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Infectious Diseases 3rd ed Philadelphia: Elsevier; 2010:1308-1322 52 Hussain FM, Boyle-Vavra S, Bethel CD, Daum RS Current trends in community-acquired methicillin-resistant Staphylococcus aureus at a tertiary care pediatric facility Pediatr Infect Dis J 2000;19(12): 1163-1166 53 Kaplan SL, Deville JG, Yogev R, et al Linezolid versus vancomycin for treatment of resistant gram-positive infections in children Pediatr Infect Dis J 2003;22(8):677-686 54 Manning ML, Archibald LK, Bell LM, Banerjee SN, Jarvis WR Serratia marcescens transmission in a pediatric intensive care unit: a multifactorial occurrence Am J Infect Control 2001;29(2):115-119 55 Courter JD, Kuti JL, Girotto JE, Nicolau DP Optimizing bactericidal exposure for beta-lactams using prolonged and continuous infusions in the pediatric population Pediatr Blood Cancer 2009;53(3):379-385 56 Lodise Jr TP, Lomaestro B, Drusano GL Piperacillin-tazobactam for Pseudomonas aeruginosa infection: Clinical implications of an extended-infusion dosing strategy Clin Infect Dis 2007;44(3): 357-363 57 Blyth CC, Palasanthiran P, O’Brien TA Antifungal therapy in children with invasive fungal infections: a systematic review Pediatrics 2007;119(4):772-784 58 Wisplinghoff H, Seifert H, Tallent SM, Bischoff T, Wenzel RP, Edmond MB Nosocomial bloodstream infections in pediatric patients in United States hospitals: Epidemiology, clinical features and susceptibilities Pediatr Infect Dis J 2003;22(8):686-691 59 Zaoutis TE, Prasad PA, Localio AR, et al Risk factors and predictors for candidemia in pediatric intensive care unit patients: implications for prevention Clin Infect Dis 2010;51(5):38 60 Klatte JM, Newland JG, Jackson MA Incidence, classification, and risk stratification for candida central line-associated bloodstream infections in pediatric patients at a tertiary care children’s hospital, 2000-2010 Infect Control Hosp Epidemiol 2013;34(12):1266-1271 61 Clancy CJ, Nguyen MH Finding the “missing 50%” of invasive candidiasis: How nonculture diagnostics will improve understanding of disease spectrum and transform patient care Clin Infect Dis 2013;56(9):1284-1292 62 Pappas PG, Kauffman CA, Andes DR, et al Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America Clin Infect Dis 2016;62(4):e1-e50 63 Zaoutis TE, Heydon K, Chu JH, Walsh TJ, Steinbach WJ Epidemiology, outcomes, and costs of invasive aspergillosis in immunocompromised children in the united states, 2000 Pediatrics 2006;117(4):711 64 Patterson TF, Thompson GR, 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 2016; 63(4):e1-e60 65 Blumental S, Mouy R, Mahlaoui N, et al Invasive mold infections in chronic granulomatous disease: a 25-year retrospective survey Clin Infect Dis 2011;53(12):159 66 Groll AH, Castagnola E, Cesaro S, et al Fourth European conference on infections in leukaemia (ECIL-4): Guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation Lancet Oncol 2014;15(8):327 67 Villarroel M, Aviles CL, Silva P, et al Risk factors associated with invasive fungal disease in children with cancer and febrile neutropenia: A prospective multicenter evaluation Pediatr Infect Dis J 2010;29(9): 816-821 68 Frange P, Bougnoux ME, Lanternier F, et al An update on pediatric invasive aspergillosis Med Mal Infect 2015;45(6):189-198 69 Brajtburg J, Powderly WG, Kobayashi GS, Medoff G Amphotericin B: current understanding of mechanisms of action Antimicrob Agents Chemother 1990;34(2):183-188 70 Godet C, Goudet V, Laurent F, et al Nebulised liposomal amphotericin B for aspergillus lung diseases: case series and literature review Mycoses 2015;58(3):173-180 71 Perfect JR, Dismukes WE, Dromer F, et al Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America Clin Infect Dis 2010;50(3):291-322 72 Koren G, Lau A, Klein J, et al Pharmacokinetics and adverse effects of amphotericin B in infants and children J Pediatr 1988;113(3): 559-563 73 Subira M, Martino R, Gomez L, Marti JM, Estany C, Sierra J Lowdose amphotericin B lipid complex vs conventional amphotericin B for empirical antifungal therapy of neutropenic fever in patients with hematologic malignancies—a randomized, controlled trial Eur J Haematol 2004;72(5):342-347 74 Lass-Florl C, Alastruey-Izquierdo A, Cuenca-Estrella M, Perkhofer S, Rodriguez-Tudela JL In vitro activities of various antifungal drugs against Aspergillus terreus: Global assessment using the methodology of the European Committee on Antimicrobial Susceptibility Testing Antimicrob Agents Chemother 2009;53(2):794-795 75 Atkinson BJ, Lewis RE, Kontoyiannis DP Candida lusitaniae fungemia in cancer patients: Risk factors for amphotericin B failure and outcome Med Mycol 2008;46(6):541-546 76 Pfaller MA, Diekema DJ Epidemiology of invasive mycoses in North America Crit Rev Microbiol 2010;36(1):1-53 77 Walsh TJ, Melcher GP, Rinaldi MG, et al Trichosporon beigelii, an emerging pathogen resistant to amphotericin B J Clin Microbiol 1990;28(7):1616-1622 78 Spellberg BJ, Filler SG, Edwards Jr JE Current treatment strategies for disseminated candidiasis Clin Infect Dis 2006;42(2):244-251 79 Luke DR, Tomaszewski K, Damle B, Schlamm HT Review of the basic and clinical pharmacology of sulfobutylether-beta-cyclodextrin (SBECD) J Pharm Sci 2010;99(8):3291-3301 80 Park WB, Kim NH, Kim KH, et al The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial Clin Infect Dis 2012;55(8): 1080-1087 81 Zeuli JD, Wilson JW, Estes LL Effect of combined fluoroquinolone and azole use on QT prolongation in hematology patients Antimicrob Agents Chemother 2013;57(3):1121-1127 e3 82 Perlin DS Echinocandin resistance, susceptibility testing and prophylaxis: implications for patient management Drugs 2014;74(14): 1573-1585 83 Bachmann SP, VandeWalle K, Ramage G, et al In vitro activity of caspofungin against Candida albicans biofilms Antimicrob Agents Chemother 2002;46(11):3591-3596 84 Fernandez-Ruiz M, Aguado JM, Almirante B, et al Initial use of echinocandins does not negatively influence outcome in Candida parapsilosis bloodstream infection: a propensity score analysis Clin Infect Dis 2014;58(10):1413-1421 85 Reboli AC, Rotstein C, Pappas PG, et al Anidulafungin versus fluconazole for invasive candidiasis N Engl J Med 2007;356(24):2472-2482 86 Andes DR, Safdar N, Baddley JW, et al Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: A patient-level quantitative review of randomized trials Clin Infect Dis 2012;54(8):1110-1122 87 McCormack PL, Perry CM Caspofungin: A review of its use in the treatment of fungal infections Drugs 2005;65(14):2049-2068 88 Marr KA, Schlamm HT, Herbrecht R, et al Combination antifungal therapy for invasive aspergillosis: a randomized trial Ann Intern Med 2015;162(2):81-89 89 Marr KA, Boeckh M, Carter RA, Kim HW, Corey L Combination antifungal therapy for invasive aspergillosis Clin Infect Dis 2004;39(6):797-802 90 Mularoni A, Furfaro E, Faraci M, et al High levels of beta-D-glucan in immunocompromised children with proven invasive fungal disease Clin Vaccine Immunol 2010;17(5):882-883 91 Bassetti M, Garnacho-Montero J, Calandra T, et al Intensive care medicine research agenda on invasive fungal infection in critically ill patients Intensive Care Med 2017;43(9):1225-1238 92 Desai R, Ross LA, Hoffman JA The role of bronchoalveolar lavage galactomannan in the diagnosis of pediatric invasive aspergillosis Pediatr Infect Dis J 2009;28(4):283-286 93 Zinter MS, Dvorak CC, Mayday MY, et al Pulmonary metagenomic sequencing suggests missed infections in immunocompromised children Clin Infect Dis 2019;68(11):1847-1855 94 Bassetti M, Kollef MH, Poulakou G Principles of antimicrobial stewardship for bacterial and fungal infections in ICU Intensive Care Med 2017;43(12):1894-1897 95 Goldman JL, Newland JG, Price M, Yu D, Lee BR Clinical impact of an antimicrobial stewardship program on high-risk pediatric patients Infect Control Hosp Epidemiol 2019;40(9):968-973 96 Owens RC Antimicrobial stewardship: application in the intensive care unit Infect Dis Clin North Am 2009;23(3):683-702 97 Gilbert DN, Eliopoulos GM, Chambers HF, Saag MS, Pavia AT The Sanford Guide to Antimicrobial Therapy 2019 50th ed Sperryville, VA: Antimicrobial Therapy, Inc.; 2019 98 Russell NE, Pachorek RE Clindamycin in the treatment of streptococcal and staphylococcal toxic shock syndromes Ann Pharmacother 2000;34(7-8):936-939 99 Silverman JA, Mortin LI, Vanpraagh AD, Li T, Alder J Inhibition of daptomycin by pulmonary surfactant: in vitro modeling and clinical impact J Infect Dis 2005;191(12):2149-2152 100 Rutter WC, Burgess DR, Talbert JC, Burgess DS Acute kidney injury in patients treated with vancomycin and piperacillintazobactam: A retrospective cohort analysis J Hosp Med 2017;12(2): 77-82 e4 Abstract: Emergence of resistant organisms is increasing in critically ill patients Timely antibiotic administration, selection of appropriate antimicrobial therapy, source control, and decontamination at the site of infection are paramount in critically ill pediatric patients Knowledge of the most likely pathogens and potential resistance mechanisms is important for the pediatric intensivist Obtaining cultures with pathogen susceptibility information is crucial to optimize therapy and minimize resistance This chapter addresses clinically important bacterial and fungal infections encountered in critically ill children Antimicrobial and antifungal therapy, mechanisms of resistance, future directions in pathogen identification with biomarkers and diagnostics, and antimicrobial stewardship strategies are reviewed Key words: antimicrobial resistance, antimicrobial stewardship program (ASP), Infectious Diseases Society of America (IDSA), vancomycin-resistant enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), candidemia, invasive aspergillosis, multidrug-resistant infection, antimicrobial toxicity, immunocompromised, infection diagnostics 108 Life-Threatening Viral Diseases and Their Treatment SURABHI B VORA, ALPANA WAGHMARE, DANIELLE M ZERR, AND ANN J MELVIN • Viral infections are a frequent cause of disease in individuals of all ages In general, the spectrum of illness is varied, with young and/or immunosuppressed children at higher risk of severe disease This chapter covers viral causes of entities commonly seen in the intensive care unit (ICU): myocarditis, hepatitis, pneumonitis, and meningitis/encephalitis, as well as certain emerging infections that may require critical care (Table 108.1) This content is focused on providing the reader with guidance for the initial management of patients with viral infections, with an emphasis on diagnosis and therapy Five primary methods are used to diagnose viral infections: (1) serologic detection of an early antibody (immunoglobulin M [IgM]) or a fourfold or higher rise in IgG antibody titers between acute phase and convalescent phase (at least 10–14 days later) serum; (2) observation of characteristic cytopathic effect in cell culture; (3) microscopic identification of viral inclusion bodies; (4) assays that link specific antibodies to viral antigens (complement fixation, neutralization, immunofluorescence assays, enzymelinked immunosorbent assay [ELISA]); and (5) molecular techniques that amplify and quantify viral deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) The latter are increasingly being used in panels of multiple pathogens for various samples, including respiratory, stool, and cerebral spinal fluid (CSF) If a viral infection is suspected, acute-phase serum should be held for later interpretation It is critical that this specimen is drawn before administration of intravenous immunoglobulin (IVIG) or blood products Samples for viral cultures and polymerase chain reaction (PCR) testing should be collected from the appropriate sites with specific swabs Nasal swabs and swabs of the base of a vesicle • • • • Clinicians should obtain serum to store for future serologic testing when viral pathogens are considered as the potential cause of a critical illness Multiplex polymerase chain reaction panels are increasingly used to diagnose viral infections from various specimens, for example, respiratory, cerebrospinal fluid, and stool Current treatment for most viral infections remains supportive, with antiviral therapy generally limited to treatment of herpes and some respiratory viruses • PEARLS Providers should initiate empiric treatment with acyclovir rapidly when herpes simplex virus encephalitis or neonatal disease is suspected Parainfluenza and influenza viruses are often associated with bacterial coinfections Infection control precautions should be initiated early to prevent spread of infection to staff and other patients when viral pathogens are suspected or ulcer (for varicella zoster virus [VZV], herpes simplex virus [HSV]) should include good cellular content to improve the sensitivity of the assay Table 108.2 outlines appropriate samples and testing for a number of specific viral pathogens In general, for most life-threatening viral infections, the primary treatment is supportive Because of improvements in intensive medical care, death from these illnesses has decreased even without the availability of specific antiviral therapy Although lacking for many infections, there are antivirals for most of the herpes group viruses and some respiratory viruses For most infections, the efficacy of antiviral therapy is decreased if therapy is delayed Thus, early diagnosis and rapid initiation of medication are essential Consultation with an infectious disease specialist is recommended because some antiviral agents are not commercially available and new treatment modalities continue to be identified A listing of antiviral agents, indications, and dosages is provided in Table 108.3 Myocarditis Epidemiology and Etiology Myocarditis accounts for approximately 0.05% of pediatric hospital discharges in the United States.1,2 In an autopsy-based study of children, myocarditis accounted for 2% of infant deaths and 5% of deaths of older children; 57% of these children presented with sudden death.3 Median age of presentation with myocarditis in children was 13.1 years in a recent multicenter cohort study.4 Although many infectious and noninfectious causes have been 1273 1274 SECTION XI Pediatric Critical Care: Immunity and Infection TABLE 108.1 Viral Etiologies of Myocarditis, Fulminant Hepatitis, Pneumonia, Meningitis, Encephalitis, and Myelitis Myocarditis Pneumonia Meningitis Encephalitis Myelitis XX X X X Arboviruses (arthropod-borne viruses) XX XX Western equine encephalitis virus X X Adenovirus XXX Liver Failure X a Eastern equine encephalitis virus X St Louis encephalitis virus X X California encephalitis virus (La Crosse) X X Colorado tick fever X X West Nile encephalitis virus X Coronaviruses (OC43, 229E, HKU1, NL63, SARS, and MERS) Enteroviruses XX XXX X Hantavirus X XXX XX XX X Hepatitis A XXX Hepatitis B X Hepatitis C X Hepatitis E X X Herpesviruses XXXa CMV X X EBV X XX HSV and X b X X HHV-6B X X Xa Xa XXa VZV HIV X a XX X XX X XX XX X X X X X X X HTLV X Influenza A X XXX Influenza B X X X X X Lymphocytic choriomeningitis virus Measles X X X Metapneumovirus XX Mumps X Parechovirusesb XX Parainfluenza virus types 1, 2, 3, c Parvovirus B19 X X X X X XXX XXX X XXX XX Polyomaviruses BK virus Xa JC virus Xa Rabies RSV X X Rhinovirus XXX X Rubella SARS-CoV-2 X X X XX XXX, Most frequent; XX, frequent; X, less common or rare CMV, Cytomegalovirus; HHV, human herpesvirus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; IVIG, intravenous immunoglobulin; JCV, John Cunningham virus; PIV, parainfluenza virus; RSV, respiratory syncytial virus; VZV, varicella zoster virus a Primarily in immunocompromised hosts b Primarily neonates and young infants c Viruses detected in myocardial biopsies appear to have shifted over the past few decades ... with pathogen susceptibility information is crucial to optimize therapy and minimize resistance This chapter addresses clinically important bacterial and fungal infections encountered in critically... (ASP), Infectious Diseases Society of America (IDSA), vancomycin-resistant enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), candidemia, invasive aspergillosis, multidrug-resistant... illness is varied, with young and/or immunosuppressed children at higher risk of severe disease This chapter covers viral causes of entities commonly seen in the intensive care unit (ICU): myocarditis,