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Antifungal Activity of D0870 against Murine Infections and Its Mechanism of Action

We evaluated the in vivo antifungal activity of D0870, a new triazole agent, in comparison with that of fluconazole in two murine infection models. The therapeutic mechanism of D0870 in these models was also investigated in vitro. In a pulmonary infection with Cryptococcus neoformans in immunosuppressed mice, D0870 at 10–100 mg/kg significantly reduced viable counts in lungs infected with C. neoformans to 1/10–1,000 of the control on day 14, whereas fluconazole, only at 100 mg/kg, showed a significant reduction in the viable counts and was less active than D0870 at 10 mg/kg. D0870 at 3–30 mg/kg also showed excellent therapeutic efficacy against murine vaginal candidiasis and completely eliminated viable yeasts from the vaginal cavity, whereas positive cultures were found in 20% of mice treated with 30 mg fluconazole/kg. At pH 7 and 37°C, D0870 was active against C. neoformans in synthetic amino acid medium, fungal or sabouraud dextrose broth. By reducing the pH of the medium, the in vitro anticryptococcal activity of D0870 was enhanced and found to be fungicidal under all culture conditions at pH 4–5. D0870 also showed a stronger fungistatic activity against Candida albicans at pH 4. These results suggest that D0870 may exhibit a potent activity against these two murine infections by exerting an excellent antifungal activity at the infection sites thought to be acidic environments.