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Fluconazole is a widely used bis-triazole antifungal agent. As with other triazoles, it has five-membered ring structures containing three nitrogen atoms. It is marketed as Diflucan® by Pfizer Pharmaceuticals (http://www.pfizer.com). Both oral and intravenous formulations of fluconazole are available.
As with all azole antifungal agents, fluconazole works principally by inhibition of cytochrome P450 14a-demethylase (P45014DM). This enzyme is in the sterol biosynthesis pathway that leads from lanosterol to ergosterol [1394, 1445, 1674].
Fluconazole is generally considered to be a fungistatic agent. It is principally active against Candida spp. and Cryptococcus spp. However, Candida krusei is intrinsically resistant to fluconazole. Also, isolates of Candida glabrata often generate considerably high fluconazole MICs, with as many as 15% of isolates being completely resistant . Acquired resistance to fluconazole among Candida albicans strains has been reported particularly in HIV-infected patients [267, 464, 1049, 1912].
Fluconazole has useful activity against Coccidioides immitis and is often used to suppress the meningitis produced by that fungus . It has limited activity against Histoplasma capsulatum , Blastomyces dermatitidis , and Sporothrix schenckii [856, 1169], and is sometimes used a second-line agent in these diseases. Fluconazole has no meaningful activity against Aspergillus spp. or most other mould fungi [267, 571].
For fluconazole MICs obtained for various types of fungi, see susceptibility patterns and the susceptibility database.
For oropharyngeal candidiasis, and other forms of mucocutaneous candidiasis, fluconazole is typically dosed at 50-150 mg/day. For invasive candidiasis, the commonly applied dose is ~6 mg/kg/day, or 400 mg in the typical 70 kg adult. Doses of ~12 mg/kg are not FDA-approved, but are used with increasing frequency due to the desire to achieve higher blood levels and thus extend the range of use of the drug. Even higher doses (up to 30 mg/kg in one report!) have been used safely [68, 236, 998, 1519, 2342]. Fluconazole is excreted by the kidneys, and the dose should be reduced in proportion to any reduction of kidney function .
Fluconazole is generally quite well tolerated. In common with all azole antifungal agents, fluconazole may cause hepatotoxicity.
Fluconazole has both oral and intravenous formulations.
Fluconazole is a very widely used antifungal agent. It is one of the first-line drugs, particularly in treatment of infections due to Candida spp. other than Candida krusei and some Candida glabrata isolates. Fluconazole is commonly used also for prophylaxis in transplant patients [1730, 2453].
68. Anaissie, E. J., D. P. Kontonyiannis, C. Huls, S. E. Vartivarian, C. Karl, R. A. Prince, J. Bosso, and G. P. Bodey. 1995. Safety, plasma concentrations, and efficacy of high-dose fluconazole in invasive mold infections. J. Infect. Dis. 172:599-602.
236. Berry, A. J., M. G. Rinaldi, and J. R. Graybill. 1992. Use of high-dose fluconazole as salvage therapy for cryptococcal meningitis in patients with AIDS. Antimicrob. Agents Chemother. 36:690-692.
267. Bodey, G. P. 1992. Azole antifungal agents. Clin. Infect. Dis. 14(Suppl 1):S161-S169.
464. Collin, B., C. J. Clancy, and M. H. Nguyen. 1999. Antifungal resistance in non-albicans Candida species. Drug Resist Update. 2:9-14.
545. Debruyne, D., and J. P. Ryckelynck. 1993. Clinical pharmacokinetics of fluconazole. Clin. Pharmacokinet. 24:10-27.
571. Denning, D. W., L. H. Hanson, A. M. Perlman, and D. A. Stevens. 1992. In vitro susceptibility and synergy studies of Aspergillus species to conventional and new agents. Diagn. Microbiol. Infect. Dis. 15:21-34.
793. Galgiani, J. N. 1993. Coccidioidomycosis. West. J. Med. 159:153-171.
856. Goldani, L. Z., V. R. Aquino, and A. A. Dargel. 1999. Disseminated cutaneous sporotrichosis in an AIDS patient receiving maintenance therapy with fluconazole for previous cryptococcal meningitis. Clin Infect Dis. 28:1337-1338.
998. Haubrich, R. H., D. Haghighat, S. A. Bozzette, J. Tilles, J. A. McCutchan, and the California Collaborative Treatment Group. 1994. High-dose fluconazole for treatment of cryptococcal disease in patients with human immunodeficiency virus infection. J. Infect. Dis. 170:238-242.
1049. Hoban, D. J., G. G. Zhanel, and J. A. Karlowsky. 1999. In vitro susceptibilities of Candida and Cryptococcus neoformans isolates from blood cultures of neutropenic patients. Antimicrob. Agents Chemother. 43:1463-1464.
1169. Kauffman, C. A., P. G. Pappas, D. S. McKinsey, R. A. Greenfield, J. R. Perfect, G. A. Cloud, C. J. Thomas, W. E. Dismukes, and National Institute of Allergy and Infectious Diseases Mycoses Study Group. 1996. Treatment of lymphocutaneous and visceral sporotrichosis with fluconazole. Clin. Infect. Dis. 22:46-50.
1394. Lyman, C. A., and T. J. Walsh. 1992. Systemically administered antifungal agents. A review of their clinical pharmacology and therapeutic applications. Drugs. 44:9-35.
1445. Marriott, M. S., and K. Richardson. 1987. The discovery and mode of action of fluconazole, p. 81-92. In R. A. Fromtling (ed.), Recent trends in the discovery, development, and evaluation of antifungal agents. J. R. Prous Science Publishers, Barcelona.
1519. Menichetti, F., M. Fiorio, A. Tosti, G. Gatti, M. B. Pasticci, F. Miletich, M. Marroni, D. Bassetti, and S. Pauluzzi. 1996. High-dose fluconazole therapy for cryptococcal meningitis in patients with AIDS. Clin. Infect. Dis. 22:838-840.
1674. Odds, F. C., S. L. Cheesman, and A. B. Abbott. 1986. Antifungal effects of fluconazole (UK 49858), a new triazole antifungal, in vitro. J. Antimicrob. Chemother. 18:473-478.
1713. Pappas, P. G., R. W. Bradsher, C. A. Kauffman, G. A. Cloud, C. J. Thomas, G. D. Campbell, Jr., S. W. Chapman, C. Newman, W. E. Dismukes, and National Institute of Allergy and Infectious Diseases Mycoses Study Group. 1997. Treatment of blastomycosis with higher doses of fluconazole. Clin. Infect. Dis. 25:200-205.
1730. Patel, R. 2000. Prophylactic fluconazole in liver transplant recipients: A randomized, double-blind, placebo-controlled trial (Reprinted from Ann Intern Med, vol 131, pg 729-737, 1999). Liver Transplant. 6:376-379.
1784. Pfaller, M. A., S. A. Messer, R. J. Hollis, R. N. Jones, G. V. Doern, M. E. Brandt, and R. A. Hajjeh. 1999. Trends in species distribution and susceptibility to fluconazole among blood stream isolates of Candida species in the United States. Diagn Microbiol Infect Dis. 33:217-222.
1912. Rex, J. H., M. G. Rinaldi, and M. A. Pfaller. 1995. Resistance of Candida species to fluconazole. Antimicrob. Agents Chemother. 39:1-8.
2342. Voss, A., and B. E. de Pauw. 1999. High-dose fluconazole therapy in patients with severe fungal infections. Eur. J. Clin. Microbiol. Infect. Dis. 18:165-174.
2414. Wheat, J., S. MaWhinney, R. Hafner, D. McKinsey, D. Chen, A. Korzun, K. J. Shakan, P. Johnson, R. Hamill, D. Bamberger, P. Pappas, J. Stansell, S. Koletar, K. Squires, R. A. Larsen, T. Cheung, N. Hyslop, K. K. Lai, D. Schneider, C. Kauffman, M. Saag, W. Dismukes, W. Powderly, and National Institute of allergy and Infectious Diseases Acquired Immunodeficiency Syndrome Clinical Trials Group and Myocses Study Group. 1997. Treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. Am. J. Med. 103:223-232.
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