Fluconazole, D0870, and flucytosine treatment of disseminated Candida tropicalis infections in mice

Abstract

D0870 is a recently developed triazole with characteristics of a broad spectrum of activity and slow clearance by nonrenal mechanisms. Herein we have evaluated the efficacy of D0870, alone and combined with flucytosine, in a murine model of disseminated Candida tropicalis infection. Four isolates of C. tropicalis were evaluated. Two were highly susceptible in vitro to fluconazole, and two were resistant to fluconazole. All were highly susceptible to flucytosine and D0870. Animals were pretreated with 5-fluorouracil 1 day before infection because C. tropicalis has reduced virulence in immunocompetent mice. This was done to render them neutropenic for > 10 days. Mice were infected intravenously and treated orally with D0870 or fluconazole, alone or combined with flucytosine. Survival and tissue burden of the spleen and kidneys were used to evaluate the efficacy of antifungal therapy. Fluconazole was less effective for treatment of resistant C. tropicalis than susceptible C. tropicalis. D0870 was more potent than fluconazole and was effective in fluconazole-resistant isolates. Flucytosine was consistently effective when used alone but did not consistently add to the benefit of D0870 or fluconazole. D0870 has potential in treatment of candidiasis caused by C. tropicalis, including fluconazole-resistant isolates.