Fluconazole

Oral or intravenous fluconazole is used in the treatment of oropharyngeal, esophageal, and vulvovaginal candidiasis in immunocompromised adults with AIDS, advanced AIDS-related complex, malignancy, or other serious underlying disease. Fluconazole appears to be at least as effective, and in some cases more effective, than other antifungal agents used in the initial treatment of these candidal infections and is considered a drug of choice.

HIV-infected patients with severe or recurrent episodes of these types of candidiasis may benefit from long-term suppressive or maintenance therapy with fluconazole to prevent relapse.
Fluconazole may also be used for primary prophylaxis and for long-term suppressive or chronic maintenance therapy to prevent recurrence or relapse of serious fungal infections in patients considered at high risk for developing such infections, such as those with AIDS.

These infections include blastomycosis, coccidiodomycosis, cryptococcosis, histoplasmosis, and mucocutaneous candidiasis. Fluconazole is also indicated for the treatment and suppression of cryptococcal meningitis as a less toxic (albeit less efficacious) course of treatment than amphotericin B plus flucytosine in AIDS patients. Although amphotericin B (with or without flucytosine) has been considered the initial treatment of choice for cryptococcal meningitis, fluconazole is an alternative for these infections in patients whose disease is not severe, since it is well tolerated and is distributed into cerebrospinal fluid (CSF) at high concentrations. In maintenance therapy, fluconazole is usually better tolerated than amphotericin B alone. Fluconazole is indicated in the prophylaxis and treatment of esophageal, oropharyngeal, disseminated, chronic mucocutaneous, and vulvovaginal candidiasis; coccidiodomycosis; cryptococcal meningitis; onychomycosis; febrile neutropenia; fungal pneumonia; fungal septicemia; tinea corporis, tinea cruris, tinea pedis, and tinea manuum.
Fluconazole is FDA approved for the treatment of systemic candidal infections and is an appropriate, less toxic alternative to amphotericin B.

Pharmacology

Fluconazole is fungistatic and may be fungicidal, depending on the concentration. Azole antifungals interfere with fungal cytochrome P450 enzyme activity necessary for the demethylation of 14-alpha-methyl sterols to ergosterol, the principal sterol in fungal cell membranes. As ergosterol is depleted, the fungal cell membrane is damaged. Unlike ketoconazole, fluconazole has a very weak, noncompetitive inhibitory effect on the liver cytochrome P450 enzyme system, while maintaining a high affinity for fungal cytochrome P450 enzyme activity. In Candida albicans, azole antifungals inhibit transformation of blastospores into invasive mycelial form.
Fluconazole has not been reported to have antiandrogenic activity at currently used doses, and does not affect cortisol metabolism in patients treated with clinically recommended doses.[8] Fluconazole is rapidly and almost completely absorbed from the gastrointestinal (GI) tract. Oral bioavailability of fluconazole exceeds 90% in healthy, fasting adults; peak plasma concentrations of the drug are generally attained within 1 to 2 hours after oral administration; limited studies indicated that bioavailability for adults with HIV appears to be similar to that seen in healthy adults. Unlike other antifungal agents (e.g., itraconazole and ketoconazole), GI absorption of fluconazole does not appear to be affected by gastric pH.
Following oral or IV administration, fluconazole is widely distributed throughout the body, with good penetration of CSF (ranging from 52% to 85% of concurrent plasma concentrations in patients with fungal meningitis), the eye, and peritoneal fluid.

The apparent volume of distribution of Pharmacology (cont.) fluconazole approximates that of total body water and has been reported to be 0.7 L/kg to 1 L/kg. It is not known if fluconazole crosses the placenta, but fluconazole is distributed into human milk in concentrations similar to those attained in plasma.
Fluconazole is in FDA Pregnancy C. Adequate and well-controlled studies have not been done in pregnant women. Fertility was not affected in male or female rats treated with oral daily doses of 5 mg/kg to 20 mg/kg or parenteral doses of 5, 25, or 75 mg/kg, although the onset of parturition was slightly delayed with oral doses of 20 mg/kg. Maternal weight gain impairment and abortions occurred in pregnant rabbits given 75 mg/kg oral doses (20 to 60 times the recommended human dose). No adverse fetal effects were detected.

Oral doses of 25 mg/kg fluconazole given to pregnant rats caused impaired maternal weight gain and increased placental weight, with a slight increase in the number of stillborn pups and a decrease in neonatal survival. At higher doses, supernumerary ribs, renal pelvis dilation, and ossification delays were observed. In rats, deaths of embyros and fetal abnormalities, including wavy ribs, cleft palate, and abnormal craniofacial ossification, occurred at fluconazole doses ranging from 80 mg/kg to 320 mg/kg (approximately 20 to 60 times the recommended human dose).

These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis, and parturition. This effect has not been observed in women treated with fluconazole. Unlike itraconazole and ketoconazole, fluconazole exhibits very low binding to proteins (11%). Metabolism of fluconazole is primarily hepatic. Biliary excretion of fluconazole occurs but only in a very small amount. The plasma elimination half-life of fluconazole in healthy adults is approximately 30 hours (ranging from 20 hours to 50 hours). In patients with impaired renal function, plasma concentrations of fluconazole are higher and the half-life prolonged; elimination half-life of the drug is inversely proportional to the patient's creatinine clearance.

Fluconazole is largely excreted in urine, and fluconazole elimination is principally renal. Renal clearance of the drug averages 0.27 ml/min per kg in adults with normal renal function. Approximately 60% to 80% of a single oral or IV dose of fluconazole is excreted in urine unchanged, and about 11% is excreted in urine as metabolites. Small amounts of the drug are excreted in feces. Fluconazole is removed by hemodialysis and peritoneal dialysis. A three-hour hemodialysis session decreases plasma levels by approximately 50%.

Resistance to fluconazole can be produced in vitro by serial passage of Candida albicans in the presence of increasing concentrations of the drug. Some Candida species are intrinsically resistant to fluconazole (e.g., C. krusei) and many strains of C. glabrata are resistant to the drug. Prolonged or intermittent use of oral fluconazole in immunocompromised patients has been suggested as a major contributing factor to the emergence of fluconazole resistance in Candida. Fluconazole-resistant fungi may also be cross-resistant to other azole antifungal agents (e.g., itraconazole and ketoconazole). While the clinical importance is unclear, fluconazole-resistant strains of C. albicans that were cross-resistant to amphotericin B have been isolated from a few immunocompromised individuals, including patients with leukemia and HIV.