Oral glucan synthase inhibitor SCY-078 is effective in an experimental murine model of invasive candidiasis caused by WT and echinocandin-resistant Candida glabrata

Abstract

Background: Echinocandins are recommended as first-line therapy against Candida glabrata infections, although increased resistance to this class has been reported worldwide and they are currently only available for parenteral administration. SCY-078 is an investigational glucan synthase inhibitor that is orally available. Objectives: To evaluate the in vivo efficacy of SCY-078 in an experimental model of invasive candidiasis due to WT and echinocandin-resistant C. glabrata isolates. Methods: Neutropenic ICR mice were inoculated intravenously with a WT isolate (SCY-078 and caspofungin MICs 0.25 and 0.125 mg/L, respectively) or an echinocandin-resistant isolate (SCY-078 and caspofungin MICs 1 and 0.5 mg/L, respectively). Treatment with placebo, SCY-078 (8, 30 or 40 mg/kg orally every 12 h) or caspofungin (1 mg/kg by intraperitoneal injection once daily) began 24 h later. Kidney fungal burden was measured on day 8 post-inoculation. Results: Significant reductions in kidney fungal burden were observed with 30 mg/kg SCY-078 against both isolates and with the 40 mg/kg dose against the echinocandin-resistant isolate. These results were supported by SCY-078 plasma concentration data at the higher doses, where levels above the MICs for both isolates were observed 12 h after the last oral dose. Reductions in fungal burden were also observed with caspofungin against the WT isolate, but not against the resistant isolate. Conclusions: SCY-078 demonstrated in vivo efficacy against infections caused by both WT and echinocandin-resistant C. glabrata isolates in this experimental model. This orally available glucan synthase inhibitor has potential as a therapy against echinocandin-resistant C. glabrata infections.