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

<div><p>Ridinilazole, a novel targeted antibacterial being developed for the treatment of <i>C</i>. <i>difficile</i> 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 <i>Bacteroides</i>, <i>C</i>. <i>coccoides</i>, <i>C</i>. <i>leptum</i>, and <i>Prevotella</i> groups at EOT with vancomycin treatment, while ridinilazole-treated participants had a modest decrease in <i>C</i>. <i>leptum</i> 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.</p></div

Comparison of alpha diversity measures between baseline and end-of-treatment (EOT) within each treatment arm (horizontal), and between treatment arms (vertical).

<p>Comparison of alpha diversity measures between baseline and end-of-treatment (EOT) within each treatment arm (horizontal), and between treatment arms (vertical).</p

Effects of vancomycin and ridinilazole on relative abundance of taxa at baseline vs end-of-therapy.

<p>Cladograms were generated by LEfSe showing taxa with significantly higher relative abundance at baseline in red, and those with significantly higher relative abundance at end-of-therapy (EOT) in green. The phylogenetic tree is represented by concentric rings with phyla located at the innermost ring and subsequent taxonomic levels descend outwards to the species level. Panel A: Ridinilazole; Panel B: Vancomycin.</p

Comparison of bacterial group median quantities at each timepoint within treatment arms.

<p>Comparison of bacterial group median quantities at each timepoint within treatment arms.</p

Microbiota levels belonging to different taxonomic groups measured by qPCR in samples from study participants and 14 healthy controls.

<p>Red circles represent participants treated with ridinilazole and blue circles represent participants treated with vancomycin. Bolded bars represent the median of all samples at that time point.</p

Beta diversity between participants receiving ridinilazole or vancomycin and normal controls.

<p>Principal co-ordinate analysis was performed between samples at baseline and EOT from participants receiving ridinilazole or vancomycin in the vegan package in R on weighted Unifrac distances generated in QIIME. For another comparator, healthy controls are also shown. Ellipses represent 95% confidence interval of each cluster. Abbreviations: RDZ, ridinilazole; VAN, vancomycin; PC1, first Principal co-ordinate; PC2, second principal co-ordinate.</p

Taxa to the genus level with ≥2-fold change in relative abundance from baseline to end of treatment (EOT) with vancomycin or ridinilazole.

<p>Taxa to the genus level with ≥2-fold change in relative abundance from baseline to end of treatment (EOT) with vancomycin or ridinilazole.</p

Longitudinal Analysis of the Intestinal Microbiota in Persistently Stunted Young Children in South India

<div><p>Stunting or reduced linear growth is very prevalent in low-income countries. Recent studies have demonstrated a causal relationship between alterations in the gut microbiome and moderate or severe acute malnutrition in children in these countries. However, there have been no primary longitudinal studies comparing the intestinal microbiota of persistently stunted children to that of non-stunted children in the same community. In this pilot study, we characterized gut microbial community composition and diversity of the fecal microbiota of 10 children with low birth weight and persistent stunting (cases) and 10 children with normal birth weight and no stunting (controls) from a birth cohort every 3 months up to 2 years of age in a slum community in south India. There was an increase in diversity indices (P <0.0001) with increasing age in all children. However, there were no differences in diversity indices or in the rates of their increase with increasing age between cases and controls. The percent relative abundance of the Bacteroidetes phylum was higher in stunted compared to control children at 12 months of age (P = 0.043). There was an increase in the relative abundance of this phylum with increasing age in all children (P = 0.0380) with no difference in the rate of increase between cases and controls. There was a decrease in the relative abundance of Proteobacteria (P = 0.0004) and Actinobacteria (P = 0.0489) with increasing age in cases. The microbiota of control children was enriched in probiotic species <i>Bifidobacterium longum</i> and <i>Lactobacillus mucosae</i>, whereas that of stunted children was enriched in inflammogenic taxa including those in the Desulfovibrio genus and Campylobacterales order. Larger, longitudinal studies on the compositional and functional maturation of the microbiome in children are needed.</p></div

Relative abundance of major phyla in cases and controls.

<p><b>a:</b> Average relative abundance of major phyla at each 3 monthly time point. <b>b:</b> inear regression model showing the change in relative abundance of each major phylum over time from 3 to 24 months of age.</p

Growth trajectories in cases and controls: Mean height, weight, HAZ and WHZ scores and corresponding 95% confidence intervals (CI) were plotted over time from birth to 24 months of age.

<p>HAZ, Height for Age, WHZ, Weight for Height, UCI, Upper Confidence Interval, LCI, Lower Confidence Interval.</p