Evaluating the Risk of Clostridioides difficile Infection After Rifaximin Treatment for Small Intestinal Bacterial Overgrowth

Background: Rifaximin is widely used in the management of small intestinal bacterial overgrowth (SIBO), but concerns remain regarding the potential risk of Clostridioides difficile infection (CDI), particularly with repeated antibiotic exposure. Aim: To evaluate the short-term risk of CDI following Rifaximin therapy in patients with SIBO. Materials and Methods: We conducted a retrospective cohort study using the TriNetX Collaborative Research Network. Adult patients with SIBO were identified and categorized based on Rifaximin exposure within 60 days of diagnosis. The primary analysis compared patients with SIBO treated with Rifaximin to those with SIBO who did not receive Rifaximin. Secondary analyses included comparisons between SIBO patients treated with Rifaximin and irritable bowel syndrome (IBS) patients receiving Rifaximin, as well as patients with SIBO receiving a single versus multiple Rifaximin courses. Propensity score matching (1:1) was performed to balance baseline characteristics. The primary outcome was CDI within 60 days of the index event. Secondary outcomes included hospitalization and emergency department (ED) visits. Results: After propensity score matching, 19,597 patients were included in each cohort in the primary comparison of SIBO treated with Rifaximin versus SIBO without Rifaximin. CDI occurred in 0.21% of Rifaximin-treated patients and 0.15% of untreated patients (p = 0.152). In the contextual comparison, CDI incidence was similar between SIBO patients receiving Rifaximin and IBS patients receiving Rifaximin (0.21% vs. 0.15%, p = 0.168). Among patients with SIBO receiving Rifaximin, CDI risk did not differ between single and multiple treatment courses (0.20% vs. 0.21%, p = 0.850). Conclusions: In this large real-world cohort, Rifaximin therapy for SIBO was not associated with a statistically significant increase in short-term CDI risk. However, given the low event rate, wide confidence intervals, and risk of type II error, these findings should be interpreted with caution.