title: Therapy of experimental meningeal and disseminated cryptococcosis.
abstract: 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.
authors.affiliation: Department of Bacteriology and Mycology, Janssen Research Foundation, Beerse, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Van Cutsem
mesh_terms: D000284:Administration, Oral; D000666:Amphotericin B / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003453:Cryptococcosis / Q000188:drug therapy* / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000472:pathogenicity*; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D006801:Humans; D007274:Injections, Intraperitoneal; D017964:Itraconazole / Q000008:administration & dosage / Q000627:therapeutic use; D016919:Meningitis, Cryptococcal / Q000188:drug therapy* / Q000382:microbiology; D051379:Mice; D012867:Skin / Q000382:microbiology
chemical_list: D000935:Antifungal Agents; D017964:Itraconazole; D000666:Amphotericin B