Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a significant pathogen in hospital-acquired infections [1]. Owing to its diverse resistance mechanisms and high morbidity and mortality rates, it has become a major challenge in clinical treatment [2]. Despite being downgraded from ‘critical’ to the ‘high’ priority level in the World Health Organization's (WHO) Priority Pathogens List [3], CRPA remains a formidable challenge due to the limited availability of effective antibiotics [4]. The typical mechanisms of resistance to carbapenem in CRPA encompass the overexpression of efflux pumps, overproduction of chromosomally encoded AmpC β-lactamases, inactivation of the outer membrane protein OprD, and acquisition of carbapenemases [5]. The global prevalence of high-risk clones, such as ST235, ST111, and ST175, along with the dissemination of carbapenemases, has made carbapenemase production the primary driver of carbapenem resistance in P. aeruginosa [6]. The dominant carbapenemases in P. aeruginosa exhibit regional diversity, with Klebsiella pneumoniae carbapenemase (KPC) -2 and Verona integron-encoded metallo-β-lactamase (VIM) -2 being the most prevalent worldwide [7]. In China, the production of KPC-2 carbapenemase, predominantly carried and disseminated by the ST463 clone, has emerged as the primary resistance mechanism in CRPA [8].

Ceftazidime-avibactam (CZA) is a novel β-lactam/β-lactamase inhibitor combination that demonstrates high efficacy against various β-lactamases and exhibits notable activity against KPC-producing strains [9]. However, the escalating clinical use of CZA has been accompanied by a progressive increase in resistance rates. In addition to acquiring metallo-β-lactamases, CZA resistance in P. aeruginosa is driven by mutations and/or overexpression of AmpC β-lactamase, overexpression of efflux pumps, and increased copy number and/or mutations in blaKPC genes [10]. KPC variants have become the primary cause of CZA resistance in Enterobacteriaceae, but they remain relatively uncommon in P. aeruginosa [11]. As of August 2025, a total of 271 KPC variants have been identified in the NCBI database. Among these, only a minority of KPC variants have been clinically reported in P. aeruginosa [12].

Here, we report the first identification of blaKPC-78, with a D179A mutation in the Ω loop, in a clinical multidrug-resistant (MDR) P. aeruginosa strain and elucidate the evolution of CZA resistance driven by a blaKPC-2 to blaKPC-78 mutation during treatment. Moreover, the co-occurrence of efflux pump overexpression and KPC-78 in P. aeruginosa contributed to high-level resistance to CZA.