Within-host resistance evolution of a fatal ST11 hypervirulent carbapenem-resistant Klebsiella pneumoniae

Danni Pu; Jiankang Zhao; Binghuai Lu; Yulin Zhang; Yongli Wu; Ziyao Li; Xianxia Zhuo; Bin Cao

doi:10.1016/j.ijantimicag.2023.106747

Within-host resistance evolution of a fatal ST11 hypervirulent carbapenem-resistant Klebsiella pneumoniae

Int J Antimicrob Agents. 2023 Apr;61(4):106747. doi: 10.1016/j.ijantimicag.2023.106747. Epub 2023 Feb 8.

Authors

Danni Pu¹, Jiankang Zhao², Binghuai Lu², Yulin Zhang², Yongli Wu¹, Ziyao Li², Xianxia Zhuo³, Bin Cao⁴

Affiliations

¹ Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Laboratory of Clinical Microbiology and Infectious Diseases, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.
² Laboratory of Clinical Microbiology and Infectious Diseases, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.
³ Laboratory of Clinical Microbiology and Infectious Diseases, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China; Department of Pulmonary and Critical Care Medicine, Capital Medical University, Beijing, China.
⁴ Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Laboratory of Clinical Microbiology and Infectious Diseases, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China; Department of Pulmonary and Critical Care Medicine, Capital Medical University, Beijing, China; Tsinghua University-Peking University Joint Center for Life Sciences, Beijing, China. Electronic address: caobin_ben@163.com.

PMID: 36758779
DOI: 10.1016/j.ijantimicag.2023.106747

Abstract

Objectives: Hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKp) has become a great threat to public health. This study reported an hv-CRKp-associated fatal infection and revealed its mechanisms of antimicrobial resistance and within-host evolution.

Methods: A carbapenem-susceptible K. pneumoniae (CSKp) and 11 KPC-producing CRKp strains were isolated from a lung transplant recipient receiving continual antimicrobial therapy for 1.5 years. Pulsed-field gel electrophoresis (PFGE) separated two clusters between CSKp and CRKp.

Results: Further whole genome sequencing analysis found that all 11 CRKp were ST11-KL64 clones, while the CSKp was ST412-KL57. Among these 11 CRKp strains, three and one were resistant to colistin and ceftazidime/avibactam (CAZ/AVI), respectively. Three different mechanisms were found to be responsible for the colistin resistance, including the insertions of two different IS (ISKpn74 and IS903B) into the same position of mgrB and one related to the efflux pump system. CAZ/AVI resistance was associated with bla_KPC-2 mutation, and it was also found that increasing bla_KPC-2 expression increased the MICs of CAZ/AVI, but not at the resistance level. All these 12 strains had iucABCDiutA virulence cluster and rmpA/rmpA2 genes, with higher siderophore production than a reference classic K. pneumoniae (cKp), which were thought to be hypervirulent K. pneumoniae (hvKp). However, only the CSKp showed higher mucoviscosity according to the mucoviscosity assay. Genomic analysis showed that the rmpA variation (interrupted by ISKpn26) existed in all CRKp strains except the CSKp strain, demonstrating that hypermucoviscous phenotype assays could not accurately identify hvKp.

Conclusion: This study depicted a rapid and diverse within-host evolution of resistance in hv-CRKp of ST11-KL64 clone.

Keywords: Carbapenem-resistant Klebsiella pneumoniae; Hypervirulence; KPC-2; Within-host evolution; mgrB.

MeSH terms

Anti-Bacterial Agents / pharmacology
Carbapenem-Resistant Enterobacteriaceae*
Carbapenems / pharmacology
Colistin / pharmacology
Humans
Klebsiella Infections* / drug therapy
Klebsiella pneumoniae

Substances

Anti-Bacterial Agents
Colistin
Carbapenems