Antifungal activities of D0870 against fluconazole-resistant Candida albicans

Abstract

We compared the in vitro and in vivo antifungal activities of D0870, a new triazole antifungal agent, with those of other antifungal agents against 8 clinical isolates of fluconazole-resistant Candida albicans. Microdilution testing was performed according to National Committee for Clinical Laboratory Standards (NCCLS) document M27-T. Minimal inhibitory concentration of D0870 (≤0.004-1.0 μ g/ml) was lower than those of fluconazole (2->64 μ g/ml) and itraconazole (0.031-8.0 μ g/ml). In systemic infection models with C. albicans in normal and immunosuppressed mice, D0870 at 0.3-30 mg/kg/day for 5 days after infection prolonged survival of the animals and showed the highest efficacy among the triazole antifungal agents. At pH7 and 37°C in Sabouraud dextrose broth (SDB), D0870 inhibited the growth of C. albicans and acted cytocidally against one of the middle-resistant strains. In an in vivo study against this strain, D0870 at 10 mg/kg/day for 5 days after infection significantly reduced kidney colony counts (2850±406 →997±537 CFU/kidney, P<0.05) on day 7 after infection in comparison with those of the control mice at 24 h after infection. Plasma concentration of D0870 after a single oral administration at 10 mg/kg maintained a sufficient level for interpretation of in vivo antifungal activities. These results suggest that D0870 has strong antifungal activities against clinical isolates of fluconazole-resistant C. albicans in vitro and in vivo, and that these strong activities are at least partially concerned with the fungicidal action.