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

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 meropenembased 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 ceftazidimeavibactam 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.