MECHANISMS OF RESISTANCE TO AZOLE ANTIFUNGALS

Until the late eighties, clinical resistance to azole antifungals was a rare phenomenon. Only a few cases of resistance to ketoconazole were found in patients with chronic mucocutaneous candidiasis (CMC). The s pread of AIDS and the widespread prophylactic and therapeutic use of t he hydrophilic azole compound fluconazole resulted both in the selecti on and induction of resistant strains and in a shift in the nature of the infecting organisms. Most azole antifungals such as itraconazole, ketoconazole and fluconazole are active against a variety of fungal di seases. However, the concentration needed to inhibit growth is depende nt on the nature of the infecting species. Mucor spp., e.g., are almos t insensitive to present available azole compounds and can be regarded as intrinsically resistant to azole treatment. Physicochemical featur es, such as the hydrophobicity and pK(a), of a given azole, define whe ther or not it will be active or cross-resistant against a given speci es. Fluconazole is almost inactive against Candida krusei and Aspergil lus fumigatus, whereas the lipophilic itraconazole is active against t hese species. A third type of resistance is acquired or induced resist ance. This is the most controversial type because, even within a given species, organisms may differ in their response to the same azole. Fo r these strains, convincing evidence can only be obtained when there i s a genotypically related strain, which does not show resistance. In a limited number of biochemical or molecular biological studies the mec hanisms of resistance have been investigated at the molecular level. T hese studies show that resistance can occur when there is an insuffici ent intracellular content of the azole. This can be due to impermeabil ity problems, inactivated uptake systems or, and more likely, the pres ence of active multidrug resistance gene products of the P-glycoprotei n type. Alteration or overexpression of the target for azole antifunga ls, the cytochrome P450-dependent 14 a-demethylase, also induces resis tance. The nature and amount of the accumulating sterols also are of g reat importance for azole-induced growth inhibition. This may explain why mutations in other enzymes of the ergosterol biosynthesis pathway, e.g. the Delta 5-6 desaturase, can contribute to azole resistance.