{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:34:20Z","timestamp":1792067660862,"version":"4.4.0"},"reference-count":41,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2017,3,1]],"date-time":"2017-03-01T00:00:00Z","timestamp":1488326400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000098","name":"HHS | NIH | NIH Clinical Center","doi-asserted-by":"publisher","award":["R21AI111037"],"award-info":[{"award-number":["R21AI111037"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"HHS | NIH | NIH Clinical Center","doi-asserted-by":"publisher","award":["K08AI114883"],"award-info":[{"award-number":["K08AI114883"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"HHS | NIH | NIH Clinical Center","doi-asserted-by":"publisher","award":["R21AI117338"],"award-info":[{"award-number":["R21AI117338"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"HHS | NIH | NIH Clinical Center","doi-asserted-by":"publisher","award":["R01AI090155"],"award-info":[{"award-number":["R01AI090155"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"HHS | NIH | NIH Clinical Center","doi-asserted-by":"publisher","award":["UM1AI104681"],"award-info":[{"award-number":["UM1AI104681"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2017,3]]},"abstract":"ABSTRACT<\/jats:title>\n \n Ceftazidime-avibactam is a novel \u03b2-lactam\/\u03b2-lactamase inhibitor with activity against carbapenem-resistant\n Enterobacteriaceae<\/jats:named-content>\n (CRE) that produce\n Klebsiella pneumoniae<\/jats:named-content>\n carbapenemase (KPC). We report the first cases of ceftazidime-avibactam resistance to develop during treatment of CRE infections and identify resistance mechanisms. Ceftazidime-avibactam-resistant\n K. pneumoniae<\/jats:named-content>\n emerged in three patients after ceftazidime-avibactam treatment for 10 to 19 days. Whole-genome sequencing (WGS) of longitudinal ceftazidime-avibactam-susceptible and -resistant\n K. pneumoniae<\/jats:named-content>\n isolates was used to identify potential resistance mechanisms. WGS identified mutations in plasmid-borne\n bla<\/jats:italic>\n KPC-3<\/jats:sub>\n , which were not present in baseline isolates.\n bla<\/jats:italic>\n KPC-3<\/jats:sub>\n mutations emerged independently in isolates of a novel sequence type 258 sublineage and resulted in variant KPC-3 enzymes. The mutations were validated as resistance determinants by measuring MICs of ceftazidime-avibactam and other agents following targeted gene disruption in\n K. pneumoniae<\/jats:named-content>\n , plasmid transfer, and\n bla<\/jats:italic>\n KPC<\/jats:sub>\n cloning into competent\n Escherichia coli<\/jats:named-content>\n . In rank order, the impact of KPC-3 variants on ceftazidime-avibactam MICs was as follows: D179Y\/T243M double substitution > D179Y > V240G. Remarkably, mutations reduced meropenem MICs \u22654-fold from baseline, restoring susceptibility in\n K. pneumoniae<\/jats:named-content>\n from two patients. Cefepime and ceftriaxone MICs were also reduced \u22654-fold against D179Y\/T243M and D179Y variant isolates, but susceptibility was not restored. Reverse transcription-PCR revealed that expression of\n bla<\/jats:italic>\n KPC-3<\/jats:sub>\n encoding D179Y\/T243M and D179Y variants was diminished compared to\n bla<\/jats:italic>\n KPC-3<\/jats:sub>\n expression in baseline isolates. In conclusion, the development of resistance-conferring\n bla<\/jats:italic>\n KPC-3<\/jats:sub>\n mutations in\n K. pneumoniae<\/jats:named-content>\n within 10 to 19 days of ceftazidime-avibactam exposure is troubling, but clinical impact may be ameliorated if carbapenem susceptibility is restored in certain isolates.\n <\/jats:p>","DOI":"10.1128\/aac.02097-16","type":"journal-article","created":{"date-parts":[[2016,12,28]],"date-time":"2016-12-28T21:30:21Z","timestamp":1482960621000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":375,"title":["Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne\n bla<\/i>\n KPC-3<\/sub>\n Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections"],"prefix":"10.1128","volume":"61","author":[{"given":"Ryan K.","family":"Shields","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"},{"name":"XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Chen","sequence":"additional","affiliation":[{"name":"Public Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoji","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalyan D.","family":"Chavda","sequence":"additional","affiliation":[{"name":"Public Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen G.","family":"Press","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avin","family":"Snyder","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchi","family":"Pandey","sequence":"additional","affiliation":[{"name":"Public Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Doi","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry N.","family":"Kreiswirth","sequence":"additional","affiliation":[{"name":"Public Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Hong","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"},{"name":"XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelius J.","family":"Clancy","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"},{"name":"XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA"},{"name":"VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","first-page":"165","article-title":"Vital signs: carbapenem-resistant Enterobacteriaceae","volume":"62","year":"2013","unstructured":". 2013. Vital signs: carbapenem-resistant Enterobacteriaceae. 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