Ketoconazole in early and late murine coccidioidomycosis.

Ketoconazole (35 mg/kg) was administered orally to mice twice daily, beginning at different intervals after intranasal infection with arthrospores of Coccidioides immitis. When treatment was begun on the fourth day after infection, before extensive extrapulmonary dissemination of the infection had occurred, all animals survived, and extension of the disease from lungs to liver, spleen, and kidneys was prevented. Mortality was 90% in untreated control animals. In most of the drug-treated animals, lung lesions were not rendered free of fungus after 21 days of treatment. When treatment was begun on the 12th day of infection, after extrapulmonary dissemination had occurred, the drug was life-preserving. However, lesions of the peritoneal organs of 30%--60% of the surviving animals and pulmonary lesions of 90% of these animals harbored viable fungi after 82 days of treatment. Mortality was lower when treatment was given from the 35th through the 120th day after infection to survivors of a challenge dose that was lethal to 28% of the animals within 30 days. These data indicate that the antifungal activity of the drug observed in vitro also operates in vivo. Mycologic cure was optimal when infections were treated early. It became difficult to eradicate the fungus once it became entrenched in lesions of the peritoneal organs or lungs.