Efficacy of UK-49,858 (fluconazole) against Candida albicans experimental infections in mice
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Abstract:
UK-49,858 (fluconazole), a new, orally absorbed bis-triazole derivative, has been evaluated against systemic infections with Candida albicans in normal and immunosuppressed mice and against an intestinal infection with C. albicans in immunosuppressed mice. Orally administered ketoconazole was used as a comparison agent throughout, and orally administered amphotericin B was included for comparative in the experimental intestinal infection. In a 10-day dosage regimen, UK-49,858 was far more active than ketoconazole against systemic infections with C. albicans in normal and immunosuppressed mice. In normal mice, extension of UK-49,858 dosing to 30 days resulted in prolongation of survival to over 90 days, and up to 60% of treated animals had no detectable C. albicans in their kidneys. In addition, over 90% of mice with intestinal candidiasis had culture-negative feces after a 3-day treatment with UK-49,858, but only 62 and 23% of mice gave this response after amphotericin B and ketoconazole therapy, respectively. These data suggest that UK-49,858 may be of value in the treatment of systemic and gastrointestinal infections due to C. albicans in humans.
Insights
UK-49,858, a new oral antifungal, demonstrated superior efficacy against Candida albicans infections in mice compared to ketoconazole. This bis-triazole derivative shows promise for treating systemic and gastrointestinal candidiasis in humans.
Area of Science:
- Mycology
- Pharmacology
- Infectious Diseases
Background:
- Systemic and gastrointestinal candidiasis are significant clinical challenges.
- Existing antifungal therapies have limitations in efficacy and safety.
Purpose of the Study:
- To evaluate the efficacy of UK-49,858 (fluconazole), an orally absorbed bis-triazole derivative, against Candida albicans infections.
- To compare UK-49,858 with ketoconazole and amphotericin B in murine models of candidiasis.
Main Methods:
- Murine models of systemic candidiasis (normal and immunosuppressed mice) and intestinal candidiasis (immunosuppressed mice) were utilized.
- UK-49,858 was administered orally and compared to orally administered ketoconazole and amphotericin B.
- Efficacy was assessed by survival rates, fungal burden in kidneys, and fecal culture negativity.
Main Results:
- UK-49,858 significantly outperformed ketoconazole in treating systemic C. albicans infections in both normal and immunosuppressed mice over a 10-day regimen.
- Extended UK-49,858 treatment (30 days) in normal mice led to prolonged survival (>90 days) and reduced kidney fungal burden (up to 60% negative).
- In intestinal candidiasis, UK-49,858 achieved higher fecal culture negativity rates (over 90%) after 3 days compared to amphotericin B (62%) and ketoconazole (23%).
Conclusions:
- UK-49,858 exhibits potent antifungal activity against Candida albicans in preclinical models.
- The compound demonstrates superior efficacy and potentially better outcomes than existing treatments for both systemic and gastrointestinal candidiasis.
- These findings support the potential clinical utility of UK-49,858 for treating human candidal infections.