{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:41:23Z","timestamp":1790642483051,"version":"4.1.0"},"reference-count":28,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2017,10,1]],"date-time":"2017-10-01T00:00:00Z","timestamp":1506816000000},"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":[[2017,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Ceftazidime-avibactam is an antibiotic with activity against serine beta-lactamases, including\n            <jats:named-content content-type=\"genus-species\">Klebsiella pneumoniae<\/jats:named-content>\n            carbapenemase (KPC). Recently, reports have emerged of KPC-producing isolates resistant to this antibiotic, including a report of a wild-type KPC-3 producing sequence type 258\n            <jats:named-content content-type=\"genus-species\">Klebsiella pneumoniae<\/jats:named-content>\n            that was resistant to ceftazidime-avibactam. We describe a detailed analysis of this isolate, in the context of two other closely related KPC-3 producing isolates, recovered from the same patient. Both isolates encoded a nonfunctional OmpK35, whereas we demonstrate that a novel T333N mutation in OmpK36, present in the ceftazidime-avibactam resistant isolate, reduced the activity of this porin and impacted ceftazidime-avibactam susceptibility. In addition, we demonstrate that the increased expression of\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>KPC-3<\/jats:sub>\n            and\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>SHV-12<\/jats:sub>\n            observed in the ceftazidime-avibactam-resistant isolate was due to transposition of the Tn\n            <jats:italic>4401<\/jats:italic>\n            transposon harboring\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>KPC-3<\/jats:sub>\n            into a second plasmid, pIncX3, which also harbored\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>SHV-12<\/jats:sub>\n            , ultimately resulting in a higher copy number of\n            <jats:italic>\n              bla\n              <jats:sub>KPC<\/jats:sub>\n            <\/jats:italic>\n            <jats:sub>-3<\/jats:sub>\n            in the resistant isolate. pIncX3 plasmid from the ceftazidime-avibactam resistant isolate, conjugated into a OmpK35\/36-deficient\n            <jats:named-content content-type=\"genus-species\">K. pneumoniae<\/jats:named-content>\n            background that harbored a mutation to the\n            <jats:italic>ramR<\/jats:italic>\n            regulator of the\n            <jats:italic>acrAB<\/jats:italic>\n            efflux operon recreated the ceftazidime-avibactam-resistant MIC of 32 \u03bcg\/ml, confirming that this constellation of mutations is responsible for the resistance phenotype.\n          <\/jats:p>","DOI":"10.1128\/aac.00989-17","type":"journal-article","created":{"date-parts":[[2017,7,25]],"date-time":"2017-07-25T00:20:23Z","timestamp":1500942023000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":152,"title":["Resistance to Ceftazidime-Avibactam Is Due to Transposition of KPC in a Porin-Deficient Strain of Klebsiella pneumoniae with Increased Efflux Activity"],"prefix":"10.1128","volume":"61","author":[{"given":"Kirk","family":"Nelson","sequence":"first","affiliation":[{"name":"The Medicines Company, San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6182-9136","authenticated-orcid":false,"given":"Peera","family":"Hemarajata","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxu","family":"Sun","sequence":"additional","affiliation":[{"name":"The Medicines Company, San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Rubio-Aparicio","sequence":"additional","affiliation":[{"name":"The Medicines Company, San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruslan","family":"Tsivkovski","sequence":"additional","affiliation":[{"name":"The Medicines Company, San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangxin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of New Mexico, Albuquerque, New Mexico, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Sebra","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Kasarskis","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoan","family":"Nguyen","sequence":"additional","affiliation":[{"name":"JAX Genomic Medicine, Farmington, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blake M.","family":"Hanson","sequence":"additional","affiliation":[{"name":"JAX Genomic Medicine, Farmington, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shana","family":"Leopold","sequence":"additional","affiliation":[{"name":"JAX Genomic Medicine, Farmington, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Weinstock","sequence":"additional","affiliation":[{"name":"JAX Genomic Medicine, Farmington, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Lomovskaya","sequence":"additional","affiliation":[{"name":"The Medicines Company, San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romney M.","family":"Humphries","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine, University of California, Los 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Performance standards for antimicrobial susceptibility testing M100S, 27th ed. 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