Cryptococcal meningitis causes significant morbidity and mortality in persons with AIDS. Of 236 AIDS patients treated with amphotericin B plus flucytosine, 29 (12%) died within 2 weeks and 62 (26%) died before 10 weeks. Just 129 (55%) of 236 patients were alive with negative cerebrospinal fluid (CSF) cultures at 10 weeks. Multivariate analyses identified that titer of cryptococcal antigen in CSF, serum albumin level, and CD4 cell count, together with dose of amphotericin B, had the strongest joint association with failure to achieve negative CSF cultures by day 14. Among patients with similar CSF cryptococcal antigen titers, CD4 cell counts, and serum albumin levels, the odds of failure at week 10 for those without negative CSF cultures by day 14 was five times that for those with negative CSF cultures by day 14 (odds ratio, 5.0; 95% confidence interval, 2.2-10.9). Prognosis is dismal for patients with AIDS-related cryptococcal meningitis. Multivariate analyses identified three components that, along with initial treatment, have the strongest joint association with early outcome. Clearly, more effective initial therapy and patient management strategies that address immune function and nutritional status are needed to improve outcomes of this disease.

We studied the effect of the severity of meningitis on the response to therapy with fluconazole and flucytosine in a murine model of cryptococcal meningitis. Meningitis was established by intracerebral injection of Cryptococcus neoformans. The severity of meningitis was varied by delaying the onset of treatment from 3 to 7 days. Animals were sacrificed after 14 days of treatment, and the numbers of C. neoformans per gram of brain tissue were quantified. The range of effective dose combinations of fluconazole and flucytosine became progressively reduced as the severity of meningitis increased. The magnitude of treatment effect, as measured by the numbers of CFU/gram of brain tissue, was also reduced with increasing severity of meningitis. In this model, as the severity of meningitis increases, higher doses of fluconazole are required to achieve equivalent levels of activity. The combination of fluconazole and flucytosine appears to have the most-potent antifungal effects. This is most readily observed in animals with more-severe 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 micrograms/g of body weight per day; flucytosine, 0 to 200 micrograms/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 micrograms/g/day alone or in combination with low doses of fluconazole had minimal fungicidal activity, whereas in combination with fluconazole at 24 to 40 micrograms/g/day, flucytosine showed fungicidal activity in the range of 45 to 65% of the animals treated at doses of 40 to 100 micrograms/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 micrograms/g daily).

Studies with animals and in vitro studies have demonstrated that flucytosine plus amphotericin B or fluconazole has significantly improved mycologic activity against meningitis caused byCryptococcus neoformans compared to the activity of amphotericin B or fluconazole used alone. However, few doses have been tested in combination. This study evaluated the antifungal efficacy of amphotericin B colloidal dispersion (ABCD) combined with flucytosine with and without fluconazole in a murine model of cryptococcal meningitis. The following dosages were tested: ABCD at 0 to 12.5 mg/kg of body weight given intravenously 3 days/week, flucytosine at 0 to 110 mg/kg/day, and fluconazole at 0 to 50 mg/kg/day. Meningitis was established in male BALB/c mice by intracerebral injection of C. neoformans. Treatment with flucytosine with or without fluconazole dissolved in the sole source of drinking water was started on day 2; animals were sacrificed at 16 days, and the numbers of fungal colonies in the brain were quantified. A survival rate of 100% was achieved with ABCD plus flucytosine without fluconazole; however, the addition of fluconazole was required to prevent weight loss (P < 0.00001) and to achieve the maximum antifungal effect (P < 0.00001). The only region of dose combinations for which the 99% confidence intervals were less than 100 CFU/g of brain was defined by ABCD at 5.0 to 7.5 mg/kg combined with flucytosine at 20 to 60 mg/kg/day and fluconazole at 30 to 40 mg/kg/day. The triple combination of ABCD plus flucytosine and fluconazole was necessary to achieve the greatest antifungal activity.