In Vivo Combination of Fluconazole (FLU) and Caspofungin (CSP) against Candida albicans (Ca).



Background: CSP is a potent antifungal inhibiting glucan synthesis in Candida species. CSP is effective in clinical trials and in open use since licensure. However, because CSP is not 100% curative in candidiasis, we explored the potential of combination CSP and fluconazole in murine candidemia. Methods: Mice were infected intravenously with 105 to 106 Ca. One day after infection mice were treated with water (controls) intraperitoneally (IP), CSP given once daily IP, or FLU given orally BID. Treatment was continued through day 7, and mice were sacrificed on day 8 for quantitative tissue fungal burden measured in the kidneys. Results are expressed as CFU/organ, and were compared using the Mann Whitney test. P 0.05 determined significance. Results: We studied two-fold decreasing doses of CSP over a range from 0.1 to 0.0005 mg/kg/day. The minimal protective dose was 0.0062 mg/kg/day for kidneys. FLU was studied over a two-fold serially decreasing range from 5 mg/kg/dose to 0.04 mg/kg BID. The minimal protective dose was 0.06 mg/kg BID. Based on the desire to use doses at or just below the minimal protective dose, we evaluated combinations of FLU at 0.06mg/kg BID and CSP ranging from 0.006 to 0.0005 mg/kg/day. In none of the 4 regimens studied did we see any additive effect of the combination over the individual drugs or controls. Conclusions: There has been increasing interest in the use of combination antifungal therapy for treatment of candidemia. Despite excellent potency and CSP alone, within the parameters of this study (concurrent drug administration, high dose infection) we could not show any benefit of combined therapy over individual antifungal drugs. CSP does not appear to add to the effect of FLU in this model of invasive candidiasis.

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42nd Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 42nd