Efficacy of Delayed #Therapy with #Fosmanogepix (APX001) in a Murine Model of #Candida auris Invasive #Candidiasis (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Efficacy of Delayed Therapy with Fosmanogepix (APX001) in a Murine Model of Candida auris Invasive Candidiasis

Nathan P. Wiederhold, Laura K. Najvar, Karen J. Shaw, Rosie Jaramillo, Hoja Patterson, Marcos Olivo, Gabriel Catano, Thomas F. Patterson

DOI: 10.1128/AAC.01120-19

 

ABSTRACT

The emerging pathogenic yeast Candida auris is associated with antifungal resistance and high mortality. The novel antifungal 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 post-inoculation, treatment began with vehicle control, fosmanogepix (104 and 130 mg/kg by intraperitoneal injection three times daily, or 260 mg/kg intraperitoneally twice daily), fluconazole (20 mg/kg by oral gavage once daily), or caspofungin (10 mg/kg intraperitoneally once daily) and continued for seven 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.

Copyright © 2019 Wiederhold et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Keywords: Candida auris; Invasive candidiasis; Drugs resistance; Fluconazole; Fosmanogepix; Capsofungin; Animal models.

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