澳大利亚墨尔本大学Glen P. Carter和Benjamin P. Howden共同合作，近期取得重要工作进展。他们研究发现，利福昔明预防性治疗会导致终极抗生素达托霉素产生抗药性。相关研究成果2024年10月23日在线发表于《自然》杂志上。

据介绍，耐万古霉素的屎肠球菌（VREfm）等多药耐药细菌病原体对人类健康构成严重威胁。达托霉素是治疗VREfm感染的最后手段抗生素，具有一种新的作用方式，但其耐药性已被广泛报道，但尚无法解释。

研究人员发现，利福昔明是一种无关的抗生素，用于预防肝病患者的肝性脑病，在VREfm中引起对达托霉素的交叉耐药性。利福昔明暴露后，细菌RNA聚合酶内发生的氨基酸变化会导致先前未鉴定的操纵子（prdRAB）上调，从而导致细胞膜重塑，并通过减少抗生素的结合对达托霉素产生交叉耐药性。

带有这些突变的VREfm在全球范围内传播，使其成为主要的耐药机制。利福昔明被认为是抗生素耐药性发展的“低风险”。研究表明，这一假设是有缺陷的，利福昔明的广泛使用，特别是在肝硬化患者中，可能会影响达托霉素的临床使用，达托霉素是治疗多重耐药病原体的主要最后手段。

总之，这一研究表明，抗生素交叉耐药性会破坏旨在保护关键抗生素临床使用的全球战略。

附：英文原文

Title: Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin

Author: 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.

Issue&Volume: 2024-10-23

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.

DOI: 10.1038/s41586-024-08095-4

Source: https://www.nature.com/articles/s41586-024-08095-4