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

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Article numbere01120-19
JournalAntimicrobial agents and chemotherapy
Volume63
Issue number11
DOIs
StatePublished - 2019

Keywords

  • APX001
  • APX001A
  • Candida auris
  • Experimental candidiasis
  • Fluconazole resistance
  • Fosmanogepix
  • Glycosylphosphatidylinositol anchor biosynthesis pathway
  • Gwt1
  • Invasive candidiasis
  • Manogepix
  • Murine model

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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