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Herein, we describe a novel\n                  <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                  genotype associated with high-level C\/T resistance (&gt;256\/4 \u00b5g\/mL) in a single patient. Whole genome sequencing of the isolate was compared to that of a susceptible isolate cultured from the same patient two months earlier. Analysis of the sequences revealed two different\n                  <jats:italic>P. aeruginosa<\/jats:italic>\n                  high-risk clones: ST111 followed by ST235. The C\/T-resistant ST235 isolate contained five copies of a genetic element comprised of an L2 \u03b2-lactamase gene (\n                  <jats:italic>bla<\/jats:italic>\n                  <jats:sub>L2<\/jats:sub>\n                  ) and a truncated\n                  <jats:italic>ampR<\/jats:italic>\n                  <jats:sub>L2<\/jats:sub>\n                  transcriptional regulator gene, which are commonly found together in\n                  <jats:italic>Stenotrophomonas maltophilia<\/jats:italic>\n                  strains and have not been reported to mediate resistance to C\/T. Comparative genomic analysis with other\n                  <jats:italic>P. aeruginosa<\/jats:italic>\n                  isolates failed to identify alternative explanations for the observed C\/T resistance. We found that exogenous expression of\n                  <jats:italic>bla<\/jats:italic>\n                  <jats:sub>L2<\/jats:sub>\n                  modestly increased C\/T MICs in genetically distinct\n                  <jats:italic>P. aeruginosa<\/jats:italic>\n                  strains. A screen of our archived isolates identified two\n                  <jats:italic>P. aeruginosa<\/jats:italic>\n                  clinical isolates, PS2045 and PS2046, with one and two copies, respectively, of the genetic element containing\n                  <jats:italic>bla<\/jats:italic>\n                  <jats:sub>L2<\/jats:sub>\n                  and truncated\n                  <jats:italic>ampR<\/jats:italic>\n                  <jats:sub>L2<\/jats:sub>\n                  . Interestingly, disruption of the gene\n                  <jats:italic>bla<\/jats:italic>\n                  <jats:sub>L2<\/jats:sub>\n                  but not the truncated\n                  <jats:italic>ampR<\/jats:italic>\n                  <jats:sub>L2<\/jats:sub>\n                  in PS2045 led to a significant decrease in C\/T MIC. Thus, we report a novel mechanism of C\/T resistance in\n                  <jats:italic>P. aeruginosa<\/jats:italic>\n                  mediated by an L2 \u03b2-lactamase independently of its canonical regulator AmpR\n                  <jats:sub>L2<\/jats:sub>\n                  .\n                <\/jats:p>","DOI":"10.64898\/2026.03.10.710737","type":"posted-content","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T13:30:15Z","timestamp":1773408615000},"source":"Crossref","is-referenced-by-count":0,"title":["A novel mechanism of ceftolozane-tazobactam resistance in\n                  <i>Pseudomonas aeruginosa<\/i>\n                  mediated by L2 \u03b2-lactamase"],"prefix":"10.64898","author":[{"given":"Preeti","family":"Garai","sequence":"first","affiliation":[{"name":"Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0791-6340","authenticated-orcid":false,"given":"Sophia H.","family":"Nozick","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline C.","family":"Jozefczyk","sequence":"additional","affiliation":[{"name":"Midwestern University College of Pharmacy Downers Grove Campus, Downers Grove, IL and Department of Pharmacy, Northwestern Medicine, Chicago, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4576-287X","authenticated-orcid":false,"given":"Hannah","family":"Nam","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine, Stanford CA, USA;"},{"name":"School of Medicine, University of California Irvine, Orange, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5184-1385","authenticated-orcid":false,"given":"J. Nicholas","family":"O\u2019Donnell","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7131-3691","authenticated-orcid":false,"given":"Egon A.","family":"Ozer","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4596-7939","authenticated-orcid":false,"given":"Alan R.","family":"Hauser","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0018-5434","authenticated-orcid":false,"given":"Nathaniel J.","family":"Rhodes","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, Midwestern University College of Pharmacy Downers Grove Campus, Downers Grove, IL, USA"},{"name":"Midwestern University College of Pharmacy Downers Grove Campus, Pharmacometrics Center of Excellence, Downers Grove, IL, USA"},{"name":"Department of Pharmacy, Northwestern Medicine, Chicago, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026031707500695000_2026.03.10.710737v2.1","doi-asserted-by":"publisher","DOI":"10.1002\/phar.1609"},{"key":"2026031707500695000_2026.03.10.710737v2.2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-013-0168-2"},{"key":"2026031707500695000_2026.03.10.710737v2.3","doi-asserted-by":"publisher","DOI":"10.1080\/14787210.2018.1447381"},{"key":"2026031707500695000_2026.03.10.710737v2.4","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix182"},{"key":"2026031707500695000_2026.03.10.710737v2.5","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(19)30403-7"},{"key":"2026031707500695000_2026.03.10.710737v2.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2018.11.001"},{"key":"2026031707500695000_2026.03.10.710737v2.7","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00834-09"},{"key":"2026031707500695000_2026.03.10.710737v2.8","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.ijid.2021.09.064","article-title":"Ceftolozane-tazobactam activity against clinical isolates of Pseudomonas aeruginosa from ICU patients with pneumonia: United States, 2015-2018","volume":"112","year":"2021","journal-title":"Int J Infect Dis"},{"key":"2026031707500695000_2026.03.10.710737v2.9","doi-asserted-by":"crossref","unstructured":"Shortridge D , Castanheira M , Pfaller MA , Flamm RK . 2017. 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