Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin

• 成果类型: Article
• 署名作者: Turner, Adrianna M.; Li, Lucy; Monk, Ian R.; Lee, Jean Y. H.; Ingle, Danielle J.; Portelli, Stephanie; Sherry, Norelle L.; Isles, Nicole; Seemann, Torsten; Sharkey, Liam K.; Walsh, Calum J.; Reid, Gavin E.; Nie, Shuai; Eijkelkamp, Bart A.; Holmes, Natasha E.; Collis, Brennan; Vogrin, Sara; Hiergeist, Andreas; Weber, Daniela; Gessner, Andre; Holler, Ernst; Ascher, David B.; Duchene, Sebastian; Scott, Nichollas E.; Stinear, Timothy P.; Kwong, Jason C.; Gorrie, Claire L.; Howden, Benjamin P.; Carter, Glen P.
• 署名单位: University of Melbourne; Peter Doherty Institute; Monash Health; University of Queensland; University of Melbourne; Peter Doherty Institute; Florey Institute of Neuroscience & Mental Health; Howard Florey Institute Affiliates; University of Melbourne; University of Melbourne; University of Melbourne; University of Melbourne; University of Melbourne; Flinders University South Australia; University of Melbourne; Peter Doherty Institute; University of Melbourne; University of Regensburg; University of Regensburg; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5220
• DOI: 10.1038/s41586-024-08095-4
• 发表日期: 2024-11-28
• 关键词: sequence typing scheme; enterococcus-faecium; mechanisms; alignment; emergence; algorithm; package; TREE

摘要

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. Rifaximin use, particularly in patients with liver cirrhosis, may be compromising the clinical use of daptomycin.