Increased risk of antimicrobial resistance in patients with cirrhosis and hepatic encephalopathy using rifaximin.

Rifaximin, a non-absorbable antibiotic used in managing recurrent hepatic encephalopathy (HE), has traditionally been considered low risk for inducing resistance. However, emerging evidence raised concerns that widespread rifaximin use may promote antimicrobial resistance (AMR). In this multi-national retrospective cohort study, we evaluate the association between rifaximin use and subsequent AMR in patients with cirrhosis and HE. After propensity score matching for 78 covariates, hazard ratios (HRs) and 95% confidence intervals (CIs) for AMR and infection-related adverse events are calculated for the one-year follow-up. We demonstrate a two-fold AMR risk associated with rifaximin use (HR = 1.89; 95% CI = 1.49-2.40), with significantly increased risks of vancomycin resistance (HR = 2.52; 95% CI = 1.64-3.88) and multidrug resistance (HR = 2.31; 95% CI = 1.38-3.85). Rifaximin use is also associated with an escalated risk of sepsis, spontaneous bacterial peritonitis, and the use of last-line antibiotics. Notably, patients receiving other antibiotics prior to rifaximin treatment exhibit greater AMR risks. These findings challenge the conventional view of rifaximin as a low-risk intervention and support mechanistic evidence linking rifaximin exposure to cross-resistance against critical antibiotics with real-world evidence.