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Ketoconazole in early and late murine coccidioidomycosis
Abstract:
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.
Insights
Early treatment with ketoconazole (35 mg/kg) prevented Coccidioides immitis dissemination in mice. While life-preserving, later treatment showed reduced fungal eradication, highlighting the importance of early intervention.
Area of Science:
- Mycology
- Pharmacology
- Infectious Diseases
Background:
- Coccidioides immitis causes pulmonary and disseminated infections.
- Antifungal drug efficacy is crucial for managing coccidioidomycosis.
- Ketoconazole's in vitro antifungal activity warrants in vivo investigation.
Purpose of the Study:
- To evaluate the in vivo efficacy of ketoconazole in a murine model of Coccidioides immitis infection.
- To determine the impact of treatment timing on ketoconazole's effectiveness against disseminated coccidioidomycosis.
Main Methods:
- Mice were infected intranasally with Coccidioides immitis arthrospores.
- Ketoconazole (35 mg/kg) was administered orally twice daily at different time points post-infection.
- Survival rates, fungal burden, and lesion progression were assessed.
Main Results:
- Early ketoconazole treatment (day 4) prevented mortality and extrapulmonary dissemination.
- Later treatment (day 12) was life-preserving but showed incomplete fungal eradication in lungs and peritoneal organs.
- Delayed treatment (days 35-120) further reduced mortality in survivors of a lethal challenge dose.
Conclusions:
- Ketoconazole demonstrates in vivo antifungal activity against Coccidioides immitis in mice.
- Optimal mycologic cure is achieved with early initiation of ketoconazole therapy.
- Eradication of established Coccidioides immitis infections, particularly in peritoneal organs, is challenging.