In vitro and in vivo activity of ceftazidime/avibactam and aztreonam alone or in combination against mcr-9, serine- and metallo-β-lactamases-co-producing carbapenem-resistant Enterobacter cloacae complex

Wengang Li; Jisheng Zhang; Yanjun Fu; Jianmin Wang; Longjin Liu; Wenzhang Long; Kaixin Yu; Xinhui Li; Chunli Wei; Xushan Liang; Jin Wang; Chunjiang Li; Xiaoli Zhang

doi:10.1007/s10096-024-04841-8

In vitro and in vivo activity of ceftazidime/avibactam and aztreonam alone or in combination against mcr-9, serine- and metallo-β-lactamases-co-producing carbapenem-resistant Enterobacter cloacae complex

Eur J Clin Microbiol Infect Dis. 2024 May 3. doi: 10.1007/s10096-024-04841-8. Online ahead of print.

Authors

Wengang Li^#^{1

2}, Jisheng Zhang^#¹, Yanjun Fu^#³, Jianmin Wang¹, Longjin Liu¹, Wenzhang Long¹, Kaixin Yu^{1

2}, Xinhui Li¹, Chunli Wei¹, Xushan Liang¹, Jin Wang¹, Chunjiang Li⁴, Xiaoli Zhang⁵

Affiliations

¹ Department of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China.
² Department of Pathogenic Biology, Jiamusi University School of Basic Medicine, Jiamusi, China.
³ Department of Clinical Laboratory, The First Affiliated Hospital of Jiamusi University, Jiamusi, China.
⁴ Department of Life Science and Technology, Mudanjiang Normal University, Mudanjiang, China. mdjlcj07@163.com.
⁵ Department of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China. jmszxl123@163.com.

^# Contributed equally.

PMID: 38700663
DOI: 10.1007/s10096-024-04841-8

Abstract

Purpose: Enterobacteriaceae carrying mcr-9, in particularly those also co-containing metallo-β-lactamase (MBL) and TEM type β-lactamase, present potential transmission risks and lack adequate clinical response methods, thereby posing a major threat to global public health. The aim of this study was to assess the antimicrobial efficacy of a combined ceftazidime/avibactam (CZA) and aztreonam (ATM) regimen against carbapenem-resistant Enterobacter cloacae complex (CRECC) co-producing mcr-9, MBL and TEM.

Methods: The in vitro antibacterial activity of CZA plus ATM was evaluated using a time-kill curve assay. Furthermore, the in vivo interaction between CZA plus ATM was confirmed using a Galleria mellonella (G. mellonella) infection model.

Results: All eight clinical strains of CRECC, co-carrying mcr-9, MBL and TEM, exhibited high resistance to CZA and ATM. In vitro time-kill curve analysis demonstrated that the combination therapy of CZA + ATM exerted significant bactericidal activity against mcr-9, MBL and TEM-co-producing Enterobacter cloacae complex (ECC) isolates with a 100% synergy rate observed in our study. Furthermore, in vivo survival assay using Galleria mellonella larvae infected with CRECC strains co-harboring mcr-9, MBL and TEM revealed that the CZA + ATM combination significantly improved the survival rate compared to the drug-treatment alone and untreated control groups.

Conclusion: To our knowledge, this study represents the first report on the in vitro and in vivo antibacterial activity of CZA plus ATM against CRECC isolates co-harboring mcr-9, MBL and TEM. Our findings suggest that the combination regimen of CZA + ATM provides a valuable reference for clinicians to address the increasingly complex antibiotic resistance situation observed in clinical microorganisms.

Keywords: Galleria mellonella; MCR-9; Aztreonam; Carbapenem-resistant Enterobacter cloacae complex; Ceftazidime-avibactam; Metallo-β-lactamase; Synergy; TEM type β-lactamase.

Abstract

Grants and funding