{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T08:09:35Z","timestamp":1786781375886,"version":"build-2736575974"},"reference-count":48,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82402720"],"award-info":[{"award-number":["82402720"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372701"],"award-info":[{"award-number":["82372701"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai Municipality","doi-asserted-by":"publisher","award":["24ZR1457300"],"award-info":[{"award-number":["24ZR1457300"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Innovation Group Project of Shanghai Municipal Health Commission","award":["2019CXJQ03"],"award-info":[{"award-number":["2019CXJQ03"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,8,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                      is a well-recognized opportunistic pathogen and a leading cause of healthcare-associated infections. The shrinking effectiveness of available antimicrobial therapies has intensified the global threat posed by carbapenem-resistant\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      (CRPA). Here, we elucidate the mechanisms of ceftazidime-avibactam (CZA) resistance mediated by the rare KPC variants, KPC-71 and KPC-78, identified during the treatment of CRPA infections. Two CZA-resistant\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      strains, SY-206885 and HZ-231016032, were isolated from critically ill male patients with severe pneumonia. Whole-genome sequencing assigned both isolates to the high-risk sequence type 463 (ST463). Isolate SY-206885 harbors the\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>KPC-71<\/jats:sub>\n                      gene, while HZ-231016032 carries\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>KPC-78<\/jats:sub>\n                      . Cloning and expression of these genes in\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      PAO1 conferred a marked increase in the CZA minimum inhibitory concentration. Notably, expression of KPC-71 or KPC-78 conferred CZA resistance while simultaneously reducing carbapenem hydrolytic activity, a trade-off previously described for some KPC variants but still rarely documented in\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      . Structural analysis and kinetic profiling showed that, relative to wild-type KPC-2, both KPC-71 and KPC-78 exhibited reduced catalytic turnover but increased substrate affinity for ceftazidime, together with significantly weakened binding to avibactam. In addition, elevated expression of MexAB-OprM and AmpC-related determinants in the clinical isolates likely further enhanced the high-level CZA resistance phenotype. These findings highlight the capacity of the ST463 CRPA lineage to evolve CZA resistance through KPC structural diversification under antimicrobial pressure and underscore the need for close surveillance during therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      In this study, we report the detection of the uncommon KPC variants KPC-71 and KPC-78 in clinical sequence type 463 (ST463) carbapenem-resistant\n                      <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                      isolates exhibiting resistance to ceftazidime-avibactam (CZA). We demonstrate that CZA resistance is driven by specific structural alterations\u2014a serine insertion between residues 182 and 183 or a D179A substitution within the \u03a9-loop\u2014that reshape the functional balance of the KPC enzyme. These changes appear to create an evolutionary trade-off by improving ceftazidime recognition while weakening avibactam-mediated inhibition. Given the widespread dissemination of the ST463 lineage in China, the emergence of these variants highlights the urgent need for clinicians to monitor for CZA resistance development during therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CLINICAL TRIALS<\/jats:title>\n                    <jats:p>\n                      This study is registered with ClinicalTrials.gov as\n                      <jats:related-object xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" document-id=\"ChiCTR2500105846\" document-id-type=\"clinical-trial-number\" source-id=\"ClinicalTrials.gov\" source-id-type=\"registry-name\" source-type=\"clinical-trials-registry\" xlink:href=\"https:\/\/www.chictr.org.cn\/showprojEN.html?proj=275495\">ChiCTR2500105846<\/jats:related-object>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01095-26","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T13:26:05Z","timestamp":1783689965000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Emergence of ceftazidime-avibactam resistance mediated by KPC variants KPC-71 and KPC-78 in ST463\n                    <i>Pseudomonas aeruginosa<\/i>"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7305-9367","authenticated-orcid":true,"given":"Fengjiao","family":"Yang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03rc6as71","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Laboratory, Shanghai Tenth People\u2019s Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/03vjkf643","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of 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