Comparison of the in vitro activities and resistance mechanisms against imipenem–relebactam and ceftazidime–avibactam in clinical KPC-producing Klebsiella pneumoniae isolated in China

Ceftazidime-avibactam (CAZ-AVI) and imipenem-relebactam (IMI-REL) are both antibiotics with promising prospects for treating Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) infections. However, differences in the in vitro activities and resistance mechanisms to CAZ-AVI and IMI-REL in clinical KPC-Kps have not been described. In this study, KPC-Kp isolates from hospitalized patients in China were collected and subjected to antimicrobial susceptibility testing of IMI-REL and CAZ-AVI using the broth microdilution method. Whole-genome sequencing (WGS) and functional validation of mutations were performed on resistant strains, and RT-qPCR was used to determine the expression levels of blaKPC. The results showed that 21 (2.7%) of 782 clinical KPC-Kp strains were CAZ-AVI-resistant, 6 (0.8%) of 782 strains were IMI-REL-resistant, and 5 strains among them were resistant to both CAZ-AVI and IMI-REL. Strains resistant to both CAZ-AVI and IMI-REL can be effectively inhibited by tigecycline and polymyxin B. WGS and complementation experiments showed that KPC mutations are linked to high-level resistance to CAZ-AVI; while OmpK36 mutations may be the vital mechanism of IMI-REL resistance, confers resistance to CAZ-AVI simultaneously. Furthermore, RT-qPCR indicated that elevated blaKPC expression may play an important role in both CAZ-AVI and IMI-REL resistance. In summary, this study suggested that IMI-REL may have superior inhibitory effects in vitro on KPC-Kps than CAZ-AVI, and described the differences in resistance mechanisms between the two antibiotics.