Journal Article

Enhanced preservation of the human intestinal microbiota by ridinilazole, a novel Clostridium difficile-targeting antibacterial, compared to vancomycin

Snydman, David R., Thorpe, Cheleste M., Kane, Anne V., Vickers, Richard J., Tai, Albert, Chang, Justin

2018

Overview

Ridinilazole, a novel targeted antibacterial being developed for the treatment of C. difficile infection (CDI) and prevention of recurrence, was shown in a recent Phase 2 study to be superior to vancomycin with regard to the primary efficacy measure, sustained clinical response (SCR), with the superiority being driven primarily by marked reductions in the rates of CDI recurrence within 30 days. Tolerability of ridinilazole was comparable to that of vancomycin. The current nested cohort study compared the effects of ridinilazole and vancomycin on fecal microbiota during and after treatment among participants in the Phase 2 study. Changes in the microbiota were assessed using qPCR and high-throughput sequencing on participants' stools collected at multiple time-points (baseline [Day 1], Day 5, end-of-treatment [EOT; Day 10], Day 25, end-of-study [EOS; Day 40], and at CDI recurrence). qPCR analyses showed profound losses of Bacteroides, C. coccoides, C. leptum, and Prevotella groups at EOT with vancomycin treatment, while ridinilazole-treated participants had a modest decrease in C. leptum group levels at EOT, with levels recovering by Day 25. Vancomycin-treated participants had a significant increase in the Enterobacteriaceae group, with this increase persisting beyond EOT. At EOT, alpha diversity decreased with both antibiotics, though to a significantly lesser extent with ridinilazole (p <0.0001). Beta diversity analysis showed a significantly larger weighted Unifrac distance from baseline-to-EOT with vancomycin. Taxonomically, ridinilazole had a markedly narrower impact, with modest reductions in relative abundance in Firmicutes taxa. Microbiota composition returned to baseline sooner with ridinilazole than with vancomycin. Vancomycin treatment resulted in microbiome-wide changes, with significant reductions in relative abundances of Firmicutes, Bacteroidetes, Actinobacteria, and a profound increase in abundance of Proteobacteria. These findings demonstrate that ridinilazole is significantly less disruptive to microbiota than vancomycin, which may contribute to the reduced CDI recurrence observed in the Phase 2 study.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Abundance / Actinobacteria - drug effects / Actinobacteria - isolation & purification / Anti-Bacterial Agents - pharmacology / Anti-Bacterial Agents - therapeutic use / Antibacterial agents / Antibiotics / Antiinfectives and antibacterials / Antimicrobial agents / Benzimidazoles - pharmacology / Benzimidazoles - therapeutic use / Biology and Life Sciences / Campeloma leptum / Clinical trials / Clostridioides difficile - drug effects / Clostridioides difficile - genetics / Clostridioides difficile - isolation & purification / Clostridium difficile / Clostridium Infections - drug therapy / Clostridium Infections - microbiology / Cohort Studies / Comparative analysis / Computer and Information Sciences / Deoxyribonucleic acid / Discriminant Analysis / DNA / DNA, Bacterial - chemistry / DNA, Bacterial - isolation & purification / DNA, Bacterial - metabolism / Dosage and administration / Drug therapy / Enrollments / Fecal microflora / Feces / Feces - microbiology / Firmicutes / Firmicutes - drug effects / Firmicutes - isolation & purification / Gastrointestinal Microbiome - drug effects / Humans / Infections / Intestinal microflora / Intestine / Medicine / Medicine and Health Sciences / Microbiomes / Microbiota / Microbiota (Symbiotic organisms) / Next-generation sequencing / Phase transitions / Preservation / Prevention / Principal Component Analysis / Proteobacteria - drug effects / Proteobacteria - isolation & purification / Pyridines - pharmacology / Pyridines - therapeutic use / Relative abundance / Taxonomy / Vancomycin / Vancomycin - pharmacology / Vancomycin - therapeutic use