{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:08:07Z","timestamp":1791331687113,"version":"4.3.1"},"reference-count":28,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"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":[[2015,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Ceftazidime-avibactam is active against most\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Enterobacteriaceae<\/jats:named-content>\n            isolates with KPC carbapenemases. We investigated whether this activity could be compromised by mutation. Single-step and multistep selections were attempted using ceftazidime-avibactam (avibactam fixed at 1 or 4 \u03bcg\/ml)\n            <jats:italic>versus<\/jats:italic>\n            two strains each of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Enterobacter cloacae<\/jats:named-content>\n            and\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Klebsiella pneumoniae<\/jats:named-content>\n            , all with the KPC-3 enzyme. Mutant\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>KPC<\/jats:sub>\n            alleles were sequenced, and their parentage was confirmed by typing. Ceftazidime-avibactam selected mutants at up to 16\u00d7 MIC, with frequencies of ca. 10\n            <jats:sup>\u22129<\/jats:sup>\n            . This contrasted with previous experience for ceftaroline-avibactam, where mutant frequencies under similar conditions were &lt;10\n            <jats:sup>\u22129<\/jats:sup>\n            . The MICs of ceftazidime with 1 \u03bcg\/ml avibactam for the ceftazidime-avibactam-selected mutants rose from 1 to 8 \u03bcg\/ml to 16 to &gt;256 \u03bcg\/ml and those of ceftazidime with 4 \u03bcg\/ml avibactam from 0.25 to 1 \u03bcg\/ml to 4 to 128 \u03bcg\/ml; ceftaroline-avibactam MICs rose less, typically from 0.5 to 1 \u03bcg\/ml to 1 to 8 \u03bcg\/ml. The MICs of carbapenems and cephalosporins except ceftazidime and piperacillin-tazobactam were reduced for many mutants. Sequencing of\n            <jats:italic>\n              bla\n              <jats:sub>KPC<\/jats:sub>\n            <\/jats:italic>\n            revealed point and insertion changes in 12\/13 mutants investigated, representing all four parents; one mutant lacked\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>KPC<\/jats:sub>\n            changes and possibly had reduced permeability. Amino acid changes commonly involved \u03a9 loop alterations or 1 to 6 amino acid insertions immediately C-terminal to this loop. The most frequent change, seen in four mutants from three strains, was Asp179Tyr, replacing a residue that ordinarily forms a salt bridge to stabilize the \u03a9 loop. Since ceftaroline-avibactam was less affected than ceftazidime-avibactam, we postulate that these mutations increase ceftazidimase specificity rather than conferring avibactam resistance. The clinical relevance remains uncertain.\n          <\/jats:p>","DOI":"10.1128\/aac.00678-15","type":"journal-article","created":{"date-parts":[[2015,6,23]],"date-time":"2015-06-23T01:45:36Z","timestamp":1435023936000},"page":"5324-5330","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":161,"title":["<i>In Vitro<\/i>\n            Selection of Ceftazidime-Avibactam Resistance in Enterobacteriaceae with KPC-3 Carbapenemase"],"prefix":"10.1128","volume":"59","author":[{"given":"David M.","family":"Livermore","sequence":"first","affiliation":[{"name":"Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, United Kingdom"},{"name":"Norwich Medical School, University of East Anglia, Norwich, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Warner","sequence":"additional","affiliation":[{"name":"Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Jamrozy","sequence":"additional","affiliation":[{"name":"Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shazad","family":"Mushtaq","sequence":"additional","affiliation":[{"name":"Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wright W.","family":"Nichols","sequence":"additional","affiliation":[{"name":"AstraZeneca Pharmaceuticals LP, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazim","family":"Mustafa","sequence":"additional","affiliation":[{"name":"Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Woodford","sequence":"additional","affiliation":[{"name":"Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.485979"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1205073109"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(13)70190-7"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkt383"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00693-09"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2007.01849.x"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00608-10"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dks079"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02247-12"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03267-14"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.4.1151-1161.2001"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.015198-0"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkn396"},{"key":"e_1_3_2_15_2","volume-title":"Approved standard M7-A9","author":"Clinical and Laboratory Standards Institute","year":"2009","unstructured":"Clinical and Laboratory Standards Institute. 2009. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A9. Clinical and Laboratory Standards Institute, Wayne PA."},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkp029"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2180-13-160"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00334-12"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/21.1.173"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2760269"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkm150"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkf151"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2006.01423.x"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.348540"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi200403e"},{"key":"e_1_3_2_26_2","volume-title":"Abstr 45th Intersci Conf Antimicrob Agents Chemother. American Society for Microbiology","author":"Winkler ML","year":"2014","unstructured":"Winkler ML, Taracila MA, Papp-Wallace KM, Page RA, Bonomo RA. 2014. Two sides to every story: exploring the functional role of D179 in the \u03a9-loop of KPC-2 \u03b2-lactamase, abstr C-153. Abstr 45th Intersci Conf Antimicrob Agents Chemother. American Society for Microbiology, Washington, DC Abstract C-153."},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dks523"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1185\/03007995.2012.748653"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkt278"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00678-15","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00678-15","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T22:55:14Z","timestamp":1645484114000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00678-15"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,9]]},"references-count":28,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2015,9]]}},"alternative-id":["10.1128\/AAC.00678-15"],"URL":"https:\/\/doi.org\/10.1128\/aac.00678-15","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,9]]},"assertion":[{"value":"2015-03-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-06-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-08-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}