Therapy of experimental meningeal and disseminated cryptococcosis

This study evaluated the efficacy of itraconazole, a broad-spectrum triazole antifungal drug, which has previously been demonstrated to exhibit activity against Candida albicans C. krusei, C. glabrata, Aspergillus, Histoplasma and Blastomyces as a potential treatment for cryptococcosis. The susceptibility of 62 strains of Cryptococcus neoformans was tested in vitro. All strains were inhibited by itraconazole 0.1 microgram ml-1. Itraconazole was fungicidal after replenishment at a concentration that can easily be achieved in vivo. When mice were infected intracerebrally with Cr. neoformans all control animals died, whereas only 11% and 26% of itraconazole-treated animals died. In a group treated with 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. Itraconazole 10 mg kg-1 produced the best results, with brain and meningeal cultures becoming negative in 55-64% of animals. In addition, intravenously infected guinea pigs received oral or intraperitoneal treatment with itraconazole or fluconazole (each 5 or 10 mg kg-1) as monotherapy or in combination. Although both treatments were active, itraconazole 10 mg kg-1 was the most effective. In two out of six immunosuppressed guinea pigs infected with Cr. neoformans oral itraconazole was effective, resulting in negative brain and meningeal cultures. A combination of itraconazole (5 mg kg-1) with flucytosine or amphotericin B was more efficacious than monotherapy. Therefore, itraconazole is a potentially effective therapy for the treatment of Cryptococcus infection when administered either alone or in combination with other antifungal drugs. It may also be effective in immunocompromised patients.