In vitro and in vivo activity of meropenem+avibactam against MBL-producing carbapenem-resistant Klebsiella pneumoniae

ABSTRACT

Background

Antibiotic resistance has become a public health problem to be solved worldwide and metallo-β-lactamase (MBL)-producing bacteria make this problem even more challenging.

Methods

The interactions of meropenem (MEM) in combination with avibactam (AVI) in growth inhibition on MBL-producing carbapenem-resistant Klebsiella pneumoniae (CRKP) strains were tested. In vitro interactions of MEM+AVI were tested using the microdilution checkerboard assay and time–kill curves. In vivo interactions of MEM+AVI were tested using the Galleria mellonella model.

Results

All strains were multi-drug resistant strains and six of them were proved to produce MBLs. We show that the combination of MEM+AVI generates profound synergistic effects on growth inhibition of all strains, which was better than that of MEM+vaborbactam or imipenem+relebactam. The time-kill curves further confirmed the potent synergistic antibacterial effects of MEM+AVI against MBL-producing CRKP strains. Galleria mellonella studies were consistent with in vitro analysis. Combining MEM with AVI improved survival rates and mean survival days were obviously prolonged compared to the drug alone and the untreated controls.

Conclusions

To our knowledge, this study is the first report of MEM+AVI collaborating against MBL-producing CRKP strains. Our findings showed that the combination of MEM+AVI has the potential for antibiotic drug development to combat MBL-producing pathogens.

KEYWORDS:

• Metallo-β-lactamase
• carbapenem resistant Klebsiella pneumoniae
• meropenem
• avibactam
• synergy
• Galleria mellonella

Acknowledgments

We are grateful for the writing assistance from AJE, a professional paper service agency.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership, or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Availability of data and material

The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Author contributions

All authors contributed to the study conception and design. Xiuyun Li and Hongxiang Lou designed the experiments. Xiuyun Li, Zhaowen Chen, Jin Jiao, Shifu Wang Yuehua Wang, and Weiwei Wu conducted the experiments. Xiuyun Li wrote the manuscript. Huijun Yang corrected the manuscript. Hongxiang Lou and Zhaowen Chen responsible for all the additional experiments and the revised versions of the manuscript. All authors read and approved the final manuscript.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14787210.2022.2153117

Additional information

Funding

This work was supported by the Shandong Provincial Natural Science Foundation [ZR2020QH365], the hospital-level project of Shandong Province Maternal and Child Health Hospital [2021SFF062] and Health and Family Planning Commission of Jinan Municipality [2019-1-37]. These funding organizations provided funds for the purchase of laboratory supplies for our study but had no role in the design of the study and the collection, analysis and interpretation of the data.