Methods: Susceptibility testing was to CLSI standards with VAN, MTZ and fidaxomicin (FDX) comparators. The Phase 2 clinical trial was a double-blind, randomised study of 100 patients assigned 1:1 to 10 days RDZ 200 mg BID or VAN 125 mg QID treatment. Primary endpoint was sustained clinical response (SCR), defined as cure at end of therapy (EOT) and no rCDI for the next 30 days. Relative effects of RDZ and VAN on the gut microbiome was examined by sequencing 16S rDNA amplicons from stool collected at baseline, days 5, 10, 25 and end of study. Bioinformatic analyses were performed in QIIME.
Results: RDZ C. difficile (N=50) MIC range was 0.125-0.25μg/mL. Clostridium spp. showed varied RDZ susceptibility; C. innocuum MIC90 1μg/mL, C. ramosum and C. perfringens MIC90 >512μg/mL. VAN showed potent to moderate growth inhibition of all Clostridium spp. (MIC range 1-16µg/mL). Limited RDZ activity was observed for Gram positive anaerobes including Bifidobacteria, Eggerthella, Finegoldia, and Peptostreptococcus (MIC90 >512, >512, 64 and 64 μg/mL) compared to VAN (MIC90 1, 4, 0.5 and 0.5 μg/mL). Bacteroides fragilis MIC90 for RDZ and VAN were >512 and 64µg/mL, respectively. These in vitro data correlate closely with human microbiome profiles. RDZ reduced C. difficile to below detection with other reductions in abundancy observed in only 2 families from the Clostridia. VAN at EOT resulted in significant losses, often below detection, in four Firmicutes families, Actinobacteria, and Bacteroidetes and a 25-fold increase in Proteobacteria abundance. The preservation of the microbiome by RDZ likely accounted for reduced rCDI compared to VAN with RDZ shown to be superior on SCR to VAN with rates of 66.7% and 42.4%, respectively (pre-specified 90% CI 3.1, 39.1).
Conclusion: These data demonstrate strong translation of in vitro spectrum to human gut microbiome preservation during therapy and support further clinical development of RDZ.
D. Citron, Summit Therapeutics: Grant Investigator , Research grant .
D. Snydman, Summit Therapeutics: Grant Investigator , Grant recipient .
C. M. Thorpe, Summit Therapeutics: Grant Investigator and Scientific Advisor , Consulting fee and Grant recipient .
A. V. Kane, Summit Therapeutics: Grant Investigator , Grant recipient .