Chapter 126 : Antifungal Agents

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Antifungal Agents , Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816728/9781555814632_Chap126-1.gif /docserver/preview/fulltext/10.1128/9781555816728/9781555814632_Chap126-2.gif


This chapter reviews the four major families of antifungal drugs that are available for systemic administration: the allylamines, the azoles, the echinocandins, and the polyenes. It discusses the characteristics of other agents that can be used for the oral or parenteral treatment of superficial, subcutaneous, or systemic fungal infections. The allylamines are a group of synthetic antifungal compounds effective in the topical and oral treatment of dermatophytoses. The azoles constitute a large group of synthetic agents containing many compounds that are effective in the topical treatment of dermatophyte infections and superficial forms of candidiasis. The activity is essentially fungistatic, although some of the newer triazoles can exert fungicidal effects against some mold species at the concentrations achieved with recommended dosages. Three echinocandins have been approved for the treatment of serious fungal infections: anidulafungin, caspofungin, and micafungin. Acquired resistance to echinocandins is rare at present, but resistant strains of several spp. have been recovered from patients failing caspofungin treatment. The echinocandins do not interact with the human hepatic cytochrome P-450 system, and their use has been associated with very few significant drug interactions. The polyenes bind to sterols, principally ergosterol, in the membranes of susceptible fungal cells causing impairment of membrane barrier function, leakage of cell constituents, metabolic disruption, and cell death. As more compounds have become licensed, the number of novel antifungal drugs entering preclinical development appears to have diminished.

Citation: Warnock D. 2011. Antifungal Agents , p 1995-2007. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch126

Key Concept Ranking

Antifungal Agents
Fungal Infections
Fungal Proteins
Antifungal Drugs
Systemic Fungal Infections
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


1. Almyroudis, N. G.,, D. A. Sutton,, A. W. Fothergill,, M. G. Rinaldi,, and S. Kusne. 2007. In vitro susceptibilities of 217 clinical isolates of zygomycetes to conventional and new antifungal agents. Antimicrob. Agents Chemother. 51:25872590.
2. Andes, D.,, A. Pascual,, and O. Marchetti. 2009. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob. Agents Chemother. 53:2434.
3. Balajee, S. A.,, J. L. Gribskov,, E. Hanley,, D. Nickle,, and K. A. Marr. 2005. Aspergillus lentulus, sp. nov., a new sibling species of A. fumigatus. Eukaryot. Cell 4:625632.
4. Balani, S. K.,, X. Xu,, B. H. Arison,, M. V. Silva,, A. Gries,, F. A. DeLuna,, D. Cui,, P. H. Kari,, T. Ly,, C. E. Hop,, R. Singh,, M. A. Wallace,, D. C. Dean,, J. H. Lin,, P. G. Pearson,, and T. A. Baillie. 2000. Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine. Drug Metab. Dispos. 28:12741278.
5. Barchiesi, F.,, A. L. Colombo,, D. A. McGough,, A. W. Fothergill,, and M. G. Rinaldi. 1994. In vitro activity of itraconazole against fluconazole-susceptible and -resistant Candida albicans isolates from oral cavities of patients infected with human immunodeficiency virus. Antimicrob. Agents Chemother. 38:15301533.
6. Barone, J. A.,, B. L. Moskovitz,, J. Guarnieri,, A. E. Hassell,, J. L. Colaizzi,, R. H. Bierman,, and L. Jessen. 1998. Enhanced bioavailability of itraconazole in hydroxypropyl-β -cyclodextrin solution versus capsules in healthy volunteers. Antimicrob. Agents Chemother. 42:18621865.
7. Barrett, J. P.,, K. A. Vardulaki,, C. Conlon,, J. Cooke,, P. Daza-Ramirez,, E. G. Evans,, P. M. Hawkey,, R. Herbrecht,, D. I. Marks,, J. M. Moraleda,, G. R. Park,, S. J. Sen,, and C. Viscoli. 2003. A systematic review of the antifungal effectiveness and tolerability of amphotericin B formulations. Clin. Ther. 25:12951320.
8. Bartizal, K.,, C. J. Gill,, G. K. Abruzzo,, A. M. Flattery,, L. Kong,, P. M. Scott,, J. G. Smith,, C. E. Leighton,, A. Bouffard,, J. F. Dropinski,, and J. Balkovec. 1997. In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872). Antimicrob. Agents Chemother. 41:23262332.
9. Bekersky, I.,, R. N. Fielding,, D. E. Dressler,, J. W. Lee,, D. N. Buell,, and T. J. Walsh. 2002. Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans. Antimicrob. Agents Chemother. 46:828833.
10. Benjamin, D. K.,, T. Driscoll,, N. L. Seibel,, C. E. Gonzalez,, M. M. Roden,, R. Kilaru,, K. Clark,, J. A. Dowell,, J. Schranz,, and T. J. Walsh. 2006. Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infection. Antimicrob. Agents Chemother. 50:632638.
11. Borst, A.,, M. T. Raimer,, D. W. Warnock,, C. J. Morrison,, and B. A. Arthington-Skaggs. 2005. Rapid acquisition of stable azole resistance by Candida glabrata isolates obtained before the clinical introduction of fluconazole. Antimicrob. Agents Chemother. 49:783787.
12. Bowman, J. C.,, P. S. Hicks,, M. B. Kurtz,, H. Rosen,, D. M. Schmatz,, P. A. Liberator,, and C. M. Douglas. 2002. The antifungal echinocandin caspofungin acetate kills growing cells of Aspergillus fumigatus in vitro. Antimicrob. Agents Chemother. 46:30013012.
13. Brammer, K. W.,, A. J. Coakley,, S. G. Jezequel,, and M. H. Tarbit. 1991. The disposition and metabolism of [14C] fluconazole in humans. Drug Metab. Dispos. 19:764767.
14. Brandt, M. E.,, M. A. Pfaller,, R. A. Hajjeh,, R. J. Hamill,, P. G. Pappas,, A. L. Reingold,, D. Rimland,, and D. W. Warnock. 2001. Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998. Antimicrob. Agents Chemother. 45:30653069.
15. Brandt, M. E.,, and D. W. Warnock. 2003. Epidemiology, clinical manifestations, and therapy of infections caused by dematiaceous fungi. J. Chemother. 15(Suppl. 2):3647.
16. Caputo, R. 2003. Itraconazole (Sporanox) in superficial and systemic fungal infections. Expert Rev. Anti-Infect. Ther. 1:531542.
17. Cauwenbergh, G.,, H. Degreed,, J. Heykants,, R. Woestenborghs,, P. Van Rooy,, and K. Haeverans. 1988. Pharmacokinetic profile of orally administered itraconazole in human skin. J. Am. Acad. Dermatol. 18:263268.
18. Chapman, S. W.,, W. E. Dismukes,, L. A. Proia,, R. W. Bradsher,, P. G. Pappas,, M. G. Threlkeld,, and C. A. Kauffman. 2008. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 46:18011812.
19. Chapman, S. W.,, P. D. Rogers,, M. G. Rinaldi,, and D. C. Sullivan. 1998. Suceptibilities of clinical and laboratory isolates of Blastomyces dermatitidis to ketoconazole, itraconazole, and fluconazole. Antimicrob. Agents Chemother. 42:978980.
20. Cleary, J. D.,, G. Garcia-Effron,, S. W. Chapman,, and D. S. Perlin. 2008. Reduced Candida glabrata susceptibility secondary to an FKS1 mutation developed during candidemia treatment. Antimicrob. Agents Chemother. 52:22632265.
21. Courtney, R.,, S. Pai,, M. Laughlin,, J. Lim,, and V. Batra. 2003. Pharmacokinetics, safety and tolerability of oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob. Agents Chemother. 47:27882795.
22. Courtney, R.,, E. Radwanski,, J. Lim,, and M. Laughlin. 2004. Pharmacokinetics of posaconazole coadministered with antacid in fasting or nonfasting healthy men. Antimicrob. Agents Chemother. 48:804808.
23. Craven, P. C.,, J. R. Graybill,, J. H. Jorgensen,, W. E. Dismukes,, and B. E. Levine. 1983. High-dose ketoconazole for treatment of fungal infections of the central nervous system. Ann. Intern. Med. 98:160167.
24. Cross, S. A.,, and L. J. Scott. 2008. Micafungin: a review of its use in adults for the treatment of invasive and oesophageal candidiasis, and as prophylaxis against Candida infections. Drugs 68:22252255.
25. Cuenca-Estrella, M.,, A. Gomez-Lopez,, E. Mellado,, M. J. Buitrago,, A. Monzon,, and J. L. Rodriguez-Tudela. 2006. Head-to-head comparison of the activities of currently available antifungal agents against 3,378 Spanish clinical isolates of yeasts and filamentous fungi. Antimicrob. Agents Chemother. 50:917921.
26. Cutler, R. E.,, A. D. Blair,, and M. R. Kelly. 1978. Flucytosine kinetics in subjects with normal and impaired renal function. Clin. Pharmacol. Ther. 24:333342.
27. Damle, B. D.,, J. A. Dowell,, R. L. Walsky,, G. L. Weber,, M. Stogniew,, and P. B. Inskeep. 2009. In vitro and in vivo studies to characterize the clearance mechanism and potential cytochrome P450 interactions of anidulafungin. Antimicrob. Agents Chemother. 53:11491156.
28. Daneshmend, T. K.,, D. W. Warnock,, M. D. Ene,, E. M. Johnson,, G. Parker,, M. D. Richardson,, and C. J. Roberts. 1983. Multiple-dose pharmacokinetics of ketoconazole and their effects on antipyrine kinetics in man. J. Antimicrob. Chemother. 12:185188.
29. Daneshmend, T. K.,, D. W. Warnock,, M. D. Ene,, E. M. Johnson,, M. R. Potten,, M. D. Richardson,, and P. J. Williamson. 1984. Influence of food on the pharmacokinetics of ketoconazole. Antimicrob. Agents Chemother. 25:13.
30. Dannaoui, E.,, J. Meletiadis,, J. W. Mouton,, J. F. Meis,, and P. E. Verweij. 2003. In vitro susceptibilities of zygomycetes to conventional and new antifungals. J. Antimicrob. Chemother. 51:4552.
31. Dannaoui, E.,, F. Persat,, M. F. Monier,, E. Borel,, M. A. Piens,, and S. Picot. 1999. In-vitro susceptibility of Aspergillus spp. isolates to amphotericin B and itraconazole. J. Antimicrob. Chemother. 44:553555.
32. Darkes, M. J.,, L. J. Scott,, and K. L. Goa. 2003. Terbinafine: a review of its use in onychomycosis in adults. Am. J. Clin. Dermatol. 4:3965.
33. DeBeule, K.,, and J. Van Gestel. 2001. Pharmacology of itraconazole. Drugs 61(Suppl. 1):2737.
34. Debruyne, D.,, and J. P. Ryckelynck. 1993. Clinical pharmacokinetics of fluconazole. Clin. Pharmacokinet. 24:1027.
35. Diekema, D. J.,, S. A. Messer,, R. J. Hollis,, R. N. Jones,, and M. A. Pfaller. 2003. Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi. J. Clin. Microbiol. 41:36233626.
36. Douglas, C. M.,, J. A. D’Ippolito,, G. J. Shei,, M. Meinz,, J. Onishi,, J. A. Marrinan,, W. Li,, G. K. Abruzzo,, A. Flattery,, K. Bartizal,, A. Mitchell,, and M. B. Kurtz. 1997. Identification of the FSK1 gene of Candida albicans as the essential target of 1,3-β -d-glucan synthase inhibitors. Antimicrob. Agents Chemother. 41:24712479.
37. Dowell, J. A.,, W. Knebel,, T. Ludden,, M. Stogniew,, D. Krause,, and T. Henkel. 2004. Population pharmacokinetic analysis of anidulafungin, an echinocandin antifungal. J. Clin. Pharmacol. 44:590598.
38. Epstein, W. L.,, V. P. Shah,, and S. Riegelman. 1972. Griseofulvin levels in stratum corneum: study after oral administration. Arch. Dermatol. 106:344348.
39. Ezzet, F.,, D. Wexler,, R. Courtney,, G. Krishna,, J. Lim,, and M. Laughlin. 2005. Oral bioavailability of posaconazole in fasted healthy subjects: comparison between three regimens and basis for clinical dosage recommendations. Clin. Pharmacokinet. 44:211220.
40. Favre, B.,, B. Hofbauer,, K. S. Hildering,, and N. S. Ryder. 2003. Comparison of in vitro activities of 17 antifungal drugs against a panel of 20 dermatophytes by using a microdilution assay. J. Clin. Microbiol. 41:48174819.
41. Fernandez-Torres, B.,, A. J. Carrillo,, E. Martin,, A. del Palacio,, M. K. Moore,, A. Valverde,, M. Serrano,, and J. Guarro. 2001. In vitro activities of 10 antifungal drugs against 508 dermatophyte strains. Antimicrob. Agents Chemother. 45:25242528.
42. Galgiani, J. N.,, N. M. Ampel,, J. E. Blair,, A. Catanzaro,, R. H. Johnson,, D. A. Stevens,, and P. L. Williams. 2005. Coccidioidomycosis. Clin. Infect. Dis. 41:12171223.
43. Gallis, H. A.,, R. H. Drew,, and W. W. Pickard. 1990. Amphotericin B: 30 years of clinical experience. Rev. Infect. Dis. 12:308329.
44. Garcia-Effron, G.,, D. P. Kontoyiannis,, R. E. Lewis,, and D. S. Perlin. 2008. Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies. Antimicrob. Agents Chemother. 52:41814183.
45. Garcia-Effron, G.,, S. Lee,, S. Park,, J. D. Cleary,, and D. S. Perlin. 2009. Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-β -d- glucan synthase: implication for the existing susceptibility breakpoint. Antimicrob. Agents Chemother. 53:36903699.
46. Gilgado, F.,, C. Serena,, J. Cano,, J. Gene,, and J. Guarro. 2006. Antifungal susceptibilities of the species of the Pseudallescheria boydii complex. Antimicrob. Agents Chemother. 50:42114213.
47. Girmenia, C. 2009. New generation azole antifungals in clinical investigation. Expert Opin. Investig. Drugs 18:12791295.
48. Gonzalez, G. M.,, A. W. Fothergill,, D. A. Sutton,, M. G. Rinaldi,, and D. Loebenberg. 2005. In vitro activities of new and established triazoles against opportunistic filamentous and dimorphic fungi. Med. Mycol. 43:281284.
49. Goodwin, M. L.,, and R. H. Drew. 2008. Antifungal serum concentration monitoring: an update. J. Antimicrob. Chemother. 61:1725.
50. Goodwin, S. D.,, J. D. Cleary,, C. A. Walawander,, J. W. Taylor,, and T. H. Grasela. 1995. Pretreatment regimens for adverse events related to infusion of amphotericin B. Clin. Infect. Dis. 20:755761.
51. Groll, A. H.,, L. Wood,, M. Roden,, D. Mickiene,, C. C. Chiou,, E. Townley,, L. Dad,, S. C. Piscitelli,, and T. J. Walsh. 2002. Safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis. Antimicrob. Agents Chemother. 46:25542563.
52. Hahn, R. C.,, C. J. Fontes,, R. D. Batista,, and J. S. Hamdan. 2002. In vitro comparison of activities of terbinafine and itraconazole against Paracoccidioides brasiliensis. J. Clin. Microbiol. 40:28282831.
53. Hall, M.,, C. Monka,, P. Krupp,, and D. O’Sullivan. 1997. Safety of oral terbinafine: results of a postmarketing surveillance study in 25,884 patients. Arch. Dermatol. 133:12131219.
54. Haria, M.,, H. M. Bryson,, and K. L. Goa. 1996. Itraconazole: a reappraisal of its pharmacological properties and therapeutic use in the management of superficial fungal infections. Drugs 51:585620.
55. Hariprasad, S. M.,, W. F. Mieler,, E. R. Holz,, H. Gao,, J. E. Kim,, J. Chi,, and R. A. Prince. 2004. Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans. Arch. Ophthalmol. 122:4247.
56. Hebert, M. F.,, H. E. Smith,, T. C. Marbury,, S. K. Swan,, W. B. Smith,, R. W. Townsend,, D. Buell,, J. Keirns,, and I. Bekersky. 2005. Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction. J. Clin. Pharmacol. 45:11451152.
57. Heykants, J.,, A. Van Peer,, V. Van de Velde,, P. Van Rooy,, W. Meuldermans,, K. Lavrijsen,, R. Woestenborghs,, J. Van Cutsem,, and G. Cauwenbergh. 1989. The clinical pharmacokinetics of itraconazole: an overview. Mycoses 32(Suppl. 1):6787.
58. Hiemenz, J.,, P. Cagnoli,, D. Simpson,, S. Devine,, N. Chao,, J. Keirns,, W. Lau,, D. Facklam,, and D. Buell. 2005. Pharmacokinetics and maximum tolerated dose study of micafungin in combination with fluconazole versus fluconazole alone for prophylaxis of fungal infections in adult patients undergoing a bone marrow or peripheral stem cell transplant. Antimicrob. Agents Chemother. 49:13311336.
59. Hope, W. W.,, E. M. Billaud,, J. Lestner,, and D. W. Denning. 2008. Therapeutic drug monitoring for triazoles. Curr. Opin. Infect. Dis. 21:580586.
60. Hospenthal, D. R.,, and J. E. Bennett. 1998. Flucytosine monotherapy for cryptococcosis. Clin. Infect. Dis. 27:260264.
61. Hyland, R.,, B. C. Jones,, and D. A. Smith. 2003. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab. Dispos. 31:540547.
62. Janknegt, R.,, S. De Marie,, I. A. Bakker-Woudenberg,, and D. J. Crommelin. 1992. Liposomal and lipid formulations of amphotericin B: clinical pharmacokinetics. Clin. Pharmacokinet. 23:279291.
63. Johnson, E. M.,, A. Szekely,, and D. W. Warnock. 1998. In-vitro activity of voriconazole, itraconazole and amphotericin B against filamentous fungi. J. Antimicrob. Chemother. 42:741745.
64. Johnson, E. M.,, D. W. Warnock,, J. Luker,, S. R. Porter,, and C. Scully. 1995. Emergence of azole drug resistance in Candida species from HIV-infected patients receiving prolonged azole therapy for oral candidosis. J. Antimicrob. Chemother. 35:103114.
65. Kahn, J. N.,, G. Garcia-Effron,, M. J. Hsu,, S. Park,, K. A. Marr,, and D. S. Perlin. 2007. Acquired echinocandin resistance in a Candida krusei isolate due to modification of glucan synthase. Antimicrob. Agents Chemother. 51:18761878.
66. Kauffman, C. A.,, B. Bustamante,, S. W. Chapman,, and P. G. Pappas. 2007. Clinical practice guidelines for the management of sporotrichosis: 2007 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 45:12551265.
67. Kerridge, D. 1986. Mode of action of clinically important antifungal drugs. Adv. Microb. Physiol. 27:172.
68. Kontoyiannis, D. P.,, M. S. Lionakis,, R. E. Lewis,, G. Chamilos,, M. Healy,, C. Perego,, A. Safdar,, H. Kantarjian,, R. Champlin,, T. J. Walsh,, and I. I. Raad. 2005. Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. J. Infect. Dis. 191:13501360.
69. Kovarik, J. M.,, E. G. Mueller,, H. Zehender,, J. Denouel,, H. Caplain,, and L. Millerioux. 1995. Multiple-dose pharmacokinetics and distribution in tissue of terbinafine and metabolites. Antimicrob. Agents Chemother. 39:27382741.
70. Krieter, P.,, B. Flannery,, T. Musick,, M. Gohdes,, M. Martinho,, and R. Courtney. 2004. Disposition of posaconazole following single-dose oral administration in healthy subjects. Antimicrob. Agents Chemother. 48:35433551.
71. Kurtz, M. B.,, and C. M. Douglas. 1997. Lipopeptide inhibitors of fungal glucan synthase. J. Med. Vet. Mycol. 35:7986.
72. Lake-Bakaar, G.,, P. J. Schuer,, and S. Sherlock. 1987. Hepatic reactions associated with ketoconazole in the United Kingdom. Br. Med. J. 294:419422.
73. Laverdiere, M.,, R. G. Lalonde,, J. G. Baril,, D. C. Sheppard,, S. Park,, and D. S. Perlin. 2006. Progressive loss of echinocandin activity following prolonged use for treatment of Candida albicans oesophagitis. J. Antimicrob. Chemother. 57:705708.
74. Li, R. K.,, M. A. Ciblak,, N. Nordoff,, L. Pasarell,, D. W. Warnock,, and M. R. McGinnis. 2000. In vitro activities of voriconazole, itraconazole, and amphotericin B against Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum. Antimicrob. Agents Chemother. 44:17341736.
75. Lortholary, O.,, D. W. Denning,, and B. Dupont. 1999. Endemic mycoses: a treatment update. J. Antimicrob. Chemother. 43:321331.
76. Lutsar, I.,, S. Roffey,, and P. Troke. 2003. Voriconazole concentrations in the cerebrospinal fluid and brain tissue of guinea pigs and immunocompromised patients. Clin. Infect. Dis. 37:728732.
77. Manavathu, E. K.,, J. L. Cutwright,, and P. H. Chandrasekar. 1998. Organism-dependent fungicidal activities of azoles. Antimicrob. Agents Chemother. 42:30183021.
78. Martins, M. D.,, M. Lozano-Chiu,, and J. H. Rex. 1998. Declining rates of oropharyngeal candidiasis and carriage of Candida albicans associated with trends towards reduced rates of carriage of fluconazole-resistant C. albicans in human immunodeficiency virus-infected patients. Clin. Infect. Dis. 27:12911294.
79. McClellan, K. J.,, L. R. Wiseman,, and A. Markham. 1999. Terbinafine: an update of its use in superficial mycoses. Drugs 58:179202.
80. McGinnis, M. R.,, N. G. Nordoff,, N. S. Ryder,, and G. B. Nunn. 2000. In vitro comparison of terbinafine and itraconazole against Penicillium marneffei. Antimicrob. Agents Chemother. 44:14071408.
81. McGinnis, M. R.,, and L. Pasarell. 1998. In vitro evaluation of terbinafine and itraconazole against dematiaceous fungi. Med. Mycol. 36:243246.
82. Mellado, E.,, G. Garcia-Effron,, L. Alcazar-Fuoli,, W. J. Melchers,, P. E. Verweij,, M. Cuenca-Estrella,, and J. L. Rodriguez-Tudela 2007. A new Aspergillus fumigatus resistance mechanism conferring in vitro cross-resistance to azole antifungals involves a combination of cyp51A alterations. Antimicrob. Agents Chemother. 51:18971904.
83. Messer, S. A.,, D. J. Diekema,, L. Boyken,, S. Tendolkar,, R. J. Hollis,, and M. A. Pfaller. 2006. Activities of micafungin against 315 invasive clinical isolates of fluconazole-resistant Candida spp. J. Clin. Microbiol. 44:324326.
84. Messer, S. A.,, G. J. Moet,, J. T. Kirby,, and R. N. Jones. 2009. Activity of contemporary antifungal agents, including the novel echinocandin anidulafungin, tested against Candida spp., Cryptococcus spp., and Aspergillus spp.: report from the SENTRY antimicrobial surveillance program (2006 to 2007). J. Clin. Microbiol. 47:19421946.
85. Moore, C. B.,, C. M. Walls,, and D. W. Denning. 2001. In vitro activities of terbinafine against Aspergillus species in comparison with those of itraconazole and amphotericin B. Antimicrob. Agents Chemother. 45:18821885.
86. Nakai, T.,, J. Uno,, F. Ikeda,, S. Tawara,, K. Nishimura,, and M. Miyaji. 2003. In vitro antifungal activity of micafungin (FK463) against dimorphic fungi: comparison of yeast-like and mycelia forms. Antimicrob. Agents Chemother. 47:13761381.
87. Nakai, T.,, J. Uno,, K. Otomo,, F. Ikeda,, S. Tawara,, T. Goto,, K. Nishimura,, and M. Miyaji. 2002. In vitro activity of FK463, a novel lipopeptide antifungal agent, against a variety of clinically important molds. Chemotherapy 48:7881.
88. Odabasi, Z.,, V. L. Paetznick,, J. R. Rodriguez,, E. Chen,, and L. Ostrosky-Zeichner. 2004. In vitro activity of anidulafungin against selected clinically important mold isolates. Antimicrob. Agents Chemother. 48:19121915.
89. Odds, F. C.,, and H. Vanden Bossche. 2000. Antifungal activity of itraconazole compared with hydroxyl-itraconazole in vitro. J. Antimicrob. Chemother. 45:371373.
90. Ogunbona, F. A.,, I. F. Smith,, and O. S. Olawoye. 1985. Fat contents of meals and bioavailability of griseofulvin in man. J. Pharm. Pharmacol. 37:283284.
91. Orozco, A. S.,, L. M. Higginbotham,, C. A. Hitchcock,, T. Parkinson,, D. Falconer,, A. S. Ibrahim,, M. A. Ghannoum,, and S. G. Filler. 1998. Mechanism of fluconazole resistance in Candida krusei. Antimicrob. Agents Chemother. 42:26452649.
92. Osaka, K.,, V. B. Ritov,, J. F. Bernardo,, R. A. Branch,, and V. E. Kagan. 1997. Amphotericin B protects cis-parinaric acid against perosyl radical-induced oxidation: amphotericin B as an antioxidant. Antimicrob. Agents Chemother. 41:743747.
93. Ostrosky-Zeichner, L.,, K. A. Marr,, J. H. Rex,, and S. H. Cohen. 2003. Amphotericin B: time for a new “gold standard.” Clin. Infect. Dis. 37:415425.
94. Paphitou, N. I.,, L. Ostrosky-Zeitner,, V. L. Paetznick,, J. R. Rodriguez,, E. Chen,, and J. H. Rex. 2002. In vitro antifungal susceptibilities of Trichosporon species. Antimicrob. Agents Chemother. 46:11441146.
95. Paphitou, N. I.,, L. Ostrosky-Zeitner,, V. L. Paetznick,, J. R. Rodriguez,, E. Chen,, and J. H. Rex. 2002. In vitro activities of investigational triazoles against Fusarium species: effects of inoculum size and incubation time on broth microdilution susceptibility test results. Antimicrob. Agents Chemother. 46:32983300.
96. Pappas, P. G.,, C. A. Kauffman,, D. Andes,, D. K. Benjamin,, T. F. Calandra,, J. E. Edwards,, S. G. Filler,, J. F. Fisher,, B. J. Kullberg,, L. Ostrosky-Zeichner,, A. C. Reboli,, J. H. Rex,, T. J. Walsh,, and J. D. Sobel. 2009. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 48:503535.
97. Park, S.,, R. Kelly,, J. N. Kahn,, J. Robles,, M. J. Hsu,, E. Register,, W. Li,, V. Vyas,, H. Fan,, G. Abruzzo,, A. Flattery,, C. Gill,, G. Chrebet,, S. A. Parent,, M. Kurtz,, H. Teppler,, C. M. Douglas,, and D. S. Perlin. 2005. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob. Agents Chemother. 49:32643273.
98. Pasqualotto, A. C.,, K. O. Thiele,, and L. Z. Goldani. 2010. Novel triazole antifungal drugs: focus on isavuconazole, ravuconazole and albaconazole. Curr. Opin. Investig. Drugs 11:165174.
99. Perea, S.,, A. W. Fothergill,, D. A. Sutton,, and M. G. Rinaldi. 2001. Comparison of in vitro activities of voriconazole and five established antifungal agents against different species of dermatophytes using a broth macrodilution method. J. Clin. Microbiol. 39:385388.
100. Perfect, J. R.,, W. E. Dismukes,, F. Dromer,, D. L. Goldman,, J. R. Graybill,, R. J. Hamill,, T. S. Harrison,, R. A. Larsen,, O. Lortholary,, M. H. Nguyen,, P. G. Pappas,, W. G. Powderly,, N. Singh,, J. D. Sobel,, and T. C. Sorrell. 2010. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 50:291322.
101. Perlin, D. S. 2007. Resistance to echinocandin-class antifungal drugs. Drug Resist. Updat. 10:121130.
102. Pfaller, M. A.,, L. Boyken,, R. J. Hollis,, S. A. Messer,, S. Tendolkar,, and D. J. Diekema. 2005. In vitro susceptibilities of clinical isolates of Candida species, Cryptococcus neoformans, and Aspergillus species to itraconazole: global survey of 9,359 isolates tested by Clinical and Laboratory Standards Institute broth microdilution methods. J. Clin. Microbiol. 43:38073810.
103. Pfaller, M. A.,, L. Boyken,, R. J. Hollis,, S. A. Messer,, S. Tendolkar,, and D. J. Diekema. 2005. In vitro activities of anidulafungin against more than 2,500 clinical isolates of Candida spp., including 315 isolates resistant to fluconazole. J. Clin. Microbiol. 43:54255427.
104. Pfaller, M. A.,, L. Boyken,, R. J. Hollis,, S. A. Messer,, S. Tendolkar,, and D. J. Diekema. 2006. In vitro susceptibilities of Candida spp. to caspofungin: four years of global surveillance. J. Clin. Microbiol. 44:760763.
105. Pfaller, M. A.,, and D. J. Diekema. 2004. Twelve years of fluconazole in clinical practice: global trends in species distribution and fluconazole susceptibility of bloodstream isolates of Candida. Clin. Microbiol. Infect. 10(Suppl. 1):1123.
106. Pfaller M. A.,, S. A. Messer,, and A. Bolmstrom. 1998. Evaluation of Etest for determining in vitro susceptibility of yeast isolates to amphotericin B. Diagn. Microbiol. Infect. Dis. 32:223227.
107. Pfaller, M. A.,, S. A. Messer,, L. Boyken,, H. Huynh,, R. J. Hollis,, and D. J. Diekema. 2002. In vitro activities of 5-fluorocytosine against 8,803 clinical isolates of Candida spp.: global assessment of primary resistance using National Committee for Clinical Laboratory Standards susceptibility testing methods. Antimicrob. Agents Chemother. 46:35183521.
108. Pfaller, M. A.,, S. A. Messer,, L. Boyken,, C. Rice,, S. Tendolkar,, R. J. Hollis,, and D. J. Diekema. 2003. Caspofungin activity against clinical isolates of fluconazole-resistant Candida. J. Clin. Microbiol. 41:57295731.
109. Pfaller, M. A.,, S. A. Messer,, L. Boyken,, C. Rice,, S. Tendolkar,, R. J. Hollis,, and D. J. Diekema. 2008. In vitro survey of triazole cross-resistance among more than 700 clinical isolates of Aspergillus species. J. Clin. Microbiol. 46:25682572.
110. Pfaller, M. A.,, S. A. Messer,, R. J. Hollis,, and R. N. Jones. 2001. In vitro activities of posaconazole (Sch 56592) compared with those of itraconazole and fluconazole against 3,685 clinical isolates of Candida spp. and Cryptococcus neoformans. Antimicrob. Agents Chemother. 45:28622864.
111. Pfaller, M. A.,, S. A. Messer,, R. J. Hollis,, and R. N. Jones. 2002. Antifungal activities of posaconazole, ravuconazole, and voriconazole compared to those of itraconazole and amphotericin B against 239 clinical isolates of Aspergillus spp. and other filamentous fungi: report from SENTRY Antimicrobial Surveillance Program, 2000. Antimicrob. Agents Chemother. 46:10321037.
112. Polak, A.,, and H. J. Scholer. 1975. Mode of action of 5-fluorocytosine and mechanisms of resistance. Chemotherapy 21:113130.
113. Pont, A.,, J. R. Graybill,, P. C. Craven,, J. N. Galgiani,, W. E. Dismukes,, R. E. Reitz,, and D. A. Stevens. 1984. High-dose ketoconazole therapy and adrenal and testicular function in humans. Arch. Intern. Med. 144:21502153.
114. Purkins, L.,, N. Wood,, K. Greenhalgh,, M. J. Allen,, and S. D. Oliver. 2003. Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety. Br. J. Clin. Pharmacol. 56(Suppl. 1):1016.
115. Purkins, L.,, N. Wood,, D. Kleinermans,, K. Greenhalgh,, and D. Nichols. 2003. Effect of food on the pharmacokinetics of multiple-dose oral voriconazole. Br. J. Clin. Pharmacol. 56(Suppl. 1):1723.
116. Raad, I. I.,, J. R. Graybill,, A. B. Bustamante,, O. A. Cornely,, V. Gaona-Flores,, C. Afif,, D. R. Graham,, R. N. Greenberg,, S. Hadley,, A. Langston,, R. Negroni,, J. R. Perfect,, P. Pitisuttithum,, A. Restrepo,, G. Schiller,, L. Pedicone,, and A. J. Ullmann. 2006. Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections. Clin. Infect. Dis. 42:17261734.
117. Restrepo, A.,, A. Tobon,, B. Clark,, D. R. Graham,, G. Corcoran,, R. W. Bradsher,, M. Goldman,, G. Pankey,, T. Moore,, R. Negroni,, and J. R. Graybill. 2007. Salvage treatment of histoplasmosis with posaconazole. J. Infect. 54:319327.
118. Revankar, S. G.,, M. D. Nailor,, and J. D. Sobel. 2008. Use of terbinafine in rare and refractory mycoses. Future Microbiol. 3:917.
119. Revankar, S. G.,, S. E. Sanche,, O. P. Dib,, M. Caceres,, and T. F. Patterson. 1998. Effect of highly active antiretroviral therapy on recurrent oropharyngeal candidiasis in HIVinfected patients. AIDS 12:25112513.
120. Rex, J. H.,, M. G. Rinaldi,, and M. A. Pfaller. 1995. Resistance of Candida species to fluconazole. Antimicrob. Agents Chemother. 39:18.
121. Roffey, S. J.,, S. Cole,, P. Comby,, D. Gibson,, S. G. Jezequel,, A. N. Nedderman,, D. A. Smith,, D. K. Walker,, and N. Wood. 2003. The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human. Drug Metab. Dispos. 31:731741.
122. Ryder, N. S. 1991. Squalene epoxidase as a target for the allylamines. Biochem. Soc. Trans. 19:774777.
123. Ryder, N. S.,, S. Wagner,, and I. Leitner. 1998. In vitro activities of terbinafine against cutaneous isolates of Candida albicans and other pathogenic yeasts. Antimicrob. Agents Chemother. 42:10571061.
124. Sabatelli, F.,, R. Patel,, P. A. Mann,, C. A. Mendrick,, C. C. Norris,, R. Hare,, D. Loebenberg,, T. A. Black,, and P. M. McNicholas. 2006. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob. Agents Chemother. 50:20092015.
125. Sandhu, P.,, W. Lee,, X. Xu,, B. F. Leake,, M. Yamazaki,, J. A. Stone,, J. H. Lin,, P. G. Pearson,, and R. B. Kim. 2005. Hepatic uptake of the novel antifungal agent caspofungin. Drug Metab. Dispos. 33:676682.
126. Sanglard, D.,, and F. C. Odds. 2002. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect. Dis. 2:7385.
127. Seibel, N. L.,, C. Schwartz,, A. Arrieta,, P. Flynn,, A. Shad,, E. Albano,, J. Keirns,, W. M. Lau,, D. P. Facklam,, D. N. Buell,, and T. J. Walsh. 2005. Safety, tolerability, and pharmacokinetics of micafungin (FK463) in febrile neutropenic pediatric patients. Antimicrob. Agents Chemother. 49:33173324.
128. Shadomy, S.,, A. Espinel-Ingroff,, and R. J. Gebhart. 1985. In-vitro studies with SF 86-327, a new orally active allylamine derivative. Sabouraudia 23:125132.
129. Shadomy, S.,, S. C. White,, H. P. Yu,, and W. E. Dismukes. 1985. Treatment of systemic mycoses with ketoconazole: in vitro susceptibilities of clinical isolates of systemic and pathogenic fungi to ketoconazole. J. Infect. Dis. 152:12491256.
130. Shah, V. P.,, W. L. Epstein,, and S. Riegelman. 1974. Role of sweat in accumulation of orally administered griseofulvin in skin. J. Clin. Investig. 53:16731678.
131. Shikanai-Yasuda, M. A.,, G. Benard,, Y. Higaki,, G. M. Del Negro,, S. Hoo,, E. H. Vaccari,, R. C. Gryschek,, A. A. Segurado,, A. A. Barone,, and D. R. Andrade. 2002. Randomized trial with itraconazole, ketoconazole and sulfadiazine in paracoccidioidomycosis. Med. Mycol. 40:411417.
132. Smith, K. J.,, D. W. Warnock,, C. T. Kennedy,, E. M. Johnson,, V. Hopwood,, J. Van Cutsem,, and H. Vanden Bossche. 1986. Azole resistance in Candida albicans. J. Med. Vet. Mycol. 24:133144.
133. Sokol-Anderson, M. L.,, J. Brajtburg,, and G. Medoff. 1986. Amphotericin B-induced oxidative damage and killing of Candida albicans. J. Infect. Dis. 154:7683.
134. Sterling, T. R.,, and W. G. Merz. 1998. Resistance to amphotericin B: emerging clinical and microbiological patterns. Drug Resist. Updat. 1:161165.
135. Stevens, D. A.,, M. Diaz,, R. Negroni,, F. Montero-Gei,, L. G. Castro,, S. A. Sampaio,, D. Borelli,, A. Restrepo,, L. Franco,, J. L. Bran,, E. G. Arathoon, et al. 1997. Safety evaluation of chronic fluconazole therapy. Chemotherapy 43:371377.
136. Stone, J. A.,, S. D. Holland,, P. J. Wickersham,, A. Sterrett,, M. Schwartz,, C. Bonfiglio,, M. Hesney,, G. A. Winchell,, P. J. Deutsch,, H. Greenberg,, T. L. Hunt,, and S. A. Waldman. 2002. Single- and multiple-dose pharmacokinetics of caspofungin in healthy men. Antimicrob. Agents Chemother. 46:739745.
137. Stone, J. A.,, X. Xu,, G. A. Winchell,, P. J. Deutsch,, P. G. Pearson,, E. M. Migoya,, G. C. Mistry,, L. Xi,, A. Miller,, P. Sandhu,, R. Singh,, F. deLuna,, S. C. Dilzer,, and K. C. Lasseter. 2004. Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma. Antimicrob. Agents Chemother. 48:815823.
138. Sutton, D. A.,, S. E. Sanche,, S. G. Revankar,, A. W. Fothergill,, and M. G. Rinaldi. 1999. In vitro amphotericin B resistance in clinical isolates of Aspergillus terreus, with a head-to-head comparison to voriconazole. J. Clin. Microbiol. 37:23432345.
139. Tawara, S.,, F. Ikeda,, K. Maki,, Y. Morishita,, K. Otomo,, N. Teratani,, T. Goto,, M. Tomashima,, H. Ohki,, A. Yamada,, K. Kawabata,, H. Takasugi,, K. Sakane,, H. Tanaka,, F. Matsumoto,, and S. Kuwahara. 2000. In vitro activities of a new lipopeptide antifungal agent, FK463, against a variety of clinically important fungi. Antimicrob. Agents Chemother. 44:5762.
140. Theuretzbacher, U.,, F. Ihle,, and H. Derendorf. 2006. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin. Pharmacokinet. 45:649663.
141. Thompson, G. R.,, N. P. Wiederhold,, A. C. Vallor,, N. C. Villareal,, J. S. Lewis,, and T. F. Patterson. 2008. Development of caspofungin resistance following prolonged therapy for invasive candidiasis secondary to Candida glabrata infection. Antimicrob. Agents Chemother. 52:37833785.
142. Trilles, L.,, B. Fernandez-Torres,, M. dos Santos Lazera,, B. Wanke,, A. de Oliveira Schubach,, R. de Almeida Paes,, I. Inza,, and J. Guarro. 2005. In vitro antifungal susceptibilities of Sporothrix schenckii in two growth phases. Antimicrob. Agents Chemother. 49:39523954.
143. Van Burik, J. A.,, R. S. Hare,, H. P. Solomon,, M. L. Corrado,, and D. P. Kontoyiannis. 2006. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin. Infect. Dis. 42:e61e65.
144. Vanden Bossche, H. 1985. Biochemical targets for antifungal azole derivatives: hypothesis on the mode of action. Curr. Top. Med. Mycol. 1:313351.
145. Vandewoude, K.,, D. Vogelaers,, J. Decruyenaere,, P. Jaqmin,, K. De Beule,, A. Van Peer,, R. Woestenborghs,, K. Groen,, and F. Colardyn. 1997. Concentrations in plasma and safety of 7 days of intravenous itraconazole followed by 2 weeks of oral itraconazole solution in patients in intensive care units. Antimicrob. Agents Chemother. 41:27142718.
146. Vazquez, J. 2006. The safety of anidulafungin. Expert Opin. Drug Saf. 5:751758.
147. Venkatakrishnan, K.,, L. L. von Moltke,, and D. J. Greenblatt. 2000. Effects of the antifungal agents on oxidative drug metabolism. Clin. Pharmacokinet. 38:111180.
148. Vermes, A.,, H. J. Guchelaar,, and J. Dankert. 2000. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J. Antimicrob. Chemother. 46:171179.
149. Vickers, A. E.,, J. R. Sinclair,, M. Zollinger,, F. Heitz,, U. Glanzel,, L. Johanson,, and V. Fischer. 1999. Multiple cytochrome P-450s involved in the metabolism of terbinafine suggest a limited potential for drug-drug interactions. Drug Metab. Dispos. 27:10291038.
150. Vogelsinger, H.,, S. Weller,, A. Djanani,, J. Kountchev,, R. Bellmann-Weiler,, C. J. Wiedermann,, and R. Bellmann. 2006. Amphotericin B tissue distribution in autopsy material after treatment with liposomal amphotericin B and amphotericin B colloidal dispersion. J. Antimicrob. Chemother. 57:11531160.
151. Walsh, T. J.,, P. C. Adamson,, N. L. Seibel,, P. M. Flynn,, M. N. Neely,, C. Schwartz,, A. Shad,, S. L. Kaplan,, M. M. Roden,, J. A. Stone,, A. Miller,, S. K. Bradshaw,, S. X. Li,, C. A. Sable,, and N. A. Kartsonis. 2005. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob. Agents Chemother. 49:45364545.
152. Walsh, T. J.,, E. J. Anaissie,, D. W. Denning,, R. Herbrecht,, D. K. Kontoyiannis,, K. A. Marr,, V. A. Morrison,, B. H. Segal,, W. J. Steinbach,, D. A. Stevens,, J. A. van Burik,, J. R. Wingard,, and T. F. Patterson. 2008. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin. Infect. Dis. 46:327360.
153. Walsh, T. J.,, M. O. Karlsson,, T. Driscoll,, A. G. Arguedas,, P. Adamson,, X. Saez-Llorens,, A. J. Vora,, A. C. Arrieta,, J. Blumer,, I. Lutsar,, P. Milligan,, and N. Wood. 2004. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob. Agents Chemother. 48:21662172.
154. Wheat, L. J.,, A. G. Freifeld,, M. B. Kleiman,, J. W. Baddley,, D. S. McKinsey,, J. E. Loyd,, and C. A. Kauffman. 2007. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 45:807825.
155. White, M. H.,, R. A. Bowden,, E. S. Sandler,, M. L. Graham,, G. A. Noskin,, J. R. Wingard,, M. Goldman,, J. A. Van Burik,, A. McCabe,, J. S. Lin,, M. Gurwith,, and C. B. Miller. 1998. Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clin. Infect. Dis. 27:296302.
156. Willemsen, M.,, P. De Doncker,, J. Willems,, R. Woestenborghs,, V. Van de Velde,, J. Heykants,, J. Van Cutsem,, G. Cauwenbergh,, and D. Roseeuw. 1992. Post-treatment itraconazole levels in the nail: new implications for treatment in onychomycosis. J. Am. Acad. Dermatol. 26:731735.
157. Wong-Beringer, A.,, R. A. Jacobs,, and B. J. Guglielmo. 1998. Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clin. Infect. Dis. 27:603618.


Generic image for table

Spectrums and extents of activity of commonly used systemic antifungal agents

This table is a general overview for comparison of the activities of some systemic drugs against various fungi. Readers are recommended to refer to the text for more detailed information.

–, no meaningful activity; +, occasional activity; ++, moderate activity but resistance is noted; +++, reliable activity with occasional resistance.

Citation: Warnock D. 2011. Antifungal Agents , p 1995-2007. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch126

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error