EFFECTS OF ANTIFUNGAL THERAPY ON INFLAMMATION, STERILIZATION, AND HISTOLOGY IN EXPERIMENTAL CANDIDA-ALBICANS MENINGITIS

To assess the effects of antifungal therapy on the course of Candida a lbicans central nervous system infection and inflammation, we inoculat ed intracisternally 10(5) CFU of C. albicans into rabbits. Fluconazole (10 mg/kg of body weight) or amphotericin B (1 mg/kg) was infused int ravenously daily for 14 days. Treatment was initiated 24 h or 5 days a fter infection. Cerebrospinal fluid (CSF) was repeatedly obtained to c ulture the organisms, assess the level of inflammation, and measure dr ug concentrations. Brain tissue was obtained at the end of therapy for culture, drug concentration determinations, and histopathology. The m edian number of days of treatment required to sterilize CSF cultures w as 4 days for fluconazole therapy and 1 day for amphotericin B therapy (P = 0.037). There was a significant reduction in tumor necrosis fact or alpha and leukocyte concentrations in the CSF of animals treated ea rly versus those in untreated control animals (P < 0.05 and P < 0.001, respectively; analysis of variance). Compared with treated animals, a higher proportion of cultured CSF samples from untreated animals were positive for Candida (P < 0.001). A cultured brain sample from 1 of t he 12 animals treated early with amphotericin B was positive for C. al bicans (P < 0.01 versus controls); cultures of brain samples from 3 of 12 animals treated early with fluconazole were positive, whereas cult ures of brain samples from 10 of 12 controls were positive (P < 0.05). The mean density of C. albicans was lower in the single culture-posit ive amphotericin B recipient (1 x 10(1) CFU/g of brain tissue) than in those treated with fluconazole (1 x 10(3) CFU/g) and in controls (8 x 10(4) CFU/g). In animals treated late, the density of C. albicans in the brain in relation to the number of days of therapy was significant ly lower in amphotericin B recipients than in those treated with fluco nazole (P < 0.01) and untreated controls (P < 0.01; analysis of covari ance). By histopathology, a larger proportion of untreated animals com pared with those treated early demonstrated features of severe infecti on such as perivasculitis, ventriculitis, and evidence of fungal organ isms. Compared with amphotericin B-treated rabbits, those given flucon azole had a trend toward more severe pathologic lesions. Reduced susce ptibility to both fluconazole and amphotericin B was observed in the C . albicans organisms isolated from the brain of one fluconazole-treate d animal. These data suggest that amphotericin B is the preferred trea tment for C. albicans infections of the central nervous system.