Treatment of disseminated Torulopsis glabrata infection with DO870 and amphotericin B

Abstract

Torulopsis glabrata, an opportunist pathogen in immunosuppressed patients, is resistant to many antifungal agents, and there are no established treatment regimens for this organism. The mouse model was used to evaluate treatment with DO870, amphotericin B, fluconazole, and their combination. Mice were immunosuppressed with 5 mg of gold sodium thiomalate given intraperitoneally 1 day prior to intravenous infection with 10(8) T. glabrata cells. Treatment with a new antifungal triazole, DO870, at doses ranging from 1 to 50 mg/kg of body weight administered per os either daily or on alternate days; fluconazole at 100 mg/kg twice a day per os; or amphotericin B at 3 mg/kg/day intraperitoneally was begun 1 day after infection. Treatment for 5 days was followed by sacrifice 2 days later for determining CFU counts in spleen and kidney tissue. For a fluconazole-sensitive isolate (MIC of DO870, < 1.25 micrograms/ml), DO870 at 5 mg/kg/day significantly reduced counts in kidney and spleen tissue (P < 0.05), amphotericin B was modestly effective, and the combination of DO870 (25 mg/kg) and amphotericin B (3 mg/kg) was markedly more effective than either drug alone (P < 0.01). Three additional isolates were resistant in vitro to DO870 (MIC, 4 micrograms/ml). No reduction in CFU in kidney or spleen tissue was observed with DO870 when compared with counts in control tissue. DO870 is effective in vivo against at least some isolates of T. glabrata and when combined with amphotericin B can exert additive effects.