Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin

Adrianna M. Turner, Lucy Li, Ian R. Monk, Jean Y. H. Lee, Danielle J. Ingle, Stephanie Portelli, Norelle L. Sherry, Nicole Isles, Torsten Seemann, Liam K. Sharkey, Calum J. Walsh, Gavin E. Reid, Shuai Nie, Bart A. Eijkelkamp, Natasha E. Holmes, Brennan Collis, Sara Vogrin, Andreas Hiergeist, Daniela Weber, Andre Gessner, Ernst Holler, David B. Ascher, Sebastian Duchene, Nichollas E. Scott, Timothy P. Stinear, Jason C. Kwong, Claire L. Gorrie, Benjamin P. Howden () and Glen P. Carter ()
Additional contact information
Adrianna M. Turner: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Lucy Li: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Ian R. Monk: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Jean Y. H. Lee: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Danielle J. Ingle: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Stephanie Portelli: Baker Heart and Diabetes Institute
Norelle L. Sherry: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Nicole Isles: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Torsten Seemann: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Liam K. Sharkey: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Calum J. Walsh: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Gavin E. Reid: The University of Melbourne
Shuai Nie: The University of Melbourne
Bart A. Eijkelkamp: Flinders University
Natasha E. Holmes: Austin Health
Brennan Collis: Austin Health
Sara Vogrin: Austin Health
Andreas Hiergeist: University Medical Center
Daniela Weber: University Medical Center
Andre Gessner: University Medical Center
Ernst Holler: University Medical Center
David B. Ascher: Baker Heart and Diabetes Institute
Sebastian Duchene: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Nichollas E. Scott: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Timothy P. Stinear: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Jason C. Kwong: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Claire L. Gorrie: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Benjamin P. Howden: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Glen P. Carter: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity

Nature, 2024, vol. 635, issue 8040, 969-977

Abstract: Abstract Multidrug-resistant bacterial pathogens like vancomycin-resistant Enterococcus faecium (VREfm) are a critical threat to human health1. Daptomycin is a last-resort antibiotic for VREfm infections with a novel mode of action2, but for which resistance has been widely reported but is unexplained. Here we show that rifaximin, an unrelated antibiotic used prophylactically to prevent hepatic encephalopathy in patients with liver disease3, causes cross-resistance to daptomycin in VREfm. Amino acid changes arising within the bacterial RNA polymerase in response to rifaximin exposure cause upregulation of a previously uncharacterized operon (prdRAB) that leads to cell membrane remodelling and cross-resistance to daptomycin through reduced binding of the antibiotic. VREfm with these mutations are spread globally, making this a major mechanism of resistance. Rifaximin has been considered ‘low risk’ for the development of antibiotic resistance. Our study shows that this assumption is flawed and that widespread rifaximin use, particularly in patients with liver cirrhosis, may be compromising the clinical use of daptomycin, a major last-resort intervention for multidrug-resistant pathogens. These findings demonstrate how unanticipated antibiotic cross-resistance can undermine global strategies designed to preserve the clinical use of critical antibiotics.

Date: 2024
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DOI: 10.1038/s41586-024-08095-4

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