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Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2015 Dec; Vol. 59 (12), pp. 7249-54. Date of Electronic Publication: 2015 Sep 14. - Publication Year :
- 2015
-
Abstract
- Coccidioidomycosis, or valley fever, is a growing health concern endemic to the southwestern United States. Safer, more effective, and more easily administered drugs are needed especially for severe, chronic, or unresponsive infections. The novel fungal CYP51 inhibitor VT-1161 demonstrated in vitro antifungal activity, with MIC50 and MIC90 values of 1 and 2 μg/ml, respectively, against 52 Coccidioides clinical isolates. In the initial animal study, oral doses of 10 and 50 mg/kg VT-1161 significantly reduced fungal burdens and increased survival time in a lethal respiratory model in comparison with treatment with a placebo (P < 0.001). Oral doses of 25 and 50 mg/kg VT-1161 were similarly efficacious in the murine central nervous system (CNS) model compared to placebo treatment (P < 0.001). All comparisons with the positive-control drug, fluconazole at 50 mg/kg per day, demonstrated either statistical equivalence or superiority of VT-1161. VT-1161 treatment also prevented dissemination of infection from the original inoculation site to a greater extent than fluconazole. Many of these in vivo results can be explained by the long half-life of VT-1161 leading to sustained high plasma levels. Thus, the efficacy and pharmacokinetics of VT-1161 are attractive characteristics for long-term treatment of this serious fungal infection.<br /> (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Subjects :
- 14-alpha Demethylase Inhibitors blood
14-alpha Demethylase Inhibitors pharmacokinetics
Animals
Antifungal Agents blood
Antifungal Agents pharmacokinetics
Coccidioides enzymology
Coccidioides growth & development
Coccidioidomycosis microbiology
Coccidioidomycosis mortality
Coccidioidomycosis pathology
Disease Models, Animal
Female
Fluconazole blood
Fluconazole pharmacokinetics
Fungal Proteins antagonists & inhibitors
Fungal Proteins genetics
Fungal Proteins metabolism
Fungemia microbiology
Fungemia mortality
Fungemia pathology
Half-Life
Humans
Mice
Microbial Sensitivity Tests
Pyridines blood
Pyridines pharmacokinetics
Sterol 14-Demethylase genetics
Sterol 14-Demethylase metabolism
Survival Analysis
Tetrazoles blood
Tetrazoles pharmacokinetics
Treatment Outcome
14-alpha Demethylase Inhibitors pharmacology
Antifungal Agents pharmacology
Coccidioides drug effects
Coccidioidomycosis drug therapy
Fluconazole pharmacology
Fungemia prevention & control
Pyridines pharmacology
Tetrazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 59
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 26369964
- Full Text :
- https://doi.org/10.1128/AAC.00593-15