In Vitro Activity of Omadacycline, a New Tetracycline Analog, and Comparators against Clostridioides difficile.

Omadacycline is a potent aminomethylcycline with <i>in vitro</i> activity against Gram-positive, Gram-negative, and anaerobic bacteria. Preliminary data demonstrated that omadacycline has <i>in vitro</i> activity against <i>Clostridioides difficile</i>; however, large-scale <i>in vitro</i> studies have not been done. The purpose of this study was to assess the <i>in vitro</i> susceptibility of omadacycline and comparators on a large biobank of clinical <i>C. difficile</i> isolates. <i>In vitro</i> <i>C. difficile</i> susceptibility to omadacycline and comparators (fidaxomicin, metronidazole, and vancomycin) was assessed using the broth microdilution method. Minimum bactericidal concentrations (MBCs) and time-kill assays were assessed for pharmacodynamics analysis, and whole-genome sequencing was performed in a subset of isolates to assess distribution of MICs and resistance determinants. Two hundred fifty clinical <i>C. difficile</i> isolates collected between 2015 and 2018 were tested for <i>in vitro</i> susceptibility of omadacycline and comparators. Ribotypes included F001 (<i>n</i> = 5), F002 (<i>n</i> = 56), F014-020 (<i>n</i> = 66), F017 (<i>n</i> = 8), F027 (<i>n</i> = 53), F106 (<i>n</i> = 45), and F255 (<i>n</i> = 17). Omadacycline demonstrated potent <i>in vitro</i> activity with an MIC range of 0.016 to 0.13 μg/ml, an MIC₅₀ of 0.031 μg/ml, and an MIC₉₀ of 0.031 μg/ml. No difference was observed for omadacycline MIC₅₀ and MIC₉₀ values stratified by ribotype, disease severity, or vancomycin susceptibility. Bactericidal activity was confirmed in time-kill studies. No difference was observed in MIC based on <i>C. difficile</i> phylogeny. Further development of omadacycline as an intravenous and oral antibiotic directed toward <i>C. difficile</i> infection is warranted.