KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and website for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

Herbrecht R et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J

Med. 2002;347:408. (176)

Johnson PC et al. Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for

induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med. 2002;137:105. (139)

Morrell M et al. Delaying the empiric treatment of candida bloodstream infection until positive blood culture results

are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother. 2005;49:3640. (71)

Odom RB et al. A multicenter, placebo-controlled, double-blind study of intermittent therapy with itraconazole for

the treatment of onychomycosis of the fingernail. J Am Acad Dermatol. 1997;36:231. (36)

Pappas PG et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious

Diseases Society of America. Clin Infect Dis. 2009;48(5):503. (57)

Patel M et al. Initial management of candidemia at an academic medical center: evaluation of the IDSA guidelines.

Diagn Microbiol Infect Dis. 2005;52:26. (70)

Pelz RK et al. Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients. Ann Surg. 2001;233:542. (116)

Perfect JR 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. (182)

Rex JH et al. Antifungal susceptibility testing: practical aspects and current challenges. Clin Microbiol Rev.

2001;14:643. (20)

Shepard JR et al. Multicenter evaluation of the Candida albicans/Candida glabrata peptide nucleic acid fluorescent

in situ hybridization method for simultaneous dual-color identification of C. albicans and C. glabrata directly from

blood culture bottles. J Clin Microbiol. 2008;46:50. (62)

Stevens DA et al. Practice guidelines for diseases caused by Aspergillus. Infectious Diseases Society of America.

Clin Infect Dis. 2000;30:696.

COMPLETE REFERENCES CHAPTER 78 FUNGAL

INFECTIONS

Anaissie E et al, eds. Clinical Mycology. New York, NY: Churchill Livingstone; 2009.

Rinaldi MG. Emerging opportunists. Infect Dis Clin North Am. 1989;3:65.

Vinh D et al. Refractory disseminated coccidioidomycosis and mycobacteriosis in interferon-gamma receptor 1

deficiency. Clin Infect Dis. 2009;49:e62.

Netea MG, Marodi L. Innate immune mechanisms for recognition and uptake of Candida species. Trends

Immunol. 2010;31:346.

Khardori N et al. Cutaneous Rhizopus and Aspergillus infections in five patients with cancer. Arch Dermatol.

1989;125:952.

Wingard JR. Importance of Candida species other than C. albicans as pathogens in oncology patients. Clin Infect

Dis. 1995;20:115.

Brajtburg J et al. Amphotericin B: current understanding of mechanisms of action. Antimicrob Agents Chemother.

1990;34:183.

Gruda I et al. Application of differential spectra in the ultraviolet-visible region to study the formation of

amphotericin B-sterol complexes. Biochem Biophys Acta. 1980;602:260.

Hitchcock CA et al. The lipid composition and permeability to azole of an azole-and polyene-resistant mutant of

Candida albicans. J Med Vet Mycol. 1987;25:29.

Pierce AM et al. Lipid composition and polyene antibiotic resistance of Candida albicans. Can J Biochem.

1978;56:135.

Brajtburg J et al. Stimulatory, permeabilizing, and toxic effects of amphotericin B on L cells. Antimicrob Agents

Chemother. 1984;26:892.

Chouini-Lalanne N et al. Study of the metabolism of flucytosine in Aspergillus species by 19F nuclear magnetic

resonance spectroscopy. Antimicrob Agents Chemother. 1989;33:1939.

Bodey GP. Azole antifungal agents. Clin Infect Dis. 1992;14(Suppl 1):S161.

Petranyi G et al. Allylamine derivatives: new class of synthetic antifungal agents inhibiting fungalsqualene epoxidase. Science. 1984;244:1239.

Manavathu EK et al. Organism-dependent fungicidal activities of azoles. Antimicrob Agents Chemother.

1998;42:3018.

Walsh TJ et al. New targets and delivery systems for antifungal therapy. Med Mycol. 2000;38(Suppl 1):335.

Clinical Laboratory Standards Institute. Approved Standard CLSI Document M27-A3, M38A, M44-A2, M44-S3,

andM51A. Wayne, PA: Clinical Laboratory Standards Institute; 2011.

Rex JH et al. Development of interpretive breakpoints for antifungalsusceptibility testing: conceptual framework

and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and Candida infections. Clin Infect

Dis. 1997;24:235.

Morace G et al. Multicenter comparative evaluation of six commercial systems and the national committee for

Clinical Laboratory Standards M27-A broth microdilution method for fluconazole susceptibility testing of

Candida species. J Clin Microbiol. 2002;40:2953.

Rex JH et al. Antifungal susceptibility testing: practical aspects and current challenges. Clin Microbiol Rev.

2001;14:643.

Vale-Silva LA, Buchta V. Antifungal susceptibility testing by flow cytometry: is it the future? Mycoses.

2006;49:261.

Lass-Florl C, Perkhofer S. In vitro susceptibility-testing in Aspergillus species. Mycoses. 2008;51:437.

Wagner C et al. The echinocandins: comparison of their pharmcokinetics, pharmcodynamics and clinical

applications. Pharmacology. 2006;78:161.

[No authors listed]. Posaconazole (Noxafil) for invasive fungal infections. Med Lett Drugs Ther. 2006;48:93.

Fulvicin (griseofulvin) [package insert]. Liberty Corner, NJ: Schering-Plough Healthcare Products; 1994.

Alexander BD et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with

presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis. 2013;56:1724.

Beyda ND et al. FKS mutant Candida glabrata; risk factors and outcomes in patients with candidemia. Clin Infect

Dis. 2014;59:819.

Pham CD et al. The role of FKS mutations in C. glabrata: MIC values, echinocandin resistance and multidrug

resistance. Antimicrob Agents Chemother. 2014;58:4690.

Rijnders BJ et al. Aerosolized Liposomal AmB for the prevention of pulmonary aspergillosis during prolonged

neutropenia: a randomized, placebo-controlled trial. Clin Infect Dis. 2008;46:1401.

Drew RH et al. Comparative safety of amphotericin B lipid complex and amphotricin B deoxycholate as

aerosolized antifungal prophylaxis in lung-transplant recipients. Transplantation. 2004;77:232.

Le J, Schiller DS. Aerosolized delivery of antifungal agents. Curr Fungal Infect Rep. 2010;4:96.

Nix DE et al. Pharmacokinetics of nikkomycin Z after single rising oral doses. Antimicrob Agents Chemother.

2009:2517.

Benincasa M et al. Fungicidal activity of five cathelicidin peptides against clinically isolated yeasts. J Antimicrob

Chemother. 2006;58:950.

Lopez-Garcia B et al. Expression and potential function of cathelicidin antimicrobial peptides in dermatophytosis

and tinea versicolor. J Antimicrob Chemother. 2006;57:877.

Pachl J et al. A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in

combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis. Clin

Infect Dis. 2006;42:1404.

Odom RB et al. A multicenter, placebo-controlled, doubleblind study of intermittent therapy with itraconazole for

the treatment ofonychomycosis ofthe fingernail. J Am Acad Dermatol. 1997;36:231.

Havu V et al. A double-blind, randomized study comparing itraconazole pulse therapy with continuous dosing for

the treatment of toenail onychomycosis. Br J Dermatol. 1997;36:230.

Scher RK et al. Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual

onychomycosis of the toenail. J Am Acad Dermatol. 1998;38:S77.

Ling MR et al. Once-weekly fluconazole (450 mg) for 4, 6, or 9 months of treatment for distal subungual

onychomycosis of the toenail. J Am Acad Dermatol. 1998;38:S95.

Gupta AK. Single-blind, randomized, prospective study of sequential itraconazole and terbinafine pulse compared

with terbinafine pulse for the treatment of toenail ony chomycosis. J Am Acad Dermatol. 2001;44:485.

Kauffman CA. Endemic mycoses: blastomycosis, histoplasmosis, and sporotrichosis. Infect Dis Clin North Am.

2006;20:645.

Breeling JL, Weinstein L. Pulmonary sporotrichosis treated with itraconazole. Chest. 1993;103:313.

McGinnis MR et al. Sporothrix schenckii sensitivity to voriconazole, itraconazole, and amphotericin B. Med

Mycol. 2001;39:369.

Chapman SW et al. Comparative evaluation of the efficacy and safety of two doses of terbinafine (500 and 1000

mg day(-1)) in the treatment of cutaneous or lymphocutaneous sporotrichosis. Mycoses. 2004;47:62.

Wishart JM. The influence of food on the pharmacokinetics of itraconazole in patients with superficial fungal

infection. J Am Acad Dermatol. 1987:220.

Barone JA et al. Food interaction and steady state pharmacokinetics of itraconazole capsules in healthy male

volunteers. Antimicrob Agents Chemother. 1993;37:778.

Smith D et al. The pharmacokinetics of oral itraconazole in AIDS patients. J Pharm Pharmacol. 1992;44:618.

Zhao Q et al. Pharmacokinetics of intravenous itraconazole followed by itraconazole oralsolution in patients with

human immunodeficiency virus infection. J Clin Pharmacol. 2001;41:1319.

Sporonox (itraconazole) oralsuspension [package insert]. Piscataway, NJ:Janssen Pharmaceuticals; 1998.

Tatro DS, ed. Drug Interaction Facts. St. Louis, MO: Wolters Kluwer. http://www.wolterskluwercdi.com/.

Accessed June 20, 2017.

Kraft WK et al. Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric

pH and gastric motility in healthy subjects. Antimicrob Agents Chemother. 2014;58:4020.

Krishna G et al. A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate

rising single-and multiple-dose pharmacokinetics and safety in healthy volunteers. J Antimicrob Chemother.

2012:67;2725.

McKeage K. Posaconazole: a review of the gastro-resistant tablet and intravenous solution in invasive fungal

infections. Drugs. 2015;75:397.

Ashbee HR et al. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for

Medical Mycology. J Antimicrob Chemother. 2014;69:1142.

Smith J, Andes D. Therapeutic drug monitoring of antifungals: pharmacokinetic and pharmacodynamic

considerations. Ther Drug Monit. 2008;30:167.

Arendrup MC et al. Invasive fungal infections in the paediatric and neonatal population: diagnostics and

management issues. Clin Microbiol Infect. 2009;15:613.

Pappas PG et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious

Diseases Society of America. Clin Infect Dis. 2009;48(5):503.

Woods GL, Gutierrez Y. Diagnostic Pathology of Infectious Diseases. Philadelphia, PA: Lea & Febiger; 1993.

Arrington JB. Bacteria, fungi, and other microorganisms. In: Prophet EB et al, eds. Laboratory Methods in

Histotechnology. Armed Forces Institute of Pathology. Washington, DC: American Registry of Pathology;

1992:203.

Jensen HE et al. The use of immunohistochemistry to improve sensitivity and specificity in the diagnosis of

systemic mycoses in patients with haematologic malignancies. J Pathol. 1997;181:100.

LischewskiA et al. Detection and identification of Candida species in experimentally infected tissue and human

blood by rRNA-specific fluorescent in-situ hybridization. J Clin Microbiol. 1997;35:2943.

Shepard JR et al. Multicenter evaluation of the Candida albicans/Candida glabrata peptide nucleic acid fluorescent

in situ hybridization method for simultaneous dual-color identification of C. albicans and C. glabrata directly

from blood culture bottles. J Clin Microbiol. 2008;46:50.

Coovadia YJ, Solwa Z. Sensitivity and specificity of a latex agglutination test for detection of cryptococcal antigen

in meningitis. S Afr Med J. 1987;71:510.

Koshi G et al. Coagglutination (CoA) test for the rapid diagnosis of cryptococcal meningitis. J Med Microbiol.

1989;29:189.

Wheat LJ et al. Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in

serum and urine specimens. N EnglJ Med. 1986;314:83.

Pasqualotto AC, Sukiennik TC. Beta-glucan in the diagnosis of invasive fungal disease. Clin Infect Dis.

2008;47:292.

Crislip MA, Edwards JE, Jr. Candidiasis [published correction appears in Infect Dis Clin North Am. 1989;3:ix].

Infect Dis Clin North Am. 1989;2:103.

Wheat LJ. Systemic fungal infections: diagnosis and treatment. I. Histoplasmosis. Infect Dis Clin North Am.

1988;2:841.

Gudiaugsson O et al. Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis. 2003;37:1172.

Patel M et al. Initial management of candidemia at an academic medical center: evaluation of the IDSA

guidelines. Diagn Microbiol Infect Dis. 2005;52:26.

Morrell M et al. Delaying the empiric treatment of candida bloodstream infection until positive blood culture

results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother. 2005;49:3640.

Walsh TH et al. All catheter-related candidemia is not the same: assessment of the balance between the risks and

.

.

.

benefit of removal of vascular catheters. Clin Infect Dis. 2002;34:600.

Nucci M, Anaissie E. Should vascular catheters be removed from all patients with candidemia? An evidencebased review. Clin Infect Dis. 2002;34:591.

Mora-Duarte J et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med.

2002;347:2020.

Rex JH et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in

patients without neutropenia. N EnglJ Med. 1994;331:1325.

Rex JH et al. Antifungalsusceptibility testing of isolates from a randomized, multicenter trial of fluconazole versus

amphotericin B as treatment of nonneutropenic patients with candidemia. NIAID Mycoses Study Group and the

Candidemia Study Group. Antimicrob Agents Chemother. 1995;39:40.

Christiansen KJ et al. Distribution and activity of amphotericin B in humans. J Infect Dis. 1985;152:1037.

Collette N et al. Tissue concentrations and bioactivity of amphotericin B in cancer patients treated with

amphotericin B-deoxycholate. Antimicrob Agents Chemother. 1989;33:362.

Rex JH et al. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo vs. fluconazole

plus amphotericin B as therapy of candidemia and its consequences in nonneutropenic patients. Clin Infect Dis.

2003;36:1221.

Cappelletty D, Eiselstein-McKitrick K. The echinocandins. Pharmacotherapy. 2007;27:369.

Pappas PG et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive

candidiasis [published correction appears in Clin Infect Dis. 2008;47:302]. Clin Infect Dis. 2007;45:883.

Abele-Horn M et al. A randomized study comparing fluconazole with amphotericin B/5-flucytosine for the

treatment of systemic Candida infections in intensive care patients. Infection. 1996;2496:426.

Wingard JR. Infections due to resistant Candida species in patients with cancer who are receiving

chromotherapy. Clin Infect Dis. 1994;19(Suppl.1):S49.

Cleary JD et al. Reduced Candida glabrata susceptibility secondary to an FKS1 mutation developed during

candidemia treatment. Antimicrob Agents Chemother. 2008;52:2263.

Cleary JD, Wasan K. Amphotericin B: a new look at cellular binding. Open Antimicrobial Agents. 2011;3:30.

Daneshmend TK, Warnock DW. Clinical pharmacokinetics of systemic antifungal drugs. Clin Pharmacokinet.

1983;8:17.

Ernst EJ et al. Postantifungal effects of echinocandin, azole, and polyene antifungal agents against Candida

albicans and Cryptococcusneoformans. Antimicrob Agents Chemother. 2000;44:1108.

Gallis HA et al. Amphotericin B: 30 years of clinical experience. Rev Infect Dis. 1990;12:308.

Cleary JD et al. Inhibition of interleukin 1 release from endotoxin- or amphotericin B-stimulated monocytes.

Antimicrob Agents Chemother. 1992;36:977.

Cleary JD et al. Pharmacologic modulation of prostaglandin E2 (PGE2) production by bacterial endotoxin (LPSat

31st Annual Interscience Conference on Antimicrobial Agents and Chemotherapy Meeting); September 19,

1991; Chicago, IL.

Tynes BS et al. Reducing amphotericin B reactions. Am Rev Respir Dis. 1963;87:264.

Hoeprich PD. Clinical use of amphotericin B and derivative: lore, mystique, and fact. Clin Infect Dis.

1992;14:S114.

Gigliotti F et al. Induction of prostaglandin synthesis as the mechanism responsible for the chills and fever

produced by infusing amphotericin B. J Infect Dis. 1987;156:784.

Burks LC et al. Meperidine for the treatment of shaking chills and fever. Arch Intern Med. 1980;140:483.

Cleary JD et al. Effect of infusion rate on amphotericin B-associated febrile reactions. Drug Intell Clin Pharm.

1988;22:769.

Oldfield EC III et al. Randomized, double-blind trial of 1- versus 4-hour amphotericin B infusion durations.

Antimicrob Agents Chemother. 1990;34:1402.

Cleary JD et al. Amphotericin B overdose in pediatric patients with associated cardiac arrest. Ann Pharmacother.

1993;27:715.

Branch RA. Prevention of amphotericin B-induced renal impairment: a review on the use of sodium

supplementation. Arch Intern Med. 1988;148:2389.

Fisher MA et al. Risk factors for amphotericin B-associated nephrotoxicity. Am J Med. 1989;87:547.

Lin AC et al. Amphotericin B blunts erythropoietin response to anemia. J Infect Dis. 1990;161:348.

Bennett WM et al. Drug prescribing in renal failure: dosing guidelines for adults. Am J Kidney Dis. 1983;3:155.

Abel S et al. Pharmacokinetics, safety and tolerance of voriconazole in renally impaired subjects. Clin Drug

Investig. 2008;28:409.

.

.

.

106.

107.

108.

109.

110.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Oude Lashof AM et al. Safety and tolerability of voriconazole in patients with baseline renal insufficiency and

candidemia. Antimicrob Agents Chemother. 2012;56:3133.

Grant SM, Clissold SP. Fluconazole: a review of its pharmacodynamic and pharmacokinetic properties and

therapeutic potential in superficial and systemic mycoses [published correction appears in Drugs. 1990;40:862].

Drugs. 1990;39:877.

GraybillJR. New antifungal agents. Eur J Clin Microbiol Infect Dis. 1989;8:402.

Van Cauteren H et al. Itraconazole pharmacologic studies in animals and humans. Rev Infect Dis. 1987;9(Suppl

1):S43.

Hardin TC et al. Pharmacokinetics of itraconazole following oral administration to normal volunteers. Antimicrob

Agents Chemother. 1988;32:1310.

Schwartz S et al. Successful treatment of cerebral aspergillosis with a novel triazole (voriconazole) in a patient

with acute leukaemia. Br J Haematol. 1997;97:663.

Grasela DM et al. Ravuconazole: multiple ascending oral dose study in healthy subjects. Paper presented at 42nd

Interscience Conference on Antimicrobial Agents Chemotherapy. San Diego, CA; September 27, 2002.

Ullmann AJ et al. Pharmacokinetics, safety, and efficacy of posaconazole in patients with persistent febrile

neutropenia or refractory invasive fungal infection. Antimicrob Agents Chemother. 2006;50:658.

Theuretzbacher U et al. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet.

2006;45:649.

Wong-Beringer A et al. Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clin Infect Dis.

1998;27:603.

Cleary JD. Amphotericin B formulated in a lipid emulsion. Ann Pharmacother. 1996;30:409.

Anaissie EJ et al. Amphotericin B lipid complex versus amphotericin B (AMB) for treatment of hematogenous

and invasive candidiasis: a prospective, randomized, multicenter trial [abstract LM21]. In: Program and

Abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC:

American Society for Microbiology; 1995:330.

Ostrosky-Zeichner L et al. MSG-01: a randomized, double-blind, placebo-controlled trial of caspofungin

prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting.

Clin Infect Dis. 2014;58:1219.

Pelz RK et al. Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients. Ann Surg. 2001;233:542.

Ezdinli EZ et al. Oral amphotericin for candidiasis in patients with hematologic neoplasms. JAMA. 1979;242:258.

DeGregorio MW et al. Candida infections in patients with acute leukemia: ineffectiveness of nystatin prophylaxis

and relationship between oropharyngeal and systemic candidiasis. Cancer. 1982;50:2780.

Cuttner J et al. Clotrimazole treatment for prevention of oral candidiasis in patients with acute leukemia

undergoing chemotherapy. Am J Med. 1986;81:771.

Yeo E et al. Prophylaxis of oropharyngeal candidiasis with clotrimazole. J Clin Oncol. 1985;3:1668.

Ang BS et al. Candidemia from a urinary tract source: microbiological aspects and clinical significance. Clin

Infect Dis. 1993;17:662.

Fong IW et al. Fungicidal effect of amphotericin B in urine: in vitro study to assess feasibility of bladder washout

for localization of site of candiduria. Antimicrob Agents Chemother. 1991;35:1856.

Vergis EN et al. A randomized controlled trial of oral fluconazole and local amphotericin B for treatment of

Candida funguria in hospitalized patients. Paper presented at: Infectious Diseases Society Meeting; September

14, 1997; San Francisco, CA.

Jacobs LG et al. Oral fluconazole compared with bladder irrigation with amphotericin B for treatment of fungal

urinary tract infections in elderly patients. Clin Infect Dis. 1996;22:30.

Fujihiro S et al. Flucytosine in the treatment of urinary fungal infections: clinical efficacy and background factors.

Jpn J Antibiot. 1991;44:14.

GraybillJR et al. Ketoconazole therapy for fungal urinary tract infections. J Urol. 1983;29:68.

Ikemoto H. A clinical study of fluconazole for the treatment of deep mycoses. Diag Microbiol Infect Dis.

1989;12(Suppl 4):239S.

Lagrotteria D et al. Treatment of candiduria with micafungin: a case series. Can J Infect Dis Med. 2007;18:149.

Parker JD et al. A decade of experience with blastomycosis and its treatment with amphotericin B. Am Rev

Respir Dis. 1969;99:895.

National Institute of Allergy and Infectious Diseases Mycoses Study Group. Treatment of blastomycosis and

histoplasmosis with ketoconazole: results of a prospective, randomized clinical trial. Ann Intern Med.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

157.

.

.

160.

161.

.

.

1985;103:861.

Bradsher RW. Blastomycosis in systemic fungal infections: diagnosis and treatment I. Infect Dis Clin North Am.

1988;2:877.

Pappas PG. Treatment of blastomycosis with higher doses of fluconazole. Clin Infect Dis. 1997;25:200.

Chapman SW. Blastomyces dermatitidis. In: Mandell GL et al, eds. Principles and Practice of Infectious

Diseases. New York, NY: Churchill Livingstone; 1990:1999.

US Food and Drug Administration. Fed Reg. 1980;44:37434.

King CT et al. Antifungal therapy during pregnancy. Clin Infect Dis. 1998;27:115.

Mølgaard-Nielsen D et al. Use of oral fluconazole during pregnancy and the risk of birth defects. N EnglJ Med.

2013;369:830.

Pursley TJ. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis. 1996;22:336.

Wheat LJ. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the

Infectious Diseases Society of America. Clin Infect Dis. 2007;45:807.

Johnson PC et al. Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B

for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med. 2002;137:105.

Cleary JD et al. Association between Histoplasma exposure and stroke. J Stroke Cerebrovasc Dis. 2008;17:312.

Pont A et al. Ketoconazole blocks adrenalsteroid synthesis. Ann Intern Med. 1982;97:370.

Lyman CA, Walsh TJ. Systemically administered antifungal agents. Drugs. 1992;44:9.

Honig PK et al. Terfenadine-ketoconazole interactions: pharmacokinetic and electrocardiographic consequences

[published correction appears in JAMA. 1993;269:2088]. JAMA. 1993;269:1513.

Glynn AM et al. Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion. Clin

Pharmacol Ther. 1986;39:654.

Brüggemann RJ et al. Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other

coadministered agents. Clin Infect Dis. 2009;48:1441.

Saubolle MA et al. Epidemiologic, clinical, and diagnostic aspects of coccidioidomycosis. J Clin Microbiol.

2007;45:26.

Peter JB. Use and Interpretation of Tests in Medical Microbiology. 3rd ed. Santa Monica, CA: Specialty

Laboratories; 1992.

GalgianiJN et al. New serologic tests for early detection of coccidioidomycosis. J Infect Dis. 1991;163:671.

Vermes A et al. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and

drug interactions. J Antimicrob Chemother. 2000;46:171.

Brammer KW et al. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis.

1990;12(Suppl 3):S318.

Phillips P et al. Tolerance to and efficacy of itraconazole in treatment of systemic mycoses: preliminary results.

Rev Infect Dis. 1987;9(Suppl1):S87.

Dodds AE et al. Comparative pharmacokinetics of voriconazole administered orally as either crushed or whole

tablets. Antimicrob Agents Chemother. 2007;51:877.

Bowden R et al. A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus

amphotericin B for treatment of invasive aspergillosis in immunocompromised patients. Clin Infect Dis.

2002;35:359.

Galgiani JN et al. Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal

coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group. Ann Intern Med. 2000;133:676.

Ratcheson RA, Ommaya AK. Experience with the subcutaneous cerebrospinal fluid reservoir: a preliminary

report of 60 cases. N EnglJ Med. 1968;279:1.

Harrison HR et al. Amphotericin B and imidazole therapy for coccidioidal meningitis in children. Pediatr Infect

Dis. 1983;2:216.

Witorsch P et al. Intraventricular administration of amphotericin B. JAMA. 1965;194:109.

Sung JP et al. Intravenous and intrathecal miconazole therapy for systemic mycoses. West J Med. 1977;126:5.

Fisher JF, Dewald J. Parkinsonism associated with intraventricular amphotericin B. J Antimicrob Chemother.

1983;12:97.

Winn RE et al. Acute toxic delirium: neurotoxicity of intrathecal administration of amphotericin B. Arch Intern

Med. 1979;139:706.

Haber RW et al. Neurological manifestations after amphotericin B therapy. BMJ. 1962;1:230.

Carnevale NT et al. Amphotericin-induced myelopathy. Arch Intern Med. 1980;140:1189.

Anaissie EJ et al. Management of invasive candidal infections: results of a prospective, randomized,

.

.

.

.

.

.

.

.

172.

.

.

.

176.

.

.

.

.

.

.

.

184.

.

.

.

multicenterstudy of fluconazole versus amphotericin B and review of the literature. Clin Infect Dis.

1996;23:964.

Prentice HG et al. A randomized comparison of liposomal versus conventional amphotericin B for the treatment

of pyrexia of unknown origin in neutropenic patients. Br J Haematol. 1997;98:711.

Walsh TJ et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy inpatients with

persistent fever and neutropenia. N EnglJ Med. 2004;351:1391.

Boogaerts M et al. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as

empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broadspectrum antibacterial therapy. A randomized, controlled trial. Ann Intern Med. 2001;135:412.

Walsh TJ et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in

patients with neutropenia and persistent fever [published correction appears in N Engl J Med. 2007;356:760]. N

EnglJ Med. 2002;346:225.

Pagano L et al. Fungal infections in recipients of hematopoietic stem cell transplants: results of the SEIFEM B2004 study [—] Sorveglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne. Clin Infect Dis.

2007;45:1161.

Caillot D et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early

thoracic computed tomographic scan and surgery. J Clin Oncol. 1997;15:139.

Nucci M et al. Early diagnosis of invasive pulmonary aspergillosis in hematologic patients: an opportunity to

improve the outcome. Haematologica. 2013;98:1657.

Denning DW et al. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the

treatment of acute invasive aspergillosis. J Infect. 2006;53:337.

Walsh TJ et al. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in

patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study.

Antimicrob Agents Chemother. 2001;45:3487.

Maertens J et al. Multicenter, noncomparative study of caspofungin in combination with other antifungals as

salvage therapy in adults with invasive aspergillosis. Cancer. 2006;107:2888.

Marr KA et al. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis. 2004;39:797.

Ellis M et al. An EORTC international multicenter randomized trial (EORTC number 19923) comparing two

dosages of liposomal amphotericin B for treatment of invasive aspergillosis. Clin Infect Dis. 1998;27:1406.

Herbrecht R et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J

Med. 2002;347:408.

Segal BH et al. Prevention and early treatment of invasive fungal infection in patients with cancer and

neutropenia and in stem cell transplant recipients in the era of newer broad-spectrum antifungal agents and

diagnostic adjuncts. Clin Infect Dis. 2007;44:402.

Maertens J et al. A phase 3 randomized, double-blind trial evaluating isavuconazole versus voriconazole for the

primary treatment of invasive fungal infections caused by Aspergillus spp. and other filamentous fungi.

Barcelona, Spain: European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); May 13,

2004.

Walsh TJ et al. Treatment of Aspergillus: clinical practice guidelines of the infectious diseases society of

America. Clin Infect Dis. 2008;46:327.

Larsen RA et al. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in

AIDS: a randomized trial. Ann Intern Med. 1990;113:183.

Bennett JE et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of

cryptococcal meningitis. N EnglJ Med. 1979;301:126.

Perfect JR 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.

Saag MS et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS associated

cryptococcal meningitis. N EnglJ Med. 1992;326:83.

Day JN et al. Combination antifungal therapy for cryptococcal meningitis. N EnglJ Med. 2013;368:1291.

Hibberd PL, Rubin RH. Clinical aspects of fungal infection in organ transplant recipients. Clin Infect Dis.

1994;19:S33.

Newton PN et al. A randomized, double-blind, placebo controlled trial of acetazolamide for the treatment of

elevated intracranial pressure in cryptococcal meningitis. Clin Infect Dis. 2002;35:769.

Kauffman CA, Frame PT. Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrob Agents

Chemother. 1977;11:244.

p. 1644

Herpes simplex virus (HSV) encephalitis is associated with significant

morbidity and mortality. Intravenous acyclovir for a 21-day period is the

therapy of choice.

Case 79-1 (Questions 2, 4)

Neonatal herpes can present with mucocutaneous, ocular infection, as

well as encephalitis and disseminated HSV infection. Transmission can

be acquired during the first trimester of pregnancy or during vaginal

delivery in an infected mother.

Case 79-2 (Questions 1, 2)

Herpes labialis is the most common oral-facial HSV infection and is

usually self-limiting in an immunocompetent host. Patients who are

immunocompromised must be treated with antiviral therapy, primarily

oral or intravenous acyclovir or oral valacyclovir.

Case 79-3 (Question 1),

Case 79-4 (Question 1)

Individuals with progressive varicella, those with extracutaneous

complications, or those at high risk for developing complications to

varicella infection benefit from antiviral therapy.

Case 79-7 (Question 1),

Case 79-8 (Question 1)

The goal of pharmacotherapy of herpes zoster is to reduce pain and

duration of rash and to prevent the development of postherpetic

neuralgia (PHN). These outcomes can be accomplished with the use of

oral acyclovir, famciclovir, or valacyclovir. For the treatment of PHN,

topical capsaicin gels, creams and patches, topical lidocaine patches,

and oral gabapentin and pregabalin are efficacious.

Case 79-9 (Question 1)

Neuraminidase inhibitors, such as zanamivir, oseltamivir, and peramivir,

are indicated for the treatment of influenza if used within 48 hours after

the onset of symptoms. Zanamivir is administered by oral inhalation with

bronchospasm the most common adverse drug reaction. Oseltamivir is

administered orally, with nausea, vomiting, and headache as common

side effects. Peramivir is administered intravenously and has been

associated with hypersensitivity reactions, such as Steven–Johnson

syndrome.

Case 79-11 (Question 2)

Influenza vaccination is the most effective mechanism to prevent the flu.

However, certain high-risk populations may require additional

prophylaxis with oseltamivir or zanamivir.

Case 79-10 (Question 2)

Infants at high risk for severe disease caused by respiratory syncytial Case 79-13 (Questions 1, 2)

virus (RSV) should receive monthly intramuscular injections of

palivizumab for a total of five doses during RSV season.

West Nile virus can cause disease ranging from a febrile infection to

encephalitis. Treatment is supportive; however, ribavirin and

interferon-α-2b have been tried in this patient population. Clinical trials

evaluating the use of immunoglobulin, monoclonal antibodies, and

vaccines are ongoing.

Case 79-14 (Questions 1, 2)

The common cold is the most prevalent viral infection. Numerous

pathogens can cause this respiratory infection, including rhinovirus,

coronavirus, parainfluenza, RSV, adenovirus, and enterovirus. There are

currently no products that have been conclusively shown to prevent or

treat the common cold.

Case 79-15 (Question 1)

p. 1645

p. 1646

Viral infections are common causes of human disease. An estimated 60% of illnesses

in developed countries result from viruses, compared with only 15% from bacteria.

These include the common cold, chickenpox, measles, mumps, influenza, bronchitis,

gastroenteritis, hepatitis, poliomyelitis, rabies, and numerous diseases caused by the

herpesvirus. Upper respiratory tract infections, such as the common cold or influenza,

are among the most common reasons for visits to a health care professional.

1 Most of

these patients have a self-limiting illness; however, certain viral infections, such as

influenza, can cause significant mortality, particularly in the elderly. During the

worldwide Spanish influenza epidemic of 1918 to 1920, 20 to 100 million people

died.

2 Although influenza vaccines reduce the morbidity and mortality associated

with this disease, for many other potentially severe viral infections, including herpes

encephalitis and neonatal herpes, no vaccine is available.

Substantial progress has been made in antiviral chemotherapy as a result of

advances in molecular virology and genetic engineering. Antiviral agents can be

designed to inhibit functions specific to viruses, which maximizes their therapeutic

benefits and minimizes adverse effects.

Current technology also permits rapid diagnosis of viral diseases. It is now

possible to make a specific diagnosis of several viral illnesses within hours to a few

days; previously, a specific diagnosis often took days to months. These improved

diagnostics have facilitated rapid selection of an appropriate antiviral drug.

This chapter describes the etiology, pathogenesis, and treatment of common viral

infections. Specific case presentations illustrate the optimal use of antiviral drugs in

patients with viral infections.

HERPES SIMPLEX VIRUS INFECTIONS

Herpes viruses are responsible for a broad spectrum of diseases including acute lifethreatening illness (herpes encephalitis and neonatal herpes), as well as more

chronic, recurrent infection (genital herpes). Antivirals significantly decrease the

morbidity and mortality in most of these infections.

3

Herpes Encephalitis

Herpes simplex virus (HSV) encephalitis is the most common sporadic viral

infection of the central nervous system (CNS). HSV encephalitis occurs in up to

500,000 people yearly, although this may be an underestimate owing to difficulties in

diagnosis. It typically occurs in two populations, those 6 months to 20 years of age

and those older than 50 years. It is characterized by the acute onset of fever,

headache, decreased consciousness, and seizures. Any child with fever and altered

behavior should be evaluated for HSV encephalitis. Without treatment, mortality

approaches 70% and some morbidity is evident in 97% of survivors. Only 2.5% of

patients recover sufficiently to lead normal lives.

3

Herpes simplex virus type 1 (HSV-1) is the etiologic agent in most patients with

herpes encephalitis, but herpes simplex virus type 2 (HSV-2) is more common in

newborns. The infection may be localized to the brain or involve cutaneous and

mucous membranes. Although any area of the brain can be involved, the orbital

region of the frontal lobes and the temporal lobes are most often affected.

4

Herpes encephalitis is often difficult to diagnose. A computed tomography (CT)

scan is usually indicated to rule out other conditions, such as brain abscess or other

space-occupying lesions. The CT or radionuclide scans may be unremarkable early

in the course of the disease.

Cerebrospinal fluid (CSF) examination usually reveals pleocytosis (predominately

lymphocytes) with 50 to 2,000 white blood cells (WBCs)/mcL. Polymorphonuclear

leukocytosis and red blood cells (RBCs) may also be seen. Many patients have an

elevated protein level in the CSF (median, 80 mg/dL; normal values differ per age,

e.g., if ≥6 months, 15–45 mg/dL).

The electroencephalogram (EEG) is the most sensitive but least specific test.

There are usually CT or brain scan abnormalities, but these may take a day or two

longer to appear. The EEG, CT, and brain scan findings compatible with HSV

encephalitis can be mimicked by other conditions, and a brain biopsy is required to

clearly establish the diagnosis. Rapid diagnosis of herpes encephalitis by a

polymerase chain reaction (PCR) assay of HSV DNA in the CSF is available at most

medical centers. This is a highly sensitive, specific, and rapid method for diagnosing

herpes encephalitis.

5

CLINICAL PRESENTATION

CASE 79-1

QUESTION 1: R.F., a 7-year-old boy weighing 20 kg, was seen in the emergency department (ED) after a

seizure. For the previous 3 days, R.F. had decreased appetite, headache, and fever (101°F–102°F), and was

lethargic and disoriented. His leukocyte count was 13,000/mcL with a shift to the left. Ceftriaxone (50 mg/kg

intravenously [IV] every 12 hours) and dexamethasone (0.15 mg/kg IV every 6 hours) were initiated for

presumed bacterial meningitis. Phenobarbital (5 mg/kg IV every 24 hours) was given for seizure control. The

CSF was normal, and no bacteria could be cultured. Acyclovir 20 mg/kg IV every 8 hours was started

immediately. A PCR analysis of HSV-1 was positive. What findings in R.F. are consistent with the diagnosis of

herpes encephalitis?

Fever, headache, lethargy, and disorientation are common features of herpes

encephalitis. As illustrated by R.F., the CSF examination can be normal in some

patients. A negative CSF culture suggests the absence of a bacterial infection.

6

However, the positive HSV-1 DNA by PCR analysis confirms the diagnosis of

herpes encephalitis.

TREATMENT: ACYCLOVIR

CASE 79-1, QUESTION 2: What is the treatment of choice for R.F.’s herpes encephalitis?

Two studies comparing acyclovir and vidarabine (no longer marketed in the

United States) have demonstrated that IV acyclovir (10 mg/kg every 8 hours for 10

days) is the treatment of choice in patients with herpes encephalitis.

7,8 The 12-month

all-cause mortality was 25% in the acyclovir-treated group and 59% in the

vidarabine-treated group. Notably, nearly one-third of the acyclovir-treated patients

returned to normal life, compared with only 12% of those treated with vidarabine.

9

Acyclovir is the treatment of choice for R.F. because it has been shown to

decrease morbidity in patients with herpes encephalitis. Acyclovir should be started

as soon as HSV encephalitis is suspected because early initiation of therapy is

associated with improved outcome. Therapy should be continued for at least 21

days.

10 The role of corticosteroids in the treatment of herpes encephalitis is not well

defined. One small, nonrandomized trial found that corticosteroid therapy, in

combination with IV acyclovir, was associated with an improved outcome.

11

However, prospective, randomized trials are needed before routine use of

corticosteroids can be recommended.

12 Acyclovir-resistant herpes

p. 1646

p. 1647

is not an important consideration in the management of herpes encephalitis in most

patients.

Adverse Effects

CASE 79-1, QUESTION 3: What adverse effects can occur with IV acyclovir therapy in R.F.? How should

these be monitored, and how can they be minimized?

Acyclovir is a relatively safe drug, but renal toxicity associated with IV acyclovir

is well described (Table 79-1). Blood urea nitrogen (BUN) and serum creatinine

(SCr) levels can increase in 5% to 10% of patients; however, these changes are

generally reversible. Acyclovir is relatively insoluble: maximal urine solubility at

37°C is 1.3 mg/mL. Consequently, the mechanism of acyclovir-associated renal

disease is a transient crystal nephropathy, which may occur at high acyclovir

concentrations.

9

Other common adverse effects include gastrointestinal (GI) complaints, such as

nausea and vomiting and, less commonly, neurologic disturbances, including lethargy,

tremors, confusion, hallucinations, and seizures.

9,25 Neurotoxicity appears to be more

common in patients with impaired renal function and is reversible. Finally, IV

acyclovir can cause phlebitis and pain at the injection site.

9 This complication can be

minimized by administering acyclovir at a concentration of 5 mg/mL (maximum, 7

mg/mL).

25