Rifaximin Use in Cirrhosis Linked to Increased Antimicrobial Resistance

A LARGE multinational study has raised significant concerns over the long-assumed safety of rifaximin regarding antimicrobial resistance (AMR), revealing that patients with cirrhosis and hepatic encephalopathy (HE) who receive the drug face notably higher risks of antibiotic-resistant infections. The findings challenge long-standing clinical assumptions and may prompt re-evaluation of prophylactic strategies in this vulnerable population.

Rifaximin, a minimally absorbed oral antibiotic, is widely used to prevent recurrent HE and has traditionally been viewed as posing little risk for selecting resistant organisms due to its limited systemic absorption. However, rising global AMR rates and emerging mechanistic studies have questioned this classification. The new study provides the strongest real-world evidence to date that rifaximin exposure may meaningfully contribute to resistance.

In this multinational retrospective cohort study, investigators examined patients with cirrhosis and HE and assessed whether rifaximin use was associated with subsequent AMR over a one-year follow-up period. After rigorous propensity-score matching across 78 covariates, the researchers calculated hazard ratios (HRs) for AMR and infection-related outcomes.

Linking Rifaximin to Antimicrobial Resistance: What the Data Show

The analysis revealed nearly a two-fold increase in AMR among rifaximin users (HR 1.89; 95% CI 1.49-2.40). Particularly concerning was the elevated risk of vancomycin-resistant organisms (HR 2.52; 95% CI 1.64-3.88) and multidrug-resistant infections (HR 2.31; 95% CI 1.38-3.85). Beyond microbiological resistance, rifaximin use correlated with higher rates of clinical complications, including sepsis, spontaneous bacterial peritonitis, and greater reliance on last-line antibiotics, all markers of severe infection and poor prognosis in cirrhotic patients.

The study also noted a compounding effect: patients previously exposed to other antibiotics before starting rifaximin exhibited even higher AMR risks, suggesting that cumulative antibiotic pressure may intensify selection for resistant organisms.

Future Research Needed to Address Antimicrobial Resistance Trends

These findings call into question rifaximin’s reputation as a low-risk therapeutic and support emerging mechanistic research indicating cross-resistance between rifaximin and other clinically important antibiotics. The data highlight the need for cautious prescribing, closer microbiological surveillance, and further prospective research to balance HE prevention with the global imperative to curb AMR.

Reference

Kuo CH et al. Increased risk of antimicrobial resistance in patients with cirrhosis and hepatic encephalopathy using rifaximin. Nat Commun. 2025; doi: 10.1038/s41467-025-67326-y