Azoles in the Management of Systemic Fungal Infections

Abstract

Azoles are a key element in the antifungal armamentarium. They act by selectively inhibiting the synthesis of ergosterol, a vital component of the fungal cell membrane. The azoles are divided into the older imidazoles (including miconazole and ketoconazole) and the more recently introduced triazoles (fluconazole, itraconazole, and voriconazole). Because of toxicity problems, high relapse rates, and their narrower spectrum, the imidazoles have largely been superseded by the triazoles. Fluconazole is an effective agent for the treatment of oropharyngeal, esophageal, and urinary candidiasis and candidemia, and has played an important role in the prophylaxis of fungal infections in immunocompromised patients. However, it lacks activity against Aspergillus and some non-albicans species of Candida, and resistance to fluconazole, most notably in people with HIV, is well documented. Itraconazole is a broad-spectrum antifungal agent-in addition to being the first azole with activity against Aspergillus, it is effective against Candida species (including non-albicans species), Coccidioides immitis, Blastomyces dermatitidis, Histoplasma species, and other pathogens. The new oral and intravenous formulations of itraconazole have improved bioavailability over the capsules and are suitable for use in a wider range of immunocompromised patients. Itraconazole has been shown to be at least equivalent to the "gold standard" amphotericin B as empirical therapy in patients with hematological malignancies and is promising in the treatment of invasive aspergillosis. Because of its wide spectrum of activity, itraconazole has ideal properties for prophylaxis against fungal infections in neutropenic patients, and the oral solution has proved to be effective in this setting. Voriconazole has demonstrated superiority to amphotericin B deoxycholate against aspergillosis in a randomized trial. Several new triazoles are currently in development, although clinical experience is limited.