Effect of fluconazole on fungicidal activity of flucytosine in murine cryptococcal meningitis

Both animal and in vitro studies have demonstrated that combinations of flucytosine with amphotericin B and with fluconazole have significantly improved activity against cryptococcal meningitis compared with the activity of each drug used alone, However, very few dose levels of these agents have been tested in combination. This study evaluated the efficacy of fluconazole plus flucytosine in a murine model of cryptococcal meningitis over a broad range of dose combinations (fluconazole, 0 to 40 mu g/g of body weight per day; flucytosine, 0 to 200 mu g/g/day). Both drugs were dissolved in drinking water, with treatment on days 2 to 11, In this highly reproducible model, fluconazole had a dramatic effect on the fungicidal activity of flucytosine. Flucytosine at dose levels of as much as 200 mu g/g/day alone or in combination with low doses of fluconazole had minimal fungicidal activity, whereas in combination with fluconazole at 24 to 40 mu g/g/day, flucytosine showed fungicidal activity in the range of 35 to 65% of the animals treated at doses of 40 to 100 mu/g/day. This striking effect of fluconazole is consistent with the results of both in vitro and clinical studies, In the clinic, the use of flucytosine is often limited by severe toxicity, while toxicity is rarely observed with fluconazole, These results suggest that when flucytosine is given with higher doses of fluconazole, the maximum therapeutic effect of the former in the clinic may be observed at dose levels that are far less than the doses commonly employed (150 mu g/g daily).