Preventing Clostridioides difficile Infection and Recurrence: Practical Strategies for Clinical Practice

Clostridioides difficile infection (CDI) is a major cause of morbidity, mortality, and healthcare utilization worldwide. Although advances in antimicrobial stewardship and infection prevention have reduced healthcare-associated disease in some settings, the incidence of community-associated CDI and the persistent burden of recurrent CDI (rCDI) continue to pose substantial clinical challenges. Because recurrent disease is fundamentally driven by persistent disruption of the intestinal microbiome and loss of colonization resistance, prevention has emerged as the central strategy for reducing long-term disease burden. This review summarizes contemporary evidence supporting prevention of both incident and rCDI, emphasizing practical approaches for gastroenterologists. Primary prevention centers on minimizing modifiable risk factors through antimicrobial stewardship, infection prevention and control, diagnostic stewardship to distinguish colonization from infection, and strategies to preserve the intestinal microbiome. For patients with CDI, we review evidence supporting extended antibiotic regimens, oral vancomycin prophylaxis during subsequent systemic antibiotic exposure, and microbiome restoration therapies, including conventional fecal microbiota transplantation and US Food and Drug Administration-approved microbiota-based therapies, which have transformed secondary prevention by restoring microbial diversity and colonization resistance. Special consideration is given to populations at particularly high risk for recurrence, including older adults, immunocompromised individuals, transplant recipients, and patients with inflammatory bowel disease. Finally, we discuss emerging preventive strategies, including precision risk stratification, microbiome- and metabolome-based biomarkers, bile acid modulation, and approaches targeting asymptomatic colonization. Together, these advances signal a paradigm shift from treating CDI episodes to implementing personalized preventive strategies that interrupt the cycle of recurrent disease and improve long-term patient outcomes.