New Antifungal Agents

Two new antifungal agents, voriconazole and caspofungin, are now available for treatment of systemic fungal infections. Voriconazole is an extended-spectrum triazole that is fungicidal for filamentous fungi, including Aspergillus, Scedosporium, Fusarium, Paecilomyces, and is active against all species of Candida. It has become first-line therapy for invasive aspergillosis. Voriconazole is given either by the oral or the intravenous route. Clinicians must be aware of drug-drug interactions and side effects, including visual disturbances and photosensitivity rash that can occur when voriconazole is used. Caspofungin is the first drug available from a new class of antifungal agents, echinocandins, that act to inhibit fungal cell wall synthesis. Caspofungin is fungicidal for all species of Candida and more slowly kills Aspergillus species. Caspofungin, available only for intravenous administration, has minimal side effects and very few drug interactions. The echinocandins will find most use for Candida infections and as second-line therapy for Aspergillus infections.

Antifungal agents - caspofungin - echinocandins - voriconazole - triazoles

REFERENCES

• 1 Manavathu E K, Cutright J L, Chandrasekar P H. Organism-dependant fungicidal activities of azoles.  Antimicrob Agents Chemother. 1998;  42 3018-3021
• 2 Kauffman C A, Zarins L T. In vitro activity of voriconazole against Candida species.  Diagn Microbiol Infect Dis. 1998;  31 297-300
• 3 Pfaller M A, Diekema D J, Jones R N et al.. International surveillance of bloodstream infections due to Candida species: frequency of occurrence and in vitro susceptibilities to fluconazole, ravuconazole, and voriconazole of isolates collected from 1997 through 1999 in the SENTRY antimicrobial surveillance program.  J Clin Microbiol. 2001;  39 3254-3259
• 4 Pfaller M A, Zhang J, Messer S A et al.. In vitro activities of voriconazole, fluconazole, and itraconazole against 566 clinical isolates of Cryptococcus neoformans from the United States and Africa.  Antimicrob Agents Chemother. 1999;  43 169-171
• 5 Espinel-Ingroff A. In vitro activity of the new triazole voriconazole (UK-109,496) against opportunistic filamentous and dimorphic fungi and common and emerging yeast pathogens.  J Clin Microbiol. 1998;  36 198-202
• 6 Manavathu E K, Cutright J L, Loebenberg D, Chandrasekar D H. A comparative study of the in vitro susceptibilities of clinical and laboratory-selected resistant isolates of Aspergillus spp. to amphotericin B, itraconazole, voriconazole, and posaconazole (SCH-56592).  J Antimicrob Chemother. 2000;  46 229-234
• 7 Arikan S, Lozano-Chiu M, Paetznick V, Nangia S, Rex J H. Microdilution susceptibility testing of amphotericin B, itraconazole, and voriconazole against clinical isolates of Aspergillus and Fusarium species.  J Clin Microbiol. 1999;  37 3946-3951
• 8 Espinel-Ingroff A. In vitro fungicidal activities of voriconazole, itraconazole, and amphotericin B against opportunistic moniliaceous and dematiaceous fungi.  J Clin Microbiol. 2001;  39 954-958
• 9 Carrillo A J, Guarro J. In vitro activities of four novel triazoles against Scedosporium spp.  Antimicrob Agents Chemother. 2001;  45 2151-2153
• 10 Li R K, Ciblak M A, Nordoff N, Pasarell L, Warnock D W, McGinnis M R. In vitro activities of voriconazole, itraconazole, and amphotericin B against Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum .  Antimicrob Agents Chemother. 2000;  44 1734-1736
• 11 Gomez-Lopez A, Cuenca-Estrella M, Monzon A, Rodriquez-Tudela J L. In vitro susceptibility of clinical isolates of Zygomycota to amphotericin B, flucytosine, itraconazole, and voriconazole.  J Antimicrob Chemother. 2001;  48 919-921
• 12 Hoffman H L, Rathbun R C. Review of the safety and efficacy of voriconazole.  Expert Opin Investig Drugs. 2002;  11 409-429
• 13 Purkins L, Wood N, Ghahramani P, Greenhalgh K, Allen M J, Kleinermans D. Pharmacokinetics and safety of voriconazole following intravenous-to oral-dose escalation regimens.  Antimicrob Agents Chemother. 2002;  46 2546-2553
• 14 Lazarus H M, Blumer J L, Yanovicjh S, Schlamm H, Romero A. Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: a dose escalation study.  J Clin Pharmacol. 2002;  42 395-402
• 15 Lutsar I, Roffey S, Troke P. Voriconazole concentrations in the cerebrospinal fluid and brain tissue of guinea pigs and immunocompromised patients.  Clin Infect Dis. 2003;  37 728-732
• 16 Walsh T J, Lutsar I, Driscoll T et al.. Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children.  Pediatr Infect Dis J. 2002;  21 240-248
• 17 Johnson L B, Kauffman C A. Voriconazole: a new triazole antifungal agent.  Clin Infect Dis. 2003;  36 630-637
• 18 Venkataramanan R, Zang S, Gayowski T, Singh N. Voriconazole inhibition of the metabolism of tacrolimus in a liver transplant recipient and in human liver microsomes.  Antimicrob Agents Chemother. 2002;  46 3091-3093
• 19 Romero A J, Le Pogamp P, Nilsson L-G, Wood N. Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients.  Clin Pharmacol Ther. 2002;  71 226-234
• 20 Ally R, Schurmann D, Kreisel W et al.. A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients.  Clin Infect Dis. 2001;  33 1447-1454
• 21 Walsh T J, Pappas P, Winston D J et al.. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever.  N Engl J Med. 2002;  346 225-234
• 22 Denning D W, Ribaud P, Milpied N et al.. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis.  Clin Infect Dis. 2002;  34 563-571
• 23 Herbrecht R, Denning D W, Patterson T F et al.. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.  N Engl J Med. 2002;  347 408-415
• 24 Perfect J R, Marr K A, Walsh T J et al.. Voriconazole treatment for less-common, emerging, or refractory fungal infections.  Clin Infect Dis. 2003;  36 1122-1131
• 25 Denning D W, Griffiths C EM. Mucocutaneous retinoid-effects and facial erythema related to the novel triazole antifungal agent voriconazole.  Clin Exp Dermatol. 2001;  26 648-653
• 26 Potoski B A, Brown J. The safety of voriconazole.  Clin Infect Dis. 2002;  35 1273-1275
• 27 Tan K KC, Brayshaw N, Oakes M. Investigation into the relationship between plasma voriconazole concentrations and liver function test abnormalities in therapeutic trials (Abstr A18). 41st Interscience Conference on Antimicrobial Agents and Chemotherapy Chicago IL; Dec 2001
• 28 Ascioglu S, Rex J H, dePauw B et al.. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus.  Clin Infect Dis. 2002;  34 7-14
• 29 Nesky M A, McDougal E C, Peacock Jr J E. Pseudallescheria boydii brain abscess successfully treated with voriconazole and surgical drainage: case report and literature review of central nervous system pseudallescheriasis.  Clin Infect Dis. 2000;  31 673-677
• 30 Munoz P, Marin M, Tornero P et al.. Successful outcome of Scedosporium apiospermum disseminated infection treated with voriconazole in a patient receiving corticosteroid therapy.  Clin Infect Dis. 2000;  31 1499-1501
• 31 Girmenia C, Luzi G, Monaco M, Martino P. Use of voriconazole in treatment of Scedosporium apiospermum infection: case report.  J Clin Microbiol. 1998;  36 1436-1438
• 32 Poza G, Montoya J, Redondo C et al.. Meningitis caused by Pseudallescheria boydii treated with voriconazole.  Clin Infect Dis. 2000;  30 981-982
• 33 Jabado N, Casanova J-L, Haddad E et al.. Invasive pulmonary infection due to Scedosporium apiospermum in two children with chronic granulomatous disease.  Clin Infect Dis. 1998;  27 1437-1441
• 34 Reis A, Sundmacher R, Tintelnot K, Agostini H, Jensen H E, Althous C. Successful treatment of ocular invasive mould infection (fusariosis) with the new antifungal agent voriconazole.  Br J Ophthalmol. 2000;  84 932-933
• 35 Consigny S, Dhedin N, Datry A, Choquet S, Leblond V, Chosidow O. Successful voriconazole treatment of disseminated Fusarium infection in an immunocompromised patient.  Clin Infect Dis. 2003;  37 311-313
• 36 Friese G, Discher T, Fussle R, Schmalreck A, Lohmeyer J. Development of azole resistance during fluconazole maintenance therapy for AIDS-associated cryptococcal disease.  AIDS. 2001;  15 2344-2345
• 37 Deresinski S C, Stevens D A. Caspofungin.  Clin Infect Dis. 2003;  36 1445-1457
• 38 Letscher-Bru V, Herbrecht R. Caspofungin: the first representative of a new antifungal class.  J Antimicrob Chemother. 2003;  51 513-521
• 39 Bartizal K, Gill C J, Abruzzo G K et al.. In vitro clinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872).  Antimicrob Agents Chemother. 1997;  41 2326-2332
• 40 Espinel-Ingroff A. Comparison of in vitro activities of the new triazole SCH56952 and the echinocandins MK-0991 (L-743,872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts.  J Clin Microbiol. 1998;  36 2950-2956
• 41 Vazquez J A, Lynch M, Boikov D, Sobel J D. In vitro activity of a new pneumocandin antifungal, L743,872, against azole-susceptible and azole-resistant Candida species.  Antimicrob Agents Chemother. 1997;  41 1612-1614
• 42 Pfaller M A, Diekema D J, Messer S A, Hollis R J, Jones R N. In vitro activities of caspofungin compared with those of fluconazole and itraconazole against 3959 clinical isolates of Candida spp., including 157 fluconazole-resistant isolates.  Antimicrob Agents Chemother. 2003;  47 1068-1071
• 43 Arikan S, Lozano-Chiu M, Paetznick V, Rex J H. In vitro susceptibility testing methods for caspofungin against Aspergillus and Fusarium isolates.  Antimicrob Agents Chemother. 2001;  45 327-330
• 44 Bowman J C, Hicks P S, Kurtz M B et al.. The antifungal echinocandin caspofungin acetate kills growing cells of Aspergillus fumigatus in vitro.  Antimicrob Agents Chemother. 2002;  46 3001-3012
• 45 Pfaller M A, Marco M F, Messer S A, Jones R N. In vitro activity of two echinocandin derivatives, LY303366 and MK-0991 (L743,872), against clinical isolates of Aspergillus, Fusarium, Rhizopus, and other filamentous fungi.  Diagn Microbiol Infect Dis. 1998;  30 251-255
• 46 Ullmann A J. Review of the safety, tolerability, and drug interactions of the new antifungal agents caspofungin and voriconazole.  Curr Med Res Opin. 2003;  19 263-271
• 47 Stone J A, Holland S D, Wickersham P J et al.. Single- and multiple-dose pharmacokinetics of caspofungin in healthy men.  Antimicrob Agents Chemother. 2002;  46 739-745
• 48 Balani A K, Xu X, Arison B H et al.. Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine.  Drug Metab Dispos. 2000;  28 1274-1278
• 49 Sable C A, Nguyen B Y, Chodakewitz J A, DiNubile M J. Safety and tolerability of caspofungin acetate in the treatment of fungal infections.  Transpl Infect Dis. 2002;  4 25-30
• 50 Villanueva A, Gotuzzo E, Arathoon E et al.. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis.  Am J Med. 2002;  113 294-299
• 51 Villanueva A, Arathoon E, Gotuzzo E et al.. A randomized double-blind study of caspofungin versus amphotericin B for the treatment of candidal esophagitis.  Clin Infect Dis. 2001;  33 1529-1535
• 52 Arathoon E G, Gotuzzo E, Noriega L M et al.. Randomized, double-blind, multi-center study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiasis.  Antimicrob Agents Chemother. 2002;  46 451-457
• 53 Mora-Duarte J, Betts R, Rotstein C et al.. Caspofungin vs amphotericin B deoxycholate in the treatment of invasive candidiasis in neutropenic and non-neutropenic patients:a multi-centre, randomized, double-blind study.  N Engl J Med. 2002;  347 2020-2029
• 54 Kohler S, Wheat L J, Connolly P et al.. Comparison of the echinocandin, caspofungin, with amphotericin B for treatment of histoplasmosis following pulmonary challenge in a murine model.  Antimicrob Agents Chemother. 2000;  44 1850-1854
• 55 Graybill J R, Najvar L K, Montalbo E M et al.. Treatment of histoplasmosis with MK-0991 (L-743,872).  Antimicrob Agents Chemother. 1998;  42 151-153
• 56 Gonzalez G M, Tijerina R, Najvar L K et al.. Correlation between antifungal susceptibilities of Coccidioides immitis in vitro and antifungal treatment with caspofungin in a mouse model.  Antimicrob Agents Chemother. 2001;  45 1854-1859