Methods: The in vitro MIC values of 28 Candida species isolated from patients with CMC due to AIRE mutations were tested against VT-1598 and fluconazole (FLC), using CLSI broth microdilution M27-S4. Plasma VT-1598 levels were measured using LC-MS/MS with electrospray ionization. Tongue fungal load was determined in IL-17 deficient Act1-/- mice following sublingual C. albicans infection and once-daily oral treatment for 4 days with 25 mg/kg FLC or 3.2, 8, and 20 mg/Kg VT-1598 starting 18 hours post-infection.
Results: Among 28 Candida isolates tested (22 C. albicans, 3 C. glabrata, and 1 each of C. utilis, C. dubiliensis, and C. krusei), 10 (36%) were not susceptible to FLC, based on CLSI breakpoints (>4 mg/mL). Remarkably, all 28 isolates were highly susceptible to VT-1598 (MIC50 and MIC90, 0.06 and 0.125 mg/mL, respectively). Oral administration of VT-1598 led to mean drug levels in mouse plasma (2.0, 3.0, and 11 mg/mL at the low, mid, and high doses, respectively) that were higher than the MIC values. In vivo, VT-1598 was significantly more effective, compared to FLC, against FLC-susceptible and –resistant C. albicans, and led to elimination of fungal growth even at the lowest tested dose (3.2 mg/Kg). After a 10-day washout period from the last dose, mice treated with VT-1598 did not have mucosal fungal growth, while mice treated with FLC had tongue fungal loads similar to vehicle control.
Conclusion: VT-1598 shows in vitro activity against mucosally-derived Candida, including FLC-resistant strains. In vivo, VT-1598 achieves high plasma concentrations and eliminates viable C. albicans, even at low doses and after an extended washout period. These data indicate that VT-1598 may be a significantly improved treatment option for patients with CMC.
T. J. Break,
M. Natarajan, None
E. Ferre, None
C. Henderson, None
A. M. Zelazny, None
C. M. Yates, Viamet Pharmaceuticals, Inc.: Employee , Salary
O. J. Cohen, Viamet Pharmaceuticals, Inc.: Employee , Salary
R. J. Schotzinger, Viamet Pharmaceuticals, Inc.: Employee , Salary
E. P. Garvey, Viamet Pharmaceuticals, Inc.: Employee , Salary
M. Lionakis, Viamet Pharmaceuticals: Research support (CRADA) , Research support