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Resistance to linezolid is considered rare but could emerge with repeated dosing. We recently reported widespread prescription of linezolid for a cohort of patients with cystic fibrosis (CF). The goals of this study were to determine the incidence of linezolid-resistant methicillin-resistant\n                    <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                    (MRSA) in CF and identify molecular mechanisms for linezolid resistance. We identified patients who cultured\n                    <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                    resistant to linezolid with minimum inhibitory concentration (MIC) &gt;4 at the University of Iowa CF Center between 2008 and 2018. We obtained isolates from these patients and retested susceptibility to linezolid using broth microdilution. We used whole genome sequencing to perform phylogenetic analysis of linezolid-resistant isolates and examine sequences for mutations or accessory genes that confer linezolid resistance. Between 2008 and 2018, 111 patients received linezolid, and 4 of these patients cultured linezolid-resistant\n                    <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                    . We sequenced 11 resistant and 21 susceptible isolates from these 4 subjects. Phylogenetic analysis indicated that linezolid resistance developed in ST5 or ST105 backgrounds. Three individuals had linezolid-resistant\n                    <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                    with a G2576T mutation in 23S rRNA. One of these subjects additionally had a\n                    <jats:italic toggle=\"yes\">\n                      mutS\n                      <jats:sup>\u2212<\/jats:sup>\n                      mutL\n                      <jats:sup>\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    hypermutating\n                    <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                    that produced five resistant isolates with multiple ribosomal subunit mutations. In one subject, the genetic basis for linezolid resistance was unclear. We conclude that linezolid resistant\n                    <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                    can occur through multiple genetic mechanisms in patients with repeated exposure to this antibiotic.\n                  <\/jats:p>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Patients with cystic fibrosis have persistent lung infections with\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                      that require extensive antibiotic treatments. Linezolid, an antibiotic given by oral or intravenous route, is prescribed repeatedly for patients whose lung disease has progressed. After treatment with linezolid,\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      strains can evolve antibiotic resistance through multiple genetic mechanisms. In addition to a common mutation in the 23S ribosomal RNA known to confer linezolid resistance,\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      strains can evolve novel resistance based on a combination of mutations affecting the bacterial ribosome. This combination of mutations was observed in a strain that exhibited hypermutation owing to the loss of the DNA repair genes\n                      <jats:italic toggle=\"yes\">mutS<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">mutL<\/jats:italic>\n                      . In this cohort of patients with cystic fibrosis, linezolid resistance was transient, possibly due to the growth disadvantage of resistant strains. However, ongoing chronic exposure to linezolid may create optimal conditions for the future emergence of resistance to this critical antibiotic.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.02084-23","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T09:00:57Z","timestamp":1695114057000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["Parallel evolution of linezolid-resistant\n                    <i>Staphylococcus aureus<\/i>\n                    in patients with cystic fibrosis"],"prefix":"10.1128","volume":"11","author":[{"given":"Nicholas J.","family":"Pitcher","sequence":"first","affiliation":[{"name":"Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andries","family":"Feder","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Philadelphia","place":["Philadelphia, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Bolden","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian F.","family":"Zirbes","sequence":"additional","affiliation":[{"name":"Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Pamatmat","sequence":"additional","affiliation":[{"name":"Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Boyken","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Iowa Carver College of Medicine","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared J.","family":"Hill","sequence":"additional","affiliation":[{"name":"Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa R.","family":"Bartels","sequence":"additional","affiliation":[{"name":"Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L.","family":"Thurman","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Iowa Carver College of Medicine","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie C.","family":"Reeb","sequence":"additional","affiliation":[{"name":"State Hygienic Laboratory at the University of Iowa","place":["Coralville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry S.","family":"Porterfield","sequence":"additional","affiliation":[{"name":"NIH Clinical Center","place":["Bethesda, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed M.","family":"Moustafa","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Philadelphia","place":["Philadelphia, USA"]},{"name":"Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Planet","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Philadelphia","place":["Philadelphia, USA"]},{"name":"Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia, USA"]},{"name":"Institute for Comparative Genomics, American Museum of Natural History","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7179-6400","authenticated-orcid":false,"given":"Anthony J.","family":"Fischer","sequence":"additional","affiliation":[{"name":"Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","unstructured":"Cystic Fibrosis Foundation . 2021. 2020 patient registry annual data report. 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