In vitro and in vivo Antimicrobial Activities of Ceftazidime/Avibactam Alone or in Combination with Aztreonam Against Carbapenem-Resistant Enterobacterales

INTRODUCTION: To examine the in vitro and in vivo antimicrobial activities of ceftazidime/avibactam (CZA) alone or in combination with aztreonam (ATM) against KPC-, NDM-, IMP-, KPC+IMP-, KPC+NDM-producing strains. METHODS: A total of 67 clinical non-repetitive carbapenem-resistant Enterobacterales (CRE) strains were selected for the microdilution broth method that was performed to analyze the minimal inhibitory concentration (MIC) and the combination antimicrobial susceptibility test using checkerboard titration method. The fractional inhibitory concentration (FIC) was calculated to determine the antimicrobial effect. The time-kill assays and the mouse infection model were used to study the bactericidal effect and therapeutic effect of CZA alone or in combination with ATM. RESULTS: The CZA minimal inhibitory concentration (MIC) values of CZA revealed that 29 KPC-producing strains and 1 OXA-producing strain were ≤4µg/mL. The CZA MIC values of 37 metal-β-lactamase (MBLs)-producing strains such as NDM-, IMP-, KPC+IMP-, KPC+NDM-producing strains were ≥128µg/mL, after combining with ATM, the FIC values were all below 0.51. The time-kill assays revealed that CZA at various concentrations of 2, 4 and 8 MIC showed significant bactericidal efficiency to the KPC-producing strains. For NDM-, IMP-producing strains, no colony growth was detected after 8 hours of incubation with CZA in combination with ATM. Six percent of the mice in the treatment group and 58% of the mice in the infection group died within 3 days. CONCLUSION: Our in vitro results showed that CZA had a good antimicrobial effect on the KPC-producing and OXA-producing strains. CZA combined with ATM showed synergistic bacteriostatic or bactericidal activity against NDM-, IMP-, KPC+IMP-, KPC+NDM-producing strains. The combination of CZA and ATM reduced mortality and prolonged lifespan of mice infected with NDM-, IMP-, KPC+IMP-, and KPC+NDM-producing strains, which provides fundamental knowledge for improving treatment strategies and initializing clinical trials.