761. Impact of ascending dosages of cadazolid or vancomycin on the intestinal microbiome during treatment of C. difficile infection
Session: Poster Abstract Session: All Things Microbiome
Friday, October 9, 2015
Room: Poster Hall
Posters
  • Actelion 2 poster draft Sept 29 2015.pdf (746.6 kB)
  • Background: To assess the microbiota sparing properties of cadazolid, fecal samples retained during the conduct of the phase 2 clinical study [NTC01222702] were cultured for C. difficilecount reductions and tested post hoc for quantification of major microbiota groups with qPCR and whole community 16S profiling using next generation sequencing (NGS). 

    Methods:

    Eligible subjects with primary or first recurrences of CDI were randomized to receive 250 mg bid, 500 mg bid, or 1000 mg bid of cadazolid, or to receive vancomycin 125 qid, each for 10 days.  Paired day 0 and day 13 fecal samples from 40 patients, 10 subjects in each treatment group, were serially diluted 10-2,4,6 and plated onto CCFA agar. QPCR was performed using primer pairs for C. difficile and 8 different major intestinal bacterial groups. For NGS the V3 region of the 16s rRNA gene was PCR amplified and sequenced on the Illumina MiSeq platform. 

    Results:

    All dosages of cadazolid and vancomycin significantly reduced C. difficile counts, as measured by quantitative culture (p<0.01) and qPCR (p<0.01). qPCR analysis showed that escalating dosages of cadazolid did not reduce Bacteroidetes, Clostridium clusters XIVa and IV counts, whereas cadazolid 500 mg and 1000 mg bid reduced Bifidobacterium counts (p< 0.02). Vancomycin treatment significantly reduced all of the foregoing groups (p<0.02). Using NGS, cadazolid treatment groups had lower numbers of significantly different operational taxonomic units (OTUs) between day 0 and 13 compared to vancomycin. Cadazolid day 13 samples had no change in α-diversity while vancomycin day 13 samples had significantly lower Shannon Diversity Index relative to the day 0 samples. Vancomycin samples were characterized by large drops in the Lachnospiraceae, Clostridiaceae, Bacteroidaceae, and Prevotellaceae families, and increases in Enterobacteriaceae, Veillonellaceae, and Lactobacillaceae.

    Conclusion:

    These findings indicate that CDI subjects treated with cadazolid have less alteration to the fecal microbiome than CDI subjects treated with vancomycin. Combined with clinical outcomes, the microbial ecologic data support the selection of the cadazolid 250 mg bid dosage being investigated the in phase 3 clinical trials.

    Kaiyu Wu, PhD1, Heidi O'grady, PhD1, Matthew Workentine, PhD2, Karen Poon, PhD1, Brendan Byrne, RN1, Joseph Kim, MD1 and Thomas Louie, MD3, (1)Medicine, University of Calgary, Calgary, AB, Canada, (2)Veterinary Medicine, University of Calgary, Calgary, AB, Canada, (3)Medicine, Microbiology Immunology and Infectious Diseases, University of Calgary, Alberta Health Services, Calgary, AB, Canada

    Disclosures:

    K. Wu, None

    H. O'grady, None

    M. Workentine, None

    K. Poon, None

    B. Byrne, None

    J. Kim, None

    T. Louie, Pfizer: Consultant , no financial benefit
    Actelion: Scientific Advisor , Research grant
    Cubis: Consultant , Research grant
    daiichi sankyo: Consultant , no financial benefit
    Pfizer: Consultant , no financial benefit
    synthetic biologics: Consultant , no financial benefit
    Rebiotix: Consultant , no financial benefit

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 7th with the exception of research findings presented at the IDWeek press conferences.