Bacterial pathogens such as vancomycin-resistantEnterococcus faecium(VREfm) that are resistant to almost all antibiotics are among the top global threats to human health. Daptomycin is a new last-resort antibiotic for VREfm infections with a novel mode-of-action, but for which resistance has surprisingly and alarmingly been widely reported. The causes of such a rapid emergence of resistance to this novel antibiotic have been unclear. Here we show that the use of rifaximin, an unrelated antibiotic used prophylactically to prevent hepatic encephalopathy in liver disease patients, is causing resistance to this last-resort antibiotic in VREfm. We show that mutations within the bacterial RNA polymerase complex confer cross- resistance to both rifaximin and daptomycin. Furthermore, VREfm with these mutations are spread globally across at least 5 continents and 20 countries, making this a major yet previously unrecognised mechanism of resistance. Until now, rifaximin has been considered ‘low-risk’ for development of antibiotic resistance. Our study shows this is not the case and that widespread rifaximin use may be compromising the clinical efficacy of daptomycin, one of the major last-resort interventions for multidrug resistant pathogens. These findings demonstrate that unanticipated antibiotic cross-resistance may potentially undermine global strategies designed to preserve the clinical use of last-resort antibiotics.