THERAPY OF EXPERIMENTAL MENINGEAL AND DISSEMINATED CRYPTOCOCCOSIS

This study evaluated the efficacy of itraconazole, a broad-spectrum tr iazole antifungal drug, which has previously been demonstrated to exhi bit activity against Candida albicans C. krusei, C. glabrata, Aspergil lus, Histoplasma and Blastomyces as a potential treatment for cryptoco ccosis. The susceptibility of 62 strains of Cryptococcus neoformans wa s tested in vitro. All strains were inhibited by itraconazole 0.1 mug ml-1. Itraconazole was fungicidal after replenishment at a concentrati on that can easily be achieved in vivo. When mice were infected intrac erebrally with Cr. neoformans all control animals died, whereas only 1 1% and 26% of itraconazole-treated animals died. In a group treated wi th ketoconazole, 67% died. After intravenous infection, 30% of control guinea pigs died, while other animals treated with itraconazole (5 or 10 mg kg-1) or amphotericin B (1.25 or 2.5 mg kg-1) all survived. Itr aconazole 10 mg kg-1 produced the best results, with brain and meninge al cultures becoming negative in 55-64% of animals. In addition, intra venously infected guinea pigs received oral or intraperitoneal treatme nt with itraconazole or fluconazole (each 5 or 10 mg kg-1) as monother apy or in combination. Although both treatments were active, itraconaz ole 10 mg kg-1 was the most effective. In two out of six immunosuppres sed guinea pigs infected with Cr. neoformans oral itraconazole was eff ective, resulting in negative brain and meningeal cultures. A combinat ion of itraconazole (5 mg kg-1) with flucytosine or amphotericin B was more efficacious than monotherapy. Therefore, itraconazole is a poten tially effective therapy for the treatment of Cryptococcus infection w hen administered either alone or in combination with other antifungal drugs. It may also be effective in immunocompromised patients.