Emergence of ceftazidime-avibactam resistance in blaKPC-33-harbouring ST11 Klebsiella pneumoniae in a paediatric patient

Jinlan Zhou; Gangfeng Yan; Chengkang Tang; Jing Liu; Pan Fu; Li Ding; Weiwei Yang; Yan Guo; Chuanqing Wang; Guoping Lu; Fupin Hu

doi:10.1016/j.ijantimicag.2024.107163

Emergence of ceftazidime-avibactam resistance in bla_KPC-33-harbouring ST11 Klebsiella pneumoniae in a paediatric patient

Int J Antimicrob Agents. 2024 Jun;63(6):107163. doi: 10.1016/j.ijantimicag.2024.107163. Epub 2024 Apr 1.

Authors

Jinlan Zhou¹, Gangfeng Yan¹, Chengkang Tang², Jing Liu¹, Pan Fu³, Li Ding², Weiwei Yang², Yan Guo², Chuanqing Wang³, Guoping Lu⁴, Fupin Hu⁵

Affiliations

¹ Intensive Care Unit, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
² Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China.
³ Department of Clinical Microbiology Laboratory, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
⁴ Intensive Care Unit, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China; Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China. Electronic address: [email protected].
⁵ Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China. Electronic address: [email protected].

PMID: 38570018
DOI: 10.1016/j.ijantimicag.2024.107163

Abstract

Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses immense threats to the health of infected patients worldwide, especially children. This study reports the infection caused by CRKP in a paediatric intensive care unit (PICU) child and its drug-resistant mutation during the treatment. Twelve Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains were isolated from the child. Broth microdilution method, plasmid transformation assay, and whole genome sequencing (WGS) were performed to investigate the antimicrobial susceptibility, resistance mechanisms, and genetic structural features of CRKPs. The results showed that 12 strains were highly resistant to most available antimicrobial agents. Among them, K. pneumoniae FD11 and K. pneumoniae FD12 were resistant to ceftazidime-avibactam (CZA, MIC >64 mg/L) and restored the carbapenem susceptibility (Imipenem, MIC =0.25 mg/L; Meropenem, MIC =2 mg/L). The patient improved after treatment with CZA in combination with aztreonam. Plasmid transformation assay demonstrated that the bla_KPC-33-positive transformant increased MICs of CZA by at least 33-fold and 8-fold compared with the recipient Escherichia coli DH5α and bla_KPC-2-positive transformants. WGS analysis revealed that all strains belonged to the ST11-KL64 type and showed highly homologous (3-26 single nucleotide polymorphisms [SNPs]). A single base mutation (G532T) of bla_KPC-2 resulted in a tyrosine to aspartic acid substitution at Ambler amino acid position 179 (D179Y), which conferred CZA resistance in K. pneumoniae. This is the first report of a drug-resistant mutation evolving into bla_KPC-33 during the treatment of bla_KPC-2-positive CRKP in paediatric-infected patients. It advises clinicians that routine sequential antimicrobial susceptibility testing and KPC genotyping are critical during CZA therapy in children infected with CRKP.

Keywords: Carbapenem-resistant Klebsiella pneumoniae; Ceftazidime-avibactam; KPC-2; KPC-33; Paediatric patient.

Publication types

Case Reports

MeSH terms

Anti-Bacterial Agents* / pharmacology
Azabicyclo Compounds* / pharmacology
Aztreonam / pharmacology
Bacterial Proteins* / genetics
Carbapenem-Resistant Enterobacteriaceae / drug effects
Carbapenem-Resistant Enterobacteriaceae / genetics
Carbapenem-Resistant Enterobacteriaceae / isolation & purification
Ceftazidime* / pharmacology
Child
Drug Combinations*
Drug Resistance, Multiple, Bacterial / genetics
Humans
Klebsiella Infections* / drug therapy
Klebsiella Infections* / microbiology
Klebsiella pneumoniae* / drug effects
Klebsiella pneumoniae* / enzymology
Klebsiella pneumoniae* / genetics
Klebsiella pneumoniae* / isolation & purification
Male
Microbial Sensitivity Tests*
Plasmids / genetics
Whole Genome Sequencing
beta-Lactamases* / genetics

Substances

Azabicyclo Compounds
avibactam, ceftazidime drug combination
Drug Combinations
Ceftazidime
beta-Lactamases
Anti-Bacterial Agents
Bacterial Proteins
carbapenemase
Aztreonam