TY - JOUR
T1 - The Fungal Cyp51-Specific Inhibitor VT-1598 Demonstrates In Vitro and In Vivo Activity against Candida auris
AU - Wiederhold, Nathan P.
AU - Lockhart, Shawn R.
AU - Najvar, Laura K.
AU - Berkow, Elizabeth L.
AU - Jaramillo, Rosie
AU - Olivo, Marcos
AU - Garvey, Edward P.
AU - Yates, Christopher M.
AU - Schotzinger, Robert J.
AU - Catano, Gabriel
AU - Patterson, Thomas F.
N1 - Funding Information:
We thank OpAns, LLC, for bioanalysis of plasma concentrations of VT-1598. This project utilized preclinical services funded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services, under contract no. HHS272201100018I and HHSN272201700039I—Task Orders A28 and A01, respectively, to the University of Texas Health Science Center at San Antonio. N.P.W. has received research support to the UT Health San Antonio from Astellas, bioMérieux, Cidara, F2G, Merck, Pfizer, and Viamet and has served on advisory boards for Astellas and Mayne Pharma and as a speaker for Gilead. T.F.P. has received research grants to UT Health San Antonio from Astellas, Merck, and Revolution Medicines and has served as a consultant for Astellas, Gilead, Merck, Pfizer, Revolution Medicines, Toyama, Viamet, and Scynexis. L.K.N. has received travel support from Viamet Pharmaceuticals, Inc. E.P.G., C.M.Y., and R.J.S. are employees of Viamet Pharmaceuticals, Inc. The findings and conclusions of this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
Funding Information:
N.P.W. has received research support to the UT Health San Antonio from Astellas, bioMérieux, Cidara, F2G, Merck, Pfizer, and Viamet and has served on advisory boards for Astellas and Mayne Pharma and as a speaker for Gilead. T.F.P. has received research grants to UT Health San Antonio from Astellas, Merck, and Revolution Medicines and has served as a consultant for Astellas, Gilead, Merck, Pfizer, Revolution Medicines, Toyama, Viamet, and Scynexis. L.K.N. has received travel support from Viamet Pharmaceuticals, Inc. E.P.G., C.M.Y., and R.J.S. are employees of Viamet Pharmaceuticals, Inc.
Funding Information:
This project utilized preclinical services funded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services, under contract no. HHS272201100018I and HHSN272201700039I— Task Orders A28 and A01, respectively, to the University of Texas Health Science Center at San Antonio.
Publisher Copyright:
Copyright © 2019 American Society for Microbiology. All Rights Reserved.
PY - 2019/3
Y1 - 2019/3
N2 - 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 g/ml and MICs ranging from 0.03 to 8 g/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.
AB - 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 g/ml and MICs ranging from 0.03 to 8 g/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.
KW - Candida auris
KW - In vitro susceptibility
KW - Invasive candidiasis
KW - Murine model
KW - VT-1598
UR - http://www.scopus.com/inward/record.url?scp=85062276915&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062276915&partnerID=8YFLogxK
U2 - 10.1128/AAC.02233-18
DO - 10.1128/AAC.02233-18
M3 - Article
C2 - 30530603
AN - SCOPUS:85062276915
VL - 63
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 3
M1 - e02233-18
ER -