A “low-risk” antibiotic is helping superbugs evolve to become nearly untreatable.

Researchers at Melbourne's Peter Doherty Institute for Infection and Immunity have found that rifaximin, commonly prescribed to liver disease patients, is driving resistance in the superbug vancomycin-resistant Enterococcus faecium (VRE). 

The study, published in Nature, reveals that rifaximin, previously seen as unlikely to cause resistance, can trigger VRE strains to resist daptomycin, one of the few remaining treatment options for severe infections. 

This makes VRE more challenging to manage in healthcare settings.

The eight-year study was led by experts from the University of Melbourne and Austin Health. 

It used large-scale genomics to identify genetic changes in VRE linked to rifaximin exposure, which resulted in cross-resistance to daptomycin. 

“We’ve shown that rifaximin makes VRE resistant to daptomycin in a way that has not been seen before,” says Dr Glen Carter of the Doherty Institute.

Rifaximin acts by inhibiting bacterial RNA polymerase, which is essential for replication. However, this selective pressure encourages bacterial adaptation. 

Dr Adrianna Turner, first author of the study, says rifaximin activates a gene cluster called prdRAB, altering the VRE cell membrane and enabling cross-resistance. 

She likened this to bacteria gaining “multiple abilities”, helping them resist even “the final boss”, daptomycin.

The findings are timely, following the United Nations General Assembly’s recent commitment to reduce antimicrobial resistance (AMR)-related deaths by 10 per cent by 2030. 

With 4.95 million AMR-related deaths each year - and estimates of over 39 million deaths by 2050 - the emergence of daptomycin-resistant VRE highlights the urgency of better antibiotic stewardship.

The researchers stress that rifaximin still has clinical value when used appropriately, especially in advanced liver disease patients. However, its use in hospitals should be carefully monitored. 

Associate Professor Jason Kwong of Austin Health, who led the clinical studies, urges clinicians to confirm daptomycin’s effectiveness before use in patients treated with rifaximin. He also calls for regulators to consider “off-target and cross-class” resistance impacts when approving new drugs.

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