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Updated: Sep 30, 2026
Passive Administration of Monoclonal Antibodies Against H. capsulatum and Others Fungal Pathogens
Published on: February 14, 2011
Antifungal therapy for central nervous system histoplasmosis, using a newly developed intracranial model of infection
Ross R Haynes1, Patricia A Connolly, Michelle M Durkin
1Histoplasmosis Reference Laboratory, Department of Medicine, Indiana University School of Medicine, 1001 W 10th Street, OPW 430, Indianapolis, IN 46202-2879, USA. rhaynes@iupui.edu
Abstract:
The outcome of central nervous system (CNS) histoplasmosis is often unfavorable. Although fluconazole plays an integral role in treatment of fungal meningitis, its role in the treatment of histoplasmosis is hampered by reduced activity and potential development of resistance. A murine model of CNS histoplasmosis was used to evaluate the hypothesis that a combination of amphotericin B and fluconazole therapy would be superior to amphotericin B monotherapy. Groups of B6C3F(1) mice were infected by injection of Histoplasma capsulatum into the subarachnoid space. The addition of fluconazole hindered the antifungal effect of amphotericin B, as determined by measurement of fungal burden, suggesting antagonism in the brain. Fluconazole was less effective as a single agent than was amphotericin B, despite the greater penetration of fluconazole into brain tissues. The hypothesis that amphotericin B-fluconazole combination therapy would be superior to amphotericin B monotherapy for treatment of CNS histoplasmosis was not supported by this study.
Insights
Combination therapy with amphotericin B and fluconazole did not improve outcomes for central nervous system (CNS) histoplasmosis in mice. This study found antagonism between the two antifungal drugs in the brain, not superiority over single-agent therapy.
Area of Science:
- Mycology
- Infectious Diseases
- Neuroscience
Background:
- Central nervous system (CNS) histoplasmosis often has poor patient outcomes.
- Fluconazole, while key for fungal meningitis, shows limited efficacy and resistance potential in histoplasmosis treatment.
- Existing treatments for CNS histoplasmosis require further optimization.
Purpose of the Study:
- To investigate if a combination therapy of amphotericin B and fluconazole is more effective than amphotericin B alone for treating experimental CNS histoplasmosis.
- To evaluate the synergistic or antagonistic effects of combining these two antifungal agents in a murine model.
Main Methods:
- A murine model of CNS histoplasmosis was established by injecting Histoplasma capsulatum into the subarachnoid space of B6C3F(1) mice.
- Mice were treated with amphotericin B monotherapy, amphotericin B plus fluconazole combination therapy, or fluconazole monotherapy.
- Fungal burden in the brain was measured to assess treatment efficacy.
Main Results:
- The addition of fluconazole to amphotericin B therapy resulted in antagonism, hindering the antifungal effect in the brain.
- Amphotericin B monotherapy was more effective than fluconazole monotherapy, despite fluconazole's superior brain tissue penetration.
- The combination therapy did not demonstrate superior efficacy compared to amphotericin B monotherapy.
Conclusions:
- The hypothesis that amphotericin B-fluconazole combination therapy would be superior to amphotericin B monotherapy for CNS histoplasmosis was not supported.
- Antagonism between amphotericin B and fluconazole may occur in the CNS, negatively impacting treatment outcomes.
- Further research is needed to identify effective combination strategies for CNS histoplasmosis.
