Infection and Drug Resistance (May 2023)
In vitro Synergistic Activity of Ceftazidime-Avibactam in Combination with Aztreonam or Meropenem Against Clinical Enterobacterales Producing blaKPC or blaNDM
Abstract
Junyang Kuai,1 Yawei Zhang,1 Binghuai Lu,2 Hongbin Chen,1 Yulin Zhang,2 Henan Li,1 Yuanyuan Wang,3 Qi Wang,1 Hui Wang,1 Xiaojuan Wang1 1Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, People’s Republic of China; 2Department 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; 3Department of Clinical Medical Laboratory, the First Affiliated Hospital of Henan University of Science and Technology, Luoyang, People’s Republic of ChinaCorrespondence: Xiaojuan Wang, Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, People’s Republic of China, Tel/Fax +86 010 8832 6310, Email [email protected]; [email protected]: 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 blaKPC-2 (CR1-blaKPC-2) and Enterobacter cloacae carrying blaNDM-1 (CR2-blaNDM-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-blaKPC-2 and CR2-blaNDM-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: ceftazidime-avibactam, checkerboard assays, time-kill assays, synergistic effect, meropenem, aztreonam
