The mechanism of action of the new antimycotic ketoconazole

Abstract

Ketoconazole is one of the new members of the imidazole series with a broad-spectrum antifungal profile. Although sharing its basic active principles with the other imidazoles, ketoconazole obtains its superior in vivo activity mainly from its good oral absorption and its lower degree of inactivation once absorbed. Its selective toxicity for yeasts and fungi is found to be primarily linked to the inhibition of ergosterol biosynthesis and to interference with other membrane lipids. In vitro growth studies revealed that ketoconazole's activity was more pronounced against the invasive morphogenetic form than against the saprophytic form of Candida albicans, which at least partly explains its prominent in vivo potency. At extremely low concentrations (10 ng/ml-1) ketoconazole prevents the development of the very form that is responsible for the expression of clinical symptoms. In contrast to other imidazoles, ketoconazole's action on the morphogenesis of the organism is not influenced by serum. The synergistic action with host defense cells, as demonstrated in culture systems, is another inherent property of this drug and may have a great impact on the eradication of systemic fungal infections. These effects of ketoconazole have been studied in a variety of fungal organisms with the aid of phase-contrast, scanning, and transmission electron microscopy in order to characterize ketoconazole's profile in comparison to the other imidazole derivatives.