Fluconazole (Diflucan)
Diflucan®
Classification:
Antiinfective Agents
Genitourinary Agents
Description: Fluconazole is a synthetic antifungal agent of the imidazole class. It is administered orally and intravenously. Its antifungal spectrum is broader than other imidazole antifungals such as ketoconazole, miconazole, and clotrimazole. Fluconazole is more resistant to first-pass metabolism and has lower lipophilicity and protein binding than does ketoconazole. Unlike ketoconazole, fluconazole’s oral absorption is not affected by the absence of stomach acid. Fluconazole has been shown equivalent to amphotericin B in the treatment of candidemia in non-neutropenic patients, however, prophylactic use of fluconazole in bone-marrow transplant patients has been associated with increased recovery of C. krusei. Fluconazole was approved by the FDA in January 1990. In June 1994, a single oral dose of fluconazole was approved for the treatment of vaginal candidiasis.
Mechanism of Action: Like other azole antifungals, fluconazole exerts its effect by altering the fungal cell membrane. Fluconazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a cytochrome P-450 enzyme that is needed to convert lanosterol to ergosterol, an essential component of the membrane. In contrast, amphotericin B binds to ergosterol after it is synthesized. Inhibition of ergosterol synthesis results in increased cellular permeability causing leakage of cellular contents. Fluconazole does not appear to have the same activity on human cholesterol synthesis. Other antifungal effects of azole compounds have been proposed and include: inhibition of endogenous respiration, interaction with membrane phospholipids, and inhibition of the transformation of yeasts to mycelial forms. Other mechanisms may involve inhibition of purine uptake and impairment of triglyceride and/or phospholipid biosynthesis. Azole compounds, including fluconazole, have a broad spectrum of antifungal activity against common fungal pathogens including Blastomyces dermatitidis, Candida species, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, and Sporothrix schenckii.
The emergence of fungal organisms resistant to fluconazole, especially Candida species, is problematic. The increased frequency of non-Candida albicans species as causes of fungemia has been correlated in epidemiologic studies with the increased use of fluconazole both for prophylaxis and treatment. These non-Candida albicans species are often more resistant to fluconazole, compared with C. albicans isolates. Data indicate the annual incidence of fluconazole-resistant oropharyngeal candidiasis in AIDS patients is roughly 5%. Susceptibility testing of invasive isolates of Candida against fluconazole has been recommended for C. albicans isolates from patients with persistent candidemia or progressive disseminated candidiasis, despite fluconazole therapy, and on non-albicans Candida isolates (e.g., C. glabrata, C. krusei, or C. parapsilosis) from patients with candidemia or invasive disease.
Pharmacokinetics: Fluconazole is administered orally and intravenously. The pharmacokinetics of both IV and oral fluconazole are similar. GI absorption is rapid and almost complete. Oral bioavailability is over 90% in fasting adults, and peak serum concentrations are attained within 1-2 hours after oral administration. Food affects neither the rate nor the extent of absorption. Unlike ketoconazole, gastric pH has no effect on fluconazole bioavailability. Peak serum concentrations and AUC increase in proportion to the dose. Steady-state fluconazole plasma concentrations are achieved within 5-10 days at doses within the range of 50-400 mg/day, and within 2 days when a loading dose of twice the usual daily dosage is first given. Fluconazole is widely distributed into body tissues and fluids. Saliva, sputum, nail, blister, and vaginal secretion concentrations are approximately equal to plasma concentrations. Urine and skin concentrations are approximately 10 times that of plasma concentrations. High concentrations also can be achieved in the cornea, aqueous humor, and vitreous body following IV administration. Fluconazole distributes well into the CSF, and achieves CSF concentrations that are 50-94% of plasma concentrations, regardless of the degree of meningeal inflammation. Protein binding ranges from 11-12%. Fluconazole’s distribution into human milk and across the placenta are not known.
Fluconazole does not appear to undergo first-pass metabolism. Elimination is mainly renal, and about 60-80% of a dose is excreted in the urine unchanged, and 11% as metabolites. Plasma elimination half-life in adults with normal renal function is approximately 30 hours (range: 20-50 hours). Elimination of the drug also can be impaired in elderly patients. Small amounts of fluconazole are excreted in the feces.
- Special Populations: Renal dysfunction prolongs the half-life and increases plasma concentrations; dosage adjustments are required in patients with renal impairment (fluconazole_diflucan_indications_and_dosage/">see Dosage). The elimination half-life of fluconazole is inversely proportional to the patient’s creatinine clearance. Fluconazole is removed by both hemodialysis and peritoneal dialysis. Three hours of hemodialysis decreases plasma concentrations by approximately 50% but depends on the type of coil used and the dialysis flow rate. In elderly patients receiving single 50 mg PO doses of fluconazole, the Cmax and AUC of fluconazole were higher than those reported in normal young male volunteers; the mean terminal half-life was 46.2 hours in the elderly vs 30 hours in normal patients. Coadministration with diuretics did not significantly alter the AUC or Cmax of fluconazole. Elderly patients had lower creatinine clearance, lower percentage of drug recovered in urine, and lower fluconazole renal clearance estimates compared to younger volunteers. The manufacturer concludes that the alteration in pharmacokinetic values in the elderly is due to the decreased renal function expected in the elderly. Mean elimination half-life in children (ages 9 months to 15 years) without HIV infection ranges from 15.2-25 hours. Fluconazole half-life in premature neonates has been reported to be roughly 88 hours after the first treatment dose; after two weeks of therapy, the half-life declines to approximately 55 hours. Hepatic dysfunction has no effect on the half-life or elimination of fluconazole.
References
. Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. N Engl J Med 1994;330:263-72.
. Borgers M. Mechanism of action of antifungal drugs, with special reference to the imidazole derivatives. Rev Inf Dis. 1980;2:520-34.
. Rex JH, Bennett JE, Sugar AM et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. N Engl J Med 1994;331:1325-30.
. Goodman JL, Winston DJ, Greenfield RA et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992;326:845-51.
. Dismukes WE. Introduction to antifungal drugs. Clin Infec Dis 2000;30:653-7.
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