The Fungal Cyp51-Specific Inhibitor VT-1598 Demonstrates In Vitro and In Vivo Activity against 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 and against Susceptibility testing was performed against 100 clinical isolates of by broth microdilution. Neutropenic mice were infe...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2019-03, Vol.63 (3)
Main Authors: Wiederhold, Nathan P, Lockhart, Shawn R, Najvar, Laura K, Berkow, Elizabeth L, Jaramillo, Rosie, Olivo, Marcos, Garvey, Edward P, Yates, Christopher M, Schotzinger, Robert J, Catano, Gabriel, Patterson, Thomas F
Format: Article
Language:English
Subjects:
14-alpha Demethylase Inhibitors
14-alpha Demethylase Inhibitors - therapeutic use
Animals
Antifungal Agents
Antifungal Agents - therapeutic use
Candida
Candida - drug effects
Candidiasis, Invasive
Candidiasis, Invasive - drug therapy
Candidiasis, Invasive - microbiology
Caspofungin - therapeutic use
Disease Models, Animal
Experimental Therapeutics
Fluconazole - therapeutic use
Humans
Mice
Microbial Sensitivity Tests
Pyridines
Pyridines - therapeutic use
Sterol 14-Demethylase - metabolism
Tetrazoles
Tetrazoles - therapeutic use
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Summary:is an emerging pathogen associated with significant mortality and often multidrug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluated and against Susceptibility testing was performed against 100 clinical isolates of by broth microdilution. Neutropenic mice were infected intravenously with , 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 activity against , 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 log 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 .
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.02233-18