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Therapy of systemic histoplasmosis in immunosuppressed mice with the triazole D0870
K V Clemons1, M Martinez, M E Homola
1Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA 95128, USA.
Abstract:
Because histoplasmosis is a life-threatening disease in AIDS and other compromised patients, we examined the efficacy of D0870 (Zeneca) in immunosuppressed mice against systemic histoplasmosis. Oral therapy with fluconazole given once daily (QD) was ineffective in prolonging survival, whereas itraconazole given once or twice daily (BID), fluconazole given BID or D0870 given QD or given every other day (QOD) were efficacious (P < 0.001). Burdens of Histoplasma capsulatum in the liver and spleen of survivors showed that D0870 given QD or QOD and itraconazole given BID caused dose-responsive reduction of infectious burden. Infection was cleared more readily from the liver than from the spleen. Overall, D0870 was > or = 20-fold more efficacious than fluconazole or itraconazole and itraconazole was > ten-fold better than fluconazole for the treatment of systemic histoplasmosis in the immunosuppressed model.
Insights
A new antifungal, D0870, effectively treats systemic histoplasmosis in immunosuppressed mice. It significantly outperformed fluconazole and itraconazole in this critical animal model.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- Histoplasmosis poses a severe threat to individuals with compromised immune systems, including AIDS patients.
- Developing effective treatments for systemic histoplasmosis in immunocompromised populations is crucial.
Purpose of the Study:
- To evaluate the efficacy of D0870, an antifungal agent, against systemic histoplasmosis in an immunosuppressed mouse model.
- To compare the therapeutic effectiveness of D0870 with fluconazole and itraconazole.
Main Methods:
- Immunosuppressed mice were infected with Histoplasma capsulatum.
- Animals received oral treatments including fluconazole (once daily), itraconazole (once or twice daily), and D0870 (once daily or every other day).
- Survival rates and fungal burdens in the liver and spleen were assessed to determine treatment efficacy.
Main Results:
- D0870 (once daily or every other day), itraconazole (twice daily), and fluconazole (twice daily) significantly prolonged survival compared to untreated controls (P < 0.001).
- D0870 and itraconazole demonstrated a dose-responsive reduction in fungal burdens in the liver and spleen.
- D0870 was at least 20-fold more efficacious than fluconazole or itraconazole; itraconazole was over 10-fold better than fluconazole.
Conclusions:
- D0870 is a highly effective agent for treating systemic histoplasmosis in an immunosuppressed model.
- D0870 exhibits superior efficacy compared to fluconazole and itraconazole, suggesting its potential as a valuable therapeutic option.
- The study highlights the differential clearance of infection from the liver and spleen, with the liver clearing more readily.