STEROL COMPOSITION OF CRYPTOCOCCUS-NEOFORMANS IN THE PRESENCE AND ABSENCE OF FLUCONAZOLE

Analysis of the sterol compositions of 13 clinical isolates of the pat hogenic yeast Cryptococcus neoformans obtained from five patients with recurring cryptococcal meningitis showed that, unlike Candida albican s, the major sterols synthesized by this yeast were obtusifoliol (rang e, 21.1 to 68.2%) and ergosterol (range, 0.0 to 46.5%). There was cons iderable variation in the sterol contents among the 13 isolates, with total sterol contents ranging from 0.31 to 5.9% of dry weight. The iso lates from the five patients who had relapses had different total ster ol contents and compositions in comparison with those of the pretreatm ent isolates, indicating either that the sterols had been changed by t herapy or that the patients were infected with new isolates with diffe rent sterol compositions. Growth of the cryptococcal isolates in the p resence of subinhibitory concentrations of fluconazole (0.25x the MIC) significantly altered the sterol content and pattern. The total stero l content decreased in nine isolates and increased in four isolates in response to pretreatment with fluconazole. Fluconazole had no consist ent effect on ergosterol levels. In contrast, fluconazole caused a dec rease in obtusifoliol levels and an increase in 4,14-dimethylzymostero l levels in all isolates. These results indicate extensive diversity i n sterol content, sterol composition, and sterol synthesis in response to subinhibitory concentrations of fluconazole in C. neoformans strai ns. We propose that fluconazole inhibits the sterol synthesis of C. ne oformans by interfering with both 14 alpha-demethylase-dependent and - independent pathways. No correlation between the sterol compositions o f C. neoformans isolates and their susceptibilities to fluconazole was found.