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The Combination Treatment of Fosmanogepix and Liposomal Amphotericin B Is Superior to Monotherapy in Treating
Teclegiorgis Gebremariam1, Yiyou Gu1, Sondus Alkhazraji1
1The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
Abstract:
Invasive pulmonary aspergillosis (IPA), invasive mucormycosis (IM), and invasive fusariosis (IF) are associated with high mortality and morbidity. Fosmanogepix (FMGX) is a first-in-class antifungal in clinical development with demonstrated broad-spectrum activity in animal models of infections. We sought to evaluate the benefit of combination therapy of FMGX plus liposomal amphotericin B (L-AMB) in severe delayed-treatment models of murine IPA, IM, and IF. While FMGX was equally as effective as L-AMB in prolonging the survival of mice infected with IPA, IM, or IF, combination therapy was superior to monotherapy in all three models. These findings were validated by greater reductions in the tissue fungal burdens (determined by quantitative PCR) of target organs in all three models versus the burdens in infected vehicle-treated (placebo) or monotherapy-treated mice. In general, histopathological examination of target organs corroborated the findings for fungal tissue burdens among all treatment arms. Our results show that treatment with the combination of FMGX plus L-AMB demonstrated high survival rates and fungal burden reductions in severe animal models of invasive mold infections, at drug exposures in mice similar to those achieved clinically. These encouraging results warrant further investigation of the FMGX-plus-L-AMB combination treatment for severely ill patients with IPA, IM, and IF.
Insights
Fosmanogepix (FMGX) plus liposomal amphotericin B (L-AMB) combination therapy significantly improved survival and reduced fungal burden in severe invasive aspergillosis, mucormycosis, and fusariosis animal models.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- Invasive pulmonary aspergillosis (IPA), invasive mucormycosis (IM), and invasive fusariosis (IF) are life-threatening fungal infections.
- Current treatments have limitations, necessitating novel therapeutic strategies.
- Fosmanogepix (FMGX) is a novel antifungal agent with broad-spectrum activity.
Purpose of the Study:
- To evaluate the efficacy of combination therapy with FMGX and liposomal amphotericin B (L-AMB) in severe murine models of IPA, IM, and IF.
- To compare combination therapy against monotherapy with either FMGX or L-AMB.
Main Methods:
- Establishment of severe delayed-treatment murine models for IPA, IM, and IF.
- Administration of FMGX, L-AMB, combination therapy, or vehicle control.
- Assessment of survival rates, tissue fungal burden (qPCR), and histopathological changes.
Main Results:
- Combination therapy demonstrated superior survival rates compared to monotherapy in all three infection models.
- Significant reductions in fungal tissue burden were observed in target organs with combination therapy.
- Histopathological findings corroborated the reduction in fungal burden.
Conclusions:
- FMGX plus L-AMB combination therapy is highly effective in reducing fungal burden and improving survival in severe invasive mold infections.
- The combination therapy achieved efficacy at clinically relevant drug exposures.
- These findings support further clinical investigation of FMGX plus L-AMB for treating invasive fungal infections.
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