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Published on: February 15, 2011
Suppression of cryptococcosis and histoplasmosis by ketoconazole in athymic nude mice
Abstract:
Congenitally athymic nude (nu/nu) mice are more susceptible to disseminated cryptococcosis and histoplasmosis than their heterozygous (nu/ + ) thymus-bearing litter-mates. The therapeutic efficacy of ketoconazole, an orally absorbable antifungal agent, was evaluated in nu/nu and nu/ + mice infected intraperitoneally with Cryptococcus neoformans and Histoplasma capsulatum. Two- to five-week courses of ketoconazole significantly prolonged the survival of nu/nu mice infected with either fungus in dose-dependent fashion, but death eventually followed discontinuance of therapy. More significant protection was seen in nu/ + mice infected with C. neoformans, and markedly lower fungal counts in organs, with some negative cultures, were seen in ketoconazole-treated nu/ + mice infected with H. capsulatum. These studies indicate that ketoconazole is effective against both fungi, although results of treatment are much better in the immunologically intact nu/ + host.
Insights
Ketoconazole shows antifungal efficacy against Cryptococcus neoformans and Histoplasma capsulatum in athymic nude mice. However, treatment outcomes are significantly better in immunocompetent mice, highlighting the role of host immunity.
Area of Science:
- Medical Mycology
- Immunology
- Pharmacology
Background:
- Congenitally athymic nude (nu/nu) mice exhibit increased susceptibility to disseminated fungal infections like cryptococcosis and histoplasmosis compared to thymus-bearing (nu/+) littermates.
- Understanding the therapeutic potential of antifungal agents in immunocompromised models is crucial for treating severe mycoses.
Purpose of the Study:
- To evaluate the therapeutic efficacy of ketoconazole, an oral antifungal, against Cryptococcus neoformans and Histoplasma capsulatum infections in both athymic nude (nu/nu) and immunocompetent (nu/+) mice.
Main Methods:
- Mice (nu/nu and nu/+) were infected intraperitoneally with C. neoformans and H. capsulatum.
- Animals received two- to five-week courses of ketoconazole.
- Survival rates and fungal burdens in organs were assessed.
Main Results:
- Ketoconazole significantly prolonged survival in nu/nu mice infected with either fungus in a dose-dependent manner, though relapses occurred after treatment cessation.
- Immunocompetent nu/+ mice showed more significant protection against C. neoformans.
- Ketoconazole treatment led to markedly lower fungal counts in organs of nu/+ mice infected with H. capsulatum, with some achieving negative cultures.
Conclusions:
- Ketoconazole demonstrates effectiveness against both C. neoformans and H. capsulatum.
- Treatment outcomes are substantially improved in immunocompetent hosts (nu/+) compared to athymic nude mice (nu/nu), underscoring the importance of host immune status in antifungal therapy.
