In vitro Synergistic Activity of Ceftazidime-Avibactam in Combination with Aztreonam or Meropenem Against Clinical Enterobacterales Producing blaKPC or blaNDM

Junyang Kuai; Yawei Zhang; Binghuai Lu; Hongbin Chen; Yulin Zhang; Henan Li; Yuanyuan Wang; Qi Wang; Hui Wang; Xiaojuan Wang

doi:10.2147/IDR.S408228

In vitro Synergistic Activity of Ceftazidime-Avibactam in Combination with Aztreonam or Meropenem Against Clinical Enterobacterales Producing bla_KPC or bla_NDM

Infect Drug Resist. 2023 May 23:16:3171-3182. doi: 10.2147/IDR.S408228. eCollection 2023.

Authors

Affiliations

¹ Department of Clinical Laboratory, Peking University People's Hospital, Beijing, People's Republic of China.
² Department of Pulmonary and Critical Care Medicine, Laboratory of Clinical Microbiology and Infectious Diseases, Center for Respiratory Diseases, National Clinical Research Center of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, People's Republic of China.
³ Department of Clinical Medical Laboratory, the First Affiliated Hospital of Henan University of Science and Technology, Luoyang, People's Republic of China.

Abstract

Background: It is often challenging to select appropriate combination therapies to treat infections caused by carbapenem-resistant Enterobacterales (CRE) with high-level resistance to carbapenem.

Methods: We investigated the in vitro synergistic activity of ceftazidime-avibactam-, polymyxin- or tigecycline-, and meropenem-based combinations using checkerboard assays against 16 CRE including Klebsiella pneumoniae carrying bla_KPC-2 (CR1-bla_KPC-2) and Enterobacter cloacae carrying bla_NDM-1 (CR2-bla_NDM-1) with meropenem MICs ≥128 mg/L. Time-kill assays were used to observe synergistic bactericidal activity.

Results: Meropenem in combination with ertapenem, amikacin, tigecycline or polymyxin B, and tigecycline plus ceftazidime-avibactam showed weak synergistic activities against CR1-bla_KPC-2 and CR2-bla_NDM-1. Polymyxin B combined with tigecycline or ceftazidime-avibactam, and ceftazidime-avibactam plus amikacin showed synergistic effects against two tigecycline-non-susceptible KPC-producers or three ceftazidime-avibactam-resistant NDM-producer, and 50% (5/10) of strains with amikacin MICs ≥4096 mg/L, respectively. Synergistic interactions of ceftazidime-avibactam plus aztreonam or meropenem in checkerboard assays were measured for 100% (16/16) and 93.8% (15/16) of strains, respectively. The time-kill assay further verified that the ceftazidime-avibactam combination had the potential to restore aztreonam susceptibility and reduced meropenem MICs to 8 mg/L.

Conclusion: Ceftazidime-avibactam plus aztreonam or meropenem could be an effective strategy for treating CRE infections, particularly those with high-level resistance to carbapenems and/or ceftazidime-avibactam.

Keywords: aztreonam; ceftazidime-avibactam; checkerboard assays; meropenem; synergistic effect; time-kill assays.