Objective To explore the molecular epidemiological characteristics of carbapenem-resistant Klebsiella pneumoniae (CRKP), and reveal its mechanism of resistance to ceftazidime/avibactam (CZA). Methods CZA-resistant CRKP strains initially isolated from the Affiliated Hospital of Xuzhou Medical University from January 2021 to September 2023 were collected. The carriage of 5 carbapenemase genes (bla_KPC, bla_NDM, bla_OXA, bla_VIM, bla_IMP) were detected with gene amplification method and colloidal gold method. The relative copy number and expression level of Klebsiella pneumoniae (KP) carbapenemase-producing KP (KPC-KP) was detected with real-time quantitative polymerase chain reaction (RT-qPCR), mutation sites of KPC mutation strains were analyzed with whole-genome sequencing, and epidemic characteristics of CRKP and resistance mechanism to CZA were analyzed. Results A total of 73 CZA-resistant CRKP strains were isolated, with 37 (50.68%) being KPC and NDM co-producing strains, 33 (45.21%) NDM-producing alone (23 strains producing NDM-5 and 10 strains producing NDM-1), and 3 KPC-producing alone. KP-2842 strain was identified as ST11-type KPC-33 variant, KP-2127 and KP-2189 strains produced KPC-2. Compared with KP ATCC BAA-1705, the copy number of bla_KPC in these strains up-regulated by 1.04-3.86 fold, and the expression increased by 6.66-12.93 fold, respectively. Colloidal gold and PCR methods demonstrated good consistency and the ability to detect the enzyme co-producing and KPC-33 variant. Conclusion In this hospital, the resistance of CRKP to CZA is primarily mediated by the metalloenzyme NDM, with co-production of NDM and KPC being a characteristic of CRKP. High copy number and expression level of bla_KPC-2 also contribute to CZA resistance. This study identified the KPC-33 variant for the first time in ST11-type CRKP in Jiangsu Province.