Dynamic evolution of ceftazidime-avibactam resistance due to interchanges between blaKPC-2 and blaKPC-145 during treatment of Klebsiella pneumoniae infection

Yili Chen; Runshi Yang; Penghao Guo; Pingjuan Liu; Jiankai Deng; Zhongwen Wu; Qingping Wu; Junqi Huang; Kang Liao

doi:10.3389/fcimb.2023.1244511

Dynamic evolution of ceftazidime-avibactam resistance due to interchanges between bla_KPC-2 and bla_KPC-145 during treatment of Klebsiella pneumoniae infection

Front Cell Infect Microbiol. 2023 Aug 21:13:1244511. doi: 10.3389/fcimb.2023.1244511. eCollection 2023.

Authors

Yili Chen¹, Runshi Yang², Penghao Guo¹, Pingjuan Liu¹, Jiankai Deng¹, Zhongwen Wu¹, Qingping Wu², Junqi Huang^{1

3

4

5}, Kang Liao¹

Affiliations

¹ Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
² Guangdong Provincial Key Laboratory of Microbial Safety and Health, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.
³ Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
⁴ Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.
⁵ Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China.

Abstract

Background: The emergence of ceftazidime-avibactam (CZA) resistance among carbapenem-resistant Klebsiella pneumoniae (CRKP) is of major concern due to limited therapeutic options.

Methods: In this study, 10 CRKP strains were isolated from different samples of a patient with CRKP infection receiving CZA treatment. Whole-genome sequencing (WGS) and conjugation experiments were performed to determine the transferability of the carbapenem resistance gene.

Results: This infection began with a KPC-2-producing K. pneumoniae (CZA MIC = 2 μg/mL, imipenem MIC ≥ 16 μg/mL). After 20 days of CZA treatment, the strains switched to the amino acid substitution of T263A caused by a novel KPC-producing gene, bla_KPC-145, which restored carbapenem susceptibility but showed CZA resistance (CZA MIC ≥ 256 μg/mL, imipenem MIC = 1 μg/mL). The bla_KPC-145 gene was located on a 148,185-bp untransformable IncFII-type plasmid. The subsequent use of carbapenem against KPC-145-producing K. pneumoniae infection led to a reversion of KPC-2 production (CZA MIC = 2 μg/mL, imipenem MIC ≥ 16 μg/mL). WGS analysis showed that all isolates belonged to ST11-KL47, and the number of SNPs was 14. This implied that these bla_KPC-positive K. pneumoniae isolates might originate from a single clone and have been colonized for a long time during the 120-day treatment period.

Conclusion: This is the first report of CZA resistance caused by bla_KPC-145, which emerged during the treatment with CZA against bla_KPC-2-positive K. pneumoniae-associated infection in China. These findings indicated that routine testing for antibiotic susceptibility and carbapenemase genotype is essential during CZA treatment.

Keywords: KPC-145; KPC-2; Klebsiella pneumoniae; carbapenem resistance; ceftazidime-avibactam resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Substitution
Carbapenem-Resistant Enterobacteriaceae*
Carbapenems
Drug Resistance, Bacterial*
Humans
Imipenem
Klebsiella Infections* / drug therapy
Klebsiella pneumoniae*

Substances

avibactam, ceftazidime drug combination
Carbapenems
Imipenem

Grants and funding

This work was supported by the Guangdong Natural Science Foundation - General Program. Yili Chen is a grant recipient of the project (2023A1515011252).