1369. Combined Analysis of the In Vitro Activity of Ridinilazole (RDZ) Against More Than 500 Clostridium difficile (CD) Clinical Isolates and Impact of RDZ on Cell Morphology. (26th November 2018) - Duperchy, Esther
Abstract: Background: Clostridium difficile infection (CDI) is one of the most urgent bacterial healthcare threats in the United States. RDZ is a targeted spectrum, GI restricted, antibacterial currently in clinical development for the treatment of CDI and reducing the recurrence of CDI. Here we report the combined analysis of previously reported and new independent studies assessing the susceptibility of CD clinical isolates collected in North America and Europe between 2010 and 2015, and the effect of RDZ on cell morphology. Methods: A total of 570 CD clinical isolates across seven independent studies were tested for susceptibility. The majority of isolates (>70%) were sourced from RDZ Phase 2 clinical trials and North American and European surveillance programs. Minimum inhibitory concentrations (MIC) were determined by agar dilution on Wilkins Chalgren agar plates after 48 hours incubation at 37 o C, or, by agar or microbroth dilution using supplemented Brucella medium following the CLSI guidelines M11-A7/A8. Up to 11 comparator antibiotics were tested alongside RDZ. PCR ribotyping was performed on 549 isolates by capillary gel electrophoresis. To investigate the impact of RDZ on cell morphology, CD strain R20291 was incubated with RDZ at 0.125–0.5 × MIC concentrations for 24 hours. DAPI and FM4-64 staining was used to visualize DNA and cell membrane by confocal microscopy. Results: RDZ was highly active against the isolates collected in North America and Europe with MICs distributed over a narrow range (0.015–0.5 μg/mL) and an overall MIC90 of 0.25 μg/mL. There was no variation in activity by geographic region or ribotype, including hypervirulent ribotype 027 isolates ( N = 83). RDZ also maintained activity against antibiotic-resistant isolates, including isolates with reduced susceptibility to metronidazole and vancomycin. When treated with sub-MIC concentrations of RDZ, CD cells formed filamentous structures with a dose-dependent effect on cell length and decreased septum formation. This preliminary data suggest that RDZ may alter CD cell division. Conclusion: These data show that RDZ was highly active against recent CD isolates independent of geographic origin, ribotype, and antibiotic resistance profile. Mechanism of action studies are ongoing and further susceptibility profiling will be undertaken during the Phase 3. Disclosures: E. Duperchy, Summit Therapeutics: Employee, Salary. E. Bassères, Summit Therapeutics: Collaborator, Research support. K. Garey, Summit Therapeutics: Collaborator, Research support. R. Vickers, Summit Therapeutics: Employee, Salary and Stock options.