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

Abstract

Candida aurisis an emerging pathogen associated with significant mortality and often multidrug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluatedin vitroandin vivoagainstC. auris. Susceptibility testing was performed against 100 clinical isolates ofC. aurisby broth microdilution. Neutropenic mice were infected intravenously withC. 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 demonstratedin vitroactivity againstC. 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 log10CFU/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 byC. auris.

The Novel Arylamidine T-2307 Demonstrates In Vitro and In Vivo Activity against Candida auris

“…In the current study, there was also a clear relationship between fungal burden and survival, as treated mice that survived to the day 21 endpoint had lower kidney and brain fungal burden compared to those that succumbed to infection. The survival and fungal burden results for the control, fluconazole, and caspofungin groups are consistent with those we have previously reported demonstrating the overall reproducibility of this model (13,14).…”

Efficacy of Delayed Therapy with Fosmanogepix (APX001) in a Murine Model of Candida auris Invasive Candidiasis

“…In addition, the tetrazole VT-1598, which acts in a similar fashion to the triazoles by inhibiting the biosynthesis of ergosterol (41), has also demonstrated in vitro and in vivo activity against C. auris (42).…”

In Vitro Activity of Ibrexafungerp (SCY-078) against Candida auris Isolates as Determined by EUCAST Methodology and Comparison with Activity against C. albicans and C. glabrata and with the Activities of Six Comparator Agents

“…A recent study from the Centers for Disease Control and Prevention (Atlanta, GA) reported that 93% of investigated C. auris isolates were resistant to fluconazole, 35% were resistant to amphotericin B, and 7% were resistant to echinocandins when susceptibility tested according to Clinical and Laboratory Standards Institute (CLSI) methodology (11). New antifungal agents, including ibrexafungerp, fosmanogepix, and VT-1578, have displayed in vitro activity against C. auris (1,(12)(13)(14)(15). Although the in vitro activity of ibrexafungerp against C. auris has been investigated by the CLSI method M27-A3, MIC data obtained using the EUCAST methodology are scarce (16).…”