Antimicrobial susceptibility of enterobacterales causing bloodstream infection in United States medical centres: comparison of aztreonam-avibactam with beta-lactams active against carbapenem-resistant enterobacterales

Background Bloodstream infection (BSI) is associated with poor outcomes especially when effective antimicrobial therapy and control of infection source are delayed. As the frequency of Enterobacterales producing metallo-beta-lactamases (MBL) and/or OXA-48-like carbapenemases is increasing in some United States (US) medical centres, effective antimicrobials to treat the infections caused by these organisms are urgently needed. Aztreonam-avibactam is under clinical development for treatment of infections caused by Gram-negative bacteria, including MBL producers. Objectives To evaluate the antimicrobial susceptibility of Enterobacterales causing BSI in US medical centres and compare the activity of aztreonam-avibactam with ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, and other antimicrobials used to treat BSI. Methods 4,802 Enterobacterales were consecutively collected (1/patient) from 72 US medical centres in 2020-2022 and susceptibility tested by broth microdilution. Aztreonam-avibactam was tested with avibactam at a fixed concentration of 4 mg/L. A pharmacokinetic/pharmacodynamic susceptible breakpoint of <= 8 mg/L was applied for aztreonam-avibactam for comparison. Carbapenem-resistant Enterobacterales (CRE) isolates were tested for beta-lactamase-encoding genes using Next-generation sequencing. Results Aztreonam-avibactam was highly active against Enterobacterales; only 2 isolates showed aztreonam-avibactam MICs > 8 mg/L: 1 meropenem-susceptible E. coli and 1 K. aerogenes (CRE). All carbapenemase producers and 98.0% of CRE were inhibited at an aztreonam-avibactam MIC of <= 8 mg/L. CRE susceptibility rates were 81.6% for ceftazidime-avibactam, 65.3% for meropenem-vaborbactam, 61.2% for imipenem-relebactam, and 87.8% for cefiderocol. Aztreonam-avibactam retained activity (MIC, <= 8 mg/L) against all (100.0%) meropenem-vaborbactam nonsusceptible (n = 17), 99.5% of imipenem-relebactam nonsusceptible (n = 206), and 90.0% of ceftazidime-avibactam nonsusceptible (n = 10) isolates. The most common carbapenemases were KPC-2/3 (57.1% of CREs), OXA-48-like (16.3%), and NDM (14.3%). A carbapenemase gene was not observed in 12.3% of CREs. Ceftazidime-avibactam and meropenem-vaborbactam were active against 100.0% of KPC producers, but ceftazidime-avibactam showed limited activity against MBL producers and meropenem-vaborbactam showed limited activity against OXA-48-like and MBL producers. The most active non-beta-lactam comparators against CRE were gentamicin (49.0% susceptible) and amikacin (44.9% susceptible). Conclusions Aztreonam-avibactam demonstrated potent activity against a large collection of Enterobacterales isolated from patients with BSI in US hospitals, including CRE, MBL producers, and isolates resistant to recently approved beta-lactamase inhibitor combinations.