Increased gene expression and copy number of mutated bla(KPC) lead to high-level ceftazidime/avibactam resistance in Klebsiella pneumoniae

BACKGROUND: Resistance to ceftazidime-avibactam was reported, and it is important to investigate the mechanisms of ceftazidime/avibactam resistance in K. pneumoniae with mutations in bla(KPC). RESULTS: We report the mutated bla(KPC) is not the only mechanism related to CZA resistance, and investigate the role of outer porin defects, efflux pump, and relative gene expression and copy number of bla(KPC) and ompk35/36. Four ceftazidime/avibactam-sensitive isolates detected wild type bla(KPC-2), while 4 ceftazidime/avibactam-resistant isolates detected mutated bla(KPC) (bla(KPC-51), bla(KPC-52), and bla(KPC-33)). Compared with other ceftazidime/avibactam-resistant isolates with the minimal inhibitory concentration of ceftazidime/avibactam ranging 128–256 mg/L, the relative gene expression and copy number of bla(KPC) was increased in the isolate which carried bla(KPC-51) and also showed the highest minimal inhibitory concentration of ceftazidime/avibactam at 2048 mg/L. The truncated Ompk35 contributes rare to ceftazidime/avibactam resistance in our isolates. No significant difference in minimal inhibitory concentration of ceftazidime/avibactam was observed after the addition of PABN. CONCLUSIONS: Increased gene expression and copy number of mutated bla(KPC) can cause high-level ceftazidime/avibactam resistance.