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

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 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 to 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 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.

The contribution of bile acid metabolism to the pathogenesis of Clostridioides difficile infection

“…A recent study longitudinally profiled stool bile acids for patients treated for CDI either with vancomycin or ridinilazole, and compared the changes seen with the two agents. 41 Over the course of treatment with vancomycin, an almost 100-fold increase in the ratio of conjugated to secondary bile acids was observed, consistent with other studies demonstrating that vancomycin use is associated with loss of faecal secondary bile acids and enrichment in primary unconjugated bile acids (likely reflecting its relatively broad anti-microbial actions). 42 , 43 However, in comparison, only very modest changes from baseline were seen in the same bile acid profiles of ridinilazole-treated patients.…”

“… 42 , 43 However, in comparison, only very modest changes from baseline were seen in the same bile acid profiles of ridinilazole-treated patients. 41 The stool bile acid ratios seen at the end of treatment were shown to be predictive of which patients experienced future recurrence. As such, this experience with ridinilazole has helped to demonstrate that, in the continued hunt for novel anti-CDI antimicrobials, it is not only potency of action against the life cycle of C. difficile that is important to consider, but also the potential impact upon the bile-metabolising functionality of gut commensal bacteria.…”

Targeted Therapeutic Strategies in the Battle Against Pathogenic Bacteria

“…Additionally, the appearance of new targets or new mechanisms seems more attractive. For example, an antibiotic termed ridinilazole was found efficient in the treatment of C. difficile infections through enhancing the preservation of microbiota-dependent bile acid metabolome without interfering with the commensal microbiota ( Qian et al, 2020 ). Moreover, antibiotics with killing modes based on energy metabolism inhibition show a novel pipeline for drug development.…”

The role of the human gut microbiota in colonization and infection with multidrug-resistant bacteria

“…[128][129][130] Potential solutions to address this issue are the development of treatment options with increased specificity or confined activity. Examples are narrow-spectrum antibiotics, 131 selective pathogen-targeting phages 96 or antibodyantibiotic conjugates, 132 localized antibiotic delivery using nanoparticle formulations, 133 and strategies to protect the gut microbiota with orally administered beta-lactamases 134 or slow-release formulations of activated charcoal that absorb antibiotics as soon as they reach the large intestine. 134…”