COMBINATION THERAPY WITH FLUCONAZOLE AND FLUCYTOSINE IN THE MURINE MODEL OF CRYPTOCOCCAL MENINGITIS

This study elucidates the role of combined fluconazole and flucytosine as therapy for cryptacorcosis in the murine model of meningitis, Thre e strains of Cryptococus neoformans for which the range of fluconazole MICs was wide-2 mu g/ml (susceptible strain), 8 mu g/ml (moderately s usceptible strain), and 32 mu g/ml (resistant strain ere used for infe ction, One day postinfection, the mice were randomized into eight trea tment groups: placebo; flucytosine (40 mg/kg of body weight/day); fluc onazole at 3 mg/kg/day (low dosage), 10 mg/kg/day !moderate dosage), o r 10 mg/kg/day (high dosage); and combined flucytosine and fluconazole at low, moderate, or high doses of fluconazole. Three major findings were demonstrated: (i) correlation between the MICs for the isolates a nd the in vivo effectiveness of fluconazole as assessed by the reducti on in cryptococcal brain burden, (iii a dose-response curve (a higher dose of fluconazole was significantly more efficacious than a lower do se [P < 0.001]), and (iii) synergism between fluconazole and flucytosi ne (therapy with a combination of fluconazole and flucytosine was supe rior to therapy with either agent alone [P < 0.01]).