In vitro susceptibilities of yeasts to a new antifungal triazole, SCH 39304: effects of test conditions and relation to in vivo efficacy

Abstract

We used six candidal strains (two Candida albicans and one each of four other species) to study the effects of test conditions on the activity of SCH 39304 compared with that of fluconazole in broth macro- and microdilution assays. Increasing the inoculum from 10(2) to 10(5) yeasts per ml raised the MICs for all isolates up to greater than 512-fold. In contrast, results with a 50% turbidimetric endpoint (50% inhibitory concentration; IC1/2) varied no more than twofold. Similar effects were seen with fluconazole, and both drugs were found to have an associated delay in onset of action. Acidity was found to increase both MICs and IC1/2s. Other effects were observed among four synthetic media, but a consistent pattern was not identified. Incubation temperatures of 37, 35, and 30 degrees C yielded equivalent results. Broth microdilution IC1/2s against most of 40 isolates of C. albicans were 0.31 microgram/ml +/- fourfold for SCH 39304 and 0.16 microgram/ml +/- twofold for fluconazole. Treatment of experimental candidiasis in rats with SCH 39304 and fluconazole resulted in 50% effective doses of 0.33 and 0.49 mg/kg per day, respectively. In contrast, another C. albicans isolate, previously identified as resistant to other azoles, had IC1/2s of 20 micrograms of SCH 39304 per ml and, in vivo, a 50% effective dose of 2.25 mg/kg per day. We conclude that the in vivo efficacy of SCH 39304 correlates with MIC results when broth macrodilution testing is performed with a small inoculum and with IC1/2 results which are independent of inoculum size.