RESISTANT P45051A1 ACTIVITY IN AZOLE ANTIFUNGAL TOLERANT CRYPTOCOCCUS-NEOFORMANS FROM AIDS PATIENTS

Azole antifungal compounds are important in the treatment of Cryptococ cosis, a major cause of mortality in AIDS patients, The target of the azole drugs is P450 mediated sterol 14 alpha-demethylase. We have inve stigated the P450 system of Cryptococcus neoformans with respect to az ole tolerance observed in clinical isolates which were obtained follow ing the failure of fluconazole therapy. The clinical failure was corre lated with in vitro tolerance of azole antifungal when compared to wil d-type strains. The microsomal P450 system was typical of yeast and fu ngi and fluconazole tolerance was not associated with defective sterol biosynthesis. The strains had slightly elevated P450 content and slig htly reduced azole levels in the cells, but a clear cause for resistan ce was the increased level of drug needed to inhibit the sterol 14 alp ha-demethylase in vitro.