TY - JOUR
T1 - The novel fungal Cyp51 inhibitor VT-1598 is efficacious in experimental models of central nervous system coccidioidomycosis caused by Coccidioides posadasii and Coccidioides immitis
AU - Wiederhold, Nathan P.
AU - Shubitz, Lisa F.
AU - Najvar, Laura K.
AU - Jaramillo, Rosie
AU - Olivo, Marcos
AU - Catano, Gabriel
AU - Trinh, Hien T.
AU - Yates, Christopher M.
AU - Schotzinger, Robert J.
AU - Garvey, Edward P.
AU - Patterson, Thomas F.
N1 - Publisher Copyright:
Copyright © 2018 American Society for Microbiology. All Rights Reserved.
PY - 2018/4
Y1 - 2018/4
N2 - Coccidioidal meningitis can cause significant morbidity, and lifelong antifungal therapy is often required. VT-1598 is a fungus-specific Cyp51 inhibitor that has potent in vitro activity against Coccidioides species. We evaluated the in vivo efficacy of VT-1598 in murine models of central nervous system coccidioidomycosis caused by C. posadasii and C. immitis. Infection was introduced via intracranial inoculation, and therapy began 48 h postinoculation. Oral treatments consisted of vehicle control, VT-1598, and positive controls of fluconazole in the C. immitis study and VT-1161 in the C. posadasii study. Treatment continued for 7 and 14 days in the fungal-burden and survival studies, respectively. Fungal burden was assessed in brain tissue collected 24 to 48 h posttreatment in the fungal-burden studies, on the days the mice succumbed to infection, or at prespecified endpoints in the survival studies. VT-1598 plasma concentrations were also measured in the C. posadasii study. VT- 1598 resulted in significant improvements in survival in mice infected with either species. In addition, the fungal burden was significantly reduced in the fungalburden studies. Plasma concentrations 48 h after dosing stopped remained above the VT-1598 MIC against the C. posadasii isolate, although levels were undetectable in the survival study after a 4-week washout. Whereas fungal burden remained suppressed after a 2-week washout in the C. immitis model, a higher fungal burden was observed in the survival arm of the C. posadasii model. This in vivo efficacy supports human studies to establish the utility of VT-1598 for the treatment of coccidioidomycosis.
AB - Coccidioidal meningitis can cause significant morbidity, and lifelong antifungal therapy is often required. VT-1598 is a fungus-specific Cyp51 inhibitor that has potent in vitro activity against Coccidioides species. We evaluated the in vivo efficacy of VT-1598 in murine models of central nervous system coccidioidomycosis caused by C. posadasii and C. immitis. Infection was introduced via intracranial inoculation, and therapy began 48 h postinoculation. Oral treatments consisted of vehicle control, VT-1598, and positive controls of fluconazole in the C. immitis study and VT-1161 in the C. posadasii study. Treatment continued for 7 and 14 days in the fungal-burden and survival studies, respectively. Fungal burden was assessed in brain tissue collected 24 to 48 h posttreatment in the fungal-burden studies, on the days the mice succumbed to infection, or at prespecified endpoints in the survival studies. VT-1598 plasma concentrations were also measured in the C. posadasii study. VT- 1598 resulted in significant improvements in survival in mice infected with either species. In addition, the fungal burden was significantly reduced in the fungalburden studies. Plasma concentrations 48 h after dosing stopped remained above the VT-1598 MIC against the C. posadasii isolate, although levels were undetectable in the survival study after a 4-week washout. Whereas fungal burden remained suppressed after a 2-week washout in the C. immitis model, a higher fungal burden was observed in the survival arm of the C. posadasii model. This in vivo efficacy supports human studies to establish the utility of VT-1598 for the treatment of coccidioidomycosis.
KW - Coccidioidal meningitis
KW - Coccidioides immitis
KW - Coccidioides posadasii
KW - Fluconazole
KW - Murine model
KW - VT-1598
UR - http://www.scopus.com/inward/record.url?scp=85044518976&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044518976&partnerID=8YFLogxK
U2 - 10.1128/AAC.02258-17
DO - 10.1128/AAC.02258-17
M3 - Article
C2 - 29437615
AN - SCOPUS:85044518976
SN - 0066-4804
VL - 62
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 4
M1 - e02258-17
ER -