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
Session: Poster Abstract Session: Novel Agents
Friday, October 5, 2018
Room: S Poster Hall
Posters
  • Summit - ID week 2018 Microbio MOA poster_FINAL26Sep2018_ED2.pdf (1.9 MB)
  • Background: Clostridium difficile infection (CDI) is one of the most urgent bacterial healthcare threats in the USA. 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 2010-2015, and, the effect of RDZ on cell morphology.

    Methods: A total of 570 CD clinical isolates across 7 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 48h incubation at 37oC, 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 0.125-0.5xMIC concentrations for 24h. DAPI and FM4-64 staining was used to visualise 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.

    Esther Duperchy, PhD1, Eugénie Bassères, PhD2, Kevin Garey, PharmD, MS3 and Richard Vickers, PhD1, (1)R&D, Summit Therapeutics, Abingdon, United Kingdom, (2)University of Houston College of Pharmacy, Houston, TX, (3)Univ. of Houston Coll. of Pharmacy, Houston, TX

    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 .

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