Emergence and rising of ceftazidime-avibactam resistant KPC-producing Pseudomonas aeruginosa in China: a molecular epidemiology study

Background Infections by Carbapenem-resistant Pseudomonas aeruginosa (CRPA) are difficult to treat and novel antibiotics are desperately needed. Till today, ceftazidime-avibactam (CAZ-AVI) has been used to treat infections caused by multidrug resistant (MDR) Gram-negative bacteria, including Klebsiella pneumoniae carbapenemase (KPC)-producing organisms. Although cases of KPC-producing P. aeruginosa (KPC-PA) have been reported sporadically, data about KPC-PA susceptibility to CAZ-AVI and its molecular characteristics are limited.

Methods CRPA were collected from seven hospitals in China from 2017 to 2018. PCR was deployed to screen for the bla_KPC gene. Antimicrobial susceptibility of KPC-PA was determined by broth microdilution method or agar dilution method. We combined Illumina sequencing and Nanopore long-read sequencing to elucidate the genomic characteristics of KPC-PA strains.

Results KPC-PA strains were found in six out of seven hospitals. 151/374 (40.4%) CRPA clinical isolates harbored the bla_KPC-2 gene. Among KPC-PA, ST463 (107/151) was predominant, followed by ST485 (14/151) and ST1212 (12/151). Approximately half of all KPC-PA (50.3%) were susceptible to CAZ-AVI. We found that the bla_KPC-2 gene copy number correlated with CAZ-AVI MIC. In more than 90% (136/151) of the strains, we found plasmids that belonged to two types carrying bla_KPC-2 gene. The Type 1 plasmid, predominant in East China, was identified in 118 strains and the Type 2 plasmid, belonged to a megaplasmid family spreading globally, was identified in 19 strains. In addition, we identified IS26-ΔTn6296 and IS6100-ΔTn6296-Tn1403 as two mobile genetic elements that mediated bla_KPC-2 gene transmission.

Conclusion Our results suggest that the bla_KPC-2 gene is becoming a remarkable mediator of carbapenem resistance in P. aeruginosa in China. The emergence and spread of such KPC-PA strains poses a threat on clinical therapy as CAZ-AVI becomes inefficient. It would be beneficial to screen