Efficacy of the Clinical Agent VT-1161 against Fluconazole-Sensitive and -Resistant Candida albicans in a Murine Model of Vaginal Candidiasis.
Antimicrob Agents Chemother. 2015 Jun 29;
Authors: Garvey EP, Hoekstra WJ, Schotzinger RJ, Sobel JD, Lilly EA, Fidel PL
Vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) remain major health problems for women. VT-1161, a novel fungal CYP51 inhibitor which has potent antifungal activity against fluconazole-sensitive Candida albicans, retained its in vitro potency (MIC50 ≤0.015 and MIC90 = 0.12 μg/ml) against 10 clinical isolates from VVC or RVVC patients resistant to fluconazole (MIC50 = 8 and MIC90 = 64 μg/ml). VT-1161 pharmacokinetics in mice displayed a high volume of distribution (1.4 L/kg), high oral absorption (73%) and long half-life (>48 h), and showed rapid penetration into vaginal tissue. In a murine model of vaginal candidiasis using fluconazole-sensitive yeast, oral doses as low as 4 mg/kg VT-1161 significantly reduced fungal burden 1 and 4 days post-treatment (P values <0.0001). Similar VT-1161 efficacy was measured when an isolate highly resistant to fluconazole (MIC = 64 μg/ml) but fully sensitive in vitro to VT-1161 was used. When an isolate partially sensitive to VT-1161 (MIC = 0.12 μg/ml) and moderately resistant to fluconazole (MIC = 8 μg/ml) was used, VT-1161 remained efficacious, whereas fluconazole was efficacious on day 1 but did not sustain efficacy 4-days post-treatment. Both agents were inactive in treating an infection with an isolate that demonstrated weaker potency (2 and 64 μg/ml for VT-1161 and fluconazole, respectively). Finally, plasma concentrations of free VT-1161 were predictive of efficacy when in excess of in vitro MIC values. These data support the clinical development of VT-1161 as a potentially more efficacious treatment of VVC and RVVC.
PMID: 26124165 [PubMed - as supplied by publisher]