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Comparison of D0870 and fluconazole in the treatment of murine cryptococcal meningitis
A L Correa1, G Velez, M Albert
1Department of Medicine University of Texas Health Science Center, San Antonio, USA.
Abstract:
Cryptococcal meningitis is a common infection in patients with AIDS. Using a murine cryptococcosis model, we compared treatment with a new triazole, D0870, and fluconazole. Groups of ICR (Institute for Cancer Research) mice were infected intracerebrally with eight different isolates of Cryptococcus neoformans variety neoformans with different in vitro susceptibilities to fluconazole. For survival studies mice were challenged with two to four times LD(50) or six to nine times LD(50). Treatment was given for 10 days. Mice were observed through to day 30. To assess the effect of treatment on fungal tissue burden, mice received a three to five times LD(50) inoculum and treatment for 10 days. They were sacrificed on day 12 and serial dilutions of brain homogenates were cultured. Fluconazole prolonged survival primarily in isolates which were susceptible in vitro. D0870 prolonged survival in all isolates except one, which was also resistant in vitro to D0870 and fluconazole. Both drugs reduced colony counts of all isolates. D0870 warrants further development for use in cryptococcosis, and appears effective for isolates relatively resistant to fluconazole. There is a relative correlation of in vivo and in vitro susceptibility to D0870 as well as fluconazole.
Insights
A new triazole, D0870, shows promise for treating cryptococcal meningitis in mice, effectively combating fluconazole-resistant strains. This finding suggests D0870 could be a valuable new antifungal therapy.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- Cryptococcal meningitis is a significant opportunistic infection in individuals with Acquired Immunodeficiency Syndrome (AIDS).
- Current antifungal treatments face challenges with drug resistance and efficacy.
Purpose of the Study:
- To compare the efficacy of a novel triazole, D0870, against fluconazole in a murine model of cryptococcosis.
- To evaluate the effectiveness of D0870 against Cryptococcus neoformans isolates with varying in vitro susceptibilities.
Main Methods:
- Intracerebral infection of ICR mice with diverse Cryptococcus neoformans isolates.
- Treatment comparison between D0870 and fluconazole over 10 days.
- Assessment of survival rates and fungal burden in brain homogenates.
Main Results:
- D0870 demonstrated survival benefits across most isolates, including those less susceptible to fluconazole.
- Fluconazole's efficacy was largely dependent on in vitro susceptibility.
- Both D0870 and fluconazole reduced fungal colony counts in the brain.
Conclusions:
- D0870 shows potential for further development as a treatment for cryptococcosis.
- D0870 appears effective against fluconazole-resistant strains.
- A correlation exists between in vivo and in vitro drug susceptibility for both D0870 and fluconazole.