Newer Therapeutics to Selectively Kill Clostridioides difficile and Restore the Microbiome

Background: The antibiotic ibezapolstat and the live biotherapeutic product live-JSLM are promising future approaches for treating Clostridioides difficile infection. Ibezapostat is a highly specific antibiotic for Clostridioides difficile, with minimal impact on the intestinal flora. Live-JSLM is designed to restore healthy intestinal microbiota, thus preventing recurrence of Clostridioides difficile infection. In this narrative review, we reviewed available data on ibezapostat and live-JSLM, considering that they are prototypes of two distinct, unique mechanisms of action against Clostridioides difficile. Methods: Data sources: PubMed and SCOPUS databases were searched from 1 January 2012 to 15 November 2025. Original articles reporting data on ibezapolstat and live-JSLM were included. Results: 31 studies were included. When compared to conventional anti-Clostridioides difficile antibiotics, ibezapolstat had a similar level of effectiveness and minimal impact on the gut microbiota. The available data confirm live-JSLM safety and efficacy in restoring the gut microbiota following the conclusion of the standard anti-Clostridioides difficile antibiotic regimen. Conclusions: The results on ibezapolstat efficacy are promising, but require confirmation in larger patient populations through double-blind, randomised phase III trials. In the near future, an integrated approach may enhance the management of Clostridioides difficile infection: starting with highly specific antibiotics, i.e., ibezapolstat, followed by microbiome-based therapies such as live-JSLM.