Ridinilazole, a narrow spectrum antibiotic for treatment of Clostridioides difficile infection, enhances preservation of microbiota-dependent bile acids.

Xi Qian,Anne V Kane,Richard J Vickers,Nicholas Alden,Karin Yanagi,Ming Lei,David R Snydman,Cheleste M Thorpe,Kyongbum Lee

doi:10.1152/ajpgi.00046.2020

Abstract

Antibiotic treatment is a standard therapy for Clostridioides difficile infection, but dysbiosis of the gut microbiota due to antibiotic exposure is also a major risk factor for the disease. Following an initial episode of C. difficile infection, a relentless cycle of recurrence can occur, where persistent treatment-related dysbiosis predisposes the patient to subsequent relapse. This study uses a longitudinal study design to compare the effects of a narrow-spectrum (ridinilazole) or broad-spectrum antibiotic (vancomycin) on intestinal bile acid profiles and their associations with gut bacteria over the course of C. difficile infection treatment. At the end of treatment (day 10), subjects receiving vancomycin showed a nearly 100-fold increase in the ratio of conjugated to secondary bile acids in their stool compared with baseline, whereas subjects receiving ridinilazole maintained this ratio near baseline levels. Correlation analysis detected significant positive associations between secondary bile acids and several Bacteroidales and Clostridiales families. These families were depleted in the vancomycin group but preserved at near-baseline abundance in the ridinilazole group. Enterobacteriaceae, which expanded to a greater extent in the vancomycin group, correlated negatively and positively with secondary and conjugated primary bile acids, respectively. Bile acid ratios at the end of treatment were significantly different between those who recurred and those who did not. These results indicate that a narrow-spectrum antibiotic maintains an intestinal bile acid profile associated with a lowered risk of recurrence.NEW & NOTEWORTHY This is the first study to demonstrate in humans the relationships between Clostridioides difficile antibiotic treatment choice and bile acid metabolism both during therapy and after treatment cessation. The results show a microbiota- and metabolome-preserving property of a novel narrow-spectrum agent that correlates with the agent's favorable sustained clinical response rates compared with broad-spectrum antibiotic treatment.

Highlights

Clostridioides difficile is a spore-forming organism that can colonize the human intestine
We have previously shown that vancomycin-treated subjects showed dramatic losses of Lachnospiraceae, Ruminococcaceae, and Bacteroidaceae in stool collected at the end of treatment (EOT), with concomitant expansion of species belonging to the phylum proteobacteria [43]
Comparison of bile acid profiles between ridinilazole- and vancomycin-treated subjects. This is the first study to demonstrate in humans the relationships between C. difficile infection (CDI) antibiotic treatment choice and bile acid metabolism both during therapy and after treatment cessation

Summary

INTRODUCTION

Clostridioides difficile is a spore-forming organism that can colonize the human intestine. Whereas murine model and human FMT studies have shown strong associations between CDI recurrence and intestinal bile acid profiles, relatively little has been reported regarding the effects of different antibiotic treatments on bile acid levels in humans. We characterize the trajectory of stool bile acid levels over time in human subjects diagnosed with CDI enrolled in a phase 2 clinical trial comparing the treatment efficacy of a broad-spectrum agent (vancomycin) against a narrow spectrum investigational agent (ridinilazole) [47]. Ridinilazole-treated subjects showed minimal disturbance in their gut microbiota compared with when the subjects enrolled in the trial (baseline) Based on these observations, we tested the hypothesis that secondary bile acid levels would be depleted in the stool of vancomycin-treated subjects compared with ridinilazoletreated subjects and that the depletion of bile acids would correlate with losses of specific gut bacteria

MATERIALS AND METHODS

RESULTS

DISCUSSION

DISCLOSURES