{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:33:53Z","timestamp":1790314433725,"version":"4.1.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T00:00:00Z","timestamp":1564531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>The \u03b2-lactam\/\u03b2-lactamase inhibitor combination ceftazidime\/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime\/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime\/avibactam-resistant K. pneumoniae isolates. Time\u2013kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime\/avibactam and imipenem alone and in combination.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The ceftazidime\/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime\/avibactam-resistant isolates were described. Time\u2013kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime\/avibactam. However, combined selection pressure with imipenem plus ceftazidime\/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime\/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Ceftazidime\/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time\u2013kill kinetics as well as an in vivo infection model we postulate a combination therapy of ceftazidime\/avibactam and imipenem as a strategy to prevent the development of ceftazidime\/avibactam resistance in KPC-producing Enterobacterales in vivo.<\/jats:p><\/jats:sec>","DOI":"10.1093\/jac\/dkz330","type":"journal-article","created":{"date-parts":[[2019,7,9]],"date-time":"2019-07-09T19:09:10Z","timestamp":1562699350000},"page":"3211-3216","source":"Crossref","is-referenced-by-count":93,"title":["Emergence of ceftazidime\/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo"],"prefix":"10.1093","volume":"74","author":[{"given":"Stephan","family":"G\u00f6ttig","sequence":"first","affiliation":[{"name":"Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Str. 40, Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denia","family":"Frank","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Str. 40, Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Mungo","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Str. 40, Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anika","family":"Nolte","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Str. 40, Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hogardt","sequence":"additional","affiliation":[{"name":"Institute of Medical 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