Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models

Abstract

Coccidioidomycosis, or valley fever, is a growing health concern endemic to the southwestern United States. Safer, more effective, and more easily administered drugs are needed especially for severe, chronic, or unresponsive infections. The novel fungal CYP51 inhibitor VT-1161 demonstrated in vitro antifungal activity, with MIC50 and MIC90 values of 1 and 2 μg/ml, respectively, against 52 Coccidioides clinical isolates. In the initial animal study, oral doses of 10 and 50 mg/kg VT-1161 significantly reduced fungal burdens and increased survival time in a lethal respiratory model in comparison with treatment with a placebo (P < 0.001). Oral doses of 25 and 50 mg/kg VT-1161 were similarly efficacious in the murine central nervous system (CNS) model compared to placebo treatment (P < 0.001). All comparisons with the positive-control drug, fluconazole at 50 mg/kg per day, demonstrated either statistical equivalence or superiority of VT-1161. VT-1161 treatment also prevented dissemination of infection from the original inoculation site to a greater extent than fluconazole. Many of these in vivo results can be explained by the long half-life of VT-1161 leading to sustained high plasma levels. Thus, the efficacy and pharmacokinetics of VT-1161 are attractive characteristics for long-term treatment of this serious fungal infection.

FIG 1

Fungal burdens in brain (A) and spinal cord (B) from mice with CNS coccidioidomycosis treated with VT-1161 or fluconazole for 7 days and sacrificed 2 days later. Horizontal bars represent mean values. All treatments significantly reduced brain and spinal cord CFU counts compared to treatment with placebo (P < 0.001). Activity of VT50 was superior to that of VT25 in both brain (P = 0.036) and spinal cord (P = 0.036) and also to that of fluconazole (P < 0.001, both comparisons). Activity of VT25 was superior to that of fluconazole in brain (P = 0.007) but not in spinal cord (P = 0.136). VT25, VT-1161 25 mg/kg; VT50, VT-1161 50 mg/kg (*, 10/11 mice had no fungal growth from spinal cord at time of sacrifice).

FIG 2

Survival of mice with CNS coccidioidomycosis. Starting 48 h after infection, mice were treated with VT-1161 and fluconazole for 14 days, after which they were observed for 28 days. Both treatments significantly lengthened survival compared to treatment with a placebo (P < 0.001), and VT-1161 prolonged survival significantly longer than fluconazole (P < 0.001; analysis by Kruskal-Wallis). Diamonds, VT-1161; triangles, fluconazole; circles, placebo.

FIG 3

Brain fungal burdens of mice from the CNS coccidioidomycosis survival study. Mice were treated for 14 days, after which they were observed for 28 days. Fungal burden was quantitated when mice required sacrifice during the study or at the study termination. CFU counts for individual mice are shown in a scatterplot, with horizontal bars representing mean values. VT-1161 significantly reduced fungal burdens compared to placebo (P = 0.001) and fluconazole (P < 0.001) treatment. No statistically significant difference was observed between placebo and fluconazole results (P = 0.197). VT25, VT-1161 25 mg/kg per day. Fluconazole was given at 25 mg/kg twice daily.