Assessing the in vitro impact of ceftazidime on aztreonam/avibactam susceptibility testing for highly resistant MBL-producing Enterobacterales

Background: Aztreonam/avibactam is a combination agent that shows promise in treating infections caused by highLy antibiotic-resistant MBL-producing EnterobacteraLes. This combination can be achieved by combining two FDA-approved drugs: ceftazidime/avibactam and aztreonam. It is unknown whether ceftazidime in the combination ceftazidime/aztreonam/avibactam has a synergistic or antagonistic effect on the in vitro activity of aztreonam/avibactam by significantly increasing or decreasing the MIC. Objectives: To determine whether increasing ceftazidime concentrations affect the MICs of aztreonam/avibactam done. Methods: A custom 8 x 8 chequerboard broth microdiLution (BMD) panel was made using a digital dispenser (Hewlett-Packard, Corvallis, OR, USA). The panel included orthogonal 2-fold dilution series of aztreonam and ceftazidime ranging from 0.5 to 64 mg/L. Avibactam concentration was kept constant at 4 mg/L throughout the chequerboard. Thirty-seven EnterobacteraLes isoLates from the CDC & FDA Antibiotic Resistance Isolate Bank or CDC's internal collection with intermediate or resistant interpretations to aztreonam and ceftazidime/avibactam were included for testing. All isolates harboured at least one of the following MBL genes: bIa(IMP), bla(NDM) or bla(VIM). Results: Regardless of the concentration of ceftazidime, aztreonam/avibactam with ceftazidime MICs for all 37 isolates were within one 2-fold doubling dilution of the aztreonam/avibactam MIC. Conclusions: Ceftazidime, in the combination ceftazidime/avibactam/aztreonam, did not affect the in vitro activity of aztreonam/avibactam in this sample of isolates. These findings can help assure clinical and public health Laboratories that testing of aztreonam/avibactam by BMD can act as a reliable surrogate test when the combination of ceftazidime/avibactam and aztreonam is being considered for treatment of highly antibiotic-resistant MBL-producing Enterobacterales.

Automated summary

This study aimed to determine whether increasing ceftazidime concentrations affect the MICs of aztreonam/avibactam. Testing on 37 Enterobacteriales isolates with intermediate or resistant interpretations to aztreonam and ceftazidime/avibactam showed that ceftazidime did not affect the in vitro activity of aztreonam/avibactam in the combination.