{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T12:05:53Z","timestamp":1778501153553,"version":"3.51.4"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T00:00:00Z","timestamp":1717632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province","award":["2022E10022"],"award-info":[{"award-number":["2022E10022"]}]},{"name":"Scientific Research Project of Department of Education of Zhejiang Province of China","award":["Y202250154"],"award-info":[{"award-number":["Y202250154"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To investigate the prevalence and mechanisms of ceftazidime\/avibactam heteroresistance in KPC-producing Klebsiella pneumoniae (KPC-KP) isolates, as well as the role of heteroresistance in the transition of ceftazidime\/avibactam susceptibility to resistance.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Clinical KPC-KP isolates were obtained from a tertiary hospital in China from 2016 to 2017 and 2019 to 2020. Antimicrobial susceptibility was determined by the broth microdilution method. Population analysis profiles were used to assess ceftazidime\/avibactam heteroresistance. WGS and molecular cloning were conducted to reveal heteroresistance mechanisms and molecular characteristics.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The findings indicated that the transition of ceftazidime\/avibactam susceptibility to resistance during the treatment of KPC-KP infection is primarily attributed to the heteroresistance exhibited by KPC-KP isolates towards ceftazidime\/avibactam. Among 355 ceftazidime\/avibactam-susceptible KPC-KP isolates (indicating a resistance rate of 0%), 41 (11.55%) exhibited ceftazidime\/avibactam heteroresistance, with the primary mechanism being the presence of KPC mutant subpopulations. These KPC variants, arising from point mutations, deletions and insertions, significantly increased ceftazidime\/avibactam resistance while alongside enhanced carbapenem susceptibility. Notably, 11 new KPC variants were identified. Furthermore, four heteroresistant isolates were caused by mixed infection involving subpopulations carrying NDM-1 or NDM-5. Phylogenetic analysis indicated that the clonal spread of ST11-KL64 KPC-KP may be correlated with the prevalence of heteroresistance.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Ceftazidime\/avibactam heteroresistance, primarily driven by pre-existing KPC variants, underscores the importance of considering heteroresistance in ceftazidime\/avibactam therapeutics. Awareness of these dynamics is crucial for the effective and sustainable clinical application of ceftazidime\/avibactam.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkae174","type":"journal-article","created":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T17:14:56Z","timestamp":1717694096000},"page":"1865-1876","source":"Crossref","is-referenced-by-count":8,"title":["The prevalence and mechanisms of heteroresistance to ceftazidime\/avibactam in KPC-producing <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1093","volume":"79","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2697-3885","authenticated-orcid":false,"given":"Xiaotuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou, Zhejiang Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiliang","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou, Zhejiang Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingchun","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Medical Lab Science, School of Laboratory Medicine and Life Science, Wenzhou Medical University , Wenzhou, Zhejiang Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeyu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou, Zhejiang Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongyun","family":"Shu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou, Zhejiang Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miran","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou, Zhejiang Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changrui","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou, Zhejiang Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunquan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou, Zhejiang Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2171-4710","authenticated-orcid":false,"given":"Tieli","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou, Zhejiang Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianzhong","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou, Zhejiang Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,6,6]]},"reference":[{"key":"2024073123515137600_dkae174-B1","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/S1473-3099(13)70190-7","article-title":"Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases","volume":"13","author":"Munoz-Price","year":"2013","journal-title":"Lancet Infect Dis"},{"key":"2024073123515137600_dkae174-B2","doi-asserted-by":"crossref","first-page":"314","DOI":"10.3389\/fcimb.2020.00314","article-title":"Dissemination of carbapenemases (KPC, NDM, OXA-48, IMP, and VIM) among carbapenem-resistant Enterobacteriaceae isolated from adult and children patients in China","volume":"10","author":"Han","year":"2020","journal-title":"Front Cell Infect Microbiol"},{"key":"2024073123515137600_dkae174-B3","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1080\/22221751.2022.2049458","article-title":"Molecular epidemiology of carbapenem-resistant hypervirulent Klebsiella pneumoniae in China","volume":"11","author":"Yang","year":"2022","journal-title":"Emerg Microbes Infect"},{"key":"2024073123515137600_dkae174-B4","doi-asserted-by":"crossref","first-page":"ofv050","DOI":"10.1093\/ofid\/ofv050","article-title":"Treatment options for carbapenem-resistant Enterobacteriaceae infections","volume":"2","author":"Morrill","year":"2015","journal-title":"Open Forum Infect Dis"},{"key":"2024073123515137600_dkae174-B5","doi-asserted-by":"crossref","first-page":"e0123121","DOI":"10.1128\/Spectrum.01231-21","article-title":"Combining colistin with furanone C-30 rescues colistin resistance of gram-negative bacteria in vitro and in vivo","volume":"9","author":"Zhang","year":"2021","journal-title":"Microbiol Spectr"},{"key":"2024073123515137600_dkae174-B6","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/cid\/cix783","article-title":"Colistin versus ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae","volume":"66","author":"van Duin","year":"2018","journal-title":"Clin Infect Dis"},{"key":"2024073123515137600_dkae174-B7","doi-asserted-by":"crossref","first-page":"27960","DOI":"10.1074\/jbc.M113.485979","article-title":"Kinetics of avibactam inhibition against Class A, C, and D beta-lactamases","volume":"288","author":"Ehmann","year":"2013","journal-title":"J Biol Chem"},{"key":"2024073123515137600_dkae174-B8","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S1473-3099(17)30747-8","article-title":"Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial","volume":"18","author":"Torres","year":"2018","journal-title":"Lancet Infect Dis"},{"key":"2024073123515137600_dkae174-B9","doi-asserted-by":"crossref","first-page":"e0171421","DOI":"10.1128\/spectrum.01714-21","article-title":"Multiple novel ceftazidime-avibactam-resistant variants of bla(KPC-2)-positive Klebsiella pneumoniae in two patients","volume":"10","author":"Shi","year":"2022","journal-title":"Microbiol Spectr"},{"key":"2024073123515137600_dkae174-B10","doi-asserted-by":"crossref","first-page":"S436","DOI":"10.1093\/cid\/ciaa1521","article-title":"Emergence and recovery of ceftazidime-avibactam resistance in blaKPC-33-harboring Klebsiella pneumoniae sequence type 11 isolates in China","volume":"71","author":"Shi","year":"2020","journal-title":"Clin Infect Dis"},{"key":"2024073123515137600_dkae174-B11","doi-asserted-by":"crossref","first-page":"e0089021","DOI":"10.1128\/AAC.00890-21","article-title":"KPC-Mediated resistance to ceftazidime-avibactam and collateral effects in Klebsiella pneumoniae","volume":"65","author":"Findlay","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"key":"2024073123515137600_dkae174-B12","doi-asserted-by":"crossref","first-page":"4627","DOI":"10.2147\/IDR.S371285","article-title":"Diversity of ceftazidime-avibactam resistance mechanism in KPC2-producing Klebsiella pneumoniae under antibiotic selection pressure","volume":"15","author":"Jiang","year":"2022","journal-title":"Infect Drug Resist"},{"key":"2024073123515137600_dkae174-B13","doi-asserted-by":"crossref","first-page":"1040.e1","DOI":"10.1016\/j.cmi.2021.03.001","article-title":"Molecular analysis of clinical isolates of ceftazidime-avibactam-resistant Klebsiella pneumoniae","volume":"27","author":"Venditti","year":"2021","journal-title":"Clin Microbiol Infect"},{"key":"2024073123515137600_dkae174-B14","doi-asserted-by":"crossref","first-page":"e01175-20","DOI":"10.1128\/AAC.01175-20","article-title":"KPC beta-lactamases are permissive to insertions and deletions conferring substrate spectrum modifications and resistance to ceftazidime-avibactam","volume":"64","author":"Hobson","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"key":"2024073123515137600_dkae174-B15","doi-asserted-by":"crossref","first-page":"e0085921","DOI":"10.1128\/mSphere.00859-21","article-title":"Molecular mechanisms driving the in vivo development of KPC-71-mediated resistance to ceftazidime-avibactam during treatment of carbapenem-resistant Klebsiella pneumoniae infections","volume":"6","author":"Li","year":"2021","journal-title":"mSphere"},{"key":"2024073123515137600_dkae174-B16","doi-asserted-by":"crossref","first-page":"106524","DOI":"10.1016\/j.ijantimicag.2022.106524","article-title":"In vivo selection of KPC-94 and KPC-95 in Klebsiella pneumoniae isolates from patients treated with ceftazidime\/avibactam","volume":"59","author":"Guzman-Puche","year":"2022","journal-title":"Int J Antimicrob Agents"},{"key":"2024073123515137600_dkae174-B17","doi-asserted-by":"crossref","first-page":"6881","DOI":"10.2147\/IDR.S387187","article-title":"Emergence of ceftazidime-avibactam resistance and decreased virulence in carbapenem-resistant ST11 Klebsiella pneumoniae during antibiotics treatment","volume":"15","author":"Xu","year":"2022","journal-title":"Infect Drug Resist"},{"key":"2024073123515137600_dkae174-B18","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.jiac.2015.02.001","article-title":"Applications of the pharmacokinetic\/pharmacodynamic (PK\/PD) analysis of antimicrobial agents","volume":"21","author":"Asin-Prieto","year":"2015","journal-title":"J Infect Chemother"},{"key":"2024073123515137600_dkae174-B19","doi-asserted-by":"crossref","first-page":"i43","DOI":"10.1093\/jac\/dkaa083","article-title":"Results from the survey of antibiotic resistance (SOAR) 2015\u201317 in Latin America (Argentina, Chile and Costa Rica): data based on CLSI, EUCAST (dose-specific) and pharmacokinetic\/pharmacodynamic (PK\/PD) breakpoints","volume":"75","author":"Torumkuney","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"2024073123515137600_dkae174-B20","doi-asserted-by":"crossref","first-page":"e1007726","DOI":"10.1371\/journal.ppat.1007726","article-title":"Heteroresistance: a cause of unexplained antibiotic treatment failure?","volume":"15","author":"Band","year":"2019","journal-title":"PLoS Pathog"},{"key":"2024073123515137600_dkae174-B21","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1128\/CMR.00058-14","article-title":"Antimicrobial heteroresistance: an emerging field in need of clarity","volume":"28","author":"El-Halfawy","year":"2015","journal-title":"Clin Microbiol Rev"},{"key":"2024073123515137600_dkae174-B22","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/s41579-019-0218-1","article-title":"Mechanisms and clinical relevance of bacterial heteroresistance","volume":"17","author":"Andersson","year":"2019","journal-title":"Nat Rev Microbiol"},{"key":"2024073123515137600_dkae174-B23","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1093\/jac\/dkv378","article-title":"Prevalence of hypermutators among clinical Acinetobacter baumannii isolates","volume":"71","author":"Komp Lindgren","year":"2016","journal-title":"J Antimicrob Chemother"},{"key":"2024073123515137600_dkae174-B24","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.ijantimicag.2010.04.010","article-title":"Hypermutability in clinical isolates of Klebsiella pneumoniae is uncommon and is unrelated to ciprofloxacin resistance","volume":"36","author":"Aathithan","year":"2010","journal-title":"Int J Antimicrob Agents"},{"key":"2024073123515137600_dkae174-B25","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/s41564-018-0342-0","article-title":"The high prevalence of antibiotic heteroresistance in pathogenic bacteria is mainly caused by gene amplification","volume":"4","author":"Nicoloff","year":"2019","journal-title":"Nat Microbiol"},{"key":"2024073123515137600_dkae174-B26","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1038\/s41564-019-0480-z","article-title":"Antibiotic combinations that exploit heteroresistance to multiple drugs effectively control infection","volume":"4","author":"Band","year":"2019","journal-title":"Nat Microbiol"},{"key":"2024073123515137600_dkae174-B27","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1089\/cmb.2012.0021","article-title":"SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing","volume":"19","author":"Bankevich","year":"2012","journal-title":"J Comput Biol"},{"key":"2024073123515137600_dkae174-B28","doi-asserted-by":"crossref","first-page":"100952","DOI":"10.1016\/j.drup.2023.100952","article-title":"Carbapenemase-loaded outer membrane vesicles protect Pseudomonas aeruginosa by degrading imipenem and promoting mutation of antimicrobial resistance gene","volume":"68","author":"Zhang","year":"2023","journal-title":"Drug Resist Updat"},{"key":"2024073123515137600_dkae174-B29","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1093\/bioinformatics\/btv681","article-title":"JSpeciesWS: a web server for prokaryotic species circumscription based on pairwise genome comparison","volume":"32","author":"Richter","year":"2016","journal-title":"Bioinformatics"},{"key":"2024073123515137600_dkae174-B30","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1038\/s41564-019-0492-8","article-title":"Epidemic of carbapenem-resistant Klebsiella pneumoniae in Europe is driven by nosocomial spread","volume":"4","author":"David","year":"2019","journal-title":"Nat Microbiol"},{"key":"2024073123515137600_dkae174-B31","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1038\/s41467-023-38061-z","article-title":"A point mutation in recC associated with subclonal replacement of carbapenem-resistant Klebsiella pneumoniae ST11 in China","volume":"14","author":"Zhou","year":"2023","journal-title":"Nat Commun"},{"key":"2024073123515137600_dkae174-B32","doi-asserted-by":"crossref","first-page":"4188","DOI":"10.1038\/s41467-021-24448-3","article-title":"A genomic surveillance framework and genotyping tool for Klebsiella pneumoniae and its related species complex","volume":"12","author":"Lam","year":"2021","journal-title":"Nat Commun"},{"key":"2024073123515137600_dkae174-B33","doi-asserted-by":"crossref","first-page":"e0157718","DOI":"10.1371\/journal.pone.0157718","article-title":"A bacterial analysis platform: an integrated system for analysing bacterial whole genome sequencing data for clinical diagnostics and surveillance","volume":"11","author":"Thomsen","year":"2016","journal-title":"PLoS One"},{"key":"2024073123515137600_dkae174-B34","doi-asserted-by":"crossref","first-page":"124.e1","DOI":"10.1016\/j.cmi.2019.08.020","article-title":"Emergence of ceftazidime\/avibactam resistance in carbapenem-resistant Klebsiella pneumoniae in China","volume":"26","author":"Zhang","year":"2020","journal-title":"Clin Microbiol Infect"},{"key":"2024073123515137600_dkae174-B35","doi-asserted-by":"crossref","first-page":"931","DOI":"10.2147\/IDR.S243032","article-title":"Dynamic epidemiology and virulence characteristics of carbapenem-resistant Klebsiella pneumoniae in Wenzhou, China from 2003 to 2016","volume":"13","author":"Zhao","year":"2020","journal-title":"Infect Drug Resist"},{"key":"2024073123515137600_dkae174-B36","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.cmi.2019.04.013","article-title":"Management of carbapenem-resistant Enterobacteriaceae infections","volume":"25","author":"Durante-Mangoni","year":"2019","journal-title":"Clin Microbiol Infect"},{"key":"2024073123515137600_dkae174-B37","doi-asserted-by":"crossref","first-page":"e0127922","DOI":"10.1128\/aac.01279-22","article-title":"The effect of beta-lactam antibiotics on the evolution of ceftazidime\/avibactam and cefiderocol resistance in KPC-producing Klebsiella pneumoniae","volume":"67","author":"Zhang","year":"2023","journal-title":"Antimicrob Agents Chemother"},{"key":"2024073123515137600_dkae174-B38","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1093\/jac\/dky082","article-title":"In vivo evolution of resistant subpopulations of KPC-producing Klebsiella pneumoniae during ceftazidime\/avibactam treatment","volume":"73","author":"Gaibani","year":"2018","journal-title":"J Antimicrob Chemother"},{"key":"2024073123515137600_dkae174-B39","doi-asserted-by":"crossref","first-page":"e02101-17","DOI":"10.1128\/AAC.02101-17","article-title":"Successive emergence of ceftazidime-avibactam resistance through distinct genomic adaptations in bla(KPC-2)-harboring Klebsiella pneumoniae sequence type 307 isolates","volume":"62","author":"Giddins","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2024073123515137600_dkae174-B40","doi-asserted-by":"publisher","first-page":"579618","DOI":"10.3389\/fmicb.2020.579618","article-title":"Co-occurrence of rapid gene gain and loss in an interhospital outbreak of carbapenem-resistant hypervirulent ST11-K64 Klebsiella pneumoniae","volume":"11","author":"Zhang","year":"2020","journal-title":"Front Microbiol"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/79\/8\/1865\/58688948\/dkae174.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/79\/8\/1865\/58688948\/dkae174.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T05:57:22Z","timestamp":1722491842000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/79\/8\/1865\/7688894"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,6]]},"references-count":40,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,6,6]]},"published-print":{"date-parts":[[2024,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkae174","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,8]]},"published":{"date-parts":[[2024,6,6]]}}}