{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:59:15Z","timestamp":1790405955832,"version":"4.1.0"},"reference-count":43,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T00:00:00Z","timestamp":1448928000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Cefepime is frequently prescribed to treat infections caused by AmpC-producing Gram-negative bacteria. CMY-2 is the most common plasmid-mediated AmpC (pAmpC) \u03b2-lactamase. Unfortunately, CMY variants conferring enhanced cefepime resistance have been reported. Here, we describe the evolution of CMY-2 to an extended-spectrum AmpC (ESAC) in clonally identical\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Escherichia coli<\/jats:named-content>\n            isolates obtained from a patient. The CMY-2-producing\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">E. coli<\/jats:named-content>\n            isolate (CMY-2-\n            <jats:italic>Ec<\/jats:italic>\n            ) was isolated from a wound. Thirty days later, one CMY-33-producing\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">E. coli<\/jats:named-content>\n            isolate (CMY-33-\n            <jats:italic>Ec<\/jats:italic>\n            ) was detected in a bronchoalveolar lavage fluid sample. Two weeks before the isolation of CMY-33-\n            <jats:italic>Ec<\/jats:italic>\n            , the patient received cefepime. CMY-33-\n            <jats:italic>Ec<\/jats:italic>\n            and CMY-2-\n            <jats:italic>Ec<\/jats:italic>\n            were identical by repetitive extragenic palindromic-PCR (rep-PCR), being of hyperepidemic sequence type 131 (ST131) but showing different \u03b2-lactam MICs (e.g., cefepime MIC, 16 and \u22640.5 \u03bcg\/ml for CMY-33-\n            <jats:italic>Ec<\/jats:italic>\n            and CMY-2-\n            <jats:italic>Ec<\/jats:italic>\n            , respectively). Identical CMY-2-\n            <jats:italic>Ec<\/jats:italic>\n            isolates were also found in a rectal swab. CMY-33 differs from CMY-2 by a Leu293-Ala294 deletion. Expressed in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">E. coli<\/jats:named-content>\n            strain DH10B, both CMYs conferred resistance to ceftazidime (\u2265256 \u03bcg\/ml), but the cefepime MICs were higher for CMY-33 than CMY-2 (8 versus 0.25 \u03bcg\/ml, respectively). The\n            <jats:italic>k<\/jats:italic>\n            <jats:sub>cat<\/jats:sub>\n            \/\n            <jats:italic>\n              K\n              <jats:sub>m<\/jats:sub>\n            <\/jats:italic>\n            or inhibitor complex inactivation (\n            <jats:italic>k<\/jats:italic>\n            <jats:sub>inact<\/jats:sub>\n            )\/\n            <jats:italic>\n              K\n              <jats:sub>i<\/jats:sub>\n            <\/jats:italic>\n            <jats:sub>app<\/jats:sub>\n            (\u03bcM\n            <jats:sup>\u22121<\/jats:sup>\n            s\n            <jats:sup>\u22121<\/jats:sup>\n            ) indicated that CMY-33 possesses an extended-spectrum \u03b2-lactamase (ESBL)-like spectrum compared to that of CMY-2 (e.g., cefoxitin, 0.2 versus 0.4; ceftazidime, 0.2 versus not measurable; cefepime, 0.2 versus not measurable; and tazobactam, 0.0018 versus 0.0009, respectively). Using molecular modeling, we show that a widened active site (\u223c4-\u00c5 shift) may play a significant role in enhancing cefepime hydrolysis. This is the first\n            <jats:italic>in vivo<\/jats:italic>\n            demonstration of a pAmpC that under cephalosporin treatment expands its substrate spectrum, resembling an ESBL. The prevalence of CMY-2-\n            <jats:italic>Ec<\/jats:italic>\n            isolates is rapidly increasing worldwide; therefore, awareness that cefepime treatment may select for resistant isolates is critical.\n          <\/jats:p>","DOI":"10.1128\/aac.01804-15","type":"journal-article","created":{"date-parts":[[2015,9,22]],"date-time":"2015-09-22T02:23:49Z","timestamp":1442888629000},"page":"7483-7488","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":20,"title":["<i>In Vivo<\/i>\n            Evolution of CMY-2 to CMY-33 \u03b2-Lactamase in Escherichia coli Sequence Type 131: Characterization of an Acquired Extended-Spectrum AmpC Conferring Resistance to Cefepime"],"prefix":"10.1128","volume":"59","author":[{"given":"Jo\u00e3o","family":"Pires","sequence":"first","affiliation":[{"name":"Institute for Infectious Diseases, University of Bern, Bern, Switzerland"},{"name":"Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Taracila","sequence":"additional","affiliation":[{"name":"Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R.","family":"Bethel","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes VA Medical Center, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Doi","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Kasraian","sequence":"additional","affiliation":[{"name":"Institute for Infectious Diseases, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regula","family":"Tinguely","sequence":"additional","affiliation":[{"name":"Institute for Infectious Diseases, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parham","family":"Sendi","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Bern University Hospital and University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Bonomo","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes VA Medical Center, Cleveland, Ohio, USA"},{"name":"Division of Infectious Diseases and HIV Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, USA"},{"name":"Infectious Diseases Section, Medical Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA"},{"name":"Department of 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