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

Yiwei Zhu; Jie Chen; Han Shen; Zhongju Chen; Qi-Wen Yang; Jin Zhu; Xi Li; Qing Yang; Feng Zhao; Jingshu Ji; Heng Cai; Yue Li; Linghong Zhang; Sebastian Leptihn; Xiaoting Hua; Yunsong Yu

doi:10.1128/mSystems.00787-21

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

mSystems. 2021 Dec 21;6(6):e0078721. doi: 10.1128/mSystems.00787-21. Epub 2021 Nov 2.

Authors

Yiwei Zhu^{1

2

3}, Jie Chen^{1

2

3}, Han Shen⁴, Zhongju Chen⁵, Qi-Wen Yang^{6

7}, Jin Zhu⁸, Xi Li⁹, Qing Yang¹⁰, Feng Zhao¹¹, Jingshu Ji¹¹, Heng Cai^{1

2

3}, Yue Li^{1

2

3}, Linghong Zhang^{1

2

3}, Sebastian Leptihn¹, Xiaoting Hua^{1

2

3}, Yunsong Yu^{1

2

3}

Affiliations

¹ Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang Universitygrid.13402.34 School of Medicine, Hangzhou, China.
² Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China.
³ Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang Universitygrid.13402.34 School of Medicine, Hangzhou, China.
⁴ Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
⁵ Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁶ Department of Laboratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.
⁷ Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Peking Union Medical College Hospitalgrid.413106.1, Peking Union Medical College, Beijing, China.
⁸ Department of Clinical Laboratory, Quzhou People's Hospital, Affiliated Quzhou Hospital of Wenzhou Medical University, Quzhou, China.
⁹ Centre of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
¹⁰ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang Universitygrid.13402.34, Hangzhou, China.
¹¹ Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang Universitygrid.13402.34 School of Medicine, Hangzhou, China.

Abstract

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-ΔTn6296 and Tn1403-like-ΔTn6296 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 β-lactam/β-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.

Keywords: Pseudomonas aeruginosa; blaKPC-2; carbapenem-resistant Pseudomonas aeruginosa; ceftazidime-avibactam.

Grants and funding

81830069/National Natural Science Foundation of China (NSF)