Genomic epidemiology and ceftazidime-avibactam high-level resistance mechanisms of in China from 2010 to 2022.

Ceftazidime-avibactam (CZA) resistance is a huge threat in the clinic; however, the underlying mechanism responsible for high-level CZA resistance in (PA) isolates remains unknown. In this study, a total of 5,763 isolates were collected from 2010 to 2022 to investigate the ceftazidime-avibactam (CZA) high-level resistance mechanisms of (PA) isolates in China. Fifty-six PER-producing isolates were identified, including 50 isolates carrying in PA, and 6 isolates carrying . Of these, 82.1% (46/56) were classified as DTR-PA isolates, and 76.79% (43/56) were resistant to CZA. Importantly, and overexpression led to 16-fold and >1024-fold increases in the MICs of CZA, respectively. WGS revealed that the gene was located in two different transferable IncP-2-type plasmids and chromosomes, whereas was found only on chromosomes and was carried by a class 1 integron embedded in a Tn-like transposon. Overexpression of efflux pumps may be associated with high-level CZA resistance in -positive strains. Kinetic parameter analysis revealed that PER-4 exhibited a similar / with ceftazidime and a high (∼3359-fold) IC50 value with avibactam compared to PER-1. Our study found that overexpression of PER-1 combined with enhanced efflux pump expression and the low affinity of PER-4 for avibactam contributes to high-level resistance to CZA. Additionally, the Tn-like transposon plays a significant role in disseminating . Urgent active surveillance is required to prevent the further spread of high-level CZA resistance in DTR-PA isolates.