Emergence of Ceftazidime- and Avibactam-Resistant Klebsiella pneumoniae Carbapenemase-Producing Pseudomonas aeruginosa in China

Klebsiella pneumoniae carbapenemase (KPC)-producing Pseudomonas aeruginosa (KPC-PA) has been reported sporadically. However, epidemiological and antimicrobial susceptibility data specific for KPC-PA are lacking. We collected 374 carbapenem-resistant P. aeruginosa (CRPA) isolates from seven hospitals in China from June 2016 to February 2019 and identified the bla(KPC-2) gene in 40.4% (n = 151/374) of the isolates. Approximately one-half of all KPC-PA isolates (n = 76/151; 50.3%) were resistant to ceftazidime-avibactam (CAZ-AVI). Combining Kraken2 taxonomy identification and Nanopore sequencing, we identified eight plasmid types, five of which carried bla(KPC-2), and 13 combination patterns of these plasmid types. In addition, we identified IS26-Delta Tn6296 and Tn1403-like-Delta Tn6296 as the two mobile genetic elements that mediated bla(KPC-2) transmission. bla(KPC-2) plasmid curing in 28 strains restored CAZ-AVI susceptibility, suggesting that bla(KPC-2) was the mediator of CAZ-AVI resistance. Furthermore, the bla(KPC-2) copy number was found to correlate with KPC expression and, therefore, CAZ-AVI resistance. Taken together, our results suggest that KPC-PA is becoming a clinical threat and that using CAZ-AVI to treat this specific pathogen should be done with caution. IMPORTANCE Previous research has reported several cases of KPC-PA strains and three KPC-encoding P. aeruginosa plasmid types in China. However, the prevalence and clinical significance of KPC-PA are not available. In addition, the susceptibility of the strains to CAZ-AVI remains unknown. Samples in this study were collected from seven tertiary hospitals prior to CAZ-AVI clinical approval in China. Therefore, our results represent a retrospective study establishing the baseline efficacy of the novel beta-lactam/beta-lactamase combination agent for treating KPC-PA infections. The observed correlation between the bla(KPC) copy number and CAZ-AVI resistance suggests that close monitoring of the susceptibility of the strain during treatment is required. It would also be beneficial to screen for the bla(KPC) gene in CRPA strains for antimicrobial surveillance purposes.

Automated summary

Klebsiella pneumoniae carbapenemase (KPC)-producing Pseudomonas aeruginosa (KPC-PA) strains were found in 40.4% of carbapenem-resistant P. aeruginosa (CRPA) isolates, with half of them resistant to ceftazidime-avibactam (CAZ-AVI). Eight plasmid types and two mobile genetic elements mediating bla(KPC-2) transmission were identified through sequencing. Curing bla(KPC-2) plasmids in 28 strains restored CAZ-AVI susceptibility, indicating its role in resistance.