Beyond conventional antibiotics: immune-based, anti-virulence, and microbiome-sparing therapies for Clostridioides difficile infection

Clostridioides difficile infection (CDI) remains a leading cause of healthcare-associated and community-acquired diarrhea with substantial morbidity and frequent recurrence. Although antimicrobial therapy effectively treats acute, it can further disrupt the gut microbiome and predispose to recurrent disease. These limitations have driven interest in therapies that target toxin activity, host immunity, and colonization resistance while minimizing collateral microbiome disruption. We conducted a narrative review of emerging immune-based, anti-virulence, and microbiome-modulating, and microbiome-sparing therapies for CDI, integrating mechanistic, preclinical, and clinical evidence. Passive toxin neutralization has demonstrated clinical efficacy in reducing recurrence, although recent changes in availability may limit their use. In contrast, parenteral toxoid vaccines have shown robust immunogenicity but mixed clinical efficacy in late-phase trials, highlighting potential roles for mucosal and colonization-directed immunity. Nontoxigenic C. difficile and selected narrow-spectrum antibacterials have shown promising randomized phase 2 results, whereas commensal organisms such as Clostridium butyricum , host-directed immune modulators, toxin-directed small molecules, and host-defense peptides remain supported predominantly by preclinical or early clinical evidence. Collectively, these approaches illustrate a shift from broad pathogen eradication toward strategies that selectively limit toxin-mediated injury, preserve or restore colonization resistance, and modify host responses. Their differing levels of evidence and mechanisms suggest that future CDI management may require rational integration of pathogen-, host-, and microbiome-directed therapies according to disease stage and individual recurrence risk. Clinical trial number Not applicable.