{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T15:07:21Z","timestamp":1789225641132,"version":"build-2803163510"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":47,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010318","name":"University of Manitoba","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010318","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Avir"},{"name":"Iterum"},{"DOI":"10.13039\/100009945","name":"Merck","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009945","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Paladin Labs"},{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100023517","name":"Sandoz","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100023517","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005612","name":"Shionogi","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005612","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009655","name":"Sunovion","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009655","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Venatorx"},{"name":"Verity"},{"name":"Xediton"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Oral fosfomycin is commonly prescribed as a single 3 g dose to empirically treat uncomplicated cystitis. This study investigated the mechanisms and frequency of fosfomycin resistance among clinical isolates of Escherichia coli from Canada.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In total, 5012 clinical isolates of E. coli collected by the CANWARD surveillance programme from 2007 to 2022 were tested for susceptibility to fosfomycin using the CLSI reference agar dilution method. MICs were interpreted by 2024 CLSI M100 breakpoints. The 19 fosfomycin-resistant (MIC \u2265256\u2005mg\/L) and 45 fosfomycin-intermediate (MIC 128\u2005mg\/L) isolates identified, and 69 fosfomycin-susceptible (MIC \u22641\u201364\u2005mg\/L) control isolates underwent WGS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In total, 98.7% (4948\/5012) of all E. coli isolates tested were fosfomycin-susceptible; 0.4% were fosfomycin-resistant and 0.9% were fosfomycin-intermediate. ST131 accounted for 42.1%, 40.0% and 20.3%, respectively, of fosfomycin-resistant, fosfomycin-intermediate and fosfomycin-susceptible isolates. Six (31.6%) fosfomycin-resistant isolates and one (2.2%) fosfomycin-intermediate isolate carried a fosA gene. All fosA genes were plasmid mediated and all but one fosA-carrying plasmid harboured multiple other antimicrobial resistance genes. A nonsense mutation in, or complete deletion of, one or more genes in the fosfomycin transport systems GlpT and UhpT were observed in 63.2% (37\/57) of fosA-negative fosfomycin-resistant and fosfomycin-intermediate isolates but were not detected in any of the 69 fosfomycin-susceptible isolates tested.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In Canada, the occurrence of mobile fosfomycin resistance determinants (fosA genes) in clinical isolates of E. coli is low (\u223c0.14% of all isolates). Our results highlight the importance of the functional transporter systems GlpT and UhpT for the in vitro activity of fosfomycin.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jacamr\/dlag020","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T12:48:28Z","timestamp":1770295708000},"source":"Crossref","is-referenced-by-count":2,"title":["Mechanisms of fosfomycin resistance observed in clinical isolates of\n                    <i>Escherichia coli<\/i>\n                    from Canada: CANWARD 2007\u20132022"],"prefix":"10.1093","volume":"8","author":[{"given":"Laura F","family":"Mataseje","sequence":"first","affiliation":[{"name":"National Microbiology Laboratory, Public Health Agency of Canada , Winnipeg, Manitoba ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cole","family":"Lysak","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, University of Manitoba , Winnipeg, Manitoba R3E 0J9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7914-9198","authenticated-orcid":false,"given":"Nicole","family":"Lerminiaux","sequence":"additional","affiliation":[{"name":"National Microbiology Laboratory, Public Health Agency of Canada , Winnipeg, Manitoba ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Baxter","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, University of Manitoba , Winnipeg, Manitoba R3E 0J9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A","family":"Karlowsky","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, University of Manitoba , Winnipeg, Manitoba R3E 0J9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George G","family":"Zhanel","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, University of Manitoba , Winnipeg, Manitoba R3E 0J9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"2026022300595998200_dlag020-B1","doi-asserted-by":"publisher","first-page":"403","DOI":"10.33073\/pjm-2019-048","article-title":"Antibiotic resistance among uropathogenic Escherichia coli","volume":"68","author":"Kot","year":"2019","journal-title":"Pol J Microbiol"},{"key":"2026022300595998200_dlag020-B2","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/S0891-5520(03)00005-9","article-title":"Epidemiology of urinary tract infections: transmission and risk factors, incidence, and costs","volume":"17","author":"Foxman","year":"2003","journal-title":"Infect Dis Clin North Am"},{"key":"2026022300595998200_dlag020-B3","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1007\/s11033-018-4254-0","article-title":"The genetic background of antibiotic resistance among clinical uropathogenic Escherichia coli strains","volume":"45","author":"Adamus-Bia\u0142ek","year":"2018","journal-title":"Mol Biol Rep"},{"key":"2026022300595998200_dlag020-B4","doi-asserted-by":"publisher","first-page":"511","DOI":"10.3390\/antibiotics9080511","article-title":"Effective treatment for uncomplicated urinary tract infections with oral fosfomycin, single center four year retrospective study","volume":"9","author":"Fajfr","year":"2020","journal-title":"Antibiotics"},{"key":"2026022300595998200_dlag020-B5","doi-asserted-by":"publisher","first-page":"e1135","DOI":"10.1002\/mbo3.1135","article-title":"Mobile fosfomycin resistance genes in Enterobacteriaceae\u2014an increasing threat","volume":"9","author":"Zurfluh","year":"2020","journal-title":"Microbiol Open"},{"key":"2026022300595998200_dlag020-B6","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.ijantimicag.2018.09.013","article-title":"Resistance to fosfomycin: mechanisms, frequency and clinical consequences","volume":"53","author":"Falagas","year":"2019","journal-title":"Inter J Antimicrob Agents"},{"key":"2026022300595998200_dlag020-B7","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/s41579-023-00926-x","article-title":"Plasmids, a molecular cornerstone of antimicrobial resistance in the One Health era","volume":"22","author":"Casta\u00f1eda-Barba","year":"2024","journal-title":"Nat Rev Microbiol"},{"key":"2026022300595998200_dlag020-B8","doi-asserted-by":"publisher","first-page":"575031","DOI":"10.3389\/fmicb.2020.575031","article-title":"Novel chromosomal mutations responsible for fosfomycin resistance in Escherichia coli","volume":"11","author":"Cattoir","year":"2020","journal-title":"Front Microbiol"},{"key":"2026022300595998200_dlag020-B9","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.3390\/antibiotics11101383","article-title":"Emergence of fosfomycin resistance by plasmid-mediated fos genes in uropathogenic ESBL-producing E. coli isolates in Mexico","volume":"11","author":"Galindo-M\u00e9ndez","year":"2022","journal-title":"Antibiotics"},{"key":"2026022300595998200_dlag020-B10","doi-asserted-by":"publisher","first-page":"e0254223","DOI":"10.1128\/spectrum.02542-23","article-title":"Fosa11, a novel chromosomal-encoded fosfomycin resistance gene identified in Providencia rettgeri","volume":"12","author":"Lu","year":"2024","journal-title":"Microbiol Spectr"},{"key":"2026022300595998200_dlag020-B11","doi-asserted-by":"publisher","first-page":"1693","DOI":"10.2217\/fmb-2018-0294","article-title":"How is fosfomycin resistance developed in Escherichia coli?","volume":"13","author":"Cattoir","year":"2018","journal-title":"Fut Microbiol"},{"key":"2026022300595998200_dlag020-B12","doi-asserted-by":"publisher","first-page":"1178547","DOI":"10.3389\/fcimb.2023.1178547","article-title":"Fosfomycin resistance mechanisms in Enterobacterales: an increasing threat","volume":"13","author":"Mattioni Marchetti","year":"2023","journal-title":"Front Cell Infect Microbiol"},{"key":"2026022300595998200_dlag020-B13","doi-asserted-by":"publisher","first-page":"8513405","DOI":"10.1155\/2020\/8513405","article-title":"Oral and intravenous fosfomycin for the treatment of complicated urinary tract infections","volume":"2020","author":"Zhanel","year":"2020","journal-title":"Can J Infect Dis Med Microbiol"},{"key":"2026022300595998200_dlag020-B14","doi-asserted-by":"publisher","first-page":"iv2","DOI":"10.1093\/jac\/dkz282","article-title":"Ten years of the CANWARD study (2007\u201316)","volume":"74","author":"Zhanel","year":"2019","journal-title":"J Antimicrob Chemother"},{"key":"2026022300595998200_dlag020-B15","volume-title":"Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically\u2014Twelth Edition: M07","author":"CLSI","year":"2024"},{"key":"2026022300595998200_dlag020-B16","volume-title":"Performance Standards for Antimicrobial Susceptibility Testing: Informational Supplement\u2014Thirty-Fourth Edition: M100","author":"CLSI","year":"2024"},{"key":"2026022300595998200_dlag020-B17","doi-asserted-by":"publisher","first-page":"3035","DOI":"10.1093\/jac\/dkac275","article-title":"In vitro activity of fosfomycin against bacterial pathogens isolated from urine specimens in Canada from 2007 to 2020: CANWARD surveillance study","volume":"77","author":"Karlowsky","year":"2022","journal-title":"J Antimicrob Chemother"},{"key":"2026022300595998200_dlag020-B18","doi-asserted-by":"publisher","first-page":"292","DOI":"10.3390\/microorganisms10020292","article-title":"Correlation between phenotypic and in silico detection of antimicrobial resistance in Salmonella enterica in Canada using Staramr","volume":"10","author":"Bharat","year":"2022","journal-title":"Microorg"},{"key":"2026022300595998200_dlag020-B19","doi-asserted-by":"publisher","first-page":"3491","DOI":"10.1093\/jac\/dkaa345","article-title":"ResFinder 4.0 for predictions of phenotypes from genotypes","volume":"75","author":"Bortolaia","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"2026022300595998200_dlag020-B20","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"Altschul","year":"1990","journal-title":"J Mol Biol"},{"key":"2026022300595998200_dlag020-B21","doi-asserted-by":"publisher","first-page":"6968","DOI":"10.1038\/s41467-022-34630-w","article-title":"Muscle5: high-accuracy alignment ensembles enable unbiased assessments of sequence homology and phylogeny","volume":"13","author":"Edgar","year":"2022","journal-title":"Nat Commun"},{"key":"2026022300595998200_dlag020-B22","volume-title":"R: a Language and Environment for Statistical Computing","author":"R Core Team","year":"2024"},{"key":"2026022300595998200_dlag020-B23","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.21105\/joss.01686","article-title":"Welcome to the tidyverse","volume":"4","author":"Wickham","year":"2019","journal-title":"J Open Source Soft"},{"key":"2026022300595998200_dlag020-B24","doi-asserted-by":"publisher","first-page":"e43","DOI":"10.1002\/imt2.43","article-title":"Complex heatmap visualization","volume":"1","author":"Gu","year":"2022","journal-title":"iMeta"},{"key":"2026022300595998200_dlag020-B25","doi-asserted-by":"publisher","first-page":"112","DOI":"10.3390\/antibiotics9030112","article-title":"Fosfomycin resistance in Escherichia coli isolates from South Korea and in vitro activity of fosfomycin alone and in combination with other antibiotics","volume":"9","author":"Seok","year":"2020","journal-title":"Antibiotics"},{"key":"2026022300595998200_dlag020-B26","doi-asserted-by":"publisher","first-page":"534","DOI":"10.3390\/antibiotics9090534","article-title":"Characterization of fosfomycin and nitrofurantoin resistance mechanisms in Escherichia coli isolated in clinical urine samples","volume":"9","author":"Sorlozano-Puerto","year":"2020","journal-title":"Antibiotics"},{"key":"2026022300595998200_dlag020-B27","doi-asserted-by":"publisher","first-page":"5470241","DOI":"10.1155\/2017\/5470241","article-title":"Mechanism of reduced susceptibility to fosfomycin in Escherichia coli clinical isolates","volume":"2017","author":"Ohkoshi","year":"2017","journal-title":"BioMed Res Inter"},{"key":"2026022300595998200_dlag020-B28","doi-asserted-by":"publisher","first-page":"e05069-22","DOI":"10.1128\/spectrum.05069-22","article-title":"Inactivation of ackA and pta genes reduces GlpT expression and susceptibility to fosfomycin in Escherichia coli","volume":"11","author":"Hirakawa","year":"2023","journal-title":"Microbiol Spectr"},{"key":"2026022300595998200_dlag020-B29","doi-asserted-by":"publisher","first-page":"e01417-24","DOI":"10.1128\/aac.01417-24","article-title":"Chromosomal genes modulating fosfomycin susceptibility in uropathogenic Escherichia coli: a genome-wide analysis","volume":"69","author":"Ma","year":"2025","journal-title":"Antimicrob Agents Chemother"},{"key":"2026022300595998200_dlag020-B30","doi-asserted-by":"publisher","first-page":"1564","DOI":"10.3201\/eid2309.170560","article-title":"Emergence of plasmid-mediated fosfomycin-resistance genes among Escherichia coli isolates, France","volume":"23","author":"Benzerara","year":"2017","journal-title":"Emerg Infect Dis"},{"key":"2026022300595998200_dlag020-B31","doi-asserted-by":"publisher","first-page":"e00137-18","DOI":"10.1128\/mSphere.00137-18","article-title":"Evolution and comparative genomics of F33:A\u2212:B\u2212 plasmids carrying blaCTX-M-55 or blaCTX-M-65 in Escherichia coli and Klebsiella pneumoniae isolated from animals, food products, and humans in China","volume":"3","author":"Wang","year":"2018","journal-title":"mSphere"},{"key":"2026022300595998200_dlag020-B32","doi-asserted-by":"publisher","first-page":"2004","DOI":"10.1093\/jac\/dkab119","article-title":"Characteristics of fosA-carrying plasmids in E. coli and Klebsiella spp. isolates originating from food and environmental samples","volume":"76","author":"Biggel","year":"2021","journal-title":"J Antimicrob Chemother"},{"key":"2026022300595998200_dlag020-B33","doi-asserted-by":"publisher","first-page":"e01403-19","DOI":"10.1128\/aac.01403-19","article-title":"Identification of FosA8, a plasmid-encoded fosfomycin resistance determinant from Escherichia coli, and its origin in Leclercia adecarboxylata","volume":"63","author":"Poirel","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2026022300595998200_dlag020-B34","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1128\/CMR.00125-13","article-title":"Escherichia coli ST131, an intriguing clonal group","volume":"27","author":"Nicolas-Chanoine","year":"2014","journal-title":"Clin Microbiol Rev"},{"key":"2026022300595998200_dlag020-B35","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1126\/science.1087619","article-title":"Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli","volume":"301","author":"Huang","year":"2003","journal-title":"Science"},{"key":"2026022300595998200_dlag020-B36","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1016\/j.bpj.2009.06.026","article-title":"Structural basis of substrate selectivity in the glycerol-3-phosphate: phosphate antiporter GlpT","volume":"97","author":"Law","year":"2009","journal-title":"Biophys J"},{"key":"2026022300595998200_dlag020-B37","doi-asserted-by":"publisher","first-page":"e0135269","DOI":"10.1371\/journal.pone.0135269","article-title":"Antimicrobial susceptibility and molecular mechanisms of fosfomycin resistance in clinical Escherichia coli isolates in mainland China","volume":"10","author":"Li","year":"2015","journal-title":"PLoS One"},{"key":"2026022300595998200_dlag020-B38","doi-asserted-by":"publisher","first-page":"2850","DOI":"10.1128\/AAC.47.9.2850-2858.2003","article-title":"Biological costs and mechanisms of fosfomycin resistance in Escherichia coli","volume":"47","author":"Nilsson","year":"2003","journal-title":"Antimicrob Agents Chemother"}],"container-title":["JAC-Antimicrobial Resistance"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jacamr\/article-pdf\/8\/1\/dlag020\/67067482\/dlag020.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jacamr\/article-pdf\/8\/1\/dlag020\/67067482\/dlag020.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T06:00:09Z","timestamp":1771826409000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jacamr\/article\/doi\/10.1093\/jacamr\/dlag020\/8494621"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,7]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,7]]}},"URL":"https:\/\/doi.org\/10.1093\/jacamr\/dlag020","relation":{},"ISSN":["2632-1823"],"issn-type":[{"value":"2632-1823","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,2]]},"published":{"date-parts":[[2026,1,7]]},"article-number":"dlag020"}}