The Fungal Cyp51-Specific Inhibitor VT-1598 Demonstrates In Vitro and In Vivo Activity against Candida auris

Abstract

Candida auris is an emerging pathogen associated with significant mortality and often multidrug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluated in vitro and in vivo against C. auris Susceptibility testing was performed against 100 clinical isolates of C. auris by broth microdilution. Neutropenic mice were infected intravenously with C. auris, and treatment began 24 h postinoculation with a vehicle control, oral VT-1598 (5, 15, and 50 mg/kg of body weight once daily), oral fluconazole (20 mg/kg once daily), or intraperitoneal caspofungin (10 mg/kg once daily), which continued for 7 days. Fungal burden was assessed in the kidneys and brains on day 8 in the fungal burden arm and on the days the mice succumbed to infection or on day 21 in the survival arm. VT-1598 plasma trough concentrations were also assessed on day 8. VT-1598 demonstrated in vitro activity against C. auris, with a mode MIC of 0.25 μg/ml and MICs ranging from 0.03 to 8 μg/ml. Treatment with VT-1598 resulted in significant and dose-dependent improvements in survival (median survival, 15 and >21 days for VT-1598 at 15 and 50 mg/kg, respectively) and reductions in kidney and brain fungal burden (reductions of 1.88 to 3.61 log₁₀ CFU/g) compared to the control (5 days). The reductions in fungal burden correlated with plasma trough concentrations. Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to those with the control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused by C. auris.

Keywords: Candida auris; VT-1598; in vitro susceptibility; invasive candidiasis; murine model.

FIG 1

Survival curves in mice inoculated intravenously with C. auris and treated with a vehicle control, fluconazole at 20 mg/kg per os (p.o.) once daily (QD), or caspofungin at 10 mg/kg intraperitoneally (i.p.) QD (A) or VT-1598 at doses of 5 mg/kg, 15 mg/kg, and 50 mg/kg p.o. QD (B). Treatment started 1 day postinoculation and continued for 7 days. Mice were then followed off therapy until day 21 postinoculation (14 days after therapy stopped). Each group included 10 mice. Black squares, vehicle control; gray circles, fluconazole at 20 mg/kg; white inverted triangle, caspofungin at 10 mg/kg; black diamonds, VT-1598 at 5 mg/kg; gray triangles, VT-1598 at 15 mg/kg; white diamonds, VT-1598 at 50 mg/kg. *, P < 0.01 versus control; **, P < 0.001 versus control.

FIG 2

Kidney (A) and brain (B) fungal burdens in mice with invasive candidiasis secondary to C. auris in the fungal burden arm. CFU were measured on day 8 postinoculation after 7 days of therapy. The vehicle control and treatment groups included 10 mice; the 24-h control group included 5 mice. *, P < 0.01 versus control; **, P < 0.0001 versus control.

FIG 3

Kidney (A) and brain (B) fungal burdens in mice with invasive candidiasis secondary to C. auris in the survival arm. CFU were measured at the time of moribundity or at the prespecified study endpoint (day 21 postinoculation). The vehicle control and treatment groups included 10 mice; the 24-h control group included 5 mice. *, P < 0.01 versus control; **, P < 0.0001 versus control.

FIG 4

VT-1598 plasma concentration response curves as measured by changes in fungal burden in kidneys (A) and brains (B) on day 8 postinoculation after 7 days of therapy.