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

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

Danni Pu  1 , Jiankang Zhao  2 , Binghuai Lu  2 , Yulin Zhang  2 , Yongli Wu  1 , Ziyao Li  2 , Xianxia Zhuo  3 , Bin Cao  4
Affiliations

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

Danni Pu et al. Int J Antimicrob Agents. 2023 Apr.

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 blaKPC-2 mutation, and it was also found that increasing blaKPC-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.

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Conflict of interest statement

Declarations Funding: This work was supported by the National Natural Science Foundation of China [grant number 82102456]; Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences [grant number CIFMS 2021-I2M-1-048 and CIFMS 2021-I2M-1-030]. Competing Interests: None declared. Ethical Approval: This study was approved by the Ethics Committee of China-Japan Friendship Hospital (2022-KY-054). Written informed consent was waived for the patient, as this research was retrospective and the patient's data were anonymised. Sequence Information: The sequences of strain K28074 were deposited in GenBank database with accession no. CP104551-CP104552 and PRJNA880246 (in progress), while those of strain K30821 were CP107014-CP107019.

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