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It has been proposed that an important driver of resistance is selection imposed on bacterial populations that are not the intended target of antimicrobial therapy. But to date, there has been limited quantitative measure of the mean and variance of resistance following antibiotic exposure. Here we focus on the important nosocomial pathogen\n                    <jats:italic>Enterococcus faecium<\/jats:italic>\n                    in a hospital system where resistance to daptomycin is evolving despite standard interventions. We hypothesized that the intravenous use of daptomycin generates off-target selection for resistance in transmissible gastrointestinal (carriage) populations of\n                    <jats:italic>E<\/jats:italic>\n                    .\n                    <jats:italic>faecium<\/jats:italic>\n                    . We performed a cohort study in which the daptomycin resistance of\n                    <jats:italic>E<\/jats:italic>\n                    .\n                    <jats:italic>faecium<\/jats:italic>\n                    isolated from rectal swabs from daptomycin-exposed patients was compared to a control group of patients exposed to linezolid, a drug with similar indications. In the daptomycin-exposed group, daptomycin resistance of\n                    <jats:italic>E<\/jats:italic>\n                    .\n                    <jats:italic>faecium<\/jats:italic>\n                    from the off-target population was on average 50% higher than resistance in the control group (\n                    <jats:italic>n<\/jats:italic>\n                    = 428 clones from 22 patients). There was also greater phenotypic diversity in daptomycin resistance within daptomycin-exposed patients. In patients where multiple samples over time were available, a wide variability in temporal dynamics were observed, from long-term maintenance of resistance to rapid return to sensitivity after daptomycin treatment stopped. Sequencing of isolates from a subset of patients supports the argument that selection occurs within patients. Our results demonstrate that off-target gastrointestinal populations rapidly respond to intravenous antibiotic exposure. Focusing on the off-target evolutionary dynamics may offer novel avenues to slow the spread of antibiotic resistance.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3000987","type":"journal-article","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T16:27:36Z","timestamp":1608222456000},"page":"e3000987","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":27,"title":["Daptomycin treatment impacts resistance in off-target populations of vancomycin-resistant Enterococcus faecium"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4126-7540","authenticated-orcid":true,"given":"Clare L.","family":"Kinnear","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1874-529X","authenticated-orcid":true,"given":"Elsa","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6805-7562","authenticated-orcid":true,"given":"Valerie J.","family":"Morley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7127-9198","authenticated-orcid":true,"given":"Kevin C.","family":"Tracy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan","family":"Forstchen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7604-7903","authenticated-orcid":true,"given":"Andrew F.","family":"Read","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0679-9998","authenticated-orcid":true,"given":"Robert J.","family":"Woods","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,17]]},"reference":[{"key":"pbio.3000987.ref001","doi-asserted-by":"crossref","first-page":"S122","DOI":"10.1038\/nm1145","article-title":"Antibacterial resistance worldwide: causes, challenges and responses","volume":"10","author":"SB Levy","year":"2004","journal-title":"Nat Med"},{"key":"pbio.3000987.ref002","doi-asserted-by":"crossref","first-page":"3659","DOI":"10.1128\/AAC.00670-13","article-title":"Antibiotic Administration Routes Significantly Influence the Levels of Antibiotic Resistance in Gut Microbiota","volume":"57","author":"L Zhang","year":"2013","journal-title":"Antimicrob Agents Chemother"},{"key":"pbio.3000987.ref003","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1128\/AAC.19.1.33","article-title":"Resistance Among Fecal Flora of Patients Taking Sulfamethoxazole-Trimethoprim or Trimethoprim Alone","volume":"19","author":"RL Guerrant","year":"1981","journal-title":"Antimicrob Agents Chemother"},{"key":"pbio.3000987.ref004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fmicb.2014.00722","article-title":"Antimicrobial resistance characteristics and fitness of Gram-negative fecal bacteria from volunteers treated with minocycline or amoxicillin","volume":"5","author":"M Kirchner","year":"2014","journal-title":"Front Microbiol"},{"key":"pbio.3000987.ref005","first-page":"2013","article-title":"Antibiotic resistance threats in the United States, 2013","author":"Centers for Disease Control and Prevention","year":"2013","journal-title":"Antibiot Resist Threat United States"},{"key":"pbio.3000987.ref006","article-title":"Bystander selection for antimicrobial resistance: implications for patient health","author":"VJ Morley","year":"2019","journal-title":"Trends Microbiol"},{"key":"pbio.3000987.ref007","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1093\/jac\/dkl529","article-title":"Bakker-Woudenberg IAJM. 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