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Testing the Role of Multicopy Plasmids in the Evolution of Antibiotic Resistance
Published on: May 2, 2018
Dynamic evolution of ceftazidime-avibactam resistance from a single patient through the IncX3_NDM-5 plasmid transfer
Chengkang Tang1, Siquan Shen1, Weiwei Yang1
1Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China.
Abstract:
The rapid dissemination of carbapenem-resistant Enterobacterales (CRE) especially carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a great threat to global public health. Ceftazidime-avibactam, a novel β-lactam/β-lactamase inhibitor combination, has been widely used due to its excellent antibacterial activity against KPC-producing K. pneumoniae. However, several resistance mechanisms have been reported since its use. Here, we conducted a series of in vitro experiments to reveal and demonstrate the dynamic evolution of ceftazidime-avibactam resistance including interspecies IncX3_NDM-5 plasmid transfer between Enterobacter cloacae and K. pneumoniae and blaKPC mutation from blaKPC-2 to blaKPC-33. Through the analysis of conjugation frequency and fitness cost, the IncX3_NDM-5 plasmid in this study showed strong transmissibility and stability in E. coli EC600 and clinical strain K. pneumoniae 5298 as recipient strain. With increasing ceftazidime-avibactam concentration, the conjugation frequency remained at 10-3-10-5, while the mutation frequency of K. pneumoniae 5298 was 10-6-10-8 at the same concentration. Further plasmid analysis (the IncX3_NDM plasmid from this study and other 658 plasmids from the NCBI database) revealed the diverse origin and genetic structure of blaNDM-5 carrying plasmids. E. coli (42.9%), China (43.9%), IncX3 (66.6%) are the most common strains, regions, and Inc types respectively. By analysing of genetic environment detected in IncX3 plasmids, the dominant structures (168/258, 65.1%) were identified: ISKox3-IS26-blaNDM-5-IS5-ISAba125-Tn3000-Tn3. In additon, several structural variations were found in the core gene structure. In conclusion, the high fitness and transmissibility of the IncX3_NDM-5 plasmids were noteworthy. More importantly, the diverse ceftazidime-avibactam resistance mechanisms including blaNDM-5 tranfer and blaKPC-2 mutation highlighted the importance of the continuous monitoring of antimicrobial susceptibility and carbapenemases subtype during ceftazidime-avibactam treatment.
Insights
Carbapenem-resistant Enterobacterales (CRE) are a global threat. This study reveals IncX3_NDM-5 plasmid transfer and blaKPC mutations as key ceftazidime-avibactam resistance mechanisms, emphasizing continuous monitoring.
Area of Science:
- Microbiology
- Genetics
- Public Health
Background:
- Carbapenem-resistant Enterobacterales (CRE), particularly Klebsiella pneumoniae (CRKP), represent a significant global health challenge.
- Ceftazidime-avibactam is a crucial treatment for KPC-producing K. pneumoniae, but resistance is emerging.
Purpose of the Study:
- To investigate the dynamic evolution of ceftazidime-avibactam resistance in Enterobacterales.
- To elucidate mechanisms including interspecies plasmid transfer and gene mutations.
Main Methods:
- In vitro experiments assessing plasmid conjugation frequency and fitness cost.
- Analysis of IncX3_NDM-5 plasmid transmissibility and stability in E. coli and K. pneumoniae.
- Bioinformatic analysis of blaNDM-5 carrying plasmids from the NCBI database.
Main Results:
- The IncX3_NDM-5 plasmid demonstrated high transmissibility and stability, with stable conjugation frequency (10^-3-10^-5) under increasing antibiotic pressure.
- A blaKPC mutation from blaKPC-2 to blaKPC-33 was observed in K. pneumoniae.
- Analysis of 658 plasmids revealed diverse origins of blaNDM-5, with E. coli, China, and IncX3 being most common.
Conclusions:
- The IncX3_NDM-5 plasmid exhibits significant fitness and transmissibility, contributing to ceftazidime-avibactam resistance.
- Diverse resistance mechanisms, including blaNDM-5 transfer and blaKPC mutation, necessitate ongoing surveillance of antimicrobial susceptibility and carbapenemase subtypes.
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