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

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.

Figure 1

Time-kill assays against CR1-bla_KPC-2 and CR2-bla_NDM-1 in incubation with ceftazidime-avibactam (CZA) alone and ceftazidime-avibactam (CZA) in combination with aztreonam (ATM) or meropenem (MEM). Curves represent average concentrations of duplicate experiments. (A) CZA in combination with ATM against CR1-bla_KPC-2 via time-kill assays at the concentration of 1/128× MIC CZA plus 1/128× MIC ATM, 1/64× MIC CZA plus 1/64× MIC ATM and 1/32× MIC CZA plus 1/32× MIC ATM. (B) CZA in combination with ATM against CR2-bla_NDM-1 via time-kill assays at the concentration of 1/128× MIC CZA plus 1/128× MIC ATM, 1/64× MIC CZA plus 1/64× MIC ATM and 1/32× MIC CZA plus 1/32× MIC ATM. (C) CZA in combination with MEM against CR1-bla_KPC-2 via time-kill assays at the concentration of 1/128× MIC CZA plus 1/128× MIC MEM, 1/64× MIC CZA plus 1/64× MIC MEM, and 1/32× MIC CZA plus 1/32× MIC MEM. (D) CZA in combination with MEM against CR2-bla_NDM-1 via time-kill assays at the concentration of 1/16× MIC CZA plus 1/16× MIC MEM, 1/8× MIC CZA plus 1/8× MIC MEM, and 1/4× MIC CZA plus 1/4× MIC MEM.