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Published on: May 25, 2017
In Vitro Activity of Omadacycline, a New Tetracycline Analog, and Comparators against Clostridioides difficile
Khurshida Begum1, Eugénie Bassères1, Julie Miranda1
1University of Houston College of Pharmacy, Houston, Texas, USA.
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 vitroC. 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.
Insights
Omadacycline shows strong in vitro activity against Clostridioides difficile, including resistant strains. This potent aminomethylcycline warrants further development as a treatment for C. difficile infections.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Omadacycline is a novel aminomethylcycline antibiotic with broad-spectrum in vitro activity.
- Preliminary data suggested potential efficacy against Clostridioides difficile (C. difficile), but large-scale studies were lacking.
Purpose of the Study:
- To evaluate the in vitro susceptibility of a large collection of clinical C. difficile isolates to omadacycline.
- To compare omadacycline's activity against C. difficile with established antibiotics: fidaxomicin, metronidazole, and vancomycin.
Main Methods:
- Broth microdilution method was used to determine minimum inhibitory concentrations (MICs) for 250 clinical C. difficile isolates.
- Minimum bactericidal concentrations (MBCs) and time-kill assays were performed for pharmacodynamic analysis.
- Whole-genome sequencing was conducted on a subset of isolates to identify resistance determinants and analyze MIC distributions.
Main Results:
- Omadacycline exhibited potent in vitro activity against C. difficile, with an MIC range of 0.016 to 0.13 μg/ml (MIC50/MIC90 = 0.031 μg/ml).
- Activity was consistent across various ribotypes, disease severities, and vancomycin susceptibility profiles.
- Time-kill studies confirmed bactericidal activity, and no significant MIC variations were observed based on C. difficile phylogeny.
Conclusions:
- Omadacycline demonstrates significant in vitro potency and bactericidal activity against a diverse panel of clinical C. difficile isolates.
- The consistent efficacy across different C. difficile strains supports omadacycline's potential as a therapeutic option.
- Further clinical development of omadacycline for treating C. difficile infections, via both oral and intravenous routes, is recommended.
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