Frequent high-level rifaximin resistance in <i>Escherichia coli</i> associated with long-term treatment of patients with liver cirrhosis: a prospective, controlled study

We conducted a prospective, controlled study to assess the prevalence of high-level rifaximin resistance in intestinal <i>Escherichia coli (E. coli</i>) among patients with liver cirrhosis (LC). Rectal swabs were collected from consenting adult LC patients at Freiburg University Medical Center. Swabs were cultured on MacConkey agar plates supplemented with rifaximin at two concentrations (32 µg/mL and 256 µg/mL), and pink/red colonies were identified as <i>E. coli</i> using standard methods. Minimum inhibitory concentrations (MICs) of rifaximin and a panel of additional agents were determined using microdilution assays. Of the 100 patients enrolled, 49 received rifaximin (median duration 22 weeks), and 51 served as controls. Patients receiving rifaximin had more advanced LC (Child B/C, 75% vs. 50%) and more frequent concurrent antibiotic use (22% vs. 12%). High-level rifaximin-resistant <i>E. coli</i> strains were recovered from 67% (33/49) of rifaximin-treated patients, compared to 12% (6/51) of controls (<i>P</i> < 0.001). Cross-resistance to rifampicin was complete, with no clear associations with other resistance phenotypes. A subset of five high-level resistance swabs was assessed for homogeneity of colonization by randomly picking <i>E. coli</i> strains from a non-supplemented MacConkey agar plate. Homogeneous colonization with high-level rifaximin-resistant <i>E. coli</i> was found in 80% of cases. The prevalence of high-level rifaximin-resistant intestinal <i>E. coli</i> in LC patients on long-term rifaximin treatment is extremely high (67% vs. 12%). While rifaximin may remain effective in preventing hepatic encephalopathy (HE), its potential use in preventing spontaneous bacterial peritonitis might be severely limited by the emergence of resistance.IMPORTANCEThis study highlights the emergence of antibiotic-resistant <i>E. coli</i> as an important consequence of long-term rifaximin use in patients with liver cirrhosis: the development of antibiotic resistance in gut bacteria. Rifaximin is commonly used to prevent complications like hepatic encephalopathy (HE) by targeting gut bacteria. However, this research shows that prolonged use can lead to the emergence of highly resistant <i>E. coli</i> strains, potentially compromising the drug's effectiveness and limiting its utility in preventing HE and infections, such as spontaneous bacterial peritonitis. By identifying specific resistance patterns and genetic mutations, this study highlights the need for cautious use of rifaximin and further research into balancing its benefits with the risks of resistance. These findings contribute to a broader understanding of how antibiotics affect gut bacteria over time and offer a basis for exploring strategies to preserve the effectiveness of this important medication for patients with advanced liver disease.