The epidemiology and virulence of carbapenem-resistant Pseudomonas aeruginosa in China

We read with interest the Article by the Antibacterial Resistance Leadership Group and Multi-Drug Resistant Organism Network Investigators, which described the divergent global distribution of carbapenem-resistant Pseudomonas aeruginosa, and the increasingly serious therapeutic problems it causes.1Reyes J Komarow L Chen L et al.Global epidemiology and clinical outcomes of carbapenem-resistant Pseudomonas aeruginosa and associated carbapenemases (POP): a prospective cohort study.Lancet Microbe. 2023; 4: e159-e170Summary Full Text Full Text PDF PubMed Google Scholar There are three main mechanisms of resistance to P aeruginosa: producing or over-expressing β-lactamase, outer membrane protein mutation, and overexpression of the efflux pump system.2Tenover FC Nicolau DP Gill CM Carbapenemase-producing Pseudomonas aeruginosa—an emerging challenge.Emerg Microbes Infect. 2022; 11: 811-814Crossref PubMed Scopus (0) Google Scholar, 3Kao CY Chen SS Hung KH et al.Overproduction of active efflux pump and variations of OprD dominate in imipenem-resistant Pseudomonas aeruginosa isolated from patients with bloodstream infections in Taiwan.BMC Microbiol. 2016; 16: 107Crossref PubMed Scopus (32) Google Scholar The virulence of P aeruginosa is closely connected to four key effectors (ExoU, ExoT, ExoY, and ExoS) in the type III secretion system which help inject the toxic proteins into host cells.4Diggle SP Whiteley M Microbe Profile: Pseudomonas aeruginosa: opportunistic pathogen and lab rat.Microbiology (Reading). 2020; 166: 30-33Crossref PubMed Scopus (0) Google Scholar In a national study of P aeruginosa in China, we discovered that most carbapenem-resistant P aeruginosa carried multiple resistance mechanisms, and most ExoU-positive strains presented hypervirulence. An emergence of clustered ST463 ExoU-positive P aeruginosa occurred in southeast China. In our study, P aeruginosa strains insusceptible to meropenem or imipenem (the minimum inhibitory concentration of ≥4 μg/mL) accounted for 38·9% (203 of 522) of strains tested, and strains insusceptible to both carbapenems made up 27·8% (145 of 522) of strains tested. Among those insusceptible to meropenem or imipenem, 5·9% (12 of 203) can be identified as difficult-to-treat P aeruginosa (meaning resistant in vitro to ceftazidime, cefepime, aztreonam, meropenem, imipenem, amikacin, and levofloxacin5Kadri SS Adjemian J Lai YL et al.Difficult-to-treat resistance in Gram-negative bacteremia at 173 US hospitals: retrospective cohort analysis of prevalence, predictors, and outcome of resistance to All first-line agents.Clin Infect Dis. 2018; 67: 1803-1814PubMed Google Scholar). We collected the highest quantities of imipenem-insusceptible P aeruginosa from southeastern China (33·0% [60 of 182]), and the lowest quantities from central China (5·5% [10 of 182]). Whole genome sequencing analysis of 182 imipenem-insusceptible P aeruginosa in this study revealed 24·7% of resistance mechanisms were only related to β-lactamase, and 9·3% were related to β-lactamase and efflux pump overexpression. 30·2% were related to β-lactamase and outer membrane protein mutation, and 35·7% were related to β-lactamase, efflux pump overexpression, and outer membrane protein mutation. 9·8% of imipenem-insusceptible P aeruginosa carried carbapenemases, Klebsiella pneumoniae carbapenemase (KPC) or imipenemase metallo-β-lactamase (IMP). The mechanism of carbapenem-resistance in P aeruginosa is diverse, and β-lactamase-producing resistance is the most prevalent. According to whole genome sequencing and PCR, 25·3% (46 of 182) of imipenem-insusceptible P aeruginosa harbored ExoU, and 32·6% (15 of 46) also harbored ExoS. We classified the virulence of these 46 Exo-positive strains in Galleria mellonella larvae infection models (appendix p 1) into three groups: hypovirulence, medium virulence, and hypervirulence. Most (56·5% [26 of 46]) strains were classified into the hypervirulence group. Furthermore, an emergence of ExoU-positive ST463 P aeruginosa (23·9% [11 of 46]) was observed in Zhejiang province, southeast China. Among them, ten strains carried KPC-2, OXA-486, PDC-8, and presented as hypervirulent. This study identified the epidemiology of carbapenem-resistance mechanisms and the virulence of P aeruginosa in China. Carbapenemase is common in China and ST463 carbapenem-resistant P aeruginosa with hypervirulence should be monitored in case of serious clinical outcomes. We declare no competing interests. This work was supported by the National High Level Hospital Clinical Research Funding (grants 2022-PUMCH-B-028, 2022-PUMCH-C-060). Download .pdf (.16 MB) Help with pdf files Supplementary appendix Global epidemiology and clinical outcomes of carbapenem-resistant Pseudomonas aeruginosa and associated carbapenemases (POP): a prospective cohort studyThe emergence of different carbapenemases among CRPA isolates in different geographical regions and the increased mortality associated with carbapenemase-producing CRPA infections highlight the therapeutic challenges posed by these organisms. Full-Text PDF Open Access