Azole antifungal drugs in treatment of coccidioidomycosis

Abstract

For two decades amphotericin B has been the only antifungal drug with proven efficacy against Coccidioides immitis. The introduction of miconazole in the late 1970s ushered in a new era of antifungal therapy. Miconazole induced remissions in patients with disease refractory to amphotericin B and in patients who had relapsed after amphotericin B treatment. Almost as important, miconazole did not have the nephrotoxicity associated with amphotericin B. However, the necessity of intravenous administration and other toxicities limited the value of miconazole. The first child of miconazole was ketoconazole, which could be administered orally and had markedly less toxicity than amphotericin B or miconazole. Because coccidioidomycosis challenges any antifungal drug, doses were increased to as much as 2,000 mg/d. Ketoconazole can be used for long terms and at high doses, with many patients brought into remission. However relapses and failures still occurred; dose-related endocrine and gastrointestinal toxicities were uncovered. A third generation of azoles, the triazoles, was introduced to minimize these adverse effects, yet retain the efficacy of ketoconazole. Early clinical trials are promising for itraconazole. Other triazoles with advantageous pharmacokinetic properties are also coming into clinical trials. Shortly, we are likely to have available a whole range of antifungal agents for treatment of this most frustrating disease.