SCY-078 Is Fungicidal against Candida Species in Time-Kill Studies

SCY-078 is an orally bioavailable beta-1,3-glucan synthesis inhibitor (GSI) and the first-in-class of structurally novel triterpene antifungals in clinical development for treating candidemia and invasive candidiasis. In vitro susceptibilities by broth microdilution, antifungal carryover, and time-kill dynamics were determined for three reference (ATCC) strains (Candida albicans 90028, Candida parapsilosis 90018, and Candida tropicalis 750), a quality-control (QC) strain (Candida krusei 6258), and four other strains (C. albicans MYA-2732, 64124, and 76485 and Candida glabrata 90030). Caspofungin (CASP), fluconazole (FLC), and voriconazole (VRC) were comparators. For time-kill experiments, SCY-078 and CASP were evaluated at 0.25, 1, 2, 4, 8, and 16 times the MIC80, and FLU and VRC were evaluated at 4 x MIC80. The time to reach 50%, 90%, and 99.9% reduction in the number of CFUs from the starting inoculum was determined. Net change in the number of CFU per milliliter was used to determine 50% and 90% effective concentrations and maximum effect (EC50, EC90, and E-max, respectively). The SCY-078 MIC range was between 0.0625 and 1 mu g/ml and generally similar to that of CASP. Antifungal carryover was not observed for SCY-078. SCY-078 was fungicidal against seven isolates at >= 4 x MIC (kill of >= 3 log(10)) and achieved a 1.7log10 reduction in CFU count/milliliter against C. albicans 90028. CASP behaved similarly against each isolate and achieved a 1.5-log(10) reduction in the number of CFU/milliliter against C. albicans 90028. Reductions of 50% in CFU count/milliliter were achieved rapidly (1 to 2.8 h); fungicidal endpoints were reached at 12.1 to 21.8 h at >= 4 x MIC. EC90 was reached at similar to 5 x MIC at each time point to 24 h. The EC50 and EC90 values were generally similar (8 to 24 h). Time-kill behavior of CASP was similar to that of SCY-078. FLC and VRC were fungistatic. Overall, SCY-078 has primarily fungicidal activity against Candida spp. and behaved comparably to CASP.