ANTIFUNGAL ACTIVITY OF RECOMBINANT HUMAN MACROPHAGE-COLONY-STIMULATING FACTOR IN MODELS OF ACUTE AND CHRONIC CANDIDIASIS IN THE RAT

Models of acute and chronic candidiasis were developed in Fischer 344 rats to evaluate the therapeutic efficacy of recombinant human macroph age colony-stimulating factor (rhM-CSF) alone and in combination with the antifungal agent fluconazole. In the acute model, rats were challe nged by intravenous injection with 2 X 10(6) Candida albicans, similar to 4 times the LD(50). Daily subcutaneous (sc) bolus injections of rh M-CSF for 10 days plus a single sc bolus dose of 0.3 mg/kg of fluconaz ole improved the median survival time from 5 days (32% survival) with fluconazole alone to >30 days (88% survival) in the rhM-CSF- and fluco nazole-treated rats. In the chronic model, daily sc bolus injections o f rhM-CSF for 10 days plus a single sc bolus dose of 1.0 mg/kg of fluc onazole decreased the median titer of C. albicans cultured from the ki dneys by 10-fold at 15 and 30 days after infection. These studies show ed that rhM-CSF treatment improved the therapeutic outcome in both the acute and chronic rat model of candidiasis when used with fluconazole , a standard fungistatic agent.