In vitro Synergistic Activity of Ceftazidime-Avibactam in Combination with Aztreonam or Meropenem Against Clinical Enterobacterales Producing bla(KPC) or bla(NDM)

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.