Rifaximin is associated with an increased risk of daptomycin-resistant VRE

Abstract

Aim: Rifaximin is a non-absorbable antibiotic predominantly prescribed to prevent recurrent hepatic encephalopathy in patients with liver cirrhosis – a high-risk cohort for colonisation and subsequent infection with vancomycin-resistant Enterococcus faecium (VREfm). Recent in vitro studies have suggested that mutations in rpoB – the gene encoding the ß-subunit of RNA polymerase where rifaximin binds to exert antibacterial activity – can lead to cross-resistance in daptomycin, one of the few therapeutic options for infections due to VREfm. To explore the plausibility of this, we assessed the association between rifaximin exposure and daptomycin-resistant VREfm in a patient cohort at Austin Health.

Methods: We conducted a single-centre retrospective cohort study of patients with VREfm collected between 2014–2022 at Austin Health. The first VREfm isolate from each patient was selected for whole-genome sequencing and antimicrobial susceptibility testing by broth microdilution. Patients with genomically identical VREfm isolates to a pre-existing patient in the cohort were excluded. Patient comorbidity and antimicrobial exposure data were retrieved from medical records. Potential associations were initially assessed through univariate analysis, with predictors of daptomycin-resistant VREfm determined through multivariable logistic regression.

Results: A total of 212 individual patients with genetically distinct VREfm collected between 2014–2022 were included in the analysis. Recent exposure to rifaximin (within the last 90 days) was significantly associated with the presence of rpoB mutations (P<0.001), and was significantly associated with carriage of daptomycin-resistant VREfm (P<0.001). After adjusting for potential confounders, recent rifaximin exposure remained an independent predictor of rpoB substitutions (OR 8.69; 95% CI 2.95-30.84; P<0.001) and daptomycin-resistant VREfm (OR 6.47; 95% CI 2.34-20.80; P<0.001) among the overall cohort of patients, and among a subgroup of patients with chronic liver disease (OR 4.37; 95% CI 1.70-12.84; P=0.004).

Conclusion: In agreement with our laboratory observations, these clinical data confirm a strong clinical association between recent rifaximin exposure and rpoB substitutions linked to daptomycin resistance among patients colonised with VREfm, suggesting exposure to rifaximin could drive daptomycin-resistant VREfm.