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

Abstract

Omadacycline is a potent aminomethylcycline with in vitro activity against Gram-positive, Gram-negative, and anaerobic bacteria. Preliminary data demonstrated that omadacycline has in vitro activity against Clostridioides difficile; however, large-scale in vitro studies have not been done. The purpose of this study was to assess the in vitro susceptibility of omadacycline and comparators on a large biobank of clinical C. difficile isolates. In vitro C. difficile 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 C. difficile isolates collected between 2015 and 2018 were tested for in vitro susceptibility of omadacycline and comparators. Ribotypes included F001 (n = 5), F002 (n = 56), F014-020 (n = 66), F017 (n = 8), F027 (n = 53), F106 (n = 45), and F255 (n = 17). Omadacycline demonstrated potent in vitro 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 C. difficile phylogeny. Further development of omadacycline as an intravenous and oral antibiotic directed toward C. difficile infection is warranted.

In Vitro Activity of Omadacycline and Five Comparators against Contemporary Ribotypes of Clostridioides difficile in Stockholm, Sweden

“…The MIC 50 and MIC 90 of omadacycline reported from the present study are comparable with the results (MIC 50 , 0.25 mg/liter, and MIC 90 , 0.5 mg/liter) from a previous study that used the agar dilution method for MIC determination among 21 clinical isolates of C. difficile ( 8 ). In contrast, our results are higher than the MIC 50 (0.031 μg/ml) and MIC 90 (0.031 μg/ml) reported in a more recent study from Texas, USA ( 11 ). The ribotypes tested and, more importantly, the method (broth microdilution) employed for MIC determination in the study reported by Begum et al were different from the ribotypes and method in our study.…”

Omadacycline and Clostridioides difficile: A Systematic Review of Preclinical and Clinical Evidence

“…In the Panel 4 study, omadacycline demonstrated potent in vitro activity, with a broth dilution MIC 50/90 value of 0.031/0.031 mg/L and MIC values ranging from 0.016 to 0.13 mg/L against 250 C. difficile isolates collected between 2015 and 2018 from 13 hospitals in the Houston, TX, region. 37 Omadacycline displayed equally potent activity among the 7 different ribotypes in this collection and regardless of CDI disease severity or vancomycin susceptibility. 37 In time-kill kinetic studies, bacterial killing was similar to (or more potent than) fidaxomicin, metronidazole, and vancomycin, with omadacycline demonstrating bactericidal effects by 24 hours (>3 log 10 colony-forming units [CFU]/mL killing).…”

“…A total of 14 studies of omadacycline and C. difficile were unanimously included covering in vitro activity, preclinical models, clinical trials, and health economics and outcomes research (HEOR); no case reports were found (Figure 1). [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]…”

Efficacy, Safety, Pharmacokinetics, and Microbiome Changes of Ibezapolstat in Adults with Clostridioides difficile Infection: A Phase 2a Multicenter Clinical Trial

“…C. difficile was strain typed using a PCR-based ribotyping method, as described elsewhere [ 14 ]. Minimum inhibitory concentrations were determined for ibezapolstat by broth microdilution in 0.1% sodium taurocholate brain heart infusion media [ 15 ].…”