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Two sequential isolates recovered before and after the ceftazidime\/avibactam treatment were characterized by antimicrobial susceptibility testing, whole-genome sequencing, and functional and biochemical analyses. The initial isolate was susceptible to ceftazidime\/avibactam, whereas the later isolate developed resistance (increase in MIC from 2 to 32 mg\/L), accompanied by collateral carbapenem susceptibility. Both isolates co-produced a novel BEL variant (designated BEL-5) and an OXA-2 enzyme, encoded by adjacent genes within a class one integron embedded in a 31,623-bp IncP plasmid. The resistant isolate harbored a previously undescribed OXA-2 variant, designated OXA-1381, carrying a W157L substitution in the \u03a9-loop. Cloning experiments demonstrated that OXA-1381 is an extended-spectrum variant conferring increased resistance to ceftazidime\/avibactam and ceftolozane\/tazobactam but decreased resistance to carbapenems. Kinetic analyses revealed a marked increase in the affinity and catalytic efficiency of OXA-1381 against ceftazidime and ceftolozane, while showing reduced hydrolytic activity against meropenem, consistent with the observed phenotypic trade-off. Inhibition assays showed similar susceptibility to avibactam for both enzymes, confirming that resistance was driven by enhanced hydrolysis rather than by impaired inhibition. The findings document the\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      evolution of ceftazidime\/avibactam resistance in an ESBL-producing\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      background, mediated by structural modification of a narrow-spectrum OXA-2 enzyme. In addition, they highlight the potential of integron-borne genes encoding \u201csilent\u201d \u03b2-lactamases to evolve under antibiotic pressure and compromise the activity of last-line agents.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00584-26","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T14:12:55Z","timestamp":1787148775000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["<i>In vivo<\/i>\n                    emergence of ceftazidime\/avibactam resistance in\n                    <i>Pseudomonas aeruginosa<\/i>\n                    driven by OXA-1381, a novel W157L \u03a9-loop variant of 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