further, TB and HIV patients share a number of behavioral risk factors that contribute to the high rates of coinfection.2,8,9

RISK FACTORS FOR DISEASE RISK FACTORS FOR INFECTION LOCATION AND PLACE OF BIRTH TB can infect anyone, but the risk is not evenly distributed across the U.S. population. The major points of entry into the United States have the most TB cases. California, Florida, Illinois, New York, and Texas accounted for over 50% of all TB cases in 2002.5 Within these states, TB is most prevalent in large urban areas.4 The percentage of foreign-born TB patients in the United States has increased annually since 1986, reaching 51% in 2002.5 Nearly two-thirds of these patients came from only seven countries, in order of highest to lowest: Mexico, the Philippines, Vietnam, India, China, Haiti, and South Korea.5 Therefore, health care workers must “think TB” when caring for patients from these countries who experience symptoms such as cough, fever, and weight loss. Close contacts of pulmonary TB patients are most likely to become infected.2−4 These include family members, coworkers, or coresidents in places such as prisons, shelters, or nursing homes. The more prolonged the contact, the greater is the risk, with infection rates as high as 30%.5,6 Although many circumstances exist, TB patients frequently have limited access to health care, live in crowded conditions, or are homeless.2,4 Many patients have histories of alcohol abuse or illicit drug use, and many are coinfected with hepatitis B or human immunodeficiency virus (HIV). These concurrent social and health problems make treating some TB patients particularly difficult.

RACE, ETHNICITY, AGE, AND GENDER 2 In the United States, TB disproportionately affects ethnic mi-

norities. In 2002, non-Hispanic blacks accounted for 30% of all TB cases, followed by Hispanics at 27%.6 Asians and Pacific Islanders accounted for 22%, whereas non-Hispanic whites accounted for only 20% of the new TB cases.6 TB is most common among people 25 to 44 years of age (35% of all U.S. cases in 2002).6 They are followed by those 45 to 64 years of age (28%) and 65+ years of age (21%). TB is more common in older

Once infected with M. tuberculosis, a person’s lifetime risk of active TB is about 10%.2,4,7 The greatest risk for active disease occurs during the first 2 years after infection. Children younger than 2 years and adults over 65 years of age have 2 to 5 times greater risk for active disease compared with other age groups. Patients with underlying immune suppression (e.g., renal failure, cancer, and immunosuppressive drug treatment) have 4 to 16 times greater risk than other patients. Finally, HIV-infected patients with M. tuberculosis infection are 100 times more likely to develop active TB than normal hosts.4,10 HIVinfected patients have an annual risk of active TB of about 10% rather than a lifetime risk at that rate. Therefore, all patients with HIV infection should be screened for tuberculous infection, and those known to be infected with M. tuberculosis should be tested for HIV infection.

ETIOLOGY M. tuberculosis is a slender bacillus with a very waxy outer layer.2,7 It is 1 to 4 microns in length, and under the microscope, it is either straight or slightly curved in shape.1,11,12 It does not stain well with Gram’s stain, so the Ziehl-Neelsen stain (ZN) or the fluorochrome stain must be used instead.1,2,7 After ZN staining with carbol-fuchsin, mycobacteria retain the red color despite acid-alcohol washes. Hence they are called acid-fast bacilli (AFB).11 After staining, microscopic examination (“smear”) detects about 8000 to 10,000 organisms per milliliter of specimen, so a patient can be “smear negative” but still grow M. tuberculosis on culture. Microscopic examination also cannot determine which of the 80+ mycobacterial species is present or whether the organisms in the original samples were alive or dead.1,11,12 On smear, they are all dead. On culture, M. tuberculosis grows slowly, doubling about every 20 hours. This is very slow compared with gram-positive and gram-negative bacteria, which double about every 30 minutes. Among the mycobacteria, only M. tuberculosis is a frequent human pathogen. Some nontuberculous mycobacteria (NTM) such as M. kansasii, M. fortuitum, and M. avium complex (MAC) cause

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infections in patients with other medical problems, especially the acquired immunodeficiency syndrome (AIDS). The treatment of these infections is discussed in Chap. 123.

CULTURE AND SUSCEPTIBILITY TESTING

TUBERCULOSIS

2017

although this number can vary significantly. A person with the uncommon laryngeal form of TB can spread organisms even when talking, so the transmission rates can be very high. HIV-infected patients acquire the organisms through the lungs just like normal hosts, but their weakened immune system puts them at very high risk for active disease.2,4,7,13

4 Direct susceptibility testing involves inoculating specialized

media with organisms taken directly from a concentrated, smearpositive specimen.1,11,12 This approach produces susceptibility results in 2 to 3 weeks. Indirect susceptibility testing involves inoculating the test media with organisms obtained from a pure culture of the organisms, which can take several more weeks. The most common agar method, known as the proportion method, uses the ratio of colony counts on drug-containing agar to that on drug-free agar.1,12 In the United States, the critical proportion for resistance is 1%. That means that if a drug-containing plate shows only 2% of the growth seen on a drug-free plate, some of the organisms from the specimen were resistant to that drug. Therefore, it is likely that many of the organisms in the patient also are resistant to that drug, and it should not be used to treat that patient. The proportion method’s limitations include many weeks to obtain results, drug degradation during the incubation, and a qualitative result (susceptible or resistant). The Bactec system (BectonDickinson, Sparks, MD) uses liquid medium (7H12 broth) and detects live mycobacteria based on the release of radiolabeled CO2 .11 Advantages of the Bactec system include reduced incubation time (as few as 9 to 14 days), reduced drug loss in the medium, and when multiple concentrations are tested, a truly quantitative end point (minimal inhibitory concentration [MIC]).1,11,12 Newer, nonradiometric rapid methods such as the MIGIT system are now being marketed.13 Rapid-identification tests are now available.13 Nucleic acid probes such as the AccuProbe (Gen-Probe, San Diego) use DNA probes to identify the presence of complementary rRNA for several mycobacterial species.7,11,14 DNA fingerprinting using restrictionfragment-length polymorphism (RFLP) analysis has been used to identify clusters of cases.1,11,14 Amplification of the genetic material can be achieved through polymerase chain reaction (PCR; Roche Molecular Systems, Branchburg, NJ), the amplified M. tuberculosis direct test (MTD; Gen-Probe), and strand-displacement amplification (SDA; Becton-Dickinson, Sparks, MD).11,15 Thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC) for mycolic acid identification, and gas chromatography (GC) for shortchain fatty acids (methyl esters) have been used to speciate mycobacterial isolates.1,11,14 Other tests are designed to detect common genetic changes associated with drug resistance, such as changes in the katG gene associated with isoniazid resistance and the rpoB gene associated with rifampin resistance.7,16−18 These tests offer clinicians a chance to know rapidly what organism they are treating and what drugs might be good initial choices.

TRANSMISSION M. tuberculosis is transmitted from person-to-person by coughing or sneezing.2,7,13 This produces “droplet nuclei” that are dispersed in the air. Each droplet nuclei contains one to three organisms. Riley and colleagues19 showed that air circulated from a hospital TB ward could cause disease in guinea pigs. When this air was filtered or treated with ultraviolet radiation, the animals were not infected. About 30% of individuals who experience prolonged contact with an infectious TB patient will become infected. A person with cavitary, pulmonary TB and a cough may infect roughly one person per month until he or she is treated effectively,

PATHOPHYSIOLOGY IMMUNE RESPONSE Good T-lymphocyte responses are essential to controlling M. tuberculosis infections.2,7,20,21 In the mouse model, two different T-cell responses—the type 1 T-helper (TH1 ) response and the type 2 Thelper (TH2 ) response—have been described. The TH1 response is the preferred response to TB, and the TH2 response, including the potentially subversive influence of interleukin 4 (IL-4), is undesirable.2,20,21 Some workers have argued that this dichotomy is clearer in the mouse model, and in many humans, the T-cell response may be classified as TH0 (elements of both TH1 and TH2 ).20 In either case, T-lymphocytes activate macrophages that, in turn, engulf and kill mycobacteria. T-lymphocytes also destroy immature macrophages that harbor M. tuberculosis but are unable to kill the invaders.20,21 CD4+ cells are the primary T cells involved, with contributions by gamma-delta T cells and CD8+ T cells.20 CD4+ T cells produce interferon-γ (IFN-γ ) and other cytokines, including IL-2 and IL-10, that coordinate the immune response to TB.20 Because CD4+ cells are depleted in HIV-infected patients, these patients are unable to mount an adequate defense to TB.20,21 Although B-cell responses and antibody production can be demonstrated in TB-infected mammals, these humoral responses do not appear to contribute much to the control of TB within the host.2,7,20 T cells are responding to certain mycobacterial antigens, but the key antigen(s) invoking the immune response have not been identified.20 Tumor necrosis factor (TNF-α) and IFN-γ important cytokines involved in coordinating the host’s cell-mediated response. Rheumatoid arthritis patients treated with TNF-α inhibitors (infliximab) have high rates of reactivation TB.22 Therefore, patients known to be deficient in the activity of TNF-α or IFN-γ should be screened for TB infection and offered appropriate treatment. M. tuberculosis has several ways of evading or resisting the host immune response.20,21 In particular, M. tuberculosis can inhibit the fusion of lysosomes to phagosomes inside macrophages. This prevents the destructive enzymes found in the lysosomes from getting to the bacilli captured in the phagosomes. This stay of execution allows time for M. tuberculosis to escape into the cytoplasm. Virulent M. tuberculosis are able to multiply in the macrophage cytoplasm, thus perpetuating their spread. Finally, lipoarabinomannan (LAM), the principal structural polysaccharide of the mycobacterial cell wall, inhibits the host immune response.20,21 LAM induces immunosuppressive cytokines, thus blocking macrophage activation, and LAM scavenges O2 , thus preventing attack by superoxide anions, hydrogen peroxide, singlet oxygen, and hydroxyl radicals.20,21 These survival mechanisms make M. tuberculosis a particularly difficult organism to control. Any defects in the host immune system make it likely that M. tuberculosis will not be controlled and that active disease will ensue.

PRIMARY INFECTION Primary infection usually results from inhaling airborne particles that contain M. tuberculosis.2,7,21 These particles, called droplet nuclei,

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contain one to three bacilli and are small enough (1 to 5 mm) to reach the alveolar surface. Ingestion (swallowing) and inoculation (puncture wound) are other rare pathways to acquire M. tuberculosis infection.21 The progression to clinical disease depends on three factors: (1) the number of M. tuberculosis organisms inhaled (infecting dose), (2) the virulence of these organisms, and (3) the host’s cell-mediated immune response.2,5,7,13,21,23 At the alveolar surface, the bacilli that were delivered by the droplet nuclei are ingested by pulmonary macrophages.21 If these macrophages inhibit or kill the bacilli, infection is aborted.21 If the macrophages cannot do this, the organisms continue to multiply. The macrophages eventually rupture, releasing many bacilli, and these mycobacteria are then phagocytized by other macrophages. This cycle continues over several weeks until the host is able to mount a more coordinated response.21 During this early phase of infection, M. tuberculosis multiplies logarithmically.21 Some of the intracellular organisms are transported by the macrophages to regional lymph nodes in the hilar, mediastinal, and retroperitoneal areas. The cycle of phagocytosis and cell rupture continues. During lymph node involvement, the mycobacteria may be held in check. More frequently, M. tuberculosis spreads throughout the body through the bloodstream.2,7,21 When this intravascular dissemination occurs, M. tuberculosis can infect any tissue or organ in the body. Most commonly, M. tuberculosis infects the posterior apical region of the lungs. This may be so because of the high oxygen content, and it may be due to a less-vigorous immune response in this area. After about 3 weeks of infection, T-lymphocytes are presented with M. tuberculosis antigens. These T cells become activated and begin to secrete IFN-γ and the other cytokines noted earlier. The processes described in the immune response section earlier then begin to occur. First, T-lymphocytes stimulate macrophages to become bactericidal.21 Large numbers of activated microbicidal macrophages surround the solid caseous (cheeselike) tuberculous foci (the necrotic area of infection).21 This process of creating activated microbicidal macrophages is known as cell-mediated immunity (CMI).21 At the same time that CMI occurs, delayed-type hypersensitivity (DTH) also develops through the activation and multiplication of T-lymphocytes. DTH refers to the cytotoxic immune process that kills nonactivated immature macrophages that are permitting intracellular bacillary replication.21 These immature macrophages are killed when the T-lymphocytes initiate Fas-mediated apoptosis (programmed cell death).21 The bacilli released from the immature macrophages then are killed by the activated macrophages.21 By this time (>3 weeks), macrophages have begun to form granulomas to contain the organisms. In a typical tuberculous granuloma, activated macrophages accumulate around a caseous lesion and prevent its further extension.21 At this point, the infection is largely under control, and bacillary replication falls off dramatically. Depending on the inflammatory response, tissue necrosis and calcification of the infection site plus the regional lymph nodes may occur. Over 1 to 3 months, activated lymphocytes reach an adequate number, and tissue hypersensitivity results. This is shown by a positive tuberculin skin test. Any remaining mycobacteria are believed to reside primarily within granulomas or within macrophages that have avoided detection and lysis, although some residual bacilli have been found in various types of cells.2,7,20 Approximately 90% of infected patients have no further clinical manifestations. Most patients only show a positive skin test (70%), whereas some also have radiographic evidence of stable granulomas (about 20%). This radiodense area on chest x-ray is called a Ghon complex. About 5% of patients (usually children, the elderly, or the immunocompromised) experience “progressive primary” disease that

occurs before skin test conversion.24,25 This presents as a progressive pneumonia, usually in the lower lobes. Disease frequently spreads, leading to meningitis and other severe forms of TB.24,25 Because of this risk of severe disease, very young, elderly, and immunocompromised patients, including those with HIV, should be evaluated and treated for latent or active TB.

REACTIVATION DISEASE 6 Roughly 10% of infected patients develop reactivation disease

at some point in their lives. Nearly half of these cases occur within 2 years of infection.2,7,13 In the United States, most cases of TB are believed to result from reactivation. Reinfection is uncommon in the United States because of the low rate of exposure and because previously sensitized individuals possess some degree of immunity to reinfection.2,21 Exceptions include patients coinfected with HIV who live in areas of higher exposure to M. tuberculosis. The apices of the lungs are the most common sites for reactivation (85% of cases).2 This reflects the fact that M. tuberculosis prefers areas with high oxygen content and possibly because the immune response may not be as effective in this region.2,21 For reasons that are not entirely known (waning cellular immunity, loss of specific T-cell clones, blocking antibody), organisms within granulomas emerge and begin multiplying extracellularly.24 The inflammatory response produces caseating granulomas, which eventually will liquefy and spread locally, leading to the formation of a hole (cavity) in the lungs. The immune response contributes to the severity of the lung damage. There is targeted killing of immature macrophages that are allowing mycobacterial multiplication (DTH).20,21 In addition, there is “innocent bystander” killing of host cells and locally thrombosed blood vessels.21 The killing of mycobacteria, macrophages, and neutrophils that have entered the battle releases cytokines and lysozymes into the infectious foci. This toxic mixture can be too much for the surrounding alveoli and airway cells, causing regional necrosis and structural collapse.2,21 These unstable foci liquefy, spreading the infection to neighboring areas of the lung, creating a cavity. Some of this necrotic material is coughed out, producing droplet nuclei. Bacterial counts in the cavities can be as high as 108 per milliliter of cavitary fluid. Partial healing may result from fibrosis, but these lesions remain unstable and may continue to expand.2,21 If left untreated, pulmonary TB continues to destroy the lungs, resulting in hypoxia, respiratory acidosis, and eventually death.

EXTRAPULMONARY AND MILIARY TUBERCULOSIS Caseating granulomas at extrapulmonary sites can undergo liquefaction, releasing tubercle bacilli and causing symptomatic disease.2,7 Extrapulmonary TB without concurrent pulmonary disease is uncommon in normal hosts but more common in HIV-infected patients. Because of these unusual presentations, the diagnosis of TB is difficult and often delayed in immunocompromised hosts.2,4,7 Lymphatic and pleural diseases are the most common forms of extrapulmonary TB, followed by bone, joint, genitourinary, meningeal, and other forms.2,7 Left untreated, these forms will spread to other organs and may result in death. Occasionally, a massive inoculum of organisms enters the bloodstream, causing a widely disseminated form of the disease known as miliary TB. It is named for the millet seed appearance of the small granulomas seen on chest radiographs, and it can be rapidly fatal.20 Miliary TB is a medical emergency requiring immediate treatment.

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INFLUENCE OF HIV INFECTION ON PATHOGENESIS 2,7,20 As 3 HIV infection is the largest risk factor for active TB.

CD4+ lymphocytes multiply in response to the mycobacterial infection, HIV multiplies within these cells and selectively destroys them. In turn, the TB-fighting lymphocytes are depleted.20 This vicious cycle puts HIV-infected patients at 100 times the risk of active TB compared with HIV-negative people.25 In addition, the combination of HIV infection and certain social behaviors increases the risk of newly acquired TB. In selected areas of the United States, up to 50% of new TB cases are the result of recent infection, particularly among HIV-infected individuals.26−28 While mycobacteria are spreading throughout the body, HIV replication accelerates in lymphocytes and macrophages. This leads to progression of HIV disease.20,29 HIV-infected patients infected with TB deteriorate more rapidly unless they receive antimycobacterial chemotherapy.30,31 Most clinicians elect to begin TB treatment first, and once this is under control, begin HIV treatment as well. Starting both treatments at the same time can lead to paradoxical worsening of the TB.13,32 This appears to result from a reinvigorated inflammatory response to TB. Because TB can be very dangerous in HIV-positive patients, they should be screened for tuberculous infection or disease soon after they are shown to be HIV-positive.2,4,7,20

CLINICAL PRESENTATION The classical presentation of TB is shown below. The onset of TB may be gradual, and the diagnosis may not be considered until a chest radiograph is performed. Unfortunately, many patients do not seek medical attention until more dramatic symptoms, such as frank hemoptysis, occur. At this point, patients typically have large cavitary lesions in the lungs. These cavities are loaded with M. tuberculosis. Expectoration or swallowing of infected sputum may spread the disease to other areas of the body.1,2,7,23 Physical examination is nonspecific but suggestive of progressive pulmonary disease. C L I N I C A L P R E S E N T AT I O N O F TUBERCULOSIS SIGNS AND SYMPTOMS

r Patients typically present with weight loss, fatigue, a productive cough, fever, and night sweats1,2,7,23

r Frank hemoptysis

PHYSICAL EXAMINATION

r Dullness to chest percussion, rales, and increased vocal fremitus are observed frequently on auscultation LABORATORY TESTS

r Moderate elevations in the white blood cell (WBC) count with a lymphocyte predominance CHEST RADIOGRAPH

r Patchy or nodular infiltrates in the apical areas of the upper lobes or the superior segment of the lower lobes2,7,23

r Cavitation that may show air-fluid levels as the infection progresses

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5 Patients

coinfected with HIV may have atypical presentations.1,2,7,23,33 As their CD4+ counts decline, HIV-positive patients are less likely to have positive skin tests, cavitary lesions, or fever. Pulmonary radiographic findings may be minimal or absent. HIV-positive patients have a higher incidence of extrapulmonary TB and are more likely to present with progressive primary disease. Because their symptoms are not specific to TB, a thorough work-up for TB is essential.2,7,20,23 Extrapulmonary TB typically presents as a slowly progressive decline in organ function.2,7,23 Patients may have low-grade fever and other constitutional symptoms. Patients with genitourinary TB may present with sterile pyuria and hematuria. Lymphadenitis often involves the cervical and supraclavicular nodes and may appear as a neck mass with spontaneous drainage. Tuberculous arthritis and osteomyelitis occur most commonly in the elderly and usually affect the lower spine and weight-bearing joints. TB of the spine is known as Pott’s disease.2 Abnormal behavior, headaches, or convulsions suggest tuberculous meningitis. Involvement of the peritoneum, pericardium, larynx, and adrenal glands also occurs.2,7,23

THE ELDERLY 5 TB in the elderly is easily confused with other respiratory dis-

eases. Many clinical findings are muted or absent altogether. Compared with younger patients, TB in the elderly is far less likely to present with positive skin tests, fevers, night sweats, sputum production, or hemoptysis.2,23,34,35 Weight loss may occur but is nonspecific. In contrast, mental status changes are twice as common in the elderly, and mortality is six times higher.2,23,34 TB is a preventable cause of death in the elderly that should not be overlooked.

CHILDREN 5 TB in children, especially those younger than 12 years of age,

may present as a typical bacterial pneumonia and is called progressive primary TB.23−25 Clinical disease often begins 1 to 2 months after exposure and precedes skin-test positivity. Unlike adults, pulmonary TB in children often involves the lower and middle lobes.23−25 Dissemination to the lymph nodes, gastrointestinal and genitourinary tracts, bone marrow, and meninges is fairly common. Because of delays in recruitment of cellular immunity, cavitary disease is infrequent, and the number of organisms present typically is smaller than in an adult. Because cavitary lesions are uncommon, children do not spread TB readily. However, TB can be rapidly fatal in a child, and it requires prompt chemotherapy.

DIAGNOSIS SKIN TESTING The key to stopping the spread of TB is early identification of infected individuals.1,2,7,23 Populations most likely to benefit from skin testing are listed in Table 110–1 (column 1 patients are at highest risk for TB, followed by those in column 2). Members of these high-risk groups should be tested for TB infection and educated about the disease. The Mantoux test is the preferred TB skin test. It uses tuberculin purified protein derivative (PPD), and unlike the Heaf or tine test, the Mantoux test is quantitative. The standard 5 tuberculin unit PPD dose is placed intracutaneously on the volar aspect of the forearm with a 26- or 27-gauge needle.2,23,30 This injection should produce a small, raised, blanched wheal. An experienced professional should

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TABLE 110–1. Criteria for Tuberculin Positivity, by Risk Group Reaction ≥5 mm of Induration

Reaction ≥10 mm of Induration

Reaction ≥15 mm of Induration

Human immunodeficiency virus (HIV)-positive persons Recent contacts of tuberculosis (TB) case patients Fibrotic changes on chest radiograph consistent with prior TB

Recent immigrants (i.e., within the last 5 yr) from high prevalence countries Injection drug users

Persons with no risk factors for TB

Patients with organ transplants and other immunosuppressed patients (receiving the equivalent of ≥15 mg/d of prednisone for 1 mo or more)a

Residents and employeesb of the following high-risk congregate settings: prisons and jails, nursing homes and other long-term facilities for the elderly, hospitals and other health care facilities, residential facilities for patients with acquired immunodeficiency syndrome (AIDS), and homeless shelters Mycobacteriology laboratory personnel Persons with the following clinical conditions that place them at high risk: silicosis, diabetes mellitus, chronic renal failure, some hematologic disorders (e.g., leukemias and lymphomas), other specific malignancies (e.g., carcinoma of the head or neck and lung), weight loss of ≥10% of ideal body weight, gastrectomy, and jejunoileal bypass Children younger than 4 yr of age or infants, children, and adolescents exposed to adults at high-risk

a

Risk of TB in patients treated with corticosteroids increases with higher dose and longer duration. For persons who are otherwise at low risk and are tested at the start of employment, a reaction of ≥15 mm induration is considered positive. Adapted from Centers for Disease Control and Prevention. Screening for tuberculosis and tuberculosis infection in high-risk populations: recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR 1995;44(No. RR-11):19–34.

b

read the test in 48 to 72 hours. The area of induration (the “bump”) is the important end point, not the area of redness. Criteria for interpretation are listed in Table 110–1.1,2,7,23,30 The CDC does not recommend the routine use of anergy panels.30,36 Aplisol and Tubersol 5 tuberculin unit products are available commercially, but because of more predictable results, Tubersol appears to be the preferred product. The “booster effect” occurs in patients who do not respond to an initial skin test but show a positive reaction if retested about a week later.23,36 Patients with past M. tuberculosis infection and some patients with past immunization with bacillus Calmette-Gu´erin (BCG) vaccine or past infection with other mycobacteria may “boost” with a second skin test. Individuals who require periodic skin testing, such as health care workers, should receive a two-stage test initially.23,36,37 Once they are shown to be skin-test–negative, any positive skin test later shows recent infection, and this requires treatment. The PPD skin test is an imperfect diagnostic tool. Up to 20% of patients with active TB are falsely skin-test–negative presumably because their immune systems are overwhelmed.20,36 False-positive

results are more common in low-risk patients and those recently vaccinated with BCG. Despite BCG vaccination, one should not ignore a positive PPD result. These patients require careful evaluation for active disease, and they may be offered preventive treatment because many come from areas where TB infection is common.

ADDITIONAL TESTS When active TB is suspected, attempts should be made to isolate M. tuberculosis from the site of infection.2,7,23,36 Sputum collected in the morning usually has the highest yield.2,11,23 Daily sputum collections over three consecutive days is recommended. For patients unable to expectorate, sputum induction with aerosolized hypertonic saline may produce a diagnostic sample. Bronchoscopy, or aspiration of gastric fluid via a nasogastric tube, may be attempted in selected patients.23 For patients with suspected extrapulmonary TB, samples of draining fluid, biopsies of the infected site, or both may be attempted. Blood cultures are positive occasionally, especially in AIDS patients.23,33,38


TREATMENT: Tuberculosis The desired outcomes for the treatment of tuberculosis are 1. Rapid identification of a new TB case 2. Isolation of the patient with active disease to prevent spread of the disease 3. Collection of appropriate samples for smears and cultures 4. Initiation of specific antituberculosis treatment 5. Prompt resolution of the signs and symptoms of disease

6. Achievement of a noninfectious state in the patient, thus ending isolation 7. Adherence to the treatment regimen by the patient 8. Cure of the patient as quickly as possible (generally at least 6 months of treatment) Secondary goals are identification of the index case that infected the patient, identification of all persons infected by both the index case and the new case of TB, and completion of appropriate treatments for those individuals.

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GENERAL APPROACHES TO TREATMENT Drug treatment is the cornerstone of TB management.2,7,13,39 Monotherapy can be used only for infected patients who do not have active TB (latent infection, as shown by a positive skin test). Once active disease is present, a minimum of two drugs and generally three or four drugs must be used simultaneously.2,7,13,39 The duration of treatment depends on the condition of the host, extent of disease, presence of drug resistance, and tolerance of medications. The shortest duration of treatment generally is 6 months, and 2 to 3 years of treatment may be necessary for cases of multidrug-resistant TB (MDR-TB).2,7,13,39 Because the duration of treatment is so long, and because many patients feel better after a few weeks of treatment, careful follow-up is required. Directly observed therapy (DOT) by a health care worker is a cost-effective way to ensure completion of treatment.2,7,13,39−41


PRINCIPLES FOR TREATING INFECTION AND TREATING DISEASE Asymptomatic patients with tuberculous infection have a bacillary load of about 103 organisms, compared with 1011 organisms in a patient with cavitary pulmonary TB.2,7,42 As the number of organisms increases, the likelihood of naturally occurring drug-resistant mutants also increases. Naturally occurring mutants are found at rates of 1 in 106 to 1 in 108 organisms for the antituberculosis drugs.2,39,42 When treating asymptomatic latent infection with isoniazid monotherapy, the risk of selecting out isoniazid-resistant organisms is low. The isoniazid mutation rate is about 1 in 106 , but only about 103 organisms are present in the body. In contrast, the risk of selecting out isoniazidresistant organisms is unacceptably high in patients with cavitary TB. One can prevent selection of these resistant mutants by adding more drugs because the rates for resistance mutations to multiple drugs are additive functions of the individual rates. For example, only 1 in 1013 organisms would be naturally resistant to both isoniazid (1 in 106 ) and rifampin (1 in 107 ).2,39,42 It is unlikely that such rare organisms are present in a previously untreated patient. Combination chemotherapy is required for treating active TB disease. The patient should receive at least two drugs to which the isolate is susceptible, and generally four drugs are given at the outset of treatment. Rifampin and isoniazid are the best drugs for preventing drug resistance, followed by ethambutol, streptomycin, and pyrazinamide.2,7,39,42,43 Three subpopulations of mycobacteria are proposed to exist within the body, and each appears to respond to certain drugs.2,39,42 Most numerous are the extracellular, rapidly dividing bacteria, often found within cavities (about 107 to 109 organisms). These are killed most readily by isoniazid, followed by rifampin, streptomycin, and the other drugs. A second group resides within caseating granulomas (possibly 105 to 107 organisms). These organisms appear to be in a semidormant state, with occasional bursts of metabolic activity. Pyrazinamide, through its conversion within M. tuberculosis to pyrazinoic acid, appears most active against these organisms. Rifampin and isoniazid also may be active against this subpopulation. The third subset is the intracellular mycobacteria present within macrophages (104 to 106 ). Rifampin, isoniazid, and the quinolones appear to be most active against intracellular M. tuberculosis. While these theories appear to

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explain what happens during the treatment of TB, there is no practical way to quantitate these populations within a given patient.


NONPHARMACOLOGIC THERAPY 7 Nonpharmacologic interventions aim to (1) prevent the spread

of TB, (2) find where TB has already spread using contact investigation, and (3) replenish the weakened (consumptive) patient to a state of normal weight and well-being. Items 1 and 2 are performed by public health departments. Clinicians involved in the treatment of TB should verify that the local health department has been notified of all new cases of TB. Workers in hospitals and other institutions must prevent the spread of TB within their facilities.2,4,13,30 All such workers should learn and follow each institution’s infection control guidelines. This includes using personal protective equipment, including properly fitted respirators, and closing doors to “negative pressure” rooms. These hospital isolation rooms draw air in from surrounding areas rather than blowing air (and M. tuberculosis) into these other areas. The air from the isolation room may be treated with ultraviolet lights and then vented safely outside. However, these isolation rooms work properly only if the door is closed. Debilitated TB patients may require therapy for other medical problems, including substance abuse and HIV infection, and some may need nutritional support. Therefore, clinicians involved in substance abuse rehabilitation and nutritional support services should be familiar with the needs of TB patients. Surgery may be needed to remove destroyed lung tissue, spaceoccupying infected lesions (tuberculomas), and certain extrapulmonary lesions.2,13,39 Vaccines against TB include BCG and M. vaccae.39 However, these vaccines are of limited value, and neither can prevent infection by M. tuberculosis. BCG (discussed below) may prevent extreme forms of TB in infants, whereas M. vaccae cannot be recommended.39,44


PHARMACOLOGIC THERAPY
TREATING LATENT INFECTION Isoniazid is the preferred drug for treating latent TB infection.2,7,13,39 Generally, isoniazid alone is given for 9 months. The treatment of latent TB infection (LTBI) reduces a person’s lifetime risk of active TB from about 10% to about 1%. Because TB is spread easily through the air, each case prevented also prevents a second wave of cases that each prevented case would have produced. Historically, the treatment of LTBI has been called prophylaxis, chemoprophylaxis, or preventive treatment. By any name, it is one of the primary mechanisms for reducing TB in the United States. The LTBI treatment options are listed in Table 110–2. Because young children, the elderly, and HIV-positive patients are at greater risk of active disease once infected with M. tuberculosis, they require careful evaluation. Once active TB is ruled out, they should receive treatment for latent infection.2,22,23,39 The keys to successful treatment of LTBI are (1) infection by an isoniazid-susceptible isolate, (2) adherence to the 9-month regimen, and (3) no exogenous reinfection.2 Isoniazid adult doses are usually 300 mg daily (5–10 mg/kg of body weight)52 (see Table 110–2). Lower doses are less effective.2,49 Isoniazid should be

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TABLE 110–2. Recommended Drug Regimens for Treatment of Latent Tuberculosis (TB) Infection in Adults Ratinga (Evidence)b Drug Isoniazid

Interval and Duration Daily for 9 moc,d

Twice weekly for 9 moc,d Isoniazid

Daily for 6 mod

Rifampin

Twice weekly for 6 mod Daily for 4 mo

Comments In human immunodeficiency virus (HIV)-infected patients, isoniazid may be administered concurrently with nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors, or non-nucleoside reverse transcriptase inhibitors (NNRTIs) Directly observed therapy (DOT) must be used with twice-weekly dosing Not indicated for HIV-infected persons, those with fibrotic lesions on chest radiographs, or children DOT must be used with twice-weekly dosing For persons who cannot tolerate pyrazinamide For persons who are contacts of patients with isoniazid-resistant, rifampin-susceptible TB who cannot tolerate pyrazinamide

HIV –

HIV +

A (II)

A (II)

B (II)

B (II)

B (I)

C (I)

B (II) B (II)

C (I) B (III)

Strength of recommendation: A = preferred; B = acceptable alternative; C = offer when A and B cannot be given. Quality of evidence: I = randomized clinical trial data; II = data from clinical trials that are not randomized or were conducted in other populations; III = expert opinion. c Recommended regimen for children younger than 18 yr of age. d Recommended regimens for pregnant women. Some experts would use rifampin and pyrazinamide for 2 mo as an alternative regimen in HIV-infected pregnant women, although pyrazinamide should be avoided during the first trimester. Adapted from Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000;49(RR-6):31. a

b

given on an empty stomach, and antacids should be avoided within 2 hours of dosing. When adherence is an issue, twice-weekly isoniazid (900 mg in an adult) can be given using DOT. Nine months of treatment is recommended, but 6 months still provides considerable benefit. Rifampin 600 mg daily for 4 months can be used when isoniazid resistance is suspected or when the patient cannot tolerate isoniazid.2,25,48,49 Rifabutin 300 mg daily might be substituted for rifampin for patients at high risk of drug interactions. The combination of pyrazinamide plus rifampin is no longer recommended because of higher than expected rates of hepatotoxicity. When resistance to isoniazid and rifampin is suspected in the isolate causing infection, there is no regimen proved to be effective.2,39 Regimens that might be effective include ethambutol plus levofloxacin, but data regarding efficacy are lacking. For recent skin-test converters of all ages, the risk of active TB outweighs the risk for drug toxicity.30,39 Pregnant women, alcoholics, and patients with poor diets who are treated with isoniazid should receive pyridoxine (vitamin B6 ) 10–50 mg daily to reduce the incidence of central nervous system (CNS) effects or peripheral neuropathies. All patients who receive treatment of LTBI should be monitored monthly for adverse drug reactions and for possible progression to active TB.


TREATING ACTIVE DISEASE 8 The treatment of active TB requires the use of multiple drugs.

There are two primary antituberculosis drugs, isoniazid and rifampin, with the rest of the drugs having specific roles.39,42,43 Isoniazid and rifampin should be used together whenever possible. Typically, M. tuberculosis is either very susceptible or very resistant to a given drug. This contrasts with M. avium, where moderately resistant organisms are a frequent occurrence. Theoretically, minimal inhibitory concentration (MIC) results could be used to guide dosing in the treatment of moderately resistant M. tuberculosis, but this remains to be studied prospectively.2,13,39 Drug-susceptibility testing should be done on the initial isolate for all patients with active TB. These data should guide the selection

of drugs over the course of treatment.2,7,13,39 However, some patients are unable to provide a suitable specimen for laboratory testing. If susceptibility data are not available for a given patient, the drugsusceptibility data for the suspected source case or regional susceptibility data should be used.2,39 Drug resistance should be expected in patients presenting for the retreatment of TB. These patients require retesting of drug susceptibility using freshly collected specimens. It is imperative to learn what drugs the patient received and for how long the patient received them.2,13,39 A treatment history, often called a “drug-o-gram,” shows the start and stop dates of all antimycobacterial drugs on a horizontal bar graph.2,39 A “drug-o-gram” should be constructed for all retreatment patients. 10 The standard TB treatment regimen is isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin for 4 months, for a total of 6 months of treatment.2,13,39 If susceptibility to isoniazid, rifampin, and pyrazinamide is shown, ethambutol can be stopped at any time. Without pyrazinamide, a total of 9 months of isoniazid and rifampin treatment is required. Table 110–3 shows the recommended treatment regimens. When intermittent therapy is used, DOT is essential. Doses missed during an intermittent TB regimen decrease its efficacy and increase the relapse rate. Note that Table 110–3 shows recommendations that differ for HIV-negative and HIV-positive patients. HIV-positive patients should not receive highly intermittent regimens. In general, regimens given daily five times each week or three times weekly can be used for HIV-positive patients. Less frequent dosing has been associated with higher failure and relapse rates and the selection of rifampin-resistant organisms.39 CLINICAL CONTROVERSY The recommended duration of treatment often is the same for HIV-negative and HIV-positive patients. However, some clinicians believe that thereapy should be extended for patients with weakened immune systems. These clinicians treat HIVpositive patients with drug-susceptible TB for 9 months rather than the usual 6 months.

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TABLE 110–3. Drug Regimens for Culture-Positive Pulmonary Tuberculosis Caused by Drug-Susceptible Organisms

Regimen 1

Initial Phase Interval and Dosesc Drugs (Minimal Duration) INH RIF PZA EMB

Seven days per week for 56 doses (8 wk) or 5 d/wk for 40 doses (8 wk)c

INH RIF PZA EMB

Seven days per week for 14 doses (2 wk), then twice weekly for 12 doses (6 wk) or 5 d/wk for 10 doses (2 wk)e then twice weekly for 12 doses (6 wk)

3

INH RIF PZA EMB

4

INH RIF EMB

2

Regimen

Continuation Phase Interval and Dosesc,d Drugs (Minimal Duration)

1a

INH/RIF

1b 1cg

Range of Total Doses (Minimal Duration)

Ratinga (Evidence)b HIV – HIV +

182–130 (26 wk)

A (I)

A (II)

INH/RIF INH/RPT

Seven days per week for 126 doses (18 wk) or 5 d/wk for 90 doses (18 wk)c Twice weekly for 36 doses (18 wk) Once weekly for 18 doses (18 wk)

92–76 (26 wk) 74–58 (26 wk)

A (I) B (I)

A (II)f E (I)

2a

INH/RIF

Twice weekly for 36 doses (18 wk)

62–58 (26 wk)

A (II)

B (II)f

2bg

INH/RPT

Once weekly for 18 doses (18 wk)

44–40 (26 wk)

B (I)

E (I)

Three times weekly for 24 doses (8 wk)

3a

INH/RIF

Three times weekly for 54 doses (18 wk)

78 (26 wk)

B (I)

B (II)

Seven days per week for 56 doses (8 wk) or 5 d/wk for 40 doses (8 wk)c

4a

INH/RIF

273–195 (39 wk)

C (I)

C (II)

4b

INH/RIF

Seven days per week for 217 doses (31 wk) or 5 d/wk for 155 doses (31 wk)e Twice weekly for 62 doses (31 wk)

118–102 (39 wk)

C (I)

C (II)

Definition of abbreviations: EMB = Ethambutol; INH = isoniazid; PZA = pyrazinamide; RIF = rifampin; RPT = rifapentine. a Definitions of evidence ratings: A = preferred; B = acceptable alternative; C = offer when A and B cannot be given; E = should never be given. b Definition of evidence ratings: I = randomized clinical trial; II = data from clinical trials that were not randomized or were conducted in other populations; III = expert opinion. c When DOT is used, drugs may be given 5 days/week and the necessary number of doses adjusted accordingly. Although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice. d Patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31 week; either 217 doses [daily] or 62 doses [twice weekly]) continuation phase. e Five-day-a-week administration is always given by DOT. Rating for 5 day/week regimens is AIII. f Not recommended for HIV-Infected patients with CD4+ cell counts 12,000 cells/mm3 , < 4,000 cells/mm3 , or > 10% immature (band) forms. The SIRS secondary to infection. Sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or acute alteration in mental status. Sepsis with hypotension, despite fluid resuscitation, along with the presence of perfusion abnormalities. Patients who are on inotropic or vasopressor agents may not be hypotensive at the time perfusion abnormalities are measured. Presence of altered organ function requiring intervention to maintain homeostasis. Compensatory physiologic response to systemic inflammatory response syndrome that is considered secondary to the actions of anti-inflammatory cytokine mediators.

Systemic inflammatory response syndrome (SIRS)

Sepsis Severe sepsis

Septic shock

Multiple-organ dysfunction syndrome (MODS) Compensatory anti-inflammatory response syndrome (CARS)

HR = heart rate; RR = respiratory rate; T = temperature. From ref. 3–6.

GRAM-POSITIVE BACTERIAL SEPSIS

1 Since 1987, gram-positive organisms are the predominant

pathogens in sepsis and septic shock, accounting for approximately 50% of all cases.1 The causes are Staphylococcus aureus, Streptococcus pneumoniae, coagulase-negative staphylococci, and enterococci. Streptococcus pyogenes and viridans streptococci are less commonly involved.7,8 S. pneumoniae sepsis is associated with an overall mortality rate of over 25%. Factors related to a higher mortality include shock, respiratory insufficiency, preexisting renal failure, and the presence

Hypotension, hypoperfusion

Pancreatitis Severe sepsis Infection

Trauma SIRS Burns

Shock

Hemorrhage

Hypotension, low CI, DIC, ARDS,MODS

FIGURE 117–1. Relationship of infection, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock.

of a rapidly fatal underlying disease. Staphylococcus epidermidis is related most often to infected intravascular devices, such as artificial heart valves and stents and the use of intravenous and intraarterial catheters. The rates of nosocomial enterococcal bacteremia and associated sepsis are also increasing. Enterococci are isolated most commonly in blood cultures following a prolonged hospitalization and treatment with broad-spectrum cephalosporins.

GRAM-NEGATIVE BACTERIAL SEPSIS A greater proportion of patients with gram-negative bacteremia develop clinical sepsis, and gram-negative bacteria are also more likely to produce septic shock in comparison with gram-positive organisms (50% versus 25%, respectively).9 Escherichia coli is the most commonly isolated pathogen in sepsis.7−9 Other common gram-negative pathogens include Klebsiella spp., Serratia spp., Enterobacter spp., and Proteus spp. Pseudomonas aeruginosa, although not considered a predominant endogenous flora, is found widely in the environment and is the most frequent cause of sepsis fatality. These commensal organisms generally are not aggressive pathogens because normal host flora inhibit the overgrowth. However, when immunity breaks down, these organisms extend beyond normal sites and often progress from colonization to illness. With the administration of antimicrobial agents having broad spectra of activity, the protective microflora presumably are removed, thus allowing overgrowth of more virulent species. Additionally, the integrity of the gastrointestinal mucosa as a mechanical barrier is critical. The infectious implications of trauma, penetrating wounds, small surface ulcerations, mechanical obstructions, and ischemic necrosis of the bowel carry a high risk of subsequent gram-negative infection that often progresses to sepsis. Gram-negative sepsis results in a higher mortality rate compared with sepsis from any other groups of organisms.10−12 The major factor

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associated with the outcome of gram-negative sepsis appears to be the severity of any underlying condition. Patients with rapidly fatal conditions, such as acute leukemia, aplastic anemia, and more than 70% body surface area burn injury, have a significantly worse prognosis than do those patients with nonfatal underlying conditions, such as diabetes mellitus or chronic renal insufficiency.1,2,9

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CELLULAR COMPONENTS FOR INITIATING THE INFLAMMATORY PROCESS

Anaerobes usually are considered low-risk organisms for the development of sepsis. If present, anaerobes often are found together with other pathogenic bacteria that are found commonly in sepsis. Epidemiology reports suggested that polymicrobial infections accounted for 5% to 39% of sepsis.1,7 Mortality rates associated with polymicrobial infections are similar to sepsis caused by a single organism. Although some clinicians believe that the particular combination of organisms present in polymicrobial sepsis may provide clues to the source of infection, no clear source for the infection can be identified in up to 25% of cases. Other less common pathogens include meningococci, gonococci, rickettsiae, chlamydiae, and spirochetes.10

The pathophysiologic focus of gram-negative sepsis has been on the lipopolysaccharide component of the bacterial cell wall. Commonly referred to as endotoxin, this substance is unique to the outer membrane of the gram-negative cell wall and generally is released with bacterial lysis. Lipid A, the innermost region of the lipopolysaccharide, is highly immunoreactive and is considered responsible for most of the toxic effects observed with gram-negative sepsis. Although lipid A may affect tissues directly, its predominant effect is to activate macrophages and trigger inflammatory cascades critical in the progression to sepsis and septic shock.14,15 The endotoxin forms a complex with a protein called a lipopolysaccharide-binding protein that then engages the specific CD14 receptor on the surface of a macrophage. Subsequently, cytokine mediators are activated and released. In gram-positive sepsis, peptidoglycan appears to exhibit proinflammatory activity. Peptidoglycan comprises up to 40% of grampositive cell mass and is exposed on the cell wall surface. Although it competes with lipid A for similar binding sites on CD14, the potency of peptidoglycan is less than that of endotoxin.14

FUNGAL SEPSIS

PRO- AND ANTI-INFLAMMATORY MEDIATORS

ANAEROBIC AND MISCELLANEOUS BACTERIAL SEPSIS

infections increased more than 200% from 2 The rate of fungal 1

1979 to 2000. Candida spp. are common causes of fungal sepsis in hospitalized patients. While C. albicans remains the most dominant species, non-albicans Candida species, particularly C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei, have emerged gradually from 24% in the 1980s to 46% between 1997 and 2000.11,12 Other fungi identified as causes of sepsis include Cryptococcus, Coccidioides, Fusarium, and Aspergillus. Risk factors for fungal infection include abdominal surgery, poorly controlled diabetes mellitus, prolonged granulocytopenia, broad-spectrum antibiotic treatment, corticosteroid treatment, prolonged hospitalization, central venous catheter, total parenteral nutrition, hematologic malignancy, and chronic indwelling bladder (Foley) catheter. Mortality ranges from 41% to 71% in patients with fungemia.13 Hematologic diseases, neutropenia, and a higher number of positive blood cultures were associated with poor outcome irrespective of patient’s gender, age, or days of antifungal drug treatment.

VIRAL SEPSIS Viremia is common to many viral illnesses, but it does not usually lead to the development of clinical sepsis. Hypotension and disseminated intravascular coagulation (DIC) may occur with unusual viruses, such as Ebola virus and Lassa fever virus, and may be seen occasionally with influenza A, arbovirus, and possibly severe measles.10

PATHOPHYSIOLOGY The pathophysiologic sequelae resulting from the interaction between the invading pathogen and the human host are diverse, complex, and incompletely understood.14 Definitive relationships between infection and progression to septic shock have been difficult to demonstrate. Furthermore, clinical and histopathologic changes attributed to infection may be similar to those of coexisting conditions. Finally, observations from work with animal models of sepsis are difficult to apply to humans because of potential marked differences in responses.

Sepsis involves activation of inflammatory pathways, and a complex interaction between proinflammatory and anti-inflammatory mediators plays a major role in the pathogenesis of sepsis. The key proinflammatory mediators include tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6), which are released by activated macrophages. Other mediators that may be important for the pathogenesis of sepsis include interleukin 8 (IL-8), platelet-activating factor (PAF), leukotrienes, and thromboxane A2 .14,16,17 The significant anti-inflammatory mediators include IL-1 receptor antagonist (IL-1ra), IL-4, and IL-10.15,17,18 These anti-inflammatory cytokines inhibit the production of the proinflammatory cytokines and downregulate some inflammatory cells. TNF-α is considered the primary mediator of sepsis.14−17 The TNF-α level is highly elevated very early in the inflammatory response in most patients with sepsis. In meningococcemia, increased morbidity and mortality are associated with high plasma concentrations of TNF-α. TNF-α release leads to activation of other cytokines (IL-1β and IL-6) associated with cellular damage. In addition, TNFα stimulates the release of cyclooxygenase-derived arachidonic acid metabolites (thromboxane A2 and prostaglandins) that contribute to vascular endothelial damage. TNF-α also causes endothelial cells to express adhesion molecules, facilitating influx of granulocytes. The net effect of a given mediator can vary depending on the state of activation of the target cell, the presence of other mediators near the target cell, and the ability of the target cell to release mediators that can augment or inhibit the primary mediator. When the balance in the localized response is lost, the patient becomes systemically ill. As Fig. 117–2 illustrates, when there is a systemic spillover of excessive proinflammatory mediators, the patient presents with SIRS SIRS

CARS

TNF-α, IL-1β, IL-6, IL-8,

IL-1Ra, IL-4, IL-10

Pro-inflammatory mediators

Anti-inflammatory mediators

FIGURE 117–2. The balance between pro- and anti-inflammatory mediators.

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Fungal infection Gram-positive infection

Viral infection

Gram-negative infection

? Endotoxin (LPS) Release of primary mediators (TNF-α; IL-1; IFN, etc.) ACTH/endorphins release

Coagulation system activation

Endothelial/leukocyte molecular activation

Complement system activation

Kallikrein–kinin stimulation

Release of secondary mediators (PAF, other interleukins, eicosanoids, etc.)

PMN stimulation

Vasodilation

Endothelial damage and capillary leak

Shock MODS

FIGURE 117–3. Cascades of sepsis. ACTH = adrenocorticotropic hormone.

and possibly MODS. Shortly after this initial phase, counterregulatory pathways become activated, and there is a systemic spillover of excessive anti-inflammatory mediators, representing a compensatory anti-inflammatory response syndrome (CARS). The balance between pro- and anti-inflammatory mechanisms determines the degree of inflammation, ranging from local antibacterial activity to systemic tissue toxicity or organ failure7,14,17

CASCADE OF SEPSIS

3 The cascade leading to the development of sepsis is com-

plex and multifactorial, involving various mediators and cell lines16,17,19 (Fig. 117–3). Through the actions of the mediators, a variety of cells become activated, initiating detrimental cascades. Initially, macrophages become activated and produce inflammatory cytokines. These cytokines then influence a wide range of cells, including endothelial cells, lymphocytes, hepatocytes, neutrophils, and platelets. Endothelial cells that respond to and produce a variety of cytokines mediate a primary mechanism of injury with sepsis. When injured, endothelial cells allow circulating cells such as granulocytes and plasma constituents to enter inflamed tissues, which may result in organ damage. The microcirculation is affected by sepsis-induced inflammation.20 The arterioles become less responsive to either vasoconstrictors or vasodilators. The capillaries are less perfused, and there is neutrophil infiltration and protein leakage into the venules. Pulmonary dysfunction may result from the destructive mechanisms of neutrophils that are attracted to lung tissue through the action mainly of IL-8. Activation of complement in sepsis leads to pathophysiologic consequences including generation of anaphylactic toxins and other substances that augment or exaggerate the inflammatory response. Stimulation of leukocyte chemotaxis, phagocytosis with lysosomal enzyme release, increased aggregation and adhesion of platelets and neutrophils, and the production of toxic superoxide radicals is attributed in part to complement activation. Among these responses is

Death

the release of histamine from mast cells and the resulting increase in capillary permeability and the “third spacing” of fluid in interstitial spaces. The inflammatory process in sepsis is also directly linked to the coagulation system. Proinflammatory mechanisms that promote sepsis are also procoagulant and antifibrinolytic, whereas fibrinolytic mechanisms may be anti-inflammatory. A key endogenous substance involved in the inflammation of sepsis is activated protein C, which enhances fibrinolysis and inhibits inflammation. Levels of protein C are reduced in patients with sepsis.21

PREDICTIVE MARKERS OF SEPSIS PROGRESSION Correlation between the plasma levels of endotoxin and cytokines and the progression of sepsis has been evaluated.22−26 While the TNF-α levels may be increased in patients with a variety of diseases and in many healthy people, there is a correlation of TNF-α levels with the severity of sepsis. High TNF-α levels are found in patients with septic shock. In contrast, IL-1 levels have been inconsistently associated with sepsis.24 IL-6 may be a more consistent predictor of sepsis because it remains elevated for a longer period of time than does TNF-α, and it appears to be related to sepsis severity and mortality.23,25 Circulating concentrations of IL-8 also have been related to the severity of sepsis and mortality.26 Although the plasma endotoxin concentration does not correlate with the development of gram-negative sepsis or outcome from infection, decreased antiendotoxin core immunoglobulin G concentrations are associated with increased mortality in patients with sepsis syndrome.27

COMPLICATIONS Shock is the most ominous complication associated with sepsis, and mortality occurs in approximately half the patients with septic shock. Severe hypotension appears to be caused in part by the release of

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vasoactive peptides such as bradykinin and serotonin and by endothelial cell damage leading to the extravasation of fluids into interstitial spaces. Septic shock is associated with several complications, including DIC, acute respiratory distress syndrome (ARDS), and MODS.

DISSEMINATED INTRAVASCULAR COAGULATION (DIC) Sepsis remains the most common cause of DIC. The incidence of DIC increases as the severity of sepsis increases. In sepsis alone, the incidence was 16%, in comparison with 38% in septic shock.28 DIC occurs in up to 50% of patients with gram-negative sepsis, but it is also common in patients with gram-positive sepsis. DIC begins with the activation and production of the proinflammatory cytokines such as TNF, IL-1, and IL-6, which appear to be the principal mediators, along with endotoxin, of endothelial injury, activation of the coagulation cascade, and inhibition of fibrinolysis. The combination of excessive fibrin formation, inhibited fibrin removal from a depressed fibrinolytic system, and endothelial injury results in microvascular thrombosis and DIC.28 Complications of DIC vary and depend on the target organ affected and the severity of the coagulopathy. DIC may produce acute renal failure, hemorrhagic necrosis of the gastrointestinal mucosa, liver failure, acute pancreatitis, ARDS, and pulmonary failure. Furthermore, since the procoagulant state appears to be the key in the pathogenesis of MODS, coagulation dysfunction and MODS often coexist in sepsis.

ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) Pulmonary dysfunction usually precedes dysfunction in other organs, and it may even initiate the development of SIRS with resulting MODS. In sepsis caused by S. aureus, pulmonary involvement was reported in 82% of the patients.29 Overall mortality rate ranges from 19% to 90% depending on the causative microorganism.29,30 Activated neutrophils and platelets adhere to the pulmonary capillary endothelium, initiating multiple inflammatory cascades with a release a variety of toxic substances. There is diffuse pulmonary endothelial cell injury, increased capillary permeability, and alveolar epithelial cell injury.31 Consequently, interstitial pulmonary edema occurs and gradually progresses to alveolar flooding and collapse. The end result is loss of functional alveolar volume, impaired pulmonary compliance, and profound hypoxemia.32

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2135

occurs without increased blood flow, the increased Vo2 is compensated by increased oxygen extraction. If perfusion decreases sufficiently in the face of high metabolic demands, then the reserve DO2 can be exceeded, and tissue ischemia results. Significant tissue ischemia leads to organ dysfunction and failure. Therefore, systemic DO2 relative to VO2 should be optimized by increasing oxygen delivery or decreasing oxygen consumption in a hypermetabolic patient.

ACUTE RENAL FAILURE Renal dysfunction such as acute oliguric or anuric renal failure occurs in approximately one-quarter of the patients, and in the event of severe sepsis and MODS, renal dysfunction is potentially lethal, with a mortality of 50% to 90%.2,31 Without normal urine output, fluid overload in the extravascular space, including the lungs, develops, leading to impairment of pulmonary gas exchange and severe hypoxemia. Consequently, compromised oxygen delivery would exacerbate peripheral ischemia and organ damage. Adequate renal perfusion and a trial of loop diuretics should be initiated promptly in oliguric or anuric patients with MODS. In addition, renal replacement therapy such as continuous hemofiltration should be used to facilitate volume and electrolytes.31

CLINICAL PRESENTATION Table 117–2 lists some of the common clinical features of sepsis, although a number of these findings are not limited to infectious processes. The initial clinical presentation can be referred to as signs and symptoms of early sepsis, and they typically include fever, chills, and change in mental status. Hypothermia may occur with a systemic infection, and this is often associated with a poor prognosis.10 In patients with sepsis caused by gram-negative bacilli, hyperventilation may occur even before fever and chills, and it may lead to respiratory alkalosis as the earliest metabolic change. Progression of uncontrolled sepsis leads to clinical evidence of organ system dysfunction, as represented by the signs and symptoms attributed to late sepsis. With the exception of rapidly progressing cases, as in meningococcemia and P. aeruginosa or Aeromonas infection, the onset of shock is slow and usually follows a period of several hours of hemodynamic instability. Oliguria often follows hypotension. Increased glycolysis with impaired clearance of the resulting lactate by the liver and kidneys and tissue hypoxia because of hypoperfusion result in elevated lactate levels, contributing to metabolic

HEMODYNAMIC EFFECTS The hallmark of the hemodynamic effect of sepsis is the hyperdynamic state characterized by high cardiac output and an abnormally low systemic vascular resistance (SVR).33 TNF-α and endotoxin directly depress cardiovascular function. Endotoxin depresses left ventricular function independent of changes in left ventricular volume or vascular resistance. Persistent hypotension raises concern for the balance of oxygen delivery to the tissues (DO2 ) and oxygen consumption by the tissues (VO2 ).31 Sepsis results in a distributive shock characterized by inappropriately increased blood flow to selected tissues at the expense of other tissues that is independent of specific tissue oxygen needs. This perfusion defect is accentuated by an increased precapillary atrioventricular (AV) shunt. If perfusion decreases, oxygen extraction increases, and the AV oxygen gradient widens. Cellular DO2 is decreased, but VO2 remains unaffected. When increased oxygen demand

TABLE 117–2. Signs and Symptoms Associated with Sepsis Early Sepsis

Late Sepsis

Fever or hypothermia Rigors, chills Tachycardia Tachypnea Nausea, vomiting Hyperglycemia Myalgias Lethargy, malaise Proteinuria Hypoxia Leukocytosis Hyperbilirubinemia

Lactic acidosis Oliguria Leukopenia DIC Myocardial depression Pulmonary edema Hypotension (shock) Hypoglycemia Azotemia Thrombocytopenia ARDS Gastrointestinal hemorrhage Coma

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60 50 40 30 20 10 0

0

1

2 3 Number of failing organs

4

5

FIGURE 117–4. Mortality related to the number of failing organs.

acidosis. Altered glucose metabolism, including impaired gluconeogenesis and excessive insulin release, is evidenced by either hyperglycemia or hypoglycemia. The distinction between early and late sepsis is arbitrary, and it is recognized that sepsis represents a spectrum of clinical findings.

PROGNOSIS

4 As the patient progresses from SIRS to sepsis to severe sepsis to

septic shock, mortality increases in a stepwise fashion. Mortality

rates are higher for patients with advanced age; preexisting disease, including chronic obstructive pulmonary disease (COPD), neoplasm, and human immunodeficiency virus (HIV) disease; ICU care; and more organ failure. Mortality increased with age from 10% in children to 38.4% in those ≥85 years.2 ICU admission was required in 51.1% of the patients with severe sepsis, and of those patients, mortality was reported in 34.1%.2 Mortality from severe sepsis and MODS is most closely related to the number of dysfunctioning organs. As the number of failing organs increased from two to five, mortality increased from 54% to 100%31 (Fig. 117–4). Duration of organ dysfunction also may affect the overall mortality rate.


TREATMENT: Sepsis and Septic Shock The primary goals of therapy for patients with sepsis include (1) timely diagnosis and identification of pathogen, (2) rapid elimination of the source of infection medically and/or surgically, (3) early initiation of aggressive antimicrobial therapy, (4) interruption of pathogenic sequence leading to septic shock, and (5) avoidance of organ failure. Supportive care such as stress ulcer prophylaxis and nutritional support is important to prevent complications during the stay in the ICU.


DIAGNOSIS AND IDENTIFICATION OF PATHOGEN


ELIMINATION OF SOURCE OF INFECTION After the source of infection is identified, prompt efforts to remove or eliminate the source should be initiated. With an infected intravascular catheter, the catheter should be removed and cultured. Urinary tract catheters should be removed if association with sepsis is suspected. Suspicion of soft tissue (cellulitis or wound infection) or bone involvement should lead to aggressive d´ebridement of the affected area. Evidence of an abscess or sepsis associated with any intraabdominal pathology should prompt surgical intervention.

5 The presence of clinical features suggesting sepsis should

prompt further evaluation of the patient. In addition to obtaining a careful history of any underlying conditions and recent travel, injury, animal exposure, infection, or use of antibiotics, a complete physical examination should be performed to determine the source of the infection. A collection of specimens should be sent for culture prior to initiating any antimicrobial therapy. Generally, at least two sets of blood samples should be obtained for aerobic and anaerobic culture, as well as the samples of urine and sputum. A lumbar puncture is indicated in case of mental alteration, severe headache, or a seizure, assuming that no focal cranial lesions have been identified by computed tomographic (CT) scan. Further tests may be indicated to assess any systemic organ dysfunction owing to severe sepsis. The laboratory tests should include hemoglobin, white blood cell count with differential, platelet count, complete chemistry profile, coagulation parameters, serum lactate concentration, and arterial blood gases.34


ANTIMICROBIAL THERAPY

6 Aggressive, early antimicrobial therapy is critical in the man-

agement of septic patients because of high incidence of complications and mortality. Because of the inherent problems associated with timely identification of the infecting organism or organisms, empirical antimicrobial regimens usually are started initially. Selection of empirical regimen should be based on the suspected site of infection, the most likely pathogens, acquisition of the organism from the community or hospital, the patient’s immune status, and the antibiotic susceptibility and resistance profile for the institution. All patients should be treated initially with parenteral antibiotics for optimal drug concentrations. Empirical therapy for an immunocompromised patient should consist of antimicrobial combinations likely to be

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TABLE 117–3. Empirical Antimicrobial Regimens in Sepsis Infection (Site or Type) Urinary tract

Antimicrobial Regimen Community-Acquired Ciprofloxacin

Piperacillin or

levofloxacin

Respiratory tract

Intra-abdominal

Skin/soft tissue

Hospital-Acquired

Newer fluoroquinolonea or ceftriaxone + clarithromycin-azithromycin β-Lactamase inhibitor combob or ciprofloxacin + metronidazole Nafcillin or cefazolin

Catheter-related Unknown

or ceftazidime, ceftriaxone or ciprofloxacin, levofloxacin Piperacillin, ticarcillin or ceftazidime, cefipime

b

       

± gentamicin

+ gentamicin or ciprofloxacin

Piperacillin-tazobactam or meropenem Ceftriaxone +/− vancomycin

Vancomycin Piperacillin or ceftazidime-cefipime or meropenem

a

     

  +gentamicin +/− vancomycin 

Levofloxacin, gatifloxacin, moxifloxacin, gemifloxacin. Ampicillin–sulbactam, ticarcillin–clavulanic acid.

synergistic. Once the pathogen and its susceptibility pattern are known, antimicrobial regimen should be modified accordingly.


SELECTION OF ANTIMICROBIAL AGENTS In a study evaluating 904 patients with microbiologically confirmed severe sepsis or septic shock, appropriate initial antimicrobial therapy was an important determinant of survival.7 The 28-day mortality was 24% in patients who received appropriate initial antimicrobial treatment versus 39% in those who received inappropriate initial treatment. Table 117–3 lists antimicrobial regimens that can be used empirically based on the possible source of infection. In the nonneutropenic patient with an urinary tract infection, a third-generation cephalosporin, fluoroquinolone, or extended-spectrum penicillin, each with or without an aminoglycoside, should be considered.35 S. pneumoniae is the most common cause of community-acquired pneumonia, and it accounts for approximately 60% of all deaths. The rising incidence of penicillin-resistant S. pneumoniae requires empirical use of newer “respiratory” fluoroquinolones. Newer fluoroquinolones, such as levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin, can be used as monotherapy because they offer excellent coverage against penicillin-resistant pneumococci and aerobic gram-negative bacteria, as well as atypical pathogens, including Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae.36,37 Newer macrolides, such as clarithromycin and azithromycin, are very effective against atypical pathogens and better tolerated than erythromycin. In nosocomial pneumonia, enteric gram-negative bacteria such as Enterobacter and Klebsiella spp., and P. aeruginosa are the major pathogens in addition to S. aureus. If P. aeruginosa infection is suspected, a dual regimen of antipseudomonal penicillin or third- or fourth-generation cephalosporin and an aminoglycoside is

recommended because of the high mortality rate associated with Pseudomonas infection.35 When an aminoglycoside is undesirable, an antipseudomonal fluoroquinolone such as ciprofloxacin or levofloxacin can be used instead. In case of methicillin-resistant S. aureus, vancomycin should be initiated. However, worldwide emergence of glycopeptide intermediately resistant S. aureus and vancomycin-resistant enterococci has led to development of alternative antimicrobial agents such as teicoplanin, quinupristin-dalfopristin, and linezolid.38−40 Secondary peritonitis as a consequence of perforation of the gastrointestinal tract usually is polymicrobial, involving enteric aerobes and anaerobes, and as many as five organisms are isolated per patient. In addition to surgical intervention, broad-spectrum antibiotics such as β-lactamase inhibitor combination agents (piperacillin-tazobactam or ticarcillin-clavulanate) are appropriate in intraabdominal infections.41 Imipenem or meropenem may be indicated if resistance patterns prohibit the use of other, less expensive therapies.42,43 Currently, most clinicians prefer meropenem to imipenem because it offers similar activity as imipenem with less propensity to cause seizures. In a multicenter study, meropenem was efficacious and safe when compared with a combination regimen of cefuroxime and gentamicin for the treatment of sepsis syndrome in patients who were 65 years of age or older.42 Metronidazole is preferred over clindamycin against anaerobes because approximately 20% of Bacteroides spp. are resistant to clindamycin.44 In soft tissue infection caused by group A Streptococcus, streptococcal toxic shock syndrome may occur. Although penicillin and cefazolin are efficacious, experimental models of group A streptococcal infection show clindamycin to be more effective than penicillin.35 In addition to selecting the most appropriate antimicrobial agents, a clinician must ensure effective antibiotic usage, such as proper dosing, interval administration, optimal duration of treatment, monitoring of drug levels when appropriate, and avoidance of unwanted drug interactions. Lack of adherence to these requirements

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may lead to suboptimal or excessive tissue concentrations that may promote antibiotic resistance, toxicity, and inadequate efficacy despite appropriate antibiotic selection.


THERAPEUTIC CONSIDERATIONS WITH AMINOGLYCOSIDES In vitro, tobramycin appears somewhat more active (based on concentrations achievable in serum relative to usual minimum inhibitory concentration) than gentamicin against P. aeruginosa. Gentamicin, however, appears more active than tobramycin against Serratia spp. Overall, amikacin exhibits most potent in vitro activity against the Klebsiella-Enterobacter-Serratia group. In addition, amikacin is less susceptible than gentamicin and tobramycin to plasmid-mediated enzyme inactivation, and it should be reserved as an alternative in situations of suspected or established resistance to gentamicin and tobramycin. CLINICAL CONTROVERSY Although aminoglycosides traditionally have been administered in divided doses, there has been increasing acceptance of administering aminoglycosides in a single daily dose of 4 to 7 mg/kg for gentamicin and tobramycin and 10 to 15 mg/kg for amikacin.45−47 A single daily dose maximizes the well-defined, concentration-dependent killing activity of aminoglycosides, as well as the prolonged postantibiotic effect against gram-negative bacterial pathogens. Furthermore, nephrotoxicity is reduced significantly. With a single daily dose, there is a prolonged drug-free period during which the reported saturable or rate-limiting uptake of aminoglycosides into proximal renal tubular cells can be completed. Because of insufficient clinical data, single daily dose administration should not be used in pediatric patients, burn victims, pregnant patients, patients with preexisting or progressive renal dysfunction, or patients requiring aminoglycosides for synergy against gram-positive pathogens.


ANTIFUNGAL THERAPY Candida species are associated most frequently with fungal infections, and the resulting candidemia frequently is associated with sepsis syndrome and a high mortality rate.11,12,48 Treatment of invasive candidiasis involves amphotericin B–based preparations, the azole antifungal agents, the echinocandin antifungal agents, or combination therapy with fluconazole plus amphotericin B. The choice depends on the clinical status of the patient, the fungal species and its susceptibility, the relative drug toxicity, the presence of organ dysfunction that would affect drug clearance, and the patient’s prior exposure to antifungal agents. In general, suspected systemic mycotic infection leading to sepsis is treated frequently with parenteral amphotericin B empirically, especially if the patient is clinically unstable, because of its greater activity against Candida species and non-albicans species including C. glabrata and C. krusei.48 Fluconazole is less toxic and easier to administer than amphotericin B. However, fluconazole resistance among C. albicans has been well described among HIV-infected individuals and is increasing in immunocompetent adults.48 C. glabrata often has reduced susceptibility to fluconazole. Itraconazole exhibits a similar activity profile to fluconazole and is well known to be active against mucosal forms of candidiasis. However, formal clinical trials using intravenous

itraconazole are not available for invasive candidiasis. Voriconazole appears to be active against Candida species, including fluconazoleresistant isolates. A recently completed worldwide study will aid in analyzing voriconazole for the indication of treatment of serious invasive, fluconzole-resistant Candida infections including C. krusei.48 CLINICAL CONTROVERSY Three new lipid formulations of amphotericin (amphotericin B lipid complex, amphotericin B cholesteryl sulfate, and liposomal amphotericin B) offer several advantages over amphotericin B deoxycholate.49 They are less nephrotoxic, allow increased daily doses, have high tissue concentrations in the reticuloendothelial organs such as lungs, liver, and spleen, and have decreased infusion-associated side effects. However, superior clinical efficacy over the conventional amphotericin B or between the lipid formulations has not established clearly in comparative clinical trials. Higher cost and the lack of overall benefit of using a lipid formulation have led to placing the lipid-associated preparations as primarily for patients who are intolerant of or have an infection refractory to the deoxycholate preparation.50 However, recent data reported an association of amphotericin B–induced nephrotoxicty with increased mortality, up to 6.6-fold, suggesting the use of a lipid formulation initially for patients at high risk of being intolerant.48,51 Caspofungin, the first echinocandin antifungal agent, appears to be potent against all Candida spp., including C. glabrata, C. krusei, and C. lusitaniae and Aspergillus spp. Intravenous caspofungin was reported to be equally effective but better tolerated than amphotericin B deoxycholate for invasive candidiasis.52


ANTIVIRAL THERAPY When sepsis is caused by a systemic viral infection, parenteral antivirals such as acyclovir, ganciclovir, foscarnet, or ribavirin are used, depending on the suspected or documented viral pathogen. Aerosol administration of ribavirin may be indicated in serious illness secondary to respiratory syncytial virus.


DURATION OF THERAPY The average duration of antimicrobial therapy in the normal host with sepsis is 10 to 14 days.7,48 However, the duration may vary depending on the site of the infection, as well as the overall response to therapy. After the patient is stable hemodynamically, has been afebrile for 48 to 72 hours, has a normalizing white blood cell (WBC) count, and is able to take oral medications, then a step-down from parenteral to oral antibiotics can be considered for the remaining duration of therapy. Treatment may continue considerably longer if the infection is persistent. In a neutropenic patient, therapy usually is continued until the patient is no longer neutropenic and has been afebrile for at least 72 hours.


HEMODYNAMIC SUPPORT A high cardiac output and a low systemic vascular resistance characterize septic shock. Patients may have hypotension as a result of

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low systemic vascular resistance and abnormal distribution of blood flow in the microcirculation, resulting in compromised tissue perfusion. Because approximately half of patients with septic shock die of MOSF, they should be monitored carefully, and aggressive hemodynamic support should be initiated. Hemodynamics change rapidly in sepsis, and noninvasive evaluation may give inaccurate assessment of filling pressures and cardiac output, requiring a right-sided heart catheter in an intensive care unit.53 Hemodynamic support can be divided into three main categories: fluid therapy, vasopressor therapy, and inotropic therapy.


FLUID THERAPY as a result of 7 Septic patients have enormous fluid requirements 53

peripheral vasodilation and capillary leakage. Rapid fluid resuscitation is the best initial therapeutic intervention for the treatment of hypotension in sepsis. The goal of fluid therapy is to maximize cardiac output by increasing the left ventricular preload, which ultimately will restore tissue perfusion.53 Fluid administration should be titrated to clinical end points such as heart rate, urine output, blood pressure, and mental status. An increased serum lactate level, a byproduct of cellular anaerobic metabolism, should normalize as the tissue perfusion improves. Isotonic crystalloids, such as 0.9% sodium chloride (normal saline) or lactated Ringer’s solution, are used commonly for fluid resuscitation. A patient in septic shock typically requires up to 10 L of crystalloid solution during the first 24-hour period. These solutions distribute into the extracellular compartment. Approximately 25% of the infused volume of crystalloid remains in the intravascular space, whereas the balance distributes to extravascular spaces. Although this could impair diffusion of oxygen to tissues, clinical impact is unproven. The most commonly used colloids are 5% albumin, naturally occurring plasma protein, and 6% hetastarch, a synthetic colloid formulation. These solutions offer more rapid restoration of intravascular volume because they produce greater intravascular volume expansion per quantity of volume infused. Colloids produce less peripheral edema than crystalloid, but there is no significant clinical impact. The use of colloid solutions and blood products may be particularly important if there is significant blood loss associated with sepsis or if the patient had severe preexisting anemia. The major complications with fluid resuscitation are pulmonary and systemic edema. Aggressive volume expansion may cause an increase in pulmonary capillary pressure leading to an increase in lung water and associated hypoxemia. Currently available studies and reports suggest that there is no significant difference in the incidence of pulmonary edema between the crystalloid and colloid solutions. A meta-analysis of clinical studies comparing crystalloid and colloid resuscitation indicated no clinical outcome differences.54

SEPSIS AND SEPTIC SHOCK

Although crystalloid solutions require two to four times more volume than colloids, they are generally recommended for fluid resuscitation owing to the lower cost. However, colloids may be preferred, especially when the serum albumin concentration is less than 2.0 g/dL.


VASOPRESSOR AND INOTROPIC THERAPY When fluid resuscitation alone provides inadequate arterial pressure and organ perfusion, vasopressors and inotropic agents should be initiated. Inotropic agents such as dopamine and dobutamine have been effective in improving cardiac output. Vasopressors should be considered when a systolic blood pressure is less than 90 mm Hg or mean arterial pressure (MAP) is lower than 60 to 65 mm Hg after adequate left ventricular preload and inotrope therapy. Although inotropes and vasopressors are effective in life-threatening hypotension and in improving cardiac index, there are significant complications, such as tachycardia and myocardial ischemia and infarction, as a result of the change in myocardial oxygen consumption in patients with coexisting coronary disease. Thus a catecholamine infusion should be titrated gradually to restore MAP without impairing stroke volume. Agents commonly considered for vasopressor or inotropic support include dopamine, dobutamine, norepinephrine, phenylephrine, and epinephrine55,56 (Table 117–4). Dopamine, an α- and β-adrenergic agent with dopaminergic activity, appears to increase MAP effectively in patients who remain hypotensive with reduced cardiac function after aggressive fluid resuscitation. Thus it is often the initial choice in sepsis because of combined vasopressor and inotropic effects. While low-dose dopamine (1 to 5 mcg/kg per minute) is effective in maintaining renal perfusion, higher doses (>5 mcg/kg per minute) exhibit α and β activity and are used frequently to support blood pressure and to improve cardiac function such as an increase in cardiac index (CI). Dobutamine is a β-adrenergic inotropic agent that many clinicians consider to be the preferred drug for improvement of cardiac output and oxygen delivery, particularly in early sepsis before significant peripheral vasodilation has occurred. Doses of 2 to 20 mcg/kg per minute increases the CI, ranging from 20% to 66%. However, heart rate often increases significantly.53 Dobutamine should be considered in severely septic patients with adequate filling pressures and blood pressure but low CI. Norepinephrine is a potent α-adrenergic agent with less pronounced β-adrenergic activity, and it can be useful in septic shock when the clinician desires potent vasoconstriction of peripheral vascular beds. Doses of 0.01 to 3 mcg/kg per minute can reliably increase blood pressure with little change in heart rate or cardiac index. Norepinephrine is a more potent agent than dopamine in refractory septic shock. Despite the earlier concern of decreased renal blood flow associated with norepinephrine, data in humans and animals demonstrate a

TABLE 117–4. Receptor Activity of Cardiovascular Agents Commonly Used in Septic Shock Agent Dopamine Dobutamine Norepinephrine Phenylephrine Epinephrine

2139

α1

α2

β1

β2

Dopaminergic

++/+++ + +++ ++/+++ ++++

? + +++ + ++++

++++ ++++ +++ ? ++++

++ ++ +/++ 0 +++

++++ 0 0 0 0

α 1 = α 1 -adrenergic receptor; α 2 = α 2 -adrenergic receptor; β 1 = β 1 -adrenergic receptor; β 2 = β 2 -adrenergic receptor; 0 = no activity; ++++ = maximal activity; ? = unknown activity.

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norepinephrine-induced renal blood flow as well as urine and cardiac output.55−57 Phenylephrine, a selective α 1 -agonist, has a rapid onset, short duration, and primary vascular effects, making it an attractive agent in the management of hypotension associated with septic shock. The limited available information suggests that it can increase blood pressure in fluid-resuscitated patients, and it does not appear to impair cardiac or renal function. Phenylephrine appears useful when tachycardia limits the use of other vasopressors. Epinephrine, a nonspecific α- and β-adrenergic agonist, is capable of increasing CI and producing significant peripheral vasoconstriction in doses of 0.1 to 0.5 mcg/kg per minute. However, because of its undesirable effects, including a propensity to increase lactate level and to impair blood flow to the splanchnic system, it should be reserved for patients who fail to respond to traditional therapies for increasing or maintaining blood pressure. During hypotension, endogenous vasopressin levels increase and maintain arterial blood pressure by vasoconstriction. However, there is a vasopressin deficiency in septic shock. Low doses of vasopressin (0.01 to 0.04 units/min) have been demonstrated to produce a significant rise in MAP in septic shock, leading to the discontinuation of other vasopressors.55,58 While it may be beneficial to patients requiring high-dose vasopressors, routine use is not currently recommended owing to a lack of large, randomized, prospective clinical trials.55,57 In summary, for the septic patient with clinical signs of shock and significant hypotension unresponsive to aggressive fluid therapy, dopamine is the preferred agent for increasing the blood pressure. If dopamine does not produce the desired hemodynamic response, norepinephrine can be used. Epinephrine should be considered for refractory hypotension. Dopamine and epinephrine are more likely to induce or exacerbate tachycardia than norepinephrine and phenylephrine. In a septic patient with low CI after adequate fluid therapy and an adequate MAP, dobutamine is the first-line agent. Alternatively, dopamine in moderate doses (5 to 10 mcg/kg per minute) also can be used as an initial agent because of its selective effect on increasing cardiac output with its minimal effect on the systemic vascular resistance.


EARLY GOAL-DIRECTED THERAPY

8 A trial evaluated the timing of the goal-directed therapy involv-

ing adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with demand prior to admission to the intensive care unit. The mortality rate was 30% in the group receiving early goal-directed therapy including a placement of central venous catheter, more fluid than with traditional therapy, dobutamine therapy to a maximum of 20 mcg/kg per minute, and red blood cell transfusions during the first 6 hours. In comparison, the mortality rate was 46.5% in the traditional therapy group consisting of fluid resuscitation followed by vasopressor therapy if required.59 Increased oxygen delivery from the red blood cell transfusions in the early goal-directed therapy group appeared to be the primary difference between the two groups.


ADJUNCTIVE THERAPIES ARDS and hypoxia are common in septic patients, even in septic patients without pulmonary infection. Oxygen therapy is indicated to

maintain oxygen saturation greater than 90%, and with progressive pulmonary insufficiency, the patient may require assisted ventilation. The management of patients with ARDS is primarily supportive. Uncontrolled reports suggest that intravenous methylprednisolone in doses of 75 to 250 mg every 6 hours may improve survival in severely ill patients with refractory late ARDS.60,61 Ketoconazole reduced the progression to ARDS and increased survival in a small study of septic surgical patients, possibly as a result of its inhibitory effects on alveolar macrophage production of leukotriene B4 and thromboxane A2 .62 Nitric oxide (NO), a potent endogenous vasodilator, improved arterial oxygenation and reduced pulmonary artery pressures in patients with ARDS. However, it is also associated with hypotension, as well as being a mediator of sepsis-induced refractoriness to the vasopressor effects of catecholamines.63 Additional work is needed to define any role for NO and ketoconazole in the management of sepsis. Hyperglycemia frequently is associated with sepsis, and it is usually quite refractory to exogenous insulin. Intensive insulin therapy, maintaining blood glucose level at 80 to 110 mg/dL resulted in lower morbidity and mortality among critically ill patients in comparison with those with blood glucose levels of 180 to 200 mg/dL.64 Insulin therapy also reduced the rate of death from multiple-organ failure among patients with sepsis, regardless of presence of diabetes prior to sepsis. The corticosteroids have been the subject of much controversy in the management of septic patients.65,66 Corticosteroids suppress the activation of polymorphonuclear leukocytes, complement activation, release of TNF, and activation of the coagulation system involved in the cascades of sepsis. A recent study demonstrated a decrease in mortality (absolute reduction of 10%) with lower doses of hydrocortisone and fludrocortisone in patients with adrenal insufficiency requiring high-dose or increasing vasopressor therapy within the first 8 hours of septic shock.67 There was no benefit for those patients without adrenal insufficiency. In summary, routine use of corticosteroids in patients with sepsis or septic shock is not recommended until further study. Heparin therapy for DIC is discouraged by most clinicians because there is no evidence that heparin prolongs the survival of patients despite its effect on the hypercoagulable condition found in DIC.68 Hemorrhage is best managed by the replacement of clotting factors, platelets, and packed red blood cells. Patients with severe sepsis are susceptible to progressive malnutrition secondary to the hypermetabolism associated with severe illness and injury.69 Hence early enteral nutrition is recommended in patients with severe sepsis and septic shock to meet the increased energy and protein requirements. Protein requirements are increased to 1.5 to 2.5 g/kg per day, and increased amounts of branched-chain amino acids may be beneficial in septic patients.70 Nonprotein caloric requirements range from 25 to 40 kcal/kg per day, and overfeeding of carbohydrates should be avoided to reduce the ventilatory requirements of the patient. The use of increased amounts of lipid to meet nonprotein caloric needs while reducing carbohydrate administration may be useful in this setting.


IMMUNOTHERAPY A number of strategies have been used to reverse or control the inflammatory process initiated during sepsis71 (Table 117–5). Despite the initial enthusiasm in immunotherapeutic interventions for sepsis,

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CHAPTER 117 TABLE 117–5. Summary of Selected Clinical Trials for Sepsis Experimental Agent

Comments

HA-1A (antilipid A MAb)

E5 (antilipid A MAb) Interleukin 1 receptor antagonist Platelet-activating factor inhibitors Bradykinin antagonists Anti-TNF MAb

TNF receptor: immunoglobulin constructs L-N-Monomethylarginine

No overall benefit; favorable trend in meningococcemia (preliminary report) No overall benefit; improved organ dysfunction in some subgroups No overall benefit No overall benefit; favorable trend in gram-negative sepsis No overall benefit; favorable trend in gram-negative sepsis No overall benefit; some evidence of improvement in subgroups of shock patients Phase II: p75 receptor worsened outcome (p 85%) than with ketoconazole (62% to 83%). Mycologic cure rates and relapse-free periods also generally are better with fluconazole and itraconazole than with ketoconazole.23,25


OROPHARYNGEAL CANDIDIASIS—NON–HIV-INFECTED PATIENTS This patient population includes patients with hematologic malignancy (e.g., leukemias) or blood and marrow transplant (BMT) with a long duration of neutropenia and chronic graft-versus-host disease, patients with solid tumors, patients with solid-organ transplants who are receiving immunosuppressive therapy, and patients with diabetes mellitus; as well as patients on prolonged courses of antibiotics or corticosteroids and the debilitated elderly. Factors to consider in deciding whether to use topical or systemic antifungal therapy include the severity and extent of mucosal involvement (oropharyngeal versus esophageal), predisposing risk factors, and risk for dissemination. Patients who develop neutropenia (e.g., leukemic and BMT patients) are usually at high risk for disseminated and invasive fungal disease, and treatment of oral candidiasis is more aggressive. Patients with cell-mediated immune deficits but normal or near-normal granulocyte function and number (e.g., solid tumors, solid-organ transplants, or diabetic patients) are at low risk for dissemination of infection. Specific antifungal therapy may be unnecessary for asymptomatic patients at relatively low risk for disseminated candidiasis, such as those who are not granulocytopenic or who are expected to have a short duration of granulocytopenia.29 Many of these infections will clear spontaneously after recovery of the granulocytes or discontinuation of antibiotic and/or immunosuppressive therapy. However, antifungal therapy usually is required for patients who have persistent infection or significant symptoms, usually pain, or who are granulocytopenic with a relatively high risk of fungal dissemination.29 Topical agents first may be given a therapeutic trial depending on the severity of infection and degree of immunosuppression. Although both nystatin and clotrimazole can be effective in treating OPC, nystatin suspension does not effectively reduce the incidence of either oropharyngeal or systemic Candida infections in immunocompromised patients receiving chemotherapy or radiation; its use often is associated with treatment failures and early relapses.21,29,30 Clotrimazole appears to more effective in reducing colonization and treating acute episodes in cancer patients who are immunocompromised. Systemic azole agents are used for treating OPC in patients who have failed or who are unable to take topical therapy.21,28,29 The preceding discussion on the relative efficacy of fluconazole, itraconazole, and ketocoanzole in HIV-infected patients may be extrapolated to the non–HIV-infected population. Fluconazole 100 to 200 mg daily is used more commonly because of more extensive experience with its use, and it is more effective and has a more favorable absorption and side-effect profile compared with ketoconazole.23,25 If the oral route is not feasible for reasons such as severe chemotherapy-induced mucositis, fluconazole may be administered intravenously. In patients unresponsive to azoles, intravenous amphotericin B in relatively low doses

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of 0.1–0.3 mg/kg per day may be tried.29 Because of the higher risk for dissemination in patients who are severely neutropenic (0.5

≤4 I: 8–16 >16

NA NA NA

a

Itraconazole

Flucytosine

Amphotericin B

Except for amphotericin B, interpretations are based on the use of a broth sensitivity test. Approximately 15% of C. glabrata isolates are resistant to fluconazole. c Approximately 46% of C. glabrata isolates and 31% of C. krusei isolates are resistant to itraconazole. d A significant proportion of C. glabrata and C. krusei isolates have reduced susceptibility to amphotericin B. e Although frank resistance to amphotericin B is not observed in all isolates, it is well described for isolates of C. lusitaniae. S = susceptible; S-DD = susceptible-dose dependent (see text); I = intermediate; R = resistant. Adapted from refs. 5, and 9. b

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amphotericin B–resistant isolates; variations of the methodology using different media appear to enhance detection of resistant isolates.5,9 It is important that the breakpoints be used following testing with the standardized, reproducible laboratory methodology (NCCLS 27-A) used to develop the test and that they be interpreted in the context of the delivered dose of the antifungal agent. Because in vitro correlations with in vivo outcomes in patients are not yet known, the role of routine susceptibility testing is unknown at this time. Several concerns need to be considered as the use of MIC breakpoints is incorporated into the clinical practice setting: First, MICs are not actual physical measurements; rather, they provide estimates of drug activity. Since the MICs obtained can span greater than three twofold dilutions for the same isolate despite meticulous technique, MICs must be interpreted with caution. Second, host factors contribute greatly to clinical outcome. The same isolate in an immunocompetent patient may not result in the same outcome as in an immunocompromised patient. Thus, in vitro susceptibility does not necessarily equate with in vivo clinical success, and in vitro resistance may not always correlate with treatment failure. Susceptibility testing occasionally is indicated, e.g., in a patient with prolonged fungemia with a presumed susceptible isolate. Because of wide interlaboratory variability in test results, isolates should be tested at specialty laboratories that routinely perform these specialized tests. Susceptibility testing is most helpful in dealing with infections caused by non-albicans species of Candida.5,9

RESISTANCE TO ANTIFUNGAL AGENTS It is important to distinguish between clinical resistance and microbial resistance. Clinical resistance refers to failure of an antifungal agent in the treatment of a fungal infection that arises from factors other than microbial resistance, such as failure of the antifungal agent to reach the site of infection or inability of a patient’s immune system to eradicate a fungus whose growth is retarded by an antifungal agent.10 Microbial resistance can refer to primary or secondary resistance, as determined by in vitro susceptibility testing using standardized methodology. NCCLS resistance breakpoints are based on data relating treatment outcomes and fungal MICs and indicate the MIC at which clinical responses demonstrate a marked decline.10 However, they do not serve as absolute predictors of therapeutic success or failure. Primary, or intrinsic, resistance refers to resistance recorded prior to drug exposure in vitro or in vivo. Secondary, or acquired resistance develops on exposure to an antifungal agent and can be either reversible, owing to transient adaptation, or acquired as a result of one or more genetic alterations. The clinical consequences of antifungal resistance can be observed in treatment failures and in changes in the prevalences of Candida spp. causing disease. The evidence for the emergence of antifungal-resistant yeasts in patients other than those with HIV infection is confounded by the lack of standardized susceptibility testing methods and definitions of resistance. Large-scale surveys of yeasts from blood cultures, tested by standardized methodology, do not yet suggest that antifungal resistance is a significant or growing therapeutic problem.10 It is possible for a patient to respond clinically to treatment with an antifungal agent despite resistance to that agent in vitro because the patient’s own immune system may eradicate the infection, or the agent may reach the site of infection in high concentrations.10 Resistance to azole antifungal agents has been studied intensively partly because of the increased number of fluconazole-resistant Candida strains isolated from AIDS patients. Resistance may be acquired (i.e., transferred from other organisms or developed during therapy as a

INVASIVE FUNGAL INFECTIONS

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result of exposure to the antifungal agent) or intrinsic (innate lack of susceptibility of the antifungal agent to a pathogen). This issue has been reviewed extensively.2,3,10 The most exhaustive and definitive accounts of antifungal resistance have been described in Candida spp., in particular Candida albicans and, to a lesser extert, C. glabrata, C. tropicalis, and C. krusei, as well as in a few Cryptococcus neoformans isolates.11−13 There are four different mechanisms that result in azole resistance: (1) mutations or upregulation of ERG11, (2) expression of multidrug efflux transport pumps that decrease antifungal drug accumulation within the fungal cell, (3) alteration of the structure or concentration of antifungal drug target proteins, and (4) alteration of membrane sterol proteins (Fig. 119–2). It is beyond the scope of this chapter to provide a complete discussion of the biochemical mechanisms of fungal resistance. Interested readers are referred to several excellent reviews concerning this topic.10−13 Efflux pumps have been identified in C. albicans, C. glabrata, C. tropicalis, and C. dubliniensis and appear to be the most common mechanism of resistance encountered in clinical isolates. It is interesting to note that some of these mechanisms (efflux pumps in particular) appear to be reversible when selective pressure of antifungal agents is withdrawn. Even though ketoconazole was used widely for the treatment of mucocutaneous candidiasis, resistant strains appeared very rarely. In patients with the uncommon syndrome of chronic mucocutaneous candidiasis, however, the chronic use of ketoconazole was associated with the emergence of ketoconazole-resistant C. albicans. Resistance likely developed in this specific population of patients because of two factors: the chronic use of ketoconazole and the inability of patients with this syndrome to eradicate the organism by normal host defense mechanisms. Fluconazole-resistant C. albicans have been noted almost entirely in AIDS patients and usually only after CD4 counts are less than 50 cells/mm3 and after fluconazole was used chronically for repeated episodes of thrush over months to years. It appears that resistance develops in a stepwise progression in patients who have repeated episodes of thrush with one or several persisting strains of C. albicans. In vitro susceptibility testing shows a progressive decrease in susceptibility to fluconazole, and this has been correlated with clinical failure. This type of resistance has not yet become a problem in hospitalized patients treated with short courses of fluconazole or in patients in whom fluconazole has been used for prophylaxis.14,15 In the last few years, among hospitalized patients, there is increasing evidence for a shift toward isolation of other resistant species, such as C. glabrata and C. krusei, that have moderate or high-level resistance to fluconazole. This phenomenon has been especially common among patients in whom fluconazole has been used extensively.2,3 Resistance has not been described widely with itraconazole. This may be partly related to the fact that the drug has been used primarily for the treatment of endemic mycoses and not candidiasis. Even in patients never treated with itraconazole, however, C. albicans strains that are resistant to fluconazole also show decreased susceptibility to itraconazole. The most commonly reported mechanisms of azole resistance among C. albicans isolates include reduced permeability of the fungal cell membrane to azoles, alteration in the target fungal enzymes (cytochrome P450) resulting in decreased binding of the azole to the target site, and overproduction of the fungal cytochrome P450 enzymes.14,15 Studies also suggest the presence of efflux pumps capable of actively pumping azoles from the target pathogen, thereby conferring multidrug resistance to azole antifungals.14,15 C. glabrata is intrinsically more resistant than C. albicans to ketoconazole. Several strains of C. glabrata have been well characterized in terms of the mechanism of ketoconazole resistance.

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Increased drug efflux

Decreased azole binding due to ERG11 mutations

Upregulation of ERG11 Alteration in sterol composition

FIGURE 119–2. Resistance mechanisms of antifungal agents.

Decreased permeability to azoles has been described, but other strains show enhanced activity of the P450 cell membrane enzymes as well. C. krusei is inherently resistant to fluconazole, but it appears to be more susceptible to the other azoles. Decreased uptake of fluconazole into the fungal cell has been noted for several C. krusei strains.14,15 While rare, in vitro intrinsic resistance to amphotericin B is described, mainly in C. lusitaniae, C. guillermondii, and some molds (Fusarium spp., and Pseudallescheria boydii).13 However, it is important to keep in mind that the current in vitro M27-A methodology discriminates poorly between rates of susceptibility of Candida spp. to amphotericin B. Although the rate of apparent resistance to amphotericin B appears to be quite low, breakthrough bacteremias in patients treated with amphotericin B have been observed. C. glabrata, C. guilliermondii, C. krusei, and C. lusitaniae appear to have a higher propensity than other Candida spp. to develop resistance to amphotericin B; this point should be kept in mind when treating patients with infections caused by one of these pathogens.10 Since polyenes target ergosterol in the membranes of fungal cells, it is not surprising that amphotericin B–resistant strains of Candida generally have a marked decrease in ergosterol content compared with amphotericin B– susceptible strains. Resistant isolates of Cryptococcus neoformans have been reported to have a mutation in the C8 isomerization step of ergosterol synthesis.13

PATHOGENESIS AND EPIDEMIOLOGY Systemic mycoses caused by primary or pathogenic fungi include histoplasmosis, coccidioidomycosis, cryptococcosis, blastomycosis,

paracoccidioidomycosis, and sporotrichosis. Primary pathogens can cause disease in both healthy and immunocompromised individuals, although disease generally is more severe or disseminated in the immunocompromised host. In contrast, mycoses caused by opportunistic fungi such as C. albicans, Aspergillus spp., Trichosporon, Torulopsis (Candida) glabrata, Fusarium, Alternaria, and Mucor generally are found only in the immunocompromised host.1 Most fungal infections are acquired as a result of accidental inhalation of airborne conidia. For example, H. capsulatum is found in soil contaminated by bat, chicken, or starling excreta, and C. neoformans is associated with pigeon droppings. Although some fungi, including C. albicans, C. neoformans, and Aspergillus spp., are ubiquitous pathogens with worldwide distribution, other fungi have regional distributions associated with specific geographic environments.1 Systemic fungal infections are a major cause of morbidity and mortality in the immunocompromised patient. Fungal infections account for 20% to 30% of fatal infections in patients with acute leukemia, 10% to 15% of fatal infections in patients with lymphoma, and 5% of fatal infections in patients with solid tumors. The frequency of fungal infections among transplant recipients ranges from 0% to 20% for kidney and bone marrow transplant recipients to 10% to 35% for heart transplant recipients and 30% to 40% for liver transplant recipients.4 Approximately 2% to 4% of all hospitalized patients develop a nosocomial infection. Of these, bacteria comprise the most common etiologic agent.1 Fungi, however, are becoming increasingly significant nosocomial pathogens. Fungi account for 10% of all bloodstream isolates. Candida spp. (primarily C. albicans) are the fourth most commonly isolated bloodstream isolate and account for 78% of all nosocomial fungal infections.8,16

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Nosocomially acquired fungal infections may arise from either exogenous or endogenous flora. Endogenous flora may include normal commensals of the skin, gastrointestinal (GI), genitourinary, or respiratory tract. C. albicans is found as a normal commensal of the GI tract in 20% to 30% of humans.8 A complex interplay of host and pathogen factors influences the acquisition and development of fungal infections. Intact skin or mucosal surfaces serve as primary barriers to infection. Desiccation, epithelial cell turnover, fatty acid content, and low pH of the skin are believed to be important factors in host resistance. Bacterial flora of the skin and mucous membranes compete with fungi for growth. Alterations in the balance of normal flora caused by the use of antibiotics or alterations in nutritional status can allow the proliferation of fungi such as Candida, increasing the likelihood of systemic invasion and infection.1 The growth of fungi within tissues is restrained by a number of mechanisms. For example, serum has fungistatic activity against Candida in part because of transferrins, the human iron-binding proteins that deprive microbes of the iron needed for synthesis of respiratory enzymes. Serum also contains globulins, which cause a nonimmunologic clumping of Candida, facilitating their elimination by inflammatory cells.1,8 Tissue reaction in the presence of fungi varies with fungal species, site of proliferation, and duration of infection. Phagocyto-

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sis by neutrophils and macrophages is the earliest mechanism that prevents the establishment of fungi. Consequently, patients with decreased neutrophil counts or decreased neutrophil function are at higher risk of infections, particularly infections caused by Candida and Aspergillus spp. Some mycoses are characterized by a low-grade inflammatory response that does not eliminate the fungi. Fungal cells sometimes can persist within macrophages without being killed, perhaps because of resistance to the effects of lysosomal enzymes.1

DIAGNOSIS 2 The diagnosis of invasive fungal infections generally is accom-

plished by careful evaluation of clinical symptoms, results of serologic tests, and histopathologic examination and culture of clinical specimens. Skin tests generally are not useful diagnostically because they do not distinguish between active and past infection. They remain useful as screening tools and in epidemiologic studies to determine endemic areas. It is beyond the scope of this chapter to discuss the relative merits of each of the immunologic tests used in the diagnosis of invasive fungal infections. Interested readers, however, are referred to several excellent reviews concerning this topic.17


TREATMENT: Invasive Mycoses Strategies for the prevention or treatment of invasive mycoses can be classified broadly as prophylaxis, early empirical therapy, empirical therapy, and secondary prophylaxis or suppression.1 In patients undergoing cytotoxic chemotherapy, antifungal therapy is directed primarily at the prevention or treatment of infections caused by Candida and Aspergillus. Prophylactic therapy with topical, oral, or intravenous antifungal agents is administered prior to and throughout periods of granulocytopenia (absolute neutrophil count < 1000/L). The potential benefits of prophylactic therapy must be weighed against the potential risks inherent in each regimen. Perfect18 suggests that each clinician consider at least six criteria before justifying antifungal prophylaxis: (1) safety, (2) efficacy, (3) cost, (4) consequence, (5) prevalence, and (6) resistance. Early empirical therapy is the administration of systemic antifungal agents at the onset of fever and neutropenia. Empirical therapy with systemic antifungal agents is administered to granulocytopenic patients with persistent or recurrent fever despite the administration of appropriate antimicrobial therapy. Secondary prophylaxis (or suppressive therapy) is the administration of systemic antifungal agents (generally prior to and throughout the period of granulocytopenia) to prevent relapse of a documented invasive fungal infection that was treated during a previous episode of granulocytopenia. Although these treatment classifications also have been applied to the treatment of fungal infections in AIDS, patients with AIDS

HISTOPLASMOSIS In humans, histoplasmosis is caused by inhalation of dust-borne microconidia of the dimorphic fungus Histoplasma capsulatum. Although there exist two dimorphic varieties of H. capsulatum, the

rarely acquire systemic infections caused by Candida or Aspergillus spp. unless they become granulocytopenic because of disease or drugs. The use of antifungal prophylaxis is much less widely studied in this population, although studies suggest that early antifungal prophylaxis decreases the incidence of invasive cryptococcal disease.19 Suppressive therapy generally is necessary following acute therapy for histoplasmosis, coccidioidomycosis, and cryptococcosis because of the high rates of relapse when antifungal therapy is discontinued.


PROPHYLAXIS OF FUNGAL INFECTION IN THE HIV-INFECTED PATIENT The use of antifungal prophylaxis to prevent fungal infections in HIVinfected patients has been assessed. Fluconazole prevented cryptococcosis and local Candida infections, including esophagitis, in HIVinfected patients, but overall mortality was not improved.14 Because of the high costs of long-term prophylaxis, improved therapeutic regimens available for treating cryptococcal meningitis, and increasing reports of fluconazole resistance among Candida isolates from AIDS patients, many clinicians prefer not to use fluconazole prophylaxis in AIDS patients. For some patients with very low CD4 counts, however, some clinicians feel that it is cost-effective to use fluconazole prophylaxis to prevent cryptococcosis.14

small-celled (2–5 microns) form (var. capsulatum) occurs globally, whereas the large-celled (8–15 microns) form (var. duboisii) is confined to the African continent and Madagascar. In tissues stained by conventional techniques, H. capsulatum appears as an oval or round, narrow-pore, budding, unencapsulated yeast.20

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EPIDEMIOLOGY 3 Although histoplasmosis is found worldwide, certain areas of

North and Latin America are recognized as endemic areas; in the United States, most disease is localized along the Ohio and Mississippi River valleys, where more than 90% of residents may be affected. Precise reasons for this endemic distribution pattern are unknown but are thought to include moderate climate, humidity, and soil characteristics. H. capsulatum is found in nitrogen-enriched soils, particularly those heavily contaminated by avian or bat guano, which accelerates sporulation. Blackbird or pigeon roosts, chicken coops, and sites frequented by bats, such as caves, attics, or old buildings, serve as “microfoci” of infections. Although birds are not infected because of their high body temperature, bats (mammals) may be infected and can pass yeast forms in their feces, allowing the spread of H. capsulatum to new habitats. Air currents carry the spores for great distances, exposing individuals who were unaware of contact with the contaminated site.20−22

PATHOPHYSIOLOGY At ambient temperatures, H. capsulatum grows as a mold. The mycelial phase consists of septate branching hyphae with terminal micro- and macroconidia that range in size from 2 to 14 microns in diameter. When soil is disturbed, these conidia become aerosolized and reach the bronchioles or alveoli.20 Animal studies demonstrate that within 2 to 3 days after reaching lung tissue, the conidia germinate, releasing yeast forms that begin multiplying by binary fission. During the next 9 to 15 days, organisms are ingested but not destroyed by large numbers of macrophages that are recruited to the infected site, resulting in small infiltrates. Infected macrophages migrate to the mediastinal lymph nodes and other sites within the mononuclear phagocyte system, particularly the spleen and liver. At this time, the onset of specific T-cell immunity in the nonimmune host activates the macrophages, rendering them capable of fungicidal activity. Tissue granulomas form, many of which develop central caseation and necrosis over the next 2 to 4 months. Over a period of several years, these foci become encapsulated and calcified, often with viable yeast trapped within the necrotic tissue.20,23 Cellular immunity, as measured by histoplasmin skin-test reactivity, wanes in the absence of occasional reexposure. Although exposure to heavy inocula may overcome these immune mechanisms, resulting in severe disease, reinfection occurs frequently in endemic areas. In the immune individual, the reactions of acquired immunity begin 24 to 48 hours after the appearance of yeast forms, resulting in milder forms of illness and little proliferation of organisms. Although viable organisms may be found within granulomas years after initial infection, the organisms appear to have little ability to proliferate within the fibrous capsules, except in immunocompromised patients.20,23

CLINICAL PRESENTATION14,17,19,20,22,23 GENERAL The outcome of infection with H. capsulatum depends on a complex interplay of host, pathogen, and environmental factors. Host factors include the degree of immunosuppression and the presence of immunity (from prior infection). Environmental factors include inoculum size, exposure within an enclosed area, and duration of exposure. Hematogenous dissemination from the lungs to other tissues probably occurs in all infected individuals during the first 2 weeks of infection

before specific immunity has developed but is nonprogressive in most cases, which leads to the development of calcified granulomas of the liver and/or spleen. Progressive pulmonary infection is common in patients with underlying centrilobular emphysema. A number of acute and chronic manifestations of histoplasmosis appear to result from unusual inflammatory or fibrotic responses to the pathogen, including pericarditis and rheumatologic syndromes during the first year after exposure, with chronic mediastinal inflammation or fibrosis, broncholithiasis, and enlarging parenchymal granulomas later in the course of disease.

ACUTE PULMONARY HISTOPLASMOSIS In the vast majority of patients, low-inoculum exposure to H. capsulatum results in mild or asymptomatic pulmonary histoplasmosis. The course of disease generally is benign, and symptoms usually abate within a few weeks of onset. Patients exposed to a higher inoculum during an acute primary infection or reinfection may experience an acute, self-limited illness with flulike pulmonary symptoms, including fever, chills, headache, myalgia, and a nonproductive cough. Patients with diffuse pulmonary histoplasmosis may have diffuse radiographic involvement, become hypoxic, and require ventilatory support. A small percentage of patients present with arthritis, erythema nodosum, pericarditis, or mediastinal granuloma.

CHRONIC PULMONARY HISTOPLASMOSIS Chronic pulmonary histoplasmosis generally presents as an opportunistic infection imposed on a preexisting structural abnormality, such as lesions resulting from emphysema. Patients demonstrate chronic pulmonary symptoms and apical lung lesions that progress with inflammation, calcified granulomas, and fibrosis. Patients with early, noncavitary disease often recover without treatment. Progression of disease over a period of years, seen in 25% to 30% of patients, is associated with cavitation, bronchopleural fistulas, extension to the other lung, pulmonary insufficiency, and often death.

DISSEMINATED HISTOPLASMOSIS In patients exposed to a large inoculum and in immunocompromised hosts, successful containment of the organism within macrophages may not occur, resulting in a progressive illness characterized by yeast-filled phagocytic cells and an inability to produce granulomas. This disease, termed disseminated histoplasmosis, is characterized by persistent parasitization of macrophages. The clinical severity of the diverse forms of disseminated histoplasmosis (Table 119–2) generally parallels the degree of macrophage parasitization observed. Acute (infantile) disseminated histoplasmosis is characterized by massive involvement of the mononuclear phagocyte system by yeast-engorged macrophages. Classically, this severe type of infection is seen in infants and young children and (rarely) in adults with Hodgkin’s disease or other lymphoproliferative disorders. In infants or children, acute disseminated histoplasmosis is characterized by unrelenting fever, anemia, leukopenia or thrombocytopenia, enlargement of the liver, spleen, and visceral lymph nodes, and GI symptoms, particularly nausea, vomiting, and diarrhea. The chest roentgenogram often demonstrates remnants of the initiating acute pulmonary lesion. Untreated disease is uniformly fatal in 1 to 2 months. A less severe “subacute” form of the disease, which occurs in both infants and immunocompetent adults, is characterized by focal destructive lesions in various organs, weight loss, weakness, fever, and malaise. Untreated disease generally is fatal in approximately 10 months.

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TABLE 119–2. Clinical Manifestations and Therapy of Histoplasmosis Type of Disease and Common Clinical Manifestations Nonimmunosuppressed Host Acute pulmonary histoplasmosis Asymptomatic or mild disease

Approximate Frequency (%)a

50–99

Self-limited disease

1–50

Mediastinal granulomas

1–50

Severe diffuse pulmonary disease

Inflammatory/fibrotic disease

0.02

Chronic pulmonary histoplasmosis

0.05

Immunosuppressed Host Disseminated histoplasmosis

0.02–0.05

Acute (Infantile) Subacute Progressive histoplasmosis (immunocompetent patients and immunosuppressed patients without AIDS)

Progressive disease of AIDS

a As

25–50h

Therapy/Comments

Asymptomatic, mild, or symptoms 4 weeks: Itraconazole 200 mg once daily × 6–12 weeksb Self-limited disease: Amphotericin Bc 0.3–0.5 mg/kg/day × 2–4 weeks (total dose 500 mg) or ketoconazole 400 mg orally daily × 3–6 months may be beneficial in patients with severe hypoxia following inhalation of large inocula Antifungal therapy generally not useful for arthritis or pericarditis; NSAIDsd or corticosteroids may be useful in some cases Most lesions resolve spontaneously; surgery or antifungal therapy with amphotericin B 40–50 mg/ day × 2–3 weeks or itraconazole 400 mg/day orally × 6–12 months may be beneficial in some severe cases; mild to moderate disease may be treated with itraconazole for 6–12 months Amphotericin B 0.7 mg/kg/day, for a total dose of ≤35 mg/kg (or 3 mg/kg/day of one of the lipid preparations) + prednisone 60 mg daily tapered over 2 weeks,e followed by itraconazole 200 mg twice daily for 6–12 weeks; in patients who do not require hospitalization, itraconazole 200 mg once or twice daily for 6–12 weeks can be used Fibrosing mediastinitis: The benefit of antifungal therapy (itraconazole 200 mg twice daily × 3 months) is controversial but should be considered, especially in patients with elevated ESRf or CFg titers ≥1:32; surgery may be of benefit if disease is detected early; late disease may not respond to therapy Sarcoid-like: NSAIDs or corticosteroids may be of benefit for some patients Pericarditis: Severe disease: corticosteroids 1 mg/kg/day or pericardial drainage procedure Antifungal therapy generally recommended for all patients to halt further lung destruction and reduce mortality Mild–moderate disease: Itraconazole 200–400 mg PO daily × 6–24 months is the treatment of choice Itraconazole and ketoconazole (200–800 mg/day orally for 1 year) are effective in 74% to 86% of cases, but relapses are common; fluconazole 200–400 mg daily is less effective (64%) than ketoconazole or itraconazole, and relapses are seen in 29% of responders Severe disease: Amphotericin B 0.7 mg/kg/day for a minimum total dose of 35 mg/kg is effective in 59% to 100% of cases and should be used in patients who require hospitalization or are unable to take itraconazole due to drug interactions, allergies, failure to absorb drug, or failure to improve clinically after a minimum of 12 weeks of itraconazole therapy Disseminated histoplasmosis: Untreated mortality 83% to 93%; relapse 5% to 23% in non-AIDS patients; therapy is recommended for all patients Nonimmunosuppressed patients: Ketoconazole 400 mg/day orally × 6–12 months or amphotericin B 35 mg/kg IV Immunosuppressed patients: (non-AIDS) or endocarditis or CNS disease: Amphotericin B >35 mg/ kg × 3 months followed by fluconazole or itraconazole 200 mg orally twice daily × 12 months Life-threatening disease: Amphotericin B 0.7–1 mg/kg/day IV for a total dosage of 35 mg/kg over 2–4 months; once the patient is afebrile, able to take oral medications, and no longer requires blood pressure or ventilatory support, therapy can be changed to itraconazole 200 mg orally twice daily for 6–18 months Non-life-threatening disease: Itraconazole 200–400 mg orally daily for 6–18 months; fluconazole therapy 400–800 mg daily) should be reserved for patients intolerant to itraconazole, and the development of resistance may lead to relapses Amphotericin B 15–30 mg/kg (1–2 g over 4–10 weeks)i or itraconazole 200 mg 3 times daily for 3 days then twice daily for 12 weeks, followed by lifelong suppressive therapy with itraconazole 200–400 mg orally daily; a study is in progress to determine whether itraconazole therapy can be discontinued after one year if CD4+ counts are >150 cells/mm3

a percentage of all patients presenting with histoplasmosis. plasma concentrations should be measured during the second week of therapy to ensure that detectable concentrations have been achieved. If the concentration is below 1 mcg/mL, the dose may be insufficient or drug interactions may be impairing absorption or accelerating metabolism, requiring a change in dosage. If plasma concentrations are greater than 10 mcg/mL, the dosage may be reduced. c Desoxycholate amphotericin B. d NSAIDs = nonsteroidal anti-inflammatory drugs. e Effectiveness of corticosteroids is controversial. f ESR = erythrocyte sedimention rate. g CF = complement fixation. h As a percentage of AIDS patients presenting with histoplasmosis as the initial manifestation of their disease. i Liposomal amphotericin B (Ambisome) may be more appropriate for disseminated disease. Compiled from refs. 20, 22, and 23. b Itraconazole

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Most adults with disseminated histoplasmosis demonstrate a mild, chronic form of the disease. Untreated patients often are ill for 10 to 20 years, demonstrating long asymptomatic periods interrupted by relapses of clinical illness characterized primarily by weight loss, weakness, and fatigue. Chronic disseminated histoplasmosis can be seen in patients with lymphoreticular neoplasms (Hodgkin’s disease) and patients undergoing immunosuppressant chemotherapy for organ transplantation or for rheumatic diseases. Although CNS involvement occurs in 10% to 20% of patients with severe underlying immunosuppressive conditions, focal organ involvement is uncommon. The disease is characterized by the development of focal granulomatous lesions, often with bone marrow involvement resulting in thrombocytopenia, anemia, and leukemia. Fever, hepatosplenomegaly, and GI ulceration are common.

HISTOPLASMOSIS IN HIV-INFECTED PATIENTS Adult patients with AIDS demonstrate an acute form of disseminated disease that resembles the syndrome seen in infants and children. Progressive disseminated histoplasmosis (PDH) can occur as the direct result of initial infection or because of the reactivation of dormant foci. In endemic areas, 50% of AIDS patients demonstrate PDH as the first manifestation of their disease. Progressive disseminated histoplasmosis is characterized by fever (75% of patients), weight loss, chills, night sweats, enlargement of the spleen, liver, or lymph nodes, and anemia. Pulmonary symptoms occur in only one-third of patients and do not always correlate with the presence of infiltrates on chest roentgenogram. A clinical syndrome resembling septicemia is seen in approximately 25% to 50% of patients.

DIAGNOSIS Detection of single, yeastlike cells 2 to 5 microns in diameter with narrow-based budding by direct examination or by histologic study of blood smears or tissues should raise strong suspicion of infection with H. capsulatum because colonization does not occur as with Aspergillus or Candida infection. Identification of mycelial isolates from clinical cultures can be made by conversion of the mycelium to the yeast form (requires 3 to 6 weeks) or via a rapid (2-hour)

and 100% sensitive DNA probe that recognizes ribosomal DNA. In patients with suspected disseminated or chronic cavitary histoplasmosis, two to three blood, sputum, and bone marrow cultures and stains should be obtained using the lysis centrifugation technique, and the cultures should be held for 14 to 21 days for optimal yield of H. capsulatum. In patients with acute self-limited histoplasmosis, extensive testing to verify the diagnosis may not be necessary. In most patients, serologic evidence remains the primary method in the diagnosis of histoplasmosis. Results obtained from commercially available complement fixation (CF), immunodiffusion (ID), and latex agglutination (LA) antibody tests are used alone or in combination. In general, the use of histoplasmin skin tests is of little value except in epidemiologic studies because histoplasmin reactivity waxes in the absence of occasional reexposure. In addition, histoplasmin skin testing may result in a false increase in the CF titer for mycelial antigen (CF-M) to H. capsulatum. A fourfold rise in the CF titer is usually indicative of recent infection, although some patients with severe disease or profound immunosuppression may demonstrate a weaker antibody response. Because the ID test is not as sensitive as CF, it should be used to assess the importance of weakly reactive results obtained by CF rather than as a screening procedure. Radioimmunoassay (RIA), which measures immunoglobulin M (IgM) and IgG antibodies against a histoplasmin extract, is the most sensitive test, but it may show a large number of false-positive reactions in patients living in an endemic area. In the AIDS patient with PDH, the diagnosis is best established by bone marrow biopsy and culture, which yield positive cultures in more than 90% of patients, although blood cultures and histopathologic examination and culture of pulmonary tissue, sputum, skin, and lymph nodes also may be helpful. Detection of H. capsulatum polysaccharide antigen (HPA) in urine, blood, or cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay (ELISA) or by modified radioimmunoassay assay offer promising new techniques for the rapid diagnosis of histoplasmosis. The HPA (RIA) levels also have been used successfully to monitor the course of therapy and to detect relapses in patients with AIDS, and the clearance of antigen from serum and urine correlates with clinical efficacy during maintenance therapy with itraconazole. Unfortunately, these tests are not yet available for clinical use.


TREATMENT: Histoplasmosis
NON–HIV-INFECTED PATIENT Table 119–2 summarizes the recommended therapy for the treatment 4 of histoplasmosis. In general, asymptomatic or mildly ill patients and patients with sarcoid-like disease do not benefit from antifungal therapy. In the vast majority of patients, low-inoculum exposure to H. capsulatum results in mild or asymptomatic pulmonary histoplasmosis. The course of disease generally is benign, and symptoms usually abate within a few weeks of onset. Therapy may be helpful in symptomatic patients whose conditions have not improved during the first month of infection. Fever persisting more than 3 weeks may indicate that the patient is developing progressive disseminated disease, which may be aborted by antifungal therapy. Whether antifungal therapy hastens recovery or prevents complications is unknown because it has never been studied in prospective trials. Patients with mild, self-limited disease, chronic disseminated disease, or chronic pulmonary histoplasmosis who have no underlying immunosuppression usually can be treated with either oral

ketoconazole or IV amphotericin B. The goals of therapy are resolution of clinical abnormalities, prevention of relapse, and eradication of infection whenever possible, although chronic suppression of infection may be adequate in immunosuppressed patients, including those with HIV disease.22,23 Patients with arthritis, erythema nodosum, pericarditis, or mediastinal granuloma may require the addition of a 2-week course of corticosteroids to their therapy.20


HIV-INFECTED PATIENT In AIDS patients, intensive 12-week primary antifungal therapy (induction and consolidation therapy) is followed by lifelong suppressive (maintenance) therapy with itraconazole. Amphotericin B dosages of 50 mg/day (up to 1 mg/kg per day) should be administered intravenously to a cumulative dose of 15 to 35 mg/kg (1 to 2 g) in patients who require hospitalization. Amphotericin B can be replaced

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with itraconazole 200 mg orally twice daily when the patient no longer requires hospitalization or intravenous therapy to complete a 12-week total course of induction therapy. In patients who do not require hospitalization, itraconazole therapy for 12 weeks may be used. Fluconazole 800 mg/day orally as induction, followed by 400 mg/day, was effective in 88% of patients, but relapses occurred in

approximately one-third of patients, and in vitro resistance developed in approximately 50% of patients who relapsed. In regions experiencing high rates of histoplasmosis (>5 cases/ 100 patient-years), itraconazole 200 mg/day is recommended as prophylactic therapy in HIV-infected patients. Fluconazole is not an acceptable alternative because of its inferior activity against H. capsulatum and its lower efficacy for the treatment of histoplasmosis.22

EVALUATION OF THERAPEUTIC OUTCOMES

on the Great Lakes, numerous cases of North American blastomycosis have been diagnosed in Africa, northern parts of South America, India, and Europe. Endemic areas have been defined primarily by analysis of sporadic cases and epidemics or clusters of disease because the lack of a dependable skin or laboratory test makes wide-scale epidemiologic testing to determine the incidence of infection unfeasible at present.23,25 Although initial review of sporadic cases suggested that males with outdoor occupations that exposed them to soil were at greatest risk for blastomycosis, more recent data suggest that there is no sex, age, or occupational predilection for blastomycosis.23,24 Although B. dermatitidis generally is considered to be a soil inhabitant, attempts to isolate the organism in nature frequently have been unsuccessful. B. dermatitidis has been isolated from soil containing decayed vegetation, decomposed wood, and pigeon manure, frequently in association with warm, moist soil of wooded areas that is rich in organic debris.23,24

Response to therapy should be measured by resolution of radiologic, serologic, and microbiologic parameters and by improvement in signs and symptoms of infection. Although investigators are limited by the lack of standardized criteria to quantify the extent of infection, degree of immunosuppression, or treatment response, response rates (based on resolution or improvement in presenting signs and symptoms) of greater than 80% have been reported in case series in AIDS patients receiving varied dosages of amphotericin B. Rapid responses are reported, with the resolution of symptoms in 25% and 75% of patients by days 3 and 7 of therapy, respectively. After the initial course of therapy for histoplasmosis is complete, lifelong suppressive therapy with oral azoles or amphotericin B (1–1.5 mg/kg weekly or biweekly) is recommended because of the frequent recurrence of infection.25 Relapse rates in AIDS patients not receiving maintenance therapy range from 50% to 90%.22 Antigen testing may be useful for monitoring therapy in patients with disseminated histoplasmosis. Antigen concentrations decrease with therapy and increase with relapse. Some investigators recommend that treatment should continue until antigen concentrations revert to negative or less than 4 units. If treatment is discontinued before antigen concentrations in serum and urine revert to negative, patients should be followed closely for relapse, and antigen levels should be monitored every 3 to 6 months until they become negative.22

BLASTOMYCOSIS North American blastomycosis is a systemic fungal infection caused by Blastomyces dermatitidis, a dimorphic fungus that infects primarily the lungs. Patients, however, may present with a variety of pulmonary and extrapulmonary clinical manifestations. Pulmonary disease may be acute or chronic and can mimic infection with tuberculosis, pyogenic bacteria, other fungi, or malignancy. Blastomycosis can disseminate to virtually every other body organ, and approximately 40% of patients with blastomycosis present with skin, bone and joint, or genitourinary tract involvement without any evidence of pulmonary disease.24 Pulmonary infection probably occurs by inhalation of conidia, which convert to the yeast form in the lung. A vigorous inflammatory response ensues, with neutrophilic recruitment to the lungs followed by the development of cell-mediated immunity and the formation of noncaseating granulomas.

EPIDEMIOLOGY Blastomycosis was renamed North American blastomycosis in 1942, when Conant and Howell named a similar fungus endemic to South America, Blastomyces braziliensis, and the disease it caused South American blastomycosis. Although the disease is now recognized to be endemic to the southeastern and south central states of the United States (especially those bordering on the Mississippi and Ohio River basins) and the midwestern states and Canadian provinces bordering

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION16,17,23,24 GENERAL Colonization does not occur with Blastomyces. Acute pulmonary blastomycosis generally is an asymptomatic or self-limited disease characterized by fever, shaking chills, and productive, purulent cough, with or without hemoptysis, in immunocompetent individuals. The clinical presentation may be difficult to differentiate from other respiratory infections, including bacterial pneumonia, on the basis of clinical symptoms alone. Sporadic (nonepidemic) pulmonary blastomycosis may present as a more chronic or subacute disease, with low-grade fever, night sweats, weight loss, and productive cough that resembles tuberculosis rather than bacterial pneumonia. Chronic pulmonary blastomycosis is characterized by fever, malaise, weight loss, night sweats, chest pain, and productive cough. Patients often are thought to have tuberculosis and frequently have evidence of disseminated disease that may appear 1 to 3 years after the primary pneumonia has resolved. Reactivation of disease may occur in the lungs or as the focus of new infection in other organs. In approximately 40% of patients, dissemination is not accompanied by reactivation of pulmonary disease. The most common sites for disseminated disease include the skin and bony skeleton, although less commonly the prostate, oropharyngeal mucosa, and abdominal viscera are involved. CNS disease, while exceedingly uncommon, is associated with the highest mortality rate.

LABORATORY AND DIAGNOSTIC TESTS The simplest and most successful method of diagnosing blastomycosis is by direct microscopic visualization of the large, multinucleated yeast with single, broad-based buds in sputum or other respiratory specimens following digestion of cells and debris with 10% potassium hydroxide. Histopathologic examination of tissue biopsies and

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culture of secretions also should be used to identify B. dermatitidis, although it may require up to 30 days to isolate and identify a small inoculum. No reliable skin test exists to determine the incidence and prevalence of disease in endemic populations, and reliable serologic diagnosis of blastomycosis has long been hampered by the lack of specific and standardized reagents. Serologic response does not always correlate with clinical improvement, although some investigators have noted that a decline in the number of precipitins or CF titers may offer evidence of a favorable prognosis in patients with established disease.

Acute pulmonary blastomycosis generally is an asymptomatic or self-limited disease characterized by fever, shaking chills, and productive, purulent cough, with or without hemoptysis, in immunocompetent individuals. The clinical presentation may be difficult to differentiate from other respiratory infections, including bacterial pneumonia, on the basis of clinical symptoms alone. Sporadic (nonepidemic) cases of pulmonary blastomycosis may present as a more chronic or subacute disease with low-grade fever, night sweats, weight loss, and productive cough that resembles tuberculosis rather than bacterial pneumonia.


TREATMENT: Blastomycosis
NON–HIV-INFECTED PATIENT 5 In patients with mild pulmonary blastomycosis, the clinical pre-

sentation of the patient, the immune competence of the patient, and the toxicity of the antifungal agents are the main determinants of whether or not to administer antifungal therapy. All immunocompromised patients and patients with progressive pulmonary disease or with extrapulmonary disease should be treated (Table 119–3). In the

case of disease limited to the lungs, cure may have occurred before the diagnosis is made and without treatment. Regardless of whether or not the patient receives treatment, however, he or she must be followed carefully for many years for evidence of reactivation or progressive disease.23,24 Some authors recommend ketoconazole therapy for the treatment of self-limited pulmonary disease, with the hope of preventing late extrapulmonary disease; however, data supporting the efficacy of these regimens are lacking.23,24 Itraconazole 200 to 400 mg/day

TABLE 119–3. Therapy of Blastomycosis Type of Disease Pulmonarya Life-threatening

Mild to moderate

Disseminated or Extrapulmonary CNS

Non-CNS Life-threatening

Preferred Treatment Amphotericin Bb IV 0.7–1 mg/kg/day IV (total dose 1.5–2.5 g)

Itraconazole 200 mg orally twice daily × ≥6 monthsc

Amphotericin B 0.7–1 mg/kg/day IV (total dose 1.5–2.5 g)

Comments

Patients may be initiated on amphotericin B and changed to oral itraconazole 200–400 mg orally daily once patient is clinically stabilized and a minimum dose of 500 mg of amphotericin B has been administered Altemative therapy: Ketoconazole 400–800 mg orally daily × ≥6 months or fluconazole 400–800 mg orally daily × ≥6 monthsd In patients intolerant of azoles or in whom disease progresses during azole therapy: Amphotericin B 0.5–0.7 mg/kg/day IV (total dose 1.5–2.5 g) For patients unable to tolerate a full course of amphotericin B, consider lipid formulations of amphotericin B or fluconazole ≥ 800 mg orally daily

Patients may be initiated on amphotericin B and changed to oral itraconazole 200–400 mg orally daily once stabilized Mild to moderate Ketoconazole 400–800 mg orally daily or fluconazole 400–800 mg orally daily × ≥6 months In patients intolerant of azoles or in whom disease progresses during azole therapy: Amphotericin B 0.5–0.7 mg/kg/day IV (total dose 1.5–2.5 g) Bone disease: Therapy with azoles should be continued for 12 months Immunocompromised Host (Including Patients with AIDS, Transplants, or Receiving Chronic Glucocorticoid Therapy) Acute disease Amphotericin B 0.7–1 mg/kg/day IV (total Patients without CNS infection may be switched to itraconazole dose 1.5–2.5 g) once clinically stabilized and a minimum dose of 1 g of amphotericin B has been administered; long-term suppressive therapy with an azole is advised Suppressive therapy Itraconazole 200–400 mg orally daily For patients with CNS disease or those intolerant of itraconazole, consider fluconazole 800 mg orally daily a

Amphotericin B 0.7–1 mg/kg/day IV (total dose 1.5–2.5 g) Itraconazole 200–400 mg orally daily × ≥6 months

Some patients with acute pulmonary infection may have a spontaneous cure. Patients with progressive pulmonary disease should be treated. Desoxycholate amphotericin B. In patients not responding to 400 mg, dosage should be increased by 200 mg increments every 4 weeks to a maximum of 800 mg daily. d Therapy with ketoconazole is associated with relapses, and fluconazole therapy achieves a lower response rate than itraconazole. CNS = central nervous system. Compiled from refs. 23, and 24. b c

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demonstrated 90% efficacy as a first-line agent in the treatment of nonlife-threatening non-CNS blastomycosis, and for compliant patients who completed at least 2 months of therapy, a success rate of 95% was noted. No therapeutic advantage was noted with the higher (400 mg) dosage as compared with patients treated with 200 mg. All patients with disseminated blastomycosis, as well as those with extrapulmonary disease, require therapy. Ketoconazole 400 mg/ day orally for 6 months cures more than 80% of patients with chronic pulmonary and nonmeningeal disseminated blastomycosis. Amphotericin B is more efficacious but more toxic and therefore is reserved for noncompliant patients and patients with overwhelming or lifethreatening disease, CNS infection, and treatment failures. Cumulative amphotericin B dosages of more than 1 g have resulted in cure without relapse in 70% to 91% of patients with blastomycosis. Relapse rates depend on the total dosage of amphotericin B administered.23,24 Patients with genitourinary tract disease should be treated initially with 600–800 mg/day of ketoconazole because of the low concentrations of drug achieved in the urine and prostate tissue. Patients should be monitored carefully for signs of clinical failure, and those who fail or are unable to tolerate itraconazole therapy or who develop CNS disease should be treated with amphotericin B for a total cumulative dose of 1.5 to 2.5 g.23,24

COCCIDIOIDOMYCOSIS EPIDEMIOLOGY Coccidioidomycosis is caused by infection with Coccidioides immitis, a dimorphic fungus found in the southwestern and western United States, as well as in parts of Mexico and South America. In North America, the endemic regions encompass the semiarid areas of the southwestern United States from California to Texas known as the Lower Sonoran Zone, where there is scant annual rainfall, hot summers, and sandy, alkaline soil. C. immitis grows in the soil as a mold, and mycelia proliferate during the rainy season. During the dry season, resistant arthroconidia form and become airborne when the soil is disturbed. Although generally considered to be a regional disease, coccidioidomycosis has increased in importance in recent years because of the increased tourism and population in endemic areas, the increased use of immunosuppressive therapy in transplantation and oncology, and the AIDS epidemic. Although there is no racial, hormonal, or immunologic predisposition for acquiring primary disease, these factors affect the risk of subsequent dissemination of disease25 (Table 119–4).

TABLE 119–4. Risk Factors for Severe, Disseminated Infection with Coccidioidomycosis Race (Filipinos > African-Americans > Native Americans > Hispanics > Asians) Pregnancy (especially when infection is acquired or reactivated in the second or third trimester) Compromised cellular immune system, including AIDS patients Patients receiving Corticosteroids Immunosuppressive agents Chemotherapy Male gender Neonates Patients with B or AB blood types From ref. 25.

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Lipid preparations of amphotericin B are effective in animal models of blastomycosis, but they have not been evaluated adequately in humans. Limited clinical experience suggests that these preparations may provide an alternative for patients unable to experience standard therapy with amphotericin B because of toxicity. Surgery has only a limited role in the treatment of blastomycosis.


HIV-INFECTED PATIENT For unclear reasons, blastomycosis is an uncommon opportunistic disease among immunocompromised individuals, including AIDS patients; however, blastomycosis may occur as a late (CD4 lymphocytes < 200 cells/mm3 ) and frequently fatal complication of HIV infection. In this population, overwhelming disseminated disease with frequent involvement of the CNS is common.23 Following induction therapy with amphotericin B (total cumulative dose of 1 g), HIV-infected patients should receive chronic suppressive therapy with an oral azole antifungal. Despite its higher cost, itraconazole has become the drug of choice for non-life-threatening histoplasmosis (mild to moderate disease) in HIV-infected patients.24

PATHOPHYSIOLOGY When individuals come in contact with contaminated soil during ranching, dust storms, or proximity to construction sites or archaeologic excavations, arthroconidia are inhaled into the respiratory tree, where they transform into spherules, which reproduce by cleavage of the cytoplasm to produce endospores. The endospores are released when the spherules reach maturity. Similar to histoplasmosis, an acute inflammatory response in the tissue leads to infiltration of mononuclear cells, ultimately resulting in granuloma formation.25

CLINICAL PRESENTATION OF COCCIDIODOMYCOSIS13,23−26 Coccidioidomycosis encompasses a spectrum of illnesses ranging from primary uncomplicated respiratory tract infection that resolves spontaneously to progressive pulmonary or disseminated infection. Initial or primary infection with C. immitis almost always involves the lungs. Although approximately one-third of the population in endemic areas is infected, the average incidence of symptomatic disease is only approximately 0.43%.

SIGNS AND SYMPTOMS In asymptomatic disease (60% of patients), patients have nonspecific symptoms that are often indistinguishable from ordinary upper respiratory infections, including fever, cough, headache, sore throat, myalgias, and fatigue. A fine, diffuse rash may appear during the first few days of the illness. Primary pneumonia may be the first manifestation of disease, characterized by a productive cough that may be bloodstreaked, as well as single or multiple soft or dense homogeneous hilar or basal infiltrates on chest roentgenogram. Chronic, persistent pneumonia or persistent pulmonary coccidioidomycosis (primary disease lasting more than 6 weeks) is complicated by hemoptysis, pulmonary scarring, and the formation of cavities or bronchopleural fistulas. Necrosis of pulmonary tissue with drainage and cavity formation occurs commonly. Most parenchymal cavities close spontaneously or form dense nodular scar tissue that may become superinfected

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with bacteria or spherules of C. immitis. These patients often have persistent cough, fevers, and weight loss. Valley fever occurs in approximately 25% of patients and is characterized by erythema nodosum and erythema multiforme of the upper trunk and extremities in association with diffuse joint aches or fever. More commonly, a diffuse, mild erythroderma or maculopapular rash is observed. Patients may have pleuritic chest pain and peripheral eosinophilia. Disseminated disease occurs in less than 1% of infected patients. The most common sites for dissemination are the skin, lymph nodes, bone, and meninges, although the spleen, liver, kidney, and adrenal gland also may be involved. Occasionally, miliary coccidioidomycosis occurs, with rapid, widespread dissemination, often in concert with positive blood cultures for C. immitis. Patients with AIDS frequently present with miliary disease. Coccidioidomycosis in AIDS patients appears to be caused by reactivation of disease in most patients. CNS infection occurs in approximately 16% of patients with disseminated coccidioidomycosis. Patients may present with meningeal disease without previous symptoms of primary pulmonary infection, although disease usually occurs within 6 months of the primary infection. The signs and symptoms are often subtle and nonspecific, including headache, weakness, changes in mental status (lethargy and confusion), neck stiffness, low-grade fever, weight loss, and occasionally, hydrocephalus. Space-occupying lesions are rare, and the main areas of involvement are the basilar meninges.

DIAGNOSIS LABORATORY TESTS Recovery of C. immitis from infected tissues or secretions for direct examination and culture provides an accurate and rapid method of diagnosis. Direct microscopic examination and histopathologic studies of infected tissues will reveal the large, mature endosporulating spherules. Young spherules without endospores may be confused, however, with other fungi. Silver stains of body fluids or tissue biopsies are also helpful.

With chronic, persistent pneumonia, C. immitis often can be cultured from the sputum for a period of several years. Chest radiographs usually demonstrate apical fibronodular lesions or slowly progressive cavitation. With CNS infection, analysis of the CSF generally reveals a lymphocytic pleocytosis with elevated protein and a decreased glucose concentration. Although serum usually is positive for coccidioidal CF antibodies, the coccidioidal skin test is often negative.

OTHER DIAGNOSTIC TESTS Most patients develop a positive skin test within 3 weeks of the onset of symptoms. Baseline evaluation of skin test reactivity and serology is essential in order to assess cell-mediated immunity. Patients who develop early positive skin-test reactivity or whose coccidioidin skintest reactivity turns from negative to positive during therapy have an improved prognosis compared with patients whose skin-test reactivity develops later or does not change during therapy. Patients with disseminated coccidioidomycosis whose skin tests are persistently negative are more likely to require prolonged therapy, and they are more likely to relapse after completion of therapy. Antibody production can be used to follow the course of disease because most patients produce antibodies in response to infection with C. immitis. Early infection is characterized by the development of the IgM antibody, which peaks within 2 to 3 weeks of infection and then declines rapidly. The IgM antibody can be detected by either tube precipitin or immunodiffusion techniques. The IgG antibody levels rise between 4 and 12 weeks after infection and decrease slowly over months to years, and IgG can be detected in many body fluids, including serum, CSF, and pleural fluid, by CF and ID techniques. Higher titers (>1:16 or 1:32) occur more frequently with severe disease. Titers can be followed serially to evaluate the efficacy of antifungal therapy. Radiographic features tend to be quite variable; hilar adenopathy with alveolar infiltrates, tissue excavation of an infiltrate (resulting in a thin-walled cavity), or small pleural effusions are all seen commonly. With chronic persistent pneumonia, chest radiographs usually demonstrate apical fibronodular lesions or slowly progressive cavitation.


TREATMENT: Coccidioidomycosis
GENERAL GUIDELINES 6 Therapy for coccidioidomycosis is difficult, and the results are

unpredictable. Guidelines are available for treatment of this disease; however, optimal treatment for many forms of this disease still generates debate.25 The efficacy of antifungal therapy for coccidioidomycosis is often less certain than that for other fungal etiologies, such as blastomycosis, histoplasmosis, or cryptococcus, even when in vitro susceptibilities and the sites of infections are similar. The refractoriness of coccidioidomycosis may relate to the ability of C. immitis spherules to release hundreds of endospores, maximally challenging host defenses.25,26 Fortunately, only approximately 5% of infected patients require therapy.26

kg per day), ketoconazole (400 mg/day orally), intravenous or oral fluconazole (usually 400 to 800 mg/day, although dosages as high as 1200 mg/day have been used without complications), and itraconazole (200 to 300 mg orally twice daily as either capsules or solution).25,26 If itraconazole is used, measurement of serum concentrations may be helpful to ascertain whether oral bioavailability is adequate. Amphotericin B generally is preferred as initial therapy in patients with rapidly progressive disease, whereas azoles generally are preferred in patients with subacute or chronic presentations. The lipid formulations of amphotericin B have not been studied extensively in coccidioidal infection but may offer a means of giving more drug with less toxicity. Fluconazole probably is the most frequently used medicine given its tolerability, although high relapse rates have been reported in some studies. Relapse rates with itraconazole therapy may be lower than with fluconazole.25,26


SPECIFIC AGENTS USED FOR THE TREATMENT OF COCCIDIOIDOMYCOSIS


PRIMARY RESPIRATORY INFECTION

Specific antifungals (and their usual dosages) for the treatment of coccidioidomycosis include intravenous amphotericin B (0.5 to 0.7 mg/

Although most patients with symptomatic primary pulmonary disease recover without therapy, management should include follow-up visits

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for 1 to 2 years to document resolution of disease or to identify as early as possible evidence of pulmonary or extrapulmonary complications. CLINICAL CONTROVERSY Because of the lack of prospective, controlled trials, there is continued disagreement among experts in endemic areas whether patients with coccidioidomycosis should be treated and, if so, which ones and for how long. The excellent tolerability of oral azoles has lowered the threshold for deciding to treat primary infection, and some clinicians treat all primary infections. Rationale for treating a primary self-limiting infection include the ability to lessen the morbidity associated with the acute infection and the possible ability to reduce the development of more serious complications. However, there is currently no evidence that treatment of the primary infection accomplishes either of these goals.26 Patients with a large inoculum, severe infection, or concurrent risk factors (e.g., HIV infection, organ transplant, pregnancy, or high doses of corticosteroids) probably should be treated, particularly those with high CF titers, in whom incipient or occult dissemination is likely. Because some racial or ethnic populations have a higher risk of dissemination, some clinicians advocate their inclusion in the highrisk group. Common indicators used to judge the severity of infection include weight loss (>10%), intense night sweats persisting more than 3 weeks, infiltrates involving more than one-half of one lung or portions of both lungs, prominent or persistent hilar adenopathy, CF antibody titers of greater than 1:16, failure to develop dermal sensitivity to coccidial antigens, inability to work, or symptoms that persist for more than 2 months.25,26 Commonly prescribed therapies include currently available oral azole antifungals at their recommended doses for courses of therapy ranging from 3 to 6 months.25,26 In patients with diffuse pneumonia with bilateral reticulonodular or miliary infiltrates, therapy usually is initiated with amphotericin B; several weeks of therapy generally are required to produce clear evidence of improvement. Consolidation therapy with oral azoles can be considered at that time. The total duration of therapy should be at least 1 year, and in patients with underlying immunodeficiency, oral azole therapy should be continued as secondary prophylaxis.


INFECTIONS OF THE PULMONARY CAVITY Many pulmonary infections that are caused by C. immitis are benign in their course and do not require intervention. In the absence of

CRYPTOCOCCOSIS EPIDEMIOLOGY Cryptococcosis is a noncontagious, systemic mycotic infection caused by the ubiquitous encapsulated soil yeast Cryptococcus neoformans, which is found in soil, particularly in pigeon droppings, although disease occurs throughout the world, even in areas where pigeons are absent. Infection is acquired by inhalation of the organism. The incidence of cryptococcosis has risen dramatically in recent years, reflecting the increased numbers of immunocompromised patients, including those with malignancies, diabetes mellitus, chronic renal failure, and organ transplants and those receiving immunosuppressive

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controlled clinical trials, evidence of the benefit of antifungal therapy is lacking, and asymptomatic infections generally are left untreated. Symptomatic patients may benefit from oral azole therapy, although recurrence of symptoms may be seen in some patients once therapy is discontinued. Surgical resection of localized cavities provides resolution of the problem in patients in whom the risks of surgery are not too high.25,26


EXTRAPULMONARY (DISSEMINATED) DISEASE
NONMENINGEAL DISEASE Almost all patients with disease located outside the lungs should receive antifungal therapy; therapy usually is initiated with 400 mg.day of an oral azole. Amphotericin B is an alternative therapy and may be necessary in patients with worsening lesions or with disease in particularly critical locations such as the vertebral column. Approximately 50% to 75% of patients treated with amphotericin B for nonmeningeal disease achieve a sustained remission, and therapy usually is curative in patients with infections localized strictly to skin and soft tissues without extensive abscess formation or tissue damage. The efficacy of local injection into joints or the peritoneum, as well as intraarticular or intradermal administration, remains poorly studied. Amphotericin B appears to be most efficacious when cell-mediated immunity is intact (as evidenced by a positive coccidioidin or spherulin skin test or low CF antibody titer). Controlled trials that document these clinical impressions are lacking, however.25,26


MENINGEAL DISEASE Fluconazole has become the drug of choice for the treatment of coccidioidal meningitis.14,15 A minimum dose of 400 mg/day orally leads to a clinical response in most patients and obviates the need for intrathecal amphotericin B. Some clinicians will initiate therapy with 800 or 1000 mg/day, and itraconazole dosages of 400–600 mg/day are comparably effective. It is also clear, however, that fluconazole only leads to remission rather than cure of the infections; thus suppressive therapy must be continued for life. Ketoconazole cannot be recommended routinely for the treatment of coccidioidal meningitis because of its poor CNS penetration following oral administration. Patients who do not respond to fluconazole or itraconazole therapy are candidates for intrathecal amphotericin B therapy with or without continuation of azole therapy. The intrathecal dose of amphotericin B ranges from 0.01–1.5 mg given at intervals ranging from daily to weekly. Therapy is initiated with a low dosage and is titrated upward as patient tolerance develops.14,15,25,26

agents. The AIDS epidemic also has contributed to the increased numbers of patients; cryptococcosis is the fourth most common infectious complication of AIDS and the second most common fungal pathogen.27 Although C. neoformans produces no toxins and evokes only a minimal inflammatory response in tissue, the polysaccharide capsule appears to allow the organism to resist phagocytosis by the host. The capsular polysaccharide of C. neoformans appears to comprise the major virulence factor for this pathogen. Four serotypes of C. neoformans (A through D) have been identified; they vary in their polysaccharide content, virulence, geographic foci, and response to antifungal therapy. Serotypes A and D are commonly associated with pigeon droppings and other environmental sites and generally require

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shorter therapy than do infections caused by serotypes B or C, which have been found only in infected humans and animals. Serotypes B and C appear more resistant to antifungal agents in vitro. Patients with AIDS are almost always infected with serotypes A and D, even in areas endemic for serotypes B and C. There is no particular geographic area of endemic focus for C. neoformans. Cell-mediated immunity appears to play a major role in host defense against infection with C. neoformans; 29% to 55% of patients with cryptococcal meningitis have a predisposing condition. Many patients with disseminated cryptococcosis demonstrate defects in cellmediated immunity. The predilection of C. neoformans for the CNS appears to be caused by the lack of immunoglobulins and complement and the excellent growth medium afforded by CSF.27 Disease may remain localized in the lungs or may disseminate to other tissues, particularly the CNS, although the skin also can be affected. Hematogenous spread generally occurs in the immunocompromised host, although it also has been seen in individuals with intact immune systems. Cryptococcemia is the most common symptomatic extraneural infection associated with C. neoformans. Cryptococcemia can be documented in 5% to 22% of non-AIDS patients, and CNS involvement of C. neoformans can be found in 18% to 50% of AIDS patients. Cryptococcal disease is present in 7.5% to 10% of AIDS patients. Therefore, patients with evidence of extraneural cryptococcosis should be evaluated for CNS disease.

CLINICAL PRESENTATION OF CRYPTOCOCCOSIS13,27,28 Primary cryptococcosis in humans almost always occurs in the lungs, although the pulmonary focus usually produces a subclinical infec-

tion. Symptomatic infections usually are manifested by cough, rales, and shortness of breath that generally resolve spontaneously. In nonAIDS patients, the symptoms of cryptococcal meningitis are nonspecific. Headache, fever, nausea, vomiting, mental status changes, and neck stiffness generally are observed. Less common symptoms include visual disturbances (photophobia and blurred vision), papilledema, seizures, and aphasia. In AIDS patients, fever and headache are common, but meningismus and photophobia are much less common than in non-AIDS patients. Approximately 10% to 12% of AIDS patients have asymptomatic disease, similar to the rate observed in non-AIDS patients.28

LABORATORY TESTS With cryptococcal meningitis, the CSF opening pressure generally is elevated. There is a CSF pleocytosis (usually lymphocytes), leukocytosis, a decreased glucose concentration, and an elevated CSF protein concentration. There is also a positive cryptococcal antigen (detected by latex agglutination). The test is rapid, specific, and extremely sensitive, but false-negative results can occur. False-positive tests can result from cross-reactivity with rheumatoid factor and Trichosporon beigelli. C. neoformans can be detected in approximately 60% of patients by india ink smear of CSF, and it can be cultured in more than 96% of patients. Occasionally, large volumes of CSF are required to confirm the diagnosis. The CSF parameters in patients with AIDS are similar to those seen in non-AIDS patients, with the exception of a decreased inflammatory response to the pathogen, resulting in a strikingly low number of leukocytes in CSF and extraordinarily high cryptococcal antigen titers.


TREATMENT: Cryptococcosis The choice of treatment for disease caused by C. neoformans depends on both the anatomic sites of involvement and the host’s immune status.


NONIMMUNOCOMPROMISED PATIENTS For asymptomatic immunocompetent hosts with isolated pulmonary disease and no evidence of CNS disease, careful observation may be warranted; in the case of symptomatic infection, fluconazole or amphotericin B is warranted (Table 119–5). In individuals with nonCNS cryptococcemia, a positive serum cryptococcal antigen titer (>1:8), cutaneous infection, a positive urine culture, or prostatic disease, the clinician must decide whether to follow the regimen for isolated pulmonary disease or the more aggressive regimen for patients with CNS (disseminated) disease.19 Prior to the introduction of amphotericin B, cryptococcal meningitis was an almost uniformly fatal disease; approximately 86% of patients died within 1 year. The use of large (1 to 1.5 mg/kg) daily doses of amphotericin B resulted in cure rates of approximately 64%. 7 When amphotericin B is combined with flucytosine, a smaller dose of amphotericin B can be employed because of the in vitro and in vivo synergy between the two antifungal agents. Resistance develops to flucytosine in up to 30% of patients treated with flucytosine alone, limiting its usefulness as monotherapy.28,29 Combination therapy with amphotericin B and flucytosine will sterilize the CSF within

2 weeks of treatment in 60% to 90% of patients, and most immunocompetent patients will be treated successfully with 6 weeks of combination therapy.27 However, because of the need for prolonged IV therapy and the potential for renal and hematologic toxicity with this regimen, alternative regimens have been advocated. Despite a lack of clinically controlled trials in this population, amphotericin B induction therapy for 2 weeks, followed by consolidation therapy with fluconazole for an additional 8 to 10 weeks, is frequently recommended based on data extrapolated from studies conducted in HIV-infected patients. Suppressive therapy with fluconazole 200 mg/day for 6 to 12 months after the completion of induction and consolidation therapy is optional.19,29−31 Pilot studies evaluating combination therapy with fluconazole plus flucytosine as initial therapy yielded unsatisfactory results, and this approach is discouraged even in “low risk” patients. Ketoconazole has been used successfully in the treatment of cutaneous cryptococcosis, but it is not useful in the treatment of CNS disease, probably because of its poor penetration into the CNS.19 Despite low CSF concentrations of amphotericin B (2% to 3% of those observed in plasma), the use of intrathecal amphotericin B is not recommended for the treatment of cryptococcal meningitis except in very ill patients or in patients with recurrent or progressive disease despite aggressive therapy with IV amphotericin B. The dosage of amphotericin B employed is usually 0.5 mg administered via the lumbar, cisternal, or intraventricular (via an Ommaya reservoir) route two or three times weekly. Side effects of intrathecal amphotericin B include arachnoiditis and paresthesias. Intrathecal

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TABLE 119–5. Therapy of Cryptococcocosisa,b Type of Disease and Common Clinical Manifestations Nonimmunocompromised Host Isolated pulmonary disease (without evidence of CNS infection)

Cryptococcemia with positive serum antigen titer (>1:8), cutaneous infection, a positive urine culture, or prostatic disease Recurrent or progressive disease not responsive to amphotericin B Isolated pulmonary disease (without evidence of CNS infection)

CNS disease Acute (induction/consolidation therapy) (follow all regimens with suppressive therapy)

CNS disease

Immunocompromised Patients Non-CNS pulmonary and extrapulmonary disease CNS disease

HIV-Infected Patients Suppressive/maintenance therapy

a When

Therapy/Comments Comparative trials for amphotericin Bc versus azoles not available Asymptomatic disease: Durg therapy generally not required; observe carefully or fluconazole 400 mg orally daily × 3–6 months Mild to moderate symptoms: Fluconazole 200–400 mg orally daily × 3–6 months; Severe disease or inability to take azoles: Amphotericin B 0.4–0.7 mg/kg/day (total dose of 1–2 g) Clinician must decide whether to follow the pulmonary therapeutic regimen or the CNS (disseminated) regimen Amphotericin Bd IV 0.5–0.75 mg/kg/day ± IT amphotericin B 0.5 mg 2–3 times weekly Mild to moderate symptoms or asymptomatic with a positive pulmonary specimen: Fluconazole 200–400 mg orally daily × lifelong or Itraconazole 200–400 mg orally daily × lifelong or Fluconazole 400 mg orally daily + flucytosine 100–150 mg/kg/day orally × 10 weeks Severe disease: Amphotericin B until symptoms are controlled, followed by fluconazole Amphotericin Bd IV 0.7–1 mg/kg/day + flucytosine 100 mg/kg/day orally × ≥2 weeks, then fluconazole 400 mg orally daily × ≥8 weekse or Amphotericin Bd IV 0.7–1 mg/kg/day + flucytosine 100 mg/kg/day orally × 6–10 weekse or Amphotericin Bd IV 0.7–1 mg/kg/day × 6–10 weekse or Fluconazole 400–800 mg orally daily × 10–12 weeks or Itraconazole 400–800 mg orally daily × 10–12 weeks or Fluconazole 400–800 mg orally daily + flucytosine 100–150 mg/kg/day orally × 6 weekse or Lipid formulation of amphotericin B IV 3–6 mg/kg/day × 6–10 weeks Note: Induction therapy with azoles alone is discouraged. Amphotericin Bd IV 0.7–1 mg/kg/day + flucytosine 100 mg/kg/day orally × 2 weeks, followed by fluconazole 400 mg orally daily for a minimum of 10 weeks (in patients intolerant to fluconazole, substitute itraconazole 200–400 mg orally daily) or Amphotericin Bd IV 0.7–1 mg/kg/day + 5-FC 100 mg/kg/day orally × 6–10 weeks or Amphotericin Bd IV 0.7–1 mg/kg/day × 10 weeks Refractory disesase: Intrathecal or intraventricular amphotericin B Same as nonimmunocompromised patients with CNS disease Amphotericin Bd IV 0.7–1 mg/kg/day × 2 weeks, followed by fluconazole 400– 800 mg orally daily 8–10 weeks, followed by fluconazole 200 mg orally daily × 6–12 months (in patients intolerant to fluconazole, substitute itraconazole 200– 400 mg orally daily) Refractory disesase: Intrathecal or intraventricular amphotericin B Fluconazole 200–400 mg orally daily × lifelong or Itraconazole 200 mg orally twice daily × lifelong or Amphotericin B IV 1 mg/kg 1–3 times weekly × lifelong

more than one therapy is listed, they are listed in order of preference. text for definitions of induction, consolidation, suppressive/maintenance therapy, and prophylactic therapy. c Deoxycholate amphotericin B. d In patients with significant renal disease, lipid formulations of amphotericin B can be substituted for deoxycholate amphotericin B during the induction. e Or until CSF cultures are negative IV = intravenous; IT = intrathecal; CNS = central nervous system. Compiled from refs. 27–31. b See

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amphotericin B therapy should be administered in combination with IV amphotericin B.31


IMMUNOCOMPROMISED PATIENTS Immunocompromised hosts with isolated pulmonary and extrapulmonary disease without CNS disease should be treated similarly to nonimmunocompromised patients with CNS disease. Immunocompromised patients with CNS infection require more prolonged therapy; treatment regimens are based on those used in the HIV-infected population and follow induction and consolidation therapy with 6 to 12 months of suppressive therapy with fluconazole.19

formulations of amphotericin B are effective, but the optimal dosage is unknown.19 In HIV-infected patients with elevated intracranial pressure at the initiation of antifungal therapy, lumbar drainage should remove enough CSF to reduce the opening pressure by 50%. Patients initially should undergo daily lumbar punctures to maintain CSF opening pressure in the normal range. When the CSF pressure is normal for several days, the procedure can be suspended. Adjunctive steroid treatment is not recommended because therapy has resulted in mixed results and its impact on outcome is unclear. Similarly, neither mannitol nor acetazolamide therapy provides any clear benefit in the management of elevated intracranial pressure.19


HIV-INFECTED PATIENTS


SUPPRESSIVE (MAINTENANCE) THERAPY FOR CRYPTOCOCCAL MENINGITIS IN THE HIV-INFECTED PATIENT

There are no controlled clinical trials evaluating the therapy of isolated pulmonary infection; thus the specific treatment of choice is unclear. However, because these patients are at high risk for disseminated infection, antifungal therapy is warranted in all patients. Lifelong therapy with fluconazole is recommended; in patients for whom fluconazole is not an option, itraconazole can be used. Fluconazole is beneficial for both acute and chronic maintenance therapy for cryptococcal meningitis. Amphotericin B 0.4–0.5 mg/kg IV daily was compared with oral fluconazole 200 mg/day. Although the overall 10-week mortality was the same in both groups, the time until the CSF culture became negative was longer and there were more deaths in the first 2 weeks of therapy in the fluconazole group.30 In later trials,31 amphotericin B 0.7 mg/kg IV daily for 2 weeks (with or without oral flucytosine 100 mg/kg per day), followed by consolidation therapy with either itraconazole 400 mg/day orally or fluconazole 400 mg/day orally, led to markedly improved outcomes in comparison with earlier regimens. This study confirmed the benefit of early high-dose (0.7 mg/kg per day) amphotericin B use, the utility of flucytosine added to amphotericin B for induction therapy, and the slight superiority of fluconazole over itraconazole for consolidation therapy. Amphotericin B combined with flucytosine is the initial treatment of choice. In patients who cannot tolerate flucytosine, amphotericin B alone is an acceptable alternative. After the initially successful 2-week induction period, consolidation therapy with fluconazole can be administered for 8 weeks or until CSF cultures are negative. In patients in whom fluconazole cannot be given, itraconazole is an acceptable, albeit less effective, alternative. Combination therapy with fluconazole plus flucytosine is effective; however, it is recommended as an alternative to the preceding therapies because of its potential for toxicity. Lipid

Relapse of C. neoformans meningitis occurs in approximately 50% of AIDS patients after completion of primary therapy. Persistence of asymptomatic urinary C. neoformans has been documented in a high percentage of AIDS patients despite seemingly adequate courses of therapy for primary meningeal disease. The prostate appears to act as a sequestered reservoir of infection in these patients, resulting in systemic relapse. Fluconazole is recommended for chronic suppressive therapy of cryptococcal meningitis in AIDS patients. The AIDS Clinical Trials Group’s (ACTG) 026 study demonstrated that oral fluconazole 200 mg/day was superior to IV administration of amphotericin B 1 mg/kg weekly in preventing relapse. In addition, the fluconazole-treated group showed a lower incidence of adverse drug reactions and bacterial infections.31 Randomized comparative trials also demonstrated the superiority of fluconazole versus itraconazole as maintenance therapy. Thus itraconazole should be reserved for patients intolerant to fluconazole. Ketoconazole is not effective as maintenance therapy. Although some preliminary studies suggest lower relapse rates of opportunistic infections when patients have been treated successfully with potent antiretroviral therapy, until proven otherwise, maintenance therapy for cryptococcal meningitis should be continued for life. For selected patients who have responded very well to highly active antiretroviral therapy (HAART), the clinician may consider discontinuation of maintenance therapy following 12 to 18 months of successful suppression of HIV viral replication. A prospective, randomized trial confirmed that discontinuation of secondary prophylaxis is safe in patients after adequate treatment for cryptococcal meningitis who had CD4 cell increases of greater than 100 cells/mm3 and an HIV viral load of fewer than 50 copies/mL for more than 3 months.19,29−32

EVALUATION OF THERAPEUTIC OUTCOMES Once the CNS is involved, the usual course is weeks to months of progressive deterioration, with 80% of untreated patients dying within the first year. The prognosis of cryptococcal meningitis depends largely on the underlying predisposing factors of the host. Although cryptococcal antigen is positive in 90% of patients with cryptococcal meningitis, fewer than half the patients with cryptococcal meningitis develop antibody to capsular polysaccharide. Those who produce antibody have a slightly improved prognosis. In contrast, the presence of headache is a favorable symptom presumably because it leads to

an earlier diagnosis. A favorable outcome is also associated with a normal mental status on diagnosis and a CSF white blood cell (WBC) count of less than 20 cells/mm3 . A poor outcome is predicted, however, by the presence of one or more underlying diseases (including hematopoietic disorders and AIDS), corticosteroid or immunosuppressive therapy, pretreatment serum cryptococcal antigen titers of 1:32, and posttherapy serum antigen titers of 1:8. In non-AIDS patients, the cryptococcal antigen titer can be followed during therapy to assess response to antifungal therapy. In AIDS patients, decreasing titers are not necessarily predictive of success, and titers rarely become negative at the completion of therapy.14,15

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CANDIDA INFECTIONS Candida spp. are yeasts that exist primarily as small (4–6 microns), unicellular, thin-walled, ovoid cells that reproduce by budding. On agar medium, they form smooth, white, creamy colonies resembling staphylococci. Although there are more than 150 species of Candida, eight species—C. albicans, C. tropicalis, C. parapsilosis, C. krusei, C. stellatoidea, C. guilliermondi, C. lusitaniae, and C. glabrata—are regarded as clinically important pathogens in human disease.8,16 Yeast forms, hyphae, and pseudohyphae may be found in clinical specimens.

PATHOPHYSIOLOGY 8 C. albicans is a normal commensal of the skin, female genital

tract, and entire GI tract of humans. Therefore, the mere presence of hyphae or pseudohyphae in a clinical specimen is insufficient for the diagnosis of invasive disease. The majority of infections with C. albicans are acquired endogenously, although human-to-human transmission also can occur. Oral candidiasis in the newborn probably is acquired during passage through the birth canal, and balanitis in the uncircumcised male may be acquired through contact with a female with vaginal candidiasis.8 Although the term fungemia refers to the presence of fungi in the blood, the most commonly isolated organism is C. albicans. Candidiasis may cause mucocutaneous or systemic infection, including endocarditis, peritonitis, arthritis, and infection of the CNS. (Mucocutaneous infections caused by Candida are discussed in further detail in Chap.118.) The role of an intact integument is crucial in the prevention of mucocutaneous or hematogenous candidiasis. After Candida invades the dermis or enters the bloodstream, polymorphonuclear leukocytes (PMNs) play a major role in the defense of the patient because PMNs are capable of damaging pseudohyphae and can phagocytize and kill blastoconidia.8 In addition to neutrophils, lymphocytes, monocytes, macrophages, complement, and eosinophils play a role in the prevention of infection. Adherence of C. albicans is important in the pathogenesis of oral candidiasis and subsequent colonization of the GI tract. Because evidence suggests that the GI tract is often the portal of entry for Candida in disseminated disease, factors that alter the adherence of Candida are crucial in the development of local and systemic infection. C. tropicalis adheres to intravascular catheters at a higher rate than C. albicans, a factor that may help to account for the increased incidence of systemic infections caused by this pathogen.

HEMATOGENOUS CANDIDIASIS EPIDEMIOLOGY The incidence of fungal infections caused by Candida spp. has increased substantially in the past two decades, and Candida infections currently constitute a significant cause of morbidity and mortality among severely ill patients. Candida spp. now constitute the fourth most common cause of bloodstream infections (BSIs) for patients hospitalized in ICUs in the United States, following coagulase-negative staphylococci, Staphylococcus aureus, and enterococci. The Centers for Disease Control and Prevention’s (CDC) National Nosocomial Infection Survey implicated fungi as the cause of 8% of nosocomial infections. Although C. albicans accounted for 53% of Candida spp.,15 non-albicans species of Candida, including C. glabrata, C. tropicalis, C. krusei, and C. parapsilosis, are increasingly frequent causes of invasive candidal infections.34−36 C. lusitaniae infections are a

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cause of breakthrough fungemia in cancer patients; C. parapsilosis has emerged as the second most common pathogen, following C. albicans, in neonatal ICU patients; and fungemia caused by C. glabrata is observed more commonly in adults whose age is greater than 65 years.34,37 The change in species is of concern clinically because certain pathogens, such as C. krusei and C. glabrata, are intrinsically more resistant to commonly used triazole drugs.

PATHOPHYSIOLOGY Candida generally is acquired via the GI tract, although organisms also may enter the bloodstream via indwelling IV catheters. Immunosuppressed patients, including those with lymphoreticular or hematologic malignancies, diabetes, and immunodeficiency diseases and those receiving immunosuppressive therapy with high-dose corticosteroids, immunosuppressants, antineoplastic agents, or broadspectrum antimicrobial agents, are at high risk for invasive fungal infections. However, a number of prospective, randomized, controlled trials have validated the efficacy of antifungal prophylaxis and the use of antifungal agents for the treatment of persistently febrile patients with neutropenia who do not respond to antibiotics.8,14,15,38 These efforts have resulted in a reduction in the frequency of bloodstream infections caused by Candida spp. and systemic candidiasis in patients with neutropenia. In fact, most bloodstream infections caused by Candida spp. now occur in patients who have been hospitalized in ICUs, especially adult and neonatal ICUs. Retrospective studies have identified a number of risk factors for candidal bloodstream infections in ICU patients, most of which have been verified in multiple studies, although some remain controversial39 (Table 119–6). Major risk factors include the use of central venous catheters, total parenteral nutrition, receipt of multiple antibiotics, extensive surgery and burns, renal failure and hemodialysis, mechanical ventilation, and prior fungal colonization. Patients who have undergone surgery (particularly surgery of the GI tract) are increasingly susceptible to disseminated candidal infections.39,40

CLINICAL PRESENTATION OF HEMATOGENOUS CANDIDIASIS8,13,16 Dissemination of C. albicans can result in infection in single or multiple organs, particularly the kidney, brain, myocardium, skin, eye, bone, and joints. In most patients, multiple micro- and macroabscesses are formed. Infection of the liver and spleen is becoming recognized as a particularly common and difficult-to-treat site of infection that

TABLE 119–6. Risk Factors for Invasive Candidiasis Neutropenia Lymphoreticular or hematologic malignancies Diabetes Immunodeficiency diseases High-dose corticosteroids Immunosuppressants Antineoplastic agents Central venous catheters Total parenteral nutrition (TPN) Receipt of multiple antibiotics Extensive surgery (particularly surgery of the GI tract) Burns Renal failure and hemodialysis Mechanical ventilation Prior fungal colonization Compiled from refs. 8, 14, 15, 39, and 40.

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characteristically occurs in patients undergoing chemotherapy for acute leukemia or lymphoma.

DIAGNOSIS SIGNS AND SYMPTOMS Several distinct presentations of disseminated C. albicans have been recognized.12 1. Patients present with the acute onset of fever, tachycardia, tachypnea, and occasionally, chills or hypotension. The clinical presentation generally is indistinguishable from that seen with sepsis of bacterial origin. 2. Patients develop intermittent fevers and are ill only when febrile. 3. Patient manifests progressive deterioration of their condition with or without fever. 4. Hepatosplenic candidiasis often is manifested only as fever while the patient remains neutropenic (80%) as unchanged drug in the urine, dosage adjustments are necessary in patients with renal dysfunction.

VORICONAZOLE The most common side effect of voriconazole is a reversible disturbance of vision (photopsia), which occurs in approximately 30% of patients but rarely leads to discontinuation of the drug. Symptoms tend to occur during the first week of therapy and decrease or disappear despite of continued therapy. Patients experience altered color discrimination, blurred vision, the appearance of bright spots and wavy lines, and photophobia. Patients should be cautioned that driving may be hazardous because of the risk of visual disturbances. The visual effects are associated with changes in electroretinogram tracings, which revert to normal when treatment with the drug is stopped; no permanent damage to the retina has been demonstrated.75

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DRUG INTERACTIONS WITH AZOLE ANTIFUNGAL AGENTS Drug interactions with azole antifungals generally can be placed into three broad categories: (1) decreases in azole bioavailability because of chelation or secondary to increases in gastric pH, (2) interactions with other cytochrome P450–metabolized drugs, and (3) interactions caused by inhibition of p-glycoprotein. Drug interactions in the latter two categories may result in increases or decreases in the azole antifungal, in the interacting drug, or in both drugs.14,15 The interaction of azole antifungal agents with other cytochromes P450–metabolized drugs is well recognized. The azoles appear to be metabolized almost entirely via the cytochrome P450 3A4 subfamily. As expected, they interact with other drugs metabolized partly or wholly via this enzyme pathway. In addition, fluconazole and voriconazole use the cytochrome P450 2C19 pathway. Numerous clinically significant interactions have been documented with azole antifungals and a variety of other drugs. In most cases, the azole interferes with the metabolism of the other cytochrome P450–metabolized drug.14,15 The interaction between ketoconazole and cyclosporine has been exploited in order to reduce drug costs associated with administration of cyclosporine following organ transplantation. Relative to ketoconazole and itraconazole, fluconazole appears to be intermediate in its ability to inhibit human cytochromes P450. The magnitude of fluconazole-induced inhibition of cyclosporine metabolism appears, however, to depend on the dosage of fluconazole. Predictably, drugs such as rifampin, rifabutin, isoniazid, phenytoin, and carbamazepine, which are known to induce the activity of cytochromes P450, result in increased metabolism of the azole antifungals and may result in therapeutic failures. Increased dosages of azole antifungals may be required in patients receiving these combinations of drugs.14,15 Itraconazole is an inhibitor of intestinal p-glycoprotein. Significant increases in digoxin (a p-glycoprotein substrate) have been observed in patients receiving both agents concurrently. Interactions with other substrates of p-glycoprotein would be expected to occur.

COMBINATION ANTIFUNGAL THERAPY Based on extensive experience in the management of bacterial and, more recently, retroviral infections, the use of combination agents for synergistic or additive effects is now common practice. However, studies supporting the use of combinations of antifungal agents have produced less definitive results. In vitro and animal data have produced conflicting results, and human studies are lacking. Thus there are as yet no firm recommendations regarding the use of such combinations in humans. A recent study comparing the use of high-dose fluconazole alone or in combination with amphotericin B in nonimmunocompromised patients with candidemia demonstrated no antagonism and a trend toward improved success and more rapid clearance of Candida from the bloodstream.49

PLASMA CONCENTRATION MONITORING OF ANTIFUNGAL AGENTS Routine monitoring of plasma concentrations of antifungal agents to assess efficacy or toxicity of these agents generally is not available. Correlations between plasma concentrations of antifungal agents and therapeutic outcomes have been poorly studied. Under certain circumstances, serum or plasma concentration monitoring is warranted, e.g., in patients susceptible to flucytosine toxicity or to document adequate

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oral absorption of ketoconazole or itraconazole in cases of suspected treatment failure, concern about compliance or absorption, or when drug interactions that might reduce the solubility or accelerate the metabolism of azoles are suspected. Although “therapeutic” levels have not been defined, some investigators recommend maintenance of serum concentrations of itraconazole (2 to 4 hours after administration) of 1 mcg/mL, measured by bioassay.6,22 Among AIDS patients, those receiving a dosage of 200 mg once or twice daily achieved median plasma concentrations of 3 or 6 mcg/mL, respectively.22

ABBREVIATIONS AIDS: acquired immunodeficiency syndrome ACTG: AIDS Clinical Trials Groups ATCC: American Type Culture Collection ABCD: amphotericin B colloid dispersion ABLC: amphotericin B lipid complex ABC: ATP-binding cassette BAE: bronchial artery embolization BPA: bronchopulmonary aspergillosis CDC: Centers for Disease Control and Prevention CNS: central nervous system CVC: central venous catheter CSF: cerebrospinal fluid CF-M: CF titer for mycelial antigen CF: complement fixation ELISA: enzyme-linked immunosorbent assay GI: gastrointestinal GVHD: graft-versus-host disease HPA: H. capsulatum polysaccharide antigen HEPA: high-efficiency particulate air HAART: highly active antiretroviral therapy ID: immunodiffusion IgM: immunoglobulin M ICUs: intensive care units IV: intravenous LA: latex agglutination MF: major facilitators PMN: polymorphonuclear leukocytes PDH: progressive disseminated histoplasmosis RIA: radioimmunoassay TPN: total parenteral nutrition WBC: white blood cell Review Questions and other resources can be found at www.pharmacotherapyonline.com.

REFERENCES 1. Bennett JE. Introduction to mycoses. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed. Philadelphia, Churchill Livingstone, 2000:2654–2656. 2. Pfaller MA, Jones RN, Messer SA, et al. National surveillance of nosocomial blood stream infection due to Candida albicans: Frequency of occurrence and antifungal susceptibility in the SCOPE program. Diagn Microbiol Infect Dis 1998;31:327–332. 3. Pfaller MA, Jones RN, Doern GV, et al. International surveillance of blood stream infections due to Candida species in the European SENTRY Program: Species distribution and antifungal susceptibility including the investigational triazole and echinocandin agents. SENTRY Participant Group (Europe). Diagn Microbiol Infect Dis 1999;35:19–25.

4. Singh N. Invasive mycoses in organ transplant recipients: Controversies in prophylaxis and management. J Antimicrob Chemother 2000;45: 749–755. 5. National Committee for Clinical Laboratory Standards (NCCLS). Reference method for broth dilution antifungal susceptibility testing of yeasts: Approved Standard. NCCLS Document M27-A. Wayne, PA, NCCLS, 1997. 6. Summers KK, Hardin TC, Gore SJ, Graybill JR. Therapeutic drug monitoring of systemic antifungal therapy. J Antimicrob Chemother 1997;40:753–764. 7. Sobel JD. Practice guidelines for the treatment of fungal infections. Clin Infect Dis 2000;30:652. 8. Bennett JE. Pathogenic fungi. In: Sherris JC, ed. Medical Microbiology, 2d ed. New York, Elsevier, 1991:440. 9. Pappas PG, Rex JH, Walsh TJ, et al. Guidelines for treatment of candidiasis. Clin Infect Dis 2004;38:161–189. 10. Sanglard D, Odds FC. Resistance of Candida species to antifungal agents:molecular mechanisms and clinical consequences. Lancet Infect Dis 2002;2:73185. 11. White TC, Marr KA, Bowden RA. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev 1998; 11:382–402. 12. Lupetti A, Danesi R, Campa M, et al. Molecular basis of resistance to azole antifungals. Trends Mol Med 2002;8:76–81. 13. Bille J. Mechanisms and clinical significance of antifungal resistance. Int J Antimicrob Agents. 2000;16:331–333. 14. Kauffman CA, Carver PL. Antifungal agents in the 1990s: Current status and future developments. Drugs 1997;53:539–549. 15. Kauffman CA, Carver PL. Use of azoles for systemic antifungal therapy. Adv Pharmacol 1997;39:143–189. 16. Edwards JE. Candida species. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed. New York, Churchill-Livingstone, 2000:2656–2671. 17. Kaufman L. Laboratory methods for the diagnosis and confirmation of systemic mycoses. Clin Infect Dis 1992;14(suppl 1):S23–29. 18. Perfect JR. Antifungal prophylaxis: To prevent or not. Am J Med 1993;94: 233–234. 19. Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000;30:710–718. 20. Deepe GS. Histoplasma capsulatum. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed. New York, Churchill-Livingstone, 2000:2718–2733. 21. Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30 years of clinical experience. Rev Infect Dis 1990;12:308–329. 22. Wheat J, Sarosi G, McKinsey D, et al. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 2000;30:688–695. 23. Wheat LJ, Kauffman CA. Histoplasmosis. Infect Dis Clin North Am 2003;17(1):1–19. 24. O’Shaughnessy EM, Shea YM, Witebsky FG. Laboratory diagnosis of invasive mycoses. Infect Dis Clin North Am 2003;17(1):135–158. 25. Galgiani JN, Ampel NM, Catanzaro A, et al. Practice guidelines for the treatment of coccidioidomycoses. Clin Infect Dis 2000;30:658–661. 26. Chiller TM, Galgiani JN, Stevens DA. Coccidioidomycosis. Infect Dis Clin North Am 2003;17:41–57. 27. Bennett JE, Dismukes WE, Duma RJ, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 1979;301:126–131. 28. Francis P, Walsh TJ. Evolving role of flucytosine in immunocompromised patients: New insights into safety, pharmacokinetics, and antifungal therapy. Clin Infect Dis 1992;15:1003–1018. 29. Powderly WG, Saag MS, Cloud GA, et al. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. N Engl J Med 1992;326:793–798. 30. Saag MS, Powderly WG, Cloud GA, et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis: The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. N Engl J Med 1992;326:83–89.

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CHAPTER 119 31. van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med 1997;37:15–21. 32. Vibhagool A, Sungkanuparph S, Mootsikapun P, et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy: A prospective, multicenter, randomized study. Clin Infect Dis 2003; 36:1329–1331. 33. Sullivan DJ, Westerneng TJ, Haynes KA, et al. Candida dubliniensis sp. nov: Phenotyping and molecular characterization of a novel species associated with oral candidosis in HIV-infected individuals. Microbiology 1995:141;1507–1521. 34. Minari A, Hachem R, Raad I. Candida lusitaniae: A cause of breakthrough fungemia in cancer patients. Clin Infect Dis 2001;32:186–190. 35. Pfaller MA, Jones RN, Doern GV, et al. International surveillance of bloodstream infections due to Candida species: Frequency of occurrence and antifungal susceptibilities of isolates collected in 1997 in the United States, Canada, and South America for the SENTRY program. J Clin Microbiol 1998;36:1886–1889. 36. Winston DJ, Chandrasekar PH, Lazarus HM, et al. Fluconazole prophylaxis of fungal infections in patients with acute leukemia: Results of a randomized placebo-controlled, double-blind, multicenter trial. Ann Intern Med 1993;118:495–503. 37. Rangel-Frausto MS, Wiblin T, Blumberg HM, et al. National Epidemiology of Mycoses Survey (NEMIS): Variations in rates of blood stream infections due to Candida species in seven surgical intensive care units and six neonatal intensive care units. Clin Infect Dis 1999;29: 253–258. 38. Edmond MB, Wallace SE, McClish DK, et al. Nosocomial bloodstream infections in United States hospitals: A three-year analysis. Clin Infect Dis 1999;29:239–244. 39. Fraser VJ, Jones M, Dunkel J, et al. Candidemia in a tertiary care hospital: Epidemiology, risk factors, and predictors of mortality. Clin Infect Dis 1992;15:414–421. 40. Wey SB, Mori M, Pfaller MA, et al. Risk factors for hospital-acquired candidemia: A matched case-control study. Arch Intern Med 1989;149: 2349–2353. 41. Pappas, PG, Rex JH, Lee J, et al. A prospective observational study of candidemia: Epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis 2003;37:634–643. 42. Wey SB, Mori M, Pfaller MA, et al. Hospital acquired candidemia: The attributable mortality and excess length of stay. Arch Intern Med 1988; 148:2642–2645. 43. Eggimann P, Francioli P, Bille J, et al. Fluconazole prophylaxis prevents intraabdominal candidiasis in high-risk surgical patients. Crit Care Med 1999;27:1066–1072. 44. Rocco TR, Reinert SE, Simms H. Effect of fluconazole administration in critically ill patients. Arch Surg 2000;135:160–165. 45. Edwards DE. International conference for the development of a consensus on the management and prevention of severe candidal infections. Clin Infect Dis 1997;25:43–59. 46. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. N Engl J Med 1994;331:1325–1330. 47. Phillips P, Shafran S, Garber G, et al. Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in nonneutropenic patients: Canadian candidemia study group. Eur J Clin Micro Infect Dis 1997;16:337–345. 48. Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002;347: 2020–2029. 49. Rex JH, Pappas PG, Karchmer AW, et al. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis 2003;36:1221–1228. 50. Goodman JL, Winston DJ, Greenfield RA, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992;326:845–851.

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51. Slavin MA, Osborne B, Adams R, et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation: A prospective, randomized, double-blind study. J Infect Dis 1995;171:1545–1552. 52. Marr KA, Seidel K, Slavin MA, et al. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: Long-term follow-up of a randomized, placebo-controlled trial. Blood 2000;96:2055–2061. 53. Menichetti F, Del Favero A, Martino P, et al. Itraconazole oral solution as prophylaxis for fungal infections in neutropenic patients with hematologic malignancies: A randomized, placebo-controlled, double-blind, multicenter trial. GIMEMA Infection Program. Gruppo Italiano Malattie Ematologiche dell’ Adulto. Clin Infect Dis 1999;28:250–255. 54. Rotstein C, Bow EJ, Laverdiere M, et al. Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: Benefit based on purpose and intensity of cytotoxic therapy. Clin Infect Dis 1999;28:331–340. 55. Boogaerts M, Winston DJ, Bow EJ, et al. Intravenous and oral itraconazole versus intravenous amphotericin B as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. Ann Intern Med 2001;135:412–422. 56. Winston DJ, Hathorn JW, Schuster MG, et al. A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer. Am J Med 2000;108:282–289. 57. Pfaller MA. Nosocomial candidiasis: Emerging species, reservoirs, and modes of transmission. Clin Infect Dis 1996;22(suppl 2):S89–94. 58. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002;346:225–234. 59. Anaissie EJ, Darouiche RO, Abi-Said D, et al. Management of invasive candidal infections: Results of a prospective, randomized, multicenter study of fluconazole versus amphotericin B and review of the literature. Clin Infect Dis 1996;23:964–972. 60. Kauffman CA, Vazquez JA, Sobel JD, et al. Prospective multicenter surveillance study of funguria in hospitalized patients. Clin Infect Dis 2000;30:14–18. 61. Sobel JD, Kauffman CA, McKinsey D, et al. Candiduria: A randomized, double-blind study of treatment with fluconazole and placebo. Clin Infect Dis 2000;30:19–24. 62. Anaissie EJ, Rex JH, Uzun O, Vartivarian S. Predictors of adverse outcome in cancer patients with candidemia. Am J Med 1998;104:238–245. 63. Nucci M, Anaissie E. Should vascular catheters be removed from all patients with candidemia? An evidence-based review. Clin Infect Dis 2002;34:591–599. 64. Nguyen MH, Peacock JE Jr, Tanner DC, et al. Therapeutic approaches in patients with candidemia:evaluation in a multicenter, prospective, observational study. Arch Intern Med 1995;155:2429–2435. 65. Stevens DA, Schwartz HJ, Lee JT, et al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 2000;342:756– 762. 66. Steinbach WJ, Stevens DA. Review of newer antifungal and immunomodulatory strategies for invasive aspergillosis. Clin Infect Dis 2003; 37(suppl 3):S157–187. 67. Jennings TS, Hardin TC. Treatment of aspergillosis with itraconazole. Ann Pharmacother 1993;27:1206–1211. 68. Harari S. Current strategies in the treatment of invasive Aspergillus infections in immunocompromised patients. Drugs 1999;58:621–631. 69. Stevens DA, Kan VL, Judson MA, et al. Practice guidelines for diseases caused by Aspergillus. Clin Infect Dis 2000;30:696–709. 70. Lin SJ, Schranz J, Teutsch SM. Aspergillus case fatality rate: Systematic review of the literature. Clin Infect Dis 2001;32:358–366. 71. Holding KJ, Dworkin MS, Wan PCT, et al. Aspergillosis among people infected with human immunodeficiency virus: Incidence and survival. Clin Infect Dis 2000;31:1253–1257. 72. Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formulations of amphotericin B: Clinical efficacy and toxicities. Clin Infect Dis 1998;27: 603–618. 73. Ellis M, Spence D, de Pauw B, et al. An EORTC international multicenter randomized trial (EORTC no. 19923) comparing two dosages of liposomal

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amphotericin B for treatment of invasive aspergillosis. Clin Infect Dis 1998;27:1406–1412. Wingard JR, White ML, Anaissie E, et al. A randomized, double-blind, comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. Clin Infect Dis 2000;31:1155–1163. Johnson LB, Kauffman CA. Voriconazole: A new triazole antifungal agent. Clin Infect Dis 2003;36:630–637. Pacetti SA, Gelone SP. Caspofungin acetate for treatment of invasive fungal infections. Ann Pharmacother 2003;37:90–98. Castiglioni B, Sutton DA, Rinaldi MG, et al. Pseudallescheria boydii (anamorph Scedosporium apispermum) infection in solid organ transplant

78.

79. 80. 81. 82.

recipients in a tertiary medical center and review of the literature. Medicine 2002;81:333–348. Boutati EI, Anaissie EJ. Fusarium, a significant emerging pathogen in patients with hematologic malignancy: Ten years’ experience at a cancer center and implications for management. Blood 1997;90:999–1008. Pfizer. Vfend (voriconazole) package insert. New York, 2002. King CT, Rogers PD, Cleary JD, et al. Antifungal therapy during pregnancy. Clin Infect Dis 1998;27:1151–1160. Ostrosky-Zeichner L, Marr KA, Rex JH, Cohen SH. Amphotericin B: Time for a new “gold standard.” Clin Infect Dis 2003;37:415–425. Stevens DA. Itraconazole in cyclodextrin solution. Pharmacotherapy 1999;19:603–611.

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120 INFECTIONS IN IMMUNOCOMPROMISED PATIENTS Douglas N. Fish and S. Diane Goodwin

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 An immunocompromised host is a patient with defects in

host defenses that predispose to infection. Risk factors include neutropenia, immune system defects (from disease or immunosuppressive drug therapy), compromise of natural host defenses, environmental contamination, and changes in normal flora of the host.

2 Immunocompromised patients are at high risk for a variety

of bacterial, fungal, viral, and protozoal infections. Bacterial infections caused by gram-positive cocci (staphylococci and streptococci) occur most frequently, followed by gramnegative bacterial infections caused by Enterobacteriaceae and Pseudomonas aeruginosa. Fungal infections caused by Candida and Aspergillus, as well as certain viral infections (herpes simplex virus, cytomegalovirus), are also important causes of morbidity and mortality.

3 Risk of infection in neutropenic patients is associated with

both the severity and duration of neutropenia. Patients with severe neutropenia (absolute neutrophil count [ANC] 40% incidence) or patients with active tissue infection at the time of chemotherapy, history of febrile neutropenia with previous courses of chemotherapy, or underlying bone marrow compromise.57


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the day of HSCT until engraftment to prevent candidiasis).7,22 Prophylaxis against fungal infection is beneficial in leukemic patients, and the choice of either fluconazole, itraconazole, or amphotericin B should be determined by the types of fungal isolates at individual institutions.22,68 Recent data indicate that itraconazole may be more effective than fluconazole for long-term antifungal prophylaxis in allogeneic HSCT recipients; however, itraconazole use was associated with more frequent GI side effects.70 After initiation, antifungal prophylaxis should be continued until resolution of neutropenia or the need for institution of antifungal therapy for suspected/documented infection.22 Antifungal prophylaxis does not decrease the incidence of invasive mold infections.65 In addition to environmental precautions, strategies being investigated for Aspergillus prophylaxis in neutropenic patients include oral itraconazole, low (0.1–0.25 mg/kg per day) to moderate (0.5 mg/kg per day) doses of amphotericin B, intranasal and aerosolized amphotericin B, and lipid-associated amphotericin B products.7 None of these interventions can be recommended routinely in clinical practice at this time.

Because neutropenic patients are at risk for mucocutaneous and invasive fungal infections that are difficult to diagnose and treat in this population, antifungal prophylaxis may be considered during highrisk periods at institutions where fungal infections in cancer patients are frequent.64 The goal of antifungal prophylaxis is to prevent development of invasive fungal infections during periods of risk, thereby reducing morbidity and mortality. A meta-analysis of antifungal prophylaxis in 38 trials involving more than 7000 cancer patients reported a decrease in the use of parenteral antifungal therapy, superficial and invasive systemic fungal infections, and fungal infection–related mortality rate.65 Antifungal prophylaxis resulted in decreased mortality in patients with prolonged neutropenia and HSCT but had no effect on rates of invasive Aspergillus infections. Although the choice of antifungal prophylaxis agents remains controversial, fluconazole prophylaxis (400 mg/day) has been particularly well studied and reduces the incidence of both superficial and systemic fungal infections, as well as significantly decreases mortality from fungal infections in patients with leukemia and HSCT recipients.63,66−68 However, the use of fluconazole prophylaxis has resulted in the emergence of infections caused by C. krusei and C. glabrata, pathogens that frequently are resistant to fluconazole and other azole-type antifungal agents.64,69 Routine antifungal prophylaxis with oral fluconazole (400 mg/day) or itraconazole oral solution (2.5 mg/kg every 12 hours) therefore should be limited to patients undergoing allogeneic HSCT (usually administered from

The use of trimethoprim-sulfamethoxazole in cancer patients at risk for P. jiroveci pneumonia has reduced the incidence of this protozoal infection substantially.27 Antiviral prophylaxis with acyclovir or newer agents (valacyclovir and famciclovir) is employed in most centers to reduce the risk of HSV reactivation in patients with acute leukemia undergoing intensive chemotherapy. Varicella vaccine provides good protection (90%) in leukemic children and also may be useful in seronegative adults, although the vaccine has been less well studied in this population. When considering use of antimicrobial (antibacterial, antifungal, antiprotozoal, and antiviral) prophylaxis in neutropenic patients with cancer, the risks and benefits of the prophylaxis versus issues with development of resistance, toxicities, and other concerns must be weighed.

PHARMACOECONOMIC CONSIDERATIONS

EVALUATION OF THERAPEUTIC OUTCOMES

10 As in all areas of modern health care, attention has been di-

10 Close monitoring of febrile neutropenic patients, including both

rected increasingly to providing cost-effective management of febrile neutropenia in cancer patients. Use of oral and/or outpatient antimicrobial therapy in low-risk patients is an effective, less costly alternative that is preferred by patients.71 Potent oral antimicrobials facilitate the conversion from IV antibiotics to oral therapy when appropriate. Judicious use of antimicrobials, such as reserving lipidassociated amphotericin B products for patients intolerant to conventional amphotericin B, helps to contain costs. In the situation of febrile neutropenia in a cancer patient, one may be tempted to “throw the kitchen sink” at suspected/documented infections; however, following guidelines such as those published by the IDSA and NCCN helps to guide the most appropriate use of available antimicrobials. Future consequences of antimicrobial overuse, such as resistance and limited treatment options, must be considered when choosing antimicrobial therapy for any indication, including management of febrile neutropenia. Each institution should examine its own infection and susceptibility patterns and use this information to guide empirical treatment decisions while individualizing therapy for each patient.


OTHER INFECTIONS

clinical and laboratory parameters, is essential for early detection and treatment of infectious complications. Three general therapeutic outcomes have been defined in the setting of febrile neutropenia: (1) success (survival during the febrile episode until resolution of neutropenia by judicious selection of empirical antimicrobial therapy), (2) success with modification (same as 1 but with additions/modifications to empirical therapy), and (3) failure (death during febrile neutropenia).10 Because many of the drugs that may be used in this setting have significant toxicity potential (e.g., aminoglycosides and amphotericin B), careful attention must be paid to the prevention and management of drug-related adverse effects. Evaluations of the parameters in the “Clinical Presentation” box are appropriate to help monitor and guide therapy. In addition, the NCCN guidelines for febrile neutropenia provide comprehensive recommendations on clinical/laboratory monitoring parameters, including schedules.6 The reader is referred to individual chapters within this book for more detailed discussions of monitoring parameters related to specific types of infections (e.g., pneumonia and urinary tract infections).

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INFECTIONS IN PATIENTS UNDERGOING HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) 1 Infection remains a major barrier to successful HSCT. Numer-

ous advances in HSCT have taken place over the past decade and have resulted in greatly improved patient outcomes. Recipients of HSCT are at enhanced risk of infection because of prolonged periods of neutropenia. In addition, patients receiving allogeneic or matched unrelated donor transplants have added immune system insults imposed by prolonged immunosuppressive drug therapy for the prevention and treatment of graft-versus-host disease (GVHD). Intensive pretransplant conditioning regimens (high-dose chemotherapy and total-body irradiation), as well as GVHD itself, often disrupt protective barriers, such as mucous membranes, skin, and the GI tract, placing patients at further risk of infection. Patients experiencing marrow graft failure have extended periods of profound neutropenia often resulting in death from infectious causes. The Food and Drug Administration (FDA) approved sargramostim for marrow graft failure in both autologous and allogeneic transplants.

ETIOLOGY AND CLINICAL PRESENTATION OF INFECTIONS 2

10 The timing with which specific types of infections typically

occur following HSCT is represented in Fig. 120–2. Although the figure illustrates the general time course for infections

in all types of HSCT, the relative incidence and importance of specific pathogens vary greatly according to the specific type of HSCT performed. Patients receiving allogeneic transplants are at greatest risk of infection at all times after HSCT and are predisposed to earlier and more severe infections with opportunistic pathogens such as Aspergillus. The presence of GVHD also has an impact on the incidence and timing of various infections. After the administration of intensive conditioning regimens to eliminate malignant cells and prevent rejection of donor marrow, patients may remain profoundly neutropenic for 3 to 4 weeks. During this preengraftment period, they are at risk for the same types of infectious complications noted in other granulocytopenic cancer patients (e.g., bacterial and fungal infections) and should be managed accordingly (see Table 120–1). Table 120–4 lists regimens for the treatment of specific infections. Fungal infections, especially those caused by Candida and Aspergillus spp., are serious and often fatal complications associated with HSCT. Fungi remain a serious cause of infection, particularly in allogeneic HSCT recipients, for up to 1 to 2 years following transplantation and may occur in as many as 10% of patients.72 Mortality rates associated with invasive aspergillosis infections may be as high as 90%.73 In addition to bacterial and fungal infections, HSCT recipients also are at risk for serious HSV infections manifesting as severe gingivostomatitis, esophagitis, genital lesions, and rarely, pneumonia during the first month after transplant. Clinical disease is more common in patients with serologic evidence (e.g., serum antibodies) Late postengraftment and late post-transplant periods (⬎180 days)

Early postengraftment and intermediate post-transplant periods (30–180 days)

Pre-engraftment and early post-transplant periods (0–30 days) Bacterial infections Surgical wound, IV catheter, UTI, pneumonia, Clostridium difficile Viral infections Herpes simplex virus Hepatitis B, hepatitis C Cytomegalovirus Epstein-Barr virus

Varicella zoster virus Influenza, parainfluenza, respiratory syncitial virus Fungal infections

Candida spp. Aspergillus spp. Cryptococcus neoformans Misc. opportunistic infections

Pneumocystis jiroveci Mycobacterium tuberculosis Toxoplasma gondii Nocardia asteroides 1 HSCT or solid organ transplant

2

3 Time (months)

4

5

6

FIGURE 120–2. Timetable for the occurrence of infections in HSCT and solid organ-transplant patients. IV = intravenous; UTI = urinary tract infection.

7

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of prior exposure and latent HSV infection pretransplant. Therefore, reactivation of latent disease during periods of immunosuppression is the most common etiology of HSV infection. Without prophylaxis, as many as 80% of HSV-seropositive patients experience mucocutaneous disease after intensive chemotherapy as compared with fewer than 25% of seronegative patients.72,74 The HSV infections often coexist with candidal infection and mucositis secondary to chemotherapy, radiation, or both.75 Acyclovir-resistant HSV infections also occur following HSCT but are not common.72,76 Painful swallowing associated with these conditions often makes it difficult for patients to take oral medications and maintain adequate nutritional intake. Because of the considerable morbidity associated with reactivation of HSV after transplantation, the HSV serologic status of patients should be determined prior to transplant. Recipients of HSCT remain at high risk for infection after bone marrow engraftment has occurred. Significant defects in neutrophil function and cell-mediated and humoral immunity, persisting for several months after transplantation, predispose patients to infectious complications. Acute and chronic GVHD also result in prolonged periods of immunosuppression and increased infection rates. Bone marrow transplant patients are at high risk for cytomegalovirus (CMV) infections during the early postengraftment period. These range in severity from asymptomatic viral shedding (urine, throat, lungs) to life-threatening disseminated disease and interstitial pneumonia.72,75 As with HSV, patients seropositive for CMV before transplantation are at high risk for recurrent disease during periods of immunosuppression; about 70% of seropositive patients develop recurrent CMV disease after transplantation compared with only 3% of seronegative patients.72,74,75 Other risk factors for CMV disease in HSCT patients include advanced age, human lymphocyte antigen (HLA) mismatch, total-body irradiation, multiagent conditioning regimens, and the presence of GVHD.72 Patients without evidence of latent CMV infection (CMV seronegative) before transplantation may

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develop primary CMV disease after receiving bone marrow or blood products from CMV-seropositive donors. Although the typical onset of both primary and recurrent CMV infection is 1 to 2 months after transplantation, late-onset infections occurring more than 100 days after transplantation are increasing in frequency.72,74,75,77 Patients receiving allogeneic transplants are at highest risk for CMV disease.72,74,75 The most serious clinical manifestation of CMV disease and the leading cause of infectious death in HSCT recipients is interstitial pneumonia (IP), which is associated with an 85% mortality rate if untreated.72,74 This clinical syndrome manifests as fever, dyspnea, hypoxia, nonproductive cough, and diffuse pulmonary infiltrates. As many as 40% of allogeneic HSCT patients will develop IP; of these patients with IP, up to 40% of cases are the result of CMV.72,74 IP also may result from other infectious (P. jiroveci, varicella-zoster virus) and noninfectious causes (pulmonary damage by radiation and chemotherapy).72 During the late postengraftment period (beginning about 100 days after transplantation), infections remain a major problem in patients suffering from chronic GVHD. Additional immunosuppressive therapy for the treatment of GVHD places these patients at added risk for infection. Infections common during the late postengraftment period include those caused by encapsulated bacteria, such as S. pneumoniae and H. influenzae, and viruses, including CMV and VZV.72,74 Patients not undergoing allogeneic transplantation or suffering from chronic GVHD generally have few infections in this period. Up to 50% of all patients surviving up to 10 months after transplantation develop an infection caused by VZV.72 Infection with VZV is most common in patients receiving allogeneic transplants with acute or chronic GVHD.72,74,75 Both primary (varicella) or recurrent disease (herpes zoster) usually present as skin lesions, most of which remain contained to local areas; however, 30% to 45% of these infections may disseminate to other cutaneous areas or body organs, causing mortality as high as 50%.72,74,75


PROPHYLAXIS AND MANAGEMENT: Infections in Recipients of HSCT 8

9 The goals of antimicrobial drug use in HSCT patients

include (1) prevention of bacterial, fungal, viral, and protozoal infections during preengraftment and postengraftment periods and (2) effective treatment of established infections. The overall goal of prophylaxis and treatment of infection in HSCT patients is the prevention of infectious morbidity and mortality. These goals must be achieved at the lowest possible toxicity and cost. Prophylactic therapy should be specifically aimed at pathogens known to cause a high incidence of infection within the HSCT population, the specific institution, or both. In addition, prophylactic therapy should be limited to regimens proved to be effective through well-designed clinical trials. Appropriate immunizations should be a primary consideration in the prevention of infections in HSCT recipients. Immunizations against common bacterial and viral pathogens are timed to avoid periods of severe immunosuppression following HSCT when the protective response to vaccination potentially would be decreased.78 Current recommendations for immunization of HSCT patients include three doses each of diphtheria-pertussis-tetanus or diphtheria-tetanus, inactivated polio, conjugated H. influenzae type b, and hepatitis B vaccines at 12, 14, and 24 months after transplantation. The 23-valent pneumococcal vaccine should be administered at 12 and 24 months after HSCT, and the influenza vaccine should be administered prior to HSCT, resumed at least 6 months after transplantation, and con-

tinued for life. Family, close contacts, and health care providers of HSCT patients also should be vaccinated annually against influenza. Finally, the measles-mumps-rubella vaccine should be administered no sooner than 24 months after HSCT when the patient is considered to be immunocompetent. The varicella vaccine is contraindicated for administration to HSCT patients owing to the live-attenuated nature of the product and the risk of VZV infection.78


BACTERIAL INFECTIONS Prophylaxis of infections in HSCT patients is in many ways similar to that used in other neutropenic patients. Selective decontamination with oral antimicrobials is used commonly; considerations are the same as those discussed previously. Although some studies have shown decreased rates of bacteremia and other bacterial infections after HSCT, overall mortality rates were not reduced.72,78 The routine use of prophylactic antibiotics in HSCT therefore is still controversial. Fluoroquinolones have become the most frequently used agents, often combined with another agent (e.g., macrolides or rifampin) for enhanced gram-positive activity.72,74 These regimens usually are begun

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either within 72 hours of beginning the chemotherapy conditioning regimens or on the day of hematopoietic stem cell infusion and continued throughout the neutropenic period. Patients who become febrile while receiving prophylaxis should be managed according to general guidelines for febrile neutropenic patients. The routine use of parenteral vancomycin for prophylactic therapy is not recommended. Prophylaxis with vancomycin has been studied because of the high incidence of gram-positive infections following transplantation. Vancomycin prophylaxis appears to decrease the overall incidence of gram-positive bacterial infections, number of days of empirical antimicrobial therapy, and cost of therapy.72,78 However, important mortality benefits were not demonstrated consistently, and there are significant concerns regarding the selection of vancomycin-intermediate S. aureus and vancomycinresistant enterococci. Prophylactic vancomycin use thus is not generally recommended except in institutions with high rates of infection with methicillin-resistant staphylococci among HSCT recipients.74,78 There is currently no role for linezolid or quinupristin-dalfopristin except in documented infections caused by VRE. Antibiotic prophylaxis against bacterial infection is recommended in the late postengraftment period (>100 days after transplantation) in certain high-risk patients, specifically allogeneic transplant recipients with chronic GVHD.78 Antibiotics should be targeted against encapsulated bacteria such as S. pneumoniae and H. influenzae and should be selected based on local susceptibility patterns for these organisms. Patients receiving trimethoprim-sulfamethoxazole for prophylaxis of other opportunistic infections may be protected adequately and do not necessarily require an additional antibiotic.72 Prophylaxis should be continued as long as the chronic GVHD is being actively treated.


VIRAL INFECTIONS Prophylaxis of recurrent HSV infection is recommended for all HSVseropositive patients undergoing HSCT.72,78 Approximately 0% to 10% of HSV-seropositive patients receiving acyclovir experienced viral shedding, clinical symptoms of viral reactivation, or both as compared with 60% to 80% of patients receiving placebo.74 Acyclovir doses recommended for prophylaxis are 250 mg/m2 (5 mg/kg) IV every 12 hours or 200 mg orally three times daily.72,78 Intravenous therapy eventually will be necessary in most patients because of the development of severe mucositis from conditioning regimens. Oral acyclovir, however, is effective and considerably less expensive in patients who can take oral medications. Valacyclovir also has been used in doses of 500–1000 mg/day, but clinical experience is limited, and it is not currently recommended as first-line prophylaxis therapy.78 Although the duration of antiviral prophylaxis differs between centers, acyclovir usually is begun at the time of the conditioning regimen and continued until bone marrow engraftment or until resolution of mucositis (approximately 30 days after HSCT).78 Besides preventing recurrence of HSV disease, acyclovir prophylaxis also may reduce the incidence of CMV reactivation.79 Patients developing active HSV or VZV infection should be treated with high-dose acyclovir (10 mg/kg IV every 8 hours). Although high-dose oral acyclovir given for 6 months after transplantation also significantly reduces reactivation of VZV infections, routine use of long-term acyclovir is controversial and not generally recommended for this indication.72,78 Patients who received HSCT within the previous 24 months or those beyond 24 months after HSCT who have chronic GVHD or are on immunosuppressive

therapy should receive varicella-zoster immunoglobulin 625 units intramuscularly within 48 to 96 hours after close contact with persons with chickenpox or shingles for prevention of VZV-related disease.78 Acyclovir-resistant HSV has been reported occasionally in HSCT patients receiving acyclovir prophylaxis. Foscarnet is the drug of choice for treatment of acyclovir-resistant HSV. Foscarnet, however, has not been well studied for HSV prophylaxis.72,74,78 Prevention of CMV disease has been studied extensively in HSCT patients and is a well-accepted indication for prophylaxis because of the high associated infectious morbidity and mortality. If possible, CMV-seronegative patients should receive donor marrow and supportive blood products from seronegative donors only; however, CMV-seropositive patients are not at additional risk by receiving blood or marrow from seropositive donors.72 Although acyclovir has relatively poor in vitro activity against CMV, a decrease in CMV infection and an improvement in overall survival were reported in HSV- and CMV-seropositive allogeneic HSCT recipients receiving IV acyclovir.79 CLINICAL CONTROVERSY Although acyclovir is used commonly in many transplant centers for prophylaxis of CMV infection, this practice is somewhat controversial and is not universally recommended because of the intrinsically poor activity of acyclovir against CMV.72 Ganciclovir also has been well studied for prophylaxis because of its superior activity against CMV compared with acyclovir. Although administration of prophylactic ganciclovir to CMV-seropositive patients may decrease the occurrence of CMV disease significantly, studies found no clear survival benefit, and ganciclovir-related bone marrow suppression frequently was problematic. Ganciclovir prophylaxis therefore is only recommended routinely among allogeneic HSCT recipients for the first 100 days after transplantation.72,78 The recommended dose of ganciclovir in these patients is 5 mg/kg IV every 12 hours for the first 5 to 7 days, followed by 5–6 mg/kg IV once daily five times per week until day 100 after HSCT.78 Perhaps a more appropriate role for ganciclovir is in early or preemptive therapy, in which ganciclovir is administered at first isolation of CMV from the blood or bronchoalveolar lavage (BAL) fluid. Detection of CMV may be accomplished through the use either of a monoclonal antibody–based test for viral antigens or by detection of viral DNA through polymerase chain reaction (PCR)–based tests. Preemptive therapy was evaluated in several studies and significantly reduced the occurrence of CMV disease (including CMV pneumonia), and it improved survival significantly up to 180 days after transplantation.72 Because CMV viremia and BAL cultures are highly predictive of subsequent CMV disease, preemptive ganciclovir therapy should be considered for autologous HSCT recipients within the first 100 days after transplantation or in allogeneic HSCT recipients at any time point after transplantation.72,78 The dose of ganciclovir for preemptive therapy is the same as that used for prophylaxis. Foscarnet may be used for either prophylaxis or preemptive therapy of CMV disease in patients intolerant of ganciclovir; the recommended foscarnet dose is 60 mg/kg IV every 12 hours for 7 days, followed by 90–120 mg/kg IV daily.80 Oral valganciclovir 900 mg every 12 hours has not been well studied in the setting of HSCT and is not recommended routinely. CSFs are beneficial in this setting, providing benefits similar to those noted in neutropenic AIDS patients receiving ganciclovir therapy for CMV retinitis.

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Pharmacologic prevention of CMV disease with either intravenous immunoglobulin (IVIG) or hyperimmune CMV-IVIG produced variable and inconclusive results.74,81 The benefits of immunoglobulins for CMV prophylaxis in HSCT patients have not been demonstrated conclusively, and their use is not currently recommended.72 Ganciclovir is the drug of choice in the treatment of active CMV infection in HSCT patients (see Table 120–4). Foscarnet is effective in the treatment of severe CMV disease in AIDS patients and also may be of benefit for the treatment or prevention of infections in HSCT patients. Foscarnet may be used as an alternative to ganciclovir because of its relative lack of bone marrow toxicity. Foscarnet-related nephrotoxicity may be problematic, however, especially in the posttransplant period when patients may be receiving other nephrotoxic agents. Use of cidofovir also is limited by the risk of nephrotoxicity, and this agent has not been well studied in HSCT patients. Numerous single-agent treatments, such as vidarabine, interferon, and ganciclovir, have been employed unsuccessfully as treatment for CMV pneumonitis. The combination of high-dose IVIG and ganciclovir, however, may decrease the mortality of this syndrome from 85% to only 30% to 50%.72 Ganciclovir plus hyperimmune CMV-IVIG is also considered to be effective for the treatment of CMV disease, although this regimen has not been studied as extensively in the HSCT population in a controlled fashion. The potential for ganciclovir-associated bone marrow suppression prior to marrow engraftment and in patients who are just recovering from granulocytopenia remains a concern, especially in patients with unstable renal function. Ganciclovir plus CMV-IVIG is employed widely as the treatment regimen of choice for severe or life-threatening CMV disease. Ganciclovir plus IVIG also is used frequently, although CMV-IVIG is replacing IVIG in most institutions.74,81


FUNGAL INFECTIONS Fluconazole prophylaxis is safe and efficacious for prevention of mucocutaneous and disseminated candidal infections in high-risk HSCT patients.22,72,78,82 Patients specifically recommended for prophylaxis include all allogeneic transplant recipients and autologous recipients who are expected to have prolonged neutropenia, have received intensive conditioning regimens associated with extensive mucositis, or have recently received fludarabine.72,78 Fluconazole 400 mg IV or orally given once daily is begun on the day of transplantation and continued until engraftment or resolution of neutropenia.22,72,78 The variable activity of fluconazole against non-albicans species of Candida may be problematic in this population, as is lack of activity against

EVALUATION OF THERAPEUTIC OUTCOMES 10 Close monitoring of HSCT patients, including both clinical and

laboratory data, is essential for early detection and treatment of infectious complications. In addition, because many of the drugs that may be used commonly in this setting have significant toxicity potential in HSCT patients (e.g., ganciclovir, amphotericin B, and trimethoprim-sulfamethoxazole), careful attention must be paid to the prevention and management of drug-related adverse effects. Monitoring parameters related to specific types of infections (e.g., pneumonia and urinary tract infections) should be applied as appropriate. The reader is referred to other chapters within this book for more specific information.

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Aspergillus.82 Prophylaxis with fluconazole (as well as itraconazole), although effectively reducing colonization and infection with yeasts, has not been demonstrated consistently to reduce overall mortality or invasive infections such as aspergillosis in HSCT recipients.72,82,83 Low-dose amphotericin B (0.10–0.25 mg/kg per day) is used occasionally in institutions with high rates of Aspergillus infection after HSCT. Low-dose liposomal amphotericin B (1 mg/kg per day) also has been studied.82,84 As with the azoles, amphotericin B prophylaxis has not been demonstrated clearly to provide benefits in either overall or infection-related mortality following HSCT.13,22,74,83 Despite the controversies regarding absolute benefits of prophylaxis, fluconazole generally is recommended for most patients undergoing HSCT.74,78,83 Low-dose amphotericin B prophylaxis should be reserved for institutions with high rates of infection owing to azole-resistant yeasts (e.g., C. krusei) or high rates of invasive disease such as aspergillosis.74 Fluconazole and other azole antifungals may cause significant elevations in serum cyclosporine concentrations and predispose to cyclosporine toxicities; this interaction should be monitored closely in HSCT patients receiving these agents concurrently.22


PROTOZOAL INFECTIONS Pulmonary infection with P. jiroveci is a relatively infrequent complication of HSCT. Mortality rates in this population, however, are approximately 60% and are especially high in patients with GVHD.72,74,78 Prophylactic use of trimethoprim-sulfamethoxazole (one double-strength tablet three times per week or one singlestrength tablet daily) is employed commonly in this setting. Toxoplasmosis is not a common infection in HSCT patients but is associated with mortality rates of approximately 70%.85 Toxoplasmosis also should be prevented by trimethoprim-sulfamethoxazole prophylaxis.72,78


USE OF COLONY-STIMULATING FACTORS Several studies have evaluated the use of filgrastim and sargramostim in HSCT patients in an effort to speed bone marrow recovery, to reduce the period of neutropenia, and to decrease infectious complications. Although the time to neutrophil recovery was consistently decreased, these studies failed to show significant differences in infection rates, transplant-related mortality, or overall survival. The use of CSFs appears to be safe, but their use in HSCT patients has not been formally recommended because of lack of clear benefits.57

INFECTIONS IN SOLID-ORGAN TRANSPLANT RECIPIENTS Since the introduction of cyclosporine in 1980, solid-organ transplantation has become an established mode of treatment for end-stage diseases of the kidney, liver, heart, lungs, and pancreas; small bowel transplantation is also now becoming more common. Both patient and allograft survival rates greatly exceed those of the past. Reasons for improved survival include continuous improvements in immunosuppressive drug therapy, candidate selection, and transplant surgery techniques and more experience in the management of complications (including infection) in these patients. Major hindrances to successful

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transplantation and extended long-term survival include problems with allograft dysfunction and rejection and infectious complications. Despite advances in diagnostic techniques and antimicrobial therapy, infection remains an important cause of morbidity and mortality.

RISK FACTORS 1 Many of the risk factors for infection discussed at the beginning

of this chapter are present in solid-organ transplant patients (see Table 120–1). The most important risk factor in this population is the immunosuppressive drug therapy that patients receive for prevention and treatment of allograft rejection. Risk of infection depends on specific immunosuppressive drug regimens as well as on the intensity (dose) and duration of immunosuppression. Most opportunistic infections in transplant patients occur during the first 6 months after transplantation when the intensity and total cumulative doses of immunosuppressive therapy are very high.84,86 Current immunosuppressive regimens may have an impact on the pattern of infections after transplantation. Tacrolimus may be associated with lower rates of serious bacterial and viral infections than are seen with cyclosporine-based immunosuppressive regimens,87 possibly because of a steroid-sparing effect of tacrolimus that enables patients to be maintained on greatly reduced doses of corticosteroids. Mycophenolate has been associated with higher rates of CMV disease and VZV infections compared with older azathioprine-based immunosuppressive regimens but conversely may have protective effects against P. jiroveci in patients undergoing renal transplantation.86 Compared with mycophenolate-based regimens, sirolimus has been associated with significantly higher rates of surgical wound infections in renal transplant patients.86 When evaluating published literature on infection patterns after solid-organ transplantation, one always must consider the organ being transplanted and the nature of the immunosuppressive drug regimens in use at reporting centers. Immunosuppressive drugs, often in escalated doses, also are used to treat episodes of graft rejection. Drugs used to treat rejection include immunoglobulins directed against T cells (e.g., antithymocyte globulin [ATG]), murine monoclonal antibodies (muronomab), antibodies against interleukin 2 receptors (daclizumab and basiliximab), and high-dose IV or oral corticosteroids. Rejection episodes often occur during the posttransplant period when the overall cumulative dose or net state of immunosuppression is highest (2 to 4 months).84 Therefore, patients already at risk for infection are placed at even higher risk if additional immunosuppressive therapy is needed to treat one or more episodes of graft rejection. Immunosuppressive drug therapy must be evaluated carefully when infections occur because, in many cases, immunosuppression may have to be reduced in order for the patient to survive the infectious episode; this is done at the expense of increased risk of graft rejection. Risk of increased infectious complications from immunosuppressive therapy used to treat rejection episodes is also determined, at least in part, by the specific therapy employed.84,86

ETIOLOGY 2 As with cancer patients, microorganisms infecting solid-organ

transplant patients are present before transplantation or are acquired from exogenous sources. All transplant recipients are at risk for mucocutaneous candidiasis from species colonizing body sites. Invasive fungal infection is less common following kidney and pancreas transplantation (5% to 15%) but also may occur in 30% to 60% of heart, lung, liver, and small bowel transplant recipients; rates are high-

est following liver and small bowel transplantation and are associated with mortality rates of up to 60% to 70%.73,84,88,89 Approximately 50% to 90% of all systemic fungal infections in transplant recipients are caused by Candida spp.73,84,88,89 Abdominal surgery, especially the demanding operations required for liver and small bowel transplantation, predispose patients to serious fungal disease most likely as a consequence of entering an area highly colonized with Candida spp.88 Lung and heart transplant recipients are particularly at risk for invasive aspergillosis; these infections may occur in up to 10% of patients.88 Liver and lung transplant recipients are also at particularly high risk for serious gram-negative bacterial infections as a result of the technically difficult surgical procedures.84 Organisms present as latent tissue infections may reactivate and cause clinical disease after transplantation after the administration of immunosuppressive drug therapy. Disease resulting from infection reactivation has been noted with viral (HSV I and II, CMV, VZV, Epstein-Barr virus [EBV]), protozoal (Toxaplasma gondii, P. jiroveci), and mycobacterial (Mycobacterium tuberculosis) pathogens. Serologic or immunologic tests are performed prior to transplantation to assess the risk for infection because of reactivation and identify other subclinical infections (hepatitis B, Legionella). Many patients with reactivated disease have no clinical symptoms; often the only evidence of active infection is a rise in antibody titer from the pretransplant baseline, a positive culture, or histologic evidence. Reactivation of latent infection also may result in severe, lifethreatening disease in immunosuppressed hosts. Exogenous sources of infection in transplant patients include environmental contamination and transmission of microorganisms via transplanted organs and blood products. Environmental sources of infection are similar to those noted in other immunocompromised hosts, such as cancer patients. Airborne pathogens, especially fungi, such as Aspergillus and C. neoformans, may cause infections in transplant patients; this is thought to be a direct cause of increased Aspergillus infections among lung transplant patients.84,88 Transplant patients are also at risk for common nosocomial infections and infections occurring as hospital outbreaks (P. aeruginosa and Legionella). Optimal prevention and management of nosocomial infections in transplant patients require knowledge of the current epidemiology of infections and susceptibility patterns in the institution. Infections transmitted via donor organs or blood products are major causes of morbidity and mortality in transplant patients and may include HSV, T. gondii, and hepatitis B and C. The most important infections transmitted from the donor, however, are caused by CMV. These infections may cause serious disease (e.g., pneumonia, hepatitis, hematologic disorders, and chorioretinitis), as well as predisposing patients to other opportunistic infections and contributing to allograft dysfunction.84 In contrast to reactivation disease, transplant patients contracting primary CMV disease are at increased risk for serious, life-threatening infections.84,90,91 The most important source of primary CMV infection in transplant patients is the donor organ. Efforts are made to avoid transplanting organs from CMV-seropositive donors into CMV-seronegative recipients because of the potentially severe consequences. With the relative scarcity of suitable organs and the rapidity with which transplant decisions often must be made, however, this is not always possible. The consequences of transplanting an organ from a CMV-seropositive donor into an already CMV-seropositive recipient are less clear. Evidence exists that CMV reinfection (as well as reactivation) syndromes may occur in these patients.84,86 Organs from donors seropositive for T. gondii or HSV generally are not withheld from seronegative patients. Organs from known HIV-infected donors, however, are not used for transplantation. Asymptomatic

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HIV-seropositive individuals with a CD4 + lymphocyte count of greater than 400 cells/mm3 may be considered for liver, heart, or lung transplantation without prohibitively high risk of acceleration of HIV disease.91,92 However, this practice is not widespread because of the shortage of donor organs. The impact of protease inhibitors and highly active antiretroviral therapy (HAART) on long-term outcome of HIVinfected patients following transplantation is not known precisely but is felt to have improved the overall feasibility of transplanting these individuals.92 In addition to transmission from donor organs, primary CMV disease also may be transmitted from seropositive blood products, although this is a much less common mode of transmission. Risk of such transmission increases with the administration of large numbers of blood products. Table 120–4 contains information on microbiology, clinical presentation, and treatment of infections in HSCT and solid-organ transplant recipients. Although opportunistic viral, fungal, and protozoal infections may occur commonly, bacterial infections remain the most frequent infectious complications after transplantation in all allograft recipients.

TIMING OF INFECTIONS AFTER TRANSPLANTATION Although risk of infection with specific pathogens varies with the type of transplant, the time course of infections is similar in all transplant recipients. The overall risk of infection is greatest during the first 6 months after transplantation when the greatest number of risk factors are present. Both daily and cumulative doses of immunosuppressive drugs are at high levels, and additional agents may be necessary for the treatment of acute rejection episodes.84,86 As with HSCT, the overall time course for infections can be divided into three general periods after transplantation (see Fig. 120–2). During the early posttransplant period (within the first month after transplantation), patients are at risk for infections already present and brought forward from the pretransplant period (e.g., hepatitis B); postoperative infections, such as surgical wound and catheter infections; infection resulting from colonized donor organs (pneumonia following lung transplant); and reactivation of HSV.84,86 In the intermediate posttransplant period (2 to 6 months after transplant), risk is highest for viral infections, including CMV, EBV, and hepatitis B and C. The combination of these “immunomodulating” viruses plus sustained immunosuppressive therapy leads to a high risk for opportunistic infections with pathogens such as P. jiroveci, Aspergillus, and Nocardia asteroides.84,86,88 In the late posttransplant period (>6 months after transplant), the patient is at risk for persistent infections (particularly viral) from earlier posttransplant periods, reactivation of VZV and C. neoformans, and routine infections affecting the general population.84 In addition, patients who have required additional immunosuppression therapy for acute or chronic rejection are at continued high risk for opportunistic infections (Aspergillus and P. jiroveci).84,86,88 Although Fig. 120–2 illustrates infection patterns common to all solid-organ transplants, the relative incidence and importance of a particular pathogen will vary according to the type of transplant.

TYPES OF INFECTIONS AND CLINICAL PRESENTATION 10 Transplant patients are at risk for infections occurring at a va-

riety of sites, including skin, surgical wound, urinary tract,

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lungs, blood, abdomen, and CNS; however, most infections occur at or near the site of the transplanted organ. For example, heart transplant and heart and lung transplant recipients most often are infected within the lungs or thoracic cavity. Urinary tract infections remain an important cause of morbidity in renal transplant patients, especially in the early posttransplant period. Administration of prophylactic antibiotics, such as trimethoprim-sulfamethoxazole, to these patients has, however, reduced the incidence and severity of urinary tract infections.84,86 Serious, life-threatening bacterial and fungal infections originating from the abdomen and GI tract are most common after liver transplantation and are related to variables such as length of surgery and surgical procedures performed. Risk of bacteremia, usually originating from the gut, is highest in liver transplant patients. Renal transplant recipients are at the lowest risk of infections and infectious deaths, whereas patients receiving heart, lung, and liver transplants are at the highest risk of infection-related morbidity and mortality.84,86,88

C L I N I C A L P R E S E N T AT I O N O F I N F E C T I O N S I N S O L I D - O R G A N T R A N S P L A N T PAT I E N T S GENERAL

r Because transplant patients are at high risk for serious infections, frequent (at least daily), careful clinical assessments must be performed to search for possible evidence of infection. r Clinical presentation of infection is variable and depends on the type and site of infection, type of transplant, time after transplantation, immune status of the host, and dose and duration of immunosuppressive therapy. r Primary viral disease usually is more symptomatic and severe than disease caused by reactivation. r Physical assessment should include examination of all common sites of infection, including mouth/pharynx, nose and sinuses, respiratory tract, GI tract, urinary tract, skin, soft tissues, perineum, and intravascular catheter insertion sites. SYMPTOMS

r Usual signs and symptoms of infection may be absent or altered in patients receiving intensive immunosuppressive regimens owing to an inability to mount a typical inflammatory response (e.g., no infiltrate on chest x-ray, urinary tract infection without pyuria). r Pain may be present at infection site(s). SIGNS

r Fever is the single most important clinical sign indicating the presence of infection. Other causes of fever unrelated to infection in this patient population include reactions to blood products, drugs, embolic events, and ischemic injury. r Usual signs of infection may be absent or altered. r Signs of allograft dysfunction may be related to infection. Distinguishing fever as a result of allograft rejection versus infection often is very difficult and frequently requires allograft biopsy.

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LABORATORY TESTS

r Blood cultures (two or more sets, including vascular access devices) for bacteria and fungi; cultures of other suspected or potential infection sites (urine, lungs, etc.). r Other cultures should be obtained as clinically indicated according to the presence of signs or symptoms. r Complete blood count and chemistries should be obtained frequently to monitor allograft function, plan supportive care, guide drug dosing, and assess patient’s overall status. r Surveillance cultures for CMV and HSV may be useful during first 3 months after transplantation for early detection of infection. OTHER DIAGNOSTIC TESTS

r Chest x-ray r Aspiration, biopsy of skin lesions r Other diagnostic tests as indicated clinically on the basis of physical examination and other assessments In contrast to febrile neutropenic patients, the threshold for initiating empirical antimicrobial therapy is higher in febrile transplant patients. As seen in Table 120–4, appropriate therapy for the large numbers of pathogens that may cause infections in transplant patients varies greatly from organism to organism. Therefore, careful attempts at definitive diagnosis of suspected infections must be made. If comprehensive work-up reveals no source of infection, careful observation of the febrile transplant patient (rather than empirical therapy) is a common practice. Surveillance cultures may be useful during the first 3 months for detecting CMV and HSV infections.84,88,90,91 Management and monitoring of documented infections, such as urinary tract infections, pneumonias, and intraabdominal infections, are similar to that in other types of patients.

PREVENTION OF INFECTION IN SOLID ORGAN TRANSPLANTATION 8 The goals of antimicrobial drug use in solid-organ transplant

recipients include (1) prevention of infectious complications in the immediate postoperative period, (2) prevention of late infectious complications associated with prolonged periods of immunosuppression, and (3) effective treatment of established infections in order to prevent graft dysfunction and rejection and decrease patient morbidity and mortality. All these goals must be achieved at the lowest possible toxicity and cost. Prevention of infection in the transplant patient can be accomplished in a number of ways. First, risk of environmental contamination should be minimized.93 Patients should be protected from institutional infectious outbreaks. Transplant patients should receive the pneumococcal vaccine once and the influenza vaccine yearly; however, their immunologic responses to these vaccines may be blunted by immunosuppressive therapy.84 Because the most important source of primary CMV disease is an infected donor organ, CMV-seronegative patients should not receive organs or blood products from seropositive donors if possible. A number of pharmacologic strategies also have been studied in an attempt to prevent CMV infection. Prophylactic ganciclovir (administered either as 5 mg/kg IV every 12 hours or as oral valganciclovir in doses ranging from 900 mg once daily to 1000 mg three times daily) is effective in reducing the incidence of both primary and reac-

tivated CMV disease in solid-organ transplantation.80,84,86,90,91 Ganciclovir prophylaxis also may reduce reactivation of CMV disease significantly in seropositive patients receiving ALG or muronomab for treatment of acute rejection.86,91 High-dose oral acyclovir effectively reduces the incidence of CMV infection and disease following renal transplantation.94 However, acyclovir is less efficacious in high-risk renal transplant patients (donor positive, recipient negative for CMV serum antibodies) and other nonrenal transplant types.84,86,91,95 Preemptive ganciclovir (initiated following actual isolation of CMV from blood, urine, BAL fluid, or other site) is more effective than acyclovir in the prevention of both primary and reactivation disease in liver transplant recipients. Preemptive ganciclovir effectively prevents CMV disease in other types of solid-organ transplants as well.90,91 Ganciclovir-related bone marrow suppression is not as problematic in solid-organ transplant recipients as in HSCT patients; most studies report the drug as being reasonably well tolerated.84,91,95 Whether prophylaxis or preemptive therapy is the best approach to prevention of CMV disease is still controversial.84,90,91 Prophylaxis is effective and easy to administer without the need for careful discrimination among suitable patients. However, universal prophylaxis results in unnecessary exposure of low-risk individuals to adverse effects of drugs, and there are concerns that prolonged exposure may increase the risk of viral resistance to drugs.90,91,95 Preemptive therapy is effective and results in exposure of fewer patients to drugs. However, this strategy requires the availability and routine use of sensitive and specific diagnostic tests in order to identify high-risk individuals at an early stage of CMV infection. Although currently available PCR-based methods make this latter consideration less of an issue, PCR testing is not available at all centers. Prophylactic therapy should be used primarily in patients at highest risk of disease (i.e., seronegative patients receiving organs from seropositive donors), whereas other lower-risk patients should receive only preemptive therapy.84,90,91 These recommendations are not universally accepted or practiced, however. A number of studies also have demonstrated the value of CMV hyperimmune globulin (CMV-IVIG) in decreasing the incidence and severity of CMV disease following kidney, heart, lung, and liver transplantation.84,90 Although prophylaxis with CMV-IVIG has been strongly recommended for CMV-seronegative transplant recipients receiving organs from seropositive donors, the benefits of CMV-IVIG relative to other therapies (e.g., prophylactic or preemptive ganciclovir) are not well known, and available studies are sometimes conflicting in their results. Whether or not the combination of CMV-IVIG plus ganciclovir offers advantages over the use of either agent alone, either for primary prophylaxis or for treatment of established CMV disease, is also unclear in solid-organ transplantation.84,90 Although the use of prophylactic acyclovir in HSV-seropositive patients undergoing HSCT is well accepted, prophylaxis in solidorgan transplant recipients remains controversial. Reactivation disease caused by HSV occurs in approximately 25% of HSVseropositive patients who are not receiving prophylaxis.84 Oral or genital mucocutaneous disease is the most common presentation, but HSV pneumonitis also is seen occasionally and is associated with a mortality rate of approximately 75%.84 Acyclovir is being used at some centers because of the high incidence of clinical HSV infection, including pneumonias, after transplantation. Prophylactic antimicrobial agents are of benefit to transplant patients in certain clinical situations. Antibiotic prophylaxis, with agents such as cefazolin begun perioperatively and continued for less than 24 hours is considered to reduce wound infection rates effectively following renal transplantation.84,93 Although the benefits of

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perioperative prophylaxis have not been well demonstrated in other types of transplantation procedures, surgical prophylaxis usually is considered mandatory in liver, heart, and lung transplant patients because of the high risk of perioperative bacterial infections.84,93 Pulmonary infections are particularly common in lung and heart-lung transplant recipients, and these infections often are caused by bacteria colonizing the airways prior to transplantation. Perioperative antibiotics for lung and heart-lung procedures therefore often are selected based on pretransplant sputum cultures.84,93 In addition, posttransplant antibiotic prophylaxis is effective in decreasing the number of bacterial infections in renal transplant patients. Prophylactic trimethoprim-sulfamethoxazole traditionally has been used because it is inexpensive and well tolerated; other antibiotics, such as the fluoroquinolones, have been evaluated.84 Administration of oral low-dose trimethoprim-sulfamethoxazole (one double-strength tablet daily) for 6 to 12 months for prevention of P. jiroveci infection following heart and lung transplantation is common, although the efficacy and optimal duration are still somewhat controversial.84,96 Selective bowel decontamination with nonabsorbable antibiotics in combination with a low-bacterial diet (no fresh fruits and vegetables) effectively reduces oropharyngeal and GI colonization with gram-negative aerobes and Candida in liver transplant patients. However, selective bowel contamination is less efficacious when administered for a period of less than 1 week prior to transplantation.93 Since liver transplantation usually is performed without advance notice as organs become emergently available, the practice of selective bowel decontamination remains controversial and is not recommended routinely.84,93 Because immunosuppressed transplant recipients are at risk for mucocutaneous fungal infections, prophylactic oral or topical antifungal agents may be indicated in these patients. Liver transplant patients are clearly at high risk for invasive fungal infections and should receive prophylaxis with fluconazole (400 mg/day).22,84,88,97 It also has been suggested that lung and heart-lung transplant recipients receive high-dose fluconazole prophylaxis, although data for this recommendation are lacking.22,88 Cyclosporine concentrations should be monitored closely in transplant patients receiving fluconazole and other azole antifungal agents. Transplant patients, especially heart and heart-lung recipients, without serologic evidence of prior exposure to T. gondii who receive organs from seropositive donors are at high risk for toxoplasmosis.84 Many of these patients will be receiving trimethoprim-sulfamethoxazole for prophylaxis of P. jiroveci infection; this agent also will provide effective prophylaxis against T. gondii, as well as against N. asteroides. Although prophylaxis is not given routinely at all centers, this therapy may be justified in high-risk patients because of the delays in diagnosis and serious infections associated with toxoplasmosis.84 The use of prophylactic isoniazid therapy for transplant patients with evidence of exposure to M. tuberculosis (those with a positive purified protein derivative skin test) remains controversial. Risk of reactivation and development of clinical tuberculosis is enhanced with posttransplant immunosuppression. Some clinicians believe, however, that the risk of isoniazid-induced hepatotoxicity, especially in liver transplant recipients, in whom the rate of hepatotoxicity has been reported as high as 40%, outweighs the benefits of treatment. Highrisk patients who may be considered for isoniazid prophylaxis include those with a positive skin test, those with previously diagnosed tuberculosis who may not have been treated adequately, patients in close contact with individuals with active pulmonary disease, and patients with abnormal chest radiographs consistent with old tuberculosis who have not received prior prophylaxis.84

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EVALUATION OF THERAPEUTIC OUTCOMES Close monitoring of transplant recipients, including both clinical and laboratory data, is essential for early detection and treatment of potentially severe opportunistic infections.

ABBREVIATIONS ANC: absolute neutrophil count ARDS: acute respiratory distress syndrome ASCO: American Society for Clinical Oncology ATG: antithymocyte globulin BAL: bronchoalveolar lavage CDC: U.S. Centers for Disease Control and Prevention CSF: colony-stimulating factor DIC: disseminated intravascualr coagulation EORTC: European Organization for the Research and Treatment of Cancer GVHD: graft versus host disease HAART: highly active anti-retroviral therapy HLA: human leukocyte antigen HSCT: hematopoietic stem cell transplantation IDSA: Infectious Diseases Society of America IP: interstitial pneumonia MRSA: methicillin-resistant Staphylococcus aureus NCCN: National Comprehensive Cancer Network NNIS: National Nosocomial Infection Surveillance PMN: polymorphonuclear leukocyte VRE: vancomycin-resistant enterococci Review Questions and other resources can be found at www.pharmacotherapyonline.com.

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CHAPTER 120 54. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002;346:225–234. 55. O’Grady NP, Alexander M, Dellinger P, et al. Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis 2002;35: 1281–1307. 56. Mermel LA, Farr BM, Sherertz RJ, et al. Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis 2001;32: 1249–1272. 57. Ozer H, Armitage JO, Bennett CL, et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. J Clin Oncol 2000;18:3558–3585. 58. Clark OA, Lyman G, Castro AA, et al. Colony-stimulating factors for chemotherapy-induced febrile neutropenia. Cochrane Database Syst Rev 2003;3:CD003039. 59. Hubel K, Dale DC, Engert A, Liles WC. Current status of granulocyte (neutrophil) transfusion therapy for infectious diseases. J Infect Dis 2001; 183:321–328. 60. Cruciani M, Rampazzo R, Malena M, et al. Prophylaxis with fluoroquinolones for bacterial infections in neutropenic patients: A metaanalysis. Clin Infect Dis 1996;23:795–805. 61. Kern W, Kurrle E. Ofloxacin versus trimethoprim-sulfamethoxazole for prevention of infection in patients with acute leukemia and granulocytopenia. Infection 1991;19:73–80. 62. Engels EA, Lau J, Barza M. Efficacy of quinolone prophylaxis in neutropenic cancer patients: A meta-analysis. J Clin Oncol 1998;16: 1179–1187. 63. Munoz L, Martino R, Subira M, et al. Intensified prophylaxis of febrile neutropenia with ofloxacin plus rifampin during severe short-duration neutropenia in patients with lymphoma. Leuk Lymphoma 1999;34:585–589. 64. Cornely OA, Ullmann AJ, Karthaus M. Evidence-based assessment of primary antifungal prophylaxis in patients with hematologic malignancies. Blood 2003;101:3365–3372. 65. Bow EJ, Laverdiere M, Lussier N, et al. Antifungal prophylaxis for severely neutropenic chemotherapy recipients: A meta-analysis of randomized-controlled clinical trials. Cancer 2002;94:3230–3246. 66. Goodman JL, Winston DJ, Greenfield RA, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992;326:845–851. 67. Slavin MA, Osborne B, Adams R, et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation: A prospective, randomized, double-blind study. J Infect Dis 1995;171:1545– 1552. 68. Rotstein C, Bow EJ, Laverdiere M, et al. Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: Benefit based on purpose and intensity of cytotoxic therapy. Clin Infect Dis 1999; 28:331–340. 69. Wingard JR, Merz WG, Rinaldi MG, et al. Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl J Med 1991; 325:1274–1277. 70. Winston DJ, Maziarz RT, Chandrasekar PH, et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients: A multicenter, randomized trial. Ann Intern Med 2003;138:705–713. 71. de Lalla F. Antibiotic treatment of febrile episodes in neutropenic cancer patients: Clinical and economic considerations. Drugs 1997;53:789–804. 72. Leather HL, Wingard JR. Infections following hematopoietic stem cell transplantation. Infect Dis Clin North Am 2001;15:483–520. 73. Lin S-J, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: Systematic review of the literature. Clin Infect Dis 2001;32:358–366. 74. Momin F, Chandrasekar PH. Antimicrobial prophylaxis in bone marrow transplantation. Ann Intern Med 1995;123:205–215.

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75. Ketterer N, Espinouse D, Chomarat M, et al. Infections following peripheral blood progenitor cell transplantation for lymphoproliferative malignancies: Etiology and potential risk factors. Am J Med 1999;106:191–197. 76. Darville JM, Ley BE, Roome AP, et al. Acyclovir-resistant herpes simplex virus infections in a bone marrow transplant transplant population. Bone Marrow Tranplant 1998;22:587–589. 77. Nguyen Q, Champlin R, Giralt S, et al. Late cytomegalovirus pneumonia in adult allogeneic blood and marrow transplant recipients. Clin Infect Dis 1999;28:618–623. 78. Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: Recommendations of CDC, the Infectious Diseases Society of America, and the American Society of Blood and Marrow Transplantation. MMWR 2000;49(RR-10):1–110. 79. Meyers JD, Reed EC, Shepp DH, et al. Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation. N Engl J Med 1988;318:70–75. 80. Razonable RR, Paya CV. Valganciclovir for the prevention and treatment of cytomegalovirus disease in immunocompromised hosts. Expert Rev Anti-Infect Ther 2004;2:27–42. 81. Barnes RA. Immunotherapy and immunoprophylaxis in bone marrow transplantation. J Hosp Infect 1995;30(suppl):223–231. 82. Marr KA. Antifungal prophylaxis in hematopoitec stem cell transplant recipients. Curr Opin Infect Dis 2001;14:423–426. 83. Gubbins PO, Bowman JL, Penzak SR. Antifungal prophylaxis to prevent invasive mycoses among bone marrow transplantation patients. Pharmacotherapy 1998;18:549–564. 84. Simon DM, Levin S. Infectious complications of solid organ transplantations. Infect Dis Clin North Am 2001;15:521–549. 85. Mele A, Paterson PJ, Prentice HG, et al: Toxoplasmosis in bone marrow transplantation: A report of two cases and systematic review of the literature. Bone Marrow Transplant 2002;29:691–698. 86. Varon NF, Alangaden GJ. Emerging trends in infections among renal transplant recipients. Expert Rev Anti-Infect Ther 2004;2:95–109. 87. The U.S. Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med 1994;331:1110–1115. 88. Singh N. Fungal infections in the recipients of solid organ transplantation. Infect Dis Clin North Am 2003;17:113–134. 89. Montoya JG, Giraldo LF, Efron B, et al: Infectious complications among 620 consecutive heart transplant recipients at Stanford University Medical Center. Clin Infect Dis 2001;33:629–640. 90. Kletzmayr J, Kreuzwieser E, Klauser R. New developments in the management of cytomegalovirus infection and disease after renal transplantation. Curr Opin Urol 2001;11:153–158. 91. Singh N. Preemptive therapy versus universal prophylaxis with ganciclovir for cytomegalovirus in solid organ transplant recipients. Clin Infect Dis 2001;32:742–751. 92. Roland ME, Adey D, Carlson LL, Terrault NA. Kidney and liver transplantation in HIV-infected patients: Case presentations and review. AIDS Patient Care Stds 2003;17:501–507. 93. Soave R. Prophylaxis strategies for solid-organ transplantation. Clin Infect Dis 2001;33(suppl 1):S26–31. 94. Singh N, Yu VL, Mieles L, et al. High-dose acyclovir compared with short-course preemptive ganciclovir therapy to prevent cytomegalovirus disease in liver transplant recipients. Ann Intern Med 1994;120:375–381. 95. Van der Bij W, Speich R. Management of cytomegalovirus infection and disease after solid-organ transplantation. Clin Infect Dis 2001;33(suppl 1): S33–S37. 96. Fishman JA. Prevention of infection caused by Pneumocystis jiroveci in transplant recipients. Clin Infect Dis 2001;33:1397–1405. 97. Paya CV. Prevention of fungal and hepatitis viral infections in liver transplantation. Clin Infect Dis 2001;33(suppl 1):S47–52.

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121 ANTIMICROBIAL PROPHYLAXIS IN SURGERY Salmaan Kanji and John W. Devlin

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Prophylactic antibiotic therapy differs from presumptive

5 One must consider the type of surgery, intrinsic patient

2 The risk of a surgical site infection (SSI) is determined from

6 Single-dose prophylaxis is appropriate for many types of

3 Timing of antimicrobial prophylaxis is of paramount impor-

7 Vancomycin as a prophylactic agent should be limited

and therapeutic antibiotic therapy in that the latter two involve treatment regimens for documented or presumed infections, whereas the goal of prophylactic therapy is to prevent infections in high-risk patients or procedures. both the type of surgery and patient-specific risk factors; however, most commonly used classification systems only account for procedure-related risk factors. tance. Antibiotics should be administered 1 hour before the surgery to ensure adequate drug levels at the surgical site prior to the initial incision.

4 Antimicrobial agents with short half-lives (e.g., cefazolin) may need to be redosed intraoperatively during long (>3 hours) procedures.

According to the National Center for Health Statistics, approximately 46 million surgical procedures are performed annually in the United States, the majority of which are done in an outpatient setting.1 Infection is the most common complication of surgery.2 Surgical-site infections (SSIs) occur in about 3% to 6% of patients and prolong hospitalization by an average of 7 days at a direct annual cost of $5 to $10 billion.3,4 SSIs are the third (14% to 16%) most frequent cause of nosocomial infections among hospitalized patients and the primary (40%) cause of nosocomial infection in surgical patients.3 The prophylactic administration of antibiotics decreases the risk of infection after many surgical procedures and represents an important component of care for this population. Antibiotics administered prior to the contamination of previously sterile tissues or fluids are deemed prophylactic antibiotics. The goal of therapy is to prevent an infection from developing. While eradication of distal (preexisting, unrelated to surgery) infections lowers the risk for subsequent postoperative infections, it does not, per se, constitute a prophylactic regimen. In fact, surgical prophylaxis often is prescribed concurrently under these circumstances because of important antimicrobial spectrum- and timing-related concerns. Both SSIs and infections not directly related to the surgical site are termed nosocomial (e.g., urinary tract infections, pneumonia, etc.). Prevention of these hospital-acquired infections is a major goal of antibiotic prophylaxis. 1 Presumptive antibiotic therapy is administered when an infection is suspected but not yet proven. Clinical scenarios where presumptive therapy is employed commonly include acute cholecystitis, open compound fractures, and acute appendicitis of less than

risk factors, the most commonly identified pathogenic organisms, institutional antimicrobial resistance patterns, and cost when choosing an antimicrobial agent for prophylaxis. surgery. First-generation cephalosporins (e.g., cefazolin) are the mainstay for prophylaxis in most surgical procedures because of their spectrum of activity, safety, and cost. to cases in which there is a documented history of lifethreatening β-lactam hypersensitivity or where the incidence of infections with organisms resistant to cefazolin (e.g., methicillin resistant Staphylococcus aureus [MRSA]) is high enough to justify use.

24 hours’ duration. In these situations, if signs of perforation or infection are absent during surgery, then routine prophylactic rather than presumptive therapy is warranted. An operative finding of a gangrenous gallbladder or a perforated appendix, however, is suggestive of an established infectious process, and thus a therapeutic antibiotic regimen would be required.3 According to the Center for Disease Control and Prevention’s (CDC) National Nosocomial Infections Surveillance System (NNIS),3 SSIs can be categorized as either incisional (e.g., cellulitis of the incision site) or organ/space (e.g., meningitis) (Fig. 121–1). Incisional SSIs are further subcategorized into superficial (involving only the skin or subcutaneous tissue) and deep (fascial and muscle layers) infections. Organ/space SSIs can involve any anatomic area other than the incision site. For example, a patient who develops bacterial peritonitis after bowel surgery would have an organ/space SSI. By definition, SSIs must occur within 30 days of surgery. If a prosthetic implant is involved, however, a deep incisional or organ/space SSI still can be reported up to 1 year from the date of surgery. Although microbiologic testing of surgical drainage material or sites may help to guide care, the specificity of a negative culture is poor and generally does not rule out an SSI.3

SSI RISK FACTORS 2 SSI incidence depends on both procedure- and patient-related

factors. Traditionally, the risk for SSIs has been stratified by surgical procedure in a classification system developed by the National 2217

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INFECTIOUS DISEASES TABLE 121–2. Patient and Operation Characteristics that May Influence the Risk of SSI Patient Age Nutritional status Diabetes Smoking Obesity Coexisting infections at distal body sites Colonization with resistant microorganisms Altered immune response Length of preoperative stay

FIGURE 121–1. Cross section of abdominal wall depicting CDC classifications of SSIs. (From ref. 3).

Research Council (NRC)5 (Table 121–1). The NRC classification system proposes that the risk of an SSI depends on the microbiology of the surgical site, the presence of a preexisting infection, the likelihood of contaminating previously sterile tissue during surgery, and events during and after surgery.5,6 A patient’s NRC procedure classification is the primary determinant of whether antibiotic prophylaxis is warranted. It should be emphasized, however, that because a patient’s NRC wound classification is influenced by surgical findings (e.g., gangrenous gallbladder) and perioperative events (e.g., major technique breaks), that categorization generally occurs intraoperatively.7

Operation Duration of surgical scrub Preoperative skin preparation Preoperative shaving Duration of operation Antimicrobial prophylaxis Operating room ventilation Sterilization of instruments Implantation of prosthetic materials Surgical drains Surgical technique

Adapted from ref. 3.

trolled perioperative blood sugars.8 Preoperative smoking has been identified as an independent risk factor for SSI because of the deleterious effects of nicotine on wound healing. Preoperative immunosuppression, including corticosteroid use, also may increase infection risk. Malnutrition is a well-described risk factor for postoperative complications, including SSI, impaired wound and colonic anastamosis healing, and prolonged hospital stay. While enteral feeding in the perioperative period can reduce bacterial translocation by maintaining the integrity of the intestinal mucosa, nutritional supplementation has not been shown to decrease the incidence of infection.9 CLINICAL CONTROVERSY

INHERENT PATIENT RISK The NRC classification system does not account for the influence of underlying patient risk factors for SSI development, instead categorizing the risks for SSIs simply based on a specific surgical procedure. Disease states and conditions known to increase SSI risk are presented in Table 121–2. Preexisting distal infections increase SSI rates and should be resolved prior to surgery whenever possible. Diabetic patients have an increased risk of SSIs, especially those with uncon-

Several recent studies have investigated the role of specialized enteral formulas fortified with a variety of immunomodulating micronutrients thought to enhance the immune response and gut function after trauma or surgery. While many clinicians are exploring the role of supplements such as glutamine, arginine, omega-3 fatty acids, and nucleotides, no study to date has shown a significant reduction in postoperative infection rates using these formulations.

TABLE 121–1. NRCa Wound Classification, Risk of SSIb , and Indication for Antibiotics SWI Rate (%) Preoperative Antibiotics

No Preoperative Antibiotics

5.1

0.8

Clean-contaminated

10.1

1.3

Contaminated

21.9

10.2

Dirty

N/A

N/A

Classification Clean

Criteria

Antibiotics

No acute inflammation or transection of gastrointestinal, oropharyngeal, genitourinary, biliary, or respiratory tracts. Elective case, no technique break Controlled opening of aforementioned tracts with minimal spillage/minor technique break. Clean procedures performed emergently or with major technique breaks. Acute, nonpurulent inflammation present. Major spillage/technique break during clean-contaminated procedure Obvious preexisting infection present (abscess, pus, or necrotic tissue present)

Not indicated unless high-risk procedurec

Prophylactic antibiotics indicated

Prophylactic antibiotics indicated Therapeutic antibiotics required

NRC = National Research Council. SSI = surgical-site infection. c High-risk procedures include implantation of prosthetic materials and other procedures where surgical-site infection is associated with high morbidity (see text). Adapted from refs. 5 and 11. a

b

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Clean

CleanContaminated

Contaminated

Dirty

0 1 2 3 4

1.1 3.9 8.4 15.8 N/A

0.6 2.8 8.4 17.7 N/A

N/A 4.5 8.3 11.0 23.9

N/A 6.7 10.9 18.8 27.4

a The Study on the Efficacy of Nosocomial Infection Control (SENIC) risk factors include abdominal operation, operations lasting >2 hours, contaminated or dirty procedures by National Research Council (NRC) classification, and more than three underlying medical diagnoses. Adapted from ref. 13.

Colonization of the nares with Staphylococcus aureus is a welldescribed SSI risk factor.3 Two small prospective trials suggest that eradication of nasal S. aureus with mupirocin significantly reduces the incidence of SSI when compared with historical controls in patients undergoing both cardiac and upper gastrointestinal surgery. Larger prospective trials, however, are needed before this therapy can be advocated routinely. Other factors shown to increase the risk of SSI include age, length of preoperative hospital stay, and obesity.3

IDENTIFYING SSI RISK Two large epidemiologic studies have objectively quantified SSI risk based on specific patient- and procedure-related factors. The Study on the Efficacy of Nosocomial Infection Control (SENIC) analyzed more than 100,000 surgery cases to identify and validate risk factors for SSI.10 Abdominal operations, operations lasting longer than 2 hours, contaminated or “dirty” procedures (as per NRC classification), and more than three underlying medical diagnoses each were associated with an increased incidence of SSI. When NRC classification was stratified by number of SENIC risk factors present, SSI incidence varied by as much as a factor of 15 within the same NRC operative category11 (Table 121–3). The NNIS, in a subsequent analysis of more than 84,000 surgical cases, attempted to simplify and refine the SENIC system by quantifying intrinsic patient risk using the American Society of Anesthesiologists’ (ASA) preoperative assessment score12,13 (Table 121–4). An ASA score of 3 or greater was found to be a strong predictor for the development of an SSI. Other factors associated with increased SSI incidence include contaminated or “dirty” operations (NRC criteria) and surgical procedures lasting longer than average. Similar to the SENIC study, the SSI rate was linked to the number of risk factors present and varied considerably within NRC class. Although evidence-based recommendations for antimicrobial prophylaxis during surgery are best established using the results of

TABLE 121–4. American Society of Anesthesiologists Physical Status Classification Class

Description

1 2 3 4 5

Normal healthy patient Mild systemic disease Severe systemic disease that is not incapacitating Incapacitating systemic disease that is a constant threat to life Not expected to survive 24 hours with or without operation

From ref. 15.

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randomized clinical trials, many studies have small sample sizes and do not stratify patients according to overall SSI risk. Future studies, particularly those involving clean procedures, should be stratified by SSI risk so that the subset of high-risk patients who might benefit the most from prophylaxis is clearly established.

BACTERIOLOGY The most important consideration when choosing antibiotic prophylaxis is the bacteriology of the surgical site. Organisms involved in an SSI are acquired one of two ways: endogenously (from the patient’s own normal flora) and exogenously (from contamination during the surgical procedure). Based on the type and anatomic location of the procedure and the NRC classification (see Table 121–1), resident flora can be predicted, and appropriate antibiotic choices can be made. According to NNIS data, S. aureus, coagulase-negative staphylococci, enterococci, Escherichia coli, and Pseudomonas aeruginosa are the pathogens most commonly isolated3 (Table 121–5). With the widespread use of broad-spectrum antibiotics, however, Candida spp. and methicillin-resistant S. aureus are becoming more prevalent.9 Factors affecting the ability of an organism to induce an SSI depend on organism count, organism virulence, and host immunocompetency. Organisms in the commensal flora generally are not pathogenic. These organisms often serve the host as a form of protection against invasive organisms that otherwise would colonize the surgical site. Opportunistic organisms usually are kept in check by normal flora and rarely are problematic unless they are found in large numbers. Loss of this normal flora through the use of broad-spectrum antibiotics can destabilize this homeostasis, thus allowing pathogenic bacteria to proliferate and infection to occur.14 If translocated to a normally sterile tissue site or fluid during a surgical procedure, normal flora can become pathogenic. For example, S. aureus or S. epidermidis may be translocated from the surface of the skin to deeper tissues or E. coli from the colon to the peritoneal cavity, bloodstream, or urinary tract. Studies in animals and healthy volunteers have shown bacterial virulence to be an important determinant in the development of secondary infections.15,16 Animal models of infection have demonstrated that while more than 1 million S. aureus per square centimeter or gram of tissue are required to produce infection, less than 100,000 Streptococcus pyogenes per square centimeter or gram of tissue would be required at the same site.16,17 Impaired host defense reduces the number of bacteria required to establish an infection. A breach of normal host defenses through surgical intervention (e.g., insertion of a prosthetic device) may TABLE 121–5. Major Pathogens in Surgical Wound Infections Pathogen

Percent of Infectionsa

Staphylococcus aureus Coagulase-negative staphylococci Enterococci Escherichia coli Pseudomonas aeruginosa Enterobacter spp. Proteus mirabilis Klebsiella pneumoniae Other Streptococcus spp. Candida albicans Group D streptococci Other gram-positive aerobes Bacteroides fragilis

20 14 12 8 8 7 3 3 3 3 2 2 2

a

Data reported by the NNIS from 1990–1996, adapted from ref. 5.

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enable organisms to cause infection. In addition, the loss of specific immune factors, such as complement activation, tissue-derived inhibitors (e.g., proinflammatory cytokines), cell-mediated response (e.g., T-cell function), and granulocytic or phagocytic function (e.g., neutrophils or macrophages) can greatly increase the risk for SSI development.18 Vascular occlusive states related to the surgical procedure or those occurring from hypovolemic shock can greatly affect blood flow to the surgical site, thus diminishing host defense mechanisms against microbial invasion. Traumatized tissue, hematomas, and the presence of foreign material also lead to more infections. When a foreign body is introduced during a surgical procedure, fewer than 100 bacterial colony-forming units (CFUs) are required to cause an SSI.19 Studies examining S. aureus–contaminated wound infections on the skin of healthy volunteers demonstrate a 10,000-fold reduction in the number of organisms required to establish a wound infection if sutures are not present.15

ANTIMICROBIAL RESISTANCE Colonization of the host with antibiotic-resistant hospital flora prior to or during surgery may lead to an SSI that is unresponsive to routine antibiotic therapy. Epidemiologic studies demonstrate that the most common cause for nosocomially acquired multiresistant organisms is transmission from hospital personnel.20 Patients treated with broadspectrum antibiotic therapy also are at increased risk of colonization with hospital flora. With cephalosporins established as first-line agents for prophylaxis over the past decade, organisms resistant to cephalosporins represent the majority of pathogens causing SSIs. The CDC has reported an alarming increase in the incidence of vancomycin-resistant enterococci (VRE) infections, particularly those with E. faecium.3 Risk factors for VRE colonization include severe concomitant diseases, immunosuppression, admission to the intensive care unit, previous intraabdominal or cardiothoracic surgery, placement of indwelling catheters, and prolonged courses of antimicrobials, 7 particularily vancomycin.21 In an effort to control the spread of VRE, the CDC has published recommendations that include strict criteria for the use of vancomycin as surgical prophylaxis.22 The guidelines suggest vancomycin substitution for cefazolin as SSI prophylaxis only when there is a high suspicion of methicillin-resistant S. aureus or in patients who have a documented history of a lifethreatening allergy to penicillins or cephalosporins. Other limitations to vancomycin use, besides the risk of inducing resistant organisms, include its narrow spectrum of activity, its poor penetration into some tissues, and the potential for infusion-related reactions. The emergence of S. aureus displaying intermediate resistance (minimum inhibitory concentration [MIC] ≥ 8 mcg/mL) further underscores the need to limit routine use of vancomycin for prophylaxis.23 Although cefazolin remains a mainstay in cardivovascular SSI prophylaxis, its failure has been reported in cases involving methicillin-sensitive S. aureus (MSSA). In a comparison trial between cefamandole and cefazolin, significantly more failures were attributed to cefazolin, even though the primary pathogen was MSSA.24 A similar trial comparing cefazolin and cefuroxime, however, did not show any difference in SSI incidence between the two regimens.25 It has been proposed that the β-lactamase expressed by some MSSA is capable of hydrolyzing cefazolin more readily than cefuroxime or cefamandole. Although this trend is disturbing, the overall incidence of cefazolin failure remains low, and cefazolin remains the drug of choice for SSI prophylaxis in cardiovascular surgery.

The increase in frequency of fungal infections in surgical patients has drawn concern. In hospitalized patients, the incidence of nosocomial Candida infections has approximately doubled from 1991 to 1996.26 Overzealous use of broad-spectrum antibiotics is the most likely cause for this increase. A study in patients undergoing cardiovascular surgery identified sex (female), length of stay in the intensive care unit, and duration of central venous catheterization as risk factors for postoperative Candida infections.27 While presurgical Candida colonization is associated with a higher risk of fungal SSIs, the routine preoperative use of prophylactic antifungal agents is not being advocated at this time.26,28

SCHEDULING ANTIBIOTIC ADMINISTRATION 3

4 The following principles must be considered when providing

antimicrobial surgical prophylaxis: (1) The agents should be delivered to the surgical site prior to the initial incision, and (2) bactericidal antibiotic concentrations should be maintained at the surgical site throughout the surgical procedure. While animal and human models have demonstrated the efficacy of a single dose of an antibiotic administered just prior to bacterial contamination, long operations often require intraoperative doses of antibiotics to maintain adequate concentrations at the surgical site for the duration of the surgery.29 Antibiotics should be administered with anesthesia just prior to the initial incision. Administration of antibiotics too early may result in concentrations below the MIC toward the end of the operation, and administration too late leaves the patient unprotected at the time of the initial incision. In a study examining the timing of antibiotics in 2847 patients receiving prophylaxis, Classen and colleagues29 evaluated patients who received prophylaxis early (2 to 24 hours before surgery), preoperative prophylaxis (0 to 2 hours prior to surgery), perioperative prophylaxis (up to 3 hours after first incision), and postoperative prophylaxis (>3 hours after the first incision). The risk of infection was lowest (0.6%) for those patients who received preoperative prophylaxis, moderate (1.4%) for those who received perioperative antibiotics, and greatest for those who received postoperative antibiotics (3.3%) or preoperative antibiotics too early (3.8%). These results indicate that the risk for an SSI increases dramatically with each hour that elapses from the initial incision to the time when antibiotics are administered eventually. For these reasons, prophylactic antibiotics should not be prescribed to be given “on call to the OR,” which can occur 2 or more hours prior to the initial incision, nor should concurrent therapeutic antibiotics be relied on to provide adequate protection. In both situations, the chance for improperly timed doses is high. Despite the importance of appropriately timed prophylactic antibiotic therapy, few patients receive antibiotics at the optimal time in relation to surgery. Potential barriers include antibiotics ordered after the patient has arrived in the operating room, delayed antibiotic preparation or delivery, and the use of antibiotics that require long infusion times. One study assessed the timing of prophylactic antibiotics in 100 patients and found that only 26% of patients received an antibiotic dose within 2 hours of the initial surgical incision.30 Although most studies comparing single versus multiple doses of prophylactic antibiotics have failed to show a benefit of multidose regimens, the duration of operations in these studies may not be as long as that which is frequently observed in clinical practice. Proponents of administering a second antibiotic dose during lengthy operations suggest that the risk for SSI is just as great at the end of surgery, during wound closing, as it is during the initial incision.31 One study in patients undergoing clean-contaminated operations suggests

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that procedures longer than 3 hours require a second intraoperative dose of cefazolin or the substitution of cefazolin with a longer-acting antimicrobial agent.32 A second study of patients undergoing elective colorectal surgery suggests that low serum antimicrobial concentrations at the time of surgical closure is the strongest predictor of postoperative SSI.33 Studies in patients undergoing cardiac surgery also have demonstrated a higher infection rate among patients with undetectable antibiotic serum concentrations at the conclusion of the procedure.34 One strategy to ensure appropriate redosing of prophylactic antibiotics during long operations is to employ a visual or auditory reminder system. One hospital has published its experience with such a system and found that an automated reminder improved compliance and reduced SSIs. However, even with the reminder system, intraoperative redosing was done in only 68% of eligible patients.35 Another strategy currently being evaluated is the role of continuous infusions of cefazolin. One pilot study has found this a feasible way to ensure adequate serum concentrations of antibiotic during prolonged surgeries.36 Further trials are required before such an intervention can be recommended. Underlying disease states that may affect antibiotic metabolism and/or elimination should be considered when developing a prophylactic regimen. For example, patients with thermal burn and spinal cord injuries eliminate certain classes of antibiotics, primarily the aminoglycosides and β-lactams, at unusually high rates compared with controls.37 Individuals undergoing cardiac bypass may have altered antibiotic disposition related to increased volume of distribution and reduced total-body clearance and thus require special dosing consideration.38

ANTIMICROBIAL CHOICE 5 The choice of prophylactic antibiotic depends on the type of

surgical procedure, the most frequent pathogens seen with this procedure, the safety and efficacy profile of the antimicrobial agent, the current literature evidence to support its use, and cost. Although most SSIs involve the patient’s normal flora, antimicrobial selection also must take into account the susceptibility patterns of nosocomial pathogens within each institution. Typically, gram-positive coverage should be included in the choice of surgical prophylaxis because organisms such as S. aureus and S. epidermidis are encountered commonly as skin flora. The decision to broaden antibiotic prophylaxis to agents with gram-negative and anaerobic spectra of activity depends on both the surgical site (e.g., upper respiratory tract, gastrointestinal tract, genitourinary tract, etc.) and whether the operation will transect a hollow viscous or mucous membrane that may contain resident flora.3 Although antimicrobial prophylaxis may be administered through a variety of routes (e.g., oral, topical, intramuscular, etc.), the parenteral route is favored because of the reliability by which adequate tissue concentrations may be acheived.39 Cephalosporins are the most commonly prescribed agents for surgical prophylaxis because of their broad antimicrobial spectrum, their favorable pharmacokinetic profile, their low incidence of adverse side effects, and low cost. First-generation cephalosporins, such as cefazolin, are the preferred choice for surgical prophylaxis, particularly for clean surgical procedures.3,7,14 In cases where broader gram-negative and anaerobic coverage is desired, antianaerobic cephalosporins, such as cefoxitin or cefotetan, are appropriate choices. Although thirdgeneration cephalosporins (e.g., ceftriaxone) have been advocated for prophylaxis because of their increased gram-negative coverage and

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prolonged half-lives, their inferior gram-positive and anaerobic activity, in addition to their high cost, has discouraged the widespread use of these agents.3,7,14 Allergic reactions are the most common side effects associated with cephalosporin use. These can range from minor skin manifestations at the site of infusion to rash, pruritus, and on rare occasions anaphylaxis (60, obesity, diabetes mellitus) Benefits of oral plus IV is controversial except for colostomy reversal and rectal resection A second intraoperative dose of cefoxitin may be required if procedure lasts longer than 3 hours Generally not recommended in patients with sterile pre-op urine cultures Give after cord is clamped

Antibiotic prophylaxis should not exceed 24 hours Addition of gentamicin to clindiamycin is controversial Second-generation cephalosporins also have been advocated In areas with high prevalence of S. aureus resistance, vancomycin should be considered Abdominal and lower extremities have the highest infection rates Open fractures assumed contaminated with gram-negative bacilli; aminoglycosides often used—see text No agents have been shown better than cefazolin in randomized control comparative trials.

One-time doses are optimally infused at induction of anesthesia except as noted. Repeat doses may be required for long procedures. See text for references.

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surgery generally is low, and thus procedures in this region can be classified as clean procedures. The risk for an SSI in this population increases with any condition that can lead to bacterial overgrowth, such as obstruction, hemorrhage, malignancy, or increasing the pH of gastroduodenal secretions with concomitant acid suppression therapy. Antimicrobial prophylaxis is of clinical benefit only in this highrisk population. In most cases, a single dose of intravenous cefazolin will provide adequate prophylaxis.45 For patients with a β-lactam allergy, oral ciprofloxacin is as efficacious as parenteral cefuroxime as prophylactic therapy for gastroduodenal surgery.46 Antimicrobial prophylaxis is only indicated in esophageal surgery in the presence of obstruction. Postoperative therapeutic antibiotics may be indicated if perforation is detected during surgery, depending on whether an established infection is present. The use of antibiotic prophylaxis for percutaneous endoscopic gastrostomy (PEG) is controversial. Although postoperative peristomal infection can occur in up to 30% of patients, clinical trials with cefazolin given 30 minutes preoperatively in this population are conflicting. A pharmacoeconomic study using a meta-analysis of available studies to determine efficacy suggested that antibiotic prophylaxis cost was effective for patients undergoing PEG placements.47,48

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counts in fecal material present in the colon (frequently exceeds 109 per gram). Anaerobes and gram-negative aerobes predominate, although gram-positive aerobes also may play an important role. Reducing this bacteria load with a thorough bowel preparation regimen (4 L polyethylene glycol solution or 90 ml sodium phosphate solution administered orally the day before surgery) is controversial, even though 99% in a recent survey of surgeons routinely use mechanical preparation.57 Risk factors for SSIs include age greater than 60 years, hypoalbuminemia, poor preoperative bowel preparation, corticosteroid therapy, malignancy, and operations lasting longer than 3.5 hours.7 CLINICAL CONTROVERSY A recent randomized trial of 380 patients undergoing elective colorectal surgery suggests that SSIs are not reduced by preoperative mechanical bowel preparation.58 This has been confirmed by a recent meta-analysis that shows that mechanical bowel preparation does not reduce the risk of anastamotic leakage or other complications, including postoperative infection.59 Despite this new evidence, mechanical bowel preparations continue to be a standard of practice prior to elective bowel surgery.

HEPATOBILIARY SURGERY Although bile is normally sterile, and the SSI rate after biliary surgery is low, antibiotic prophylaxis has been proved to be of benefit in this population. Bile contamination (bactobilia) can increase the frequency of SSIs and is present in many patients (e.g., acute cholecystitis, biliary obstruction, and advanced age).45 In general, however, the correlation between bactobilia in surgical specimens and the subsequent pathogens implicated in an SSI is poor. The most frequently encountered organisms include E. coli, Klebsiella spp., and enterococci. Pseudomonas is an uncommon finding in the absence of cholangitis. Trials comparing first-, second-, and third-generation cephalosporins have not demonstrated benefit over single-dose cefazolin prophylaxis even in high-risk patients (e.g., age greater than 60 years, previous biliary surgery, acute cholecystitis, jaundice, obesity, diabetes, and common bile duct stones).49 Ciprofloxacin and levofloxacin are effective alternatives for β-lactam-allergic patients undergoing open cholecystectomy.50,51 In fact, orally administered levofloxacin appears to provide similar intraoperative gallbladder tissue concentrations.51 For low-risk patients undergoing elective laparoscopic cholecystectomy, antibiotic prophylaxis is not of benefit and is not recommended.52 The risk for SSIs in cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) surgery may be reduced with a single prophylactic dose of ceftriaxone53 but not with single doses of shorter-acting cephalosporins.54 Antibiotic prophylaxis is not currently recommended prior to endoscopic retrograde cholangiopancreatography (ERCP).55 While surgeons may use presumptive antibiotic therapy for patients with acute cholecystitis or cholangitis and defer surgery until the patient is afebrile in an effort to decrease the risk of subsequent infections, this practice is controversial. Detection of an active infection during surgery (e.g., gangrenous gallbladder, suppurative cholangitis) is an indication for a course of postoperative therapeutic antibiotics. In either case, antibiotics with additional antianaerobic activity (e.g., cefoxitin or cefotetan) are indicated.56

COLORECTAL SURGERY In the absence of adequate prophylactic therapy, the risk for SSI after colorectal surgery is large because of the significant bacterial

Antimicrobial prophylaxis reduced mortality from 11.2% to 4.5% in a pooled analysis of trials comparing antimicrobial prophylaxis with no prophylaxis for colon surgery.60 Effective antibiotic prophylaxis reduces the risk for an SSI even further. Several oral regimens designed to reduce bacterial counts in the colon have been studied.61 The combination of 1 g neomycin and 1 g erythromycin base given orally 19, 18, and 9 hours preoperatively is the most commonly used regimen in the United States.61 Neomycin, while poorly absorbed, provides intralumenal concentrations that are high enough to effectively kill most gram-negative aerobes. Oral erythromycin, although partially absorbed, still produces concentrations in the colon that are sufficient to suppress common anaerobes. If surgery is postponed, the antibiotics must be readministered to maintain efficacy. Optimally, the bowel preparation regimen should be completed prior to starting the oral antibiotic regimen. This is of particular concern because most procedures are now performed electively on a “same-day surgery” basis. In this case, the bowel preparation regimen is self-administered by the patient at home on the day prior to hospital admission, and thus compliance cannot be monitored carefully. Patients who cannot take oral medications should receive parenteral antibiotics. Cefoxitin or cefotetan is used most commonly, but a number of other second-generation and some third-generation cephalosporins are also effective.62 The role of metronidazole in combination with cephalosporin therapy is unclear. Currently, only retrospective evidence suggests that the addition of metronidazole to a cephalosporin or extended-spectrum penicillin may provide additional benefit.63 Until this can be confirmed in prospective studies, metronidazole should be reserved for combination therapy with cephalosporins with poor anaerobic coverage (e.g., cefazolin). At this time, there is not enough evidence to recommend the addition of metronidazole to cephalosporins with anaerobic activity (e.g., cefotaxime, cefoxitin, and ceftriaxone). For β-lactam-allergic patients, perioperative doses of gentamicin and metronidazole have been used.64 It is controversial whether the addition of preoperative parenteral antibiotics to the standard preoperative oral antibiotic regimen described earlier will decrease SSI rates lower than oral prophylaxis alone; however, combination therapy is superior to parenteral therapy alone.65 Postoperative antibiotics generally are unnecessary in the absence of any untoward events or findings during surgery. Intravenous

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antibiotics are required for colostomy reversal and rectal resection because enterally administered antibiotics will not reach the distal segment that is to be reanastomosed or resected.66

APPENDECTOMY Suspected appendicitis is a frequent cause for abdominal surgery. Numerous antibiotic regimens, all with activity against gram-positive and gram-negative aerobes and anaerobic pathogens, have been studied and found to be effective in reducing SSI incidence. A cephalosporin with antianaerobic activity, such as cefoxitin or cefotetan, is recommended as first-line therapy; however, a comparative trial of cefoxitin and cefotetan suggests that cefotetan may be superior, possibly because of its longer duration of action.67 In the case of β-lactam allergy, metronidazole in combination with gentamicin is also an effective regimen. Broad-spectrum antibiotics covering nosocomial pathogens (e.g., Pseudomonas) do not further reduce SSI risk68 and instead may increase the cost of therapy and promote bacterial resistance. While single-dose therapy with cefotetan is adequate, prophylaxis with cefoxitin may require intraoperative dosing if the procedure extends beyond 3 hours in duration. Established intraabdominal infections (e.g., gangrenous or perforated appendix) require an appropriate course of postoperative therapeutic antibiotics. Laparoscopic appendectomy produces lower postoperative infection rates that open appendectomy; however, antimicrobial prophylaxis was used in all patients in these studies, and thus the role for prophylaxis in this population remains unstudied.69

UROLOGIC PROCEDURES Preoperative bacteruria is the most important risk factor for development of an SSI after urologic surgery. All patients should have a preoperative urinalysis and should receive therapeutic antibiotics if bacteruria is detected. Patients with sterile urine preoperativey are at low risk for developing an SSI, and the benefit of prophylactic antibiotics in this setting is controversial.70 Reviews suggest that antibiotic prophylaxis is warranted in high-risk patients (e.g., prolonged indwelling catheterizaton, positive urine cultures, and neutropenia) undergoing transurethral, perineal, or suprapubic resection of the prostate, resection of bladder tumors, or cystoscopy.70 The exact incidence of SSIs in this population is obscured, however, by the frequent use of postoperative urinary catheters and the subsequent risk of bacteriuria. E. coli is the most frequently encountered organism. Routine use of broadspectrum antibiotics such as third-generation cephalosporins and fluoroquinolones has not been demonstrated to decrease SSI rates more than cefazolin, and thus such regimens are not recommended. One comparative trial determined that a single dose of oral ciprofloxacin was as effective as intravenous cefazolin and suggests that this may be a cheaper and easier alternative for outpatient urologic surgery.71 Regimens longer than a single dose do not improve outcome. Urologic procedures requiring an abdominal approach, such as a nephrectomy or cystectomy, require antibiotic prophylaxis similar to that which would be used for a clean-contaminated abdominal procedure.70

CESAREAN SECTION Cesarean section is the most frequently performed surgical procedure in the United States.7 Prophylactic antibiotics are given to avoid endometritis, the most commonly occurring SSI. In the past, antibiotics were recommended for only high-risk patients, including those with premature membrane rupture or those not receiving prenatal care. Several large trials, as well as a meta-analysis, have shown bene-

fit in administering prophylactic antibiotics to all women undergoing emergent cesarean section regardless of their underlying risk factors.72 Cefazolin remains the drug of choice despite a wide spectrum of potential pathogens, and a single 2-g dose appears to be superior to single or multiple 1-g doses.73 Providing a broader spectrum of coverage with cefoxitin (for anaerobes) or piperacillin (for Pseudomonas or enterococci), does not lower postoperative infection rates further. For patients with a β-lactam allergy, preoperative metronidazole is an acceptable alternative.72 During a cesarean section, unlike other surgical procedures, antibiotics should be administered after the initial incision is made and after the umbilical cord is clamped. This will minimize infant drug exposure and thus potentially decrease the incidence of neonatal sepsis. Longer durations of prophylactic therapy have not been shown to result in lower infection rates.74

HYSTERECTOMY The most important factor affecting the incidence of SSI after hysterectomy is the type of procedure that was performed. Vaginal hysterectomies are associated with a high rate of postoperative infection when performed without the benefit of prophylactic antibiotics because of the polymicrobial flora normally present at the operative site.75 As with cesarean sections, cefazolin is the drug of choice for vaginal hysterectomies despite the wide spectrum of possible pathogens.75 Single-dose therapy should be adequate, but most reports use a 24-hour regimen. The American College of Obstetricians and Gynecologists (ACOG) recommends the use of a first-, second-, or third-generation cephalosporin.76 For patients with a β-lactam allergy, a single preoperative dose of doxycycline also is effective.75 Prophylactic antibiotics are recommended for abdominal hysterectomy despite the lack of bacterial contamination from the vaginal flora. Both cefazolin and antianaerobic cephalosporins (e.g., cefoxitin and cefotetan) have been studied extensively. Single-dose cefotetan is superior to single-dose cefazolin,78 and the investigators suggest that cefotetan should be the drug of choice for abdominal hysterectomies. However, other authors suggest that either agent is appropriate, provided that 24 hours of antimicrobial coverage is not exceeded.7 ACOG guidelines suggest that first-, second-, or thirdgeneration cephalosporins can be used for prophylaxis.76 Metronidazole is also effective and may be used if patients are allergic to β-lactam antibiotics.75 Antibiotic prophylaxis may not be required in laparoscopic gynecologic surgery or tubal microsurgery.79 Similar to other surgical procedures, perioperative events and findings may require the use of therapeutic antibiotics after surgery.

HEAD AND NECK SURGERY Use of prophylactic antibiotics during head and neck surgery depends on the procedure type. Clean procedures (as per NRC definition), such as parotidectomy or simple tooth extraction, are associated with a very low incidence of SSI. Head and neck procedures involving an incision through a mucosal layer carry with them a higher risk for SSI. The normal flora of the mouth is polymicrobial; both anaerobes and gram-positive aerobes predominate. While typical doses of cefazolin usually are ineffective for anaerobic infections, a 2-g dose produces concentrations high enough to inhibit these organisms. A pharmacokinetic study suggested that a single dose of clindamycin is adequate for prophylaxis in maxillofacial surgery unless the procedure lasts longer than 4 hours, when a second dose should be administered intraoperatively.80 A combination of clindamycin plus gentamicin also has been described but was found to offer no advantage over

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clindamycin alone.81 For most head and neck cancer resection surgeries, including free-flap reconstruction, 24 hours of clindamycin is appropriate, and there is no additional benefit in extending therapy beyond 24 hours.82 Topical therapy with clindamycin, amoxicillinclavulanate, and ticarcillin-clavulanate has been described in small trials, but the exact role for topical antibiotics has yet to be defined.83 Antimicrobial prophylaxis is not indicated for endoscopic sinus surgery without nasal packing.39

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infrequently (3% to 5%), the associated morbidity and mortality are extensive because treatment often requires surgical graft removal along with therapeutic antibiotic therapy.92 Prophylactic antibiotics are of benefit, particularly for procedures involving the abdominal aorta and the lower extremities. Cefazolin is regarded as the drug of choice.93 Twenty-four hours of prophylaxis with cefazolin is adequate; longer courses may lead to bacterial resistance.94 For patients with β-lactam allergy, 24 hours of oral ciprofloxacin also has been shown to be effective.92

CARDIOTHORACIC SURGERY Although cardiac surgery generally is considered a clean procedure, antibiotic prophylaxis has been demonstrated to lower SSI incidence. The substantial morbidity related to an SSI in this population, coupled with the routine implementation of prosthetic devices, further justifies the routine use of prophylaxis.84 Patients who develop SSIs after coronary artery bypass graft (CABG) surgery have a mortality rate of 22% at 1 year compared with 0.6% for those who do not develop an SSI.85 Risk factors for developing an SSI after cardiac surgery include obesity, renal insufficiency, connective tissue disease, reexploration for bleeding, and poorly timed administration of antibiotics.84 Skin flora pathogens predominate; gram-negative organisms are rare. Cefazolin has been studied extensively and is considered the drug of choice.25 Although several studies and a meta-analysis have been published that advocate the use of second-generation cephalosporins (e.g., cefuroxime) rather than cefazolin, various methodologic flaws in these studies have limited the extrapolation of these results to practice. Cefazolin is as effective as cefuroxime in a large randomized trial of 702 patients undergoing open heart surgery and thus remains the standard of care.86 Both patient weight and timing of cefazolin administration relative to surgery must be considered when developing a dosing strategy. Patients weighing more than 80 kg should receive 2 g cefazolin rather than 1 g. Doses should be administered no earlier than 60 minutes before the first incision and no later than at the beginning of induction.84 Extending therapy beyond 48 hours does not lower SSI rates further.87 Single-dose cefazolin therapy, in fact, may be sufficient.88 Routine vancomycin administration is potentially justified in hospitals having a high incidence of MRSA or when sternal wounds are to be explored surgically for possible mediastinitis. However, a recent large comparative trial enrolling almost 900 patients in a single center with a high prevalence of MRSA infections found that both cefazolin and vancomycin had similar efficacy in preventing SSI in patients undergoing cardiac surgery that required sternotomy.89 Mediastinitis constitutes a failure of a prior prophylactic regimen. Continued postoperative vancomycin should be guided by culture and sensitivity data.40 Subsequent antibiotic therapy is guided by intraoperative findings. Pulmonary resection is associated with significant SSI risk, and prophylactic antibiotics have an established role in preventing postoperative infectious morbidity. Pleuropulmonary infections are much more common than wound infections, and pathogenic organisms likely migrate from the oral cavity or pharynx.90 First-generation cephalosporins are inadequate; 48 hours of cefuroxime is preferred. A regimen of ampicillin-sulbactam is superior to first-generation cephalosporins, but further studies are required before this agent can be recommended as first-line prophylactic therapy.91

VASCULAR SURGERY Vascular surgery, like cardiac surgery, generally is considered a clean surgery by NRC criteria. Although vascular graft infections occur

ORTHOPEDIC SURGERY Most orthopedic surgery is clean by definition, and thus prophylactic antibiotics generally are indicated only when prosthetic materials (e.g., pins, plates, and artificial joints) are implanted.19 A lateoccurring infectious complication in this surgical population can result in substantial morbidity and may lead to prosthesis failure and subsequent removal. Staphylococci are the most frequently encountered pathogens; gram-negative aerobes are infrequent. Similar to many other surgical sites, cefazolin use is supported by substantial literature evidence and therefore is the prophylactic agent of choice. Vancomycin, although effective, is not recommended for routine use unless a patient has a documented history of a serious allergy to β-lactams or the propensity for MRSA infections at a particular institution necessitates its use. The current recommended duration of prophylaxis for joint replacement and hip fracture surgery is 24 hours.7 Antibiotic-impregnated cement and beads have been used to lower SSI rates, but conclusive data regarding their efficacy are lacking.19 Patients suffering open (compound) fractures are particularly susceptible to infection because bacterial contamination almost always has occurred already. The use of antibiotics is presumptive under these circumstances. Cefazolin is often combined with an aminoglycoside in this setting, but controlled trials are lacking.95 A clinical trial comparing clindamycin and cloxacillin suggests that clindamycin is superior and may be appropriate as monotherapy for Gustillo type I and II open fractures but not for type III fractures, where added gramnegative activity is recommended.96 Duration of antibiotic therapy is highly variable and depends on surgical findings during d´ebridement, results of intraoperative cultures, and clinical status. A prospective trial comparing short (24 hours) courses of antimicrobial prophylaxis for severe trauma suggests that longer courses of antibiotics do not offer additional benefit and may be associated with the development of resistant infections.97 However, established joint infections and osteomyelitis require an extended course of therapeutic antibiotics.

NEUROSURGERY Definitive recommendations on the role of antibiotic prophylaxis in neurosurgery cannot yet be made at this time.98 While the rates of SSI after these generally clean operations are low, the morbidity and mortality of SSI, should it occur, are high. Procedures involving cerebrospinal fluid (CSF) shunt placement should be considered separately because this involves placement of a foreign body and is associated with higher infection rates. When choosing an antibiotic, one must consider not only the spectrum of activity but also the penetration of the agent into the site of action (CSF). A meta-analysis suggested that single doses of cefazolin or, where required, vancomycin appear to lower SSI risk after craniotomy.99 The largest prospective, randomized trial to date of 826 patients undergoing clean neurosurgical procedures suggested that a single dose of ceftizoxime was as effective

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as a combination regimen of single-dose vancomycin and gentamicin. The authors also report that ceftizoxime was better tolerated and more consistently achieved adequate CSF levels to inhibit the most common organisms.100 A more recent study of 780 patients undergoing neurosurgical procedures that included shunt surgery reported that single doses of cefotaxime and trimethoprim-sulfamethoxazole are equally effective in preventing SSIs.101 Studies performed on procedures involving a shunt have been small in size and do not consistently show lower infection rates with antibiotic prophylaxis, although the results of two meta-analyses suggest that they may.102,103 Since no trials have shown superiority of any one agent, single doses of cefazolin appear to be an acceptable choice.99 SSIs associated with spinal surgery are rare but devastating when they occur. The use of antimcrobial prophylaxis in this setting therefore is warranted and recommended by a meta-analysis.104 Large randomized, controlled trials are lacking, but cefazolin is the antibiotic recommended most commonly. Cefazolin penetration into both intervertebral disks and CSF may not be adequate, and a combination of cefuroxime and gentamicin may be better. There is a paucity of clinical trials comparing these two regimens.105

MINIMALLY INVASIVE AND LAPAROSCOPIC SURGERY Laparoscopic surgeries are being performed more frequently for a variety of different operations, including gynecologic, orthopedic, and biliary surgeries. This minimally invasive technique is associated with smaller wounds, fewer infectious complications, less of an inflammatory response, and therefore a better-preserved immune response to infection when compared with the open surgical approach.106 The role of antimicrobial prophylaxis in this setting depends on the type of surgery performed and preexisting risk factors for infection. Unfortunately, there are few large prospective, placebo-controlled trials to determine in which patients and surgeries antimicrobial prophylaxis is warranted. In addition to the recommendations for previously mentioned laparoscopic procedures, there is a variety of levels of evidence for prophylaxis in other laparoscopic and endoscopic procedures. Patients undergoing endoscopic retrograde cholaniopancreatography (ERCP) do not need antimicrobial prophylaxis unless biliary obstruction is evident. In these situations, a single 1-g dose of cefazolin will suffice.107 The role of antimicrobial prophylaxis for transurethral resection of the prostate (TURP) is better established. A third-generation cephalosporin such as ceftriaxone (or cotrimoxazole for severely βlactam-allergic patients) can be recommended as single-dose prophylaxis, especially for patients with nonsterile urine preoperatively or indwelling catheters.107 The insertion of peritoneal dialysis catheters by laparoscopic technique is associated with significantly lower rates of postoperative infection. With SSI rates of less than 5%, prophylactic antimicrobial therapy may not be warranted, but this has not been studied in a large enough placebo-controlled trial. If the decision to provide antimicrobial prophylaxis is made, a single dose of cefazolin will suffice.107

NONPHARMACOLOGIC INTERVENTIONS Besides antimicrobial strategies and aseptic technique, other strategies have been investigated in different types of surgeries to reduce postoperative infections. The most commonly cited and practiced interventions include maintenance of normothermia intraoperatively,

provision of supplemental oxygen in the perioperative period, and aggressive perioperative glucose control. Core body temperature can fall by 1 to 1.5◦ C intraoperatively in patients under general anesthesia. Intraoperative hypothermia has been associated with impaired immune function, decreased blood flow to the surgical site, decreased tissue oxygen tension, and an increased risk of SSI. Efforts to maintain intraoperative normothermia should be exercised and may include the use of warming blankets and intravenous fluid warmers to mainatain core body temperature above 36◦ C. One prospective trial of 200 patients undergoing colorectal surgery found that maintenance of normothermia reduced postoperative infection rates along with other morbidity parameters, including length of stay.108 Low oxygen tension in the tissues that make up the surgical site increases the risk of bacterial colonization and subsequent SSI by decreasing the efficiency of neutrophil activity. Administration of high concentrations of oxygen (80% via ventilator or 12 L/min via a nonrebreather mask) reduced postoperative infection rates significantly in a multicenter randomized trial of 500 patients undergoing colorectal surgery.109 Diabetes and poor glucose control are well-known risk factors for SSI. The increased risk of infection is thought to be due to both macrovascular (vasculopathy and venoocclusive disease) and microvascular (subtle immunologic deficiencies, including neutrophil dysfunction and reduced complement and antibody activity) complications. Aggressive control of perioperative blood glucose decreases the incidence of SSI in diabetics undergoing cardiac surgery and is currently being evaluated in other types of surgery and in nondiabetic patients.110 CLINICAL CONTROVERSY Although interventions to maintain normothermia intraoperatively, provide supplemental oxygen in the perioperative period, and aggressively control perioperative glucose show a significant reduction in SSI, they cannot be generalized to all types of surgeries. However, given the simplicity and low cost of these interventions, many clinicians are considering the applicability of such measures outside the studied population. At this time, pending further research, these interventions can only be recommended for routine use in the type of patient or surgery for which it was studied.

PHARMACOECONOMIC AND SAFETY IMPLICATIONS It is paramount to consider the cost implications of pharmacotherapy guidelines that affect a large number of patients. While investigators have incorporated basic financial analysis into the results of antibiotic prophylaxis comparative trials,40,44,47,85 robust pharmacoeconomic studies of various regimens of antimicrobial prophylaxis in surgery are lacking. Most of these studies are cost-minimization studies because only drug acquisition costs are considered. Studies that incorporate all relevant drug and treatment costs in relation to pertinent patient outcomes such as incidence of SSIs, hospital length of stay, and antibiotic related adverse events are needed. The recommendations and literature reviewed in this chapter show that SSIs are preventable with appropriately chosen and timed prophylactic therapy in combination with meticulous aseptic technique and a variety of nonantimicrobial methods. Despite this, infection is the most common complication postoperatively. For this

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CHAPTER 121 TABLE 121–7. Strategies for Implementing an Institutional Program to Ensure the Appropriate Use of Antimicrobial Prophylaxis in Surgery 1. Educate Develop an educational program that enforces the importance and rationale of timely antimicrobial prophylaxis. Make this educational program available to all health care practitioners involved in the patient’s care. 2. Standardize the Ordering Process Establish a protocol (e.g., a preprinted order sheet) that standardizes antibiotic choice according to current published evidence, formulary availability, institutional resistance patterns, and cost. 3. Standardize the Delivery and Administration Process Employ as system that ensures that antibiotics are prepared and delivered to the holding area in a timely fashion. Standardize the administration time to less than 1 hour preoperatively. Designate responsibility and accountability for antibiotic administration. Provide visible reminders to prescribe/administer prophylactic antibiotics (e.g., checklists). Develop a system to remind surgeons/nurses to readminister antibiotics intraoperatively during long procedures. 4. Provide Feedback Follow up with regular reports of compliance and infection rates.

reason, many institutions, including the Joint Commission on Accreditation of Healthcare Organizations (JCAHO), have mandated a formalized approach to improving patient safety and reducing SSIs. Standardized institutional guidelines can effectively ensure appropriate prophylactic antimicrial therapy and ultimately reduce SSIs at individual institutions. Strategies to implement such a program are outlined in Table 121–7.

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sis implantation, up to 1 year later. Thus the true incidence of SSI can only be determined by completing comprehensive postdischarge surveillance. All studies investigating the efficacy of surgical prophylaxis must include adequate postdischarge follow-up in order to be able to thoroughly assess the success of any prophylactic regimen.

ABBREVIATIONS ACOG: American College of Obstetricians and Gynecologists ASA: American Society of Anesthesiologists CABG: coronary artery bypass graft CDC: Centers for Disease Control and Prevention CFU: colony-forming units CSF: cerebrospinal fluid ERCP: endoscopic retrograde cholangiopancreatography JCAHO: Joint Commission on Accreditation of Healthcare Organizations MIC: minimum inhibitory concentration MRSA: methicillin-resistant S. aureus MSSA: methicillin-sensitive S. aureus NNIS: National Nosocomial Infections Surveillance System NRC: National Research Council PEG: percutaneous endoscopic gastrostomy SENIC: Study on the Efficacy of Nosocomial Infection Control SSI: surgical-site infection TIPS: transjugular intrahepatic portosystemic shunt TURP: transurethral resection of the prostate VRE: vancomycin-resistant enterococci Review Questions and other resources can be found at www.pharmacotherapyonline.com

REFERENCES EVALUATION OF THERAPEUTIC OUTCOMES When evaluating the outcome of surgical antibiotic prophylaxis, it is important to differentiate any potential SSI from other postoperative infection or complication. While fever and leukocytosis are common in the immediate postoperative period, they typically resolve with prompt ambulation, timely removal of invasive devices, prevention and/or resolution of atelectasis through optimal respiratory care, and effective analgesia. It is also important to remember that the emergence of distal infections, such as pneumonia, does not constitute a failure of surgical prophylaxis. Prophylaxis should be as short as possible because prolonged prophylactic regimens may contribute to the selection of resistant organisms and may make any infection more difficult to treat. Surgical-site appearance is the most important determinant of the presence of an infection. Drainage of pus from the incision accompanied by redness, warmth, and pain or tenderness is highly suggestive of an SSI. By definition, any surgical site that requires incision and drainage by the surgeon is considered infected regardless of appearance. Failure to heal and wound dehiscence also are seen commonly with SSIs, although surgical technique and nutritional status may be important contributing factors. The presentation of signs and symptoms consistent with an SSI in relation to previous surgery is an important consideration when evaluating therapeutic outcomes after surgical prophylaxis. Many SSIs will not be evident during acute hospitalization. In fact, SSIs may not become evident until up to 30 days later or, in the case of prosthe-

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88. Bucknell SJ, Mohajeri M, Low J, et al. Singe-versus multiple-dose antibiotics prophylaxis for cardiac surgery. Aust NZ J Surg 2000;70: 409–411. 89. Finkelstein R, Rabino G, Masiah T, et al. Vancomycin versus cefazolin prophylaxis for cardiac surgery in the setting of a high prevalence of methicillin-resistant staphylococcal infections. J Thorac Cardiovasc Surg 2002;123:326–332. 90. Sok M, Dragas AZ, Erzen J, et al. Sources of pathogens causing pleuropulmonary infections after lung cancer resection. Eur J Cardiothorac Surg 2002;22:23–27. 91. Boldt J, Piper S, Uphus D, et al. Preoperative microbiologic screening and antibiotic prophylaxis in pulmonary resection operations. Ann Thorac Surg 1999;68:208–211. 92. Pratesi C, Russo D, Dorigo W, et al. Antibiotic prophylaxis in clean surgery: Vascular surgery. J Chemother 2001;13:123–128. 93. Marroni M, Cao P, Fiorio M, et al. Prospective, randomized, doubleblind trial comparing teicoplanin and cefazolin as antibotic prophylaxis in prosthetic vascular surgery. Eur J Clin Microbiol Infect Dis 1999; 18:175–178. 94. Terpstra S, Noorkhoek GT, Voesten HG, et al. Rapid emergence of resistant coagulase-negative staphylococci on the skin after antibiotic prophylaxis. J Hosp Infect 1999;43:195–202. 95. Gillespie WJ, Walenkamp G. Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures. Cochrane Database Syst Rev 2001;1:CD000244. 96. Vasenius J, Tulikoura I, Vainionpaa S, Rokkanen P. Clindamycin versus cloxacillin in the treatment of 240 open fractures: A randomized, prospective study. Ann Chir Gynaecol 1998;87:224–228. 97. Velmahos GC, Toutouzas KG, Sarkisyan G, et al. Severe trauma is not an excuse for prolonged antibiotic prophylaxis. Arch Surg 2002;137: 537–541. 98. Hosein IK, Hill DW, Hatfield RH. Controversies in the prevention of neurosurgical infection. J Hosp Infect 1999;43:5–11. 99. Barker FG. Efficacy of prophylactic antibiotics for craniotomy: A metaanalysis. Neurosurgery 1994;35:484–492. 100. Pons VG, Denlinger SL, Guglielmo BJ, et al. Ceftizoxime versus vancomycin and gentamicin in neurosurgical prophylaxis: A randomized, prospective, blinded clinical trial. Neurosurg 1993;33:416–422. 101. Whitby M, Johnson BC, Atkinson RL, Stuart G. The comparative efficacy of intravenous cefotaxime and trimethoprim-sulfamethoxazole in preventing infection after neurosurgery: A prospective, randomized study. Brisbane Neurosurgical Infection Group. Br J Neurosurg 2000;14:13–18. 102. Haines SJ, Walters BC. Antibiotic prophylaxis for cerebrospinal fluid shunts: A meta-analysis. Neurosurgery 1994;34:87–93. 103. Langley JM, Leblanc JC, Drake J, Milner R. Efficacy of antimicrobial prophylaxis in placement of cerebrospinal fluid shunts: Meta-analysis. Clin Infect Dis 1993;17:98–103. 104. Barker FG. Efficacy of prophylactic antibiotic therapy in spinal surgery: A meta-analysis. Neurosurgery 2002;51:391–400. 105. Riley LH 3d. Prophylactic antibiotics for spine surgery: Description of a regimen and its rationale. J South Orthop Assoc 1998;7:212–217. 106. Balague Ponz C, Trias M. Laparoscopic surgery and surgical infection. J Chemother 2001;13:17–22. 107. Wilson APR. Antibiotic prophylaxis in endoscopic and minimally invasive surgery. J Chemother 2001;13:102–107. 108. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N Engl J Med 1996;334:1209–1215. 109. Greif R, Akca O, Horn EP, et al. Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection. Outcomes Research Group. N Engl J Med 2000;342:161–167. 110. Furnary AP, Zerr KJ, Grunkemeier GL, et al. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg 1999;67:352–360. 111. Olson M, O’Connor M, Schwartz ML. Surgical wound infection: A 5-year prospective study of 20,193 wounds at the Minneapolis VA Medical Center. Ann Surg 1984;199:253–259.

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122 VACCINES, TOXOIDS, AND OTHER IMMUNOBIOLOGICS Mary S. Hayney

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

Vaccines have become modern medical miracles along with bypass surgery and the CAT scan, but with this difference—vaccines have saved more lives and prevented more deaths than any other modern medical intervention since the chlorination of water and the pasteurization of milk. Richard M. Krause, “The Jordan Report: Accelerated Development of Vaccines 1996,” NIAID/NIH Immunization is defined as rendering a person protected from an infectious agent. Immunity to an infectious agent can be acquired by exposure to the disease, by the transfer of antibodies from mother to fetus, through the administration of immune globulin, and from vaccination. Immunization is the process of introducing an antigen into the body to induce protection against the infectious agent without causing disease. An antigen is a substance that induces an immune response. The antibody produced by the humoral arm of the immune system is usually the response that is measured as evidence of successful vaccination. However, increasing evidence exists that the cellular immune response, which is much more difficult to measure, is also a very important aspect of vaccine response. This chapter introduces the reader to three groups of agents: vaccines, toxoids, and immune sera (together known as immunobiologics). These groups are defined, and related agents are dealt with concurrently to illustrate total immunotherapy. Obscure agents and agents with a limited scope of use, such as agents for bioterrorism, are not included in the interest of brevity.

PRODUCTS TO PRODUCE IMMUNIZATION Vaccines and toxoids are separate and distinct products. Both types of products, however, act to induce active immunity, i.e., immunity generated by a natural immunologic response to an antigen. Viral vaccines can be live attenuated or killed. Killed viral vaccines may consist of whole or split viral particles, specific viral fragments (subunits), or virus-like particles. Bacterial vaccines generally are killed whole bacteria or specific bacterial antigens or conjugates. Live attenuated vaccines induce an immunologic response more consistent with that occurring with natural infection. Because the organisms in live attenuated vaccines undergo limited replication in the vaccinated individual after administration, they may confer lifelong immunity with one dose (as does a primary natural infection). Multiple doses of killed vaccines usually are needed to induce long-lasting, effective immunity. Often, additional doses at varying time intervals (booster doses) are required to maintain immunity. The booster doses of such

vaccines elicit memory responses from the B cells that produce immunoglobulin G (IgG). The immune system has developed an array of antibodies to the antigen already, and on restimulation with a booster dose, the B cells that produce the most specific antibodies against the antigen are activated. This restimulation allows the most active antibodies against the antigen to be selected and maintained in the “immunologic memory.” Thus the booster dose results in a rapid, intense antibody response that is long-lasting. Killed vaccines also can differ in immunity potential depending on their composition. For example, polysaccharide vaccines tend to be poorly immunogenic in infants, whereas conjugated vaccines of the same antigen tend to be highly immunogenic (e.g., pneumococcal polysaccharide vaccine versus pneumococcal conjugated vaccine). A T-cell–independent immune response is made to polysaccharide antigens that stimulate B cells directly.1 There is no maturation or booster response with a T-cell– independent immune response, and children younger than 2 years of age cannot make this type of response. Protein-polysaccharide conjugate vaccines stimulate T cells and promote interactions between T cells and B cells when producing the protective immune responses consisting of immunologic memory and high-affinity IgG. Toxoids are inactivated bacterial toxins that generally are combined with aluminum salts to enhance their antigenicity by prolonging antigen absorption and exposure. These adjuvants also increase local tissue irritation when injected. Toxoids stimulate the production of antibodies against the bacterial toxins rather than the infecting bacterial pathogens. Immune sera are sterile solutions containing antibody derived from human (immunoglobulin) or equine (horse antitoxin) sources. Immunoglobulins are derived from donor pools of blood plasma and are processed using cold ethanol fractionation in order to inactivate known potential pathogens. Antitoxins are made by immunizing animals with an antigen and then harvesting the antibodies (antitoxins) made against the antigens. These sera are indicated for induction of passive immunity (temporary immunity to infection as a result of the administration of antibodies not produced by the host). Human immune sera is preferred because of its lower incidence of serum sickness and other allergic reactions as compared with equine derived sera (see the section “Other Immunobiologics” below). In addition to the active component in an immunobiologic, other active and inert ingredients are often present. Suspending agents, such as water, saline, or complex fluids containing proteins (such as albumin) or antigens, are used as the vehicle for the immunobiologic agent. Preservatives, stabilizers, and antibiotics often are added to help maintain sterility. Immunized individuals may respond with allergic reactions not to the immunobiologic agent itself but to the other components of the pharmaceutical preparation. Different manufacturers of the same immunobiologic may have different active and 2231

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inert ingredients or different quantities of these ingredients in their products. The use of combination vaccines can decrease the number of injections required at a single visit. The childhood immunization schedule has become increasingly complex with up to seven injections in a single immunization visit. Licensed combination vaccines should be used whenever any of their components are indicated.2 Certain vaccines manufactured by various companies are considered interchangeable. Hepatitis A and hepatitis B vaccines are considered interchangeable. It is preferable to use diphtheria-tetanusacellular pertussis (DTaP) vaccine from the same manufacturer to complete the entire primary series. However, immunization should not be delayed if the particular type of vaccine administered for the initial doses cannot be ascertained easily. Finally, all licensed Hemophilus influenzae type b conjugate vaccines are considered interchangeable for the primary series of three doses of vaccine.3 In general, vaccines and toxoids must be kept refrigerated because breaking the “cold chain” may result in loss of potency. Certain vaccines, such as measles-mumps-rubella (MMR), also may be frozen. Immune sera generally should be kept refrigerated and not frozen except for lyophilized intravenous human immunoglobulin (IVIG), which can be stored at room temperature. Certain vaccines, such as yellow fever, live attenuated influenza, and varicella, are sensitive to increased temperature. While some vaccines may be stored below 0◦ C (32◦ F), toxoids in general tend to aggregate on freezing, leading to increased adverse local effects. On the other hand, some vaccines, when stored under incorrect conditions, may not be easily distinguished from potent vaccines.

FACTORS AFFECTING RESPONSE TO IMMUNIZATION Various factors are known to affect response to vaccines and toxoids. Viability of the antigen is an important factor (live attenuated versus killed), as discussed previously. Total dose is also important because there seems to exist a threshold dose above which no further increase in antibody titer is seen. The use of split doses or multiple reduced doses of a vaccine (such as those used in patients with allergies to some immunobiologic component as both a desensitization and an immunization program), however, may result in inadequate protection. In such instances, serologic testing should be performed to ascertain whether or not protection to the antigen had been attained. The interval between immunization doses, the number of doses given, or both may change immune response to an agent. For hepatitis B vaccine nonresponders, a significant proportion of individuals will mount a vaccine response when given additional doses of vaccine.4 Alternatively, additional doses of influenza vaccine are minimally effective in immunocompetent elderly individuals, individuals with human immunodeficiency virus (HIV) infections, or patients with cancer.5,6 Generally, intervals longer than those recommended between vaccine doses do not reduce immune response.3 The route and site of administration of the immunobiologic also are important. This is best illustrated by the hepatitis B vaccine, which elicits a satisfactory antibody response when given in the deltoid muscle but not consistently when administered in the gluteal area.7 Injections should be administered in a site where there is little likelihood of site damage. Immunobiologics containing adjuvants should be given into muscle mass because they can cause irritation when given subcutaneously or intradermally. Host factors also influence vaccine response. Immunodeficiency, increasing age, underlying disease, and genetic background have been associated with poor response rates.8−11

VACCINE ADMINISTRATION Subcutaneous injections should be administered into the thigh of infants and in the upper arm area of older children and adults. A 5/8 -in, 25-gauge needle should be used, being careful not to administer the dose intradermally or intramuscularly. For intramuscular (IM) injection, the anterolateral aspect of the upper thigh (infants and toddlers) or the deltoid muscle of the upper arm (children and adults) should be used. When giving an IM injection to an adult, at least a 1-in needle should be used for persons weighing less than 90 kg and a 1.5-in needle for persons weighing more than 90 kg to ensure injection in the muscle.7 The buttock should not be used because of the potential for inadequate immunologic response and because of the potential risk of injury to the sciatic nerve. When the buttock must be used (as for large doses of immunoglobulin), only the upper outer quadrant should be used, with the needle being inserted anteriorly. Intradermal injections should be administered on the volar surface of the forearm, except for human diploid cell (rabies) vaccine (HDCV), which should be given into the deltoid area to reduce reactions. A 3/8 - to 3/4 -in, 25- or 27-gauge needle should be used, with care being taken to not inject the immunobiologic substance into the subcutaneous tissue. For orally administered vaccines, the general recommendation is to readminister the vaccine at the same visit if the vaccine is regurgitated within 5 to 10 minutes of administration. If the second dose is not retained, that dose should not be counted, and the vaccine should be readministered at the next visit. The live attenuated influenza vaccine is administered intranasally. A specially designed sprayer is inserted just inside the nostril, and the dose is squirted by depressing the plunger of the sprayer. The clip is removed from the plunger so that the second half of the dose can be administered into the other nostril. The vaccinated individual should breathe normally. There is no need to repeat the dose if the individual sneezes during or shortly after administration.12 Questions often arise concerning the simultaneous administration of vaccines. In general, inactivated and live attenuated vaccines can be administered simultaneously at separate sites. If two or more killed antigens cannot be administered simultaneously, they may be administered without regard to spacing between doses. Killed and live antigens may be administered simultaneously or, if they cannot be administered simultaneously, at any interval between doses, with the exception of cholera (killed) and yellow fever (live) vaccine, which should be given at least 3 weeks apart. If live vaccines are not administered simultaneously, their administration should be separated by at least 4 weeks. Live viral vaccines may interfere with purified protein derivative (PPD) response; thus tuberculin testing should be postponed 4 to 6 weeks after live virus vaccine administration. The simultaneous administration of immunoglobulin and live attenuated vaccines may inhibit host antibody response because of impairment of viral replication. A dose relationship between administration of immunoglobulin and inhibition of immune response to a vaccine exists (Table 122–1). Whole blood and other blood products containing antibodies may interfere with the response to the MMR and varicella vaccines. For rubella-seronegative women who are immediately postpartum and have received a blood product in the last trimester or anti-RhoD immunoglobulin (IG) at the time of delivery, vaccination with MMR should be done immediately, with rubella antibody testing at least 3 months later to determine vaccine response. In any patient, if vaccination with MMR or varicella is followed by emergency immunoglobulin administration, the vaccine can be repeated or seroconversion to the viral antigens can be confirmed after sufficient time has elapsed (see Table 122–1). Immunoglobulin does not interfere with the response to oral vaccines or yellow fever vaccine.3

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TABLE 122–1. Suggested Intervals Between Administration of Antibody-Containing Products for Different Indications and Measles-Containing Vaccine and Varicella Vaccinea Dose, Including mg Immunoglobulin G (IgG)/kg of Body Weighta

Product/Indication Respiratory syncytial virus immune globulin (IG)b Tetanus IG Hepatitis A IG Contact prophylaxis International travel Hepatitis B IG Rabies IG Varicella IG Measles prophylaxis IG Standard (i.e., nonimmunocompromised) contact Immunocompromised contact Blood transfusion Red blood cells (RBCs), washed RBCs, adenine-saline added Packed RBCs (hematocrit 65%)c Whole blood (hematocrit 35%–50%)c Plasma/platelet products Cytomegalovirus intravenous immune globulin (IVIG) Respiratory syncytial virus prophylaxis IVIG IVIG Replacement therapy for immune deficienciesd Immune thrombocytopenic purpura Kawasaki disease

15 mg/kg intramuscularly (IM) 250 units (10 mg IgG/kg) IM

Recommended Interval before Measles or Varicella (months) None 3

0.02 mL/kg (3.3 mg IgG/kg) IM 0.06 mL/kg (10 mg IgG/kg) IM 0.05 mL/kg (10 mg IgG/kg) IM 20 IU/kg (22 mg IgG/kg) IM 125 units/10 kg (20–40 mg IgG/kg) IM

3 3 3 4 5

0.25 mL/kg (40 mg IgG/kg) IM 0.50 mL/kg (80 mg IgG/kg) IM

5 6

10 mL/kg negligible IgG/kg 10 mL/kg (10 mg IgG/kg) IV 10 mL/kg (60 mg IgG/kg) IV 10 mL/kg (80–100 mg IgG/kg) IV 10 mL/kg (160 mg IgG/kg) IV 150 mg/kg maximum 750 mg/kg 300–400 mg/kg IVd 400 mg/kg IV 1000 mg/kg IV 2 g/kg IV

None 3 6 6 7 6 9 8 8 10 11

a

This table is not intended for determining the correct indications and dosages for using antibody-containing products. Unvaccinated persons might not be fully protected against measles during the entire recommended interval, and additional doses of Immune globulin or measles vaccine might be indicated after measles exposure. Concentrations of measles antibody in an immune globulin preparation can vary by manufacturer’s lot. Rates of antibody clearance after receipt of an immune globulin preparation might vary also. Recommended intervals are extrapolated from an estimated half-life of 30 days for passively acquired antibody and an observed interference with the immune response to measles vaccine for 5 months after a dose of 80 mg IgG/kg. [Source: Mason W, Takahashi M, Schneider T. Persisting passively acquired measles antibody following gamma globulin therapy for Kawasaki disease and response to live virus vaccination (abstract 311). Presented at the 32nd meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles, California, October 1992.] b Contains antibody only to respiratory syncytial virus. c Assumes a serum IgG concentration of 16 mg/mL. d Measles and varicella vaccination is recommended for children with asymptomatic or mildly symptomatic human immunodeficiency virus (HIV) infection but is contraindicated for persons with severe immunosuppression from HIV or any other immunosuppressive disorder. From MMWR 2002;53(2).

Simultaneous administration of killed vaccines along with immunoglobulins is not contraindicated. Different sites are recommended, however, for killed vaccine and immunoglobulin administration. It is not recommended to increase the dose or number of vaccines used in this circumstance.

IMMUNIZATION OF SPECIAL POPULATIONS NEONATES, INFANTS, AND PREGNANT WOMEN The age of the recipient is another important determining factor in vaccine and toxoid response. In the first few months of life, maternal antibodies acquired via transplacental transfer during the third trimester of gestation protect an infant. However, the maternal antibody also inhibits the immune response to live vaccines because the circulating antibodies neutralize the vaccine before the infant has the opportunity to mount an immune response. For this reason, live vaccines are not administered until maternal antibody has waned, generally by age 12 months.3 Premature infants should be vaccinated at the same chronologic age using the same schedule and precautions as full-term infants. The full recommended doses of vaccines should be used, regardless of

age or birth weight. Hepatitis B vaccine should be administered if the infant weighs 2000 g, or it should be held until the infant is 2 months of age. Breast-fed infants should be vaccinated according to standard pediatric schedules. Most vaccines are pregnancy category C. As with most drugs, this category assignment is not because there is a known risk to the fetus but rather because of lack of information. No birth defect has ever been attributed to vaccine exposure.3 For example, no cases of congenital rubella syndrome from inadvertent administration of rubella vaccine to a pregnant woman have ever been reported. Despite this, vaccination of pregnant women generally is deferred until after delivery because of concern over potential risk to the fetus. Universal influenza immunization is recommended for women who will be pregnant during influenza season. Tetanus-diphtheria (Td) vaccine is recommended for pregnant women who have not received a Td booster in the past 10 years. Although live vaccines generally are avoided because of the theoretical risk of transmission of the vaccine organism to the fetus, inactivated vaccines may be administered to pregnant women when the benefits outweigh the risks.3 Hepatitis B, hepatitis A, meningococcal, inactivated polio, and pneumococcal polysaccharide vaccines should be administered to pregnant women who are at risk for contracting these infections.13

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IMMUNOCOMPROMISED HOSTS Vaccination in compromised hosts (e.g., those with chronic disease, such as diabetes, connective tissue disease, or alcoholics or those with cancer or HIV disease) must be individualized based on the disease state and its treatment. The Centers for Disease Control and Prevention (CDC) has classified persons with immunocompromised conditions into three groups14 : 1. Persons with a condition that causes limited immune deficiency (e.g., renal disease, diabetes, liver disease, and asplenia) 2. Individuals who are severely immunocompromised but not as a result of HIV infection (e.g., congenital immunodeficiency, drug- or radiation-induced disease, hematologic disease, or solid tumor) 3. Persons with HIV infection Patients with chronic pulmonary, renal, hepatic, or metabolic disease who are not receiving immunosuppressants may receive both live attenuated and killed vaccines and toxoids to induce active immunity. These patients often need higher doses of vaccines or more frequent dosing to induce immunity. Generally, immunization should be considered early in the course of the disease in an attempt to induce immunity at a point when the disease is less severe. Patients with active malignant disease may receive killed vaccines or toxoids but should not be given live vaccines. The MMR vaccine is not contraindicated for close contacts, however. Live virus vaccines may be administered to persons with leukemia who have not received chemotherapy for at least 3 months. Vaccines should be timed to avoid coinciding with the start of chemotherapy or radiation therapy. Annual influenza vaccine should be administered 2 weeks prior to chemotherapy or between cycles.6 If vaccines cannot be given at least 2 weeks or more before the start of these therapies, immunization should be postponed until 3 months after the therapy has been completed. Passive immunization with immunoglobulin may be used in place of active immunization regardless of the history of immunization. Glucocorticoids may cause suppressed responses to vaccines. For the purposes of immunization, the immunosuppressing dose of corticosteroids is prednisone 20 mg or more daily or 2 mg/kg daily, or an equivalent dose of another steroid, for at least 2 weeks. Patients receiving long-term alternate-day steroid therapy with short-acting agents, administration of maintenance physiologic doses of steroids (such as 5–10 mg/day of prednisone) via topical, aerosol, intraarticular, bursal, or tendon steroid injections require no special consideration for immunization. If patients have been receiving high-dose corticosteroids or have had a course lasting longer than 2 weeks, then at least 1 month should pass before immunization with live virus vaccines.3 The patient with HIV infection requires special consideration. Responses to live and killed antigens generally are suboptimal and decrease as the disease progresses because HIV produces defects in cell-mediated immunity and humoral immunity. For children up to age 16 years with HIV infection, immunization following the standard schedules is recommended for hepatitis B, DTaP, pneumococcal conjugate vaccine (PCV7), H. influenzae type b (Hib), inactivated polio vaccine (IPV), and annual influenza. Two doses of MMR vaccine should be administered at least 1 month apart as soon as possible after the first birthday. MMR should be administered only to children who have no evidence or moderate evidence of immunosuppression. Two doses of varicella vaccine separated by 3 months are recommended only in children with no evidence of

immunosuppression.15 Children with HIV infection are at high risk for invasive pneumococcal disease, so children aged 24 to 59 months who did not receive the primary series as infants also should receive two doses of PCV7 separated by at least 2 months. These children also should receive pneumococcal polysaccharide vaccine (PPV23). Other killed vaccines may be used without concern for increased risk. Live typhoid vaccine should be avoided. Yellow fever vaccine may be used if absolutely necessary, but it may pose a theoretical risk of encephalitis.16

TRANSPLANT PATIENTS SOLID-ORGAN TRANSPLANT PATIENTS Organ transplantation has become a routine treatment for end-stage organ disease of many causes. Although the number of organ transplants performed is severely limited by the availability of donor organs, survival of transplant recipients is increasing. Solid-organ transplant patients remain on immunosuppressive regimens for the rest of their lives. These immunosuppressive regimens result in a higher risk of infection and also decrease the protection conferred by immunization.17 Whenever possible, transplant patients should be immunized prior to transplantation. Live vaccines generally are not given after transplantation. Posttransplantation diphtheria, tetanus, pneumococcal, and influenza vaccine responses are unpredictable. Decreased immune response has been documented following hepatitis B vaccine.18−23

HEMATOPOIETIC STEM CELL TRANSPLANT PATIENTS Reimmunization of hematopoietic stem cell transplant (HSCT) patients is necessary because antibody concentrations wane rapidly. Annual influenza immunization may begin as soon as 6 months following successful engraftment. Reimmunization with diphtheriatetanus-pertussis (DTaP) vaccine if age 7 or younger, H. influenzae type b, inactivated polio, hepatitis B, and pneumococcal polysaccharide vaccines should begin approximately 12 months following HSCT. MMR can be administered at 24 months. Varicella, meningococcal, and pneumococcal conjugate vaccines are not recommended. Immunization of household contacts and health care workers is also necessary.24

CONTRAINDICATIONS AND PRECAUTIONS There are very few contraindications to the use of vaccines except those outlined earlier. These contraindications include a history of anaphylactic reactions to the vaccine or a component of the vaccine or an unexplained encephalopathy occurring within 7 days of a dose of pertussis vaccine. Immunosuppression and pregnancy are temporary contraindications to live vaccines. An interval of time must elapse based on the dose of immunoglobulin before a live vaccine can be administered (see Table 122–1). Precautions for DTaP administration include hypotonic hyporesponsive episode, fever of 40.5◦ C (104.9◦ F) or greater, crying lasting more than 3 hours within 48 hours of a previous dose, and seizures with or without fever within 3 days after a dose.3 Generally, mild to moderate local reactions, mild acute illnesses, concurrent antibiotic use, prematurity, family history of adverse events, diarrhea, and breast-feeding are not contraindications to immunization.

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OBTAINING AN IMMUNIZATION HISTORY An immunization history should be obtained from every patient, regardless of the reason for the health care visit. Ideally, any history provided by the patient from memory should be verified by reviewing the patient’s personal written immunization record or a database that contains the complete immunization history. State-based immunization registries are being developed to improve immunization coverage by allowing health care providers access to records at any contact with the health care system. Registries are aimed primarily at facilitation childhood immunization records.25 If an official written record is not available, patient characteristics (e.g., military service, travel history, and occupation) may provide clues as to the immunization history. Serologic testing for immunity against certain diseases can provide specific information, but it is employed routinely for only a few selected diseases (e.g., measles, rubella, hepatitis A and B, and varicella) and selected circumstances (e.g., employment in a health care facility). If a written record does not exist, one should be generated at the time of initiation of immunization. Patients without a written record should be considered susceptible and an immunization program started and completed unless a serious adverse reaction occurs. As a general rule, the risks associated with overimmunization are minimal relative to the risks associated with contracting vaccinepreventable diseases.3

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means to compensate victims for injury owing to vaccination. The program offers liability protection to manufacturers and an efficient means of recovering damages for individuals potentially injured by vaccines. Compensation for vaccine-related injuries is outlined in the Vaccine Injury Table.28 The act also instituted mandatory record keeping by health care providers in the permanent medical record. Specifically, the manufacturer and lot number of the vaccine, date of administration, and name, address, and title of the person giving the vaccine must be recorded. Additionally, the act mandates that health care providers report to their local health department or to the Food and Drug Administration (FDA) any occurrence of adverse reactions. Health care providers must report all events requiring medical attention within 30 days of vaccination to the Vaccine Adverse Event Reporting System (VAERS), which serves as a central depot for vaccine-related adverse effects. Only a temporal association between the adverse event and vaccine administration needs to be made. No adverse event rates can be determined because only the number of adverse events reported is known; the number of vaccines administered is not known. This database can be used to determine changes in adverse-event frequencies, to evaluate risk factors for adverse events, and to find rare adverse events.29 VAERS report forms can be obtained by calling 1-800-822-7967, or reports can be made online at www.vaers.com.

USE OF VACCINES AND TOXOIDS VACCINE DELIVERY Shortfalls in vaccine coverage targets exist in both the adult and pediatric populations.26 Among children, those of preschool age historically have been the most neglected. Entry into public school is contingent on receipt of certain required immunizations, resulting in vaccine coverage rates above 97% in children 6 years of age and older. The lack of a similar enforcement mechanism in younger patients, however, has contributed to exceptionally low immunization rates (7) minimize nephrotoxicity. Reduce dose for renal dysfunction; avoid use in severe renal impairment Emetogenic potential generally low, but higher emetogenicity with high-dose therapy CNS toxicity: malaise, dizziness; may be more severe with IT administration (nausea, vomiting, seizures, headache) Hepatotoxicity: cirrhosis/portal fibrosis (more common with chronic administration) Photosensitivity Myelosuppression: increased in patients with elevated cystathioneine or homocysteine concentrations. Folic acid and vitamin B12 supplementation decrease myelosuppression by decreasing elevated cystathionine and homocysteine levels. Stomatitis, pharyngitis Rash, desquamation. Premedicate with dexamethasone 4 mg twice daily the day before, day of, and day after administration.

Monitor methotrexate levels with high-dose administration Toxicities (mucositis, BM suppression) correlate with MTX levels >1 µM (1 × 10−6 M) for >48 hours. High-dose regimens must include leucovorin (LCV) rescue to prevent irreversible BM toxicity. LCV continued until MTX level 1 g/m2 per dose) regimens is a cerebellar syndrome of dysarthria, nystagmus, and ataxia. Risk of CNS toxicity is strongly correlated with advanced age and renal dysfunction. Renal insufficiency permits accumulation

of high levels of ara-CTP, which is believed to be neurotoxic. Hepatic dysfunction, high cumulative doses, and bolus dosing may also increase the risks of neurotoxicity.36,45,46

Gemcitabine Gemcitabine is a fluorine-substituted deoxycytidine analog related structurally to cytarabine (see Table 124–11). Its activation and mechanism of action are similar to those of cytarabine. Gemcitabine is incorporated into DNA, where it inhibits DNA polymerase activity. It also inhibits ribonucleotide reductase. Compared with cytarabine,

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gemcitabine achieves intracellular concentrations about 20 times higher than does ara-C, secondary to increased penetration of cell membranes, and greater affinity for the activating enzyme deoxycytidine kinase. Gemcitabine that is incorporated into DNA has a prolonged intracellular half-life. Its stereoconfiguration causes another normal base pair to be added next to the fraudulent gemcitabine base pair in the DNA strand. This “masked chain termination” protects the gemcitabine from excision and elimination.36,45,47,48

Azacytidine Azacytidine was approved in 2004 for the treatment of patients with myelodysplastic syndrome, a disorder of hematopoietic cell maturation that can progress to acute leukemia. Azacytidine, a cytidine nucleoside analog, causes hypomethylation of DNA. Hypomethylation may normalize the function of genes that control cell differentiation and proliferation, promoting normal cell maturation.49

PURINES AND PURINE ANTIMETABOLITES 6-Mercaptopurine and 6-Thioguanine Some of the oldest and newest anticancer agents are synthetic analogs of the naturally occurring purines guanine and adenine (see Table 124–11). 6-Mercaptopurine (6-MP) was the first purine analog to be used in cancer chemotherapy. Thioguanine (6-TG) is the two-amino analog of 6-MP. Both drugs are rapidly converted to ribonucleotides that inhibit purine biosynthesis. They also undergo purine interconversion reactions needed to supply purine precursors for synthesis of nucleic acids. Clinical cross-resistance is generally observed.36 6-MP depends on xanthine oxidase for an initial oxidation step. Its metabolism is markedly decreased by concomitant administration of the xanthine oxidase inhibitor allopurinol, and serious toxicity may result. Oral 6-MP doses must be reduced when allopurinol is administered together with 6-MP.36

Fludarabine Monophosphate Fludarabine monophosphate (FAMP) is an analog of the purine adenine. Like cytarabine, fludarabine interferes with DNA polymerase, causing chain termination. Unlike ara-C, fludarabine is also incorporated into RNA, resulting in inhibited transcription. The usual dose-limiting toxicity is myelosuppression. Fludarabine is also immunosuppressive, with associated opportunistic infections.36,50,51

Cladribine Cladribine (2-chlorodeoxyadenosine; 2-CDA) is a purine nucleoside analog that is resistant to inactivation by adenosine deaminase. The triphosphate form of this agent is incorporated into DNA, resulting in inhibition of DNA synthesis and early chain termination. Cladribine’s antitumor activity is unusual for an antimetabolite in that it affects both actively dividing and resting cancer cells. Like fludarabine, cladribine possesses immunosuppressive effects that place patients at risk for serious opportunistic infections.36,45

ANTIFOLATES Folate vitamins are essential cofactors in DNA synthesis. They carry one-carbon groups in transfer reactions that are required for purine and thymidylic acid synthesis, and in turn for formation of DNA and for cell division. Natural folates circulating in the blood have a single glutamic acid group, but within cells they are converted to polyglutamates, which are more efficient cofactors and which are preferentially retained inside the cells.52

Dietary folates must be chemically reduced to their tetrahydro forms, with four hydrogens on the pteridine ring, to be active. The enzyme responsible for this reduction is dihydrofolate reductase (DHFR), a key enzyme whose actions are inhibited by methotrexate and other antifolates. The result of this inhibition is depletion of intracellular pools of reduced folates (tetrahydrofolates) essential for thymidylate and purine synthesis. Lack of either thymidine or purines prevents synthesis of DNA. The DHFR-mediated effects of antifolate drugs on normal and probably also on cancerous cells may be neutralized by supplying reduced folates exogenously. The reduced folate used clinically for “rescue” is leucovorin (folinic acid), which bypasses the metabolic block induced by DHFR inhibitors.52

Methotrexate The folic acid analog methotrexate (MTX) is the best understood of all drugs in the broad category of antimetabolites (see Table 124–11). It has been in clinical use for about 50 years. Like physiologic folates, methotrexate is transported intracellularly by an active transport system. In high doses, passive diffusion may overcome tumor cell resistance caused by saturated active transport systems. Resistance to the antifolates can also be caused by increased production of DHFR. Other potential causes of resistance are slow rates of thymidylate synthesis, decreased affinity of DHFR for methotrexate, and lack of polyglutamation within tumor cells. Polyglutamated forms of folates are better retained within cells. Malignant cells may achieve greater MTX polyglutamate levels than normal cells, which may in part explain the selective effects of MTX on malignant versus normal cells.52 Accurate and readily available assays for serum MTX levels have made therapeutic drug monitoring of MTX a valuable clinical tool. The threshold for cytotoxic effects of MTX is approximately 5×10−8 M. Toxicity and efficacy are related not only to peak concentrations, but more importantly, to time that concentrations remain above this threshold level. For MTX doses requiring leucovorin rescue (generally doses greater than 100 mg/m2 ), leucovorin must be administered until levels fall below 5×10−8 M. Therapeutic drug monitoring is also an effective means of increasing the likelihood of therapeutic success, by individualizing doses based on target parameters.52

Pemetrexed Pemetrexed is a multitargeted antifolate that inhibits at least three biosynthetic pathways in thymidine and purine synthesis (see Table 124–11). In addition to inhibition of DHFR, it also inhibits thymidine synthase and glycinamide ribonucleotide formyltransferase, decreasing the risk of development of drug resistance. Supplementation of folic acid and vitamin B12 is required to decrease myelosuppression.52,53

MICROTUBULE-TARGETING DRUGS VINCA ALKALOIDS Vincristine, vinblastine, and vinorelbine are natural alkaloids derived from the periwinkle (vinca) plant. They act as mitotic inhibitors, or “spindle poisons.” Although the alkaloids are very similar structurally, they have different activities and patterns of toxicity (Table 124–12). Vinca alkaloids bind to tubulin, the structural protein that polymerizes to form microtubules. These are the hollow tubes that make up the mitotic spindle and that are also important in nerve conduction and neurotransmission. Vinca alkaloids disrupt the normal balance between polymerization and depolymerization of microtubules, inhibiting assembly of microtubules and disrupting microtubule dynamics. This interferes with formation of the mitotic spindle and

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TABLE 124–12. Antimicrotubule Agents Agent/Major Uses Taxanes Docetaxel (Taxotere)a Breast cancer; NSCLC; prostate cancer; ovarian cancer; SCLC; bladder cancer; gastric cancer; head and neck cancers; melanoma; soft tissue sarcomas

Paclitaxel (Taxol)c Ovarian cancer; breast cancer; KS; NSCLC; SCLC; esophageal and head and neck cancers; testicular cancer; bladder cancer; cervical and endometrial cancers

Mechanism

Adverse Effects

Comments

Similar to paclitaxel, promotes microtubule assembly; inhibits depolymerization of tubulin; inhibits cell division

Myelosuppression; fluid retention syndrome: edema, weight gain, pleural effusions, ascites; typically occurs when cumulative dose exceeds 400 mg/m2 ; alopecia; rash: forearms, hands; nail disorders: onycholysis, banding, hypo- or hyperpigmentation; mild peripheral neuropathy; mildly emetogen; hypersensitivity reactions

Induces polymerization of microtubules, stabilizing the microtubules to make them nonfunctional; derived from the Pacific yew tree (Taxus brevifolia)

Myelosuppression may be dose-limiting; hypersensitivity reactions (preventable with appropriate premedications); peripheral neuropathy: paresthesias may be cumulative, dose-related; myalgias/ arthralgias typically occur 3–5 days after administration and persist for 3–5 days; mucositis: more common with high doses; mildly emetogen: cardiac: asymptomatic bradycardia most common; ventricular arrhythmias, third-degree heart block, and MI rarely reported; alopecia: total body

Dexamethasone 8 mg orally twice daily for 3 days (starting 1 day prior to docetaxel) is recommended to lower risk of fluid retention syndrome; shorter dexamethasone regimens used for weekly docetaxel dosing Requires dose reduction for liver dysfunction (elevated total bilirubin, elevated transaminases and/or alkaline phosphatase) Prepare and administer using glass or non-PVC IV bags and tubing Premedicate patients to prevent hypersensitivity reactions: dexamethasone 20 mg IV or orally 12 hours and 6 hours prior to paclitaxel, and diphenhydramine 50 mg IV 30 minutes prior to paclitaxel, and ranitidine 50 mg IV or cimetidine 300 mg IV 30 minutes prior to paclitaxel Reduce dose in patients with elevated total bilirubin (>1.5 mg/dL) and/or elevated transaminases (guidelines not well established) Neurotoxicity may be severe enough to require discontinuation; treat myalgias/arthralgias with NSAIDs, narcotic analgesics In paclitaxel-cisplatin combination regimens, give paclitaxel first to decrease neutropenia

Nitrogen-mustard type alkylating agent Estramustine (Emcyt)b Structurally is a combined Prostate cancer estrogen and alkylating agent, but functions mainly as an antimicrotubule agent; interferes with microtubule associated proteins (MAPs)

Vinca alkaloids Vinblastine (Velban)b Testicular cancer; NHL; HD; KS; bladder cancer; breast cancer; NSCLC; melanoma; prostate cancer; renal cell carcinoma

Antimicrotubule agent/vinca alkaloid; derived from the periwinkle plant; disrupts formation of microtubules

Nausea and vomiting (may be dose-limiting); diarrhea; cardiovascular: lowers arterial circulation; ischemic heart disease patients with CHF may develop increased symptoms of heart failure; thromboembolic events; gynecomastia, nipple tenderness; increased liver function tests

Patients with pre-existing heart disease, cerebrovascular disease, and hypertension should be closely monitored during treatment; most cardiovascular complications occur within the first 2 months to 1 year of treatment; low-dose warfarin (1–2 mg/day) is commonly used to decrease risk of thromboembolic events, but its value is not proven Doses should be taken on an empty stomach (1 hour before or 2 hours after a meal); avoid concurrent administration with dairy products or calcium compounds; refrigerate

Myelosuppression may be dose-limiting; mucositis; mildly emetogen; neurotoxicity: less common than with vincristine; myalgias; SIADH (rarely); vesicant: extravasation injury

Treat extravasation injury with warm soaks, and injection of hyaluronidase Reduce dose by 50% for total bilirubin 1.5–3 mg/dL; by 75% for total bilirubin >3 mg/dL (continued )

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TABLE 124–12. (Continued) Agent/Major Uses

Mechanism

Adverse Effects

Comments Prevent ileus: treat constipation aggressively; doses range from 1–1.4 mg/m2 (max); doses are traditionally capped at 2 mg to minimize neurotoxicity, but capping is controversial Reduce dose by 50% for total bilirubin 1.5–3 mg/dL; by 75% for total bilirubin >3 mg/dL; treat extravasation injury with warm soaks, and injection of hyaluronidase LETHAL if administered intrathecally! Eliminated primarily by metabolism and biliary excretion: follow package insert for dose adjustments Drug interaction with phenytoin: decreases phenytoin levels; drug interaction with erythromycin (may inhibit vinorelbine metabolism): increased risk of vinorelbine toxicity

Vincristine (VCR, Oncovin)b ALL; HD; NHL; multiple myeloma; breast cancer; SCLC; KS; brain tumors; soft tissue sarcomas; osteosarcomas; neuroblastoma; Wilms’ tumor

Antimicrotubule agent/vinca alkaloid; derived from the periwinkle plant; disrupts formation of microtubules

Peripheral neuropathy: primary dose-limiting toxicity; motor, sensory, autonomic, and cranial nerves may all be affected (paresthesias, ileus, urinary retention, facial palsies); may be irreversible; mild emetogen; SIADH; vesicant: extravasation injury

Vinorelbine (Navelbine)b NSCLC; breast cancer; HD; cervical cancer; ovarian cancer; prostate cancer

Antimicrotubule agent/synthetic vinca alkaloid; disrupts formation of microtubules

Myelosuppression (neutropenia); neurotoxicity: peripheral neuropathy (less common than with vincristine); constipation; low back pain; mild emetogen; vesciant: causes painful phlebitis with administration; alopecia is uncommon

a From Rowinsky et al,54 Hainsworth et al,55 and Krieger et al.56 b From Kitamura et al.36 c From Rowinsky et al54 and Krieger et al.56 All, acute lymphocytic leukemia; CHF, congestive heart failure; HD, Hodgkin’s disease; KS, Kaposi’s sarcoma; MI, myocardial infarction; NHL, non-Hodgkin’s lymphoma; NSAID, nonsteroidal anti-inflammatory drug; NSCLC, non-small-cell lung cancer; PVC, polyvinyl chloride; SIADH, syndrome of inappropriate secretion of antidiuretic hormone; SCLC, small cell lung cancer.

causes cells to accumulate in mitosis. They also disturb a variety of microtubule-related processes in cells, and induce apoptosis. Resistance to the vinca alkaloids develops primarily from P-glycoprotein– mediated multidrug resistance, which decreases drug accumulation and retention within tumor cells.54

TAXANES Paclitaxel and docetaxel are taxane plant alkaloids with antimitotic activity (see Table 124–12). Paclitaxel was isolated from the bark of the Pacific yew tree, Taxus brevifolia, but is now produced semisynthetically from the needles of the European yew, Taxus baccata. Docetaxel is a semisynthetic taxoid extracted from 10-deacetyl baccatin III, a noncytotoxic precursor found in the renewable needle biomass of yew plants.54 Paclitaxel and docetaxel both act by binding to tubulin, but unlike the vincas do not interfere with tubulin assembly. Instead, the taxanes promote microtubule assembly and interfere with microtubule disassembly. They induce tubulin polymerization, resulting in formation of inappropriately stable, nonfunctional microtubules. The stability of the microtubles damages cells, because the dynamics of microtubuledependent structures required for mitosis and other cellular functions are disrupted. Taxanes also have some nonmitotic actions that can promote cancer cell death, such as inhibition of angiogenesis. Resistance to the antitumor effects of the taxanes is attributable to alterations in tubulin or tubulin binding sites, or to P-glycoprotein–mediated multidrug resistance. Although paclitaxel and docetaxel have very similar mechanisms of action, cross-resistance between the two agents is incomplete.54−56

ESTRAMUSTINE Estramustine is an unusual drug in that it structurally combines the alkylating agent nor-nitrogen mustard with the hormone estradiol. It was designed with the intent that the estradiol portion of the molecule would facilitate uptake of the alkylating agent into hormone-sensitive prostate cancer cells. Despite the inclusion of an alkylator, estramustine does not function in vivo as an alkylating agent. Estrogens are released after its administration and are responsible for much of the toxicity of estramustine, but are not believed to contribute to its cytotoxic effect. In the mid-1980s, estramustine was redefined as an antimicrotubule agent. It binds covalently to microtubule-associated proteins that are part of the structural support for microtubules. The binding causes the separation of microtubule-associated proteins from the microtubules, inhibiting microtubule assembly and eventually causing their disassembly.57

TOPOISOMERASE INHIBITORS Topoisomerases are essential enzymes involved in maintaining DNA topologic structure during replication and transcription. DNA topoisomerase enzymes relieve torsional strain during DNA unwinding by producing strand breaks. They cleave DNA strands and form intermediates with the strands, producing a gap through which DNA strands can pass, then reseal the strand breaks. Topoisomerase I produces single-strand breaks; topoisomerase II produces double-strand breaks.58 Several important anticancer agents target topoisomerase enzymes: anthracyclines, camptothecins, and the epipodophyllotoxins (Table 124–13).

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TABLE 124–13. Topoisomerase-Active Agents Agent/Major Uses Topoisomerase I inhibitors Irinotecan (CPT-11; Camptosar)a Colon cancer; NSCLC; SCLC; cervical and ovarian cancers; gastric cancer; pancreatic cancer

Topotecan (Hycamtin)b Ovarian cancer; SCLC; MDS

Topoisomerase II inhibitors Daunorubicin (Daunomycin, Dauno, Cerubidine)c Liposomal daunorubicin (DaunoXome) ANLL; ALL; KS (liposomal)

Doxorubicin (Adriamycin, Adria, Doxo, hydroxydaunorubicin)c Liposomal doxorubicin (Doxil) Breast cancer; osteosarcoma and soft tissue sarcomas; NHL; HD; ALL; ANLL; bladder cancer; ovarian cancer; thyroid cancer; Wilms’ tumor; neuroblastoma; SCLC; KS (liposomal); gastric cancer; multiple myeloma; NSCLC; endometrial cancer

Mechanism

Adverse Effects

Comments

Topoisomerase I inhibitor; inhibits DNA binding activity of topoisomerase I, resulting in multiple DNA single-strand breaks; ultimately interferes with DNA synthesis

Diarrhea: acute (cramping, flushing, vomiting, diaphoresis within 1 hour of completion; related to cholinergic effects) and delayed (>12 hours after administration; usually after the second or third dose); may be severe; moderately high emetogenic potential; myelosuppression: neutropenia; alopecia; fatigue; increased liver function tests; pulmonary toxicity: diffuse infiltrates, fever, dyspnea

Topoisomerase I inhibitor; inhibits DNA binding activity of topoisomerase I, resulting in multiple DNA single-strand breaks; ultimately interferes with DNA synthesis

Myelosuppression (neutropenia); mucositis (dose-related; worse with continuous infusion); very low to low emetogenic potential; diarrhea (mild); reversible elevations in transaminases

Acute diarrhea is best treated or prevented with atropine; delayed diarrhea managed with antimotility agents (loperamide 4 mg at first sign of diarrhea then 2 mg every 2 hours until no diarrhea for 12 hours); octreotide is not usually effective; ensure that patients have a supply of antimotility agents to take with the first symptoms of diarrhea; ensure fluid and electrolyte replacement in patients with severe diarrhea Dose should be reduced in patients with elevated total bilirubin, no specific guidelines available Drug administration sequence affects pharmacokinetics and tolerability of irinotecan in 5-FU + irinotecan regimens Dose adjustments may be necessary for Clcr 550 mg/m2 ; lower total cumulative doses cause damage to myocardium in children (e.g., 350 mg/m2 ) Myelosuppression; mucositis: worse with continuous infusion; moderate emetogenic potential: may cause acute and delayed (by 24–48 hours) emesis; vesicant: severe extravasation injury; cardiac toxicities: acute—not related to cumulative dose; arrhythmias, pericarditis; chronic—cumulative injury to myocardium (total dose >550 mg/m2 ); lower total cumulative doses cause damage to myocardium in children (e.g. 350 mg/m2 ); radiation recall reactions

Antitumor antibiotic; topoisomerase II inhibitor; DNA intercalator; free-radical formation (thought to be related to cardiac toxicity and tissue injury)

Apply ice to areas of extravasation to lessen extent of injury Dose reduction required for total bilirubin >1.5 mg/dL (50% of full dose) and >3 mg/dL (25% of full dose) May discolor urine (red-orange) Liposomal form: decreased risk of cardiac and vesicant toxicity

Apply ice to areas of extravasation to lessen extent of injury; dose reduction required for total bilirubin >1.5 mg/dL (50% of full dose) and >3 mg/dL (25% of full dose) May discolor urine (red-orange) Dexrazoxane (Zinecard), a cardioprotectant, decreases risk of cardiotoxicity; approved for use in breast cancer patients with >300 mg/m2 doxorubicin; concerns over possible tumor protection limit its use Liposomal form: decreased risk of cardiac and vesicant toxicities (continued )

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TABLE 124–13. (Continued) Agent/Major Uses

Mechanism

Adverse Effects

Comments

Epirubicin (Ellence)e Breast cancer; gastric cancer

Antitumor antibiotic (see daunorubicin and doxorubicin)

Apply ice to areas of extravasation to lessen extent of injury; dose reduction required for total bilirubin >1.5 mg/dL (50% of full dose) and >3 mg/dL (25% of full dose) May discolor urine (red-orange)

Etoposide (VP-16; Vepesid), Etoposide phosphate (Etopophos)d Testicular cancer; SCLC; NSCLC; ANLL; KS; HD; NHL; BMT preparative chemotherapy; gastric cancer

Plant alkaloid, epipodophyllotoxin; inhibits DNA binding activity of topoisomerase II, resulting in multiple DNA double-strand breaks

Myelosuppression; mucositis: worse with continuous infusion; moderately emetogenic: may cause acute and delayed (by 24–48 hours) emesis; vesicant: severe extravasation injury; cardiotoxicity (similar to other anthracyclines); may be less cardiotoxic than doxorubicin; controversy about equivalent doses; cardiac toxicity associated with cumulative doses >900 mg/m2 Myelosuppression; moderately emetogenic: may be worse with oral and high-dose regimens; alopecia; mucositis; hypotension: infusion rate–related; etoposide phosphate can be given IV push without hypotension risk; hypersensitivity reactions: especially common in children

Idarubicin (Idamycin)e ANLL; oral preparation investigational

Antitumor antibiotic (similar to daunorubicin and doxorubicin, but more potent); topoisomerase II inhibition; DNA intercalation; free-radical formation

Mitoxantrone (Novantrone)f ANLL; prostate cancer; NHL; HD; breast cancer Multiple sclerosis

Anthracenedione (not an anthracycline); topoisomerase II inhibitor; DNA intercalator; low potential compared with anthracyclines for formation of free radicals

Myelosuppression; mucositis; moderately emetogenic; vesicant: extravasation; alopecia; cardiac toxicities: acute and chronic, as with daunorubicin and doxorubicin (total cumulative dose not well established; >150 mg/m2 reported to be associated with decreased LVEF Myelosuppression; low emetogenic potential; mucositis; alopecia; less cardiotoxic than the anthracyclines

Requires large volumes of fluid for IV administration due to limited solubility (max concentration 0.4 mg/mL); if hypotension occurs, stop infusion until BP stable, then resume at decreased rate Available orally in liquid-filled gelatin capsules; approximately 50% bioavailability, but absorption is variable and greater at lower oral doses Apply ice to areas of extravasation to lessen extent of injury Dose reduction required for total bilirubin >1.5 mg/dL (50% of full dose) and >3 mg/dL (25% of full dose) May discolor urine red-orange Produces cumulative cardiotoxicity with other anthracyclines Not a vesicant (may cause vein irritation, but not associated with severe tissue injury like anthracyclines) May discolor urine blue-green

a

From Rubin et al,58 Kellner et al,60 Ulukan et al,61 Vanhoefer et al,62 Raymond et al,63 and Falcome et al.64 From Rubin et al58 and Kellner et al.60 c From Rubin et al58 and Danesi et al.65 d From Rubin et al58 and Hande.59 e From Rubin et al58 and Danesi et al.65 f From Rubin et al.58 ALL, acute lymphocytic leukemia; ANLL, acute nonlymphocytic leukemia; BMT, bone marrow transplantation; BP, blood pressure; Clcr , creatinine clearance; HD, Hodgkin’s disease; KS, Kaposi’s sarcoma; LVEF, left ventricular ejection fraction; MDS, myelodysplastic syndrome; NHL, non-Hodgkin’s lymphoma; NSCLC, non-small-cell lung cancer; SCLC small cell lung cancer. b

ETOPOSIDE AND TENIPOSIDE Etoposide and teniposide are semisynthetic podophyllotoxin derivatives (see Table 124–13). Podophyllin is extracted from the mayapple or mandrake plant. Like the vinca alkaloids, podophyllin itself binds to tubulin and interferes with microtubule formation. Unlike the parent compound, however, etoposide and teniposide damage tumor cells by causing strand breakage through inhibiting topoisomerase II.58,59 Resistance may be caused by differences in topoisomerase II levels, by increased cell ability to repair strand breaks, or by increased levels of P-glycoproteins. Etoposide and teniposide are usually clinically cross-resistant. They are cell-cycle phase–specific and arrest cells in

the S or early G2 phase. As a result, activity is much greater when they are administered in divided doses over several days, rather than in large single doses.58,59

CAMPTOTHECIN DERIVATIVES Camptothecin, a plant alkaloid derived from Camptotheca acuminata, is a potent inhibitor of DNA topoisomerase I. Clinical trials failed to show expected antitumor activity, and the drug produced severe, unpredictable toxicity. The camptothecin analogs irinotecan and topotecan were synthesized to reduce toxicity and improve therapeutic

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effects. Both irinotecan and topotecan, through its active metabolite SN-38, poison the actions of the topoisomerase I enzymes. Topoisomerase I enzymes stabilize DNA single-strand breaks and inhibit strand resealing (see Table 124–13).58,60−64

ANTHRACENE DERIVATIVES The most widely used and best understood anthracene derivative is doxorubicin, also commonly known by its earliest trade name, Adriamycin or “Adria.” Other members of the anthracene group include daunorubicin (daunomycin), idarubicin, epirubicin, and mitoxantrone (see Table 124–13). All of these agents except mitoxantrone are anthracyclines and share a common, four-membered anthracene ring complex with an attached aglycone or sugar portion. The ring complex is a chromophore and accounts for the intense colors of these compounds. Doxorubicin differs from its parent compound daunorubicin by the addition of a hydroxyl group on the attached sugar, and it is sometimes referred to as hydroxydaunorubicin. A hydroxyl group on epirubicin is in the epi conformation compared with doxorubicin (epidoxorubicin), and idarubicin is demethoxydaunorubicin. Mitoxantrone is an anthracenedione rather than an anthracycline, and has no sugar group attached to the three-membered anthracene ring complex.58,65

Doxorubicin, Daunorubicin, Idarubicin, and Epirubicin Anthracyclines have been classified as antitumor antibiotics, but it is more accurate to refer to them as intercalating topoisomerase inhibitors (see Table 124–13). Intercalating agents are compounds that insert or stack between base pairs of DNA. Although it is well established that the planar groups of the anthracene ring complex do intercalate with DNA, causing structural changes that interfere with DNA and RNA synthesis, this is not their primary mechanism of cytotoxicity. The anthracyclines are primarily topoisomerase II poisons, producing double-strand DNA breaks.58,65 The anthracyclines also undergo electron reductions to reactive compounds that can damage DNA and cell membranes. Free radicals formed from reduction of the anthracyclines first donate electrons to oxygen to make superoxide, which can react with itself to make hydrogen peroxide. Cleavage of hydrogen peroxide produces the highly reactive and destructive hydroxyl radical. This last step requires iron, and the anthracyclines are potent iron binders. Iron-anthracycline complexes can bind to DNA and react rapidly with hydrogen peroxide to produce the hydroxyl radicals that actually cleave DNA. Human cells have natural defenses against oxygen radical damage, in the form of enzymes that can convert the radicals to less reactive compounds, or that can repair DNA damage. Differences in distribution of these defensive enzymes may account for characteristic sites of toxicities of the anthracyclines. For example, cardiac muscle has low levels of defensive enzymes and high levels of enzymes that activate anthracyclines. Oxygen free-radical formation is firmly established as a cause of cardiac damage and extravasation injury, but is not a major mechanism of tumor-cell killing. Resistance to the anthracyclines is usually secondary to P-glycoprotein–dependent multidrug resistance, causing the anthracyclines to be actively pumped out of tumor cells. Altered topoisomerase II activity may also be clinically important.58,65

Mitoxantrone The anthracenedione mitoxantrone was synthesized in an attempt to develop agents with comparable antitumor activity to doxorubicin, but with an improved safety profile (see Table 124–13). Like the anthracyclines, mitoxantrone is an intercalating topoisomerase II inhibitor,

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but its potential for free-radical formation is much less than that of the anthracyclines. Perhaps because of the decreased tendency for freeradical formation, the risks of cardiac toxicity and ulceration after extravasation, although still present, are markedly reduced.57,65

ALKYLATING AGENTS The alkylating agents are among the oldest and most useful of antineoplastic drugs. Their clinical use evolved from the observation of bone marrow suppression and lymph node shrinkage in soldiers exposed to sulfur mustard gas warfare during World War I. In an effort to develop similar agents that might be useful in treating cancerous overgrowths of lymphoid tissues, less reactive derivatives were synthesized. Their effectiveness as anticancer agents was confirmed by clinical trials in the middle 1940s.66 All of the alkylating agents work through the covalent bonding of highly reactive alkyl groups or substituted alkyl groups with nucleophilic groups of proteins and nucleic acids. Some alkylating agents react directly with biologic molecules; others form an intermediate compound that reacts with the targets. The most common binding site for alkylating agents is the seven-nitrogen group of guanine. These covalent interactions result in cross-linking between two DNA strands or between two bases in the same strand of DNA. Reactions between DNA and RNA and between drug and proteins may also occur, but the main insult that results in cell death is inhibition of DNA replication, because the interlinked strands do not separate as required. Because the alkylating agents can damage DNA during any phase of the cell cycle, they are not cell-cycle–phase specific. However, their greatest effect is seen in rapidly dividing cells. As a class, alkylators are cytotoxic, mutagenic, teratogenic, carcinogenic, and myelosuppressive. Resistance to these agents can occur from increased DNA repair capabilities, from decreased entry into or accelerated exit from cells, from increased inactivation of the agents inside cells, or from lack of cellular mechanisms to result in cell death following DNA damage. They react with water and are inactivated by hydrolysis, making spontaneous degradation an important component of their elimination.67

CYCLOPHOSPHAMIDE AND IFOSFAMIDE Cyclophosphamide and ifosfamide are nitrogen mustard derivatives, and are widely used alkylating agents (Table 124–14). They are closely related in structure, clinical use, and toxicity. Neither agent is active in its parent form and must be activated by mixed hepatic oxidase enzymes. The active metabolite of cyclophosphamide is phosphoramide mustard. Another metabolite, 4-hydroxycyclophosphamide is cytotoxic, but is not an alkylating agent. Ifosfamide is hepatically activated to ifosfamide mustard. Acrolein, a metabolite of both cyclophosphamide and ifosfamide, has little antitumor activity, but is responsible for some of their toxicity.67,68

NITROSOUREAS The nitrosoureas are alkylating agents characterized by lipophilicity and ability to cross the blood-brain barrier. Carmustine or bischloroethylnitrosourea (BCNU) and lomustine (CCNU) are commercially available. BCNU is available as an intravenous preparation and as a drug-impregnated biodegradable wafer (Gliadel) for direct application to residual tumor tissue following surgical resection of brain tumors. The nitrosoureas decompose to reactive alkylating metabolites and to isocyanate compounds that have several effects on reproducing cells (see Table 124–14).67

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TABLE 124–14. Alkylating Agents Agent/Major Uses

Class/Mechanism

Major Side Effects

Comments Bone marrow recovery may be delayed (3–6 weeks); pulmonary fibrosis associated with >3 years exposure, prior chest radiation; seizure prophylaxis (phenytoin 300 mg/day with BMT doses) Pharmacokinetic monitoring is required with IV busulfan, preferably in an experienced BMT setting IV and oral preparations are not interchangeable; put tablets in gelatin capsules for easier administration with high-dose administration Reduce dose for Clcr 100 mL/hour); potassium chloride and magnesium sulfate in IV fluid to replace losses; with or without mannitol 12.5–50 g to increase urine flow; dose reductions with CLcr 2 g/m2 ); secondary malignancies (bladder cancers, acute leukemia); infertility, sterility

Dacarbazine (DTIC; dimethyltriazeno-imidazolecarboxamide)a Melanoma; HD; soft-tissue sarcomas; brain tumors

Exact mechanism unclear; alkylation most likely mechanism, but does not cause DNA cross-linking; also appears to inhibit DNA, RNA, and protein synthesis; activated by hepatic microsomal mixed function oxidases (CYP450 enzymes) Alkylating agent; cross-links DNA strands; activated in the liver by microsomal (CYP450) mixed function oxidases

Myelosuppression; highly emetogenic; flu-like syndrome: fever, myalgia, malaise (may last for several days after dacarbazine administration); facial flushing; photosensitivity: use caution with sun exposure

Hydration needed to prevent hemorrhagic cystitis (oral/IV ∼3 L/ day × 72h); mesna may be required with high-dose regimens (see ifosfamide) Instruct patients to take oral tablets in the morning to allow for elimination of toxic metabolite; absorbed through skin: avoid spills Drug interactions: CYP450 inducers (e.g., barbiturates) may increase formation of toxic metabolites; CYP450 inhibitors (e.g., cimetidine) may increase myelosuppression Not a vesicant, but may cause burning pain at injection site Light-sensitive: dispense in lightproof bags; pink color indicates decomposition

Mechlorethamine (nitrogen mustard; H2 N; Mustargen)a HD; NHL; Mycosis fungoides (topical)

Bifunctional alkylating agent (two reactive groups); forms inter-and intrastrand DNA cross-links; inhibits DNA, RNA, and protein synthesis

Myelosuppression; highly emetogenic: rapid onset, within 1–2 hours of dose; vesicant: extravasation injury; secondary malignancies; sterility and infertility

Oxaliplatin (Eloxatin)d Colorectal cancer; ovarian cancer; gastric cancer

Platinum agent (see cisplatin, carboplatin)

Procarbazine (Matulane)a HD; brain tumors; NSCLC Only available orally

Exact mechanism unclear; alkylation most likely mechanism of action; also appears to inhibit DNA, RNA, and protein synthesis; activated by hepatic microsomal mixed function oxidases (CYP450 enzymes); good CNS penetration

Peripheral neuropathy >50% patients: acute form: 14 days, mainly hands and feet; may affect proprioception; may be permanent; pharyngolaryngeal dysesthesias in 1–2%; nausea, vomiting: moderately emetogenic; abdominal pain, diarrhea; anaphylaxis risk Myelosuppression: thrombocytopenia, neutropenia (may be prolonged 4–6 weeks); low emetogenic potential may be more severe initially; diarrhea; neurotoxicity: paresthesias, neuropathy; flu-like syndrome; infertility and sterility; secondary malignancies

Ifosfamide (Ifex)d Testicular cancer; soft-tissue sarcomas; NHL; NSCLC; cervical cancer; head and neck cancers

Hemorrhagic cystitis: always given with mesna and hydration; nephrotoxicity: renal tubular acidosis; potassium, magnesium, and phosphate wasting, especially in high-dose regimens; myelosuppression; CNS effects: somnolence, confusion, disorientation, cerebellar symptoms that are dose-related; moderately emetogenic; alopecia

3–4 L/day fluid for hydration; potassium, magnesium, and phosphate may be required to replace losses Mesna dose is typically 60–100% of ifosfamide dose (1:1 for continuous infusion ifosfamide); ifosfamide and mesna are physically compatible and may be delivered in same IV bag CNS toxicity and nausea and vomiting may be more severe with rapid infusion; case reports suggest methylene blue may be effective treatment for CNS toxicity Antidote for extravasation: sodium thiosulfate; very short stability in aqueous solutions, about 1 hour Used as topical solution or in compounded ointments for mycosis fungoides Renally eliminated; reduce dose in patients with impaired renal function Glutathione, magnesium, and calcium supplementation being evaluated for prevention of neuropathies Avoid exposure to cold

Administered as a single, daily dose on an empty stomach Monoamine oxidase inhibitors: drug-food interactions with tyramine-rich foods such as red wines, dark beers, aged cheeses, yogurt; may precipitate hypertensive crisis; drug interactions: tricyclic antidepressants and SSRIs, sympathomimetics; disulfiram-like reaction with alcohol (continued )

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TABLE 124–14. (Continued) Agent/Major Uses

Class/Mechanism

Major Side Effects

Comments

Temozolomide (Temodar)f Brain tumors; brain metastases; melanoma

Similar to dacarbazine; same reactive metabolite as dacarbazine (MTIC); does not require liver for activation; well absorbed orally; achieves therapeutic levels in CNS

Headache and fatigue; moderately emetogenic; myelosuppression: neutropenia, thrombocytopenia; myalgias, back pain; diplopia; lymphopenia, especially in chronic dosing

Thiotepa (thiethylene thiophosphoramide; ThioTEPA)a Breast cancer; bladder cancer (instillation); BMT preparation

Trifunctional alkylating agent; active metabolite TEPA; crosses blood-brain barrier

Myelosuppression (dose-limiting); nausea and vomiting: severe at high doses for BMT preparation; mucositis; pruritus and dermatitis

Crosses blood-brain barrier in therapeutic concentrations Administer on an empty stomach; capsules should not be opened or chewed Drug interaction: valproic acid may decease clearance of temozolomide slightly PCP prophylaxis should be considered for patients who develop lymphopenia Very old drug, now most commonly used as preparative regimen for stem cell transplants

a

From Bast et al.66 From Bast et al,66 Su et al,70 and Guminski et al.71 c From Bast et al,66 Su et al,70 Guminski et al.71 O’Dwyer et al.72 d From Bast et al,66 Colvin.67 e From Bast et al,66 Su et al,70 and Pace et al.73 f From Bast et al,66 Boddy et al,68 and Stupp et al.69 ALL, acute lymphocytic leukemia; ANLL, acute nonlymphocytic leukemia; AUC, area under the curve; BMT, bone marrow transplantation; Clcr , creatinine clearance; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CNS, central nervous system; CYP450, cytochrome P450 isoenzyme; HD, Hodgkin’s disease; NHL, non-Hodgkin’s lymphoma; NSCLC, non-small-cell lung cancer; PCP, Pneumocystis carinii pneumonia; PVC, polyvinyl chloride; SCLC, small cell lung cancer; SIADH, syndrome of inappropriate secretion of antidiuretic hormone; SLE, systemic lupus erythematosus; SSRI, selective serotonin reuptake inhibitor; TEPA, thiethylene phosphoramide. b

NONCLASSIC ALKYLATING AGENTS Several other cytotoxic agents appear to act as alkylators, although their structures do not include the classic alkylating groups. They are capable of binding covalently to cellular components and include procarbazine, dacarbazine, temozolamide, the heavy metal compounds, and some antitumor antibiotics (see Table 124–14).67

Dacarbazine and Temozolomide Dacarbazine, or dimethyl triazeno-imidazole-carboxamide (DTIC), and temozolomide (dihydro methyl oxoimidazo tetrazino carboxamide) are nonclassic alkylating agents (see Table 124–14). Both compounds undergo demethylation to the same active intermediate (monomethyl triazeno imidazole carboxamide [MTIC]) that interrupts DNA replication by causing methylation of guanine. Unlike dacarbazine, temozolomide does not require the liver for activation, and is chemically degraded to MTIC at physiologic pH. Both drugs inhibit DNA, RNA, and protein synthesis.67,69,70 Important pharmacokinetic differences exist between the two drugs. Dacarbazine is poorly absorbed, and must be administered by intravenous infusion. Temozolomide is rapidly absorbed after oral administration, and is approximately 100% bioavailable when given on a completely empty stomach. Darcarbazine penetrates the CNS poorly, but temozolomide readily crosses the blood-brain barrier, achieving therapeutically active concentrations in cerebrospinal fluid and brain tumor tissues.67,69,70

HEAVY METAL COMPOUNDS CISPLATIN, CARBOPLATIN, AND OXALIPLATIN The platinum derivatives, cisplatin, carboplatin, and oxaliplatin are anticancer agents with remarkable usefulness in cancer treatment (see Table 124–14). Recognition of cisplatin’s cytotoxic activity was

the result of a serendipitous observation that bacterial growth in culture was altered when an electric current was delivered to the media through platinum electrodes. The growth change was noted to be similar to that produced by alkylating agents and radiation. It was found that a platinum-chloride complex, now known as cisplatin, generated by the current was responsible for the changes. Carboplatin is a structural analog of cisplatin in which the chloride groups of the parent compound are replaced by a carboxycyclobutane moiety. It shares a similar spectrum of clinical activity with cisplatin, and crossresistance is common. Oxaliplatin is an organoplatinum compound in which the platinum is complexed with an oxalate ligand as the leaving group and to diaminocyclohexane. Its spectrum of activity differs substantially from the other platinum compounds, and includes notable activity against colorectal cancers.67,71 The cytotoxicity of the platinum derivatives depends on platinum binding to DNA and the formation of intrastrand cross-links or adducts between neighboring guanines. These intrastrand links cause a major bending of the DNA. They may cause cellular damage by distorting the normal DNA conformation and preventing bases that are normally paired from lining up with each other. Interstrand cross-links also occur.67,71 The cytotoxic form of cisplatin is the aquated species, in which hydroxyl groups or water molecules replace the two chloride groups. This reaction occurs readily in low concentrations of chloride, such as the concentrations present within cells, and produces a positively charged compound that can react with DNA. The aquated species is responsible for both the efficacy and toxicity of cisplatin. Carboplatin also undergoes aquation, but at a slower rate. Oxaliplatin becomes active when the oxalate ligand is displaced in physiologic solutions.67,71 Resistance to the therapeutic effects of platinum compounds may occur through several mechanisms. The ability to repair platinum-induced DNA damage may be increased, or the agents may be inactivated by increased levels of intracellular glutathione,

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metallothioneins, or other thiol-containing proteins. Altered uptake into cells may also affect sensitivity to platinum compounds.67,71,72 Cisplatin is a highly toxic antineoplastic agent, with potential for producing serious nephrotoxicity, ototoxicity, peripheral neuropathy, emesis, and anemia. The significant efficacy of cisplatin against many tumor types makes it a valuable agent despite these toxicities, most of which can be prevented or managed with aggressive supportive care measures.67,72,73 In contrast, carboplatin administration is limited by hematologic toxicity. Patients with compromised renal function require dose reductions to limit myelosuppressive toxicity. The most widely used dosage schema, the Calvert formula (see Table 124–14), uses a target area under the curve and renal function parameters to estimate the carboplatin dose.67,71 Carboplatin’s potential to cause renal damage, peripheral neuropathy, ototoxicity, and nausea and vomiting is much less than that of comparable cisplatin doses.67 Oxaliplatin is not nephrotoxic, ototoxic, or highly emetogenic, but produces peripheral neuropathies and unique cold-induced neuropathies.74 All of the platinum derivatives have significant potential to cause hypersensitivity reactions, including anaphylaxis.

supplies and inhibits protein synthesis. Increased L-asparagine synthetase activity within tumor cells causes resistance to L-asparaginase treatment.76

MISCELLANEOUS AGENTS

IMMUNE THERAPIES

BLEOMYCIN Bleomycin or “bleo” is an antitumor antibiotic (Table 124–15). It is a mixture of peptides from fungal Streptomyces species, and as such its strength is expressed in units of drug activity. One unit is roughly equal to 1 mg of polypeptide protein. The predominant peptide is bleomycin A2, which makes up approximately 70% of the commercial product. Bleomycin’s cytotoxicity is secondary to DNA strand breakage, or scission, which it produces via free-radical formation. Cytotoxicity depends on binding of an iron-bleomycin complex to DNA. The bleomycin-iron complex then reduces molecular oxygen to free oxygen radicals that cause primarily single-strand breaks in DNA. Bleomycin has greatest effect on cells in the G2 phase of the cell cycle and in mitosis.75 Bleomycin is inactivated within cells by the enzyme aminohydrolase. This enzyme is widely distributed, but is present in only low concentrations in the skin and the lungs, explaining the predominant toxicities of bleomycin to those sites. The presence of hydrolase enzymes in tumor cells is the primary mechanism of resistance to bleomycin. Cells can also become resistant by repairing the DNA breaks produced by bleomycin.75

HYDROXYUREA Hydroxyurea is a unique drug that inhibits ribonucleotide reductase, the enzyme required to convert ribonucleotides into the deoxyribonucleotide forms required for both DNA synthesis and repair (see Table 124–15). Cells accumulate in the S phase because DNA synthesis is inhibited, and only abnormally short DNA strands are produced.36 L-ASPARAGINASE

L-Asparaginase is unique among cytotoxic drugs in its unusual mechanism of action, patterns of toxicity, and source (see Table 124–15). It is an enzyme produced by Escherichia coli and other bacteria. L-Asparagine is a nonessential amino acid that can be synthesized by most mammalian cells, except for those of certain lymphoid human malignancies, which lack or have very low levels of the synthetase enzyme required for L-asparagine formation. L-Asparagine is degraded by the enzyme L-asparaginase, which depletes existing

ARSENIC TRIOXIDE Arsenic is an organic element and a well-known poison that is an effective treatment for acute promyelocytic leukemia (see Table 124–15).77 As an antineoplastic, arsenic trioxide acts as a differentiating agent, inducing the growth progression of cancerous cells into mature, more normal cells. It also induces programmed cell death or apoptosis.

MITOMYCIN C Mitomycin C is a natural product sometimes classified as an antitumor antibiotic (see Table 124–15).67,78 It has functional similarities to nitrogen mustard compounds and may function as an alkylating agent, although its toxicity pattern differs from conventional alkylators.

8 An intact immune system is believed to play an important role

in the control of cancer growth, as evidenced by the high incidence of cancers in immunosuppressed patients such as solid organ transplant recipients or those with human immunodeficiency virus infections. There are also rare but well documented spontaneous remissions of immunologically-linked cancers, particularly melanoma and renal cell carcinoma. Immune therapies attempt to harness the immune system to treat cancer (Table 124–16).79−81

INTERFERONS The interferons (IFNs) are a family of proteins produced by nucleated cells and by recombinant DNA technology, with antiviral, antiproliferative, and immunoregulatory activities. They are classified as α, β, or γ interferons based on antigenic, biologic, and pharmacologic properties. Many subtypes of IFN α are known. IFN α-2a and IFN α-2b, approved for anticancer indications, are very similar single-species recombinant products. The mechanisms of IFN α’s antitumor action are complex. IFN increases the activity of cytotoxic cells within the immune system, but direct antiproliferative effects also play a role. IFNs prolong the cell cycle, which results in cytostasis, an increase in cell size, and apoptosis. They can inhibit new blood vessel formation in tumors and can increase the expression of antigens on tumor cell surfaces, making the cancerous cells more easily recognized by the cells of the immune system. They also inhibit or block certain oncogenes that can direct the unregulated cell growth that is characteristic of cancerous cells. Alterations in gene expression may change the levels of receptors for other cytokines, or the concentration of regulatory proteins on immune cells, or may activate enzymes that alter cellular growth and function.79,80

INTERLEUKIN-2 (ALDESLEUKIN) Interleukin-2 (aldesleukin; IL-2) is a lymphokine produced by recombinant DNA technology that promotes B- and T-cell proliferation and differentiation and initiates a cytokine cascade with multiple interacting immunologic effects. The IL-2 receptor is expressed in increased amounts on activated T cells and mediates most of the effects of IL-2. Antitumor effects depend on proliferation of

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TABLE 124–15. Miscellaneous Agents Agent/Major Uses

Class/Mechanism

Major Side Effects

Comments

Arsenic trioxide (Trisenox)a APL

Differentiating agent; exact mechanism unclear; causes morphologic changes and DNA fragmentation characteristic of apoptosis

Retinoic acid syndrome must be treated promptly with corticosteroids; weight gain secondary to fluid retention may be dose limiting

Asparaginase (L-asparaginase, Elspar) Pegaspargase (Oncospar)b ALL

Antitumor enzyme, hydrolyzes L-asparagine in bloodstream, depriving tumor cells of the essential amino acid; results in inhibition of protein, DNA, and RNA synthesis and cell proliferation; derived from Escherichia coli

Retinoic acid syndrome: pulmonary infiltrates, respiratory distress, and hypotension; cardiovascular: tachycardia, edema, QT prolongation, chest pain, hypotension; low to moderate emetogenic potential; electrolyte abnormalities: hypokalemia or hyperkalemia, hypomagnesemia, hyperglycemia; rash; lightheadedness or vasomotor symptoms; fatigue; musculoskeletal pain Hypersensitivity reactions (fever, hypotension, rash, dyspnea in 25%), much lower risk with polyethylene glycol form; low emetogenic potential; pancreatitis; decreased synthesis of proteins, clotting factors; CNS: lethargy

Bleomycin (Bleo, Blenoxane)c NHL, HD; testicular cancer; squamous cell cancers of the head and neck, cervix, skin, penis, or vulva; malignant pleural effusions; KS

Antitumor antibiotic, causes single- and double-strand DNA scission (free-radical mediated); inhibition of protein, DNA, and RNA synthesis

Anaphylaxis and hypersensitivity reactions; fever and flu-like symptoms; mucositis; pulmonary fibrosis secondary to oxygen free-radical formation; low emetogenic potential; alopecia; not myelosuppressive

Mitomycin C (Mutamycin)d Gastric cancer, breast cancer; bladder cancer (instillation); esophageal cancer; cervical cancer; colorectal cancer; NSCLC

Antitumor antibiotic activated to an alkylating agent; cross-links DNA; inhibits DNA and RNA synthesis; superoxide free radicals may produce DNA strand breaks

Myelosuppression: may be delayed and prolonged (up to 8 weeks); mucositis; moderately emetogenic; extravasation: severe vesicant; pulmonary toxicity: pneumonitis, fibrosis (worse with concurrent vincristine or vinblastine); hemolytic anemia and uremic syndrome

Skin test prior to administration; anaphylaxis precautions; Pegaspargase complexed with polyethylene glycol to decrease immunogenicity and prolong duration of action (dose every 2 weeks vs. 2–5 times/week); more costly, may be difficult to obtain Monitor clotting function Test dose (1 unit) is recommended, but controversial: premedicate for subsequent doses with acetaminophen Dose reduction for CLcr 30 units, cumulative dose >400 units, bolus administration; risk factors: age >70, pre-existing pulmonary disease, prior chest radiation, exposure to high oxygen concentrations Apply ice or cold packs to site for extravasation; tissue damage may be delayed for 3–4 months after extravasation Sometimes administered intra-arterially, but systemic side effects may still occur

a

From Kurtzberg et al.76 From Laxo et al. 75 c From Andre et al.74 d From Bast et al,66 Soignet et al.77 ALL, acute lymphocytic leukemia; APL, acute promyelocytic leukemia; CLcr , creatinine clearance; CNS, central nervous system; HD, Hodgkin’s disease; KS, Kaposi’s sarcoma; NHL, non-Hodgkin’s lymphoma; NSCLC, non-small-cell lung cancer. b

cytotoxic immune cells that can recognize and destroy tumor cells without damaging normal cells. Some of these cytotoxic cells are natural killer cells, lymphokine-activated killer cells, and tumorinfiltrating lymphocytes.81 The toxicity of IL-2 is related to dose, route, and duration of therapy, but in general, IL-2 is toxic therapy that requires vigorous supportive care. The most common dose-limiting toxicities are hypotension, fluid retention, and renal dysfunction. IL-2 decreases peripheral vascular resistance, producing peripheral vasodilation, tachycardia, and hypotension. A characteristic vascular- or

capillary-leak syndrome produces fluid retention, which in turn can cause respiratory compromise. These toxicities require administration of vasopressors in most patients, judicious use of fluid support and diuretics, and supplemental oxygen. Patients with underlying cardiovascular or renal abnormalities are more susceptible to these adverse effects, making careful patient selection important.81 Most patients treated with IL-2 in full doses experience thrombocytopenia, anemia, eosinophilia, reversible cholestasis, and skin erythema with burning and pruritus, and some have neuropsychiatric changes, hypothyroidism, and bacterial infections.82−85 In general, the

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TABLE 124–16. Immune Therapies Agent/Major Uses

Mechanism

Adverse Effects

Comments Patients should be advised to administer interferon in the evening to reduce excessive daytime sedation; premedication and scheduled dosing with acetaminophen or an NSAID may alleviate flu-like symptoms Flu-like symptoms typically subside with chronic use; no tolerance to fatigue, may necessitate dose reduction; antidepressants valuable for depressive symptoms Polyethylene glycol interferon forms have sustained duration of effect Addition of dopamine in ”renal” doses (1–5 mcg/kg per minute) may help maintain good renal blood flow and blood pressure Pulmonary edema can be managed with cautious use of diuretics; short courses of albumin may also be beneficial Patients with history of cardiac arrhythmias may require cardiac monitoring during IL-2 administration Itching may respond to treatment with antihistamines (hydroxyzine or diphenhydramine); emollient skin creams or occlusive agents are effective for dry, peeling skin; avoid corticosteroids: may counteract the antitumor effects of IL-2.

Interferon alfa (interferon α-2b; Intron A and Interferon α-2a; Roferon-A, IFN)a KS; CML; melanoma; hairy cell leukemia; renal cell carcinoma; NHL; multiple myeloma Hepatitis B and C; condyloma acuminata

Stimulates the immune system against tumor cells; direct and indirect cytotoxic activity; increases expression of tumorassociated antigens

Flu-like syndrome: fever, malaise, chills, headaches; fatigue: often dose-limiting; anorexia and altered taste; increased liver function tests (transient); myelosuppression: mild leukopenia, thrombocytopenia; depression; vivid dreams or nightmares

Aldesleukin (interleukin-2, IL-2; Proleukin)b Renal cell cancer; melanoma

Stimulates growth, differentiation, and proliferation of activated T cells; generates lymphokineactivated killer cell activity and other killer cells; stimulates the immune system against tumor cells

Flu-like syndrome: fevers, chills, malaise; vascular or capillary leak syndrome: hypotension, pulmonary and peripheral edema; GI: moderately emetogenic, diarrhea; nephrotoxicity: partially due to hypotension or decreased renal perfusion; myelosuppression: thrombocytopenia, leukopenia, generally transient; cardiac: arrhythmias, reflex tachycardia; skin rash, flushing, itching, peeling, dryness; CNS: somnolence, confusion; bacterial infections common, especially staphylococcal

a

From Bradner78 and Border.79 From Kirkwood et al.80 CML, chronic myelogenous leukemia; CNS, central nervous system; KS, Kaposi’s sarcoma; NHL, non-Hodgkin’s lymphoma; NSAID, nonsteroidal anti-inflammatory drug. b

poisons. Although a few, such as methotrexate, capecitabine, and the immune therapies demonstrate some degree of selectivity for malignant cells, the selectivity is incomplete, and dose-limiting damage to normal cells also occurs. Recently anticancer research has focused on development of anticancer agents that target malignant cells more specifically, or the biochemical processes that control cancerous cell growth.

the “payload” of the fusion protein, however, its cytotoxic effects are directed toward cells that express the high-affinity form of the IL-2 receptor, such as cancer cells of some patients with cutaneous T-cell lymphoma. Once denileukin diftitox interacts with the IL-2 receptors, the toxin inhibits protein synthesis in the cancer cells and causes cell death.66 Although denileukin diftitox is directed therapy, its targeting of cells that express high-affinity IL-2 receptors is not specific; that is, these receptors are expressed on cells other than cancer cells. Denileukin diftitox produces acute hypersensitivity reactions, flu-like symptoms, sometimes with prominent diarrhea, and vascular-leak syndrome. It differs from the vascular-leak syndrome produced by high-dose IL-2 in that it occurs in fewer patients, is delayed in onset, is usually self-limited, and does not consistently recur on retreatment.81

DENILEUKIN DIFTITOX

ENDOCRINE THERAPIES

toxicities from IL-2 therapy reverse quickly once therapy is stopped, and can be managed or prevented by careful prospective monitoring and pharmacologic supportive care.81

BIOLOGICALLY DIRECTED THERAPIES 9 Most anticancer drugs are relatively indiscriminant cellular

L-asparaginase,

Denileukin diftitox (Ontak) is a recombinant fusion protein that combines the active sections of both IL-2 and diphtheria toxin. Unconjugated diphtheria toxin is much too toxic to administer to humans. As

10 Perhaps the earliest successful approach to target the growth

processes of cancerous cells was the use of endocrine therapies. Endocrine manipulation is an option for management of

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hormonal therapies in the treatment of cancer. Individual agents are described in Table 124–17.86−93 Corticosteroid hormones are also useful anticancer agents because of their lymphotoxic effects. Their primary use is in management of hematologic malignancies, especially lymphomas, lymphocytic leukemias, and multiple myeloma. In addition to their cytotoxic effects, corticosteroids have many other applications in

cancers from tissues whose growth is under gonadal hormonal control, especially breast, prostate, and endometrial cancers. These cancers may regress if the “feeding” hormone is eliminated or antagonized. Major organ system toxicity is uncommon from hormonal treatment, making it the least toxic of systemic anticancer therapies. Increasingly specific agents such as the selective estrogen receptor modulators (SERMs) and aromatase inhibitors have increased the utility of

TABLE 124–17. Endocrine Agents Commonly Used in Cancer Treatment Agent/Major Uses Antiandrogens Bicalutamide (Casodex)a Prostate cancer

Class/Mechanism

Major Side Effects

Nonsteroidal antiandrogen; androgen receptor antagonist; inhibits testosterone and dihydrotestosterone uptake and binding in prostate cells

Hot flashes; gynecomastia, breast tenderness; decreased libido; hepatotoxicity, elevated transaminases; diarrhea

Flutamide (Eulexin)a Prostate cancer

Nonsteroidal antiandrogen; androgen receptor antagonist; inhibits testosterone and dihydrotestosterone uptake and binding in prostate cells

Hot flashes; gynecomastia, breast tenderness, nipple pain; decreased libido; diarrhea; low emetogenic potential; mild transient elevations in liver transaminases

Nilutamide (Nilandron)a Prostate cancer

Nonsteroidal antiandrogen; androgen receptor antagonist; inhibits testosterone and dihydrotestosterone uptake and binding in prostate cells

Pulmonary: dyspnea; may cause interstitial pneumonitis (dyspnea on exertion, chest pain, fever) symptom onset in the first 3 months; hot flashes; gynecomastia; low emetogenic potential; testicular atrophy, decreased libido; hepatic toxicity: elevated transaminases; rare fatal hepatitis; visual disturbances: delayed adaptation to darkness, photophobia, cataracts; isolated cases of aplastic anemia reported; disulfiram-like reaction with alcohol

Nonsteroidal aromatase inhibitor; inhibits conversion of cholesterol to delta-5-pregnenolone; results in decreased synthesis of corticosteroid hormones (glucocorticoids, estrogens, and androgens); also blocks conversion of androgens to estrogens Selective, nonsteroidal aromatase inhibitor; inhibits conversion of androgens to estrogens

Adrenocorticoid suppression and insufficiency; skin rash, typically within the first week, usually self-limiting, disappears after 5–8 days, but may require discontinuation of therapy; lethargy, somnolence, dizziness; mild nausea, anorexia; leukopenia and agranulocytosis have been rarely reported Hot flashes; vasodilation, peripheral edema; weakness; arthralgias; elevated transaminases; hyperlipidemia; thrombosis less common than with tamoxifen

Antiestrogens Aminoglutethimide (Cytadren)b Breast cancer; prostate cancer

Anastrazole (Arimidex)c Breast cancer

Comments Monitor serum transaminases Drug interactions: may displace warfarin from protein binding sites, increasing anticoagulant effects Often used in combination with an LHRH agonist at initiation of therapy to prevent symptoms of tumor flare Use with caution in G6PD deficiency: may lead to methemoglobinemia Monitor serum transaminases Drug interactions: substrate of CYP450 1A2, CYP450 3A4; inhibits CYP450 1A2; may lead to increased warfarin anticoagulant effects Often used in combination with LHRH agonist at initiation of therapy to prevent symptoms of tumor flare Visual disturbances (impaired adaptation to darkness) may reverse with dose reduction; monitor serum transaminases; obtain chest x-ray if patient reports dyspnea; evidence of interstitial pneumonitis necessitates discontinuation of treatment Often used in combination with an LHRH agonist at initiation of therapy to prevent symptoms of tumor flare

Mineralocorticoid (fludrocortisone) and glucocorticoid (e.g., hydrocortisone 20–30 mg/day) replacement therapy may be required in as many as 50% of patients Salvage therapy for breast cancer and prostate cancer

Should not be used concurrently with tamoxifen; not indicated for premenopausal women or women with ER-negative tumors; used in postmenopausal women because peripheral conversion of adrenal androgens to estrogens is the primary source of estrogen; not used in premenopausal women because it does not interfere with production of ovarian estrogens

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TABLE 124–17. (Continued) Agent/Major Uses

Class/Mechanism

Major Side Effects

Comments

Exemestane (Aromasin)c Breast cancer

Irreversible steroidal aromatase inactivator; prevents conversion of androgens to estrogens by inhibiting the aromatase enzyme

Hot flashes; fatigue; depression, anxiety, insomnia; mild nausea, anorexia; edema; dyspnea; elevated transaminases

Fulvestrant (Faslodex)d Breast cancer

Antiestrogen; estrogen receptor antagonist; downregulates estrogen receptor protein in human breast cancer cells; no estrogen agonist properties

Hot flashes; low emetogenic potential; diarrhea, constipation, abdominal pain; headache; back pain and myalgia; pharyngitis; dizziness; insomnia; depression

Letrozole (Femara)e Breast cancer

Selective, nonsteroidal aromatase inhibitor; inhibits conversion of androgens

Hot flashes; arthralgias, myalgias; headache; fatigue; low emetogenic potential; dyspnea, cough; breast pain; hyperlipidemia; elevated transaminases

Megestrol acetate (Megace)f Breast cancer; endometrial cancer; cancer cachexia and anorexia; prostate cancer

Synthetic progestin with antiestrogen properties; interferes with normal estrogen cycle; may also have direct effects on the endometrium

Tamoxifen (Nolvadex)e Breast cancer

Nonsteroidal estrogen receptor antagonist; competitively binds to estrogen receptors on estrogen-dependent breast cells

Toremifene (Fareston)e Breast cancer; endometrial cancer; desmoid tumors

Nonsteroidal antiestrogen; estrogen receptor antagonist

Fluid retention and edema; weight gain; hot flashes; vaginal bleeding and spotting, amenorrhea and menstrual irregularities; decreased libido; breast tenderness; adrenal corticoid suppression and adrenal insufficiency; hepatotoxicity; thrombosis; photosensitivity Hot flashes; fluid retention; weight loss; mood swings, depression; bone pain, tumor pain; thrombosis; vaginal bleeding and spotting, vaginal discharge, menstrual irregularities, decreased libido; endometrial and uterine cancer; low emetogenic potential; hyperlipidemia; decreased visual acuity, retinopathy, corneal changes, cataracts; rash, photosensitivity; hepatotoxicity, elevated transaminases; thrombocytopenia Hot flashes; vaginal discharge or bleeding; low emetogenic potential; diaphoresis; thromboembolism; dizziness; hypercalcemia; dry eyes, visual acuity changes

Not indicated for premenopausal women Drug interactions: CYP450 3A4 substrate, but no significant interactions yet reported; St. John’s wort may decrease exemestane levels Food interactions: plasma levels increase when taken with a fatty meal; recommended to be taken after a meal Available in prefilled syringes for IM injection once a month IM injection should be administered into buttocks; should not be used in patients with thrombocytopenia or on anticoagulant therapy Not indicated for premenopausal or women with ER-negative tumors Not indicated for premenopausal women; emerging evidence supports the use of letrozole for 5 years following completion of 5 years of adjuvant tamoxifen to further prolong survival in postmenopausal women Drug interactions: substrate of CYP450 2A6 and 3A4; inhibits CYP450 2A6 and C19; potential for interactions with inhibitors or inducers of these enzymes as well as other substrates, but specific drug interactions have not been identified Suspension is compatible with water, apple juice, and orange juice High doses required for appetite stimulation

Breast cancer treatment or adjuvant therapy in ER-positive patients; preventive therapy in women at high risk for breast cancer Monitor patients closely for endometrial hyperplasia or cancer; monitor serum transaminases CYP450 substrate (CYP450 2A6, 2B6, 2C8/9, 2D6, 2E1, 3A4) and inhibitor (CYP450 3A4, 2B6, 2C8/9); significantly increases anticoagulant effects of warfarin

Hypercalcemia and tumor flare have been reported during the first weeks of treatment Drug interactions: substrate of CYP450 1A2, 3A4; enzyme inhibitors may increase toremifene blood levels; toremifene can increase anticoagulant effects of warfarin; anticonvulsants can decrease toremifene blood levels (continued )

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TABLE 124–17. (Continued) Agent/Major Uses LHRH Agonists Goserelin (Zoladex)g Prostate cancer; breast cancer

Leuprolide (Lupron, Lupron Depot, Eligard)g Prostate cancer; breast cancer

LHRH Antagonists Abarelix (Plenaxis)h Prostate cancer

Class/Mechanism

Major Side Effects

Comments

LHRH agonist; initially stimulates steroidogenesis by increasing levels of LH and FSH, but ultimately inhibits gonadotropin secretion with continuous administration by negative feedback mechanism; results in decreased testosterone and estrogen levels LHRH agonist; initially stimulates steroidogenesis by increasing levels of LH and FSH, but ultimately inhibits gonadotropin secretion with continuous administration by negative feedback mechanism; ultimately results in decreased testosterone and estrogen levels

Testicular atrophy, decreased libido, impotence; gynecomastia, breast tenderness; hot flashes; low emetogenic potential; depression, confusion; angina, CHF; thrombosis; elevated liver function tests; injection site reactions or abscess; hyperlipidemia; decreased bone density

Antiandrogens are coadministered during initial therapy to decrease symptoms of tumor flare (bone pain, urinary tract obstruction, or spinal cord compression) associated with the initial increase in serum testosterone levels Administered as a subcutaneous injection of implanted pellets every 1–3 months

Testicular atrophy, decreased libido, impotence; gynecomastia, breast tenderness; hot flashes; low emetogenic potential; depression, confusion; angina, CHF, thrombosis; elevated liver function tests; pain at injection site; hyperlipidemia; decreased bone density

Antiandrogens are coadministered during initial therapy to decrease symptoms of tumor flare (bone pain, urinary tract obstruction, or spinal cord compression) associated with the initial increase in serum testosterone levels Administered as IM injection every 1–4 months

GnRH antagonist; directly competes with GnRH receptors in pituitary, suppressing LH and FSH production, and reducing testosterone secretion by testes

Life-threatening hypersensitivity reactions, sometimes severe and immediate, limit use: urticaria, hypotension, syncope; reactions may occur after any dose; risk increases with cumulative dosing; hot flashes; breast enlargement or pain; can prolong QT interval

No initial surge in testosterone production, therefore no risk of tumor flare Observe patients for allergic reactions for at least 30 minutes after each dose Patients must sign consent before drug administration to confirm understanding of risks and benefits; risks limit use to men who require androgen suppression, cannot risk tumor flare, and refuse orchiectomy

a

From Jordan.86 From Plosker et al.84 c From Anonymous.85 d From Schally et al.88 e From Anonymous82 and Witzig et al.83 f From Osborne et al.87 g From Plosker et al84 and Jordan.86 h From Budzar et al.89 CBC, complete blood cell count; CHF, congestive heart failure; CYP450, cytochrome P450 isoenzyme; G6PD, glucose-6-phosphate dehydrogenase; ER, estrogen receptor; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; IM, intramuscular; LH, luteinizing hormone; LHRH, luteinizing-hormone releasing hormone. b

supportive care of cancer patients. Corticosteroids have diverse toxicities in chronic or high-dose use, but are generally well tolerated in the short-term therapies usually used in cancer patient care.94

RETINOIDS Vitamin A and its metabolites, collectively referred to as the retinoids, play important roles in numerous biologic processes, including normal cellular differentiation. Because cancerous growth is characterized by abnormal cellular differentiation, retinoids are proving to have important therapeutic roles in the treatment and perhaps in the prevention of cancers. Tretinoin (all-trans-retinoic acid) is a naturally occurring derivative of vitamin A (retinol). Other retinoids indicated for treatment of cancers include alitretinoin (9-cis-retinoic acid), available in gel form for topical management of Kaposi’s sarcoma lesions and bexarotene (Targretin) gel or capsules for treatment of cutaneous T-cell lymphoma (Table 124–18).95,96

Retinoids are classed as morphogens, small molecules released from one type of cells that can affect the growth and differentiation of neighboring cells. Their normal roles in the human body are to induce differentiation of some cells, stop the differentiation of others, and both suppress and induce apoptosis in different cell types. Their diverse actions come from the diversity of their receptors. The two classes of retinoid receptors are retinoid X receptors (RXRs) and retinoic acid receptors (RARs), each with α, β, and γ subclasses. RXRs are versatile; they bind to RARs and to other nuclear receptors such as thyroid hormone receptors. Once activated, the receptors act as transcription factors that in turn regulate the expression of genes that control cellular growth and differentiation.95 Tretinoin binds primarily to the RAR-α receptors. Alitretinoin is considered a panagonist; that is, it binds to all known retinoid receptors, producing diverse regulatory effects. Bexarotene is synthetic and is classed as a rexinoid. It is the first RXR-selective retinoid agonist. The exact mechanism of action of alitretinoin and bexarotene as anticancer agents is unknown.95,96

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TABLE 124–18. Biologically-Directed Therapies Agent/Major Uses Molecular targets Bexarotene (Targretin)a Cutaneous T-cell lymphoma

Bortezomib (PA-341, Velcade)b Multiple myeloma; prostate cancer

Gefitinib (Iressa)c NSCLC

Class/Mechanism Retinoid analog that may activate retinoid receptors

Boronic acid dipeptide that reversibly inhibits the proteosome; proteosomes are enzyme complexes in cells that degrade proteins that regulate cell-cycle progression; actions are mediated through inhibition of the degradation of NF-κB EGFR tyrosine kinase inhibitor; inhibits signal transduction pathways essential for tumor cell proliferation, differentiation, angiogenesis, and metastasis

Major Side Effects

Comments

Peripheral edema; insomnia, headache; fever, chills; lipid abnormalities, increased triglycerides, cholesterol, reduced high-density lipoproteins; hypothyroidism (reduced thyroxine, thyroid-stimulating hormone); diarrhea; low emetogenic potential; leukopenia and anemia; dry skin; increased liver function tests; pancreatitis Fatigue or malaise; nausea, diarrhea, anorexia, constipation, vomiting; low to moderate GI effects; myelosuppression, especially thrombocytopenia; hyponatremia, hypokalemia; peripheral neuropathy may be dose-limiting, cumulative, and dose-related, but reversible; fever Pulmonary toxicity: interstitial lung disease (ILD), symptoms of cough, dyspnea, and fever (∼1% overall incidence, but 1/3 of cases have been fatal); diarrhea; skin reactions: acne-like rash, dry skin, may require interruption of treatment; low emetogenic potential; hepatotoxicity; eye pain

Drug interactions: metabolized by CYP450 3A4, may interact with drugs that inhibit or induce this enzyme May cause hypoglycemia in patients receiving insulin, sulfonylureas, or metformin; contraindicated in pregnant women Limit vitamin A supplements

Imatinib mesylate (Gleevec, STI 571)d CML (adults and pediatrics); GIST; Ph + ALL

Tyrosine kinase inhibitor; relatively specific for the tyrosine kinase coded for by the bcr-abl translocation in CML patients

Moderate emetogenic potential: take with meals and a full glass of water; edema: periorbital edema is characteristic; pleural effusions, ascites, or pulmonary edema also occur; rash; diarrhea; neutropenia, thrombocytopenia (sometimes difficult to distinguish from CML-induced cytopenias); increased liver function tests

Tretinoin (All-trans-retinoic acid [ATRA], Vesenoid)e APL

Vitamin A derivative (retinoid); induces differentiation, maturation of immature promyelocytic cells

Headache is most common side effect; severe headache may be sign of pseudotumor cerebri (intracranial hypertension); “ATRA syndrome”: pulmonary symptoms (dyspnea, respiratory distress, fever, pleural effusions); low emetogenic potential; dry skin and mucous membranes, mucositis; bone pain; transient elevations in transaminases, bilirubin

First proteosome inhibitor; administered as rapid IV bolus twice weekly for 2 weeks in 21-day cycle Increased risk of severe neuropathy in patients with pre-existing neuropathy

Therapy should be interrupted if patients develop symptoms of ILD and drug should be discontinued if ILD is confirmed Patients with symptoms of eye pain should be evaluated for aberrant eyelash growth Drug interactions: metabolized by CYP450 3A4, gefitinib effects may be decreased by CYP450 3A4 inducers (e.g., rifampin, phenytoin) and increased by CYP450 3A4 inhibitors (e.g., ketoconazole, voriconazole); major interaction with warfarin leading to increased anticoagulant effects and increased bleeding risk; histamine-2 blockers may decrease gefitinib levels Metabolized primarily by CYP450 3A4; competitive inhibitor of CYP450 3A4, 2C9, and 2D6, so beware of drug interactions; may increase warfarin effects Dose reductions should be considered for liver dysfunction and myelosuppression per manufacturer recommendations Usual dose: 400 mg orally per day; cost ∼$2,400 per month Headaches are usually manageable with mild analgesics; ATRA syndrome treated with corticosteroid administration (initiate when WBC ≥10,000) and/or holding ATRA until symptoms resolve; bone pain typically responds to mild analgesics; teratogenic: contraindicated in pregnancy; female patients should be educated about proper contraceptive measures Give daily dose orally in two divided doses; round to nearest 10 mg (available only as 10 mg capsules) (continued )

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TABLE 124–18. (Continued) Agent/Major Uses

Class/Mechanism

Major Side Effects

Comments

Anti-CD52 monoclonal antibody, results in antibody-dependent lysis of CD52+ B and T lymphocytes

Myelosuppression and immunosuppression; infection; infusion-related nausea and vomiting; fever; hypotension; rash; headache; fatigue

Bevacizumab (Avastin)g Colorectal cancer; renal cell carcinoma

Recombinant humanized MoAB; binds to vascular endothelial growth factor to prevent it from binding to its receptors; this inhibits new vessel formation (angiogenesis)

Most serious adverse effect (2% incidence, idiosyncratic) is GI bleeding or perforation, sometimes with intra-abdominal abscess formation; impaired wound healing; hypertension; proteinuria; rare severe pulmonary hemorrhage

Cetuximab (Erbitux)h Colorectal cancer

Recombinant human/mouse MoAB that binds to the EGFR and inhibits the binding of EGFR and other growth factors; EGFR is overexpressed in some solid tumors such as colorectal cancer; cetuximab inhibits cell cycle progression; induces apoptosis; may enhance the effects of some chemotherapy agents and radiation Humanized anti-CD33 antibody linked to calicheamicin, a potent toxin; binding to the CD33 receptor results in internalization of the antibody-antigen complex; calicheamicin is then released intracellularly and exerts cytotoxicity by causing DNA double-strand breaks, resulting in cell death Anti-CD20 MoAB linked to radioactive yttrium (Y90 ); murine version of the rituximab antibody; monoclonal antibody to CD20 (a B-lymphocyte surface antigen)–positive cells; binds complement and increases antibody dependent cellular cytotoxicity; radioactive linkage delivers radiation dose directly to tumor cells to decrease damage to normal cells Monoclonal antibody that reacts with CD20 (a B-lymphocyte surface antigen)–positive cells; binds complement and increases antibody dependent cellular cytotoxicity

Acne-like rash in most patients, sometimes severe, on face and upper torso, onset in 1–3 weeks, may improve with continued treatment, reversible; paronychial cracking in fingers or toes, may take several months to heal; asthenia; abdominal pain, nausea, constipation, diarrhea; infusion and hypersensitivity reactions

Patients should be started on antiviral and PCP prophylaxis during and 6 months posttreatment; some evidence suggests that subcutaneous administration may be associated with less acute toxicity Presenting symptoms of GI bleeding or perforation: abdominal pain, nausea, vomiting, and constipation; risk not correlated with duration of therapy; treat hypertension with standard antihypertensives; avoid within 28 days after major surgery; suspend treatment before elective surgery Acne-like rash is poorly responsive to standard acne treatments; dose reductions may be required; skin rash may correlate with response; premedicate with antihistamine; medical resources for the treatment of severe infusion reactions should be available; reduce infusion rate for mild to moderate infusion reactions, discontinue infusion for severe toxicity Premedicate with acetaminophen 1000 mg and diphenhydramine 50 mg; requires 4–8 hours of observation postinfusion; lightsensitive Requires preparation in darkened hood and light protective bag for administration

Monoclonal antibodies Alemtuzumab (Campath)f B-cell CLL

Gemtuzumab ozogamicin (Mylotarg)i CD33+ ANLL

Ibrotumomab tiuxetan (Zevalin)j NHL (low-grade CD20+ )

Rituximab (Rituxan)k Low-grade NHL; CLL; intermediate-grade NHL Idiopathic thrombocytopenic purpura; rheumatoid arthritis

Infusion reactions: fevers, chills, nausea, vomiting, hypotension, dyspnea; myelosuppression may be severe and prolonged; tumor lysis syndrome: WBCs should be reduced to 3 months; nausea, vomiting, abdominal pain (within days), diarrhea (within days to weeks after infusion); infusion reactions: fever, rigors, chills, sweating, hypotension, dyspnea, bronchospasm; anaphylaxis may occur; premedicate; hypothyroidism: all patients must receive thyroid-blocking agents; asthenia, myalgias, arthralgias; cough; rash

Trastuzumab (Herceptin)m Breast cancer; prostate cancer; pancreatic cancer; lung cancer; ovarian cancer

MoAB directed against HER2 receptors, overexpressed in some breast cancer patients and related to epidermal growth factor

Cardiac toxicity: congestive cardiomyopathy, usually reversible with medical management; infusion reactions

Radiopharmaceutical, to be prepared and administered only by personnel trained in radiopharmaceuticals; premedicate with acetaminophen and antihistamines; slow infusion rate or interrupt infusion for infusion reactions; medications for treatment of hypersensitivity reactions should be available for immediate use; avoid in pregnant females; may cause hypothyroidism in fetus; two-step administration; MoAB and low radioisotope dose is followed after 1–2 weeks by MoAB and therapeutic radioisotope dose; renally excreted; impaired renal function may increase exposure to radioactive components; patients must be trained in precautions to decrease radiation exposure to family, friends, and general public Do not administer with anthracyclines; best response seen in patients highly positive for HER2 overexpression

a

From McCarty et al91 and McKeage et al.92 From Peng et al99 and Croom et al.100 c From Anonymous,93 Heinrich et al,97 and Druker.98 d From Anonymous,93 McKay et al,94 Sporn et al,95 and Duvic et al.96 e From McCarty et al.91 f From Ekmekcioglu et al81 and Giaccone et al.102 g From Richardson et al,103 Mitchell,104 and Harris.105 h From Harris,105 Frampton et al,106 and Miller et al.107 i From Ekmekcioglu et al,81 Hurwitz et al,108 and Anonymous.109 j From Reynolds et al110 and Saltz et al.111 k From Ekmekcioglu et al81 and Giles et al.112 l From Ekmekcioglu et al81 and Larson et al.113 m From Ekmekcioglu et al,81 Vogel et al,114 and Perez et al.115 ANLL, acute nonlymphocytic leukemia; APL, acute promyelocytic leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; EGFR, epidermal growth factor receptor; GIST, gastrointestinal stromal tumor; MoAB, monoclonal antibody; NF-κB, nuclear factor-κB; Ph+ ALL, Philadelphia chromosome–positive acute lymphocytic leukemia; PCP, Pneumocystis carinii pneumonia; WBC, white blood cell. b

TYROSINE KINASE INHIBITORS Imatinib Imatinib mesylate was the first tyrosine kinase inhibitor to be approved for treatment of cancer (see Table 124–18). It inhibits deregulated bcr-abl tyrosine kinase, the molecular abnormality in patients with chronic myelogenous leukemia that results from the characteristic “Philadelphia chromosome” translocation. The deregulated tyrosine kinase constantly drives leukemic cell proliferation. Imatinib inhibits cell proliferation and induces apoptosis in the Philadelphia chromosome–positive cells. It is relatively, but not completely, selective for these cells.97−100

Gefitinib Gefitinib is a selective inhibitor of epidermal growth factor receptor [EGFR] tyrosine kinase (see Table 124–18). EGFR is a cell surface receptor expressed or overexpressed in many solid tumors. When ligand binds to the EGFR receptor, tyrosine kinase activity initiates a cascade of signaling events within the cancer cells that stimulates their proliferation and promotes their survival. Gefitinib inhibits EGFR ac-

tivity by competing with adenosine triphosphate for its binding site on the EGFR tyrosine kinase. This blocks the tyrosine kinase cascade of downstream signaling, and ultimately interferes with the proliferation and growth of cancer cells. It is orally administered and well tolerated, most commonly producing diarrhea and mild skin rashes.97,101,102

PROTEOSOME INHIBITORS Proteosomes are protein complexes within cells that are responsible for degrading and eliminating cellular proteins. Some of the proteins that are degraded by proteosomes are proteins that regulate critical functions for successful cancer growth, such as regulation of the cell cycle, transcription factors, apoptosis, angiogenesis, and cell adhesion.103,104 One proteosome inhibitor, bortezomib, is commercially available (see Table 124–18). Bortezomib has very specific affinity for the catalytic portion of the proteosome. It can induce apoptosis in cancer cells indirectly. Although many actions may contribute to its effects, one pathway of action is well established. Bortezomib interferes with degradation of the inhibitory partner protein of a transcription factor, nuclear factor-κB [NF-κB]. NF-κB induces

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transcription of genes that block cell death pathways and promote cell proliferation, but in order for it to do so, NF-κB must be released from its inhibitory partner protein in the cytoplasm and move to the nucleus. When NF-κB’s partner protein fails to degrade, through the actions of bortezomib, NF-κB is held in the cytoplasm and prevented from transcribing the genes that promote cancer growth. Bortezomib is approved for the treatment of patients with multiple myeloma.103,104

MONOCLONAL ANTIBODIES 9 The monoclonal antibodies have become established agents in

the treatment of cancer. Monoclonal antibodies (MoABs) consist of immunoglobulin sequences that are known to recognize a specific antigen or protein on the surface of cells. There are several mechanisms by which monoclonal antibodies may induce death of cancer cells. Direct mechanisms include induction of apoptosis, blockade of growth factor receptors, or induction of anti-idiotype antibodies. Important indirect mechanisms include antibody-dependent cellular toxicity and complement-mediated cellular toxicity.66,105 Antibodies may also be carriers for cytotoxic drugs or toxins (i.e., immunoconjugates) that are targeted by the antibody directly to the antigen-bearing cancer cells. Once the antibody binds to its cellular surface receptor, the complex can be internalized, and the toxic “payload” liberated into the cytoplasm to cause cell damage. MoABs can also serve as carriers for radioisotopes. Delivery of radiation therapy in this manner is called radioimmunotherapy. Drug and toxin conjugates kill only the targeted cell, but radiation delivered via MoAB is less narrowly targeted. Depending on the penetration of the radioisotope through tissue, the radiation can also damage nearby cells that do not express the targeted antigen.66,105 Table 124–18 summarizes the characteristics and clinical uses of monoclonal antibodies.82−85,106−115 Several limitations affect the success and specificity of treatment with MoABs. Although monoclonal antibodies are designed to be specific to a particular target antigen, that target antigen may also be expressed on normal tissues to some degree, decreasing their selectivity. Thus toxicity often occurs when the monoclonal antibodies bind to normal cells, or are recognized by the immune system. All of the monoclonal antibodies are also associated with some degree of infusionrelated reactions. The severity of these reactions can range from mild (e.g., fever, chills, nausea, and rash) to severe, life-threatening anaphylaxis with cardiopulmonary collapse. Many patients also experience chest or back pain during the infusion. Patients with circulating tumor cells in the bloodstream are at highest risk for more severe reactions. For these reasons, patients must be monitored closely during drug infusion. The reactions tend to be more severe with the initial infusion, and subside with subsequent treatment. Most agents require premedication with antihistamines and acetaminophen. Recommended infusion rates are usually lower for the initial dose, with incremental increases as tolerated by the patient. For patients experiencing signs or symptoms of infusion-related reactions, the infusion should be interrupted and prompt treatment with antihistamines, corticosteroids, and other supportive measures should be initiated. Pulmonary toxicity may occur as part of the infusion-related reaction or may occur as a distinct entity.66,82−86,105−115

ANGIOGENESIS INHIBITORS

develop new blood vessels by means of antiangiogenic drugs can limit or prevent tumor growth.107 There are many potential means of interfering with angiogenesis. Examples are targeting vascular growth factors, or the production and control of the endothelial cells that make up the vessel linings. Most antiangiogenic drugs are cytostatic rather than truly cytotoxic, since they prevent new vessel growth and thus cause growth delay of the tumors. Some vascular targeting agents, however, can destroy existing blood vessels. These could be cytotoxic.107,116 Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), a growth factor that regulates proliferation and permeability of blood vessels (see Table 124–18). VEGF acts through two receptors. Bevacizumab inhibits the signaling process for new blood vessels by binding VEGF ligand to prevent it from interacting with its receptors. It was approved in 2004 for treatment of patients with colorectal cancer.107−109

THALIDOMIDE Thalidomide, the infamous drug that caused severe limb deformities (phocomelia or “seal limbs”) when used by pregnant women as an over-the-counter sedative in the 1960s, is approved for treatment of leprosy and has orphan drug status for multiple myeloma. It also has documented clinical activity in several other types of cancer. Thalidomide is a glutamic acid derivative, and is broadly classed as an immunomodulatory agent. It has many potential mechanisms of action as an anticancer agent. It is an angiogenesis inhibitor, interfering with the growth of new blood vessels needed for tumor growth. This action is also linked to its teratogenic effects. Other possible mechanisms include: direct inhibition of cancer cells, free-radical oxidative damage to DNA, interfering with adhesion of cancer cells, inhibiting tumor necrosis factor-α production, or altering secretion of cytokines that affect the growth of cancer cells. Great care must be taken to prevent thalidomide’s use during pregnancy.107,116,117

GENERAL SUPPORTIVE CARE ISSUES The treatment of cancer with most antineoplastic drugs is complicated by the risk of multiple serious toxicities, many of which are life threatening. Drug-specific toxicities, such as doxorubicin-induced cardiotoxicity and bleomycin-related pulmonary toxicity, were summarized in the previous section (see Tables 124–11 through 124–18). Several adverse effects are common to many antineoplastic agents. These include nausea and vomiting, myelosuppression, mucositis, alopecia, infertility, and carcinogenesis. Nutritional support and pain management are also important supportive care issues, although malnutrition and pain are not usually direct results of drug toxicity. The management of chemotherapy-induced nausea and vomiting and the basic principles of nutritional support and pain management are discussed in detail in other sections of this text. Because many antineoplastic drugs affect DNA synthesis, any cell with a high turnover rate will be more sensitive to the toxic effects of chemotherapy. Cancer cells do not necessarily proliferate faster than normal cells. Normal tissues that consist of rapidly proliferating cells are targets for the toxicities of many anticancer drugs.14 The bone marrow, intestinal mucosa, and hair follicles are such tissue sites where drug effects are manifested.

11 Angiogenesis refers to the development of new capillaries to

increase vascular supply of tissue. Although angiogenesis is a normal function, and is essential to wound healing, reproduction, and growth, it is also central to the successful growth of tumor masses. Tumors need blood supply to grow. Interference with their ability to

MYELOSUPPRESSION 12 Although not seen with all antineoplastic agents, myelosuppres-

sion is the most common dose-limiting side effect of cytotoxic

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agents. Bone marrow suppression does not usually occur immediately after chemotherapy administration. Blood components that have already been produced must be consumed before the effect is evident. White blood cells (WBCs), especially neutrophil precursors, are most significantly affected because of their rapid proliferation and short life-span (6 to 12 hours). Platelets (5- to 10-day life-span) are also affected, but to a much less degree than neutrophils. Erythrocytes, with a 120-day life-span, are affected the least. Usual nadirs, or lowest blood cell counts, occur at 10 to 14 days following chemotherapy administration, with recovery by 3 to 4 weeks. There are some exceptions to this general rule. The nitrosoureas and mitomycin C exhibit a delayed pattern of nadir (4 to 6 weeks) and recovery (6 to 8 weeks). Planned courses of chemotherapy may have to be delayed while waiting for the granulocyte count to return to normal. For a patient to safely receive another cycle of myelosuppressive chemotherapy, a WBC count ≥3,000/mm3 or an absolute neutrophil count (ANC) of ≥1,500/mm3 and a platelet count of ≥100,000/mm3 are usually required. Myelotoxicity is a desired therapeutic effect in leukemia patients during induction chemotherapy. However, myelosuppression is an undesirable side effect during chemotherapy for other malignancies. If significant myelosuppression has occurred with prior courses of chemotherapy, the doses of the offending agent(s) in subsequent courses may be reduced. The magnitude of dose reduction is dictated by the degree of myelosuppression incurred and the incidence and severity of infection or bleeding. Empiric dosage reductions may be made for the first chemotherapy treatment if the patient has a low baseline WBC or platelet count, has diminished bone marrow reserve, has impaired drug-elimination capabilities, or is to receive a combination of several drugs that cause myelosuppression. Patients who have received multiple prior courses of other myelotoxic chemotherapy regimens or extensive radiation therapy, especially to the pelvis, may have a decreased bone marrow reserve. They are more sensitive to the myelosuppressive effects of chemotherapy, and normal doses may produce profound marrow toxicity. The pharmacokinetic profile of a myelosuppressive agent is also important in determining the appropriate dose. For example, the anthracyclines produce bone marrow suppression as an acute dose-limiting toxicity, and these agents depend on biliary excretion as their primary route of elimination. A patient with biliary obstruction may have compromised elimination of anthracyclines and is at increased risk for severe bone marrow suppression. Although dosage reduction can prevent myelotoxicity, it may also compromise antitumor response for some tumors (e.g., breast cancer or lymphoma). For such tumors, empiric use of hematopoietic growth factors provides an alternative to dose reduction in patients at high risk for toxicity.

NEUTROPENIA 3 12 When the ANC falls below 500/mm , infection risk in-

creases.118−120 The ANC may be calculated by multiplying the percentage of neutrophils (segmented plus banded neutrophils) by the total WBC count. The risk of infection is also directly proportional to the duration of neutropenia. Other risk factors for infection include alteration in the integrity of physical defense barriers and the functional integrity of WBCs. The patient’s underlying cancer, as well as treatment with cytotoxic drugs and radiation, can affect neutrophil function. The diagnosis of infection in the neutropenic patient is complicated by the lack of WBCs. Usual signs and symptoms of infection, such as pus, abscesses, and infiltrates on chest x-ray, depend on the presence of WBCs. The only reliable indication of infection in these patients is fever. Definitive culture results may take days, and a septic neutropenic cancer patient can die within hours if not treated. Therefore the basic approach to the manage-

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ment of the febrile neutropenic cancer patient is prompt initiation of empiric antibiotics. The antibiotics are chosen based on reliable coverage of the most likely organisms, antibiotic sensitivities at the institution, the patient’s signs and symptoms (if present), side-effect profiles, and cost.120 The most common source of infection in these patients is self-infection with body flora, which includes both grampositive and gram-negative bacteria. Although bacteria cause most early infections, fungi become important pathogens as the course of neutropenia is prolonged. Traditionally, all febrile neutropenic cancer patients have received intravenous antibiotics in the hospital setting until full recovery of neutrophils. However, it is possible to identify patients at low risk for infectious complications who are candidates for alternative treatment strategies, including early discharge from the hospital and outpatient oral or intravenous antibiotics.120,121 Specific treatment of infections in immunocompromised hosts is discussed elsewhere in this text. Numerous methods have been explored to prevent infections in cancer patients.120,122 Colony-stimulating factors (CSFs) are commonly employed for this purpose.122−124 These hormones are naturally occurring proteins that are essential for the normal growth and maturation of blood cell components (Fig. 124–13). The CSFs have the ability to enhance the production and also the function of their target cells. Two agents, G-CSF (granulocyte colony-stimulating factor) and GM-CSF (granulocyte-macrophage colony-stimulating factor) are commercially available in the United States. G-CSF (filgrastim) specifically stimulates the production of neutrophilic granulocytes. GM-CSF (sargramostim) promotes the proliferation of granulocytes (neutrophils and eosinophils) and monocytes/macrophages. Although GM-CSF stimulates megakaryocytes, no consistent effect on platelet production has been observed in clinical trials. Both agents initially enhance demargination and mobilization of mature cells from the marrow and then provide constant stimulation of stem cell progenitors. Colony-stimulating factors are produced by recombinant DNA technology, and several host cells are used to produce CSFs, including bacteria (Escherichia coli), yeast, and mammalian cells (Chinese hamster ovary cells) (Table 124–19). Products derived from yeast or mammalian sources are glycosylated to varying degrees, as are naturally occurring CSFs, whereas those derived from E. coli are nonglycosylated. This difference does not result in any clinically significant effects on neutrophil production. Pegfilgrastim is a longacting CSF, created by addition of a polyethylene glycol molecule to G-CSF. Clinical trials have demonstrated that a single dose of pegfilgrastim provides equivalent effects to 10 to 11 days of daily G-CSF, with similar side-effect profiles. The CSFs reduce the incidence, magnitude, and duration of neutropenia when used as preventive therapy following a variety of myelosuppressive chemotherapy regimens.122−124 These effects have been accompanied by a modest decrease in febrile days, fewer infections, and fewer days on antibiotics. In some studies, use of CSFs also resulted in a decrease in the incidence of mucositis. Growth factors have also permitted the administration of subsequent chemotherapy courses on schedule, resulting in enhanced dose intensity. However, the increased dose intensity provided by the CSFs has not yet been found to translate into improved tumor response or survival. Because of lack of impact on response rates and survival, decisions regarding appropriate use of growth factors are based on weighing proven clinical benefits against economic considerations. The American Society of Clinical Oncology has developed evidence-based clinical practice guidelines to promote appropriate use of the CSFs.123−124 Growth factors may be used in either the primary or secondary prophylaxis of neutropenia. Primary prophylaxis refers to the use of CSFs to prevent neutropenia with the first cycle of chemotherapy. This strategy is only clinically and economically appropriate for

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FIGURE 124–13. Sites of action of hematopoietic growth factors in the differentiation and maturation of marrow cell lines. A selfsustaining pool of marrow stem cells differentiates under the influence of specific hematopoietic growth factors to form a variety of hematopoietic and lymphopoietic cells. Stem cell factor (SCF), FTL-3 ligand (FL), interleukin-3 (IL-3), and granulocyte/macrophage colonystimulating factor (GM-CSF), together with cell– cell interactions in the marrow, stimulate stem cells to form a series of burst-forming units (BFU) and colony-forming units (CFU): CFUGEMM, CFU-GM, CFU-Meg, BFU-E, and CFU-E (GEMM, granulocyte, erythrocyte, monocyte, and megakaryocytes; GM, granulocyte and macrophage; Meg, megakaryocyte; E, erythrocyte). After considerable proliferation, further differentiation is stimulated by synergistic interactions with growth factors for each of the major cell lines—granulocyte colony-stimulating factor (G-CSF), monocyte/macrophage-stimulating factor (M-CSF), thrombopoietin, and erythropoietin. Each of these factors also influences the proliferation, maturation, and, in some cases, the function of the derivative cell line. (Adapted from Hillman RS. Hematopoietic agents: Growth factors, minerals and vitamins. In: Hardman JG, Limbird LE, Gilman AG, eds. Goodman & Gilman’s The Pharmacologic Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001:1489.)

ERYTHROPOIETIN GM-CSF / IL-3

BFU-E/CFU-E

SCF / FL

Red blood cells

Totipotent/pluripotent stem cells

GM-CSF / G-CSF Granulocytes Eosinophils

CFU-GM

Basophils

CFU-GEMM

GM-CSF / M-CSF

Monocytes

CFU-Meg

Lymphocyte Progenitor B cells

NK cells

Platelets

T cells Megakaryocyte IL-1 / IL-2 / IL-3 / IL-4 / IL-6 IL-6 / IL-11 / THROMBOPOIETIN

patients who are receiving a chemotherapy regimen associated with febrile neutropenia in more than 40% of patients.124 Models to predict the likelihood of developing neutropenia after chemotherapy are under development, and if validated, may serve to identify patients most likely to benefit from primary prophylaxis.125 Secondary prophylaxis refers to the use of growth factors to prevent recurrent neutropenia in patients who experienced neutropenia with the prior cycle of chemotherapy. Because this method of using CSFs has not been demonstrated to improve disease-free or overall survival, it is recommended that secondary prophylaxis be reserved for patients with curable malignancies where dose should not be compromised.124 Although both G-CSF and GM-CSF are used clinically to prevent febrile neutropenia after administration of standard doses of chemotherapy, only G-CSF is FDA-approved for this indication. One exception is in the induction treatment of acute myelogenous leukemia, in which both G-CSF and GM-CSF have been demonstrated to reduce the duration of neutropenia, often accompanied by modest decreases in hospitalization and infectious complications. Benefits

have been most clearly documented in patients older than age 55 years. Similar data are available for G-CSF in the treatment of patients with acute lymphoblastic leukemia. These beneficial effects, however, have not resulted in improved response rates or overall survival.124 Only a few studies have addressed the role of CSFs in the treatment of established neutropenia.123,124 These studies suggest no or only minimal clinical benefit from use of CSFs. At this time, the CSFs should not be routinely employed in patients with established neutropenia, regardless of the presence of fever. Both CSFs have also proven effective in acceleration of hematopoietic engraftment and in treatment of graft failure following hematopoietic stem cell transplantation. Other uses for the CSFs include peripheral blood stem cell mobilization, neutropenia in patients with acquired immune deficiency syndrome, myelodysplastic syndromes, congenital neutropenia, and aplastic anemia. Growth factors should not be used in patients receiving concomitant chemotherapy and radiotherapy, especially if the radiation involves the mediastinum. These patients appear to experience more significant thrombocytopenia when administered CSFs.

TABLE 124–19. Granulocyte Colony-Stimulating Factor (G-CSF) and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Products and Sources CSF

Generic Name

Brand Name

Manufacturer

G-CSF

Filgrastim Pegfilgrastim Lenograstim Sargramostim Molgramostim

Neupogen Neulasta Granocytea Leukine Leucomaxa

Amgen Amgen Chugai/Rhone Poulenc Berlex Novartis/Schering-Plough

GM-CSF a

Not approved by the FDA; available outside the U.S.

Recombinant DNA Source Escherichia coli Chinese hamster ovary cells Saccharomyces cerevisiae (yeast) E. coli

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At currently recommended doses, the CSFs are well tolerated. Side effects are more commonly seen with GM-CSF and may be related to the drug’s ability to enhance binding of neutrophils to endothelial cells or to activation of monocytes/macrophages, which may stimulate the release of cytokines such as IL-1 and tumor necrosis factor.122 The most common toxicity of the CSFs is bone pain (20% to 25% of patients), which can be treated with acetaminophen or nonsteroidal anti-inflammatory drugs. Bone pain was the most significant toxicity seen in clinical trials with G-CSF. Other side effects of G-CSF include an increase in lactate dehydrogenase, alkaline phosphatase, and uric acid levels. Additional toxicities of GM-CSF include constitutional symptoms, such as low-grade fever, myalgias, arthralgias, lethargy, and mild headache. GM-CSF may also produce an elevation in liver transaminases. At higher doses of GM-CSF, pleural and pericardial effusions, capillary-leak syndrome, and thrombus formation may occur. A first-dose reaction described after GM-CSF administration has been reported more commonly with the E. coli–derived product (molgramostim), which is not commercially available in the United States. This reaction is more common after intravenous infusion and consists of dyspnea, facial flushing, hypotension, hypoxia, and tachycardia. Both G-CSF and GM-CSF may produce mild erythema at subcutaneous injection sites, as well as a generalized maculopapular rash with either subcutaneous or intravenous administration. For prophylaxis of chemotherapy-induced neutropenia, CSF therapy should not begin sooner than 24 hours after the last dose of chemotherapy and should be continued until the ANC exceeds a safe level following the expected chemotherapy nadir. In the setting of bone marrow transplantation, CSFs should not begin sooner than 24 hours after the last dose of chemotherapy or 12 hours after the last radiotherapy treatment. The recommended starting dose of G-CSF is 5 mcg/ kg per day in all settings except for peripheral blood stem cell mobilization, where doses of 10 mcg/kg per day are usually used. For pegfilgrastim, a single dose of 6 mg administered 24 hours after chemotherapy is used. The recommended dose of yeast-derived GM-CSF is 250 mcg/m2 per day. Pharmacokinetic data favor subcutaneous injection as the most effective route. However, in patients in whom subcutaneous injections are not feasible (e.g., where there is anasarca), G-CSF and GM-CSF may be given intravenously. Pegfilgrastim should not be given intravenously. Because of the high cost associated with CSF use, alternative dosing regimens have been explored. These regimens attempt to decrease the total amount of CSF used by either delaying the start of CSFs (e.g., to day 3 after chemotherapy), decreasing the dose (e.g., to 3 mcg/kg per day of G-CSF), or decreasing the duration of CSF therapy. Specifically, the posttreatment target ANC of 10,000/mm3 recommended by product information is often reduced to an ANC of greater than 2,000 or 5,000/mm3 in clinical practice. Standardized doses of 300 mcg or 480 mcg of G-CSF and 500 mcg of GM-CSF, based on product vial sizes, are often used to minimize waste. For patients receiving pegfilgrastim, it is important that additional CSF not be administered for the 10 days following administration, as additional benefit is not realized.

THROMBOCYTOPENIA Chemotherapy-induced thrombocytopenia puts the patient at risk for significant bleeding. To date, platelet transfusions remain the mainstay of management.126 At most centers, platelet transfusion is indicated for patients with a platelet count of 12 g/dL discontinue therapy and resume at 75% dose when hemoglobin ≤12 g/dL

Titrate dosage to maintain optimal hemoglobin (12 g/dL)

Hb rise ≥1.0 g/dL

Asymptomatic Risk factors present

Asymptomatic No risk factors present

Observation and periodic re-evaluation

FIGURE 124–14. 2004 National Comprehensive Cancer Network clinical practice guidelines for cancer and treatment-related anemia.

Discontinue epoetin alfa or darbepoetin alfa

Hb rise 30%) with LCIS, and the opposite breast is affected in up to 50% of patients. It is unclear whether LCIS proceeds to invasive carcinoma or serves as a marker for a high probability of invasive carcinoma developing elsewhere in the breast. Thus the management of LCIS is very controversial. Some experts favor a program of breast examination, periodic physician examination, and mammography as management of LCIS. In selected patients who are particularly anxious about the development of cancer, bilateral total mastectomies and prompt reconstruction represent a reasonable approach. Radiation and systemic chemotherapy has no role in the management of LCIS. Patients with LCIS were included in the Tamoxifen Chemoprevention Trial and thus patients with LCIS should be offered tamoxifen as a preventive strategy.

PROGNOSTIC FACTORS The natural history of breast cancer varies between patients, with some having an extremely aggressive disease that progresses rapidly, whereas others follow a more indolent course. The ability to predict which patients have a better disease prognosis is extremely important in designing treatment recommendations to maximize quantity and quality of life. A number of potential pathologic prognostic and predictive factors have been identified. Prognostic factors are measurements available at diagnosis or time of surgery, that in the absence of adjuvant therapy are associated with recurrence rate, death rate, or other clinical outcome. Predictive factors are measurements available at diagnosis that are associated with the response to a specific therapy. Prognostic and predictive factors fall into three categories: patient characteristics that are independent of the disease such as age; disease characteristics such as tumor size or histologic type; and biomarkers that are measurable parameters in tissues, cells, or fluids, such as hormone receptor status. The median age for the diagnosis of breast cancer is between the ages of 60 and 65 years.2 Younger women, particularly women younger than 35 years of age, have a more aggressive form of the disease, and elderly women, particularly those older than 70 years of age with breast cancer, frequently have hormone receptor protein in their malignant tissue, suggesting a more indolent tumor pattern and a higher likelihood of response to hormonal therapy. Race appears to be prognostic but not predictive. Black breast cancer patients are generally younger and often have larger tumors at diagnosis, and a smaller percentage have hormone receptors in their tumor tissue. These factors contribute to a poorer prognosis. It should be emphasized that for both age and race, in cases of similar clinical presentation, adjuvant treatment confers similar benefits to black and white women. Tumor size and the presence and number of involved axillary lymph nodes are established primary factors in assessing the risk for breast cancer recurrence and subsequent metastatic disease. Table 125–5 shows the 5-year relapse rate according to size of the primary tumor and axillary node involvement from results of three investigations.43−45 These data clearly demonstrate that the major factor that influences the likelihood of recurrence is the presence of positive axillary nodes. But regardless of axillary node studies, the size of the primary tumor remains an independent prognostic factor for disease recurrence. In axillary node–negative patients, a tumor size of less than 2 cm is associated with a very favorable prognosis. However, there does not appear to be a large difference between prognosis in patients with large (>5 cm) tumors and negative nodes, as

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5

12 13 8

24 19 24

27 25 19

50 39 37

60 50 64

79 65 74

compared to patients with 2- to 5-cm tumors and negative nodes. Thus the size of the primary tumor in patients with negative axillary lymph nodes may not provide as much information regarding prognosis as in node-positive patients. The number of affected nodes is directly related to disease recurrence. The recently revised staging system for breast cancer differs from the 1988 version in that it recognizes the absolute number of positive nodes as a prognostic factor, with N1 representing one to three positive nodes, N2 representing four to nine positive nodes, and N3 representing ten or more positive nodes in its pathologic staging system.44 In addition, metastases to ipsilateral internal mammary and supraclavicular nodes are noted as N2 and N3 , respectively (if detected macroscopically, but N1 if detected only by microscopy), compared to axillary lymph node metastases alone, which are designated N1 . Although determination of the number of involved axillary nodes by hematoxylin and eosin staining is still the preferred technique, identifiers have been added to indicate the use of sentinel lymph node dissection and use of immunohistochemical and molecular techniques (microscopic vs. macroscopic) to determine presence of metastases. Aside from the tumor-node-metastasis (TNM) stage of the disease, hormone receptor studies have received the most attention in the characterization of primary breast cancer. Hormone receptors are used clinically as indicators of prognosis and to predict response to hormone therapy. Hormone receptors are cytoplasmic proteins that transmit signals to the nucleus of the cell for growth and proliferation. The hormone receptors clinically useful in discussions of breast cancer include the estrogen receptor (ER) and the progesterone receptor (PR). The presence of these proteins in the primary tumor (or less often metastases) is routinely measured by enzyme-linked immunochemical assays and radioassays (enzyme-linked immunosorbent assay). Concentrations of hormone receptors less than 3 femtomoles (fmol) per milligram of cytosol protein are considered negative, 3 to 10 fmol/mg of cytosol protein are intermediate, and concentrations of hormone receptors greater than 10 fmol/mg of cytosol protein are positive. The level (i.e., quantitative) of hormone receptor and the methodology used to assess hormone receptors are important for predictive ability. Although the estrogen receptor has received the most attention to date, more recent data suggest that the presence of the progesterone receptor protein is required for the functional effects of the estrogen receptor protein to occur. This is evidenced by studies that have reported that response to hormonal manipulation and prognosis are highly correlated with the presence of both positive estrogen receptor protein and positive progesterone receptor protein. Hormone receptors are most valuable in predicting response to hormone therapy. About 70% to 80% of patients who are ER-positive and PR-positive will respond to hormonal manipulation. ER-negative patients rarely

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respond to hormonal manipulation. The response rate in patients who are ER-negative and PR-positive is somewhere in between. About 50% to 70% of patients with primary or metastatic breast cancer have hormone receptor–positive tumors. The median level and frequency of hormone receptor–positive tumors are higher in postmenopausal patients as compared to premenopausal patients. That difference is the primary reason for the different recommendations for adjuvant and metastatic treatment of breast cancer between premenopausal and postmenopausal patients that are discussed in later sections of this chapter. Many experts suggest that breast cancer in postmenopausal women is substantively different than that occurring in premenopausal women. Breast cancer is predominantly a disease of the elderly. When it occurs in younger patients, the course of the disease is more aggressive. Hormone receptor positivity, more common in postmenopausal women, is associated with a superior response to hormone therapy and a longer disease-free interval between primary and subsequent metastatic disease, and overall a more favorable prognosis. The presence of hormone receptors in tumors is associated with a favorable disease-free interval and perhaps an overall survival difference of 5% to 10% (as compared to hormone receptor–negative patients). The rate of tumor cell proliferation also has prognostic significance in breast cancer recurrence. Rate of cell proliferation can be determined with either the tritiated thymidine-labeling index or DNA flow cytometry, which determines the percentage of tumor cells actively dividing (S-phase fraction). Both techniques have shown that patients with rapidly proliferating tumors have a decreased disease-free survival as compared to patients with slowly proliferating tumors.46 Flow cytometry can also detect abnormal DNA content, or aneuploidy, in breast cancer cells. Although there are conflicting reports regarding the clinical significance of ploidy status, some studies report that patients with aneuploid tumors have significantly shorter relapse-free survival times than do patients with diploid tumors.46 Newer methods of determining proliferative rate include the use of monoclonal antibodies to antigens in proliferating cells, such as Ki67. As an example, in one report of 371 node-negative breast cancer women with a high Ki-67 labeling index, they had a 20-fold greater mortality rate than those with a labeling index of ≤10%.47 Nuclear grade and tumor (histologic) differentiation are known, independent prognostic indicators. Several histologic grading systems have been developed and shown to have prognostic value in the evaluation of breast cancer. Fisher and associates47 have shown a 5-year survival of 93% for patients with good nuclear grade, compared to 79% for patients with poor nuclear grade. However, lack of concordance between pathologists’ grading results has thwarted the use of this prognostic indicator in clinical trials. A number of additional potential prognostic factors have been identified in the past 5 years. These include overexpression of the erbB-2 (or HER-2/neu) oncogene, cathepsin D, angiogenic growth factors, mutations in the tumor suppressor p53 gene, and others.48 Many of the new potential prognostic factors have been shown to be strongly correlated with established risk factors. For example, many ER-positive tumors are also HER-2–negative and cathepsin D– negative, which makes it difficult to discern the relative importance of potential prognostic factors. Identification of these numerous factors and correlations between these and known prognostic factors that affect clinical outcome is of interest because each correlation allows basic mechanistic insights into disease processes. Practically, they allow prediction of probable clinical outcomes that can guide therapeutic decision making. Several of these new prognostic factors, specifically the HER-2 oncogene overexpression and p53 mutations, have shown early promise as predictors of efficacy of adjuvant chemotherapy.

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The HER-2/neu gene is located on 17q21 and is transcribed into a 4.5-kd mRNA, which is translated into a 185-kd glycoprotein. The HER-2/neu protein is expressed at low levels in the epithelial cells of normal breast tissue. HER-2/neu is a member of the erbB (or HER) growth factor receptor family and its overexpression is associated with transmission of growth signals that control aspects of normal cell growth and division. Preclinical and clinical studies indicate that HER-2 overexpression may have prognostic and predictive value. In some studies, HER-2/neu gene amplification and protein overexpression, measured by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively, correlates with factors associated with a poor prognosis. However, not all studies have found this association. A number of reports have found that HER-2/neu amplification and overexpression are significant independent predictors of shorter disease-free survival and reduced overall survival in node-positive breast cancer.49,50 The relationship between HER-2/neu amplification and overexpression in node-negative patients has also been reported to confer less favorable outcomes in some, but not all, studies. The data regarding the predictive value of HER-2/neu and response to hormonal and chemotherapy is similarly conflicted. However, most experts would agree that women whose tumors overexpress HER-2/neu appear to be relatively resistant to alkylating agent–based adjuvant therapy, and they might derive greater benefit from an anthracycline-based adjuvant therapy regimen.51 It is important to note that the strength of the evidence to support anthracycline-based adjuvant regimens in women with HER-2/neu–overexpressing tumors is not considered adequate to warrant a recommendation by most consensus groups. Although some evidence supports that HER-2/neu overexpression is associated with relative resistance to adjuvant endocrine therapy, particularly tamoxifen, data are conflicting. HER-2/neu overexpression more likely represents a negative prognostic factor in hormone receptor–positive women. Hormone receptor–positive women who are also HER-2/neu positive should receive adjuvant hormonal therapy. Clearly, HER-2/neu positively predicts response to trastuzumab therapy, which is a monoclonal antibody directed against the HER2/neu receptor. Currently, the use of trastuzumab is indicated for treatment of metastatic breast cancer in patients who have tumors that overexpress HER-2/neu. However, trials in the adjuvant set-

ting are ongoing. A final controversy surrounds the testing method employed to determine HER-2/neu status. Although there are many methods, HER-2/neu gene amplification measured by FISH and overexpression of the HER-2/neu protein product measured by IHC are the most commonly used methods. Discordant FISH and IHC assays are most commonly the result of false-positive results in patients with a 2+ screen by IHC testing, which suggests that overexpression of HER-2/neu in these cases should be confirmed by FISH.52 Although there is a growing understanding of the prognostic significance of individual factors, it is not clear how to practically use multiple prognostic factors in concert. The development of decisionmaking systems for clinical applications will require improvements in the areas of (1) standardization of methodologies and interlaboratory quality control for prognostic factor determinations, (2) definition of a limited set of prognostic markers that are independently predictive, and (3) staging systems that integrate this information. The National Institutes of Health (NIH) convened an expert panel to develop a consensus statement on adjuvant therapy for breast cancer.53 One question addressed by the Consensus Development Panel was which factors should be used to select systemic adjuvant therapy. The panel identified age, tumor size, axillary node status, histologic tumor type, standardized pathologic grade, and hormone receptor status as the only currently accepted prognostic and predictive factors. In addition, the updated International Expert Consensus on the Primary Therapy of Early Breast Cancer concluded that ER and PR expression of the primary tumor cells are the only tumor-related markers with clear predictive value for treatment response that has unequivocal clinical utility regarding adjuvant therapy.42 This central importance of the steroid hormone receptors emphasizes the absolute necessity to measure ER and PR, report results in a standardized quantitative manner (e.g., percentage of cells stained), and use quality-assured procedures in experienced laboratories. The predictive utility of HER-2 overexpression, cell proliferation markers, and the interaction of these factors with steroid hormone receptor expression await confirmation. The prognostic usefulness of features such as expression of the components of uPA and PAI-1,54,55 deregulated expression of cyclin E,56,57 and presence of tumor cells in bone marrow and in circulating blood is not clear.58−60


TREATMENT: Early Breast Cancer
EARLY BREAST CANCER
LOCAL-REGIONAL THERAPY 2 Most patients presenting with breast cancer today have either an

in situ tumor, a small tumor with negative lymph nodes (stage I), or a small stage II cancer. Surgery alone can cure most, if not all, patients with in situ cancers and approximately half of all patients with stage II cancers. The choice of surgical procedures has changed drastically over the past 50 years. This in part is a result of changes in our understanding of the biology of breast cancer, and is due in part to a series of well-conducted trials performed over this time period. The Halstedian theory and concept of tumor growth, formulated at the end of the nineteenth century, held that breast cancer was a local-regional disease that spread to involve larger contiguous areas of the breast, chest wall, and adjacent lymph nodes. This hypothesis gave rise to emphasis throughout most of the twentieth century on the Halsted radical mastectomy, the hallmark of an approach maintain-

ing that cure of early disease could best be achieved with expansive, meticulously performed surgical procedures. The radical mastectomy involves removal of the breast and both major and minor pectoralis muscles. The axillary nodes on the same side (ipsilateral) as the breast lesion are also removed. Substantial morbidity is associated with this procedure. Muscle resection decreases strength and range of motion, and removal of axillary lymph nodes can produce edema of the arm and resected breast area. This procedure was often followed by external beam radiation therapy to the involved area. During the 1960s, it was recognized that breast cancer is often microscopically disseminated at the time of initial diagnosis. The evolutionary concept that breast cancer is not only a local, but also a systemic, disease has resulted in major changes in local and systemic therapy. In 1980, the Commission on Cancer of the American College of Surgeons reported that there had been an apparent gradual shift from a radical to modified radical mastectomy since December of 1972.61 The modified radical mastectomy, also termed total mastectomy with axillary lymph node dissection, is not as precisely defined or

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standardized as the radical mastectomy. The pectoralis minor muscle may be excised, divided, or left intact, and more importantly, there may be variation in the extent of axillary lymph node dissection, ranging from sampling to full dissection. It was recognized during this time period that a major factor in prognosis was involvement of axillary lymph nodes rather than the type of initial surgical procedure performed. Results of a large trial conducted in the United States by the NSABP repudiated the Halsted theory and supported the alternative systemic hypothesis. NSABP B-04, randomized nearly 2,000 women among three treatment regimens: radical mastectomy, simple mastectomy with local-regional irradiation, and simple mastectomy and removal of nodes if they later became clinically positive.62 Forty percent of patients who underwent the radical mastectomy had pathologically positive lymph nodes; thus it can be assumed that 40% of patients in the other two groups had positive axillary nodes that were not removed. Despite the disparity in local-regional treatment, no significant difference in treatment failure, distant metastases, or overall survival was observed through more than 25 years of follow-up. Based on the results of that trial, the NSABP instituted a second trial (B-06) in which patients with stage I or stage II breast cancer with a tumor size 4 cm or less were treated with either modified radical mastectomy or lumpectomy with or without radiation therapy.63 Lumpectomy followed by radiation resulted in a 5-year survival of 85% compared to 76% for modified radical mastectomy; the 20-year results were consistent with the earlier results. This study also found that radiation therapy reduced the probability of local tumor recurrence by about 30% in patients treated with lumpectomy. The local failure rate of modified radical mastectomy was 8.1% compared to 7.2% for lumpectomy alone and 1.1% for lumpectomy and radiation therapy. Neither the rate of development of distant metastases nor contralateral breast cancer was different in the treatment groups. The NIH Consensus Conference on the Treatment of Early Stage Breast Cancer addressed the roles of modified radical mastectomy versus breast conservation and concluded that primary therapy for breast cancer stages I and II should be breast conservation.53 Breast conservation consists of lumpectomy, also referred to as segmental mastectomy or partial mastectomy, and is defined as excision of the primary tumor and adjacent breast tissue, followed by radiation therapy to reduce the risk of local recurrence. Removal of level I/II axillary lymph nodes is recommended for completeness of staging and prognostic information. The reason given for favoring breast conservation therapy is that it achieved similar results to more extensive surgical procedures, and had cosmetically superior results. Most patients with breast cancer can be treated by lumpectomy and radiation therapy. Several factors should be considered in selecting patients for breast conservation therapy. Multiple sites of cancer within the breast and the inability to attain negative pathologic margins on the excised breast specimen are predictive for an increased risk of recurrence with breast-conserving therapy and are indications for mastectomy. Some pre-existing collagen vascular diseases (e.g., scleroderma and systemic lupus erythematosus) are a contraindication for the use of breast-conserving radiation and surgery. Although local recurrence following breast-conservation therapy is not associated with increased mortality, it is distressing to the patient and requires surgical removal of the breast. In addition, reconstructive therapy is often not feasible in a breast that has previously received irradiation. Another major consideration in selecting patients for breast-conserving therapy is the expected cosmetic result. Although the size of the tumor is not an important consideration for breast cancer recurrence, the relationship of the size of the tumor to the total breast volume is

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an important cosmetic consideration. If the volume of the tissue removed is large in a woman with small breasts, better results can often be obtained with mastectomy and reconstruction. Despite the desire of the patient and the willingness of the surgeon to avoid mastectomy, in some circumstances a lumpectomy will approximate so closely a mastectomy that both the patient and the physician will agree that preservation of a very limited amount of breast tissue would not justify the inconvenience of radiation therapy. Another approach to therapy for these patients would be primary systemic therapy to potentially shrink the tumor and minimize surgery (see section on adjuvant systemic therapy for further details). Aside from the probability of local recurrence and the ability to achieve a satisfactory cosmetic result, consideration must be given to the availability of an external beam radiation facility and the patient’s willingness to comply with the prescribed course of radiotherapy. In most instances, external beam radiation therapy used in conjunction with breast-conserving procedures involves 4 to 6 weeks of radiation therapy directed to the breast tissue (a total of 5,000 cGy administered in 200-cGy doses daily to eradicate residual disease). Complications associated with radiation therapy to the breast are minor and include reddening and erythema of the breast tissue and subsequent shrinkage of total breast mass beyond that predicted on the basis of breast tissue removal. Some clinical situations also require postmastectomy radiation therapy as well (see section on locally advanced breast cancer). Simple or total mastectomy involves removal of the entire breast without dissection of the underlying muscle or axillary nodes. The major disadvantage of this procedure is that axillary nodal status is not determined, and therefore important prognostic information may be lost. This procedure is used in patients with carcinoma in situ, in whom there is a 1% incidence of axillary node involvement, or in cases of local recurrence following breast-conservation therapy. While axillary lymph node dissection with histopathologic study of the axillary specimen was the gold standard for detecting axillary nodal involvement and determining the number of lymph nodes containing tumor, the importance of stage I/II axillary dissection is being challenged. Although highly accurate, its morbidity is significant, with an acute complication rate as high as 20% to 30% and rates of chronic lymphedema also on the order of 20% to 30%.64,65 A new procedure involving lymphatic mapping and sentinel lymph node biopsy is becoming more acceptable at many academic centers across the United States.66 This procedure was first utilized in melanoma, but has been adapted for use with breast tumors.67 The sentinel lymph node is the first lymph node that drains a cancer. Injection of a vital blue dye around the primary breast tumor results in identification of the sentinel lymph node in the majority of patients, and the status of this lymph node may predict the status of the remaining nodes in the nodal basin. In more recent series, the use of a radiolabeled colloid alone or in addition to the blue dye is generally associated with a higher rate of identification of the sentinel lymph node, but this is a controversial topic and may be related to experience of the surgeon or other factors. Regardless of the mapping technique and patient populations studied, a sentinel lymph node can be identified in 90% of patients, and can accurately predict the status of the remaining axillary nodes in 95% of patients.67 Contraindications to this procedure are patients with clinically apparent lymph node involvement, tumors >5 cm in size or locally advanced, neoadjuvant chemotherapy, multicentric cancers, prior axillary surgery, and/or a large biopsy cavity. Patients who are pregnant or lactating are also not eligible for this procedure. Another issue that is raised is the experience and mastery of the procedure by the surgical team. It has been shown that an individual surgeon must perform approximately

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20-60 procedures to attain competency.68,69 At present the long-term outcome of patients undergoing this procedure alone (without completion axillary dissection) are not available. Ongoing clinical trials will hopefully answer these questions, but this is a very controversial subject with much debate amongst even the most highly regarded breast surgeons. Thus, simple mastectomy may be a reasonable alternative for women who wish to avoid the inconvenience of radiation therapy and preserve their option for breast reconstruction in the future, understanding the lack of long-term data with sentinel lymph node biopsy alone. The NSABP B-04 and B-06 trials are widely credited with the finding that breast conservation is an appropriate primary therapy for most women with stages I and II disease, and is preferable because it provides survival rates equivalent to those of modified radical mastectomy. But these trials were also important for the valuable information they provided regarding the natural history of the disease and the identification of pathologic prognostic factors associated with early cancer spread. The preponderance of information available regarding selecting women most likely to benefit from systemic adjuvant therapy was derived from pathologic evaluation of tissues archived from these trials. It is hoped that further investigation into less extensive surgery (now focused on the axilla) will continue to provide valuable information for the future.


SYSTEMIC ADJUVANT THERAPY 3 Systemic adjuvant therapy is defined as the administration of

systemic therapy following definitive local therapy (surgery, radiation, or a combination of these) when there is no evidence of metastatic disease, but a high likelihood of disease recurrence. The concept of breast cancer being a systemic disease and the rationale of adjuvant chemotherapy was based on a series of laboratory and clinical investigations conducted during the 1960s and 1970s that were directed primarily toward achieving a better understanding of tumor metastases. Table 125–6 illustrates the laboratory findings, clinical ab-

TABLE 125–6. Laboratory Findings, Clinical Observations, and Biologic Hypothesis of Breast Cancer as a Systemic Disease and the Value of Adjuvant Chemotherapy r By the time cancer becomes clinically detectable, it is advanced

(about 30 doublings) and has had ample opportunity to establish distant micrometastases. r There is no orderly pattern of tumor cell dissemination, and the bloodstream is of considerable importance in tumor spread. r Operable breast cancer is often a systemic disease and variations in local-regional therapy have not substantially affected survival. Only by control of distant disease can there be an improvement in the outcome of breast cancer patients. r Likelihood of disease recurrence is related to size of tumor mass and axillary node involvement at diagnosis. r Recurrence of breast cancer following local-regional therapy is most commonly at sites distant from the breast. r Tumor growth fraction is inversely related to tumor population site. Therefore, optimal kinetic conditions to achieve cure with chemotherapy exist in the setting of micrometastatic disease. r Efficacy of chemotherapy is dose dependent and optimal doses of combination chemotherapy can be more safely and effectively administered in the adjuvant setting as opposed to the setting of advanced disease.

normalities, and biologic hypothesis that lead to recognition of breast cancer as a systemic disease and documented the value of adjuvant chemotherapy. The very earliest adjuvant trials in breast cancer consisted of perioperative administration of alkylating agents with the intent of eradicating micrometastases that were disseminated at the time of surgical excision of the tumor. Many collaborative research groups have conducted stepwise series of studies designed to identify appropriate candidates for systemic adjuvant therapy, as well as optimal regimens and duration of systemic adjuvant therapy. Several hundred randomized clinical trials evaluating various systemic adjuvant modalities have been reported. Most published results confirm that chemotherapy, hormonal therapy, or both, result in improved disease-free survival (DFS) and/or overall survival (OS) for all treated patients, or more commonly for patients in specific prognostic subgroups (e.g., nodal involvement, menopausal status, hormonal receptor status, growth fraction, or nuclear grade). The huge amount of data generated by these trials has resulted in a great deal of controversy, with different conclusions being reached by various experts. A number of factors make interpretation of results of systemic adjuvant therapy trials difficult. These include differences in the patient populations studied, the variation in natural history of breast cancer, the absence of information regarding pathologic prognostic factors in many studies, and differences in treatment approach and methods of analysis. It is important to remember that the goal of systemic adjuvant therapy is cure. Therefore patients in these studies must be followed for long periods of time before results can be determined. In addition, because most patients with early breast cancer (50% to 90%) in the various trials are cured with local-regional therapy alone, large numbers of patients are required to show a statistically significant difference that can be attributed to systemic adjuvant therapy. For these reasons, combined analysis, or meta-analysis, of all breast cancer trials has been conducted, and until recently was the most frequently referred to information regarding systemic adjuvant therapy. This effort, organized by the Early Breast Cancer Trialists’ Collaborative Group, is based on a worldwide collaboration involving 133 randomized trials conducted between 1957 and 1985.70 The results of the Early Breast Cancer Trialists’ Collaborative Group meta-analyses were published in 1988, 1992, and 1998. Many important questions regarding the optimal way to administer adjuvant chemotherapy70,71 and hormonal therapy,70−73 and the degree of benefit in terms of DFS or OS to clinically relevant subsets of patients have been answered by these meta-analyses. Simply stated, the results of the meta-analyses support the use of adjuvant hormonal therapy in all patients with positive hormone-receptor status, and this finding is reflected in the 2000 NIH Consensus Development Conference Statement53 that adjuvant hormonal therapy should be recommended to women whose tumors contain hormone receptor protein regardless of age, menopausal status, involvement of axillary lymph nodes, or tumor size. The results of these meta-analyses also support a benefit of adjuvant chemotherapy, again reflected in the 2000 NIH Consensus Development Conference Statement that it is accepted practice to offer cytotoxic chemotherapy to most women with lymph node metastases or with primary breast cancers larger than 1 cm in diameter (both node-negative and nodepositive).53 It is important to understand the relative and absolute magnitude of the benefit associated with adjuvant systemic therapy in breast cancer. Table 125–7 shows the proportional reduction in the annual odds of recurrence and death by age for adjuvant polychemotherapy and adjuvant tamoxifen given for 5 years in women with tumors that are positive for hormone receptors based on the results of these metaanalyses. Throughout these reports, the results are presented as they

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TABLE 125–7. Ten-Year Results of the Overview Analysis Tamoxifen

Polychemotherapy

Reduction in Annual Odds Age

Recurrence (%)

All patients 2 cm, grade 2 or 3, or age 50 years)

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TABLE 125–9. Absolute Benefits of Adjuvant Chemotherapy by Age and Nodal Status

Disease-free survival Age 10% in the 6 months preceding diagnosis). Pruritus is also commonly noted in patients with Hodgkin’s lymphoma, but its presence does not appear to have significant prognostic value.2,6

DIAGNOSIS, STAGING, AND PROGNOSTIC FACTORS The diagnosis and pathologic classification of Hodgkin’s lymphoma can only be made by review of a biopsy (preferably an excisional biopsy) of the enlarged node by an expert hematopathologist. Full evaluation of extent of disease, or staging, is necessary with Hodgkin’s

Stage III

Stage IV

Involvement of a single lymph node region or structure (I) or of a single extralymphatic organ or site (IE ) Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm (IIE ). The number of nodal regions involved should be indicated by a subscript (e.g., II2 ) Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE ) or by involvement of the spleen (IIIS) or both (IIISE ). III1 : with or without splenic, hilar, celiac, or portal node involvement. III2 : with para-aortic, iliac, or mesenteric node involvement Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node enlargement A—No symptoms B—Fever, night sweats, weight loss (>10%) X—Bulky disease >one-third the width of the mediastinum >10 cm maximal dimension of nodal mass E—Involvement of extralymphatic tissue on one side of the diaphragm by limited direct extension from an adjacent, involved lymph node region S—Involvement of the spleen CS—Clinical stage PS—Pathologic stage

Adapted from Lister et al.14

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TABLE 129–4. Prognostic Groups for Hodgkin’s Lymphoma EORTC

GHLSG

A. Large mediastinal massa B. Age ≥50 years C. Elevated ESRb D. ≥4 involved regions

A. Large mediastinal massa B. Extranodal disease C. Elevated ESRb D. ≥3 involved regions

Treatment groups Early-stage favorable Early-stage unfavorable

CS I–II supradiaphragmatic, no RF CS I–II supradiaphragmatic with ≥1 RF

Advanced-stage

CS III–IV

CS I–II with no RF CS I, CSIIA with ≥1 RF CS IIB with C/D but without A/B (see above) CS IIB with A/B (see above) CS III–IV

Risk factors

a

Defined as a mediastinal mass larger than one-third of the greatest chest diameter on x-ray. Erythrocyte sedimentation rate (≥50 without or ≥30 with B symptoms). CS, clinical stage; EORTC, European Organization for Research and Treatment of Cancer; GHLSG, German Hodgkin’s Lymphoma Study Group; RF, risk factor. Adapted from Diehl et al.11

b

bone, skin, spleen, and abdominal nodes) with an invasive procedure such as a laparoscopy or laparotomy. Those patients with extranodal disease (muscle, skin, bone, of Waldeyer’s ring) contiguous to involved nodes are classified with the subscript “E” in the Cotswolds staging system.14 Invasive staging procedures such as laparotomy and lymphangiogram are not usually performed during staging. These tests can detect occult disease in the abdomen, which would require systemic chemotherapy in addition to radiation for patients with early-stage supradiaphragmatic disease. Therefore these tests should only be considered for patients who will be treated with radiation alone if the results are negative. When the treatment plan includes systemic therapy, the use of these procedures does not impact treatment decisions or patient prognosis. Clinicians rarely order either procedure because the availability of lymphangiography is low and the complications of laparotomy are relatively high (about 5%).11,16,17 Analyses of early studies led to the identification of prognostic factors that could predict poor treatment outcomes of Hodgkin’s lymphoma. Patient characteristics that have been determined as unfavorable prognostic factors include advanced stage, advanced age, male gender, presence of B symptoms, higher number of involved nodal regions, large mediastinal mass, extranodal disease, elevated erythrocyte sedimentation rate (ESR), presence of anemia, leukocytosis, lymphocytopenia, and low serum albumin. Clinical trials performed by large cancer groups (e.g., European Organization for Research and Treatment of Cancer [EORTC] and German Hodgkin’s Lymphoma Study Group [GHLSG]) have used combinations of these prognostic factors to stratify patients into earlystage favorable, early-stage unfavorable (intermediate) disease, or advanced disease (Table 129–4). Canadian and United States cooperative groups use similar criteria. In the NCCN guidelines, bulky disease, elevated ESR, and number of involved nodal sides are de-

fined as unfavorable features.15 Although the exact criteria between groups or studies are not identical, stage, advanced age, bulky disease, and signs of systemic disease (B symptoms, elevated ESR, or extranodal disease) are of most prognostic significance.11 Some of these factors can also be used to predict prognosis in patients with advanced disease. The International Prognostic Factors Project uses seven factors to generate an International Prognostic Score (IPS), which can be used to predict progression-free and overall survival (Table 129–5).18

TABLE 129–5. The International Prognostic Factors Project Score for Advanced Hodgkin’s Lymphoma Risk factors Serum albumin (4 Abnormal lactate dehydrogenase level Hemoglobin 60 years, (2) advanced tumor stage (Ann Arbor stages III or IV), (3) low hemoglobin level (15 centroblasts/hpf ).13 The clinical behavior and treatment outcome of grades 1 and 2 follicular lymphoma are similar, and they are usually treated as indolent lymphomas. In contrast, grade 3 follicular lymphoma is synonymous with what is often referred to as follicular large cell lymphoma, and is usually treated as an aggressive lymphoma. Follicular lymphomas tend to occur in older adults, with a slight female predominance (see Table 129–8). Most patients have advanced disease at diagnosis, but about 25% to 33% of patients have localized disease (clinical stage I or II) at diagnosis.48 Extranodal disease, bulky disease, and B symptoms (constitutional symptoms) are

uncommon features at diagnosis. Most patients with follicular lymphoma have the chromosomal translocation t(14;18) at the time of diagnosis. The clinical course is generally indolent, with median survivals of 8 to 10 years. Most patients have dramatic responses to initial therapy, and their disease course is characterized by multiple relapses, with responses to salvage therapy becoming progressively shorter after every relapse, eventually leading to death from disease-related causes.59 The natural history of follicular lymphoma shows a pattern of constant relapses over time (i.e., no evidence of a survival plateau), which suggests that patients are not cured of their disease. But the natural history of follicular lymphoma can be unpredictable. Spontaneous regression of objective disease has been noted in as many as 20% to 30% of patients.59 There is also a high conversion rate of follicular lymphoma to a more aggressive histology over time that steadily increases after diagnosis and reaches 40% to 70% at 8 to 10 years.59 At autopsy, 95% of patients with follicular lymphoma have some evidence of diffuse large B-cell lymphoma. Patients with transformed indolent lymphoma should be treated in the same way as an aggressive lymphoma. Certain subsets of patients with follicular lymphoma have a much better or worse prognosis. Some studies suggest that the natural history of follicular large cell lymphoma (i.e., grade 3 follicular lymphoma) is similar to that of other aggressive lymphomas, and that treatment with intensive combination chemotherapy regimens may result in long-term disease-free survival, including a possible plateau in the survival curve.57,60 The recent development of the FLIPI prognostic model should help clinicians to identify patients in different prognostic groups based on disease characteristics at the time of diagnosis.52 Patients who are predicted to have a poor prognosis (i.e., high-risk) could then be offered aggressive or experimental therapy, while those who are predicted to have a good prognosis (i.e., low-risk) would be treated with standard therapy, therefore avoiding unnecessary toxicity.


Therapy of Localized Disease (Stages I and II) Radiation therapy is the standard treatment for early-stage follicular lymphoma. Involved-field, extended-field, and total nodal irradiation have been used. Carefully staged patients with either stage I or contiguous stage II disease treated with radiation therapy alone can achieve disease-free survival rates of 40% to 50% and overall survival rates of 60% to 70% at 10 years.57 Late relapses are uncommon; only 10% of patients who reached 10 years without relapse subsequently experienced a recurrence. Chemotherapy is not usually given in most patients with localized follicular lymphoma, but it may be helpful in some patients with high-risk stage II disease (e.g., multiple sites of involvement or bulky disease).61 8 About 40% to 50% of patients with clinical stage I or II follicular lymphoma are cured of their disease with radiation therapy alone.57 Most centers use radiation at a dose of 30 to 40 Gy to either involved (i.e., local) or regional fields, which would consist of irradiation to the involved nodal region plus one additional uninvolved region on each side of the involved nodes. Extended-field irradiation is not usually used because of the absence of a survival benefit and possible increased risk of secondary malignancies. In addition, previous use of extended-field irradiation compromises the ability of that patient to receive subsequent chemotherapy. The 2004 NCCN guidelines state that locoregional radiation therapy, chemotherapy followed by radiation therapy, or extended-field radiation therapy are appropriate options for patients with early-stage follicular lymphoma.50

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Therapy of Advanced Disease (Stages III and IV) 8 The management of stage III and IV indolent lymphomas re-

mains controversial, as standard therapeutic approaches have not been shown to be curative despite the high complete remission rates to initial therapy. Therapeutic options for these patients are diverse and include watchful waiting, radiation therapy, singleagent chemotherapy, combination chemotherapy, biologic therapy, and combined-modality therapy.38,57,62 Although complete remission can be achieved in 50% to 80% of patients with various treatments, the median time to relapse is usually only 18 to 36 months. About 20% of patients who have a complete response remain in remission for longer than 10 years. After relapse, patients are re-treated and again high remission rates can be achieved (see below). Unfortunately, the response rates and duration of response both decrease with each re-treatment. Two different initial treatment approaches exist and are described as conservative or aggressive. Patients treated with the conservative approach receive no initial therapy followed by single-agent chemotherapy or radiation therapy when treatment is needed. Candidates for the conservative approach are usually older, asymptomatic, and have minimal tumor burden. Patients with symptoms, extensive extranodal involvement, bulky disease, or impaired end-organ function at the time of diagnosis are not candidates for conservative treatment. With the aggressive approach, patients usually receive rituximab, combination chemotherapy, or both, early in the disease course. There are no convincing data to indicate that immediate aggressive therapy significantly improves survival as compared with conservative therapy. More than 80% of patients with stage III or IV follicular lymphoma are alive at 5 years, and the median survival is about 7 to 8 years. CLINICAL CONTROVERSY The management of advanced indolent lymphomas is controversial because none of the therapeutic approaches have been shown to be curative despite the high complete remission rates to initial therapy. Therapeutic options for these patients are diverse and include watchful waiting, radiation therapy, single-agent chemotherapy, combination chemotherapy, biologic therapy, and combined modality therapy. Although more intensive therapies have a higher complete response rate, they have not been shown to increase overall survival as compared with more conservative approaches. At the time of relapse, many treatment options are available.63 At the time of relapse, the following factors must be considered: age, symptomatic status of the patient, tumor burden, rate of regrowth (based on previous assessment of active disease sites), presence or absence of characteristics suggesting transformation or biologic progression, prior therapy, degree and duration of response to prior therapy, availability of clinical trials, and patient preferences.


No Initial Therapy. Because there are no convincing data that standard treatment approaches have improved survival, some clinicians have adopted a “watch and wait” approach for asymptomatic patients in which therapy is delayed until the patient experiences systemic symptoms or disease progression such as rapidly progressive or bulky adenopathy, anemia, thrombocytopenia, or disease in threatening sites such as the orbit or spinal cord.59 The median time until treatment is required is 3 to 5 years, and about 20% of patients do not require therapy for up to 10 years. The 10-year survival is 73%, which is not significantly different from patients who received therapy at the time of diagnosis. In a randomized study of asymptomatic patients

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with indolent lymphomas (mostly follicular), patients who underwent watchful waiting had similar cause-specific and overall survival as compared with those who received immediate chlorambucil.64 With a median length of follow-up of 16 years, about 17% of patients who were randomized to the watchful waiting group died of other causes without receiving chemotherapy and an additional 9% are alive and have not yet had chemotherapy. As described above, patients with follicular lymphoma who are followed without therapy sometimes have spontaneous regressions that can be complete, while the disease in other patients can convert to a more aggressive histology. If the watchful waiting approach is chosen, the patient should be evaluated at least every 2 months for the first year and quarterly thereafter, so that intervention can occur before serious problems occur.


Radiation. Follicular lymphoma is sensitive to radiation therapy, and total lymphoid irradiation or whole body irradiation has been used to treat patients with advanced follicular lymphoma. Although the results with total lymphoid irradiation have been excellent in selected patients with limited stage III follicular lymphoma,57 extensive radiation therapy is rarely used for patients with advanced follicular lymphoma requiring systemic therapy because of concerns regarding prolonged myelosuppression and difficulties in administering future treatments. Total lymphoid irradiation has been given in combination with chemotherapy, but studies have failed to show a survival advantage for combined modality treatment.38,57 As a result, new high-dose chemotherapy regimens usually do not include the use of total lymphoid irradiation.
Chemotherapy. Oral alkylating agents, given either alone or in combination, have been the mainstay of treatment for follicular lymphoma. More intensive chemotherapy has not been shown to improve patient outcome. In a randomized trial of oral chlorambucil (0.1 to 0.2 mg/kg per day), oral cyclophosphamide (1.5 to 2.5 mg/kg per day), or CVP (cyclophosphamide, vincristine, and prednisone) in patients with indolent lymphoma, no significant difference in overall survival or freedom from relapse between the three groups was observed.59 In a more recently published randomized trial of single-agent cyclophosphamide (100 mg/m2 per day) versus CHOP-B (cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin), no significant difference in overall time to failure or overall survival was observed at 10 years.65 The dosage of single-agent chlorambucil or cyclophosphamide is usually adjusted to maintain a platelet count above 100,000/mm3 and a white blood cell count above 3,000/mm3 . Although single-agent alkylating agents have a high initial complete remission rate, the time required to achieve a complete response is slow (median time is 9 to 12 months). Complete responses occur more rapidly with combination chemotherapy, particularly with doxorubicin-containing regimens. Many clinicians will therefore give CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like chemotherapy when a rapid response is necessary. Table 129–11 shows the CHOP regimen that is widely used in the

TABLE 129–11. CHOP Regimen Drug Cyclophosphamide Doxorubicin Vincristine Prednisone One cycle is 21 days

Dose (mg/m2 )

Route

Treatment Days

750 50 1.4 100

IV IV IV Oral

1 1 1 1–5

Note: Another name for doxorubicin is hydroxydaunomycin

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treatment of NHL. In those who achieve a complete response, the duration of response is relatively short (about 2.5 years). There is no benefit of maintenance therapy. After the best response is achieved, many experts will discontinue therapy and observe. Both single-agent alkylating agents and CVP are well tolerated by most patients. The advantages of oral chlorambucil are no hair loss, little or no nausea, and minimal myelosuppression. Because of its mild side-effect profile, oral chlorambucil is usually recommended for older patients who are minimally symptomatic or who have other comorbidities. There are some concerns with the risk of secondary acute leukemia in patients receiving continuous exposure to alkylating agents.


Purine Analogues. Several studies have reported encouraging results with two adenosine analogues, fludarabine phosphate and 2-chlorodeoxyadenosine (2-CdA; cladribine), in previously untreated and relapsed advanced follicular lymphoma. The mechanism of action for both drugs is not well understood, but both agents accumulate in lymphocytes and are resistant to adenosine deaminase. In patients with relapsed or refractory indolent lymphoma, single-agent fludarabine has an overall response rate of almost 50% and a complete response rate of 10% to 15%. Response rates are higher in previously untreated patients, with overall and complete response rates of 70% and almost 40%, respectively.62 The median time to progression is less than 6 months for relapsed disease and more than 12 months for previously untreated patients. Although the response rates to 2-CdA in previously untreated patients is similar to those with fludarabine, the duration of response appears to be shorter with 2-CdA. Combination regimens that include one of these purine analogues are also being investigated.62 Fludarabine and mitoxantrone (FN) and fludarabine, mitoxantrone, and dexamethasone (FND) are examples of fludarabine-containing regimens that have shown encouraging results in patients with indolent lymphoma.66,67 Purine analogues usually do not cause nausea and vomiting or hair loss, but they are associated with cumulative and prolonged myelosuppression and profound immunosuppression, which increases the risk of opportunistic infections such as fungal infections, Pneumocystis carinii pneumonia, and viral infections.
Interferon Alfa. Single-agent interferon alfa (IFN-α) is active in the treatment of follicular lymphoma, with objective response rates of 30% to 50% in patients with relapsed disease.68 About 10% of patients have a complete response to IFN-α. Several randomized controlled trials have evaluated the potential benefit of adding IFN-α to combination chemotherapy. Based on the results of one of these trials, IFNα-2b (Intron A) was granted FDA approval as initial treatment for patients with clinically aggressive follicular lymphoma and a large tumor burden, in combination with an anthracycline-containing regimen. Its approval was based on the Groupe d’Etude des Lymphomes Folliculaires trial, which compared CHVP (cyclophosphamide, doxorubicin, teniposide, and prednisone) to CHVP and IFN-α-2b.69 CHVP was given monthly for six cycles, then every 2 months for six more cycles, whereas IFN-α-2b was given at a dose of 5 million units three times a week for 18 months. Patients who received concurrent IFNα-2b had a significantly higher response rate (85% vs. 69%), which translated into significant differences in median progression-free interval (2.9 years vs. 1.5 years) and overall survival (not reached versus 5.6 years). At least ten randomized controlled trials in the United States and Europe have evaluated the role of IFN-α either during induction, as maintenance therapy, or in both settings. The results of these trials have been inconsistent.62,70 In a meta-analysis of more than 1,500

newly diagnosed patients from the various randomized trials, the efficacy of IFN-α depended on the intensity of the chemotherapy regimen and response to induction chemotherapy. The major conclusion of the meta-analysis was that IFN-α was probably beneficial in responsive patients (those who had a partial or complete response to induction chemotherapy) who were receiving more intensive chemotherapy (an anthracycline- or anthracene-containing regimen). In the most recent randomized controlled trial, 571 patients with stage III or IV indolent NHLs (mostly follicular) were studied as part of a Southwest Oncology Group (SWOG) trial. Patients who responded to intensive chemotherapy that consisted of six to eight cycles of prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide/mechlorethamine, vincristine, procarbazine, and prednisone (ProMACE/MOPP) or chemotherapy plus irradiation therapy were randomized to receive either consolidation IFN-α-2b (2 million units/m2 given three times weekly SC) for 2 years or observation.71 With a median follow-up of more than 6 years, no difference in progression-free or overall survival was observed. The reasons for the divergent results cannot be easily explained.70 Based on these negative results, the significant cost and toxicities associated with this agent, and the recent availability of other treatment options, most clinicians no longer use IFN-α in patients with indolent lymphomas.


Rituximab. The approval of rituximab is arguably the most important recent development in the treatment of NHL. Its initial approval was based on an open-label multicenter study that enrolled 166 patients with relapsed or recurrent indolent lymphoma.72 Rituximab, given intravenously at a dose of 375 mg/m2 weekly for 4 weeks, resulted in an overall response of 48% (complete response [CR]: 6%; partial response [PR]: 42%). Median time to progression for responders was 13.2 months and median duration of response was 11.6 months. Other studies of single-agent rituximab in patients with relapsed or refractory indolent NHL have reported overall response rates of 40% to 60% and complete response rates of 5% to 10%.55,73 Investigators have evaluated different dosages and dosage schedules of single-agent rituximab, including higher dosages (up to 2 g/m2 ), more frequent administration (three times per week), and more doses (weekly for 8 weeks). Although these alternative dosages or dosage schedules have been well tolerated (i.e., no dose-limiting toxicity was observed), they do not appear to increase the antitumor activity of rituximab. Another advantage of rituximab is that it can be safely used as a retreatment option. About 40% of patients who relapsed after a response to rituximab have an objective response to re-treatment with rituximab.74 Interestingly, patients who respond the second time usually have longer durations of remission than they did to the first course. Therefore, many clinicians will consider retreatment with rituximab for patients who have a sustained (i.e., more than 6 months) first remission and if their tumor has continued expression of CD20 antigen. Based on the activity of rituximab in relapsed or refractory patients, it is increasingly being used as first-line therapy, either alone or in combination with chemotherapy.55,73 When given as a single agent to patients with previously untreated indolent NHL, the overall response rate is 60% to 70% and the complete response rate is 20% to 30%. It is interesting to note that many of these patients remain in molecular remission (i.e., PCR-negative) at 12 months.75 In patients who respond to the standard rituximab regimen (375 mg/m2 weekly for 4 weeks), some studies have evaluated the role of maintenance rituximab, given at a dose of 375 mg/m2 weekly for 4 weeks every 6 months, in an attempt to improve the initial therapeutic response

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and prolong duration of remission.76 With continued maintenance therapy, the final response rate increased to 73%, with 37% complete responses. Median progression-free survival was 34 months. Based on these encouraging results, the role of maintenance rituximab is being investigated in a multicenter cooperative group randomized trial. The rationale for the use of rituximab in combination with conventional agents is based on clinical activity of both agents/regimens, non–cross-resistant mechanisms of action, non-overlapping toxicities, and synergistic antitumor activity in vitro. Many clinical trials have evaluated the use of rituximab in combination with other chemotherapy agents.55,73 In a phase II trial of six courses of rituximab and CHOP chemotherapy (R-CHOP), the overall and complete response rate in 40 patients with previously untreated or relapsed indolent lymphoma was 95% and 55%, respectively.77 More than 70% of patients are progression-free after 4 years of follow-up. In an updated analysis, median time to progression was reached at 82 months. Rituximab and CHOP chemotherapy can be combined in many different ways. In the R-CHOP regimen developed by Czuczman and associates,77 two doses of rituximab are given before the start of CHOP therapy, two more doses are given in the middle of the six cycles of CHOP, and two additional doses are given at the end of CHOP therapy. No significant additional toxicity was observed in patients who received R-CHOP. Similar overall and complete response rates have been reported with clinical trials of rituximab combined with other chemotherapy regimens.55,73 Most of the adverse effects of rituximab are infusion related, particularly after the first infusion, and consist of fever, chills, respiratory symptoms, fatigue, headache, pruritus, and angioedema.55 Premedication with oral acetaminophen 650 mg and diphenhydramine 50 mg is usually given 30 minutes before rituximab infusion.


Radioimmunotherapy. The recent approval of the antiCD20 radioimmunoconjugates 131 I-tositumomab (Bexxar) and 90 Y-ibritumomab tiuxetan (Zevalin) has provided clinicians with a novel treatment option for patients with indolent NHLs.78,79 Both 131 I-tositumomab and 90 Y-ibritumomab tiuxetan are mouse antibodies linked to a radioisotope, either iodine 131 (131 I) or yttrium 90 (90 Y). Indolent lymphomas are known to be responsive to radiation therapy (i.e., radiosensitive), and the rationale of radioimmunotherapy is that the antibody will act as a “guided missile” to deliver its payload (i.e., radiation) to its target (i.e., lymphoma cells that express the CD20 antigen). The specificity of the monoclonal antibody allows delivery of the radiation selectively to the tumor (and adjacent normal tissues). Radioimmunoconjugates have some advantages and disadvantages over unlabeled (“naked”) monoclonal antibodies such as rituximab. Tumor cell kill following rituximab depends on binding of the antibody to the tumor cell and the host immune system. Therefore tumor cells that do not express the target antigen are not accessible to the antibody, or are resistant to immune-mediated attacks and may escape treatment. Radioimmunoconjugates, because of their ability to deliver radiation over a distance from a source, can not only kill tumor cells that are in contact with the antibody, but also adjacent tumor cells which may not have been in contact with the antibody or may not express the target antigen. This effect is sometimes referred to as the relevant bystander or “crossfire” effect. However, one disadvantage of radioimmunotherapy is that it can also damage adjacent normal tissues, such as bone marrow cells. Both 131 I-tositumomab and 90 Y-ibritumomab tiuxetan have shown activity in relapsed and refractory patients with indolent or transformed lymphomas.78,79 In patients who respond to radioimmunotherapy, the duration of remission can be more than several

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years. Based on these encouraging results, some clinicians are considering radioimmunotherapy earlier in the disease course, including patients with previously untreated disease. In a phase II study, patients with previously untreated follicular lymphoma were treated with six cycles of CHOP chemotherapy followed 4 to 8 weeks later by 131 I-tositumomab.80 The overall response rate to the entire treatment regimen was 90%, including 67% complete remissions, and the 2-year progression-free survival is estimated to be 81%. A current multicenter cooperative group study (SWOG S0016) randomizes patients with advanced indolent lymphomas to either CHOP or rituximab (given concurrently, based on the Czuczman regimen77 ) or CHOP and 131 I-tositumomab (given sequentially). Radioimmunotherapy is generally well tolerated. The major acute toxicities with both radioimmunoconjugates are infusionrelated reactions and myelosuppression. 131 I-tositumomab can also cause thyroid dysfunction. The primary concern with radioimmunotherapy is the development of treatment-related myelodysplastic syndrome or acute myelogenous leukemia.81 The decision to use radioimmunotherapy must be made carefully because of the complexity, risks, and costs of the treatment regimen. Although oncologists usually select patients for therapy, the radioimmunotherapy regimen must be administered at a radiation oncology or nuclear medicine facility. Because of safety concerns related to delivery of radiation to bone marrow, candidates for radioimmunotherapy usually have limited bone marrow involvement and adequate absolute neutrophil and platelet counts.


Hematopoietic Stem Cell Transplantation. High-dose chemotherapy, followed by autologous or allogeneic HSCT, is another option for patients with relapsed follicular lymphoma.63,82,83 In patients who are transplanted at the time of initial treatment failure, 5-year eventfree survival is about 40% to 50%. Although the rate of recurrence is lower after allogeneic HSCT as compared with autologous HSCT, that benefit is offset by increased treatment-related mortality after allogeneic HSCT.83 The presence of a survival plateau after allogeneic HSCT suggests that some patients may be cured of their disease. In a recently published randomized trial, patients with relapsed follicular lymphoma who received autologous HSCT had significantly longer progression-free and overall survival than those who received additional courses of combination chemotherapy.84 Based on these encouraging results, some studies have evaluated autologous HSCT as consolidation therapy after CHOP or CHOPlike chemotherapy in patients with poor-risk follicular lymphoma.82 Several large randomized trials are ongoing, and the results of these trials should further define the role of autologous HSCT as first-line therapy of follicular lymphoma. Rituximab is being evaluated in the setting of autologous HSCT.73,85 It is given pretransplant as an in vivo purging agent prior to stem cell collection. In other studies, rituximab is given as posttransplant consolidation. High-dose myeloablative transplants are usually reserved for younger patients without serious comorbidities, but nonmyeloablative allogeneic transplants may be an option for older patients who would not otherwise be eligible for autologous or allogeneic HSCT.
Investigational Therapies. As discussed above, the idiotype present on the patient’s tumor cells serves as a potential target for immunotherapy. This idiotype can be used to manufacture a patientspecific vaccine.53 Vaccines would potentially produce both humoral and cellular immune responses, and would also be longer acting than passive immunotherapy. Several vaccines are being evaluated in clinical trials.39

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OTHER INDOLENT LYMPHOMAS Marginal zone B-cell lymphomas, MALT (extranodal) and nodal types, are two of the new forms of NHL not previously recognized in the International Working Formulation.86 Extranodal and nodal types of marginal zone B-cell lymphomas represent approximately 7.6% and 1.8% of new cases of NHLs.48 Clinically, MALT lymphomas tend to be indolent. Most patients present with localized disease involving extranodal sites, which involves glandular epithelial tissues of various sites, such as the stomach, lungs, parotid gland, thyroid, and orbit (see Table 129–8). The stomach is the most frequent site and gastric MALT lymphomas are frequently associated with chronic gastritis and Helicobacter pylori infection. Because MALT lymphomas tend to remain localized for long periods, local treatment (surgery or local/regional radiation therapy) is effective and offers the opportunity for cure. Patients with gastric MALT lymphomas who are positive for H. pylori should be treated for their infection (e.g., antibiotics). Patients with disseminated MALT lymphoma should be treated with the same type of chemotherapy used in patients with follicular lymphoma.


AGGRESSIVE LYMPHOMAS
DIFFUSE LARGE B-CELL LYMPHOMA Diffuse large B-cell lymphomas (DLBCLs) are the most common lymphoma in the International NHL Classification Project, accounting for about 30% of all NHLs.48 Most DLBCLs are classified as diffuse large cell cleaved, noncleaved, or immunoblastic or diffuse mixed cell in the International Working Formulation.46,87 DLBCLs are characterized by the presence of large cells, which are similar in size to or larger than tissue macrophages and usually more than twice the size of normal lymphocytes. The median age at the time of diagnosis is in the seventh decade, but DLBCL can affect individuals of all ages, from children to the elderly. Patients often present with a rapidly enlarging symptomatic mass, with B symptoms in about one-third of the cases.38,88 About 30% to 40% of patients with DLBCL present with extranodal disease; common sites include the head and neck, gastrointestinal tract, skin, bone, testis, and CNS. DLBCL is the most common type of diffuse aggressive lymphoma, which share in common an aggressive clinical behavior that leads to death within weeks to months if the tumor is not treated. Diffuse aggressive lymphomas are also sensitive to many chemotherapeutic agents, and some patients treated with chemotherapy can be cured of their disease. Several factors have been shown to correlate with response to chemotherapy and survival in patients with aggressive lymphoma. Since the IPI was originally developed based on patients with aggressive lymphoma, IPI score correlates with prognosis (see Table 129–9).51 Although IPI is a clinically useful tool to estimate prognosis, the factors used to calculate the IPI score probably represent clinical surrogates for the biologic heterogeneity among DLBCLs, and many researchers are interested in determining the prognostic importance of certain phenotypic and molecular characteristics of DLBCLs. For example, markers of apoptosis, cell-cycle regulation, cell lineage, and cell proliferation are being evaluated as potentially clinically useful prognostic factors. Gene expression profiling with biochips may also correlate with survival. Using gene expression profiling, investigators identified three molecularly distinct forms of DLBCL based on gene expression patterns indicative of different

stages of B-cell differentiation: germinal center B-cell-like, activated B-cell-like, and type 3.89 The type 3 subgroup did not express either set of genes at a high level. The investigators used 17 genes to construct a model that correlated with overall survival after chemotherapy. In another study, investigators were able to develop a predictive model based on only six genes.90 These results suggest that molecular classification of tumors on the basis of gene expression may allow identification of clinically significant subtypes of cancer. Therapy of DLBCL is based on the Ann Arbor stage, IPI score, and other prognostic factors. About one-half of patients present with localized (stage I or II) disease. However, many patients present with large bulky masses (i.e., larger than 10 cm), and patients with bulky stage II disease are treated with the same approach as that used with those with advanced disease (stage III or IV).


Therapy of Localized Disease (Stages I and II) Before 1980, radiation therapy was the primary treatment for patients with localized DLBCL. Five-year disease-free survival with radiation therapy alone was about 50% and 20% in patients with stage I and stage II disease, respectively.38,87,88 Randomized trials in the 1980s showed that radiation therapy followed by chemotherapy resulted in significantly longer disease-free and overall survival as compared with radiation therapy alone. Other studies reported excellent results with a short course of chemotherapy (three cycles) followed by involved-field radiotherapy or six to eight cycles of CHOP chemotherapy, with or without consolidation radiotherapy. With either of these approaches, 5-year progression-free survival was >90% for patients with stage I disease and about 70% for patients with stage II disease.38,87,88 9 Since it was not clear which approach was more effective, the SWOG performed a randomized trial that compared three cycles of CHOP and involved-field radiotherapy or eight cycles of CHOP in patients with stage I and nonbulky stage II aggressive lymphoma.91 Patients treated with three cycles of CHOP plus radiotherapy had significantly better 5-year progression-free (77% vs. 64%) and overall (82% vs. 72%) survival than patients treated with CHOP alone. The incidence of life-threatening toxicity was higher in patients who received CHOP alone. Based on the results of this trial, the current standard for therapy of most patients with localized nonbulky aggressive lymphoma is three to four cycles of CHOP followed by locoregional radiation therapy (30 to 40 Gy).38,50,88 A stage-modified IPI score is sometimes used to identify patients with localized lymphoma who may have a poor prognosis. Patients with one or more of these poor prognostic factors (i.e., stage II, elevated LDH levels, age >60 years, or performance status ≥2) may benefit from more aggressive chemotherapy (six to eight cycles of CHOP) followed by locoregional radiation therapy. At some institutions, R-CHOP has replaced CHOP as standard therapy.


Therapy of Advanced Disease (Bulky Stage II and Stages III and IV) It has been known since the late 1970s that intensive combination chemotherapy can cure some patients with disseminated DLBCL.38,40,88 Initial studies with COP (same as CVP) produced a plateau on the survival curve of just 10%, with a median survival of less than 1 year. Based on the activity of single-agent doxorubicin, McKelvey and colleagues developed the CHOP regimen (see Table

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129–11).92 A few years later, a SWOG study showed that CHOP was more active than COP, and CHOP chemotherapy rapidly became the treatment of choice for patients with aggressive lymphomas.93 Studies in larger numbers of patients showed that about 50% of patients had a complete remission to CHOP chemotherapy, and 50% to 75% of the patients who had a complete response (about one-third of all patients) experienced long-term disease-free survival and cure of their disease. In an effort to improve these results, many investigators used several general approaches to develop second- and third-generation regimens in the 1980s and early 1990s.40,88 The first approach was to add a nonmyelotoxic drug, most often bleomycin, to the threeweek cycle (e.g., CHOP-Bleo or BACOP). The second approach was to add nonmyelosuppressive agents between cycles of CHOP or BACOP. One example of this strategy was the M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone) regimen, in which high-dose methotrexate with leucovorin rescue was administered on day 10. M-BACOD was later modified to m-BACOD, which included the same drugs but had a lower methotrexate dosage. Another variation on this strategy was to give semicontinuous or weekly therapy; relatively small doses of myelosuppressive agents are administered, alternating over a 12-week period with nonmyelosuppressive agents. An example of this strategy is MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin). The third approach was to give as many drugs as possible, as flexibly as possible (e.g., ProMACE/MOPP). ProMACE/MOPP was later modified to ProMACE/CytaBOM (prednisone, doxorubicin, cyclophosphamide, and etoposide, followed by cytarabine, bleomycin, vincristine, and methotrexate with leucovorin rescue). Results of phase II trials suggested that these second- and third-generation regimens were more active than CHOP, with slightly higher complete response rates and improved disease-free survival rates.38,40,88 However, they were also more difficult to administer, more toxic, and more expensive. Based on these results, oncologists generally adopted one of these second- or third-generation combination regimens as their standard regimen for patients with advanced aggressive lymphomas. Many randomized studies have compared different combination regimens in patients with aggressive lymphoma.38,40,88 Although the results of these studies show that no one regimen is clearly superior to another, they show the superiority of anthracycline-containing regimens over those that do not contain an anthracycline. In the largest and most widely quoted study, the SWOG initiated a randomized trial in 1986 that compared CHOP to three of the most commonly used third-generation regimens (m-BACOD, ProMACE/CytaBOM, and MACOP-B) in nearly 900 patients with bulky stage II, stage III, or stage IV aggressive lymphoma. At the time of the initial publication (median follow-up = 35 months), no differences in disease-free and overall survival were observed between the four groups.94 Furthermore, no significant differences in disease-free or overall survival were observed in any subgroup of patients. The risk of treatmentrelated mortality, however, was higher in patients receiving one of the third-generation regimens. Extended follow-up of that trial shows that about 35% of patients who participated in that trial are probably cured of their disease, regardless of the initial combination chemotherapy regimen.87 Interestingly, the overall survival is about 10% higher than the disease-free survival, which probably reflects the effectiveness of salvage high-dose chemotherapy with autologous HSCT (see below). Based on the lack of survival benefit with the newer combination chemotherapy regimens, the less complicated and less expensive CHOP regimen should be considered as the treatment of choice for most patients with DLBCL and other aggressive lymphomas.

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Unfortunately, the major conclusion from these studies is not that all of these regimens are extremely effective, but that all of these regimens are equally bad. Less than 50% of patients with DLBCL are currently cured of their disease with combination chemotherapy, and most patients who relapse after an initial response do so in the first 2 years. New treatment approaches are clearly needed. The IPI score should be calculated for every patient with DLBCL and incorporated into treatment decisions for individual patients (see Table 129–9). Patients with a low IPI score should be treated with conventional CHOP (or R-CHOP) therapy. But patients with a highintermediate or high-risk IPI score should be identified as candidates for more aggressive treatments. These include addition of rituximab to CHOP, dose-intense or dose-dense chemotherapy with growth factor support, or high-dose chemotherapy with autologous HSCT. Based on the encouraging results of R-CHOP in indolent lymphomas, several studies have evaluated this combination in aggressive lymphomas.55 In a multicenter pilot study of 33 patients with previously untreated CD20+ aggressive NHL, the addition of rituximab to six cycles of CHOP chemotherapy produced a 94% objective response rate, with 61% of patients achieving a complete response.95 Rituximab was given at a dosage of 375 mg/m2 on day 1 of each cycle; cyclophosphamide, doxorubicin, and vincristine was given intravenously on day 3, and oral prednisone was given on days 3 to 7. In an updated analysis (62 months), progression-free and overall survival was 80% and 87%, respectively. In the 18 patients with an IPI score of ≥2, the overall response rate was 89% and complete response rate was 56%. No significant additional toxicity was noted. Based on these encouraging results, including the results of the GELA study in elderly patients (see below), many institutions currently recommend R-CHOP in all patients with aggressive lymphoma.50 Several studies have attempted to improve treatment results by increasing chemotherapy dose (i.e., dose-intensity), shortening the interval between chemotherapy cycles (i.e., dose-density), or both. Because of the increased risk of severe neutropenia, these approaches require growth factor support. Although results of these studies have not consistently shown improved survival, encouraging results from several recently published studies suggest that these approaches be evaluated in future randomized trials.96,97 Another approach in high-risk patients is to give high-dose chemotherapy with autologous HSCT as intensive consolidation in high-risk patients with DLBCL who achieve a remission with standard chemotherapy.87 Several randomized controlled trials have been conducted in patients with aggressive NHLs, and the results of these trials have been critically reviewed recently by two independent panels of experts.98,99 Based on a review of the available evidence, it was concluded that high-dose chemotherapy with autologous HSCT is effective in high-risk (i.e., high-intermediate/high-risk based on IPI score) patients who have a complete remission to conventional therapy (first complete remission in high-risk patients) and in untreated high-risk patients (high-dose sequential therapy in untreated highrisk patients).99 There was inadequate evidence to make a treatment recommendation for the other possible clinical situations, such as in patients who do not respond to standard induction therapy (primary refractory disease) or in patients who have a partial remission to standard induction therapy (first partial remission after full-course induction therapy). Since those recommendations were published, another randomized study showed that high-dose chemotherapy with autologous HSCT improves event-free survival in patients with a lower IPI score (i.e., low, low-intermediate, or high-intermediate risk).100 Unfortunately, the available evidence has led to a discussion of when high-dose chemotherapy with autologous HSCT should be

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offered to high-risk patients with aggressive NHLs: early (i.e., when patients are in their first complete remission) or later (i.e., after patients have relapsed). To address this question, the various cooperative groups in the United States have agreed to conduct a randomized clinical trial of early versus delayed high-dose chemotherapy for patients with high-risk (high-intermediate or high-risk based on IPI score) DLBCL. In this trial, referred to as the North American High-Dose Therapy Trial, patients younger than 65 years old will receive five courses of CHOP chemotherapy. Patients who have a partial or complete response will then be randomized to receive either three more cycles of CHOP or one additional cycle of CHOP followed by highdose chemotherapy with autologous HSCT. Patients on the standard CHOP treatment who relapse will then receive the same high-dose chemotherapy. CLINICAL CONTROVERSY Because of high relapse rate in patients who have a complete response to CHOP, some clinicians believe that highdose chemotherapy with autologous HSCT should be given as consolidation therapy in high-risk patients with aggressive NHLs who have a complete remission to CHOP or R-CHOP chemotherapy. To address this question, the North American High-Dose Therapy Trial is a randomized clinical comparison of early versus delayed high-dose chemotherapy for patients with high-risk (high-intermediate or high-risk based on IPI score) diffuse large B-cell lymphoma. The results of this trial should determine when high-risk patients with aggressive lymphoma should receive high-dose chemotherapy with autologous HSCT.

9 In summary, all younger patients with bulky stage II, stage III, or

stage IV disease should be treated with CHOP (or R-CHOP) or CHOP-like chemotherapy until a complete response is achieved (usually three to four cycles).50 A rapid response to chemotherapy (i.e., a complete response achieved in the first three treatment cycles) is associated with a more durable remission compared with patients requiring longer treatment. Two or more cycles of chemotherapy should be given following attainment of a complete response (a total of six to eight cycles). The use of long-term maintenance therapy following a complete response has not been shown to improve survival. High-dose chemotherapy with autologous HSCT should be considered in highrisk patients who respond to standard chemotherapy. Patients should be enrolled in clinical trials of new treatment approaches whenever possible.


Therapy of Elderly Patients with Advanced Disease More than one-half of patients with NHL are older than 60 years of age at diagnosis, and about one-third are over the age of 70 years. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project showed that patients older than 60 years of age had a significantly lower complete response rate and overall survival.51 The reasons for the poorer outcome in elderly patients are not clear. Older patients do not tolerate intensive chemotherapy as well as younger patients, and some studies have reported that older patients have a higher risk of treatment-related mortality. As a result, many clinicians treat elderly patients with reduced-dose or less-aggressive chemotherapy regimens. In general, these less intensive regimens have used anthracyclines with less cardiotoxicity than doxorubicin, have substituted

mitoxantrone for doxorubicin, or have used short-duration weekly therapy.38,88 Over the past few years, several nonrandomized and randomized trials have evaluated different treatment approaches in older patients with aggressive NHL.38,88 The results of these studies suggest that carefully selected elderly patients with good performance status and without significant comorbidities may tolerate aggressive anthracycline-containing regimens as well as younger patients. These patients should be treated initially with full-dose CHOP or similar regimens; dosages can be reduced later if severe toxicity occurs. Hematopoietic growth factors may allow elderly patients to maintain dose intensity. The combination of rituximab and CHOP (R-CHOP) has replaced CHOP as standard treatment for elderly patients with aggressive lymphoma, based on the results of the GELA study.101 In that study of 399 elderly patients with DLBCL, patients who were randomized to receive R-CHOP had a significantly higher complete response rate (76% vs. 63%) and longer event-free and overall survival as compared with those who received CHOP. In an updated analysis of that trial, significant differences in 4-year event-free survival (51% vs. 29%) and overall survival (59% vs. 47%) were observed between the two treatment groups. Further analysis of that study showed that the treatment benefit was primarily observed in patients with tumors that overexpressed BCL-2 (BCL-2+ ).102 It is important to note that rituximab is given differently in the GELA study as compared with the Czuczman study in patients with indolent lymphomas. In the R-CHOP regimen developed by Czuczman and associates,77 two doses of rituximab are given before the start of CHOP therapy; two more doses are given in the middle of the six cycles of CHOP; and two additional doses are given at the end of CHOP therapy. In the GELA study, rituximab is given on day 1 (the same day that cyclophosphamide, doxorubicin, and vincristine are administered) with each cycle of CHOP chemotherapy.


Salvage Therapy Although many patients with aggressive NHL experience long-term survival and cure with intensive chemotherapy, nearly 50% of patients fail to achieve a complete remission, and of those patients who do achieve a complete remission, about 20% to 30% subsequently relapse. Therefore about 60% to 70% of all patients with aggressive NHL will require salvage therapy at some time during their disease course. Response to salvage therapy depends on the initial responsiveness of the tumor to chemotherapy. Patients who achieve an initial complete remission and then relapse generally have a better response to salvage therapy than those who are primarily or partially resistant to chemotherapy. Many conventional-dose salvage chemotherapy regimens have been used in patients with relapsed or refractory NHL. Many patients who respond to salvage therapy (i.e., chemosensitive relapse) will then receive high-dose chemotherapy with autologous HSCT. In an effort to avoid cross-resistance, most salvage regimens incorporate drugs not used in the initial therapy. Some of the more commonly used salvage regimens include DHAP (dexamethasone, cytarabine, and cisplatin), ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin), and MINE (mesna, ifosfamide, mitoxantrone, and etoposide), and no one regimen appears to be clearly superior to any other regimen.38,40,88,103 Rituximab is sometimes added to these salvage regimens. With these salvage regimens, about 25% to 35% of patients achieve a complete response, with a median duration of remission of

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1 to 2 years. Only about 5% to 10% of patients will have long-term disease-free survival. ICE (ifosfamide, carboplatin, and etoposide) chemotherapy is a newer regimen that has been used in patients with refractory disease. Some clinicians believe that ICE is better tolerated than older cisplatin-based regimens, particularly in older patients. The combination of ICE and rituximab (RICE) is currently being evaluated as a salvage regimen, and early results are encouraging.104 Rituximab is given before the first dose of ICE and then weekly during the regimen. 10 To improve the cure rate, many studies have evaluated highdose chemotherapy with autologous HSCT as intensive consolidation therapy in patients who respond to salvage therapy.98,99 In the PARMA study, 215 patients with relapsed aggressive NHL who had a response to DHAP salvage therapy were randomized to receive either high-dose chemotherapy or continued DHAP therapy.105 Patients who received high-dose chemotherapy had significantly longer 5-year disease-free survival (46% vs. 12%) and overall survival (53% vs. 32%) than those treated with conventional salvage therapy. Further analysis of that study showed that patients who relapsed within 12 months of their initial diagnosis were less likely to benefit from high-dose chemotherapy than patients who relapsed after 12 months. Based on a review of the available evidence, including the PARMA study, it was concluded that high-dose chemotherapy with autologous HSCT is effective in patients who relapse for the first time and have responded to salvage therapy (first chemotherapy-sensitive relapse).98,99 Unfortunately, there was inadequate evidence to make a treatment recommendation for patients who relapse and have not responded to salvage therapy (chemotherapy-resistant relapse). Based on these studies, high-dose chemotherapy with autologous HSCT is considered to be the treatment of choice in younger patients with chemotherapy-sensitive relapse.38,50,88,106 High-dose chemotherapy with autologous HSCT is not recommended in patients with untested or chemotherapy-refractory relapse. Rituximab is being evaluated in the setting of autologous HSCT.73,85 It is given pretransplant as an in vivo purging agent prior to stem cell collection. In one study of patients with aggressive lymphoma, two courses of rituximab (starting at day 42 and 6 months posttransplant) were given as posttransplant consolidation.85


OTHER AGGRESSIVE LYMPHOMAS Mantle cell lymphoma (MCL) is one of the new disease entities previously unrecognized by other classification systems.107 This histologic type was found in 6% of cases in the International Non-Hodgkin’s Lymphoma Classification Project.48 The chromosomal translocation t(11;14) occurs in most cases of MCL. MCL usually occurs in older adults, particularly in men, and most patients have advanced disease at the time of diagnosis (see Table 129–8).107 Extranodal involvement is found in about 90% of cases. The course of the disease is moderately aggressive; the median overall survival is about 3 years, with no evidence of a survival plateau. Patients with disseminated MCL are usually treated with the same intensive combination chemotherapy regimens that are used in diffuse aggressive lymphomas. Overall response rates to these regimens is about 80%, with about one-half of patients achieving a complete response.107 Median progression-free and overall survival was 20 and 36 months, respectively. In patients who respond to initial therapy, interferon alfa may have a role as maintenance or consolidation therapy. Despite the high response rates, MCL is not considered curable with standard chemotherapy. Therefore younger patients who

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have an initial response to chemotherapy often undergo autologous or allogeneic HSCT as consolidation therapy.108 Because MCL usually expresses CD20, rituximab, either alone or combined with CHOP, has been used with some success in patients with newly diagnosed and relapsed MCL.55,107 The NCCN Guidelines recommend that patients with advanced-stage MCL be treated initially with combination chemotherapy, either alone or combined with rituximab.50 Primary mediastinal large B-cell lymphoma (PMBL) is a distinct clinicopathologic entity, accounting for about 7% of all DLBCLs and 2.4% of all NHLs in the International NHL Classification Project.48 This type of lymphoma tends to occur in younger patients (median age at presentation is 30 years old) and has a female predominance (see Table 129–8).109 Patients present with a locally invasive mediastinal mass originating in the thymus, with frequent airway compromise and superior vena cava syndrome. Although the disease course is similar to that of other aggressive lymphomas, the biologic features of PMBL clearly differentiate PMBL from other types of DLBCL.109 Patients with PMBL should be treated similarly to other patients with localized DLBCL.


NON-HODGKIN’S LYMPHOMA IN AIDS The risk of NHL for patients with AIDS is increased about 150- to 250-fold as compared to the general population.110 AIDS-related lymphoma arises as a consequence of long-term stimulation and proliferation of B lymphocytes from HIV and the reactivation of prior EBV infection due to HIV-induced immunosuppression.38,40,111 AIDS-related lymphoma usually occurs late in the course of HIV infection and is the cause of death in about 15% of HIV-infected individuals. Although HIV infects T cells, more than 95% of AIDSrelated lymphomas are B-cell neoplasms. About 60% of AIDS-related lymphomas are classified as Burkitt’s (30%) or diffuse large B-cell type (30%).111 The clinical presentation is similar to that observed in other immunocompromised states. Most patients with AIDS-related lymphoma present with B (constitutional) symptoms and have advanced stage (III or IV) disease at the time of diagnosis.38,40,111 Involvement of extranodal sites is common. The clinical course of AIDS-related lymphoma is aggressive; median survival is about 6 months and 2-year survival is only 10% to 20%. Factors associated with decreased survival include age greater than 35 years, history of injection drug use, CD4 cell count 75% in lymph node masses, and a normal or indeterminate bone marrow biopsy. A partial response is defined as shrinkage of tumor in the lymph nodes or lymph node masses by ≥50%, or a completely normal exam except a positive bone marrow biopsy. Relapse or progression is defined as new nodes involved or an increase in nodal or spleen mass size. Patients with Hodgkin’s and aggressive non-Hodgkin’s lymphoma are usually evaluated for response at the end of four cycles of therapy or at the end of treatment if less than four cycles of therapy are planned. If patients are treated with chemotherapy alone, two additional cycles of chemotherapy are given after the patient has achieved a complete remission. The rapidity of response to therapy in patients with indolent NHL depends on the choice of therapy. Responses occur slowly with therapy with oral alklylating agents, but occur much more rapidly with aggressive therapies such as combination chemotherapy with or without rituximab. If radiation alone is used, then a therapeutic evaluation should occur at the end of treatment.

CONCLUSIONS Several decades ago, lymphomas were considered a fatal disease. Today most patients with Hodgkin’s disease and many patients with aggressive NHLs can be cured with radiation therapy, chemotherapy, or a combination of radiation and chemotherapy. Our ability to achieve long-term survival and cure in these patients is the result of many factors, including development of accurate and reproducible classification systems; a more uniform approach to the staging of lymphoma; and advances in treatment strategies, especially the use of intensive combination chemotherapy. The routine use of hematopoietic growth factors allows oncologists to maintain dose intensity, which may be important for the treatment of aggressive lymphomas. The use of highdose chemotherapy with autologous HSCT as intensive consolidation therapy for selected patients with aggressive NHL who respond to initial induction therapy, or as salvage therapy after relapse for patients with Hodgkin’s lymphoma or aggressive NHL, has also contributed to increased cure rates. New treatment approaches are needed, particularly for indolent NHLs. Although many new therapies have been developed recently

ABBREVIATIONS ABVD: doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine AIDS: acquired immunodeficiency syndrome ATL: adult T-cell leukemia/lymphoma BACOP: bleomycin, cyclophosphamide, doxorubicin (hydroxydaunomycin), vincristine (Oncovin), and prednisone BEACOPP: bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone 2-CdA: cladribine CDE: cyclophosphamide, doxorubicin, and etoposide cHL: classical Hodgkin’s lymphoma ChlVPP: chlorambucil, vincristine (Oncovin), procarbazine, and prednisone CHOP-B: cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin CHOP: cyclophosphamide, doxorubicin (hydroxydaunomycin), vincristine (Oncovin), and prednisone CHVP: cyclophosphamide, doxorubicin (hydroxydaunomycin), teniposide, and prednisone COPP: cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone

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CR: complete response CS: clinical stage CT: computed tomography CVP: cyclophosphamide, vincristine, and prednisone CVPP: cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone DHAP: dexamethasone, cytarabine, and cisplatin DLBCL: diffuse large B-cell lymphoma EBV: Epstein-Barr virus EBVP: epirubicin, bleomycin, vinblastine, and prednisone EORTC: European Organization for Research and Treatment of Cancer EPOCH: etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin ESHAP: etoposide, methylprednisolone, cytarabine, and cisplatin ESR: erythrocyte sedimentation rate FLIPI: Follicular Lymphoma International Prognostic Index FND: fludarabine, mitoxantrone, and dexamethasone FN: fludarabine and mitoxantrone G-CSF: granulocyte colony-stimulating factor GHLSG: German Hodgkin’s Lymphoma Study Group HAART: highly active antiretroviral therapy HIV: human immunodeficiency virus HPF: high-power field HSCT: hematopoietic stem cell transplantation HTLV-1: human T-cell lymphotropic virus type 1 ICE: ifosfamide, carboplatin, and etoposide IFN-α: interferon alfa IPI: International Prognostic Index IPS: International Prognostic Score LDH: lactate dehydrogenase MACOP-B: methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin MALT: mucosa-associated lymphoid tissue M-BACOD: methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), and dexamethasone MCL: mantle cell lymphoma MINE: mesna, ifosfamide, mitoxantrone, and etoposide MOPP: mechlorethamine, vincristine (Oncovin), procarbazine, and prednisone MRI: magnetic resonance imaging MVPP: mechlorethamine, vinblastine, procarbazine, and prednisone NCCN: National Comprehensive Cancer Network NCI: National Cancer Institute NHL: non-Hodgkin’s lymphoma NLPHD: nodular lymphocyte-predominant Hodgkin’s disease PCR: polymerase chain reaction PMBL: primary mediastinal large B-cell lymphoma PR: partial response ProMACE/CytaBOM: prednisone, doxorubicin, cyclophosphamide, and etoposide, followed by cytarabine, bleomycin, vincristine, and methotrexate with leucovorin rescue ProMACE/MOPP: prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide/mechlorethamine, vincristine, procarbazine, and prednisone PS: pathologic stage R-CHOP: rituximab, cyclophosphamide hydroxydaunomycin, vincristine (Oncovin), and prednisone REAL-WHO: Revised European-American Classification of Lymphoid Neoplasms and World Health Organization RICE: rituximab, ifosfamide, carboplatin, and etoposide SWOG: Southwest Oncology Group

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Review Questions and other resources can be found at www.pharmacotherapyonline.com.

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21. Engert A, Schiller P, Josting A, et al. Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin’s lymphoma: results of the HD8 trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 2003;21:3601–3608. 22. Horning SJ, Hoppe RT, Breslin S, et al. Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: mature results of a prospective clinical trial. J Clin Oncol 2002;20:630–637. 23. DeVita VT Jr, Simon RM, Hubbard SM, et al. Curability of advanced Hodgkin’s disease with chemotherapy. Long-term follow-up of MOPP-treated patients at the National Cancer Institute. Ann Intern Med 1980;92:587–595. 24. Longo DL, Young RC, Wesley M, et al. Twenty years of MOPP therapy for Hodgkin’s disease. J Clin Oncol 1986;4:1295–306. 25. Longo DL. The use of chemotherapy in the treatment of Hodgkin’s disease. Semin Oncol 1990;17:716–735. 26. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992;327:1478–1484. 27. Goldie JH, Coldman AJ, Gudauskas GA. Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep 1982;66: 439–449. 28. Glick JH, Young ML, Harrington D, et al. MOPP/ABV hybrid chemotherapy for advanced Hodgkin’s disease significantly improves failure-free and overall survival: the 8-year results of the intergroup trial. J Clin Oncol 1998;16:19–26. 29. Duggan DB, Petroni GR, Johnson JL, et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol 2003;21: 607–614. 30. Prosnitz LR. Consolidative radiotherapy in the treatment of advanced Hodgkin’s disease: is it dead? Int J Radiat Oncol Biol Phys 2003;56: 605–608. 31. Loeffler M, Brosteanu O, Hasenclever D, et al. Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin’s disease. International Database on Hodgkin’s Disease Overview Study Group. J Clin Oncol 1998;16:818–829. 32. Aleman BMP, Raemaekers JMM, Tirelli U, et al. Involved-field radiotherapy for advanced Hodgkin’s lymphoma. N Engl J Med 2003;348:2396–2406. 33. Horning SJ, Williams J, Bartlett NL, et al. Assessment of the Stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkin’s disease: Eastern Cooperative Oncology Group pilot study E1492. J Clin Oncol 2000;18:972–980. 34. Diehl V, Franklin J, Hasenclever D, et al. BEACOPP, a new doseescalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin’s lymphoma: interim report from a trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 1998;16:3810–3821. 35. Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med 2003;348:2386–2395. 36. Bierman PJ, Nademanee A. Autologous and allogeneic hematopoietic cell transplantation for Hodgkin’s disease. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas’ Hematopoietic Cell Transplantation. Malden, MA, Blackwell Science, 2004:1191–1206. 37. Longo DL, Duffey PL, Young RC, et al. Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin’s disease after combination chemotherapy: the low probability for cure. J Clin Oncol 1992;10:210–218. 38. Armitage JO, Mauch PM, Harris NL, Bierman P. Non-Hodgkin’s lymphoma. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology, 6th ed. Philadelphia, Lippincott Williams & Wilkins, 2001:2256–2316. 39. Vose JM, Chiu BC-H, Cheson BD, et al. Update on epidemiology and therapeutics for non-Hodgkin’s lymphoma. Hematology (Am Soc Hematol Educ Program) 2002:241–262.

40. Lister TA, Armitage JO. Non-Hodgkin’s lymphoma. In: Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE, eds. Clinical Oncology, 2nd ed. New York, Churchill Livingstone, 2000:2658–2719. 41. Macintyre E, Willerford D, Morris SW. Non-Hodgkin’s lymphoma: molecular features of B cell lymphoma. In: Schechter GP, Berliner N, Telen MJ, eds. Hematology 2000, 2000:180–204. 42. Harris NL, Stein H, Coupland SE, et al. New approaches to lymphoma diagnosis. Hematology (Am Soc Hematol Educ Program) 2001: 194–220. 43. Freeman AS, Neuberg D, Mauch P, et al. Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 1999;94:3325–3333. 44. Trumper LH, Brittinger G, Diehl V, Harris NL. Non-Hodgkin’s lymphoma: a history of classification and clinical observations. In: Mauch PM, Armitage JO, Coiffier B, et al, eds. Non-Hodgkin’s Lymphomas. Philadelphia, Lippincott Williams & Wilkins, 2004:3–19. 45. Kuppers R, Klein U, Hansmann M-L, Rajewsky K. Cellular origins of human B-cell lymphomas. N Engl J Med 1999;341:1520–1529. 46. Harris NL, Jaffe ES, Stein H. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;84:1361–1392. 47. Harris NL. Revised European-American and World Health Organization Classifications of Non-Hodgkin’s Lymphoma. In: Mauch PM, Armitage JO, Coiffier B, et al, eds. Non-Hodgkin’s Lymphoma. Philadelphia, Lippincott Williams & Wilkins, 2004:45–58. 48. The Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of nonHodgkin’s lymphoma. Blood 1997;89:3909–3918. 49. Harris NL, Jaffe ES, Diebold J, et al. World Health Organization Classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835–3849. 50. Non-Hodgkin’s Lymphoma Guidelines. Practice Guidelines in Oncology: National Comprehensive Cancer Network, 2004. 51. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993;329:987–994. 52. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood 2004;104:1258–1265. 53. Levy R. Karnofsky lecture: immunotherapy of lymphoma. J Clin Oncol 1999;17:7–13. 54. Grillo-Lopez AJ, White CA, Varns C, et al. Overview of the clinical development of rituximab: first monoclonal antibody approved for treatment of lymphoma. Semin Oncol 1999;26(Suppl 14):66–73. 55. Plosker GL, Figgitt DP. Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Drugs 2003;63:803–843. 56. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphoma. J Clin Oncol 1999;17:1244–1253. 57. Freedman AS, Friedberg JW, Mauch PM, et al. Follicular lymphoma. In: Mauch PM, Armitage JO, Coiffier B, et al, eds. Non-Hodgkin’s Lymphoma. Philadelphia, Lippincott Williams & Wilkins, 2004:367–388. 58. The Non-Hodgkin’s Lymphoma Classification Project: National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas. Summary and description of a working formulation for clinical usage. Cancer 1982;49:2112–2135. 59. Horning SJ. Natural history of and therapy for the indolent nonHodgkin’s lymphomas. Semin Oncol 1993;20(Suppl 5):75–88. 60. Rodriguez J, McLaughlin P, Hagenmeister FB, et al. Follicular large cell lymphoma: an aggressive lymphoma that often presents with favorable prognostic features. Blood 1999;93:2202–2207. 61. Seymour JF, Pro B, Fuller LM, et al. Long-term follow-up of a prospective study of combined modality therapy for stage I–II indolent nonHodgkin’s lymphoma. J Clin Oncol 2003;21:2115–2122. 62. Cheson BD. New therapeutic strategies for the treatment of indolent non-Hodgkin’s lymphoma. In: Schechter GP, Hoffman R, Schrier S, eds. Hematology (Am Soc Hematol Educ Program), 1999:291–829.

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CHAPTER 129 63. Cabanillas F, Horning S, Kaminski M, Champlin R. Managing indolent lymphomas in relapse: working our way through a plethora of options. Hematology (Am Soc Hematol Educ Program) 2000:166–179. 64. Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin’s lymphoma: a randomised controlled trial. Lancet 2003;362:516–522. 65. Peterson BA, Petroni GR, Frizzera G, et al. Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the Cancer and Leukemia Group B. J Clin Oncol 2003;21:5–15. 66. McLaughlin P, Hagemeister F, Romaguera J, et al. Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma. J Clin Oncol 1996;14:1262–1268. 67. Velasquez WS, Lew D, Grogan TM, et al. Combination of fludarabine and mitoxantrone in untreated stages III and IV low-grade lymphoma: S9501. J Clin Oncol 2003;21:1996–2003. 68. Parkinson DR, Sznol M, Cheson BD. Biologic therapies for low-grade lymphomas. Semin Oncol 1993;20(Suppl 5):111–117. 69. Solal-Celigny P, Lepage E, Brousse N, et al. Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphoma: final analysis of survival and toxicity in the Groupe d’Etude des Lymphomes Folliculaires 86 Trial. J Clin Oncol 1998;16:2332–238. 70. Cheson BD. The curious case of the baffling biological. J Clin Oncol 2000;18:2007–2009. 71. Fisher RI, Dana BW, LeBlanc M, et al. Interferon alfa consolidation after intensive chemotherapy does not prolong the progression-free survival of patients with low-grade non-Hodgkin’s lymphoma: results of the Southwest Oncology Group Randomized Phase III Study 8809. J Clin Oncol 2000;18:2010–2016. 72. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituxumab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16:2825–2833. 73. Cohen Y, Solal-Celigny P, Polliack A. Rituximab therapy for follicular lymphoma: a comprehensive review of its efficacy as primary treatment, treatment for relapsed disease, re-treatment and maintenance. Haematologica 2003;88:811–823. 74. Davis TA, Grillo-Lopez AJ, White CA, et al. Rituxumab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: safety and efficacy of re-treatment. J Clin Oncol 2000;18:3135–3143. 75. Colombat P, Salles G, Brousse N, et al. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood 2001;97:101–106. 76. Hainsworth JD, Litchy S, Burris HA, et al. Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin’s lymphoma. J Clin Oncol 2002;20:4261–4267. 77. Czuczman MS, Grillo-Lopez AJ, White CA, et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999;17:268–276. 78. Cheson BD. Radioimmunotherapy of non-Hodgkin lymphomas. Blood 2003;101:391–398. 79. Emmanouilldes C. Radioimmunotherapy for non-Hodgkin’s lymphoma. Semin Oncol 2003;30:531–544. 80. Press OW, Unger JM, Braziel RM, et al. A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911. Blood 2003;102:1606–1612. 81. Armitage JO, Carbone PP, Connors JM, et al. Treatment-related myelodysplasia and acute leukemia in non-Hodgkin’s lymphoma patients. J Clin Oncol 2003;21:897–906. 82. Hunault-Berger M, Ifrah N, Solal-Celigny P, et al. Intensive therapies in follicular non-Hodgkin lymphomas. Blood 2002;100:1141–1152. 83. van Besien K, Loberiza FR, Bajorunaite R, et al. Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 2003;102:3521–3529.

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84. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular nonHodgkin’s lymphoma: results from the randomized European CUP trial. J Clin Oncol 2003;21:3918–3927. 85. Horwitz SM, Negrin RS, Blume KG, et al. Rituximab as adjuvant to high-dose therapy and autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma. Blood 2004;103:777–783. 86. Cavalli F, Isaacson PG, Gascoyne RD, Zucca E. MALT lymphomas. Hematology (Am Soc Hematol Educ Program) 2001:241–258. 87. Fisher RI, Shah P. Current trends in large cell lymphoma. Leukemia 2003;17:1948–1960. 88. Armitage JO, Mauch PM, Harris NL, et al. Diffuse large B-cell lymphoma. In: Mauch PM, Armitage JO, Coiffier B, et al, eds. NonHodgkin’s Lymphoma. Philadelphia, Lippincott Williams & Wilkins, 2004:427–453. 89. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002;346:1937–1947. 90. Lossos IS, Czerwinski DK, Alizadeh AA, et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 2004;350:1828–1837. 91. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediateand high-grade non-Hodgkin’s lymphoma. N Engl J Med 1998;339: 21–26. 92. McKelvey EM, Gottleib JA, Wilson HE, et al. Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer 1976;38:1484–1493. 93. Jones SE, Grozea PN, Metz EN, et al. Superiority of Adriamycin containing combination chemotherapy in the treatment of diffuse lymphoma: a Southwest Oncology Group study. Cancer 1979;43:417–425. 94. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 1993;328:1002– 1006. 95. Vose JM, Link BK, Grossbard ML, et al. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin’s lymphoma. J Clin Oncol 2001;19:389–397. 96. Blayney DW, LeBlanc ML, Grogan T, et al. Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group (SWOG 9349). J Clin Oncol 2003;21:2466–2473. 97. Coiffier B. Increasing chemotherapy intensity in aggressive lymphoma: a renewal? J Clin Oncol 2003;21:2457–2459. 98. Shipp MA, Abeloff MD, Antman KH, et al. International consensus conference on high-dose therapy with hematopoietic stem cell transplantation in aggressive non-Hodgkin’s lymphomas: report of the jury. J Clin Oncol 1999;17:423–429. 99. Haln T, Wolff SN, Czuczman M, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of diffuse large cell B-cell non-Hodgkin’s lymphoma: an evidence-based review. Biol Blood Marrow Transplant 2001;7:308–331. 100. Milpied N, Deconinck E, Gaillard F, et al. Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 2004;350:1287–1295. 101. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235–242. 102. Mounier N, Briere J, Gisselbrecht C, et al. Rituximab plus CHOP (R-CHOP) overcomes bcl-2-associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood 2003;101:4279–4284. 103. Rodriguez-Monge EJ, Cabanillas F. Long-term follow-up of platinumbased lymphoma salvage regimens. The M.D. Anderson Cancer Center experience. Hematol Oncol Clin North Am 1997;11:937–947.

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104. Kewalramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood 2004;103:3684–3688. 105. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995;333:1540–1545. 106. Lister TA. High-dose therapy for follicular lymphoma revisited: not if, but when? J Clin Oncol 2003;21:3894–3896. 107. Hiddemann W, Lenz G, Weisenburger DD, Dreyling MH. Mantle cell lymphoma. In: Mauch PM, Armitage JO, Coiffier B, et al, eds. NonHodgkin’s Lymphoma. Philadelphia, Lippincott Williams & Wilkins, 2004:461–476. 108. Press OW. Treatment of mantle-cell lymphoma: stem-cell transplanta-

109.

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tion, radioimmunotherapy, and management of mantle-cell lymphoma subsets. In: ASCO Education Book, 2002:407–415. van Besien K, Kelta M, Bahaguna P. Primary mediastinal B-cell lymphoma: a review of pathology and management. J Clin Oncol 2001;19:1855–1864. Goedert JJ. The epidemiology of acquired immunodeficiency syndrome malignancies. Semin Oncol 2000;27:390–401. Levine AM, Said JW. Management of acquired immunodeficiency syndrome-related lymphoma. In: Mauch PM, Armitage JO, Coiffier B, et al, eds. Non-Hodgkin’s Lymphoma. Philadelphia, Lippincott Williams & Wilkins, 2004:613–627. Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with doseadjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood 2003;101:4653–4659.

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130 OVARIAN CANCER William C. Zamboni, Laura L. Jung, and Margaret E. Tonda

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Patients with local disease have a 5-year survival rate

greater than 90%, but most patients present with disseminated disease because symptoms are nonspecific and go unrecognized until late in the disease course. Patients with advanced disease have a 5-year survival rate of 10% to 30%.

2 Ovarian cancer usually occurs in postmenopausal women in the sixth decade of life; the risk of developing ovarian cancer is increased in women with a family history involving two or more first-degree relatives.

ease treated with optimal debulking (2 cm of residual disease) have less than a 10% long-term survival rate.

7 Current recommended treatment of advanced ovarian cancer (stage III or IV) is based on initial surgical debulking followed by paclitaxel plus carboplatin for six cycles.

8 Approximately 20% to 50% of patients without evidence

3 CA-125 is an antigen common to most nonmucinous epithelial ovarian carcinoma and is a useful marker for ovarian cancer; rising or falling CA-125 titers correlate with the disease extent.

of disease on second-look laparotomy will relapse. In addition, patients who were initially sensitive to chemotherapy and whose response lasted the longest have the greatest likelihood of achieving a response to retreatment with the initial treatment regimen or treatment with salvage therapy.

4 Ovarian cancer management is based on the histologic

9 Patients with disease that was refractory to the initial

type, pathologic grade, and disease stage at initial presentation. In general, the treatment of patients with ovarian cancer involves surgical debulking at the time of staging laparotomy and primary or adjuvant chemotherapy.

5 The beneficial effects of adjuvant chemotherapy in the treat-

ment of local disease depend on the stage and disease subtype. Postoperative adjuvant chemotherapy is not required in stage IA or IB grade 1, whereas patients with stage IA or IB grade 2 or 3, and stage IC require adjuvant chemotherapy. All patients with stage II disease require adjuvant treatment. Paclitaxel plus carboplatin or cisplatin for three to six cycles is the current recommended adjuvant therapy for these patients.

6 Survival of patients with advanced ovarian cancer is a func-

tion of stage at initial diagnosis and the amount of residual disease after surgical debulking. Patients with stage III dis-

Ovarian cancer is the fifth most common noncutaneous malignancy diagnosed in women.1 Overall, it is the fifth leading cause of cancer-related death and the most common death from gynecologic malignancy.1 The incidence of ovarian cancer is highest in the United States, Europe, and Israel, and lowest in Japan and developing countries.2 In the United States alone, it is estimated that 22,220 new cases of ovarian cancer will be diagnosed, and 16,210 women will die from this disease in 2005.1 Based on Surveillance, Epidemiology, and End Results data collected from 1995 to 2000, 5-year survival

platinum-containing chemotherapy or that recurs within 6 months after treatment (platinum-refractory) are unlikely to benefit from standard-dose platinum therapy. However, patients who relapse more than 6 months after the initial platinum-containing regimen (platinum-sensitive) have a response rate of 27% to 59% with a standard-dose secondline platinum regimen.

10 The NCCN guidelines recommend retreatment with either

paclitaxel or platinum, or the combination of paclitaxel and a platinum compound if disease recurs more than 6 months after the initial treatment with paclitaxel in combination with a platinum analog. Treatment options for patients with refractory disease or disease recurrence within 6 months after treatment include topotecan, altretamine, oral etoposide, liposomal doxorubicin, gemcitabine, tamoxifen, referral for a clinical trial, or supportive care therapy.

for all stages is nearly 50%, although it dramatically increases to over 90% in patients with localized disease.1 1 Unfortunately, most patients have disseminated disease at diagnosis because symptoms are nonspecific and may not be recognized until late in the disease course.4 Overall 5-year survival is slightly higher for white Americans (44%) as compared with AfricanAmericans (38%). Survival for patients with localized disease is similar for white Americans and African-Americans (93%).1 Surgery is an integral part of ovarian cancer management.3 Chemotherapy, 2467

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primarily the combination of a taxane plus a platinum analog, plays an important role for adjuvant therapy of localized and advanced disease.3

EPIDEMIOLOGY 2 Ovarian cancer usually occurs in2postmenopausal white women

during the sixth decade of life. Only 5% to 10% of ovarian cancer is familial; the majority of ovarian cancer occurs sporadically. For women in the United States, the overall lifetime risk of developing ovarian cancer is 1.4% to 1.8%.2 The most important risk factor appears to be family history of ovarian cancer. The lifetime risk for developing ovarian cancer markedly increases to 7% to 9% in women with a family history involving two or more first-degree relatives.2 The risk for ovarian cancer is decreased to 0.6% in women who have had several pregnancies, especially in women who first became pregnant before age 25, and is increased to 3.4% in nulliparous women, suggesting that uninterrupted ovulation may be a contributing factor.2 Prolonged oral contraceptive use or breast-feeding lowers the risk for developing ovarian cancer.2 An increased risk has been associated with environmental exposure to asbestos or talc.2

GENETICS Several hereditary ovarian cancer syndromes have been described, which include the development of breast and ovarian cancers or ovarian, endometrial, and nonpolyposis colon cancers.2,3,5 These syndromes tend to occur at an earlier age than the usual development for each of the individual malignancies and account for about 5% of the total ovarian cancer incidence.2,5 These syndromes may be linked to a number of genetic abnormalities that have been detected in patients with ovarian cancer.6−8 The most common genetic alterations include mutations in BRCA1 and BRCA2, but may also in involve p21, Her-2/Neu, p53, OVAC1, OVAC2, and Rb gene function, and loss of heterozygosity on chromosomes 6, 9, 13q, 17, 18q, 19p, and 22q. BRCA1 and BRCA2 are tumor suppressor genes thought to be involved in one or more pathways of DNA damage recognition and repair. The BRCA1 gene is located on chromosome 17q12-21 and the BRCA2 gene is located on chromosome 13q12-13. Current risk estimates for the development of ovarian cancer in women with mutations in BRCA1 are 26% to 85% by 70 years of age, whereas mutations in BRCA2 appear to confer a lesser risk of developing this disease with an estimated risk of 2 cm in diameter or nodal involvement Distant organ involvement, including or splenic liver parenchyma or pleural space

Diaphragm Liver surface Omentum Paracolic gutter Small intestinal and mesenteric surface

Pelvic and para-aortic nodes

Serosal surface of rectosigmoid, bladder, and uterus

Lateral pelvic peritoneum

International Federation of Gynecology and Obstetrics

Cul-de-sac

FIGURE 130–1. Staging laparotomy for ovarian cancer.

of developing ovarian cancer. Although no data indicate that screening will reduce mortality, annual rectovaginal pelvic examination, CA-125 determinations, and TVS are recommended in these women until age 35 or when childbearing is complete. Prophylactic bilateral oophorectomy should then be considered to reduce the overall risk. With regard to possible ovarian cancer development, current recommendations for follow-up care for individuals with BRCA1 and/or possibly BRCA2 mutations include genetic counseling and annual or semiannual transvaginal ultrasound with color flow Doppler and serum CA-125 beginning at age 25 to 35 years.17 There is not enough information to recommend for or against prophylactic oophorectomy or prophylactic use of oral contraceptives in BRCA1 carriers. Participation in ongoing ovarian cancer screening trials should be encouraged.

STAGING The stage of ovarian cancer depends on the extent of disease found at surgical exploration (Table 130–1). Epithelial ovarian cancer spreads by peritoneal surface shedding and lymphatic dissemination (Fig. 130–1).16 A careful and accurate surgical staging laparotomy is necessary to properly stage the patient; it is therefore recommended that a gynecologic-oncologic surgeon do this procedure to prevent understaging.25,26 Total abdominal hysterectomy, bilateral salpingooophorectomy, and partial omentectomy are performed.16,17 A care-

ful examination of all serosal surfaces is done and biopsies of any grossly involved areas are taken. Ovarian capsule rupture, if present, is noted. Ascites and peritoneal washings are collected. Integral to the initial surgical staging procedure, the surgeon attempts to debulk as much gross tumor as possible because the amount of residual disease in patients with stage III ovarian cancer correlates with survival.20

PROGNOSIS 6 The prognosis for patients with epithelial ovarian cancer is re-

lated to disease stage, pathologic grade, and cell histology. Patients with well-differentiated stage IA or IB tumors have a 5-year survival rate of greater than 90% with no additional benefit derived from adjuvant therapy.17,24 With adjuvant therapy, patients with any poorly differentiated stage I, stage IC, or stage II disease have an 80% 5-year survival rate.17,27 Survival in patients with stage III disease is decreased compared to earlier stages, and is directly related to the size of residual tumors present after debulking surgery. Patients with implants less than 0.5 cm have a median survival of 40 months, those with implants 0.5 to 2 cm have a median survival of 18 months, and those with residual tumor greater than 2 cm have a median survival of 6 to 12 months.28,29 The 5-year survival rate for stage IV patients is only 5% to 10%.2 Patients with borderline ovarian cancer have an excellent prognosis, with a 5-year survival rate of 93% and a 10-year survival rate of 91%.2


TREATMENT: Ovarian Cancer 4 Ovarian cancer management is based on the histologic type,

pathologic grade, and the stage of disease at initial presentation (Fig. 130–2). In general, the treatment of patients with ovarian cancer initially involves surgical debulking at the time of staging laparotomy followed by adjuvant chemotherapy.30 However, the effect of debulking on outcome in patients with stage IV disease is unclear.31 Second-line therapy is recommended if residual disease is found after adjuvant chemotherapy. Although response rates are high, many patients with ovarian cancer still die from their disease, so it is important to diagnose patients earlier, and

it is appropriate to enroll patients with any disease stage into clinical trials.


TREATMENT BY STAGE
EARLY-STAGE DISEASE (STAGES I AND II) Approximately one-third of ovarian cancer patients present with localized disease (stage I or II) at initial diagnosis.24 In patients with

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apparent early stage disease, comprehensive surgical staging is of utmost importance because approximately one-third of patients will have metastatic disease that is not apparent on gross total resection.32 4 During laparotomy, the patient should undergo comprehensive staging, total abdominal hysterectomy, and bilateral salpingooophorectomy.30 Women with stage IA, grade 1 ovarian tumors who wish to preserve ovarian and reproduction function can undergo a unilateral salpingo-oophorectomy without significant risk of decreased survival.30,33 The beneficial effects of adjuvant chemotherapy in localized disease depend on the stage and the disease subtype. 5 Postoperative adjuvant chemotherapy is not required in grade 1, stage IA or IB ovarian cancer, whereas patients with grade 2 or 3, stage IA or IB, and stage IC ovarian cancer benefit from adjuvant chemotherapy (see Fig. 130–2).16,24,30 All patients with stage II disease should receive adjuvant treatment.16,24,30 The role of adjuvant chemotherapy for patients with stage I disease is controversial. Recent data suggest that the outcome of patients with stage I disease who relapse following no adjuvant chemotherapy is similar to that of patients with stage III disease who relapse following chemotherapy.34 For localized ovarian cancer (stage I or II), the recommended adjuvant regimen is paclitaxel plus cisplatin or carboplatin given for three to six cycles.30


ADVANCED DISEASE (STAGES III AND IV) 7 The majority of women3 with ovarian cancer present with

stage III or IV disease. The approach to the treatment of advanced ovarian cancer is initial surgical debulking followed by adjuvant/consolidative paclitaxel plus cisplatin or carboplatin for six cycles30 (see Fig. 130–2). Overall survival is a function of the initial disease stage (stage III vs. IV) and the amount of residual disease left after surgical debulking.


PRIMARY CYTOREDUCTIVE SURGERY 4 The surgical removal of ovarian tumors should be as complete

as possible to increase the likelihood of response to chemotherapy. The amount of residual disease after debulking is also a strong prognostic factor. Patients with stage III disease who have optimal debulking (2 cm of residual tumor) have less than a 10% chance of long-term survival.28


PRIMARY ADJUVANT CHEMOTHERAPY
TREATMENT REGIMENS Systemic chemotherapy following optimal surgical debulking is the cornerstone of first-line treatment of advanced epithelial ovarian cancer. Although there have been only modest improvements in long-term survival, there have been significant improvements in 5-year survival of patients with advanced ovarian cancer. Table 130–2 summarizes the chemotherapeutic regimens used as the initial treatment of newly diagnosed ovarian cancer. The combination of cyclophosphamide and cisplatin or carboplatin was once the first-line adjuvant therapy of choice in women with advanced-stage ovarian cancer.29,35 However, paclitaxel alone, and in combination with platinum analogs, has shown significant

FIGURE 130–2. Initial management of epithelial ovarian cancer. All recommenFigure 130-2 is not available in digital format. dations are category 2A unless otherwise indicated. BSO, bilateral salpingooophorectomy; TAH, total abdominal hysterectomy; USO, unilateral salpingooophorectomy. *Clear-cell pathology is considered high grade regardless of the stage. (Reproduced with permission from NCCN cancer practice guidelines in oncology, 2005. Copyrighted by the National Comprehensive Cancer Network. All rights reserved. These guidelines and illustrations may not be reproduced in any form without the express permission of the NCCN.)

activity in ovarian cancer.36−38 McGuire and colleagues reported that the combination of paclitaxel 135 mg/m2 over 24 hours and cisplatin 75 mg/m2 achieved better response rates and survival outcomes than cyclophosphamide 750 mg/m2 and cisplatin 75 mg/m2 in patients with newly diagnosed, suboptimally debulked, stage III and IV ovarian cancer.39 Survival improved significantly in the paclitaxel arm, with an increase in median progression-free survival (18 months vs. 13 months) and an overall survival (38 months vs. 24 months). Neutropenia, alopecia, and peripheral neuropathy were more severe in the paclitaxel/cisplatin group. Similar results have been reported in a large European-Canadian Phase III randomized trial study.40 Cisplatin and carboplatin have been used as single agents and in combination therapy in previously untreated ovarian cancer.41 Combination chemotherapy regimens containing cisplatin achieved higher response rates and overall survival than regimens without cisplatin in patients with stage III or IV ovarian cancer.17 A meta-analysis comparing treatment with platinum analogs, either as single agents or in combination regimens, reported a higher overall response rate and longer survival in the combination treatment group. Single-agent carboplatin has been compared to platinum combination chemotherapy (paclitaxel plus carboplatin, or cyclophosphamide, doxorubicin, and cisplatin [CAP]) for first-line treatment of ovarian cancer in 2,074 patients with ovarian cancer, regardless of their stage at diagnosis.42 No difference was found in overall survival after 51 months of follow-up between paclitaxel plus carboplatin and single-agent carboplatin or CAP. A small increase (1.2 months) in progression-free survival was noted in favor of paclitaxel plus carboplatin in comparison to either carboplatin or CAP. However, this

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TABLE 130–2. Initial Chemotherapeutic Regimens of Epithelial Ovarian Cancer Drug(s)

Dose(s)

Cisplatin Carboplatin Cisplatin + cyclophosphamide Carboplatin + cyclophosphamide Cisplatin + doxorubicin + cyclophosphamide

100 mg/m2 IV day 1 400–800 mg/m2 IV day 1 50–100 mg/m2 IV day 1 500–1,000 mg/m2 IV day 1 200–300 mg/m2 IV day 1 500–1,000 mg/m2 IV day 1 50–60 mg/m2 IV day 1 40–50 mg/m2 IV day 1 500–750 mg/m2 IV day 1 135 mg/m2 IV (24-h infusion) day 1 75 mg/m2 IV day 1 175 mg/m2 IV (3-h infusion) day 1 Dosed to AUC 5–7.5 IV day 1 75 mg/m2 IV day 1 Dosed to AUC 5 IV day 1

Paclitaxel + cisplatin Paclitaxel + carboplatin Docetaxel + carboplatin

Cycle Frequency Every 28 days Every 28–35 days Every 21–28 days Every 28 days Every 28 days

Every 21 days Every 21 days Every 21 days

AUC, area under the curve

increase in progression-free survival was associated with more alopecia, fever, and sensory neuropathy than single-agent carboplatin, and more sensory neuropathy than CAP. Carboplatin has been used in place of cisplatin in combination therapy for patients with advanced ovarian cancer because of better tolerability, ease of administration, and apparent equivalent survival.43−47 Several prospective, randomized phase III trials comparing carboplatin plus paclitaxel versus cisplatin plus paclitaxel in patients with advanced ovarian cancer have been conducted.48−52 Results concluded that carboplatin plus paclitaxel is the preferred regimen because of equal efficacy and less toxicity. In the U.S. study (Gynecologic Oncology Group [GOG] 158), 840 previously untreated patients with optimally resected stage III disease (no residual tumor nodule >1 cm) were randomized to carboplatin (area under the curve [AUC] = 7.5) plus paclitaxel 175 mg/m2 over 3 hours, or cisplatin 75 mg/m2 plus paclitaxel 135 mg/m2 over 24 hours administered every 21 days for 6 cycles.48,49 The study was designed for equivalence with the primary end point being time to progression. Results demonstrated no difference in recurrence-free survival with median times of 19.4 months for the cisplatin arm versus 20.7 months for the carboplatin arm. More toxicity was observed in the cisplatin arm. The incidence of grade 4 leukopenia, grade 3 or 4 gastrointestinal toxicity, grade 1 to 4 fever, and grade 1 to 4 metabolic toxicity was higher for patients in the cisplatin arm, whereas patients in the carboplatin arm experienced more grade 3 or 4 thrombocytopenia and grade 1 or 2 pain. Neurotoxicity was similar between the two treatment arms, which may be related to the carboplatin dose (AUC = 7.5). These results suggest carboplatin plus paclitaxel is preferred over cisplatin plus paclitaxel because of equivalent efficacy, better tolerability, and ease of administration. Docetaxel plus carboplatin may be emerging as the combination regimen of choice for first-line treatment of ovarian cancer. Preliminary results of the Scottish Randomized Trial in Ovarian Cancer (SCOTROC) Phase III trial comparing carboplatin (at an AUC of 5) in combination with docetaxel (75 mg/m2 over 1 hour) or paclitaxel (175 mg/m2 over 3 hours) administered every 21 days for 6 cycles as first-line chemotherapy for stages IC to IV epithelial ovarian cancer have been reported.54 Although survival analyses are ongoing, the progression-free survival at 1 year, clinical response, and CA-125 responses were similar in the two treatment arms. The docetaxel-carboplatin regimen produced more myelotoxicity, edema, and hypersensitivity reactions than paclitaxel-carboplatin. However,

docetaxel-carboplatin was associated with significantly less neurotoxicity. The overall incidence of grade 3 and 4 toxicities was 1-cm residual masses) and any stage IV disease, randomized patients to receive cyclophosphamide 500 mg/m2 IV plus either cisplatin 50 mg/m2 IV or 100 mg/m2 IV every 3 weeks.55 Patients in the cisplatin 50 mg/m2 group received eight cycles and patients in the cisplatin 100 mg/m2 group received four cycles (same total cisplatin dose). Clinical and pathologic response rates, response duration, and survival were similar in both groups. Hematologic and gastrointestinal effects, febrile episodes,

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septic events, and renal toxicities were significantly more common and severe in the patients receiving the higher cisplatin dose. Similarly, Kaye and colleagues reported no survival difference in patients receiving six cycles of cyclophosphamide plus cisplatin 100 mg/m2 IV or 50 mg/m2 IV.56 Neurotoxicity persisted in more patients in the high-dose arm (10 of 31), as compared to the low-dose arm (1 of 24). Likewise, dose-intensity analyses with carboplatin have demonstrated equivocal results.57−59 Accumulating evidence seems to indicate that the dose-response curve for the platinum compounds levels off within the clinically useful dosage range.57 However, it is not clear that providing higher cumulative platinum doses confers any survival advantage over the standard cisplatin 75 mg/m2 IV dose.


Duration of Therapy The duration of consolidative chemotherapy has been evaluated in several studies. In advanced ovarian cancer, the administration of five cycles of cyclophosphamide, cisplatin, and doxorubicin was equally effective and less toxic as compared to 10 cycles of chemotherapy.60 Six to nine cycles of chemotherapy has become the standard approach and results in clinical response rates of approximately 60% to 70%, with 5-year survival rates of 10% to 20%. Because approximately 50% of patients with a confirmed pathologic response will ultimately relapse,16 chemotherapy may be extended for two or three cycles beyond best response.21 The NCCN guidelines recommend three to six cycles of treatment for lower stage tumors and at least six cycles of treatment for patients with stage III or IV disease.30 However, results of a recent randomized study showed that 12 months of maintenance paclitaxel significantly prolongs the duration of progression-free survival in patients with advanced ovarian cancer who attain a complete response to initial platinum and paclitaxel-based chemotherapy.61 Many questions still need to be answered about initial therapy for advanced stages of ovarian cancer. Ongoing clinical trials are addressing whether some of the paclitaxel-containing regimens are better than current regimens for early-stage disease. There are also several comparative trials for advanced-stage ovarian cancer. These studies include determining the optimal paclitaxel dose, schedule, and treatment duration, and determining whether dose intensification aided by growth factor support will achieve higher response rates and improve survival. The results of the SCOTROC trial may result in the combination of docetaxel and carboplatin becoming first-line therapy in newly diagnosed ovarian cancer.54 In addition, low-dose weekly carboplatinpaclitaxel, new triplet combinations of carboplatin-paclitaxel with agents such as gemcitabine or topotecan, and sequential doublets such as cisplatin-topotecan followed by cisplatin-paclitaxel, are also under investigation.61,62


RECURRENT OR /REFRACTORY DISEASE 8 The choices for effective treatment of recurrent ovarian can-

cer are limited. In addition, approximately 20% to 50% of patients without evidence of residual disease on second-look laparotomy will relapse. Options include secondary cytoreductive surgery, salvage chemotherapy, hormonal therapy, radiotherapy, intraperitoneal chemotherapy, and high-dose chemotherapy with stem-cell support. Patients who respond to initial chemotherapy and whose response lasts the longest have the greatest likelihood of achieving a response to the same first-line regimen or to second-line treatment.64 Also,

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patients with recurrent or refractory disease after initial chemotherapy historically have a poor overall prognosis. Improved outcomes have been achieved in recurrent and refractory ovarian cancer with the use of high-dose chemotherapeutic agents such as cisplatin, carboplatin, and paclitaxel, and the use of combination regimens containing these agents. In addition, topotecan, pegylated liposomal doxorubicin, and gemcitabine have shown antitumor activity in patients with relapsedrefractory ovarian cancer.64−72 Table 130–3 summarizes some of the chemotherapeutic regimens used in the treatment of recurrent or refractory ovarian cancer.


SECONDARY CYTOREDUCTIVE SURGERY AND INTERVAL SURGICAL DEBULKING Operative re-exploration (or secondary laparotomy) was once an integral part of the management of advanced ovarian carcinoma. However, the role of secondary cytoreduction (or interval debulking) after consolidative chemotherapy is currently unclear. Several conflicting studies exist with regard to the survival advantages of secondary cytoreduction. A nonrandomized GOG study evaluated 112 International Federation of Gynecology and Obstetrics (FIGO) stage I or II ovarian cancer patients who first underwent initial surgical staging and then underwent a restaging operation following adjuvant therapy. The study reported that only 5% of the patients who were asymptomatic prior to surgery had disease confirmed by second-look laparotomy, as compared to half of the patients who were symptomatic prior to second-look laparotomy.73 In patients with optimal (no residual tumor nodule >1 cm) stage III disease, preliminary results indicate second-look surgery does not influence the recurrence-free survival in this patient population. These data suggest that second-look laparotomy may not be warranted in asymptomatic patients with early-stage disease. In addition, the National Cancer Institute (NCI) consensus conference recommends that second-look operations should be performed only when the results will change management or as part of a clinical trial.24 Randomized trials of secondary surgical cytoreduction have reported conflicting results. In an older randomized trial, van der Burg and colleagues performed interval debulking surgery on 140 stage IIB to stage IV suboptimally debulked (>1 cm of residual disease) ovarian cancer patients after receiving three cycles of cisplatin plus cyclophosphamide.74 Patients then received an additional three cycles of these same drugs after surgery. Patients randomized to the nonsurgical treatment arm received six cycles of chemotherapy. Interval debulking surgery significantly prolonged overall and progression-free survival and reduced the death risk by 33%. However, in a recently published study of 550 women with stage III or IV treated with maximal primary cytoreductive surgery and three cycles of paclitaxel and cisplatin, patients randomized to receive secondary cytoreductive surgery followed by three more cycles of chemotherapy had similar progression-free survival and overall survival as compared with those randomized to receive three more cycles of chemotherapy alone.75 The overall effect of interval debulking is influenced by several factors including initial response to chemotherapy, the amount of residual disease before and after second-look surgery, and the presence of microscopic residual disease. The results of recent trials suggest that secondary surgical cytoreduction does not prolong survival in patients who are treated with maximal primary cytoreductive surgery followed by appropriate postoperative chemotherapy.

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tinuing treatment are defined as platinum-refractory. These patients are unlikely to benefit from additional platinum or paclitaxel therapy and would be candidates for treatment with second-line salvage chemotherapy.30 Patients who respond to the initial chemotherapy and relapse more than 6 months after discontinuation of chemotherapy are termed platinum-sensitive. These patients often benefit from secondary treatment with paclitaxel alone, a platinum agent alone, or paclitaxel in combination with a platinum analog.77−83 Patients who had a long disease-free interval with a locally recurrent tumor might benefit from a second cytoreductive surgery. Carboplatin has been used in the treatment of platinum-refractory ovarian cancer. Kavanagh and colleagues treated 33 platinumrefractory ovarian cancer patients with disease progression after taxane salvage therapy with carboplatin 300 mg/m2 every 28 days.84 These investigators noted a 21% partial response rate, a 39% stabilization rate, and a median response duration greater than 7 months. However, all responding patients had a platinum-free interval of at least 12 months. Paclitaxel has also shown significant activity in platinumrefractory ovarian cancer.37,85−90 At the approved dose of 175 mg/m2 over 3 hours every 21 days, the response rate was 15% in patients with relapsed ovarian cancer.85 Dose-intense paclitaxel regimens (250 mg/m2 over 24 hours every 21 days plus filgrastim support) appear to produce higher objective response rates compared to conventional-dose regimens.86−88 Altering infusion schedules of paclitaxel has been explored to maximize the cytotoxic activity of paclitaxel against ovarian cancer cells.63 Weekly infusions may increase the dose intensity of paclitaxel while minimizing bone marrow suppression and other toxicities associated with paclitaxel administration.63,89−90 Paclitaxel can be safely administered weekly at a dose of 80 mg/m2 over 1 hour to heavily pretreated patients with advanced ovarian cancer, resulting in clinical response rates of approximately 30% in patients with relapsed ovarian cancer.89−90 Ongoing and future clinical trials will help define the role of weekly paclitaxel in the treatment of patients with advanced ovarian cancer. Docetaxel offers an alternative taxane treatment in patients with platinum-refractory ovarian cancer.91−93 Preclinical studies show that docetaxel has more potent in vitro activity than does paclitaxel.94 Docetaxel has produced overall response rates of 20% to 40% in patients with platinum-sensitive and platinum-refractory advanced

CLINICAL CONTROVERSY Some clinicians believe secondary cytoreduction improves survival in patients with ovarian cancer, while others do not. Factors that will affect the results of interval debulking are initial response to chemotherapy, amount of residual disease before and after secondary cytoreduction, and the presence of microscopic disease.


SALVAGE CHEMOTHERAPY The NCCN guidelines for salvage therapy for recurrent or refractory disease include several treatment options (Fig. 130–3).30 A useful guideline when treating a patient with refractory or relapsed disease is to administer a salvage regimen for two courses and then to evaluate for response.64 If no response is observed, then an alternative salvage regimen may be selected. For topotecan or liposomal doxorubicin, evidence suggests continuation of treatment for four cycles and then re-evaluation for response. Patients with prior low-stage, low-grade disease who have disease recurrence and who have never received chemotherapy should be treated as if they are newly diagnosed advanced-stage patients, undergoing surgical debulking and adjuvant chemotherapy with the combination of paclitaxel and a platinum agent. The NCCN guidelines suggest that tamoxifen is an appropriate therapy in patients with stage I or II ovarian cancer with a rising CA-125 as their only manifestation of disease progression.30,76


PLATINUM SENSITIVE VERSUS REFRACTORY DISEASE 10 The choice of retreatment with platinum-containing chemother-

apy depends on the time frame in which the disease recurs.3 Patients with advanced ovarian cancer that experience disease recurrence following initial chemotherapy are divided into two therapeutic groups. Patients who do not respond to the initial platinum-containing chemotherapy or who have recurrence within 6 months after discon-

TABLE 130–3. Chemotherapeutic Regimens for Relapsed or Refractory Ovarian Cancer Drug(s) Gemcitabine Docetaxel

a b

Dose(s) 800–1,200 mg/m2 IV days 1, 8, and 15 2

100 mg/m IV day 1 2

Cycle Frequency Every 28 days Every 21 days

Pegylated-liposomal doxorubicin

40–50 mg/m IV day 1

Paclitaxel

80 mg/m2 IV (1-h infusion) day 1

Every week

Paclitaxel Carboplatin

135–250a mg/m2 IVb day 1 400–800 mg/m2 IV day 1

Every 21 days Every 28–35 days

Paclitaxel Cisplatin

135 mg/m2 IV (3-h infusion) day 1 75 mg/m2 IV day 1

Every 21 days

Topotecan

1.5 mg/m2 IV once daily for 5 days

Every 21 days

Tamoxifen

20 mg orally twice a day

Continuous

Etoposide

50 mg/m2 orally once daily for 21 days

Every 28 days

Altretamine

260 mg/m2 orally (total daily dose divided in four doses) for 14–21 days

Every 28 days

Filgrastim used with 250 mg/m2 dose. 3-hour or 24-hour infusion.

Every 28 days

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FIGURE 130–3. Management of recurrent/relapsed/progressive epithelial ovarian cancer. All recommendations are

Figure 130-3 is not available in digital format. category 2A unless otherwise indicated. (Reproduced with permission from NCCN clinical practice guidelines in oncology, 2005. Copyrighted by the National Comprehensive Cancer Network. All rights reserved. These guidelines and illustrations may not be reproduced in any form without the express permission of the NCCN.)

ovarian cancer.91−93 The response rates ranged from 17% to 20% in patients who were platinum-refractory, defined as a treatment-free interval of 0 to 4 months.92 Neutropenia is the dose-limiting toxicity of docetaxel and fluid retention appears to be a cumulative toxicity, which can be managed with diuretics and steroids. Docetaxel is active in patients who have received prior platinum therapy, but it is important to assess the activity of docetaxel after paclitaxel failure, particularly because paclitaxel is considered a standard in front-line regimens. Further studies are also indicated to determine if docetaxel has a role as part of initial chemotherapy. The combination of paclitaxel/platinum versus conventional platinum-based chemotherapy has been assessed in women with platinum-sensitive relapsed ovarian cancer.95 A total of 802 patients were randomized between the two treatment groups and balanced for initial treatment with paclitaxel/platinum chemotherapy. Overall survival curves favored treatment with paclitaxel/platinum therapy with a hazard ratio of 0.82 (p = 0.02), corresponding to an absolute difference in 2-year survival of 7%. Progression-free survival curves also favored paclitaxel/platinum therapy, with a hazard ratio of 0.76 (p = 0.0004), corresponding to an absolute difference in 1-year progression-free survival of 10%. CLINICAL CONTROVERSY In patients with relapsed ovarian cancer that is platinumsensitive, some clinicians believe patients should be immediately re-treated with a chemotherapy regimen including a platinum agent. Other clinicians believe the platinum-free interval for these patients should be extended by treating with a non-platinum regimen (i.e., topotecan) and reserving the platinum agent until the next relapse.


Regimens Not Containing Taxane or Platinum As most patients will receive a taxane in combination with a platinum agent as initial therapy, there is a need for effective non–cross-resistant agents for use as second-line and salvage chemotherapy. In addition, the optimal chemotherapeutic agent or regimen in the treatment of platinum-refractory disease is currently unclear.

Topotecan, an analog of the plant alkaloid 20(S)-camptothecin, is active in patients with metastatic ovarian cancer and is non– cross-resistant with platinum-based chemotherapy.65,66,96,97 Preclinical studies suggest that protracted schedules of administration using low doses of topotecan achieve the greatest antitumor response.99 Topotecan has demonstrated efficacy in phase II trials as second-line and salvage therapy in patients who have relapsed after, or progressed during, platinum-based therapy.65,66,96,97 A randomized phase III trial compared topotecan and paclitaxel in patients with advanced ovarian cancer who had failed one platinum-based regimen.65 Patients were randomized to receive topotecan 1.5 mg/m2 per day as a 30-minute infusion for 5 days repeated every 21 days or paclitaxel 175 mg/m2 as a 3-hour infusion every 21 days. The overall response rate was 20.5% and 13.2% for the topotecan- and paclitaxel-treated groups, respectively. The median time to progression for topotecan-treated patients (32 weeks) was not significantly different than for paclitaxel-treated patients (20 weeks). Median survival was 61 weeks in the topotecantreated group and 43 weeks in the paclitaxel-treated group. Topotecan was well tolerated with minimal nonhematologic toxicities.65,66,96,97 Pegylated liposomal doxorubicin is an emerging option for patients with recurrent ovarian cancer.67−69 In an early phase II study, 35 patients with progressive disease after at least one platinum and paclitaxel–based regimen received pegylated liposomal doxorubicin 50 mg/m2 every 3 weeks (with a dose reduction to 40 mg/m2 in the event of grade 3 or 4 toxicities or a lengthening of the interval to 4 weeks);67 the overall response rate was 25.7%. A large randomized phase III study was completed comparing pegylated liposomal doxorubicin 50 mg/m2 every 4 weeks to topotecan 1.5 mg/m2 per day for 5 days repeated every 21 days in patients who failed first-line platinum therapy.69 A total of 474 patients were randomized, 239 to pegylated liposomal doxorubicin and 235 to topotecan. The overall confirmed response rate for the pegylated liposomal doxorubicin and topotecan groups were 20% and 17%, respectively. Overall survival tended to favor pegylated liposomal doxorubicin, with a median of 108 weeks versus 71.1 weeks for topotecan. Differences in toxicity were observed between the arms, with more hematologic toxicity occurring in the topotecan arm and more palmar-plantar erythrodysesthesia in the pegylated liposomal doxorubicin arm. Gemcitabine, a novel pyrimidine antimetabolite, has achieved overall response rates of approximately 13% to 19% as a single agent

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therapy in patients with no residual disease and as consolidation therapy in patients with minimal residual disease. Abdominal irradiation111,112 and intraperitoneal isotopes113,114 have not shown improvements in response and are associated with greater toxicity. Ovarian cancer patients treated with abdominopelvic radiation were analyzed for posttreatment complications.112 The incidence of acute complications associated with treatment were vomiting (61%) and diarrhea (68%). Serious late complications included bowel obstruction in 4.2% of patients; 64% required surgical intervention. The incidence of bowel obstruction was significantly higher in the intraperitoneal 32 P-treated versus the cisplatin-treated groups (11% and 2%, respectively; p = 0.004).114 There is currently no study reporting the use of radiation therapy to be superior to chemotherapy for ovarian cancer in any treatment setting.

in patients with platinum-sensitive and platinum-refractory recurrent ovarian cancer.70−72 The main toxicities include myelosuppression, fatigue, myalgias, and skin rash. Gemcitabine is a promising agent in combination with other agents in previously untreated and treated patients with advanced ovarian cancer.99 Because of the non–crossresistant activity and in vivo synergy with platinum agents, the NCI is sponsoring clinical studies evaluating gemcitabine in doublet regimens in patients with refractory disease and with carboplatin/taxane regimens in previously untreated patients.100,101 Other agents that have shown an overall response rate of 15% to 25% in patients with recurrent ovarian cancer include altretamine, etoposide, ifosfamide, 5-fluorouracil, tamoxifen, vinorelbine, gemcitabine, and oxaliplatin.76,102−107 Response rates tend to be higher in the platinum-sensitive subgroups. There are limited data in the scientific literature in well-defined refractory patient populations. Of these agents, altretamine, etoposide, and tamoxifen are available in oral formulations, allowing for easy administration. Altretamine is approved as single-agent therapy at doses of 260 mg/m2 per day administered in four divided doses for 14 to 21 days given every 28 days.103 Much progress has been made in the treatment of refractory and relapsed ovarian cancer. However, because most patients will receive paclitaxel and platinum combinations as first-line adjuvant therapy, there is still a need to develop non–cross-resistant agents that are active in patients who have progressed on, or relapsed after, this combination regimen. Management of advanced ovarian cancer that is refractory to first-line therapy is not well defined. Selection of salvage regimens is based on the mechanisms of action and toxicity profiles of the particular agents. Additionally, there are a variety of innovative treatment options that may have a role in the treatment of patients with advanced ovarian cancer, including antitumor vaccines, gene therapy, and angiogenesis inhibitors. Therapies directed at reversing p53 gene–associated resistance are also being investigated.108,109 There is also evidence suggesting the growth and proliferation of ovarian tumors depends on neovascularization, or angiogenesis.110 Hence antiangiogenic agents may have a future role in the treatment of patients with advanced ovarian cancer.


INTRAPERITONEAL CHEMOTHERAPY Significant advances have occurred in understanding the advantages, limitations, and administration methods of intraperitoneal (IP) chemotherapy for ovarian cancer treatment.115−117 Following initial treatment of advanced ovarian cancer, many patients who achieve a complete clinical response will have persistent disease or will develop recurrent disease. Overall, the proportion of patients achieving long-term survival is small. Ovarian cancer is an ideal disease for IP chemotherapy because the bulk of the disease remains in the peritoneal cavity.115−117 The theoretical advantage of IP administration is to increase the dose intensity and total drug exposure directly to the tumor, while decreasing the systemic exposure and possible toxicity. With IP administration, cytotoxic agents are instilled directly into the peritoneal cavity in large volumes to allow these agents to reach all sites within the peritoneal cavity. Studies show potential value in IP administration for initial, consolidation, and salvage therapy. Data suggest that patients with small-volume tumors (50,000/mm3 4 mm). It is now thought that patients with satellitosis have a worse prognosis than patients with thick primary lesions, and prognosis is more similar to that of patients with nodal metastases. There are a number of prognostic factors, in addition to tumor thickness and level of invasion, that are associated with the risk of developing metastatic disease.11 The American Joint Committee on Cancer (AJCC) developed a staging system for melanoma that divides patients with localized melanoma into four stages according to microstaging criteria of

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Breslow and Clark. In addition to consideration of the primary lesion, the AJCC staging system includes aspects of the tumor satellite, extent of lymph node involvement, and presence of metastatic disease. Recent analysis of several large databases worldwide has identified areas in which the AJCC staging system published in 1997 did not reflect the natural history of melanoma. Issues such as the appropriate cutoff values for primary tumor thickness, ulceration of the melanoma, and the satellite lesions of the primary tumor are important for determining the natural history of the disease in an individual, and should be considered when making decisions about therapy. The cutoff values initially proposed by Breslow for primary tumor thickness were initially used in the AJCC staging system, but it appears that cutoff depths of 1, 2, and 4 mm of thickness may better predict overall survival. Melanoma ulceration is associated with increased mitotic rate within a primary melanoma. The presence of ulceration of the primary lesion has been correlated with poorer survival for patients with very thin or thick lesions, but ulceration of the melanoma was not included in the 1997 AJCC staging system. A revised staging system for cutaneous melanoma was approved by the AJCC.12 Revisions of the new melanoma staging system include (1) melanoma thickness and ulceration for all tumors (except T1 tumors); (2) the number of metastatic lymph nodes versus gross dimensions, and the delineation of clinically occult versus clinically apparent nodal metastases; (3) the site of distant metastases and the presence of elevated serum lactate dehydrogenase for metastatic disease; (4) upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; and (5) a new convention for separating clinical and pathologic staging to include information obtained from intraoperative lymphatic mapping and sentinel node biopsy. Clinical staging includes microstaging of the primary melanoma and clinical and radiologic evaluation. It is used after the complete excision of the primary melanoma with clinical assessment for regional and distant metastasis. Pathologic staging includes the microstaging of the primary melanoma and pathologic information about the regional nodes after partial or complete lymphadenectomy. At this time it appears that patients with very limited disease (stage 0 or 1A disease) do not require pathologic evaluation of lymph nodes (Tables 133–4 and 133–5). It is important to look closely at the staging system used in clinical trials to appropriately interpret the results. As with other solid tumors, the presence of regional lymph node involvement is a powerful predictor of tumor burden and patient outcome. In the past, the primary method to determine nodal status was by surgical resection and analysis of the lymph nodes via a regional lymph node dissection. In recent years, preoperative lymphoscintigraphy and intraoperative sentinel node mapping have become more widely used methods to identify the first or sentinel lymph node in the direct pathway of lymph drainage from the primary cutaneous melanoma. The rationale for lymphatic mapping and subsequent sentinel node biopsy is based on the observation that regions of the skin have patterns of lymphatic drainage to specific lymph nodes in the regional lymphatic basin. The sentinel lymph node is believed to be the first node in the lymphatic basin into which the primary melanoma drains. Unlike other solid tumors, melanoma appears to progress in an orderly nodal distribution. The evaluation of sentinel nodes has been used for detection of micrometastases in breast cancer and is gaining popularity in melanoma. Sentinel lymph node biopsy provides an avenue to perform a more thorough examination of a single sentinel node than is possible when examining multiple lymph nodes with a lymph node dissection, and may be most useful in melanomas located in ambiguous drainage sites such as the head and neck areas.

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TABLE 133–4. Melanoma TNM Classification T Classification

Thickness

T1

≤1 mm

T2

1.01–2 mm

T3

2.01–4 mm

T4

>4 mm

N Classification

Ulcerative Status A: without ulceration and level II/III B: with ulceration or level IV/V A: without ulceration B: with ulceration A: without ulceration B: with ulceration A: without ulceration B: with ulceration

No. of Metastatic Nodes

Nodal Metastatic Mass

N1

1 node

A: micrometastasis B: macrometastasis A: micrometastasis B: macrometastasis C: in-transit metastases/satellite(s) without metastatic nodes

N2

2–3 nodes

N3

4 or more metastatic lymph nodes, matted nodes, ulcerated melanoma, metastatic lymph nodes, or intransit metastatic or satellite lesions

M Classification M1a M1b M1c

Serum Lactate Dehydrogenase

Site Distant skin, subcutaneous, or nodal metastatic disease Lung metastases All other visceral metastases Any distant metastasis

Normal Normal Normal Elevated

Micrometastases are diagnosed after sentinel or elective lymphadenectomy. Macrometastases are defined as clinically detectable lymph node metastases confirmed by therapeutic lymphadenectomy or when any lymph node metastasis exhibits extracapsular extension. Barch.12

tases in biopsied lymph nodes with more sensitive reverse transcriptase polymerase chain reaction assays to detect the presence of tyrosinase messenger RNA. This may be a method for broad clinical use to detect occult melanoma cells in the blood of patients with small clinical lesions.13

Additionally, the detection of clinically undetectable disease in a lymph node basin that is not directly adjacent to the primary lesion may allow for the upstaging of patients who are initially believed to have node-negative disease. Currently, there is increasing interest in developing methods to improve the detection of occult micrometas-

TABLE 133–5. American Joint Committee on Cancer Tumor (T), Node (N), Metastasis (M) Stage Grouping for Cutaneous Melanoma Pathologic Stage 0 IA IB IIA IIB IIC IIIA IIIB IIIC IV

T

N

M

Clinical Stage

Tis T1a T1b T2a T2b T3a T3b T4a T4b T1–4a

N0 N0 N0 N0 N0 N0 N0 N0 N0 N1a

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0

0 IA IB

T1–4a T1–4a Any T Any T Any T

N1b N2a N2b , N2c N3 Any N

M0 M0 M0 M0 M1

IIIB

IIA IIB IIC IIIA

IIIC IV

T Tis T1a T1b T2a T2b T3a T3b T4a T4b Any T1–4a Any T1–4a Any T Any T Any T

N

M

N0 N0 N0 N0 N0 N0 N0 N0 N0 N1b

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0

N2b

M0

N2c N3 Any N

M0 M0 M1

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The stage of the melanoma at time of diagnosis is one of the primary indicators of natural history of the disease; other factors have been shown to influence survival of primary melanoma. Factors such as tumor growth phase, mitotic rate, density of TILs infiltrating the tumor tissue, anatomic site of the primary tumor, gender and age, have all been demonstrated to have an impact on survival (Table 133–6). In addition, a number of additional prognostic factors have been identified for patients with advanced disease. The number of metastatic sites, disease involvement of the gastrointestinal tract, liver, pleura, or lung, or a Eastern Cooperative Oncology Group (ECOG) performance status of ≥1, male, and patients with prior immunotherapy have been associated with poor prognosis.

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TABLE 133–6. Prognostic Factors for Cutaneous Melanoma Tumor-related factors Tumor thickness Level of tumor invasion Anatomic site of primary tumor (increased survival in tumors of extremities versus axial, neck, head, and trunk tumors) Mitotic rate (correlated with decreased survival) Angiogenesis Occurrence of microsatellites Area of tumor regression Presence of tumor-infiltrating lymphocytes (correlated with increased survival) Patient-related factors Age (decreased survival in patients >60 years of age) Gender (survival: female >male)


TREATMENT: Melanoma The treatment of a patient with cutaneous melanoma depends on the stage of the disease. Local disease is managed and often cured with surgical ablation. Regional disease is treated with surgical resection of the primary lesion, and depending on the risk of recurrence, possibly adjuvant therapy. The use of adjuvant therapy after surgical resection and the role of interferon-α as adjuvant therapy remain controversial. Treatment for disseminated melanoma remains a challenge. Although the literature provides numerous clinical trials of single-agent and combination chemotherapy, immunotherapy, and biotherapy regimens, there is not a single standard approach for management of the individual with metastatic melanoma.


SURGERY 2 Patients that present with a suspicious pigmented lesion should

undergo a full thickness excisional biopsy, if possible. Sites in which excisional biopsy are inappropriate include the face, palm of the hand, sole of the foot, distal digit, and subungual lesions. A full thickness incisional or punch biopsy is preferred in these cases to provide microstaging and ultimately to determine therapy. Cutaneous melanoma that is localized can often be cured with surgical excision. The extent of the excision margin is important in the prevention of local recurrence and ultimate survival. For melanoma in situ, excision of the lesion or biopsy site with 0.5 to 1 cm border of clinically normal skin and a layer of subcutaneous tissue is recommended at this time. Excision with a 1-cm margin of clinically normal skin and underlying subcutaneous tissue is recommended for invasive melanoma ≤1 mm thick.14 This recommendation is a significant reduction from the previous recommendation of a 5-cm margin. The appropriate margin of excision for melanomas between 1 and 2 mm in thickness is controversial. A recent study suggests there is a greater risk of locoregional recurrence when melanomas that are at least 2 mm thick are excised with a 1-cm margin rather than a 2-cm margin.15 Lesions that are 2 to 4 mm thick should be excised with a 2-cm margin. Primary tumors more than 4 mm thick require at least a 2-cm margin, but it is not clear if a larger margin is beneficial.16 Surgical management of lentigo maligna melanoma is problematic, as subclinical extension of atypical junctional melanocytic hyperplasia may extend beyond the visible margins; it is important to completely excise these lesions.

When isolated regional lymph nodes are detected via physical exam in the absence of distant disease, therapeutic lymphadenectomy is recommended. The extent of therapeutic lymph node dissection is often modified according to the anatomic area of the lymphadenopathy. The role of lymphadenectomy is not as established in situations in which the regional lymph nodes do not appear to be involved under clinical examination. Although a subgroup of patients with stage I melanoma will have microscopic metastatic disease in nonpalpable lymph nodes, prophylactic regional lymph node dissection has not been shown to prolong survival or decrease time to relapse in randomized clinical trials. Selective regional lymphadenectomy performed after scintigraphic and dye lymphographic identification of the affected sentinel draining lymph node(s) is becoming increasingly common. If the sentinel node is found to have micrometastatic melanoma, regional dissection of the involved nodal basin is performed. If lymphatic mapping with sentinel node biopsy is available, it should be considered in patients with melanomas that are over 1 mm thick or Clark level IV. One of the most important aspects of the surgical management of cutaneous melanoma is the role of patient follow-up. Postsurgical follow-up of patients who have had a melanoma excised is essential to monitor for undetected metastatic disease and the development of a second primary cutaneous melanoma or second nonmelanoma primary malignancy. Scheduled screening in addition to routine surgical follow-up is required for any patient with a melanoma; the frequency and duration recommended depends on the stage of melanoma. The optimal duration of follow-up remains controversial. The majority of patients who are going to have recurrent disease will do so in the first 5 years following treatment, but late recurrences seen in patients over 10 years following surgery have been observed. The increased lifetime risk of developing a second primary melanoma supports lifetime dermatologic surveillance for all patients. The role of curative surgery is limited to that of early-stage disease in cutaneous melanoma. The role of surgery beyond that of cure is less clear, although surgery may offer palliation for patients with isolated metastases. Resection of isolated lesions in the brain and the lungs may be appropriate in certain cases and should be evaluated based on individual patient criteria. Surgery can be an option in situations in which the lesion is accessible and when the lesion may cause problems if not removed. Melanoma in the gastrointestinal tract can lead to bowel obstruction, and appropriate resection or bypass may allow the patient significant relief of symptoms. Despite the lack of

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controlled clinical trials, the impact on palliative surgery should be evaluated in the context of a patient’s comfort and quality of life. Surgery may be an appropriate option if the perceived outcome is to provide patient comfort. On the other hand, surgery may constitute a significant physical challenge or financial burden to a patient with a limited life expectancy. The clinical scenarios involving surgical resection should be fully evaluated in terms of overall quality of life. The risk of relapse and death after the resection of a local or regional cutaneous melanoma is the primary determinant for the use of adjuvant therapy after primary resection. Adjuvant trials have focused on patients at intermediate or high risk of recurrence.


IMMUNOTHERAPY Melanoma is considered one of the most immunogenic solid tumors; it appears to interact with and respond to the immune system of the host in which it arises. Spontaneous regressions of melanoma suggest the importance of the immune system in disease modulation. Lymphoid infiltration into the primary melanoma also suggests that immunomodulation may impact the biology of melanoma. Early work with nonspecific immunomodulators, such as levamisole and bacille Calmette-Gu´erin, in melanoma demonstrated that tumor regression could occur with these therapies, although many of these regressions were limited and short-lived. Coupled with the fact that melanoma is one of the tumors most resistant to other standard systemic treatment modalities used for cancer (i.e., radiation and chemotherapy), immunotherapy offers an avenue of treatment if surgery fails or is not an option. Although the complete response (CR) rate seen in those patients with melanoma treated with biotherapy is low, the durability of the responses can be significant. This has led to increasing research in the optimization of biotherapeutic approaches for patients with metastatic melanoma and for the establishment of biotherapy in the adjuvant setting.


INTERFERON The interferons consist of a group of antigenically and genetically distinct species and subspecies; the interferons have differing immunomodulatory activity and are directly cytostatic and cytotoxic. A number of studies have evaluated various doses and schedules of recombinant interferon for the treatment of metastatic melanoma, but no standard strategy is recommended. Response rates in metastatic melanoma range from 10% to 30%, and overall response rates are approximately 15% for interferon-α. Unfortunately the optimal dose, treatment schedule, and treatment combination/regimens have not been established for the management of metastatic melanoma. In initial clinical trials with interferon therapy for patients with metastatic cutaneous melanoma, response rates were highest in those patients with minimal disease. Additionally, responses were seen in all sites of disease, but were most frequent in subcutaneous, lymph node, and pulmonary metastases. Success of interferon in a setting with minimal disease has encouraged investigators to evaluate the benefit of interferon in patients after curative surgical resection who were at high risk for recurrent disease (bulky disease or regional lymph node involvement). Early trials of short-term and/or low-dose regimens of interferon-α did not demonstrate a survival benefit in the adjuvant setting. In an attempt to optimize response in the adjuvant setting, a strategy was developed to administer maximum tolerated doses of interferon-α for 1 month, followed by prolonged therapy of

interferon-α at more tolerable doses for 48 weeks. The rationale for the induction phase was to provide peak levels of interferon sufficient to inhibit tumor growth and provide both antiangiogenesis and immunomodulatory effects while avoiding production of anti-interferon antibodies. A large, multicenter, cooperative group trial of interferonα 2b versus observation was designed for patients with high-risk (stage IIB and III disease based on the 1997 AJCC staging criteria) melanoma following curative surgical resection. Interferon-α 2b was given intravenously as an induction therapy at maximum tolerated doses of 20 million international units/m2 per dose 5 days per week for 4 weeks in an outpatient setting; treatment was continued for 48 weeks with subcutaneous interferon-α 2b 10 million international units/m2 per dose three times per week at home. This therapy is now often referred to as high-dose interferon (HDI). Analysis of the 280 patients demonstrated a disease-free survival and an overall survival advantage with interferon-α treatment for patients with stage IIB and III disease following surgical resection.17 With longer follow-up, however, the difference in overall survival is no longer significant.18 The prolongation of overall survival was approximately 1 year, and the most significant reduction in melanoma recurrence was during the early treatment period. Subgroup analysis of this study indicated that patients with large primary tumors and node-negative disease (T4 N0 M0 ) did not receive the same benefit from therapy, but the small number of patients in this group made it difficult to draw definite conclusions about the role of interferon treatment for adjuvant therapy in this subgroup. Whether the information from this trial should be extrapolated to patients with local recurrences, satellite lesions, or in-transit metastases is not known, and should be evaluated on an individual case basis. Toxicities for the interferon therapy were common and severe in a majority of the patients at some point during therapy and necessitated dose reductions and/or delays during both the induction and maintenance phases of the study. Dose modifications were required for dose-limiting constitutional symptoms, hematologic toxicity, and hepatic toxicities, but 74% of the patients were able to complete the year of therapy in an outpatient setting. The optimal dose of interferon in the adjuvant setting is not clear. A subsequent ECOG trial designed to evaluate the impact of lower doses of interferon (LDI; 3 million units per dose subcutaneous three times weekly) for 24 months compared to the high-dose regimen (HDI) described above versus observation did not demonstrate a survival advantage of HDI versus observation.19 At a median followup of 52 months, the 5-year estimated relapse-free survival for HDI was 44%, LDI 40%, and observation 35%. HDI was shown to be statistically superior for relapse-free survival, prolonging the median time to relapse by 10 months compared to observation and LDI. With longer follow-up, however, the difference in relapse-free survival is no longer significant.18 An overall survival benefit was not seen for HDI or LDI compared to observation, although the investigators speculated that this analysis of survival was affected by the number of patients in the observation arm that received interferon therapy after disease progression.19 The frequency and severity of toxicity seen with HDI in the adjuvant setting and the lack of overall survival benefit has raised several important questions: (1) Are the toxicities associated with HDI treatment worth the potential benefits for patients? (2) What are the mechanism(s) and best standard(s) of care for patients who experience interferon toxicity? (3) Is the regimen/schedule of interferon used in the initial positive trial (HDI) necessary to achieve the benefits seen in this study? Aggressive toxicity evaluation and individualized management is essential to help preserve quality of life in those individuals receiving interferon therapy.

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4 One of the categories of toxicities seen with interferon-α therapy

is actually a diverse group of side effects referred to as constitutional symptoms; this can include acute symptoms such as fever, chills, myalgia, and fatigue, and can encompass some of the more chronic toxicities such as fatigue, anorexia, and depression.20 Acetaminophen may be used to prevent or minimize acute dose-related symptoms such as fever, myalgia, and chills. Opiates such as meperidine are often required when patients experience severe chills or rigors, most commonly during the initial month of the high-dose intravenous interferon-α induction phase. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used to manage interferon-related myalgia, but may have overlapping side effects with interferon, such as a decrease in renal blood flow and nausea. NSAIDs, like acetaminophen, may mask fevers that occur in those patients who experience neutropenia while on therapy. Fatigue is one of the most frequently observed dose-limiting toxicities seen with interferon therapy.20 The mechanisms of interferon-induced fatigue are not fully understood at this time, and are often multifactorial in individual patients. Interferoninduced fatigue appears to be dose-related and may worsen with continued therapy. Pharmacologic (e.g., amantadine) and nonpharmacologic interventions (e.g., exercise, psychosocial techniques, distraction, energy management, and dietary modifications) are currently being evaluated to treat cancer-related fatigue and now interferonrelated fatigue.20,21 Anorexia was reported in approximately 70% of patients receiving adjuvant interferon therapy for melanoma and is thought to be mediated through direct effects on hypothalamic neurons, modification of normal hypothalamic neurotransmitters/ neuropeptides, or effects from stimulation of other cytokines.20,22 Depression is common and should be fully evaluated and treated based on patient-related symptoms.20 Contributing factors such as interferoninduced hypothyroidism and/or concomitant interferon symptoms (e.g., nausea and fatigue) should be evaluated concurrently with depression symptoms to optimize treatment decisions. Taste alterations may contribute to anorexia. Investigational strategies for ameliorating interferon-induced anorexia include nutritional intervention, use of appetite stimulants such as megestrol acetate, and patient education. Glucocorticoids should not be used for appetite stimulation or as part of an antiemetic therapy, as they may adversely impact the immunomodulatory effects of the interferon. Other toxicities such as hematologic or hepatic toxicities require monitoring and appropriate dose modification. Because of the associated toxicity and adverse effects seen with interferon-α therapy there has been worldwide concern about the usefulness of this intensive adjuvant therapy for melanoma despite the possible benefits in relapse-free and overall survival.23 A subsequent report from the cooperative group study demonstrated a qualityof-life benefit with interferon therapy based on the quality-of-lifeadjusted survival analysis.24 This analysis calculates the quality-oflife-adjusted years gained as a result of interferon-α treatment or the clinical benefit of time without toxicities and without disease. The role of interferon as adjuvant therapy is not clear at this time. The issue of patient side effects and cost needs to be carefully weighed against the disease-free survival benefit seen in those individuals with high risk of recurrence. As high-dose interferon remains the only therapy to demonstrate benefit in large comparative trials, it should be considered for patients with high-risk disease. According to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for melanoma, interferon alfa is one of several options for select patients with high-risk disease.25 Observation was also listed as an option. Individuals should be prescreened for potential problems associated with therapy; relative contraindications to high-dose interferon therapy include autoimmune diseases, immunosuppression,

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decompensated liver disease, severe neuropsychiatric diseases, or lifethreatening infection.20 Efforts continue to better define the optimal treatment regimen for high-dose interferon versus other strategies in well designed clinical trials. CLINICAL CONTROVERSY There is significant controversy regarding the role of interferon-α as adjuvant therapy in high-risk patients after surgical resection of melanoma. Assessment of patient risk factors, availability of clinical trials, and cost of therapy should be evaluated prior to initiation of therapy. The role of interferon in advanced disease is even more unclear, especially for those patients who have recurred after treatment with adjuvant interferon therapy. Interferon-α has been used as a single agent in patients with metastatic disease who have not received adjuvant therapy, and in combination with chemotherapy and/or other biotherapy for metastatic melanoma. The challenges of combination therapy are that many of the toxicities seen with interferon can be exacerbated by concomitant chemotherapy (e.g., nausea, vomiting, and neutropenia). In an attempt to limit systemic toxicity and to potentate local benefits, the regional administration has been evaluated in a variety of settings. Intralesional and perilesional application of interferon has been shown to have some efficacy in small lesions and appears to be well tolerated.26


INTERLEUKIN-2 Interleukin-2 (IL-2), a glycoprotein produced by activated lymphocytes, has been extensively studied in the management of metastatic melanoma. The precise mechanism of cytotoxicity of IL-2 is unknown; high concentrations of IL-2 have not been shown to have a direct antitumor effect on cancer cells in vitro. In vitro and in vivo, IL-2 stimulates the production and release of many secondary monocyte-derived and T-cell-derived cytokines, including IL-4, IL-5, IL-6, IL-8, tumor necrosis factor-α, granulocyte macrophage-colony stimulating factor, and interferon-γ , which may have direct or indirect antitumor activity. In addition, interleukin-2 appears to stimulate the cytotoxic activities of natural killer cells, monocytes, lymphokineactivated killer (LAK) cells, and cytotoxic T lymphocytes (CTLs). Although the clinical significance is not currently understood, preliminary studies have shown that several human melanoma cell lines express both α and β chains of the interleukin receptor that specifically bind to interleukin-2. 6 Based on preclinical studies that showed a dose-response relationship between recombinant IL-2 (aldesleukin) and tumor response, the initial clinical trials of aldesleukin in the treatment of patients with melanoma used relatively high doses of the drug as a single agent or in combination with LAK cells. The response rates seen in these trials ranged from 15% to 25%, and 2% to 5% of patients achieved complete responses, some of which were durable. Responses were seen at a number of metastatic sites such as lung, liver, bone, lymph nodes, and subcutaneous tissue. Based on the re-evaluation of early clinical trials,27 recombinant IL-2 (aldesleukin) was approved by the FDA for treatment of metastatic melanoma. Overall, objective response rates were about 16%, but in some cases there were durable responses and responses seen in patients with large tumor burdens. The high aldesleukin doses used in the initial clinical trials and recommended in the labeling of the drug are associated with serious toxicities and may limit the practicality of therapy for individual patients and broad application in certain health care systems. At the

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high doses (600,000 international units/kg per dose every 8 hours for 14 doses maximum) approved for treatment of metastatic melanoma, cytokine-induced capillary leak syndrome is a common problem and may be accompanied by hypotension, visceral edema, dyspnea, tachycardia, and arrhythmias. Increased permeability of capillary walls allows for a fluid shift from the intravascular space into tissue. As the patient becomes intravascularly dehydrated, hypotension may occur, resulting in reflex tachycardia and arrhythmias. In addition, the decrease in blood volume may result in decreased renal blood flow and urine output, manifesting as an increase in blood urea nitrogen, serum creatinine, edema, and weight gain, and a decrease in urine output (input greater than output). Visceral edema can result in pulmonary congestion, pleural effusions, and edema. The management of patients receiving high-dose aldesleukin requires careful monitoring and a staff trained in aspects of critical care such as hypotension management. Although some institutions manage patients receiving high-dose aldesleukin in an intensive care unit, most patients can be managed on a designated oncology unit. Additional side effects seen with aldesleukin include constitutional symptoms, pruritus and eosinophilia, bone marrow suppression including thrombocytopenia, an increase in liver function tests, and nausea.28 CLINICAL CONTROVERSY Although aldesleukin has been associated with long-term durable responses in a small subset of patients with metastatic melanoma, the toxicity profile, intensity of therapy, and cost has limited acceptance within the United States. Patients should be evaluated for treatment prior to initiation of therapy. In an attempt to provide the benefit of aldesleukin therapy without the serious side effects, a number of studies have evaluated continuous-infusion aldesleukin therapy, and lower-dose aldesleukin alone or with chemotherapy and interferon therapy. Response rates have been promising, but survival has not been significantly affected. At this time, direct head-to-head comparisons of various dosing schedules and regimens are needed to determine the optimum approach to aldesleukin therapy in metastatic melanoma. The coadministration of LAK cells with aldesleukin does not appear to significantly improve clinical response. Although some studies have suggested improved response with coadministration of TILs with recombinant IL-2, the therapy is technically difficult and costly, and the overall clinical benefit has not been clearly demonstrated. Histamine has been shown to inhibit the generation of reactive oxygen species by phagocytes and ultimately preserve natural killer cell and T-cell responsiveness to IL-2. Preclinical work led to a series of clinical trials evaluating the combination of aldesleukin and histamine dihydrochloride with the hope that the combination would increase the efficacy of aldesleukin in patients with metastatic melanoma. It was also hoped that lower doses of aldesleukin would allow for outpatient treatment for metastatic melanoma. In initial clinical trials, aldesleukin was administered subcutaneously with or without histamine dihydrochloride. A survival advantage was seen with the combination in a subset of patients, those patients with liver metastases.29 Constitutional toxicities were common but less than those seen with high-dose aldesleukin; patients were able to maintain therapy at home. The addition of histamine dihydrochloride resulted in a significant toxicity secondary to the effects of the histamine, including vasodilation, cardiovascular effects, and injection-site reactions. Most toxicities were mild, except for headaches, and were managed symptomatically.30 One of the greatest challenges in the management of patients with metastatic melanoma with immunotherapy is to determine for

an individual patient if the potential benefits of aldesleukin therapy outweigh the substantial risk. It is obvious from the reports of longterm responses (greater than 10 years) in some patients that the risk is certainly worth the benefit for those individuals. A number of parameters such as human leukocyte antigen (HLA) expression and pretreatment immunologic status have been evaluated as potential predictors to therapy. Unfortunately, at this time it is difficult to determine which individuals will respond to aldesleukin therapy, as no biologic or immunologic parameters have been found to correlate with response. The decision to treat an individual with high-dose aldesleukin should be based on an analysis of an individual patient’s risk versus potential benefit. Patients with inadequate pulmonary function, cardiac function, renal insufficiency, active infection, or poor performance status are poor candidates for this therapy. Aldesleukin can be safely administered with a properly trained health care team, and is one of only two approved therapies for treatment of metastatic melanoma.


VACCINES 7 The rationale for vaccination as a therapeutic modality is based

on the observation that tumor cells differ antigenically from normal cells, and the hope that vaccines might induce effective tumorspecific immune responses with fewer toxicities than conventional chemotherapy or other immunotherapies. Greater knowledge about tumor antigens and the mechanism of antigen presentation and immune response to antigens has led to the development of several vaccination strategies for the treatment of early and advanced melanoma. A number of these vaccine approaches are being evaluated in both metastatic disease and in the adjuvant setting (Table 133–7).31,32 Active immunization is one of the well-characterized strategies for immunotherapy of melanoma. Current melanoma vaccines upregulate the antibody response of CTLs to specific tumor antigens. Melanoma antigens are either tumor-associated antigens (TAAs) or melanoma-associated antigens (MAAs). TAAs are common to melanoma cells and other tumor cells, while MAAs are usually proteins or glycoproteins found predominantly in melanomas and less commonly in normal melanocytes. The use of TAAs or MAAs for melanoma vaccines can be difficult, as the expression of antigens in melanoma cells is often heterogeneous and may change in response to the patient’s immune response. Unfortunately, MAAs and TAAs also tend to be weakly immunogenic, although immunogenicity can be increased by physical alterations. Melanoma vaccines range from complex antigen mixtures to purified antigens. Complex vaccines are polyvalent and can stimulate an immune response to a number of tumor antigens and are less TABLE 133–7. Melanoma Vaccines Whole melanoma cells Autologous cells Allogeneic cells Haptenized cells Melanoma cell lysates Viral oncolysates Shed melanoma cell supernatant Defined antigen vacciness Gangliosides (GM2, GD2) Anti-idiotype monoclonal antibodies Anti-GD3 gangliosides Dendritic cell Protein antigens DNA vaccination Recombinant viral vaccines

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susceptible to antigenic modulation by the cancer cells. Single-antigen vaccines can be problematic if a single-resistant-antigen-negative tumor cell develops. Melanoma vaccines can be prepared from a patient’s own tumor (autologous preparations), and will therefore target antigens from that patient’s melanoma cell. Autologous vaccines may involve modification of the tumor cells with a hapten to increase immunogenicity of the preparation. Allogeneic preparations do not require patient tissue to prepare the vaccine. Allogeneic preparations often include a number of cell lines to increase the content of immunogenic TAAs and MAAs. Melanoma vaccines may also be prepared with tumor cell lysate. Lysate vaccines can be prepared from the whole cells or from the cellular elements most likely to contain the antigens important for the induction of protective immune responses. Material shed from the melanoma cells is believed to be rich in cell-surface antigens and has been used for preparation of a melanoma vaccine. Melacine is a lysate vaccine prepared from two human melanoma cell lines administered with an adjuvant immunostimulant monophosphoryl lipid A and purified mycobacterial cell-wall skeleton called DETOX.33 Initial reports from uncontrolled clinical trials with Melacine have suggested a role in the treatment of patients with surgically resected and metastatic melanoma. It is thought that a subset of patients defined by HLA subtypes showed benefit, suggesting that this vaccine therapy may be a targeted approach for select patients. CancerVax is a polyvalent allogeneic whole-cell vaccine developed by Morton,34 which is comprised of an irradiated live-cell preparation of three allogeneic melanoma cell lines selected for their high content of MAAs and TAAs. BCG is used as an adjuvant and the vaccine is administered intradermally. CancerVax is being evaluated for the postsurgical treatment of stage III melanoma and in stage IV disease after surgical resection. An alternative approach to vaccine construction is to develop a vaccine from a single highly-specific antigen. Preparations currently in clinical trials include vaccines prepared from gangliosides, peptides such as MAGE or MART, and anti-idiotype monoclonal antibodies. Gangliosides GM2 , GD2 , GM3 , GD3 , and O-acetyl-GD3 are present on the surface of many melanoma cells, but GM2 is the most consistently expressed and immunogenic antigen. One vaccine composed of the ganglioside GM2 coupled with keyhole limpet hemocyanine is being evaluated in the adjuvant setting. The vaccines from a single antigen have the advantage that they can be prepared in a reproducible manner on a large scale. The problem with this approach is that it is unclear if targeting a single antigen or peptide on a melanoma will be sufficient to kill the tumor cell. As with other approaches for targeted therapy, there is a concern that cancer cells will develop strategies to circumvent the targeted treatment approach.


OTHER APPROACHES Dendritic cells are potent antigen-presenting cells for the initiation of antigen-specific immune responses. Dendritic cells express high levels of major histocompatibility complex class I and class II molecules, which are essential in antigen presentations. Activation of T cells and recruitment of non–antigen specific effectors, such as natural killer cells and macrophages, result in a broad immune response. One strategy to use dendritic cells for inducing antitumor immune responses has been done with peptide-pulsed dendritic cells. Antimelanoma CTLs can be generated from healthy donors and patients with melanoma with dendritic cells pulsed with melanoma-derived peptides. A number of clinical trials are evaluating dendritic cell–based immunotherapy.35 Monoclonal antibodies have been used for the diagnosis and treatment of melanoma. Two strategies have been pursued: treatment

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with a monoclonal antibody to activate the host immune system, and treatment with a conjugated monoclonal antibody (i.e., immunoconjugate). Monoclonal antibodies have been conjugated to cytotoxic agents, radioisotopes, and toxins such as ricin A. Trials of monoclonal antibodies were initially limited secondary to the production of the monoclonal antibody. A problem seen in current studies is the induction of neutralizing antibodies to the murine monoclonal antibodies. Chimeric, humanized, or pure human monoclonal antibodies against MAAs could potentially avoid the development of human antimouse antibody. A vaccine which is composed of three monoclonal anti-idiotype antibodies that include the internal image of several determinants of the MAA has been developed and looked at in clinical trials. One of the problems with this antibody is the inability to directly induce a cell-mediated antitumor effect; therefore adjuvants are now being used to increase the ability of the anti-idiotype antibodies to induce a greater immune response. Gene therapy of human melanoma is still in its infancy, but suggests several exciting approaches to the management of metastatic melanoma. Several strategies for gene therapy are currently under investigation for the treatment of melanoma. One approach to gene therapy for melanoma is the modification of melanoma cells with the insertion of one or more cytokine genes, and then administering these altered allogeneic or autologous cells as a vaccine. Cytokine gene transduction has been accomplished with a number of cytokines including aldesleukin (IL-2), tumor necrosis factor-α, IL-4, and interferon. It is hoped that the insertion of cytokine genes into melanoma cells will significantly increase the cells’ immunogenicity. Genes can also be transferred in vitro into TILs associated with melanoma in an attempt to potentiate the cytotoxicity of these cells. Rosenberg and colleagues were the first to attempt to transduce the gene coding for resistance to neomycin into human TILs. This approach has since been used to transfer the tumor necrosis factor gene into TILs. Thalidomide and thalidomide analogs are also being evaluated in the management of melanoma. Thalidomide, given as either a single agent or in combination with chemotherapy or cytokines, is being evaluated in a variety of studies. Thalidomide analogs are also being evaluated to try and avoid toxicities associated with the parent compound. The thalidomide analogs are grouped into two classes; the selective cytokine inhibitory drugs and the immunomodulatory derivatives. Both classes appear to have antiangiogenic and antiinflammatory properties, but the selective cytokine inhibitory drugs are phosphodiesterase inhibitors. Immunomodulatory derivatives also have effects on T-cell stimulation and inhibition of tumor necrosis factor-α. Several of these agents are being evaluated in clinical trials in metastatic melanoma.


CHEMOTHERAPY A number of cytotoxic agents have demonstrated in vitro activity to melanoma; only a few drugs have consistently shown a response rate greater than 10% in patients with melanoma. Since chemotherapy has rarely cured a patient with melanoma, the primary goal of chemotherapy is palliation.36 The results of clinical trials are generally expressed in terms of response rates. The response rate usually includes the fraction of patients who experience a partial response plus those who experience a complete response. Partial response criteria vary but may require a 50% reduction of the tumor for a minimum of 1 month. A complete response would require total regression of all metastases for at least 1 month and is uncommon ( 50

Skin Desquamation

Liver

Bilirubin (mg %)

Diarrhea (mL/d) Intestine

FIGURE 134–5. Clinical grading of acute GVHD. The left panel summarizes the grading by organ system; the right panel shows the overall clinical grade. With grade I, only the skin can be involved. With more extensive involvement of the skin or involvement of liver and intestinal tract and impairment of the clinical performance status, either alone or in any combination, the severity grade advances from II to IV.

damage with the use of reduced intensity or nonmyeloablative conditioning regimens. The second and most widely used approach is to modulate donor T cells by reducing T-cell numbers (T-cell depletion), inhibiting T-cell activation (most immunosuppressive agents), or inhibiting T-cell proliferation (antiproliferative agents). The third approach is to block inflammatory stimulation and effectors (e.g., tumor necrosis factor-α inhibitors). The principal target organs for acute GVHD are the skin, liver, and gastrointestinal tract. Acute GVHD is classified into four grades, depending on the number of organs involved and the degree of involvement of each organ (Fig. 134–5). Grade I disease involves only the skin, while grades II through IV involve the skin and either the liver or gastrointestinal tract or both. The initial sign of acute GVHD is usually a generalized maculopapular rash that involves the face, ears, palms, soles, and upper trunk. The skin rash can spread to the rest of the body. Acute GVHD usually progresses to involve other organs. Gastrointestinal GVHD is manifested as diarrhea, but may progress to abdominal pain/cramping and ileus. GVHD of the upper intestinal tract has also been described presenting as nausea, vomiting, anorexia, and dyspepsia. The diagnosis of gastrointestinal GVHD must be made by mucosal biopsy. Hepatic GVHD is usually asymptomatic, consisting of hyperbilirubinemia and increases in serum aminotransferase and alkaline phosphatase levels. The diagnosis is usually made by biopsy, although many patients are not biopsied. The overall incidence of moderate to severe (grades II to IV) GVHD ranges from 10% to more than 80% after alloHSCT. Mortality directly attributable to acute GVHD or its treatment occurs in 10% to 20% of patients. The incidence of GVHD is related to the degree of histocompatibility, number of T cells in the graft, donor and recipient age, and prophylactic regimen. In patients receiving PBSC grafts, CD34+ cell dose and type of prophylactic regimen are also risk factors. The risk of acute GVHD is lower in recipients of NMT and UCB transplants as compared with myeloablative allogeneic transplants,26,65 and is slightly higher in recipients of allogeneic PBSC transplants as compared with allogeneic BMT.24 The most severe acute GVHD is observed in alloHSCT with nonHLA-identical related or unrelated donors. In these settings, the incidence of grades II to IV acute GVHD exceeds 50%, despite aggressive GVHD prophylaxis. The risk of acute GVHD is lower in

Pain/ileus

Impairment of performance

I

II

III

IV

1+ 2+ 3+ 4+

2–3 3–6 6–15 > 15

1+ 2+ 3+ 4+

500–1000 1000–1500 > 1500

1+ 2+ 3+ 4+

1+ 2+ 3+

patients with a certain interleukin-10 genotype.91 Interleukin-10 secreted by antigen-presenting cells promotes the development of immunologic tolerance and suppresses the production of inflammatory cytokines. Multiorgan acute GVHD and the drugs given to prevent or treat it are associated with delayed immunologic recovery and increased susceptibility to infections. Infection is often the primary cause of death in patients with GVHD. Patients with GVHD on immunosuppressive therapy should receive prophylactic antiviral, antibacterial, and antifungal therapy. 10 Because treatment of established acute GVHD is often unsatisfactory, aggressive preventive measures are usually taken. The most common strategy used to prevent acute GVHD is to block the activation of T cells by administration of immunosuppressive agents.89,90 Several immunosuppressive agents have been used, including methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, antithymocyte globulin, corticosteroids, and monoclonal antibodies directed at T cells. The pharmacology of these drugs is reviewed elsewhere.92 Most GVHD prophylaxis regimens combine two or more immunosuppressive agents that affect different stages of T-cell activation. Another strategy is to remove or deplete most T cells from donor bone marrow ex vivo prior to transplant by physical separation (i.e., lectin agglutination) or by treatment with monoclonal antibodies directed at T cells (see Fig. 134–3).81 In alloHSCT with HLA-identical sibling donors, the combination of cyclosporine and either methotrexate or corticosteroids reduces the incidence of grades II to IV acute GVHD to 25% to 40%. Intravenous cyclosporine is usually started around day 0 at an initial dosage of 3 to 5 mg/kg per day, given in two divided doses. Dosages are adjusted based on trough cyclosporine concentrations. Patients are converted to oral cyclosporine when they can tolerate oral medications. Cyclosporine is given at full doses until about day 50 and in the absence of GVHD, is then gradually tapered and discontinued by day 180. Methotrexate is given intravenously on days 1, 3, 6, and 11 posttransplant. The methotrexate dosage is 10 mg/m2 , except for the first dose given on day 1 (15 mg/m2 ). Some protocols omit the day 11 dose because of its myelosuppressive effects. When cyclosporine is given in combination with corticosteroids, methylprednisolone is usually started during the first 2 weeks

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posttransplant, given at full dosages for several weeks, and gradually tapered in the absence of GVHD. Although the efficacy of cyclosporine-methotrexate and cyclosporine-corticosteroids appears to be similar, the use of methotrexate may increase the risk of early graft failure, while corticosteroid administration has been associated with a higher incidence of infections. It is not clear whether three-drug regimens are more effective than two-drug regimens. In one prospective randomized study, the addition of methylprednisolone did not further increase the efficacy of the cyclosporine-methotrexate regimen.93 Unexpectedly, patients who received the three-drug combination had a higher incidence of acute and chronic GVHD and infection than did those given cyclosporine and methotrexate.94 In contrast, two other prospective randomized studies showed a benefit for the three-drug regimen versus a two-drug regimen.95,96 It is not completely clear why the trials reached different conclusions, but the different schedules of methylprednisolone may have had some influence on the results. In the first trial, methylprednisolone was given from days 0 to 35 posttransplant. In contrast, methylprednisolone was not started in the other trials until after day 7 posttransplant. Some investigators speculate that early administration of methylprednisolone may have interfered with the antiproliferative effects of methotrexate on T cells.93 Tacrolimus, given either alone or combined with methotrexate or methylprednisolone, has also been studied as GVHD prophylaxis after alloHSCT.89 Two large multicenter randomized trials compared cyclosporine and methotrexate with tacrolimus and methotrexate. One study was done in patients undergoing HLA-identical sibling alloHSCT,97 while the other study was done in patients undergoing matched unrelated alloHSCT.98 Both studies found the tacrolimus combination to be significantly superior to the cyclosporine combination in preventing grades II to IV acute GVHD. The incidence of renal impairment was higher in patients receiving tacrolimus, and more tacrolimus-treated patients in the HLA-sibling transplantation trial required hemodialysis. The incidence of hypertension was significantly higher in cyclosporine-treated patients in the HLAmatched sibling alloHSCT trial. No difference in the overall or relapse-free survival rate was reported in the two trials, although in the subgroup of patients with advanced disease in the HLA-sibling alloHSCT trial, cyclosporine-treated patients had significantly better overall and disease-free survival rates at 2 years as compared to those patients who received tacrolimus. The authors also explained that lowering the target blood levels to less than 20 ng/mL might reduce the renal toxicity of tacrolimus. Based on the results of these two studies, some transplant centers currently use tacrolimus and methotrexate as first-line acute GVHD prophylaxis. Acute GVHD prophylaxis regimens used in NMT are usually similar to those used in myeloablative alloHSCT. Some centers, however, have developed novel prophylactic regimens specifically for patients undergoing NMT. An example of such a regimen is cyclosporine and mycophenolate mofetil,58,62 which was developed based on preclinical studies.99 The role of ex vivo T-cell depletion from donor grafts is controversial (see Fig. 134–3).81 Although the use of T-cell–depleted marrow can reduce the incidence and severity of acute GVHD, it is associated with an increased risk of graft failure, delayed immune reconstitution, leukemic relapse, cytomegalovirus reactivation, and Epstein-Barr virus–related lymphoproliferative disorders. As a result, this approach does not improve the survival rate in recipients of HLA-identical sibling donor marrow. These observations suggest that important cell populations are being eliminated in the depletion process. Various approaches are being investigated to selectively remove the T cells responsible for GVHD while leaving those cells that

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mediate engraftment, antileukemic effect, and suppression of EpsteinBarr virus–transformed lymphocytes. Another approach is to infuse the T cells originally depleted from the graft later in the posttransplant period to prevent leukemic relapse.100 Because of the higher risk of GVHD in alloHSCT with HLA-mismatched or matched unrelated donors, T-cell depletion is sometimes included as part of the GVHD prophylaxis regimen in that setting. With HLA-mismatched or matched unrelated donors, the risk of moderate-to-severe (grades II to IV) acute GVHD is 50% or higher with conventional two-drug prophylaxis. Several approaches are used to reduce the risk of acute GVHD in this high-risk group of patients: three-drug GVHD prophylaxis, pretransplant administration of antithymocyte globulin, or ex vivo T-cell depletion of donor bone marrow (see Fig. 134–3). Encouraging results have been reported with the addition of novel immunosuppressive agents such as sirolimus to two-drug prophylaxis regimens.101 The addition of rabbit antithymocyte globulin to the pretransplant conditioning regimen reduced the risk of acute GVHD, but increased the risk of lethal infections.102 Uncontrolled studies suggest that ex vivo T-cell depletion significantly reduces the risk of early graft failure and acute GVHD, with apparent preservation of the GVL effect.81 If a patient develops grade II to IV acute GVHD, prophylactic agents are continued and high-dose corticosteroids, given as intravenously administered methylprednisolone, are started. The usual dosage is 2 mg/kg per day, given in two divided doses. The initial dosage is as high as 10 mg/kg per day in some protocols, although there is no convincing evidence that higher dosages are more effective. About 20% to 40% of patients with established acute GVHD respond to high-dose corticosteroids. If the patient responds, the corticosteroid dose is tapered gradually over several weeks, depending on response. In patients who experience a flare in their GVHD during the taper phase, therapy consists of increasing the steroid dose. GVHD-associated mortality is strongly correlated to response to initial treatment, and ranges from about 25% in patients who had a complete response to about 80% in those patients who had no response or progressive disease. Several randomized trials have evaluated other agents combined with methylprednisolone.89 In particular, the addition of anti-T-cell antibodies such as antithymocyte globulin or monoclonal antibodies to methylprednisolone has not been shown to improve patient outcome. Administration of enteric beclomethasone dipropionate capsules to systemic methylprednisolone is more effective than systemic methylprednisolone alone in the treatment of gastrointestinal acute GVHD.103 In patients who fail initial treatment with corticosteroids, salvage therapy with antithymocyte globulin, mycophenolate mofetil, thalidomide, sirolimus, or pentostatin has been given with some success.89 In addition, a variety of humanized mononclonal antibodies or fusion proteins are being evaluated in the treatment of steroid-refractory acute GVHD: denileukin difitox (Ontak), daclizumab (Zenapax), infliximab (Remicade), and etanercept (Enbrel).104−106

Chronic Graft-Versus-Host Disease Chronic GVHD usually occurs after day 100 and is the major determinant of late transplant-related morbidity and mortality.89,90,107−109 The pathophysiology of chronic GVHD is poorly understood. Chronic GVHD is often considered an autoimmune disease because of its similarity to other autoimmune disorders. The incidence of chronic GVHD in patients who survive more than 150 days ranges from 20% to 70%.89,107 The risk of chronic GVHD increases with increasing donor and recipient age, and is higher in patients who receive transplants from HLA-nonidentical

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related or unrelated donors, patients who receive PBSC transplants, and patients who receive DLI. A meta-analysis reported that the risk of chronic GVHD is increased by about 50% in patients who receive allogeneic PBSC transplants as compared with BMT.24 The risk of chronic GVHD is lower after UCB transplantation.26 The incidence of chronic GVHD is increasing because of increasing use of alternative donors, PBSCs as the graft source, DLI for treatment of recurrence, and older recipient age. Previous acute GVHD increases the risk of chronic GVHD, but about 20% to 30% of patients who receive HLAmatched alloHSCT develop chronic GVHD with no history of acute GVHD (de novo). Unlike acute GVHD, prophylactic immunosuppression does not appear to reduce the incidence or severity of the chronic form of the disease. The clinical manifestations of chronic GVHD can involve virtually all major organ systems.89,107,109 The diagnosis of chronic GVHD requires at least one manifestation that is characteristic of chronic GVHD: lichenoid oral or vaginal findings, ocular sicca, skin dyspigmentation, scleroderma, bronchiolitis obliterans, and esophageal web formation.107 The most common sites of involvement are the skin, mouth, liver, and eye. Since signs and symptoms are sometimes not noticeable for several months, many centers require their alloHSCT patients to undergo screening studies to detect early clinical chronic GVHD. The most commonly used staging system is the limited/extensive classification proposed by the Seattle HSCT program.89,107,109 In that system, chronic GVHD is classified as limited or extensive, depending on pathologic findings and the extent of systemic involvement. Limited chronic GVHD indicates localized skin involvement, mild hepatic dysfunction, or both. Most patients have extensive disease, with involvement of the skin, liver, eyes, mouth, esophagus, or other organs. Extensive disease is associated with a worse prognosis. The clinicopathologic findings of chronic GVHD are similar to those observed in various autoimmune diseases, with a marked increase in collagen deposition in the target organs. Several investigators have proposed improved staging systems based on larger numbers of patients and survival.110 If no functional impairment is present, patients with limited disease are not treated with systemic therapy. A variety of topical preparations may be used in patients with skin-only disease, such as clobetasol, tacrolimus, and pimecrolimus. Many patients with extensive chronic GVHD, if left untreated, will die of infections or become disabled. The long-term survival rate is worse in certain subgroups of patients, such as patients with extensive skin involvement, thrombocytopenia, progressive onset of chronic GVHD, and those who fail to respond to immunosuppressive therapy. 11 Initial treatment in patients with standard-risk chronic GVHD consists of prednisone (1 mg/kg per day) alone or alternateday therapy with prednisone and cyclosporine (10 to 12 mg/kg per day in two divided doses).90,107−109 Although many clinicians prefer alternate-day prednisone and cyclosporine, a recently published randomized trial showed no differences in response or survival between the two regimens in standard-risk patients.111 Tacrolimus is substituted for cyclosporine at some centers. Patients with high-risk disease should be treated with alternate-day therapy with prednisone and cyclosporine or tacrolimus. The calcineurin inhibitor is given daily rather than on alternate days at some centers. Treatment is continued until signs and symptoms of the disease have resolved, usually over a period of several months. As chronic GVHD improves, immunosuppressive therapy is gradually tapered and finally discontinued provided there is no flare of GVHD. About 60% of standard-risk patients and 40% of high-risk patients treated for chronic GVHD

have all of their immunosuppressive therapy successfully discontinued. Patients who fail initial therapy have a very poor prognosis and several therapies have been investigated with varying degrees of success: thalidomide, ultraviolet A irradiation after oral treatment with β-methoxypsoralen, extracorporeal photophoresis, tacrolimus, sirolimus, pentostatin, mycophenolate mofetil, hydroxychloroquine, and others.89,107,109 CLINICAL CONTROVERSY The choice of initial treatment of chronic GVHD is controversial. Many clinicians will treat standard- and high-risk patients with alternate-day prednisone and either daily or alternateday cyclosporine. However, a randomized trial showed no differences in response or survival between prednisone alone and alternate-day prednisone and cyclosporine in standardrisk patients. Other clinicians will substitute tacrolimus for cyclosporine. Several randomized trials are in progress, and the results of these trials should help to determine the optimal initial therapy for chronic GVHD. Infection is the primary cause of death in patients with chronic GVHD, and antimicrobial prophylaxis is an important component of the care of patients being treated for chronic GVHD. Patients should receive oral trimethoprim-sulfamethoxazole, penicillin, and acyclovir to prevent those infections commonly seen in immunocompromised patients.89,107,108 Some centers will also administer intravenous immunoglobulin to patients with low serum immunoglobulin G levels.

INFECTION Patients undergoing high-dose chemotherapy with autoHSCT or alloHSCT are severely immunocompromised and therefore at high risk for bacterial, fungal, and viral infection. Management of these infections is discussed in detail in Chap. 120. Comprehensive guidelines for monitoring, prophylaxis, and treatment of infections in HSCT recipients are available at http://www.cdc.gov/mmwr/preview/ mmwrhtml/rr4910a1.htm.

LATE COMPLICATIONS With the success of HSCT, the number of long-term survivors has grown. Many survivors experience delayed complications of transplantation, especially those receiving alloHSCT, and primary care physicians will care for them.112 Major late complications include restrictive and obstructive pulmonary disease; bone and joint disease; cataract formation; endocrine dysfunction, including sterility; impaired growth and development; infections; cardiovascular disease; and cirrhosis as a result of chronic hepatitis C infection and secondary malignancies.113,114 Physical recovery tends to occur earlier than psychological or work recovery.115 Full recovery usually takes several years, and about two-thirds of patients do not have major limitations by 5 years.

CONCLUSIONS Over the last few decades, HSCT has evolved from an idea into a well-established therapy used to treat thousands of patients with

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serious malignant and nonmalignant hematologic diseases. Transplantation is also being investigated as a treatment modality in patients with certain solid tumors or life-threatening autoimmune diseases. Because myelosuppression is the dose-limiting toxicity for many anticancer agents, HSCT allows the administration of higher and potentially more effective doses of chemotherapy. In patients who receive alloHSCT, cells in the graft can mediate a GVT effect. Although HSCT is a potentially curative therapy, this modality is associated with many serious and potentially life-threatening complications. With improved supportive care and management of infection, transplant-related mortality after alloHSCT with HLA-matched sibling donors has been reduced over the last few years. Causes of death are usually related to transplant-related organ toxicity, GVHD, or immunosuppression. Until recently, alloHSCT was usually restricted to patients younger than 50 years old with an HLA-identical sibling donor. With the availability of NMT, alloHSCT is now being offered to patients who would not otherwise be candidates for alloHSCT because of age or comorbidities. The risk of transplant-related mortality after autoHSCT is very low, and is primarily related to regimen-related toxicity. Many long-term survivors of HSCT will experience delayed complications.

ABBREVIATIONS ALL: acute lymphoblastic leukemia alloHSCT: allogeneic hematopoietic stem cell transplantation AML: acute myelogenous leukemia autoHSCT: autogenous hematopoietic stem cell transplantation BEAC: BCNU, etoposide, ara-C, and cyclophosphamide BEAM: BCNU, etoposide, ara-C, and melphalan BMT: bone marrow transplant BuCy: busulfan and cyclophosphamide CBV: cyclophosphamide, carmustine (BCNU), and etoposide (VP-16) CML: chronic myelogenous leukemia CyTBI: cyclophosphamide and total body irradiation DAH: diffuse alveolar hemorrhage DLI: donor lymphocyte infusion G-CSF: granulocyte colony-stimulating factor GM-CSF: granulocyte macrophage-colony stimulating factor GVHD: graft-versus-host disease GVL: graft-versus-leukemia (effect) GVT: graft-versus-tumor (effect) 4-HC: 4-hydroperoxycyclophosphamide HLA: human leukocyte antigen HSCT: hematopoietic stem cell transplantation IIP: idiopathic interstitial pneumonitis IL-2: interleukin-2 MHC: major histocompatibility complex MLC: mixed lymphocyte culture MLR: mixed lymphocyte reaction MUD: matched unrelated donor NMDP: National Marrow Donor Program NMT: nonmyeloablative transplant PBPC: peripheral blood progenitor cell PBSC: peripheral blood stem cell PCR: polymerase chain reaction TBI: total body irradiation UCB: umbilical cord blood VOD: (hepatic) veno-occlusive disease

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Review Questions and other resources can be found at www.pharmacotherapyonline.com.

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CHAPTER 134 60. Loberiza F. Report on the state of the art in blood and marrow transplantation—Part I of the IBMTR/ABMTR summary slides with guide. IBMTR/ABMTR Newsletter 2003;10:7–10. 61. Bethge A, Hegenbart U, Stuart MJ, et al. Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Blood 2004; 103:790–795. 62. Mielcarek M, Storb R. Non-myeloablative hematopoietic cell transplantation as immunotherapy for hematologic malignancies. Cancer Treat Rev 2003;29:283–290. 63. Junghanss C, Marr KA, Carter RA, et al. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant 2002;8:512–520. 64. Junghanss C, Boeckh M, Carter RA, et al. Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation: a matched control study. Blood 2002;99:1978–1985. 65. Mielcarek M, Martin PJ, Leisenring W, et al. Graft-versus host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003;102:756–762. 66. Diaconescu R, Flowers CR, Storer B, et al. Morbidity and mortality with nonmyeloablative compared to myeloablative conditioning before hematopoietic cell transplantation from HLA matched related donors. Blood 2004;104:1550–1558. 67. Maris MB, Niederwieser D, Sandmaier BM, et al. HLA-Matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 2003; 102:2021–2030. 68. Blaise D, Bay JO, Faucher C, et al. Reduced-intensity preparative regimen and allogeneic stem cell transplantation for advanced solid tumors. Blood 2004;103:435–441. 69. Ueno NT, Cheng YC, Rondon G, et al. Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem-cell transplantation for metastatic solid tumors. Blood 2003;102:3829–3836. 70. Fung HC, Cohen S, Rodriguez R, et al. Reduced-intensity allogeneic stem cell transplantation for patients whose prior autologous stem cell transplantation for hematologic malignancy failed. Biol Blood Marrow Transplant 2003;9:649–656. 71. Maloney DG, Molina AJ, Sagebi F, et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003;102:3447–3454. 72. Kumar S, DeLeve LD, Kamath PS, Tefferi A. Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation. Mayo Clin Proc 2003;78:589–598. 73. Wadleigh M, Richardson PG, Zahrieh D, et al. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood 2003;102:1578–1582. 74. Chalandon Y, Roosnek E, Mermillod B, et al. Prevention of venoocclusive disease with defibrotide after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2004;10:347–354. 75. Richardson PG, Murakami C, Jin Z, et al. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe venoocclusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood 2002;100:4337–4343. 76. Horak DA. Pulmonary complications after hematopoietic cell transplantation. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas’ Hematopoietic Cell Transplantation, 3rd ed. Malden, MA, Blackwell Science, 2004:873–882. 77. Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant 2001;27:893–898. 78. Fukuda T, Hackman RC, Guthrie KA, et al. Risks and outcomes of idiopathic pneumonia syndrome after nonmyeloablative compared to conventional conditioning regimens for allogeneic hematopoietic stem cell transplantation. Blood 2003;102:2777–2785.

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79. Palmas A, Tefferi A, Meyers JL, et al. Late-onset noninfectious pulmonary complications after allogeneic bone marrow transplantation. Br J Haematol 1998;100:680–687. 80. Dudek AZ, Mahaseth H, DeFor TE, Weisdorf DJ. Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes. Biol Blood Marrow Transplant 2003;9:657–666. 81. Soiffer RJ. T-cell depletion to prevent graft-versus-host disease. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas’ Hematopoietic Cell Transplantation, 3rd ed. Malden, MA, Blackwell Science, 2004: 221–233. 82. Ozer H, Armitage JO, Bennett CL, et al. Update of recommendations for the use of hematopoietic colony stimulating factors: Evidence-based, clinical practice guidelines. J Clin Oncol 2000;18:3558–3585. 83. Finke J, Mertelsmann R. Recombinant growth factors after hematopoietic cell transplantation. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas’ Hematopoietic Cell Transplantation, 3rd ed. Malden, MA, Blackwell Science, 2004:613–623. 84. Bolwell B, Goomastic M, Dannley R, et al. G-CSF post-autologous progenitor cell transplantation: A randomized study of 5, 10, and 16 mcg/kg/ day. Bone Marrow Transplant 1997;19:215–219. 85. Bolwell B, Pohlman B, Andresen S, et al. Delayed G-CSF after autologous progenitor cell transplantation: prospective randomized trial. Bone Marrow Transplant 1998;21:369–373. 86. Ho VT, Mirza NQ, Junco DD, et al. The effect of hematopoietic growth factors on the risk of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a meta-analysis. Bone Marrow Transplant 2003;32:771–775. 87. Ringden O, Labopin M, Gorin N-C, et al. Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus-host disease and death: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2004; 22:416–423. 88. Ferrara JLM, Antin J. The pathophysiology of graft-versus-host disease. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas’ Hematopoietic Cell Transplantation, 3rd ed. Malden, MA, Blackwell Science, 2004:353–368. 89. Sullivan KM. Graft-versus-host disease. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas’ Hematopoietic Cell Transplantation, 3rd ed. Malden, MA, Blackwell Science, 2004:635–664. 90. Vogelsang GB, Lee L, Bensen-Kennedy DM. Pathogenesis and treatment of graft-versus-host disease after bone marrow transplant. Annu Rev Med 2003;54:29–52. 91. Lin M-T, Storer B, Martin PJ, et al. Relation of an interleukin-10 promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation. N Engl J Med 2003;349:2201–2210. 92. Chao NJ. Pharmacology and the use of immunosuppressive agents after hematopoietic cell transplantation. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas’ Hematopoietic Cell Transplantation, 3rd ed. Malden, MA, Blackwell Science, 2004:209–220. 93. Storb R, Pepe M, Anasetti C, et al. What role for prednisone in prevention of acute graft-versus-host disease in patients undergoing marrow transplants? Blood 1990;76:1337–1345. 94. Sayer HG, Longton G, Bowden R, et al. Increased risk of infection in marrow transplant patients receiving methylprednisolone for graftversus-host disease prevention. Blood 1994;84:1328–1332. 95. Chao NJ, Schmidt GM, Niland JC, et al. Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone alone for the prophylaxis of acute graft-versus-host disease. N Engl J Med 1993; 329:1225–1230. 96. Ruutu T, Volin L, Parkkli T, et al. Cyclosporine, methotrexate, and methylprednisolone compared with cyclosporine and methotrexate for the prevention of graft-versus-host disease in bone marrow transplantation from HLA-identical sibling donor: A prospective randomized study. Blood 2000;96:2391–2398. 97. Ratanatharathorn V, Nash RA, Przepiorka D, et al. Phase III study comparing methotrexate and tacrolimus (Prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after

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98.

99.

100.

101.

102.

103.

104.

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HLA-identical sibling bone marrow transplantation. Blood 1998;92: 2303–2314. Nash RA, Antin JH, Karanes C, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood 2000;96:2062–2068. Yu C, Seidel K, Nash RA, et al. Synergism between mycophenolate mofetil and cyclosporine in preventing graft-versus-host disease among lethally irradiated dogs given DLA-identical unrelated marrow grafts. Blood 1998;91:2581–2587. Elmaagacli AH, Peceny R, Steckel N, et al. Outcome of transplantation of highly purified peripheral blood CD34+ cells with T-cell add-back compared with unmanipulated bone marrow or peripheral blood stem cells from HLA-identical sibling donors in patients with first chronic phase chronic myeloid leukemia. Blood 2003;101:446–453. Antin JH, Kim HT, Cutler C, et al. Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. Blood 2003;102: 1601–1605. Bacigalupo A, Lamparelli T, Bruzzi P, et al. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood 2001;98:2942–2947. McDonald GB, Bouvier M, Hockenbery DM, et al. Oral beclomethasone dipropionate for treatment of intestinal graft-versus-host disease: a randomized, controlled trial. Gastroenterology 1998;115: 28–35. Bruner RJ, Farag SS. Monoclonal antibodies for the prevention and treatment of graft-versus-host disease. Semin Oncol 2003;30:509–519.

105. Ho VT, Zahrieh D, Hochberg E, et al. Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood 2004;104:1224–1226. 106. Couriel D, Saliba R, Hicks K, et al. Tumor necrosis factor alpha blockade for the treatment of acute GVHD. Blood 2004;104:649–654. 107. Lee SJ, Vogelsang G, Flowers MED. Chronic graft-versus-host disease. Biol Blood Marrow Transplant 2003;9:215–233. 108. Bhushan V, Collins RH. Chronic graft-vs-host disease. JAMA 2003;290: 2599–2603. 109. Vogelsang GB. Chronic graft-versus-host disease. Br J Haematol 2004; 125:435–454. 110. Akpek G, Lee SJ, Flowers ME, et al. Performance of a new clinical grading system for chronic graft-versus-host disease: a multicenter study. Blood 2003;102:802–809. 111. Koc S, Leisenring W, Flowers MED, et al. Therapy for chronic graftversus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood 2003;100:48–51. 112. Antin JH. Long-term care after hematopoietic-cell transplantation in adults. N Engl J Med 2002;347:36–42. 113. Socie G, Salooja N, Cohen A, et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood 2003;101:3373–3385. 114. Flowers MED, Deeg HJ. Delayed complications after hematopoietic cell transplantation. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas’ Hematopoietic Cell Transplantation, 3rd ed. Malden, MA, Blackwell Science, 2004:944–961. 115. Syrjala KL, Langer SL, Abrams JR, et al. Recovery and long-term function after hematopoietic cell transplantation for leukemia and lymphoma. JAMA 2004;291:2335–2343.

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135 ASSESSMENT OF NUTRITION STATUS AND NUTRITION REQUIREMENTS Katherine Hammond Chessman and Vanessa J. Kumpf

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Classification of nutrition status is often desired as a means to identify those who are nutritionally at risk or malnourished.

2 Nutrition screening programs should identify those at risk for poor nutrition-related outcomes due to either over- or undernutrition.

3 Nutrition assessment is the first step in formulating a patient-

specific nutrition care plan for a patient who is found to be nutritionally at risk or malnourished.

4 A nutrition-focused medical and dietary history and a

nutrition-focused physical examination are key components of nutrition assessment and will reveal risk factors for and the likelihood of malnutrition and nutrient deficiencies.

5 Appropriate anthropometric measurements are essential in a complete nutrition assessment and should be evaluated based on published standards.

6 Biochemical (laboratory) tests are also essential for nutri-

tion assessment, but must be interpreted in the context of the physical findings, medical history, and clinical status of the patient, as well as specific test limitations.

Nutrition care is a vital component of quality patient care. This chapter reviews the current tools most commonly used for nutrition screening and accurate, relevant, and cost-effective nutrition assessment. Determination of patient-specific micro- and macronutrient requirements and potential drug-nutrient interactions are also discussed.

CLASSIFICATION OF NUTRITION DISEASE 1 Undernutrition usually results from starvation (inadequate nutri-

ent intake) or altered metabolism (inappropriate use of ingested nutrients). Pure starvation occurs when inadequate amounts of appropriate nutrients are available to support tissue repair or synthesis, and changes can be reversed by adequate feeding.1 An alteration in nutrient metabolism exists when the cell has altered substrate demands

7 Nutrient deficiencies involving micronutrients (e.g., vita-

mins or trace elements) or macronutrients (e.g., fat, protein, or carbohydrate) are possible, and a comprehensive nutrition assessment will identify the presence of these.

8 When determining patient-specific nutrition requirements,

goals should be established based on the patient’s clinical condition and the need for maintenance or repletion in adults, as well as for continued growth and development in children.

9 Drug-nutrient interactions can affect a patient’s nutrition status as well as the response to or adverse effects seen with drug therapy and must be considered when evaluating a patient’s nutrition care plan.

10 An initial nutrition assessment and determination of nutri-

tion requirements only defines an empirical starting point for a nutrition care plan. Close monitoring is required so that timely adjustments to the nutrition care plan can be made based on patient-specific responses to ensure appropriate nutrition-related outcomes.

or use such as cachexia associated with inflammatory or neoplastic conditions. In such situations, enhancing nutritional intake may not be sufficient to meet the increased demand.1 Regardless of the cause, undernutrition results in changes in subcellular, cellular, and/or organ function that expose the individual to increased risks of morbidity and mortality (see Chap. 136). In general, deficiency states can be categorized as those involving protein and calories or those involving single nutrients such as individual vitamins or trace elements. Depletion of individual nutrients leads to symptoms related to that nutrient’s function. Protein-calorie malnutrition may be classified as marasmus, kwashiorkor, or mixed marasmus/kwashiorkor. Marasmus is a chronic condition resulting from a prolonged deficiency in total intake and/or nutrient utilization. Somatic protein (skeletal muscle) and adipose tissue (subcutaneous fat) wasting occurs, but visceral protein production (e.g., albumin and transferrin) is 2559

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preserved. Weight loss usually exceeds 10% of usual weight. When severe, cell-mediated immunity, measured by delayed cutaneous hypersensitivity (DCH), and muscle function are impaired. Patients with wasting diseases such as cancer commonly have marasmus and a prototypical starved, wasted appearance. Kwashiorkor develops when there is adequate calorie but a relatively inadequate protein intake. These patients generally are well nourished but are extremely catabolic, usually secondary to trauma, infection, or burns. There is depletion of visceral (and to some degree somatic) protein pools with relative adipose tissue preservation, and hypoalbuminemia and edema are commonly seen. In the setting of severe metabolic stress and protein deprivation, kwashiorkor may develop rapidly and may result in impaired immune function. Mixed marasmus/kwashiorkor is a form of severe protein-calorie malnutrition that develops in chronically ill, starved patients during periods of hypermetabolic stress. There is reduced visceral protein synthesis superimposed on wasting of somatic protein and energy (adipose tissue) stores. Immunocompetence is lowered, increasing the incidence of infection, and wound healing is compromised. Obesity (overnutrition) is a major health care concern in the United States. Between 2000 and 2001, the prevalence of obesity in American adults (defined as a body mass index [BMI] of 30 kg/m2 or greater) increased from 19.8% to 20.9%.2 Additionally, approximately 15% of children and adolescents (ages 6 to 19 years) are obese (BMI at or above the 95th percentile for age3 on the gender appropriate BMI-for-age growth chart published by the Centers for Disease Control National Center for Health Statistics [NCHS]).4 Many more children are considered to be at-risk for obesity (BMI at or above the 85th percentile for age). Nutrition assessment allows identification of obese individuals or those at risk of becoming obese, and the numerous consequences of overnutrition, including type II diabetes mellitus, cardiovascular disease, and stroke (see Chap. 140).

NUTRITION SCREENING 2 Because a thorough nutrition assessment on every patient is

not practical (or warranted), nutrition screening provides a systematic way of identifying individuals at risk for malnutrition. Risk factors for undernutrition include any disease state, complicating condition, treatment, or socioeconomic condition that may result in a decreased nutrient intake, altered metabolism, and/or malabsorption. Nutrition screening can be done in the home by the patient or home health care professional, in long-term care facilities, in ambulatory care clinics, or in the hospital. Various rating and classification systems have been proposed to assess nutrition risk and guide subsequent interventions.5−7 Checklists are used in many clinical settings to quantify a person’s food and alcohol consumption habits; ability to buy, prepare, and eat food; weight history; diagnoses; or medical/surgical procedures. Depending on the specific criteria evaluated, three to four risk factors may put a person at risk for malnutrition. Pediatric screening programs most often evaluate growth parameters against the NCHS growth charts4 and medical conditions known to increase nutrition risk.8 Hospital screening programs must also identify patients receiving specialized nutrition support, or enteral or parenteral nutrition prior to admission. The Joint Commission on Accreditation of Healthcare Organizations hospital standards state: “Based on the results of the nutrition screen and, when appropriate, nutrition assessment and re-assessment, the nutrition treatment plan is implemented for all patients determined to be at nutrition risk.”9 For inpatients, a nutrition screening process should occur within an institution-designated

period of time (usually 24 to 72 hours after admission). In the hospital setting, patients initially determined to be “not at risk” should be reevaluated every 7 to 14 days to detect deterioration in nutrition status secondary to changes in food intake or clinical condition. By identifying at-risk individuals, nutrition screening can be a cost-effective way to help decrease complications and length of hospital stay.10 Nutrition screening should also occur frequently in the outpatient setting, especially in young children and the elderly, to ensure that potential nutritional issues are addressed before they become significant problems.

NUTRITION ASSESSMENT 3 A comprehensive nutrition assessment is the first step in formu-

lating a patient-specific nutrition care plan. Nutrition assessment has four major goals: (1) identification of the presence or risk of developing malnutrition, including disorders resulting from micro- or macronutrient deficiencies (undernutrition), obesity (overnutrition), or impaired metabolism, (2) determination of risk of malnutritionassociated complications, (3) establishment of estimated nutrition needs, and (4) establishment of baseline parameters against which to measure nutrition therapy outcomes. A comprehensive nutrition assessment should include a nutrition-focused medical and dietary history, a physical examination including anthropometric measurements and laboratory measurements, and provides a basis for determining the patient’s nutrition requirements and the optimal type and timing of nutrition intervention.

CLINICAL EVALUATION 4 Clinical evaluation with a nutrition-focused medical and dietary

history and physical examination remains the oldest, simplest, and most widely used method of evaluating nutrition status. Clinical evaluation of nutrition status correlates well with objective evaluations (e.g., laboratory parameters and anthropometric measurements). The medical and dietary history components of the clinical evaluation will provide information about factors that predispose to malnutrition (e.g., prematurity, chronic diseases, gastrointestinal [GI] malfunction, and alcohol abuse). The clinician should direct the interview to elicit any history of weight loss, anorexia, vomiting, diarrhea, and decreased or unusual food intake (Table 135–1). The nutrition-focused physical examination consists of an assessment of lean body mass (LBM) and the physical findings of vitamin deficiency, trace element deficiency, and essential fatty acid deficiency. The assessment should characterize the presence and degree of muscle wasting, edema, loss of subcutaneous fat, dermatitis, glossitis, cheilosis, and/or jaundice11 (Table 135–2). In the 1970s, an initial, comprehensive nutritional assessment required up to 3 days to complete and cost several thousand dollars. In the 1980s, the subjective global assessment (SGA), a streamlined, simplified, reproducible, cost-effective approach to nutrition assessment that took only 20 minutes to complete was introduced and is used extensively today. Five aspects of the medical and dietary history are used in the SGA: weight changes in the previous 6 months, dietary intake changes, GI symptoms, functional capacity, and disease states. Weight loss of less than 5% of usual body weight is considered a “small” loss, 5% to 10% loss is a “potentially significant loss,” and more than a 10% loss is a “definitely significant loss.” Dietary intake should be characterized as either normal or abnormal, and the length of time and degree of abnormal intake should be noted. The presence of GI symptoms (e.g., anorexia, nausea, vomiting, or diarrhea) on a daily basis for longer than 2 weeks is significant. Functional

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TABLE 135–1. Pertinent Data from Nutrition-Focused Medical and Dietary History Nutrition intake and dietary habits Anorexia or unusual or absent taste Dietary intake and special diets, including enteral or parenteral nutrition Formula or breast-feeding and age at initiation of solid foods Supplemental vitamin, mineral, or herbal intake Food allergies or intolerance Underlying pathology with nutritional effects Chronic infections or inflammatory states Neoplastic diseases Endocrine disorders Chronic illness including pulmonary disease, cirrhosis, and renal failure Hypermetabolic states such as trauma, burns, and sepsis Digestive or absorptive disease, nausea, vomiting, or diarrhea Hyperlipidemia Prematurity End-organ effects Weight change or failure to thrive Skin or hair changes Activity and energy level, exercise tolerance, and fatigue Obesity Gastrointestinal tract symptoms: diarrhea, vomiting, constipation Miscellaneous Catabolic medications or therapies: corticosteroids, immunosuppressive agents, radiation, or chemotherapy Other medications: diuretics, laxatives, or anabolic steroids Genetic background: body habitus of parents, siblings, and family Alcohol or drug abuse

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capacity assesses the patient’s energy level and whether the patient is active or bedridden. Finally, disease states present are assessed as to their impact on metabolic demands (i.e., no stress, low, moderate, or high stress). Four physical examination findings are rated as normal, mild, moderate, or severe: loss of subcutaneous fat (triceps and chest), muscle wasting (quadriceps and deltoids), edema (ankle and sacral), and ascites. The clinician then ranks the patient’s nutritional status as adequately nourished, moderately malnourished, or severely malnourished.

ANTHROPOMETRIC MEASUREMENTS 5 Anthropometric measurements, gross measurements of body

cell mass, are used to evaluate LBM and fat stores. The most common measurements are stature (height or length, depending on age), weight, head circumference (for children younger than 3 years of age), and measurements of limb size, such as skinfold thickness, midarm muscle circumference (MAMC), wrist circumference, and waist circumference. Bioelectrical impedance analysis (BIA) is also an anthropometric assessment tool. These parameters are used to compare an individual with normative standards for a population and as repeated measurements in an individual to monitor response to a nutrition care plan. In adults, nutrition-related changes in anthropometric measurements occur slowly; several weeks or more are usually required before detectable changes are noted. In infants and young children, however, changes may occur more quickly. Acute changes in anthropometric measurements, specifically weight and skinfold thickness, usually reflect changes in hydration status, and this must be considered when interpreting these parameters, particularly in hospitalized patients.

WEIGHT, STATURE, AND HEAD CIRCUMFERENCE TABLE 135–2. Physical Findings Suggestive of Malnutrition General appearance Edema (especially ankle and sacral) Cachexia or obesity Ascites Signs and symptoms of dehydration: poor skin turgor, sunken eyes, orthostasis, or dry mucous membranes Muscle wasting or loss of subcutaneous fat Obesity Skin and mucous membranes Thin, shiny, or scaling skin Decubitus ulcers Ecchymoses or perifollicular petechiae Poorly healing of surgical or traumatic wounds Pallor or redness of gums or fissures at mouth edge Glossitis, stomatitis, or cheilosis Musculoskeletal Retarded growth Bone pain or tenderness or epiphyseal swelling Muscle mass less than expected for habitus, genetic history, and level of exercise Neurologic Ataxia, positive Romberg test, or decreased vibratory or position sense Nystagmus Convulsions or paralysis Encephalopathy Failure to meet age-appropriate developmental milestones Hepatic Jaundice Hepatomegaly

Body weight is a nonspecific measure of body cell mass, representing skeletal mass, body fat, and the energy-using component referred to as LBM. Change in weight over time, particularly in the absence of edema, ascites, and voluntary losses, is an important indicator of altered LBM. Interpretation of any actual body weight (ABW) measurement should take into consideration ideal weight-for-height, also referred to as ideal body weight (IBW) or LBM, usual body weight (UBW), fluid status, and age (Table 135–3). Dehydration will result in

TABLE 135–3. Evaluation of Actual Body Weight Actual body weight (ABW) compared to ideal body weight (IBW) Undernutrition ABW 120% IBW ABW ≥150% IBW ABW ≥200% IBW

Severe malnutrition Moderate malnutrition Mild malnutrition Normal Overweight Obese Morbidly obese

Actual body weight (ABW) compared to usual body weight (UBW) ABW 85–95% UBW ABW 75–84% UBW ABW 60 y may be decreased in winter, fat malabsorption Excess intake: hemorrhagic toxicity; anticoagulant effect should be monitored carefully if taking supplements Anticoagulant therapy can be affected by supplements or diet

Folic acid

Ascorbic acid (C)

Fat-soluble vitamins A

Acylcarnitine concentrations are more helpful in secondary causes of carnitine deficiency. When only total and free concentrations are available, the free is subtracted from the total to give the acylcarnitine concentration.

MUSCLE FUNCTION TESTS A relatively new approach to nutrition assessment is to evaluate muscle function as an end-organ response. Hand-grip strength (forearm muscle dynamometry), respiratory muscle strength, and muscle re-

Serum folate

Decreased with increased cellular/tissue turnover (pregnancy, malignancy, hemolytic anemia); masks neurologic complications of vitamin B12 deficiency; decreases risks of neural tube defects Decreased absorption in the elderly, distal ileal resection, loss of gastric intrinsic factor

sponse to electrical stimulation have been used.66 Hand-grip strength has been shown to correlate with patient outcome. Forearm muscle dynamometry is a relatively simple, noninvasive, and inexpensive procedure. Ulnar nerve stimulation causes measurable muscle contraction. In the setting of malnutrition, increased fatigue and a slowed muscle relaxation rate have been noted; these indices return to normal after refeeding. Both these parameters have the advantage of being indicators of tissue function rather than composition. Their utility in clinical practice is currently hampered by a lack of appropriate reference standards and limited data confirming their sensitivity and specificity as nutrition assessment tools.

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OTHER NUTRITION ASSESSMENT TOOLS Various methods to determine body composition have been used in the research setting. These methods generally are complex, require expensive technology, and at present are limited to research centers. One of the most promising for clinical practice is dual-energy x-ray absorptiometry (DEXA). This procedure is now available in many hospitals and clinics for measuring bone density. DEXA also can be used to quantify the mineral, fat, and LBM compartments. Ultrasound and infrared interactance can be used to measure subcutaneous fat. The latter uses an inexpensive and portable device, but these measurements have not been used extensively for nutrition assessment. MRI and computed tomography can measure subcutaneous, intraabdominal, and regional fat distribution. Neutron activation is a means of measuring body nitrogen, calcium, sodium, chloride, and phosphorus. These measurements can then be used to calculate total body fat, bone, and protein. Isotope dilution methods determine TBW and underwater weighing determines density. In addition, these methods can be used to estimate LBM and body fat. Furthermore, LBM also can be estimated using total body electrical conductivity and by measuring the naturally occurring isotope 40 K.

ASSESSMENT OF NUTRIENT REQUIREMENTS 8 Nutrition requirements depend on an individual’s clinical condi-

tion and the need for continued maintenance of adequate nutrition, or whether starvation or ongoing metabolic stress dictate a need for repletion. For obese patients, usual nutrition requirements may be altered due to the need for weight loss. In children, there is the added consideration of sustaining or re-establishing normal growth and development. Organ function (e.g., intestine, kidney, liver, and pancreas) may affect nutrient utilization. Nutrient requirements vary with age, gender, size, disease state, clinical condition, nutrition status, and physical activity level. An estimate of nutrient requirements therefore must be made using guidelines interpreted in the context of these patient-specific factors. The recommended dietary allowances (RDAs) initially were intended to provide information to be used to prevent nutritional deficiencies in a healthy population of individuals,67 but have often been used inappropriately to evaluate the diets of individuals. In the early 1990s, the Food and Nutrition Board began the task of revising the RDAs, and created a new family of nutrition reference values, the dietary reference intakes (DRIs) and seven nutrient groups.68 The four categories of the new DRIs are estimated average requirements (EARs), recommended dietary allowances (RDAs), adequate intakes (AIs), and tolerable upper intake level (UL). EARs can be used for planning recommended nutrient intake for groups, as they are defined as the amount of the nutrient that meets the needs of 50% of persons in a given group. The RDA is designated as nutrient intake that meets the needs of almost all persons in the designated group. The RDA is approximately two standard deviations above the EAR for nutrients for which the requirement is well defined, and 1.2 times the EAR for nutrients for which there is more variability. AIs are defined as the average intake of a designated group that appears to sustain a particular nutrition state, growth, or other functional indication of health. This category is reserved for nutrients for which no EAR or RDA has been determined. Finally the UL is the maximum nutrient intake that is unlikely to pose adverse affects in almost all persons in a designated group. DRIs have been established for six of the seven established nutrient groups: (1) calcium, phosphorus, mag-

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nesium, vitamin D, and fluoride;69 (2) folate and other B vitamins;70 (3) antioxidants (e.g., selenium and vitamins C and E);71 (4) trace elements;72 (5) macronutrients (e.g., protein, fat, carbohydrates, and fiber);73 and (6) electrolytes and water.74 Recommendations for group 7, which includes other food components (e.g., phytoestrogens), are still in development.

ENERGY REQUIREMENTS The DRIs for macronutrients73 recommend that adults consume 45% to 65% of their total calories from carbohydrates, 20% to 35% from fat, and 10% to 35% from protein. The recommendations for children are similar, except that infants and younger children need a higher proportion of fat (approximately 40% to 50% of total calories) in their diets. An RDA for total carbohydrates for adults and children of 130 g/day was set with the most recent revisions.73 CLINICAL CONTROVERSY Clinicians have debated whether calorie requirements should be expressed in terms of total or nonprotein calories. Those that use nonprotein calories base the decision on the theory that protein should be used for synthesis, not energy production. Those that correctly use total calories know that in the presence of adequate calorie intake, protein is not necessarily prioritized solely for anabolism. Also, standard equations such as the HBEs used to estimate energy needs were derived from measurement of energy expenditure and thus estimate total calories. In fact, while daily protein intake is used primarily for synthesis, protein is constantly being metabolized to energy. Approximately 15% of the total caloric expenditure comes from the breakdown of protein and other nitrogencontaining molecules. Additionally, calorie goals should be consistent among enteral, parenteral, and oral routes, necessitating the use of total calories. There are numerous published methods for determining an individual’s total energy or calorie (kcal) requirement. The most commonly used methods to determine energy requirements use calories per kilogram of body weight (kcal/kg), equations that estimate energy expenditure, or indirect calorimetry. The simplest method to assess energy requirements is to use population estimates of calories required per kilogram of body weight. This method assumes standard values for the energy requirements associated with various disease states or clinical conditions, as well as the additional requirements for repletion of a malnourished individual. It does not take into consideration age- or gender-related differences in energy needs. Daily adult requirements determined by this method, using actual body weight or adjusted body weight in kilograms, generally are accepted to be: Healthy, normal nutrition status: 20 to 25 kcal/kg per day Malnourished or mildly metabolically stressed: 25 to 30 kcal/kg per day Critically ill, hypermetabolic: 30 to 35 kcal/kg per day Major burn injury (>50% total body surface area): 35 to 40 kcal/kg per day Suggested calorie intakes for maintenance and normal growth of healthy infants and children are shown in Table 135–10.73 For children, these maintenance energy requirements are approximately 150% of basal metabolic rate (BMR) with the additional calories

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TABLE 135–10. Dietary Reference Intakes for Energy and Protein in Healthy Children Age (Reference age/wt) 0–6 mo (3 mo/6 kg) 7–12 mo (9 mo/9 kg) 1–2 yr (24 mo/12 kg) 1–3 yr (24 mo/12 kg) 3–8 yr (6 y/20 kg) 4–8 yr (6 y/20 kg) 9–13 yr (11 y/M: 36 kg; F: 37 kg) 14–18 yr (16 y/M: 61 kg; F: 54 kg)

Estimated Energy Requirement (kcal/day) Male 570 743 1046

Female 520 676 992

1742

1642

2279 3152

2071 2368

Protein RDA (g/kg/day) 1.52a 1.5 1.1 0.95 0.95 0.85

F, female; M, male; RDA, recommended dietary allowance. a Adequate intake.

needed to support activity and growth. Caloric requirements increase with fever, sepsis, major surgery, trauma, burns, and long-term growth failure, and in the presence of chronic conditions such as bronchopulmonary dysplasia, congenital heart disease, and cystic fibrosis. Caloric needs may decrease with obesity and neurologic disability (e.g., cerebral palsy). Clinical judgment and close monitoring are essential to ensure that the desired nutrition therapy outcomes are attained. Various equations are used to estimate energy needs (Table 135–11). The Harris-Benedict equations, which were first published in 1919, remain one of the most popular means used to assess energy requirements in adults. They have the advantage of taking into consideration the patient’s age, height, weight, gender, and clinical condition. The HBEs were derived from oxygen consumption

TABLE 135–11. Equations to Estimate Basal Energy Expenditure in Adults and Children Harris-Benedict (kcal/day): Males: BEE = 66 + [(13.7W(kg)] + [5H(cm)] − (6.8A) Females: BEE = 655 + [(9.6W(kg)] + [1.8H(cm)] − (4.7A) Modified Harris-Benedict (kcal/day) for adults >60 years of age: Males: BEE = [(8.8W(kg)] + [1128H(m)] − 1071 Females: BEE = [(9.2W(kg)] + [637H(m)] − 302 Caldwell-Kennedy (kcal/day) for children 70 y: 15 15

5 (200 IU)

90–120 mcg

0.7–2.5 mg

Vitamin E (mg TE) (α-tocopherol) Vitamin K

10 (10 IU)

Enteral 0–12 mo: 125–150 1–8 y: 200–250 9–18 y: 375–550 0–12 mo: 0.4–0.5 1–8 y: 0.9–1.2 9–18 y: 1.8–2.4 0–12 mo: 65–80 1–8 y: 150–200 9–18y: 300–400 0–12 mo: 2–4 1–8 y: 6–8 9–18 y: 12–16 0–12 mo: 1.7–1.8 1–8 y: 2–3 9–18 y: 4–5 0–12 mo: 0.1–0.3 1–8 y: 0.5–0.6 9–18 y: 1–1.3 0–12 mo: 0.3–0.4 1–8 y: 0.5–0.6 9–18 y: 0.9–1.3 0–12 mo: 0.2–0.3 1–8 y: 0.7–1 9–18 y: 2–3 0–12 mo: 400–500 1–8 y: 300–400 9–18 y: 600–900 All ages: 5 (200 IU)

0–12 mo: 4–5 1–8 y: 6–7 9–18 y: 11–15 0–12 mo: 2–2.5 1–8 y: 30–55 9–18 y: 60–75

Parenteral Not established

1

140

17

5

1

1.4

1.2

700 (2300 IU)

5 (200 IU)

7 (7 IU)

200 mcg

a

Adapted from Food and Nutrition Board,67 Food and Nutrition Information Center,68 Food and Nutrition Board,69 Food and Nutrition Board,70 Food and Nutrition Board,71 Jefferson,90 Fuhr,91 and Kirk.92 Data represent either the RDA or the AI for each nutrient where established. b As needed to maintain acid-base balance. c Newborns and low-birth-weight or very-low-birth-weight infants or with concomitant disease (e.g., necrotizing enterocolitis) may have higher requirements. Intake in nonhealthy children must be individualized. d No RDA or AI has been established. e An additional 20 mcg of chromium per day is recommended in patients with intestinal losses. f May accumulate in cholestasis. g Long-term parenteral nutrition only; no topicals containing iodide or table salt are used. h An additional 12.2 mg zinc/L of small bowel fluid lost and 17.1 mg zinc/kg of stool or ileostomy output is recommended; add an additional 2 mg zinc per day for acute catabolic stress. i Higher doses (15 mcg) recommended in those over 70 years of age. AI, adequate intakes; NE, niacin equivalents; PN, parenteral nutrition; RDA, recommended dietary allowances; RE, retinal equivalents; TE, tocopherol equivalent.

agent propofol and may contribute a large amount of calories when continuous propofol infusions are used. In these instances, nutrition support regimens must be adjusted to accommodate the calories and other nutrients delivered through other therapies.

PRACTICAL GUIDELINES FOR NUTRITION ASSESSMENT 10 The value of any given marker used for nutrition assessment

is only as great as its ability to accurately identify the patient with malnutrition and to correlate with malnutrition-associated com-

plications. Most of the currently available markers of nutrition status were first used in epidemiologic studies to define large populations suffering from malnutrition caused by famine. The response of the various nutritional status markers to nutrition therapy and the correlation between improvement in these markers and decreased morbidity and mortality further support their validity. However, when applied to an individual, most of these markers lack specificity and sensitivity, which makes the development of a clinically useful, cost-effective approach to individual patient nutrition assessment challenging. The importance of the nutrition-focused history and physical examination in both nutrition screening and nutrition assessment cannot be overemphasized. The least amount of objective data that can further

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TABLE 135–15. Drug Effects on Vitamin Status Drug Antacids Antibiotics Anticonvulsants Antineoplastics Antipsychotics Cathartics Cholestyramine Colestipol Corticosteroids Diuretics (loop) Histamine2 antagonists Isoniazid Mineral oil Orlistat Pentamidine Proton pump inhibitors

Effect Thiamin deficiency Vitamin K deficiency Vitamin D and folic acid malabsorption Folic acid antagonism and malabsorption Decreased riboflavin Increased requirements for vitamins D, C, and B6 Vitamins A, D, E, and K, β-carotene malabsorption Vitamins A, D, E, and K, β-carotene malabsorption Decreased vitamins A, D, and C Thiamin deficiency Vitamin B12 deficiency Vitamin B6 deficiency Vitamins A, D, E, and K malabsorption Vitamins A, D, E, and K malabsorption Folic acid deficiency Vitamin B12 deficiency

substantiate the clinical impression and provide a baseline for subsequent monitoring are those markers which show the best correlation with outcome: weight and serum albumin concentration. The costeffectiveness of the addition of further biochemical parameters is yet to be determined. The assessment of other anthropometric measures is most useful in the setting of anticipated long-term nutrition support in which these measurements will serve as a longitudinal marker of an individual’s response to the nutrition care plan. Initially, nutrition requirements are determined on the basis of assumptions made about the patient’s clinical condition and the nutrition needs associated with repletion or growth, if needed. Once a nutrition intervention has been initiated, periodic reassessment of nutrition status is critical to determine the accuracy of the initial estimate of nutrition requirements. Also, nutrition requirements are dynamic in the setting of acute or critical illness—as the patient’s clinical status changes, so will protein and energy requirements, further emphasizing the need for continued reassessment. Better markers of nutrition status and methods for determining patient-specific nutrition requirements are needed to allow further refinement of estimates of individual nutrition needs. Functional tests and simple, noninvasive tests for body composition analysis hold promise for the future. However, until better methods of assessment become available clinically and are demonstrated to be cost-effective, the currently available battery of tests will continue to be the mainstay of nutrition assessment. Information in this chapter can be used to establish empiric goals for nutrition care. However, as with other forms of therapy, continuous monitoring and reassessment are required to determine if these goals are appropriate for an individual patient.

ABBREVIATIONS ABW: actual body weight AI: adequate intake AIDS: acquired immunodeficiency syndrome ALB: albumin BEE: basal energy expenditure BIA: bioelectrical impedance analysis

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BMI: body mass index BMR: basal metabolic rate DCH: delayed cutaneous hypersensitivity DEXA: dual-energy x-ray absorptiometry DRI: dietary reference intake EAR: estimated average requirement HBE: Harris-Benedict equation HIV: human immunodeficiency virus IBW: ideal body weight LBM: lean body mass MAMC: midarm muscle circumference NCHS: National Center for Health Statistics RDA: recommended dietary allowance REE: resting energy expenditure RQ: respiratory quotient SGA: subjective global assessment T3 : triiodothyronine T4 : thyroxine TBW: total body water TFN: transferrin TIBC: total iron-binding capacity TLC: total lymphocyte count TSF: triceps skinfold thickness TUN: total urine nitrogen UBW: usual body weight UL: tolerable upper intake level UUN: urine urea nitrogen VCO2 : carbon dioxide production VO2 : oxygen consumption Review Questions and other resources can be found at www.pharmacotherapyonline.com.

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35. Nielson FH. Other trace elements. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition, 7th ed. Washington, ILSI Press, 1996:353–377. 36. Shenkin A. Micronutrients. In: Rombeau JL, Rolandelli RH, eds. Clinical Nutrition: Enteral and Tube Feeding, 3rd ed. Philadelphia, Saunders, 1997:96–111. 37. Weber CW, Nelson GW, Vasquez-de-Vaquera M, et al. Trace elements in the hair of healthy and malnourished children. J Trop Pediatr 1990;36: 230–234. 38. Tamura H, Hirose S, Watanabe O, et al. Anemia and neutropenia due to copper deficiency in enteral nutrition. JPEN J Parenter Enteral Nutr 1994;18:185–189. 39. Wasa M, Satani M, Tanano H, et al. Copper deficiency with pancytopenia during parenteral nutrition. JPEN J Parenter Enteral Nutr 1994;18:190– 192. 40. Stoeker BJ. Chromium. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition, 7th ed. Washington, ILSI Press,1996:344–352. 41. Verhage AH, Cheong WK, Jeejeebhoy KN. Neurologic symptoms due to possible chromium deficiency in long-term parenteral nutrition that closely mimic metronidazole-induced syndromes. JPEN J Parenter Enteral Nutr 1996;20:123–127. 42. Alves G, Thiebot J, Tracqui A, et al. Neurologic disorders due to brain manganese deposition in a jaundiced patient receiving long-term parenteral nutrition. JPEN J Parenter Enteral Nutr 1997;21:41–45. 43. Fell JME, Reynolds AP, Meadows N, et al. Manganese toxicity in children receiving long term parenteral nutrition. Lancet 1996;347:1218–1221. 44. Keen CL, Zidenbery-Cherr S, Lonnerdal B. Nutritional and toxicological aspects of manganese intake: An overview. In: Mertz W, Abernathy CO, Olin SS, eds. Risk Assessment of Essential Elements. Washington, ILSI Press, 1994:221–235. 45. Matasuda A, Kimura M, Takeda T, et al. Changes in manganese content of mononuclear blood cells in patients receiving total parenteral nutrition. Clin Chem 1994;40:829–832. 46. Malecki EA, Lo HC, Yang H, et al. Tissue manganese concentrations and antioxidant enzyme activities in rats given total parenteral nutrition with and without supplemental manganese. JPEN J Parenter Enteral Nutr 1995;19:222–226. 47. Abrams CK, Siram SM, Galsim C, et al. Selenium deficiency in long-term total parenteral nutrition. Nutr Clin Pract 1992;7:175–178. 48. Lockitch G, Jacobson B, Quigley G, et al. Selenium deficiency in low birth weight neonates: An unrecognized problem. J Pediatr 1989;114:865–870. 49. Rannem T, Ladefoged K, Hylander E, et al. The effect of selenium supplementation on skeletal and cardiac muscle in selenium-depleted patients. JPEN J Parenter Enteral Nutr 1995;19:351–355. 50. Rannem T, Persson-Moschos M, Huang W, et al. Selenoprotein P in patients on home parenteral nutrition. JPEN J Parenter Enteral Nutr 1996;20:287–291. 51. Levander OA, Burk PF. Selenium. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition, 7th ed. Washington, ILSI Press, 1996:320–328. 52. Friel JK, MacDonald AC, Mercer CN, et al. Molybdenum requirements in low-birth-weight infants receiving parenteral and enteral nutrition. JPEN J Parenter Enteral Nutr 1999;23:155–159. 53. Sardesai VM. Molybdenum: An essential trace element. Nutr Clin Prac 1993;8:277–281. 54. Nichoalds GE. Iodine. In: Baumgartner TG, ed. Clinical Guide to Parenteral Micronutrition, 3d ed. Deerfield, IL, Fujisawa USA, 1997:361–374. 55. Moukarzel AA, Buchman AL, Salas JS, et al. Iodine supplementation in children receiving long-term parenteral nutrition. J Pediatr 1992;121:252– 254. 56. Jordan NS. Hematology: Red and white blood cells. In: Traub SL, ed. Basic Skills in Interpreting Laboratory Data, 2d ed. Bethesda, MD, American Society of Health-System Pharmacists, 1996:297–320. 57. Centers for Disease Control and Prevention. Lactic acidosis traced to thiamin deficiency related to nationwide shortage of multivitamins for total parenteral nutrition—United States, 1997. JAMA 1997;278:109–111. 58. Adolph M, Hailer S, Echart J. Serum phospholipid fatty acids in severely injured patients on total parenteral nutrition with medium chain/long chain triglyceride emulsions. Ann Nutr Metab 1995;39:251–260.

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59. Sacks GS, Brown RO, Collier P, Kudsk KA. Failure of tropical vegetable oils to prevent essential fatty acid deficiency in a critically ill patient receiving long-term parenteral nutrition. JPEN J Parenter Enteral Nutr 1994;18:274–277. 60. Foote KD, MacKinnon MJ, Innis SM. Effect of early introduction of formula versus fat-free parenteral nutrition on essential fatty acid status of preterm infants. Am J Clin Nutr 1991;54:93–97. 61. Tibboel D, Delemarre FMC, Przyrembel H, et al. Carnitine deficiency in surgical neonates receiving total parenteral nutrition. J Pediatr Surg 1990;25:418–421. 62. Borum PR. Carnitine in neonatal nutrition. J Child Neurol 1995;10(Suppl 2):S25–S31. 63. Broquist HP. Carnitine. In: Shils ME, Olson JA, Shike M, eds. Modern Nutrition in Health and Disease, 8th ed. Philadelphia, Lea & Febiger, 1994:459–465. 64. Scaglia F. Carnitine deficiencies. EMedicine.com, Inc., March 4, 2004. http://www.emedicine.com/ped/topic321.htm. Accessed June 4, 2004. 65. Borum PR. Carnitine. In: Baumgartner TG, ed. Clinical Guide to Parenteral Micronutrition, 3rd ed. Deerfield, IL, Fujisawa USA, 1997:629– 641. 66. Cerra FB, Benitez MR, Blackburn GL, et al. Applied nutrition in ICU patients: A consensus statement of the American College of Chest Physicians. Chest 1997;111:769–778. 67. Food and Nutrition Board, National Research Council. Recommended Dietary Allowances, 10th ed. Washington, National Academy of Sciences, 1989. 68. Food and Nutrition Information Center. Dietary Reference Intakes (DRI) and Recommended Dietary Allowances (RDA). http://www.nal.usda.gov/ fnic/etext/000105.html#q2. Accessed June 4, 2004. 69. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, National Academy Press, January 1, 1999. http:// www.nap.edu/books/0309063507/html/index.html. Accessed June 4, 2004. 70. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6 , Folate, Vitamin B12 , Pantothenic Acid, Biotin, and Choline. Washington, National Academy Press, January 1, 2000. http://www.nap.edu/books/0309065542/html/ index.html. Accessed June 4, 2004. 71. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, National Academy Press, January 1, 2000. http://www.nap.edu/books/ 0309069351/html/. Accessed June 4, 2004. 72. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, National Academy Press, January 9, 2001. http:// www.nap.edu/books/0309072794/html/. Accessed June 4, 2004. 73. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. September 5, 2002. http://www.nap.edu/books/ 0309085373/html/. Accessed June 4, 2004. 74. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. February 11,

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136 PREVALENCE AND SIGNIFICANCE OF MALNUTRITION Gordon Sacks and Pamela D. Reiter

Learning Objectives and other resources can be found at www.pharmacotherapyonline.com.

KEY CONCEPTS 1 Weight loss is a hallmark sign of malnutrition in the can-

cer patient and correlates with decreased survival for some cancer types.

2 Nutritional problems in human immunodeficiency virus/

acquired immunodeficiency syndrome (HIV/AIDS) patients have shifted from complications of severe wasting to metabolic changes associated with subcutaneous fat atrophy, visceral fat accumulation, hypertriglyceridemia, and insulin resistance.

3 Immune function, growth, and survival can be improved in HIV-positive children with aggressive nutritional and antiviral therapy.

4 Enteral nutrition (EN) decreases septic complications when

compared with parenteral nutrition (PN) in severely injured trauma patients.

6 Adults with less than 60 cm remaining of small bowel after massive surgery will require PN for months to years.

7 EN supplemented with immune-enhancing nutrients low-

ers metabolic and infectious complications in adult surgical patients.

8 Catch-up growth can be achieved more rapidly in infants with bronchopulmonary dysplasia if they receive a diet higher in protein, calcium, phosphorus, and zinc.

9 Optimizing nutritional status of pediatric solid organ transplant patients pre- and post-transplantation can improve outcomes and reduce morbidity.

10 Malnutrition is associated with increased utilization of

health care resources and nutritional interventions can contribute to cost savings by lowering length of hospital stay and morbidity associated with malnutrition.

5 EN and PN promote remission in the majority of patients with acute Crohn’s disease.

The term malnutrition has been used to characterize a broad range of altered nutritional states. Overnutrition is the term used to describe excess nutrient intake, whereas undernutrition is used to describe insufficient intake or substrate use. Both nutritional states can contribute to the poor outcome of many disease states. Unless specifically stated, this chapter will use the nomenclature of malnutrition as synonymous with undernutrition (refer to Chap. 140 for a discussion on overnutrition/obesity). In children, malnutrition can be defined by a variety of criteria. Stages (e.g., Waterlow stages) have been developed to define the severity of protein-energy malnutrition. Anthropometric evaluations, using established age-based growth curves, can define acute and chronic malnutrition using either Z scores or height and weight percentiles. In general, malnutrition in children is defined as growth that is below the fifth percentile for age or less than 90% to 95% of the median value for age. In this chapter, the prevalence of malnutrition as defined by a variety of nutrition assessment parameters is documented, and the significant impact of abnormalities in these nutrition assessment parameters on the morbidity and mortality of selected disease states is presented. Interventional strategies for the prevention and management of malnutrition and the economic consequences of malnutrition are also presented.

PREVALENCE Although malnutrition occurs throughout the world, it is most prevalent in underdeveloped countries, where food supply, ignorance, poverty, overcrowding, and poor sanitation are contributing factors. The most susceptible individuals in developed and underdeveloped countries are infants (especially premature infants), pregnant or lactating women, and the elderly. Factors that contribute to malnutrition in developed countries include poor maternal nutrition before and during pregnancy, misconceptions about the use of certain foods, fad diets, maternal illiteracy, household poverty, and alcohol or drug abuse. The relationship between malnutrition and breast-feeding is time-dependent. While the benefit of breast-feeding during the first 6 months of life in reducing mortality and improving growth is well known, prolonged breast-feeding (beyond 6 months to 1 year) has been associated with a higher risk of malnutrition. However, this latter association may be due to lower use of complimentary foods within poor households, rather than breastfeeding per se.1 Malnutrition is associated most commonly with exacerbations of chronic disease and acute illness and thus is prevalent in the hospital setting. Recognition of the scope of the problem coincides with the 2579

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systematic application of nutrition assessment techniques to hospitalized individuals in the last two decades. The prevalence of previously unrecognized malnutrition is 40% to 55% among adult patients from varying socioeconomic backgrounds hospitalized in a variety of institutions.2 The prevalence of malnutrition has declined and there has been a heightened awareness of nutritional disease and better in-hospital nutrition management since the mid-1970s.3 Worldwide, nearly 200 million children are moderately to severely underweight, and 70 million are severely malnourished.4 Over one-half of global childhood deaths under 5 years of age can be attributed directly or indirectly to malnutrition.5 Chronic malnutrition in children less than 2 years of age is an independent predictor of poor cognitive development lasting up to 11 years of age.6 Severe malnutrition is both a medical and social disorder and successful management requires attention to both of these factors. Fortunately, the global trend indicates a modest but consistent decline in malnutrition-associated mortality in children less than 5 years of age.7 Because children have both limited body stores and high metabolic demands, they are at particular risk for developing malnutrition, especially during illness. While the majority of undernourished children are from underdeveloped countries, malnutrition is also seen in the United States and other industrial countries. In 1974, a publicly funded health and nutrition program known as the Pediatric Nutrition Surveillance System was established to generate data on the prevalence of malnutrition in children generally younger than 5 years of age. The most recent report published in 1998 revealed a reduction in the incidence of malnutrition.8 The prevalence of shortness (height for age) in children younger than 24 months of age has declined from 10.5% in 1989 to 9.7% today, a value still more than twice the expected value. In older children (aged 2 to 5 years), the prevalence of shortness in 1989 of 7.5% was only slightly higher than expected and the prevalence has now fallen to 5.7%. Recent values for thinness, or weight for height, have also declined since 1989 and are currently at 3.1% in infants less than 24 months old and 1.9% in children aged 2 to 5 years old. These values are lower than the expected value of 5% and indicate that the prevalence of acute malnutrition in this population is low. Anemia, hematologic evidence of poor nutrition status, and/or iron deficiency was very high between 1980 and 1985 (20% to 30%), but has declined to 18.4% in those less than 24 months of age and 16.9% in those between 2 and 5 years of age.8 Admittedly, the

nutritional health of children in the United States has changed over the past decade. The focus on malnutrition has now been shifted to the prevention and treatment of childhood obesity, which has reached epidemic proportions (see Chap. 140). Children with chronic disease and those in periods of rapid growth have the highest prevalence of malnutrition. Hendricks and colleagues described the change in prevalence of protein-energy malnutrition in hospitalized children over a 15-year period.9 Overall prevalence was high, but significant reductions were detected in acute malnutrition (weight for height 4 × 109 cells/L) commonly observed in mononucleosis, pertussis, measles, chickenpox or lymphoid malignancies. Lymphogranuloma venereum—Inflammation of the lymph nodes caused by Chlamydia trachomatis resulting in destruction and scarring of tissue. Macule—Flat, nonpalpable, variable colored lesion. Maculopapular—Skin eruption containing both macules and papules. Magnetic resonance angiography (MRA)—A noninvasive method to evaluate the patency of blood vessels using magnetic resonance imaging. Magnetic resonance imaging (MRI)—An imaging technique based upon the magnetic properties of the hydrogen atom. It provides an accurate, computer-processed image that can be more sensitive than computed tomography. Major histocompatibility complex (MHC)—A set of genes responsible for most of the proteins on the surface of cells in the body that are responsible for recognition of “self.” Mania—An abnormally and persistently elevated, expansive, or irritable mood that lasts at least one week, and causes marked impairment in functioning. Mass effect—An increase in intracranial pressure due to a spaceoccupying lesion in the brain, usually leading to a “shift” in brain contents, evident by imaging techniques. Mastalgia or mastodynia—Pain in the breast. Mean arterial pressure—The mean arterial pressure is the product of the cardiac output and systemic vascular resistance. Since the cardiac output is pulsatile, rather than continuous, and since 2/3 of the normal cardiac cycle is spent in diastole, the mean arterial pressure is not the arithmetic mean of the systolic and diastolic blood pressures. Mean arterial pressure = diastolic blood pressure + 1/3 (systolic blood pressure–diastolic blood pressure). Meconium ileus—Intestinal obstruction due to meconium.

Lichenification—Thickening of epidermis due to irritation.

Megakaryocytes—Precursors of platelets.

Lipid peroxidation—A pathophysiologic process involving the ironcatalyzed attack of lipid membranes by reactive oxygen species.

Melanin—Dark pigment that is part of determining skin color.

Liposomes—Spherical amphiphilic vesicles capable of sustained release of water-soluble substances. Locus ceruleus—A small area in the brainstem containing norepinephrine neurons that is considered to be a key brain center for anxiety and fear.

Melena—Dark-colored stools resulting from upper gastrointestinal bleed. Membrane stripping—When the cervix is dilated, a practitioner can use a hand to separate the amniotic membranes from the uterus. This technique has been shown to reduce the need for labor induction. Menarche—The time of the first menstrual period or flow.

Lower urinary tract symptoms—Term that collectively refers to obstructive and irritative urinary voiding symptoms of benign prostatic hypertrophy (BPH).

Meningitis—Inflammation, usually infectious, of the meninges, a covering of the brain.

Lumbar puncture—The procedure used to withdraw cerebrospinal fluid via a needle inserted in the lumbar region of the spinal column.

Menopause—The permanent cessation of menses following the loss of ovarian follicular activity.

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Menses—Periodic bloody discharge from the uterus.

Necrosis—Local death of cells or tissue.

Methionine—The l-isomer is a nutritionally essential amino acid and the most important natural source of “active methyl” groups in the body, hence usually involved in methylations in vivo.

Necrotizing fasciitis—A rare, but very severe infection of the subcutaneous tissue that may be caused by aerobic and/or anaerobic bacteria and results in progressive destruction of the superficial fascia and subcutaneous fat.

Microalbuminuria—A condition in which a small amount of albumin (30 to 300 mg/day) is present in the urine; indicative of an early stage of chronic kidney disease (CKD). Microcomedo—Microscopic lesion formed from the combination of sloughed, clumping keratinocytes reacting with sebum and fatty acids from the sebaceous gland.

Neonates—Newborns who are 1 day to 1 month of age. Nephritis—Inflammation of the kidney. Nephrolithiasis—Presence of one or more stones in the renal pelvis, collecting system, or ureters.

Midsystolic—Middle of systole.

Nephron—The working unit of the kidney that is comprised of a glomerulus and tubule. Each kidney is made up of about 1 million nephrons, which collectively remove drugs, toxins, and fluid from the blood.

Milia—Small, white, cysts containing keratin.

Nephropathy—Refers to a pathologic alteration of the kidney.

Mixed states—Rapidly alternating mood states (mania and major depressive episodes) that last at least one week, and cause marked impairment in functioning.

Nephrotic range proteinuria—Proteinuria >3 grams/day associated with glomerular disease and nephrotic syndrome.

Micrographia—Handwriting that is small, trails off in size, or very slow.

Nephrotoxicity—Toxic insult to the kidney. Molds—Fungal organisms that grow as multicellular branching, thread-like filaments (hyphae) that are either septate (divided by transverse walls) or coenocytic (multinucleate without cross walls). On agar media, molds grow outward from the point of inoculation by extension of the tips of filaments, and then branch repeatedly, interweaving to form fuzzy, matted growths called mycelium. Germ tubes are the beginning of hyphae, which arise as perpendicular extensions from the yeast cell, with no constriction at their point of origin. Molybdenum (Mo)—A bioelement found in a number of proteins. Mood—A more pervasive and sustained emotional state that colors a person’s perception of the world. Morbilliform—Maculopapular lesions that becomes confluent on the face and body. Mucolytic—The ability to break down mucus. Mucositis—Inflammation of the mucosa. Multiple organ dysfunction syndrome (MODS)—Presence of altered organ function requiring intervention to maintain homeostasis. Multiple sclerosis (MS)—A demyelinating disease, caused by inflammation, leading to neurologic deficits and often, disability. Mutism—A state in which a person either had the inability or they refuse to speak or vocalize sounds. Myoclonic seizures—Brief shock-like muscular contractions of the face, trunk, and extremities. They usually begin in adolescence and are referred to as juvenile myoclonic epilepsy (JME). Myoclonus—A sudden twitching of muscles or parts of muscles, without any rhythm or pattern. Mycotic—A fungal infection. National Kidney Foundation (NKF)—A voluntary health organization that seeks to prevent kidney and urinary tract diseases, improve the health and well being of individuals and families affected by these diseases, and increase the availability of all organs for transplantation. Nausea—An unpleasant sensation associated with an awareness of the urge to vomit.

Nerve conduction studies—Measurement of the speed of electrical conduction through a nerve. Neuritic plaques—Hallmark pathological marker of Alzheimer’s disease comprised of beta amyloid protein and masses of broken neurites. Neurofibrillary tangles—Hallmark pathological marker of Alzheimer’s disease derived from abnormal phosphorylation of tau protein filaments. Neuropathic pain—Pain sustained by abnormal processing of sensory input by the peripheral or central nervous system. Neutropenia—An abnormally reduced number of neutrophils circulating in peripheral blood; although exact definitions of neutropenia often vary, an absolute neutrophil count of 2 micturitions per night). Nodule—Elevated, palpable, solid, round or oval lesion more than 0.5 cm in diameter. Nonoliguria—Production of >450 mL urine/day. Nonulcer dyspepsia—Ulcer-like dyspepsia that has been investigated, but endoscopic findings yield no evidence of mucosal injury (ulcer). Norepinephrine (NE)—A hormone secreted by the adrenal medulla and also released at synapses. Nosocomial infection—An infection acquired in a health care facility. NSAID—Nonsteroidal anti-inflammatory drug.

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Oblique lie—The fetus is at an angle to the cervix. The head is not the presenting part, and often the patient will need to be delivered by cesarean section. Obsession—Recurrent and persistent thoughts, images, or impulses experienced as intrusive and distressing. Unwanted thoughts or ideas that intrude into a person’s thinking. Obsessive-compulsive disorder (OCD)—An anxiety disorder characterized by obsessions and/or compulsions that are time-consuming and interfere significantly with normal routine, social, or occupational functioning or relationships. Oliguria—Diminished volume of urine output (volume 6 cm with acute colitis and signs of systemic toxicity. Toxic shock syndrome—Sudden onset of fever, muscle ache, vomiting and diarrhea, accompanied by a peeling rash and followed by low body temperature and shock; caused by staphylococcal endotoxin, especially from infection of the vagina associated with tampon use. Toxoplasmosis—Clinical infection with Toxoplasma gondii. Transverse lie—The fetus is perpendicular to the mother. Usually the shoulder is the presenting part. Fetuses in this position must be delivered by cesarean section. Traveler’s diarrhea—Diarrhea caused by contaminated food or water and usually attributed to enterotoxic Escherichia coli (ETEC), Shigella, Campylobacter, Salmonella, or viruses.

Tumor necrosis factor alpha (TNF-α)—A proinflammatory cytokine. Type I reaction—An immediate, IgE-mediated allergic reaction. Ulcer—Loss of epidermis and dermis caused by sloughing of necrotic tissue. Upper respiratory tract infection—Otitis media, sinusitis, pharyngitis, laryngitis (croup), rhinitis, or epiglottitis. Uremia—An array of symptoms associated with accumulation of metabolic by-products and endogenous toxins in the blood due to impaired kidney function. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. Urethritis—Inflammation of the urethra. Urinalysis—The diagnostic analysis of urine and its components; can be microscopic or macroscopic in nature. Urinary incontinence—Involuntary leakage of urine. May result from urethral underactivity (stress urinary incontinence), urethral overactivity (overflow incontinence), or mixed pathophysiologic mechanisms. Urine—Fluid waste resulting from filtration of blood by the kidneys; transferred to the bladder by ureters and expelled from the body through the urethra by the act of voiding or urinating. Urticaria—A dermatologic reaction noted by elevated, erythematous patches that are pruritic. Vacuum erection device—Medical device used to manually induce an erection. Vagal nerve stimulator (VNS)—A medical device that is surgically implanted in patients with refractory epilepsy. Vasculitis—A hypersensitivity process characterized by inflammation and necrosis of blood vessels. Vasopressin—A posterior pituitary hormone that controls fluid balance by acting on the renal collecting ducts to prevent water loss. Vegetation—Bacterial growth on heart valves. Ventricular remodeling—Alterations in myocardial cells and the extracellular matrix that result in changes in the size, shape, structure, and function of the heart. The remodeling process leads to reductions

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in myocardial systolic and/or diastolic function that, in turn, leads to further myocardial injury, perpetuating the remodeling process and the decline in ventricular dysfunction and progression of heart failure. Vesicle—Clear blister (