Abstract
The emerging pathogenic yeast Candida auris is associated with antifungal resistance and high mortality. The novel antifungal agent manogepix (APX001A) inhibits glycosylphosphatidylinositol-anchored protein maturation and has demonstrated activity against numerous pathogenic fungi, including C. auris Our objective was to evaluate the in vivo efficacy of fosmanogepix, the N-phosphonooxymethyl prodrug (APX001), following delayed initiation of therapy in a murine model of C. auris invasive candidiasis. Neutropenic mice were intravenously infected with a fluconazole-resistant clinical isolate of C. auris Twenty-four hours postinoculation, treatment began with vehicle control, fosmanogepix (104 and 130 mg/kg of body weight by intraperitoneal injection three times daily, or intraperitoneal 260 mg/kg twice daily), fluconazole (20 mg/kg by oral gavage once daily), or caspofungin (intraperitoneal 10 mg/kg once daily) and continued for 7 days. Fungal burden was assessed via colony count in the kidneys and brains on day 8 in the fungal burden arm and on day 21 as the mice became moribund in the survival arm. Significant improvements in survival were observed in each group administered fosmanogepix and caspofungin. Similarly, reductions in fungal burden were also observed in both the kidneys and brains of mice treated with the highest dose of fosmanogepix in the fungal burden arm and in each fosmanogepix group and with caspofungin in the survival arm. In contrast, no improvements in survival or reductions in fungal burden were observed in mice treated with fluconazole. These results demonstrate that fosmanogepix is effective in vivo against fluconazole-resistant C. auris even when therapy is delayed.
Highlights
The emerging pathogenic yeast Candida auris is associated with antifungal resistance and high mortality
The objective of this study was to evaluate the in vivo efficacy of fosmanogepix in an experimental model of invasive candidiasis caused by C. auris, where the start of therapy was delayed until 24 hours after inoculation
Echinocandins are recommended for initial therapy for patients with C. auris infections
Summary
The emerging pathogenic yeast Candida auris is associated with antifungal resistance and high mortality. No improvements in survival or reductions in fungal burden were observed in mice treated with fluconazole These results demonstrate that fosmanogepix is effective in vivo against fluconazole-resistant C. auris even when therapy is delayed. Manogepix (APX001A, formerly E1210; Amplyx Pharmaceuticals, Inc., San Diego, CA) is a novel antifungal agent that inhibits the inositol acyltransferase Gwt in the glycosylphosphatidylinositol (GPI) anchor biosynthesis pathway, thereby preventing GPI-anchored protein maturation [14] This agent is administered as the N-phosphonooxymethyl prodrug fosmanogepix (APX001, formerly E1211), which is rapidly converted to the active moiety following intravenous (i.v.) or oral administration. The objective of this study was to evaluate the in vivo efficacy of fosmanogepix in an experimental model of invasive candidiasis caused by C. auris, where the start of therapy was delayed until 24 hours after inoculation
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