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

By Yiwei Zhu, Jie Chen, Han Shen, Zhongju Chen, Qiwen Yang, Jin Zhu, Xi Li, Qing Yang, Feng Zhao, Jingshu Ji, Heng Cai, Yue Li, Linghong Zhang, Sebastian Leptihn, Xiaoting Hua, Yunsong Yu

Posted 16 Dec 2020
medRxiv DOI: 10.1101/2020.12.15.20248268

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 blaKPC 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 blaKPC-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 blaKPC-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 blaKPC-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-{Delta}Tn6296 and IS6100-{Delta}Tn6296-Tn1403 as two mobile genetic elements that mediated blaKPC-2 gene transmission. Conclusion: Our results suggest that the blaKPC-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 for the blaKPC gene in CRPA strains for antimicrobial surveillance.

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