Pediatric infectious diseases : essentials for practice [Second ed.] 9781259861536, 1259861538

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Pediatric Infectious Diseases: Essentials for Practice

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 authors 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 clinical practices accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors 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.

Pediatric Infectious Diseases: Essentials for Practice Second Edition Editor Samir S. Shah, MD, MSCE Director, Division of Hospital Medidne James M. Ewell Endowed Chair Attending Physidan in Hospital Medicine and Infectious Diseases Cincinnati Children's Hospital Medical Center Professor of Pediatrics University of Gndnnati College of Medicine Gndnnati, Ohio

Associate Editors Alex R. Kemper, MD, MPH, MS

Adam J. Ratner, MD, MPH

Chief, Division ofAmbulatory Pediatrics Nationwide Children's Hospital Professor of Pediatrics Ohio State University College of Medicine Columbus, Ohio

Chief, Division of Pediatric Infectious Diseases Hassenfeld Children's Hospital at NYU Langone Assodate Professor of Pediatrics and Microbiology New York University School of Medicine New York, NewYork

New York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto

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To our mentors for sharing their wisdom and knowledge To ourfamilies for providing love and support for all ofour endeavors To our patients for teaching us and to their families for trusting us

Contents Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Prefoce. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xix Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxi

SECTION 1 Practical Aspects . . . . . . . . . . . . . . . . . . . . 1 1. Laboratory Diagnosis of Bacterial, Parasitic, and Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Alexander J. McAdam

18. Noisy Breathing....... ......... ....... .. .... 148 Roger Nicome and Ricardo Quinonez

SECTION 3 Neurologic Infections ................ 157 19. Meningitis..... .... . .......... ........... . 159 Marvin B. Harper 20. Encephalitis ..................... .... ... . .. 167 Jennifer L McGuire

2. Laboratory Diagnosis ofV'nllnfections . . . . . . . . . . . . . . . 12 Richard L Hodinka

21. Transverse Myelitis ................. .... ...... 181 Mark P. Gorman

3. Yllcdne Safety and Risk Comm111lcatlon . . . . . . . . . . . . . . . 26 Michael J. Smith

22. Pediatric Movement Disorders and Infectious Disease . . . . . . . 185 Samay Jain and Houman Homayoun

4. Infection Prevention and Control in the Office . . . . . . . . . . . . 31 Ann-Christine Nyquist

SECTION 4 Ophthalmologic Infections ............. 193

S. Infection Prevention and Control in the Hospital . . . . . . . . . . 37

23. Conjunctivitisin the Neonate . . . . . . . . . . . . . . . . . . . . . 195 Margaret R. Hammerschlag and Natalie Banniettis

larry K. Kociolek and Maria Bovee

6. Infectious Diseases Epidemiology. . . . . . . . . . . . . . . . . . . 43 Lilliam Ambroggio and Amanda C. Schondelmeyer

24. Conjunctivitis in the Older Child . . . . . . . . . . . . . . . . . . . . 199 Natalie Banniettis and Margaret R. Hammerschlag

7. Quality Improvement in Infectious Diseases . . . . . . . . . . . . . 47 Amanda C. Schondelmeyer and Lilliam Ambrogglo

25. Periorbital and Orbital Infections . . . . . . . . . . . . . . . . . . . 205 Blair E. Simpson, L.atania K. logan, and Tina Q. Tan

8. Antibacterial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Joshua D. Courter and Jennifer E. Girotto

9. Antifungal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Talene A. Metjian and Brian Fisher 10. AntiYII'ill Agerrts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 Claudette l. Poole and David W.Kimberlin

SECTION 2 Sign and Symptoms .......... ....... 107

26. Infectious Keratitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 Anne K. Jensen and Gil Binenbaum

SECTION 5 Oral Cavity and Neck Infections . . ... . .... 219 27. Pharyngitis and Stomatitis . . . . . . . . . . . . . . . . . . . . . . 221 Sanyukta Desai and MarkS. Pasternack 28. Peritonsillar and Retropharyngeal Abscess. . . . . . . . . . . . . . 230 Jenna W. Briddell, Karen A. Ravin, and Udayan K. Shah

11. Chronic Abdominal Pain ............ .. .... ...... 109 Daniel Mallon

29. Cervical Lymphadenitis ....... . ... ............. 236 Yemisi Jones, Benjamin Hanisch, and Nallnl Singh

12. Ataxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Claudio M. de Gusmao and Jeffrey L. Waugh

30. Dental Caries and Gingival and Periodontal Infections . . . . . . . 244 Margherita Fontana, Nadeem Y.Karimbux, carlos Gonzalez cabezas, David M. Kim, and Irina F. Dragan

13. Dysuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 Robyn A. Bockrath, Erin 0. Harvey, and Virginia Hsu 14. Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Robert A. Avery

SECTION 6 Upper Respiratory Infections. . . . . . . . . . . . 253

15. Joint Complaints . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Brian E. Nolan, S 1 hour, transport at 4"( Grows on 5% sheep blood agar or modified Thayer-Martin in humidified microaerobic environment (S% ~ Vibrio species Transport media (e.g., modified Stool preferred to swabs Cary-Blair) needed iftransport Contact laboratory to time >1 hour determine availability of Grow on MacConkey's or 5% selective broth and media sheep's blood media, but NAAT, including syndromic selective alkaline broth and panels, are available thiosulfate dtrate bile sucrose (TCBS) media enhance recovery Yeninia Transport media {e.g., modified Stool preferred to swabs enterocolltlca Cary-Blair) needed Iftransport Cold enrichment (4"() time >1 hour enhances recovery from stool Grow on MacConkey agar but takes weeks and so is of at 37"C, but culture at 2S°C limited utility enhances recovery NAAT, including syndromic panels, are available

IMymJF lytic bottle from Becton Dickinson and Company.

rare in immunized populations, and so the positive predictive value of

this test is low for some pathogens, making false-positive results more likely.l'-27 Results of this assay should be interpreted in the context of other CSF values, such as glucose, protein, and white blood cell (WBC)

levels.

• STOOL Routine stool culture usually includes Salmonella, Shigella, and Campylobacter. If other pathogens, such as enterohemorrhagic E. coli (EHEC, including E. coli 0157:H7), Yersinia enterocolitica, or Vibrio are suspected, culture for these organisms should be specifically requested. Excreted stool is preferable to swab specimens; swab specimens should be collected only from infants or patients who are unable to produce a specimen. If a stool specimen cannot be transported to the laboratory in less than an hour, it should either transported at 4ac, or with transport media to preserve the bacteria. Enteric pathogens that require special culture conditions are shown in Table 1-4.

Enterohemorrhagic E. coli is among the most common bacterial causes of diarrhea in children.46 It can be detected either by culture or by immunoassay for the Shiga toxins that it produces. Approximately half of EHEC are of the serotype 0 157:H7, and these can be detected using MacConkey agar containing sorbitol, which these organisms do not ferment. Most laboratories in the United States use sorbitol-containing media for detection of EHEC, although some may use more specific chromogenic agars.'7 Assays for Shiga toxins, which are produced by all serotypes of EHEC, will detect significantly more cases of EHEC infection.46 Shiga-like toxins can be detected by immunoassays for the protein toxin, or by more sensitive NAAT for the genes encoding the toxins. 411 Most laboratories perform both a culture for E. coli 0157:H7 and an assay for Shiga toxins, so they will detect most cases of EHEC. There are several different methods available for detection of Clostridium dijficile-associated diarrhea. Unfortunately, none of these tests performs perfectly, and the best test or group of tests for detecting C. dijficile disease is an area of active investigation and debate. 49•50 The most common and recommended initial tests for C. dijficile are NAAT

8

SEGION 1: Practical Aspects

that detect the genes for C. difftcile toxins, or immunoassays for the glutamate dehydrogenase (GDH) protein produced by all C. difftcile. Both of these assays are highly sensitive for detection of C. difflcile, but there are concerns about the specificity of the tests. NAAT will detect even small numbers of organisms and may be positive in people who are colonized with the organism. Most laboratories that perform NAAT as the initial test for C. difftcile will not perform additional testing, but some laboratories will use an immunoassay for C. difftcile toxin as a confirmatory test on NAAT-positive specimens to increase the stringency for detecting C. di.fftcile disease. GDH is produced by all C. difftcile, including a significant number of C. difftcile that do not produce toxins, and so GDH assays should not be used alone but can be used along with an assay that detects C. difftcile toxin, usually an immunoassay. Finally, if the GDH assay and toxin immunoassay give different results, one positive and the other negative, some laboratories will perform a NAAT for the toxin. Regardless of the method used, positive results for C. difftcile, particularly in younger children, should be interpreted carefully in the context of the patient's history and testing for other appropriate pathogens. Diagnosis of C. difftcile-associated diarrhea in young children is difficult because a large proportion of healthy children younger than one year are colonized by C. difftcile, which can lead to positive test results in any of the available assays. 51 There are several FDA-approved syndromic gastrointestinal panels available. All of these include detection of Campylobacter, Salmonella, Shigella, and ETEC.12•13 The detection of other bacteria varies between assays. They can include detection of common pathogens, such as enterotoxigenic E. coli, the cause of traveler's diarrhea, as well as less common pathogens such as Vibrio species. Some panels detect organisms whose pathogenicity is poorly understood, such as enteropathogenic and enteroaggregative E. coli, both of which can be members of the normal microbiota, and so interpretation of the results can be difficult. These panels can also include detection of parasites, including Giardia, Cryptosporidium, C. cayetanensis, and Entamoeba histolytica, and some include detection of viral pathogens as well. A few of these panels include detection of C. difftcile; however, many labs do not report C. difftcile results from these assays because of the very different risk factors for C. difftcile infection and other infectious forms of gastroenteritis.

•

RESPIRATORY SPECIMENS

Sputum samples are rarely performed in children, given the challenge of obtaining an adequate sample for testing and the preponderance of viruses as a cause of lower respiratory tract infection in otherwise healthy children. When obtained, sputum should be submitted for Gram stain and bacterial culture. Bacteria that commonly cause pneumonia, including streptococci, staphylococci, and H. injluenzae, can be grown in routine respiratory culture. A sample collected by tracheal aspiration or bronchoalveolar lavage may be necessary in some circumstances (e.g., in a child with chronic granulomatous disease). As discussed above, the test for S. pneumoniae antigen is sensitive but not specific for invasive pneumococcal disease in children.10•11 There are few studies on interpretation of respiratory Gram stains in children. In adults, a high number of polymorphonuclear leukocytes and a low number of epithelial cells on Gram stain suggests that a respiratory specimen is from the lower respiratory tract and that bacterial growth is likely to be significant. A study that evaluated the utility of Gram stain in endotracheal aspirates from mechanically ventilated children revealed that the absence of bacteria on Gram stain suggests that culture is unlikely to detect a pathogen, and a separate study indicated that omitting these cultures would have little effect on patient care.52.s3 Respiratory pathogens that are not detected by routine culture are listed in Table 1-5, and comments on some of these follow. The appropriate specimen for diagnosis of pulmonary tuberculosis depends on the child's age and ability to produce sputum. If sputum can be produced, three sputum samples collected on separate days should be submitted for stain and culture for acid-fast bacteria.sus If sputum cannot be obtained, gastric aspirate specimens should be collected. The sensitivity of gastric aspirate culture can be increased by collection

I Hl !J (j Pathogen Bordetefla pertussis

Burlcholderia

cepacia complex

Corynebacterium d/phtherlae

leglonefla pneumophila

Respiratory Pathogens Detected by Special Techniques Culture Requires enriched media, Regan-Lowe Transport media with charcoal (Amies with charcoal or ReganLowe transport media) will enhance survival Requires selective media, B. cepacia-selective agar (BCSA) or oxldatlon-rermentatlon with polymyxin B, bacitracin, and lactose (OFPBL) Use commercial swab and transport media to swab beneath membrane, if possible Requires selective media, cystine tellurite blood agar (OBA) or tinsdale agar Requires enriched media, buffered charcoal-yeast extract (BCYE)

Mycobacterium

spedes

Mycoplasma pneumoniat!

If specimen must be transported before rulture, transport at 4"C Collect sputum if possibl~. or bronchoalveolar lavage or three gastric aspirates (see text) for culture Agarose media (e.g., Middlebrook agars) and broth media [mycobacteria growth indicator tube (MGin system, MB/Bacl, Bactec Myco/F lytle bottles] both inoculated for fastest recovery Takes up to8weeks If culture needed, use Mycoplasma transport media (2SP) or culture media (SP-4) Requires selective media, SP-4, methylene blue-glucose, or others Takes up to4weeks

Comments Consider serology or NAAT (more sensitive than culture) Direct fluorescent antibody (DFA) tests are not adequately sensitive or spedfic if used alone Consider in patients with cystic fibrosis Diffirult to identify and so may require reference laboratory Contact laboratory to determine availability of media or need for sendout to reference laboratory

Consider urine antigen tests (detects only serogroup 1, the cause of 80% of infections)

Stain for add-fast organisms recommended (carbolfuchsin or auramine-90% sensitive for both organisms and that the specificities are >97%.66.67 Use of urine from females may be somewhat less sensitive for both organisms than for other acceptable specimens.66 The selection of tests for diagnosis of C. trachomatis and N. gonorrhoeae in children who may have been sexually abused is complex. Detection of these bacteria requires a sensitive test (e.g., NAAT), while the significant legal, social, and psychological consequences of a false-positive test require a very specific test (e.g., culture). A summary of the tests for bacteria and parasites recommended by the Centers for Disease Control and Prevention {CDC) at initial visit and to be considered 2 weeks later for children in cases of suspected sexual abuse is presented in Table 1-7.66 The CDC does not recommend use of NAAT for N. gono"hoeae if culture is available; however, NAAT can be used for detection of C. trachomatis in urine from girls and in vaginal secretions.

10

I

SEOION 1: Practical Aspects

iJ :l! j 0 Pathogen

Tests for Sexualy Transmitted Organisms In S1spected Sexual Abuse Spedmen(s) Test(s)

Neisseria gonorrhoeoe

Pharynx and anus in both boys and girls Vagina (not cervix) in girls and urethra in boys

Chlomydta

Anus In both boys and girls Vagina (not cervix) in girls Meatal swab if urethral discharge present in boys

trachomatis

Trichomonas vagina/is and bacterial vaglnosls

Vagina (not cervix) in girls

Culture for all NAAT are an alternative for vaginal secretions and urine from girls, but wlture preferred Notify laboratory that sexual abuse is suspected Culture NAAT are an alternative for vaginal secretions and urine from girls Request that specimen and isolates be preserved in laboratory Wet-mount for T. vagina/is and bacterial vaginosis Culture for T. vagina/is

Syphilis can be diagnosed by microscopic detection of Treponema pallidum or by serology. If lesions (e.g., chancre) are present, treponemes can be detected by dark-field microscopy or immunofluorescent stain. More commonly, the diagnosis is made by serology in the absence of primary lesions. Nontreponemal serological tests [rapid plasma regain (RPR) and venereal disease research laboratory (VDRL) tests] detect antibodies against a lipid antigen, cardiolipin, rather than against the bacteria. The treponema! serological tests [fluorescent treponema! antibody absorption (FTA-abs) and treponema pallidum particle agglutination {TPPA) tests] detect antibodies specific forT. pallidum. Nontreponemal tests are recommended for use as screening tests for syphilis (e.g., in sexually active adolescents) and for following the course of disease, as the titers of the nontreponemal tests fall with successful treatment. Treponema! tests are recommended to confirm the nontreponemal results, but the treponema! tests usually stay positive for the life of the individual even after successful treatment Because treponema! tests can be performed inexpensively by automated platforms, there is an increasing use of these tests for screening purposes. Results are generally the same as those obtained by the conventional algorithm, but discrepancies occur in a small number of cases.69.70 The risk of congenital syphilis should be determined by a nontreponemal antibody test of the pregnant woman in the first trimester of pregnancy and, if the risk of syphilis is high, early in the third trimester and at delivery.68 Testing the mother is preferred to testing the child, as a low level of maternal antibody may not be detectable in the newborn. However, once the diagnosis of syphilis is made in the mother, follow-up testing in the newborn should include the same quantitative nontreponemal test as was used in the mother. A higher titer in the newborn {at least fourfold greater than the titer in the mother) is highly suggestive of congenital syphilis.68 Physical manifestations of congenital syphilis and anatomic pathology of the placenta and newborn are also important in determining the risk of congenital syphilis, and current guidelines should be consulted Trichomonas vaginalis can be detected by several different methods.71 Microscopic examination of a wet mount of vaginal secretions in adolescents is rapid but only 40-60% sensitive. More sensitive tests include culture as well as a DNA probe test, Affirm VP {Becton, Dickinson and Company, which also separately detects Candida and Gardnerella vaginalis. A rapid antigen detection test approved for point-of-care use, OSOM 'frichomonas Rapid Test (Genzyme Diagnostics), is available, and is -80% sensitive. The most sensitive tests, typically over 95%, for T. vaginalis are NAAT. Several NAAT are FDA-approved for detection of T. vaginalis. These run on the same automated systems and, for the most part, use the same samples as the NAATs for C. trachomatis and N. gonorrhoeae, so testing for all three pathogens can be performed on a single specimen.71

•

URINE

Urine culture is the gold standard for diagnosis of urinary tract infection {UTI), but culture results require a minimum of 24 hours, so rapid screening tests are also valuable. Screening tests for UTI include biochemical tests by rapid dipstick methods (nitrite and leukocyte esterase) and microscopic examination of the urine for bacteria and leukocytes. A meta-analysis of studies of screening tests for UTI in children found that detection of any bacteria by Gram stain was a valuable screening test for UTI, with an estimated sensitivity of 91% and specificity of 96%.72 Unfortunately, Gram stain results do not often influence antibiotic selection. Thus, their value has been questioned.73 Dipstick assays, which are less technically demanding than Gram stain, also performed well as a screen for UTI. If either leukocyte esterase or nitrite is positive {trace or greater), the dipstick has an estimated sensitivity of 88% and specificity of 79%.72 In the meta-analysis, microscopic examination of urine for leukocytes was inferior to other tests as a screening assay for UTI.72 When tested by dipstick methods, urine collected by bag has sensitivity comparable to that of urine collected by catheter; however, the specificity of urine collected by bag is significantly lower than that collected by catheter.7"-75 Culture of urine is important because use of the screening tests alone will miss a significant number of UTI. Collection of specimens from children who are not toilet-trained is very important in making an accurate diagnosis. Bag urine specimens are not acceptable for culture as they are frequently contaminated with normal skin and genital microbiota/5 Specimens collected by suprapubic aspiration should be sterile, and growth of any number of Gram-negative rods or a few a thousand Gram-positive coed per milliliter very likely indicates a UTI. Pure growth of >50,000 pure colonies per milliliter of a uropathogen collected by transurethral catheterization is likely to indicate true infection in a child 2-24 months of age with pyuria.76 In adolescents and adult women, over 100,000 CFU/mL of a single uropathogen from midstream urine is likely to indicate true infection. The presence of small numbers of urogenital microbiota (e.g., Lactobacillus) will usually be ignored by the laboratory, but if normal urogenital microbiota are present in quantities roughly equal to a uropathogen, the laboratory will report the culture as mixed, and collection of a new culture will be needed

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CHAPTER 1: Laboratory Diagnosis of Bacterial, Parasitic, and FungallnfecUons 8. Girard V, Mailler S, Welker M, et al. Identification of Mycobacterium spp. and Nocardia spp. from solid and liquid cultures by matrixassisted laser desorption ionization-time of flight mass spectrometry {MAI.DI-TOF MS). Diagn Microbial Infect Dis. 2016;86{3): 277-283. 9. Cohen JF, Bertille N, Cohen R. Chalumeau M. Rapid antigen detection test for group A Streptococcus in children with pharyngitis. The Cochrane Database Syst Rev. July 4, 2016;7:Cd010502. 10. Charkaluk ML, Kalach N, Mvogo H, et a1 Assessment of a rapid urinary antigen detection by an inununochromatographic test for diagnosis of pneumococcal infection in chlldren. Diagn Microbial Infect Dis. 2006;55{2):89-94. 11. Vandkova Z. 'frojanek M, Zemlickova H, et al. Pneumococcal urinary antigen positivity in healthy colonized children: is it age dependent? Wien Klin Wochenschr. 2013;125(17-18):495-500. 12. Hanson KE. The first fully automated molecular diagnostic panel for meningitis and encephalitis: how well does it perform, and when should it be used? J Clin MicrobiaL 2016;54{9):2222-2224. 13. Binnicker MJ. Multiplex molecular panels for diagnosis of gastrointestinal infection: performance, result interpretation, and costeffectiveness. J Clin Microbiol. 2015;53(12):3723-3728. 14. BuchanBW, Ledeboer NA. Advances in identification ofclinical yeast isolates by use of matrix-assisted laser desorption ionization-time of flight mass spectrometry. J Clin Microbiol. 2013;51(5):1359-1366. 15. Sanguinetti M, Posteraro B. Identification of molds by matrixassisted laser desorption ionization-time of flight mass spectrometry. J Clin MicrobiaL 2017;55(2):369-379. 16. Vergidis P, Walker RC, Kaul DR. et al. False-positiVI: Aspergillus galactomannan assay in solid organ transplant recipients with histoplasmosis. Transpl Infect Dis. 2012;14(2):213-217. 17. Lehmbecher T, Robinson PD, Fisher BT, et al. Galactomannan, beta-D-glucan, and polymerase chain reaction-based assays for the diagnosis of invasive fungal disease in pediatric cancer and hematopoietic stem cell transplantation: a systematic review and metaanalysis. Clin Infect Dis. 2016;63(10):1340-1348. 18. Hoenigl M, Prattes J, Spiess B, et al. Performance of galactomannan, beta-d-glucan, Aspergillus lateral-flow device, conVl:ntional culture, and PCR tests with bronchoalveolar lavage fluid for diagnosis of invasive pulmonary aspergillosis. J Clin MicrobiaL 20 14;52(6) :2039-2045. 19. Mutschlechner W, Risslegger B, Willinger B, et al BronchoalVl:olar lavage fluid (1,3)beta-D-glucan for the diagnosis of invasive fungal infections in solid organ transplantation: a prospective multicenter study. Transplantation. 2015;99(9}:e140-e144. 20. Shi XY, Liu Y, Gu XM, et al. Diagnostic value of (1 ~ 3}-beta-Dglucan in bronchoalVl:olar lavage fluid for invasiVl: fungal disease: a meta-analysis. Resp Med. 2016;117:48-53. 21. Mohammadi S, Khalilzadeh S, Goudarzipour K, et al. BronchoalVl:olar galactomannan in invasiVl: pulmonary aspergillosis: a prospective study in pediatric patients. Med MycoL 2015;53{7):709-716. 22. Patterson TF, Thompson GR. 3rd, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 15 2016;63(4):e1-e60. 23. Ostrosky-Zeichner L, Alexander BD, Kett DH, et al. Multicenter clinical evaluation of the (1~3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis. 2005;41 (5) :654-659. 24. Koltze A, Rath P, Schoning S, et al Beta-D-glucan screening for detection of invasiVl: fungal disease in children undergoing allogeneic hematopoietic stem cell transplantation. I Clin MicrobiaL 2015;53(8):2605-2610. 25. Odabasi Z, Mattiuzzi G, Estey E, et al. Beta-D-glucan as a diagnostic adjunct for invasiVl: fungal infections: validation, cutoff deVl:lopment, and performance in patients with acute myelogenous leukemia and m.ydodysplastic syndrome. Clin Infect Dis. 2004;39(2):199-205. 26. Myionakis E, Clancy CJ, Ostrosky-Zeichner L, et al. T2 magnetic resonance assay for the rapid diagnosis of candidemia in whole blood: a clinical trial. Clin Inject Dis. 2015;60(6):892-899.

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27. Leber AL, Everhart K, Balada-Ilasat JM, et al. Multicenter evaluation of BioFire FilmArray meningitis/encephalitis panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens. J Clin Microbial. 2016;54(9}:2251-2261. 28. Buchheidt D, Reinwald M, Spiess B, et a1 Biomarker-based diagnostic work-up of invasive pulmonary aspergillosis in immunocompromised paediatric patients-is Aspergillus PCR appropriate? Mycoses. 2016;59(2):67-74. 29. Hanson KE, Couturier MR. Multiplexed molecular diagnostics for respiratory, gastrointestinal, and central nervous system infections. Clin Infect Dis. 2016;63(10}:1361-1367. 30. Farcas GA, Zhong KJ, Lovegrove FE, Graham CM, Kain KC. Evaluation of the Binax NOW ICT test versus polymerase chain reaction and microscopy for the detection of malaria in returned travelers. Am J Trop Med Hygiene. 2003;69(6):589-592. 31. Dien Bard J, McElvania TeKippe E. Diagnosis of bloodstream infections in children. J Clin Microbial. 2016;54(6}:1418-1424. 32. Belding ME, KlebanoffSJ. Effect ofsodium polyanetholesulfonate on antimicrobial systems in blood. Appl Microbiol. 1972;24(5):691-698. 33. McDonald JC, Knowles K, Sorger S. Assessment of gelatin supplementation of PEDS Plus BACTEC blood culture medium. Diagn Microbial Infect Dis. 1993;17(3}:193-196. 34. Kellogg JA, Manzella JP, Bankert DA. Frequency oflow-leVl:l bacteremia in children from birth to fifteen years of age. J Clin Microbiol. 2000;38(6):2181-2185. 35. Isaacman DJ, Karasic RB, Reynolds EA, Kost Sl. Effect of number of blood cultures and volume of blood on detection of bacteremia in chlldren. J Pediatr. 1996;128(2):190-195. 36. Yaacobi N, Bar-Meir M, Shchors I, Bromiker R. A prospective controlled trial of the optimal volume for neonatal blood cultures. Pediatr Infect Dis J. 2015;34{4):351-354. 37. Campigotto A, Richardson SE, Sebert M, McElvania TeKippe E, Chakravarty A, Doem CD. Low utility of pediatric isolator blood culture system for detection of fungemia in children: a 10-year review. J Clin MicrobiaL 2016;54(9}:2284-2287. 38. Tissot F, Prod'hom G, Manuel 0, Greub G. Impact of round-the-clock CSF Gram stain on empirical therapy for suspected central nervous system infections. Bur J Clin Microbial Infect Dis. 2015;34(9):1849-1857. 39. He T, Kaplan S, Kamboj M, Tang YW. Laboratory diagnosis of central nervous system infection. Curr Infect Dis Reports. 2016;18(11):35. 40. Pittman ME, Thomas BS, Wallace MA, Weber CJ, Burnham CA. Routine testing for anaerobic bacteria in cerebrospinal fluid cultures improVl:s recovery of clinically significant pathogens. l Clin Microbial. 20 14;52(6}: 1824-1829. 41. Williamson PR. Jarvis JN, Panackal AA, et al. Cryptococcal meningitis: epidemiology, inununology, diagnosis and therapy. Nat Rev NeuroL 2017;13(1):13-24. 42. Huang HR. Fan LC, Rajbanshi B, Xu JF. Evaluation of a new cryptococcal antigen lateral flow immunoassay in serum, cerebrospinal fluid and urine for the diagnosis of cryptococcosis: a meta-analysis and systematic review. PLoS One. 2015;10(5}:e0127117. 43. Abhilash KP, Mitra S, Arul JJ, et al. Changing paradigm of cryptococcal meningitis: an eight-year experience from a tertiary hospital in South India. Indian JMed MicrobiaL 2015;33(1}:25-29. 44. Sato Y, Osabe S, Kuno H, Kaji M, Oizumi K. Rapid diagnosis of cryptococcal meningitis by microscopic examination of centrifuged cerebrospinal fluid sediment. J Neurol Sci. 1999;164(1}:72-75. 45. Dien Bard J, Naccache SN, Bender JM. Use of a molecular panel to aid in diagnosis of culture-negatiVl: meningitis. J Clin Microbial. 2016;54(12):3069-3070. 46. Bryan A, Youngster I, McAdam AJ. Shiga toxin producing Escherichia coli. Clin Lab Med. 2015;35(2):247-272. 47. Zelyas N, Poon A, Patterson-Fortin L, Johnson RP, Lee W, Chui L. Assessment of commercial chromogenic solid media for the detection of non-0157 Shiga toxin-producing Escherichia coli (STEC). Diagn Microbiol Infect Dis. 2016;85(3):302-308. 48. Faron ML, Ledeboer NA, Connolly J, Granato PA. Clinical evaluation and cost analysis of Great Basin Shiga toxin direct molecular assay for detection of Shiga toxin-producing Escherichia coli in diarrheal stool specimens. J Clin Microbial. 2017;55(2}:519-525.

CHAPTER 2: laboratory Diagnosis ofVIrallnfectlons

I

iJ :l!Jjl Methods Used In Diagnostic VIrology Laboratory Primary Applications Methods Cell rulture systems Any virus that will grow In a defined cell culture system Conventional tube Shell vial or multiwell CMV, HSV, VN, respiratory viruses (e.g., RSV; influenza plate virus types Aand B; parainfluenza virus types 1, 2, 3, 4; adenovirus; metapneumovlrus), enterovirus, and others (e.g., measles and rubella viruses) Direct immunologic tests Immunofluorescence CMV, EBV, HSV, VN, respiratory viruses (e.g., RSV; influenza virus types Aand B; parainfluenza virus types 1, 2, 3, 4; adenovirus; metapneumovlrus), measles, mumps, rubella, and rabies viruses; for CMV, antlgenemla assay can be used to quantify the levels of virus in blood from immunocompromised patients lmmunoassays RSV, influenza virus types Aand B, metapneumovirus, rotavirus, adenoviruses (induding adenovirus types 40/41), norovirus, and astrovirus Molecular amplification Any virus for which conserved gene sequences are known; assays quantitative molecular assays are often used to monitor viral loads of HIV, CMV, EBV, HBV, HCV, HHV~, BK virus, and adenovirus in defined patient populations Electron microscopy Enteric viruses and poxviruses Cytology CMV, HSV, VN, HHV-8, adenovirus, BK and JC viruses, measles virus, rabies virus, HPV, and poxviruses Histology Any virus for which immunohistochemistry can be done; primarily CMV, EBV, HSV, BKV, HBV, HPV, parvovlrus 819, and adenovirus Serology Any virus for which virus-specific lgM and/or lgG antibodies can be measured Detection of drug-resistant strains of HIV, CMV, HSV, VN, Genotypic and phenotypic assays and influenza virus, and genetic variants of HBV and HCV that may not respond to therapy Next-generation Detection of expected or unexpected pathogens directly sequendng from dinical samples, analysis of human microbiome, transcriptome, and resistome, pathogen discovery, and public health surveillance and outbreak identification

Abbrevltnlons: BK, JC =B. K. (1971 kidney transplant patient's Initials) and John Cunningham vlnJSI!S; CMV =cytomegalovirus; EBV =Epstein-Barr virus; HBV, HCV =hepatitis B, Cviruses; HHV =human herpesvirus; HIV = human immunodeficiency virus; HPV =human papilloma virus; HSV =herpes simplex virus; RSV = respiratory syncytial virus; YZV =varicella zoster virus.

and cytologic techniques for detection of virus-induced morphological changes within tissues and exfoliated cells; (6) genotypic and phenotypic assays to detect antiviral drug resistance and to identify genetic variants that may not respond to therapy; and, most recently, (7) genomic sequencing for direct detection of anticipated or unexpected viruses from clinical specimens, the study of viral diversity, and the interactions between viral and host transcriptomes during disease, the discovery of new viral pathogens, and surveillance to detect and monitor outbreaks and public health emergencies. There are notable differences in the use and clinical performance of these methods, and the relative importance of certain tests has changed over the years. The most significant transformation in the clinical virology laboratory has involved the continuous development and introduction of rapid and highly accurate molecular assays for viral diagnosis. Where applicable, these tests have largely replaced the more traditional methods of virus culture and antigen detection for the direct identification of viruses from clinical specimens. For many viral illnesses, serology continues to play a meaningful role in the diagnosis of recent or chronic viral infections, for the determination of immune status to a specific virus, and to verify the immune response following immunization. Therefore, the selection of which assays to

13

perform and the choice of specimens to collect for testing should be made judiciously and in consultation with appropriate laboratory personnel and will depend on the patient population and clinical situation, the intended use of the individual tests, and the capabilities and resources of individual laboratories.

SPECIMEN COLLECTION AND HANDLING Appropriate specimen collection and handling is absolutely critical to the success oflaboratory testing for diagnosis of viral infections. 21 Irrespective of the location of testing or techniques used, specimens that are poorly collected, ill timed, or incorrectly handled between the time of collection and testing are less likely to yield accurate test results. A comprehensive listing of the selection of viral specimens based on clinical infections, the suspected viral agents, and the tests to be performed are listed in Tables 2-2 through 2-11. In general, specimens should be collected as close to clinical onset as possible (e.g., within the first 1-3 days). Vrral shedding is at its maximum at this time and increases the likelihood of virus detection. Most acute viral infections are self-limiting and last for approximately 5-10 days, so delays in specimen collection may adversely affect laboratory testing. The amount ofvirus present and the duration of viral shedding will vary, however, and depends on the age of the patient, the virus, a competent immune system, the anatomical site chosen for specimen collection, and whether the infection is localized or systemic. Young infants and immunosuppressed children may shed virus for more extended times. The specimen site should be determined by the clinical presentation and the pathogenic potential of the suspected virus (Tables 2-2 to 2-11). Recovery from a given virus may be enhanced by collecting the same specimen type over the course of several days or by collecting various specimens from different body sites during the onset and progression of symptoms. Specimens should be transported to the laboratory as quickly as possible after collection. This is especially true when attempting to grow viruses from clinical specimens since some viruses, particularly those with envelopes, are quite labile outside their natural hosts and do not survive well under adverse environmental conditions. When immediate transport is not possible, refrigerate the specimens or keep them on wet ice. For delays of more than 24-48 hours, specimens should be processed as needed and rapidly frozen to -70"C and then transported to the laboratory on dry ice. Specimens to be used for the direct detection of viruses (e.g., culture, antigen assays, or molecular methods) should never be stored at room temperature or frozen at - 20"C; it is acceptable to freeze serum or plasma at -20"C for transport to and extended storage in the laboratory when being used for detection of virus-specific antibodies. It is recommended that all specimens for molecular testing be stored at 4"C immediately after collection and then promptly sent to the laboratory for appropriate processing and storage for testing. This is critical to ensure the stability and amplification of nucleic acids, particularly for the detection of RNA viruses since RNA is unstable and easily degraded by RNases from the surrounding environment.

•

COLLECTION INSTRUCTIONS FOR SELECTED SPECIMEN TYPES

Blood for Plasma or White Blood Cells Approximately 4-7 mL of whole blood should be collected in a suitable anticoagulant such as ethylenediamine tetraacetic acid (EDTA), sodium heparin, sodium citrate, or acid citrate dextrose. EDTA is currently the preferred anticoagulant for most viral studies that require plasma or white blood cells and is considered to be the best stabilizer of nucleic acids for molecular testing. Blood for Serum Serum is the preferred specimen for most serological assays. Approximately 1-2 mL of blood should be collected for every two to three tests ordered; collection tubes should not contain anticoagulants or preservatives. A single serum specimen is sufficient to determine the inunune status of an individual or for the detection ofvirus-specific IgM antibody. For the diagnosis of current or recent viral infections, paired serum specimens collected 10-14 days apart are needed when testing for virus-specific IgG antibody. There are exceptions to this general rule,

14

SECTION 1: Practical Aspects

l! JJI Common Specimens and Laboratory Tests for Diagnosis of VIral Respiratory Disease

li;) :

Preferred Methods for Diagnosis General Disease Category Respiratory

Possible Virus RSV Influenza virus Parainfluenza virus Adenovirus Rhinovirus Coronavirus Metapneumo virus CMV HSV

Culture X X X X X

X X X X

Antigen Detection X X X X

X X X X

NAAT X X X X X X X X

Cytology/ Histology

EM

Serology

X X X X X

X

MERS--coronavirus*

X

X

Hantavirus*

X

VlV

EBV Enteroviruses SARS--coronavirus*

X

Influenza HSNl Influenza H7N9

X

X

X

X

X

X

Suggested Specimens NPA or NPW preferred; NPS, OS, BAL, TA, lung tissue acceptable

BAL. lung tissue, blood BAL. lung tissue BAL. lung tissue Blood for serology; OS for PCR NPA, NPW, NPS, OS Blood for serology; NPA, NPW, NPS, OS, BAL, TA, stool, blood, lung tissue acceptable for PCR Blood for serology; NPA, NPW, NPS, OS, BAL, TA, blood, lung tissue acceptable for PCR Blood for serology; lung, kidney, spleen tissue for PCR, histology; blood for PCR Blood for serology; NPA, NPW, NPS, OS, BAL, TA, lung tissue acceptable for PCR

A/Jbrtvlattons: BAL = bronchoalveolar lavage; EM= electron mlaoscopy; MERS =Middle East respiratory syndrome; NAAT = nudelc add ampllflcadon tests (e.g., PCR or other molecular ampllflcatlon technologies); NPA = nasopharyngeal aspirate; NPS = nasopharyngeal swab; NPW = nasopharyngeal wash; OS= oropharyngeal swab; SARS = seveR acute respiratory syndrome; TA =tracheal aspirate. *TesHng Is done p~ma~ly In state publk health or commerdal reference laborato~es or the Centets for Disease Control and Prevendon (CDC).

li;) :)

!J§l Common Specimens and Laboratory Tests for Diagnosis of VIral Infections of Skin and M1cous Membranes Preferred Methods for Diagnosis

General Disease Category Possible Virus Skin and HSV mucous VlV membranes EBV CMV HHV-6 HHV-7 HHV-8 Parvovirus B19

Papilloma viruses Poxviruses* Enterovirus Measles virus Rubella virus Hlvt Dengue virus West Nile virus Chikungunya virus Zika virus

Culture

Antigen Detection

NAAT

X X

X X

X X

X

X

X X

X

X X X

Cytology/ Histology

EM

Serology

X

X

X X X X X

X X X X X

X X X X

X

X X

X X

X

X

X X X X X

X X X X X

Suggested Spedmens Lesion swab/scrapings Lesion swab/scrapings Blood Blood for serology, PCR, antigen; urine, respiratory for culture, PCR Blood Blood Blood for serology and PCR; saliva, lesion tissue for PCR Blood for serology most practical for fifth disease and polyarthropathy; PCR preferred for transient aplastic crisis, red cell aplasia, and hydrops fetalis or congenital anemia Lesion scrapings, tissue Lesion scrapings, tissue, tonsillar swab Lesion swab, respiratory, stool, urine, blood, CSF Respiratory, eye swab for culture, antigen and PCR; urine for culture and PCR; blood for serology Respiratory, urine, blood for rulture and PCR; blood for serology Blood Blood Blood Blood Blood

Abbrmotions: EM= electron miaoscopy; NAAT =nucleic add amplification tests (e.g., PCR or other molecular amplification technologies). *Poxviruses include viruses such as varioloa virus (smallpox), vacdnia virus, monkeypox virus, cowpox virus, parapoxviruses Unduding Orf virus), and molluscum contagiosum virus. 1

HIV culture requires specialized facilities and expertise and Is not available In most diagnostic virology laboratories. For serology, the currenHy preferred S99 >99 >99 99 >99

*Imported 'f PO) and duration, so does the need for laboratory monitoring. In patients that are receiving oral penicillins beyond 2 weeks or IV penicillins longer than a week, obtaining weekly CBC with differential and chemistries should be considered. Special Considerations It should be noted that the intramuscular formulations of penicillin should never be given intravenously, as this route can cause Hoigne syndrome, including confusion, acoustic and visual hallucinations, palpitations, tachycardia, cyanosis, acute fear of death, and generalized seizures.13.l4 Emboli have been found in the lungs of patients experiencing Hoigne syndrome, potentially explaining some of the symptoms.23 Role ofCombiiNifion Therapy The combination of an aminopenicillin and an aminoglycoside may provide synergistic activity against enterococci, with gentamicin and tobramycin providing benefit, while amikacin does not.25 Additionally, in cases of renal impairment the combination of ampicillin and ceftriaxone has been shown to be an alternative regimen. Another common use of combination therapy employing ampicillin is the combination with gentamicin for severe group B streptococcal infections (e.g., meningitis).

•

Penidlllns Cephalosporins Carbapenerns Monobactams Penidllins Cephalosporlns Carbapenerns Monobactams Penidllins Cephalosporins Carbapenerns Monobactams Penidllins Cephalosporins Carbapenerns Monobactams Penidllins Cephalosporins Carbapenerns Monobactams

High-dose amoxlclllin or ceftriaxone

Switch antibiotic dass (i.e.,lincosamides or glycopeptides) or ceftaroline

Switch antibiotic dass (i.e., glycopeptides)

Switch antibiotic dass (i.e., fluoroquinolones)

New agents like cefiderocol

Cephalosporins belong to the ~-lactam group of antibiotics. They differ from penicillins in that they have a six-membered, dihydrothiazide ring instead of a five-membered ring. The cephalosporins work by binding to penicillin-binding proteins, impairing the peptidoglycan layer of the cell wall. This is important as alterations to the peptidoglycan layer results in impaired structure and leads to cell death. 26 Cephalosporins can have bactericidal or bacteriostatic activity corresponding to the percentage of time that the antibiotic remains above the minimum inhibitory concentration of the bacteria.7 Spectrum of Activity The cephalosporin class of antibiotics can be divided into five numbered generations, namely, cefamycins and cephalosporin/~-lactamase inhibitor combinations (Table 8-5). The first generation generally covers methicillin-susceptible Staphylococcus aureus (MSSA), Streptococcus pyogenes (group A streptococcus), Streptococcus agalactiae (group B Streptococcus), and some weak Gramnegative pathogens, such as susceptible E. coli, Klebsiella spp., and some isolates of Proteus mirabilis. 27.21 The second-generation agents gain a bit of broader coverage against susceptible Streptococcus pneumoniae as well as adding to the

In j!IlJ CJtegorles of Cephalosporlns Category 1st generation 2nd generation

Parenteral Agents Cefazolin (IM, IV) Cefuroxime (1M, IV)

3rd generation

Cefutaxime (IM, IV) Ceftrlaxone (1M, IV) Ceftazidime (1M, IV) (efepime (IM, IV) Ceftaroline (IV) (efuxitin (IM, IV) Cefotetan (1M, IV) Ceftolozaneltazobactam (IV) (eftazidime/avibactam (IV)

4th generation Sth generation (efamycins

CEPHALOSPORINS

Mechanism of Action The primary action mechanism involves the cell wall.

Strategies to Bypass Resistance

Cephalosporin/ ~lactamase inhibitors

Enteral Agents Cephalexin Cefadroxil Cefuroxime Cefprozil (efaclor Cefdinir Cefpodoxlme (efixime None None None None

CHAPTER 8: Antibacterial Agents Gram-negative coverage of the first-generation cephalosporin& to provide a higher likelihood of susceptibility to some enterobacteriaceae (e.g., susceptible E. coli, Klebsiella spp., P. mirabilis), and also add some reliable coverage against Haemophilus influenzae and Mora:x:ella catarrhalis. It is important to note, however, that although these secondgeneration agents broaden in these aforementioned areas, they lose some activity against MSSA. Cefuroxime deserves special consideration as it provides coverage against Borellia burgdorferi and has the best coverage against S. pneumoniae from this generation.29-~1 The third-generation cephalosporin& actually consist of two separate groups with regard to coverage. The first group includes ceftriaxone, cefotaxime, cefdinir, and cefpodoxime. This group expands on the coverage of cefuroxime and provides excellent coverage against S. pneumoniae and variable coverage against viridans streptococci. For viridans streptococci, data conflict with regard to the susceptibility of the S. mitis and S. mutans strains to these agents. Some report poor susceptibility, while others report that susceptibility may vary with patient age, with children being less likely to have third-generation agents susceptible.n.~~ These cephalosporins also provide broad Gram-negative coverage and include reliable Neisseria species as well as susceptible enterobacteriaceae (E. coli, Klebsiella spp., P. mirabilis, Serratia spp., Citrobacter spp.). Enterobacteriaceae that produce extended-spectrum ~-lactamases (ESBLs) or AmpC ~-lactamases are not covered by this class. Most recent data suggest that at least 90% of E. coli, Klebsiella spp., and P. mirabilis remain susceptible to ceftriaxone and ceftazidirne.~• This class should not be used for the treatment of severe infections caused by Enterobacter, Serratia, Citrobacter, and Morganella species, as they are likely to produce ESBLs or AmpC ~-lactamases.~ 5 Ceftazidirne is the sole member of the second group of the third-generation cephalosporin&. Ceftazidirne does not have any reliable Gram-positive coverage, but instead gains even further Gram-negative coverage than the other group of third-generation agents. Recent US national surveillance data suggest that whereas ceftazidirne has similar susceptibility against enterobacteriaceae, it is additionally active against approximately 80% of Pseudomonas species and 40% of Acinetobacter species.~• The fourth-generation cephalosporin class includes only cefepime, which combines the best of the first- and third-generation cephalosporin coverage and extends reliability against resistant organisms. Specifically, cefepirne has reliable activity against most Gram-positive organisms, including MSSA, groups A and B Streptococcus, and S. pneumoniae. Its Gram-negative coverage is similar in many respects to that of ceftazidirne, but adds some stability against ArnpC-produdng enterobacteriaceae such as Enterobacter and Serratia species.36 Ceftaroline is the only currently approved fifth-generation cephalosporin. The fifth -generation class is unique in that it is very susceptible not only to MSSA but also to methicillin-resistant Staphylococcus aureus {MRSA). In addition to being active against strains of S. aureus, it also demonstrates potent activity against groups A, B, C, and G streptococci; S. pneumoniae (including penicillin-nonsusceptible strains) coagulase-negative Staphylococcus; and H. injluenzae.37- 39 Ceftaroline appeared to have similar activity to ceftriaxone against Enterobacteriaceae.38.~9 Ceftaroline has recently been FDA-approved in pediatrics for the treatment of skin infections as well as communityacquired pneumonia.«> The cefamycins, often included with the second-generation cephalosporin&, have distinct structural features that result in expanded coverage. This group includes the antibiotics cefoxitin and cefotetan. These antibiotics have aerobic Gram-positive and Gram-negative coverage similar to that of the second-generation class, but also have coverage against anaerobes. Although they both initially had reliable coverage against Bacteroides species, which is important for intraabdominal or other infections caused by enteric bacteria, in more recent years, resistance has limited the effectiveness of cefotetan. Cefoxitin continues to be recommended for Bacteroides spp. coverage.41 The most recent addition to the cephalosporin class are the cephalosporin ~-lactamase inhibitor combination products. Two of these products are currently available: ceftazidirne/avibactam and ceftolozane/ tazobactam, but at this point both of these agents have limited data (a phase I study for ceftazidirne/avibactam and a case report for ceftoloza.ne/tazobactam) in pediatric patients. Both ofthese agents are reserved

59

for the treatment of multi-drug-resistant organisms.4W Specifically, the addition of avibactam to ceftazidirne provides activity against some resistant Pseudomonas aeruginosa and enterobacteriaceae such as ArnpC producers and extended-spectrum ~-lactamases (ESBLs), specifically, coverage against KPC, TEM, SHV, CTX-M, and OXA.o.-u Ceftolozane/ tazobactam also provides coverage against the multi-drug-resistant P. aeruginosa (AmpC, outer-membrane porins, and eftlux pumps) and enterobacteriaceae such as ArnpC producers and extended-spectrum ~-lactamases {ESBLs; examples are TEM, SHY, CTX-M, and OXA). Importantly, it does not cover KPC ESBLs or metallo-~-lactamases. It has also been approved to treat anaerobic (including Bacteroides fragilis) and limited Gram-positive bacteria, including some viridans group streptococci (Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius).05. MIC) for a substantial portion of the dosing interval? This is important, as cephalosporins have a brief postantibiotic effect. It is this %T > MIC pharmacodynamic parameter that has been most associated with determining whether the antibiotic will provide bacteriostatic or bactericidal killing. Specifically, cephalosporins are believed to exhibit bacteriostatic activity when they remain above the MIC for 30-40% of the dosing interval and bactericidal activity when the concentration is above the MIC for 60-70% of the interval? Many oral and parenteral cephalosporins are available in the United States. Many of these agents are available orally only, and as such the bioavailability data are misleading because even with high bioavailability the resultant concentrations are significantly lower than the IV formulations and often do not meet bacteriostatic targets, limiting their likelihood of success. Therefore, these agents are seldom recommended as first line for any infections and should be considered only in nonsevere infections in immunocompetent patients.47In order to adequately treat bacterial infections, it is important to choose an antibiotic that penetrates sufficiently to the site of infection. Areas that often generate discussion are the bones, the ears, the central nervous system (CNS), and the lungs. Cephalosporins, such as cefazolin and cephalexin, that have been studied in osteomyelitis, demonstrate adequate penetration in bone to achieve bactericidal activity. Cefazolin and cephalexin are often used for osteomyelitis against sensitive organisms.50 In children, the penetration of antibiotics into the middle-ear fluid is also important for the successful treatment of acute otitis media. Oral cephalosporins have demonstrated a range of middle-ear fluid concentrations of 5-52% of serum concentrations (cefprozil 30% at hours 2 and 4, but somewhat unpredictable by hour 6, cefuroxime 5-61%, cefdinir 15%, and cefpodoxime 52% at 6 hours). Importantly, cefpodoxime and cefuroxime appeared to have more than 50% concentrations throughout the dosing interval These two medications are likely the best cephalosporin, alternatives to amo:xicillin or amoxicillin/ clavulanate for the treatment of otitis media in children due to drug penetration; however, the susceptibility of pneumococcus may be a concern for cefuroxirne. Additionally, IM ceftriaxone not only has a high peak concentration in the middle ear (35 flglmL at 24 hours) but also has a very long middle-ear fluid half-life of25 hours, ensuring concentrations above the MIC of most susceptible pathogens for up to 6 days. 51 Therefore, if compliance is a potential issue, ceftriaxone as a single dose IM is a reasonable option for susceptible pneumococci. Bacterial meningitis is a potentially devastating condition, and as such, it is very important to choose antibiotics that will result in significant concentrations in the cerebrospinal fluid (CSF). Cefotaxime, ceftriaxone,

60

SEGION 1: Practical Aspects

ceftazidime, and cefepime achieve sufficient concentrations in the CSF when used at high doses and are commonly recommended for the treatment of bacterial meningitis and/or ventriculitis.52 Cefuroxime, however, has demonstrated concentrations in the CSF, but because of inferior outcomes, it is not recommended for treating these infections.s~.s' Cefazolin and the oral cephalosporins should also not be used for treating CNS infections as they do not provide reliable concentrations into the CSF. To date, there have only been case reports using ceftaroline fosamil in CNS infections, and these have occurred in adult patients where outcomes appeared to improve with higher doses. 55.s Although it appears promising, ceftaroline should not be used routinely for CNS infections in children, until more data are available. Pediatric pneumonia is one of the more common infectious conditions affecting children, so it is important to choose an antibiotic that achieves appropriate epithelial lung fluid (ELF) concentrations. Unfortunately, the data regarding ELF have many limitations, including timing, data from adult studies, and various measurement methods used. The concentrations in the lung, like the concentrations of serum, are highest initially after the dose is administered and then decrease over time. Although the concentration decreases over time, the ELF : plasma ratio is generally consistent and thus will be used in this review.57 For the oral cephalosporins, the ELF : plasma ratio is in general low, showing limited lung penetration. The exception is cefaclor, which has a higher ratio.57 In rank order from high to low, ELF : plasma concentrations of the oral agents are as follows: cefaclor, 0.88-3.2; cefdinir, 0.12-0.15; cefpodoxime, 0.06-0.11; and cefuroxime, undetectable at only 0.15.57.sa These low ELF ratios are important, as they provide another reason why oral cephalosporins may be an inferior choice for the treatment of pediatric pneumonia as compared with aminopenicillin options. Parenteral cephalosporins continue to be an effective choice for pediatric pneumonia when penicillin-resistance is present because they achieve very high serum levels, ensuring high lung concentrations, despite a low ELF: plasma ratio.57•59 Key Side Effects Cephalosporins are generally well tolerated. As with many antibiotics, the most common adverse effects are gastrointestinal in nature, including nausea, vomiting, and diarrhea. Although not common, cephalosporins have been associated with Clostridium d!ffidle-associated disease. Overall, cephalosporins have been shown to increase the risk of C. d!fficile in children 2.4-fold, with IV cephalosporins increasing the risk by sixfold This is likely due to the increased concentrations and resultant killing of healthy bacteria.60.61 Severe side effects are also possible with cephalosporins. 1J'pes that have prompted visits to the emergency room (ER) include mild and moderate to severe allergic reactions (2.8 per 10,000 outpatient visits and 1.3 per 10,000 outpatient visits, respectively), gastrointestinal adverse events (0.7 per 10,000 outpatient visits), neurologic and/or psychiatric adverse events (0.3 per 10,000 outpatient visits), and other or unspecified adverse events (0.4 per 10,000 outpatient visit).Q Eosinophilia was rare(< 0.5%) but was most common with ceftriaxone, cefazolin, and cephalexin.60 Other rare but important side effects include CNS toxicity, often resulting in seizures that are most common with cefepime and often are associated with high dosing or impaired kidney function. 63 Hematologic suppression is also possible, and is more common with prolonged or high doses.M Some cephalosporins that have occasionally been associated with worsening kidney function and renal failure are cefazolin, ceftazidime, cephalexin, and ceftriaxone.60 Ceftriaxone specifically has been associated with urolithiasis and nephrolithiasis as a cause of renal injury.65,66 In addition to kidney issues, ceftriaxone has also been associated with biliary sludging and stones117 and a rare ceftriaxone-induced hemolytic anemia that is severe and acute, often within 30 minutes.61 Twenty-three pediatric cases have been reported, and it has been noted to be more common in patients with chronic hematologic or immunologic conditions.611 Cefotetan has a unique side effect due to its N-methylthiotetrazole sidechain, which is associated with hypoprothrombinemia.611 Finally, cefaclor has been associated with serum sickness, which has been estimated to be as high as 0.4% of all courses, with children being at higher risk than adults.10•71

Monitoring Since cephalosporins are well tolerated, minimal monitoring is recommended with renal function tests and complete blood count with differential recommended weekly if therapy is to exceed 7-14 days, especially when using parenteral routes.M Special Considerations The oral agents are often administered as suspensions to children. Most of them can be taken with or without food, but cefuroxime should be taken with food to ensure optimal absorption, and cefadroxil should be taken with food to decrease gastrointestinal upset?.l-7'J Storage of the suspensions can also vary. Most are stored in the refrigerator and are stable for 14 days. 72- 75,80 Exceptions include cephalexin, cefixime, and cefdinir, which are stored at room temperature?6-78 Suspensions that are stable for only 10 days are cefuroxime and cefdinir.7s.79

• MONOBACTAMS Aztreonam is a primary example of the monobactams, and most of the antibiotic activity involves the cell wall. Mechanism of Action Aztreonam has high affinity for penicillinbinding proteins found in Gram-negative organisms, but has low affinity for types found in Gram-positive organisms.81 Spectrum of Activity Aztreonam's spectrum of activity is limited to aerobic Gram-negative organisms, including Pseudomonas aeruginosa and Enterobacteriaceae, due to penicillin-binding protein (PBP) selectivity.81 Mechanism of Resistance Some resistance mechanisms listed in Table 8-4 also apply to aztreonam. Specifically, organisms with TEM-3, SHV-2, CTX-M15, SME, or IMI-1 often result in resistance to aztreonam. Some OXA remain susceptible to aztreonam, and aztreonam generally resists hydrolysis by IMP or VIM resistance. Bioavailability, Pharmacokinetics, and Pharmacodynamics Aztreonam distributes widely and achieves therapeutic concentrations in pericardia! fluid, pleural fluid, synovial fluid, bile, and most organ tissue.12 Aztreonam has a relatively short serum half-life ( 1month to children aged s2 years; limited data available Children aged >2 years

400 mg once daily Not available Initial dose: 70 mg/m2 for 1 day {maximum dose 70 mg) Maintenance dose: SO mg/m2 once daily (maximum dose 50 mg); may increase to 70 mg/m2 once daily if clinical response inadequate (maximum dose 70 mg)

IV

s30 kg: 3 mg/kg daily >30 leg: 2.5 mglkg dally (maximum 50 mg/day) 2 mg/kg once daily (maximum 100 mg daily)

IV

1 mg/kg dally (maximum SO mg/day)

Anidulfungin

IV

Not available

Terbinafine

Oral, granules

Griseofulvin

Oral

10 mglkg daily in single or divided doses

Oral

Microsize: 20-25 mglkg once daily (maximum daily dose 1000 mg) Ultramicrosize: 10-15 mglkg once daily (maximum daily dose 750 mg)

35 kg: 250 mg once daily for 6weeks

*Posaconazole delayed-release tablet and oral suspension have differences in their formulations and are not interdlangeable.

The pharmacokinetic (PK) parameters of the polyenes are complicated and sometimes inconsistent with known clinical effectiveness. Mter administration, amphotericin B achieves low tissue and fluid concentrations in the liver, spleen, pleura, peritoneal fluid, synovial fluid, vitreous and aqueous humor, and central nervous system (CNS).15•16 Despite low measured concentrations in these locations, the polyenes have been shown to be clinically effective for the treatment of various forms of invasive fungal disease, including fungal meningitis. 17•18 Distribution to the liver, lung, and spleen is improved with lipid formulations11 (Table 9-3), and animal data suggest that cerebrospinal fluid (CSF) and brain parenchymal distribution are optimized with liposomal amphotericin B (Ambisome