CUBESCAPE ─ Dither version ─ GIF 1080x1080px 2026

The occurrence of infections caused by Gram-negative bacteria with difficult-to-treat resistance (DTR) is rapidly increasing, generally requiring the use of recently approved, last-resort antimicrobial agents or old compounds that are more toxic and/or less effective. We evaluated the activity of aztreonam–avibactam and comparators against DTR Enterobacterales.MethodsA total of 42 295 Enterobacterales isolates were consecutively collected (one per patient) from 85 US medical centres in 2020–24 and susceptibility tested by Clinical Laboratory Standards Institute broth microdilution. The collection included 450 carbapenem-resistant Enterobacterales (CRE) and 284 DTR isolates, which were screened for β-lactamases by whole genome sequencing.ResultsAztreonam–avibactam was active against 98.2% of DTR (minimum inhibitory concentration for 50%/90% of the collection, 0.25/1 mg/L) and 97.1% of CRE isolates and retained potent activity (≥90.0% susceptibility) against DTR isolates non-susceptible to ceftazidime–avibactam, meropenem–vaborbactam and/or cefiderocol. Cefiderocol was active against 92.8% of DTR isolates, whereas ceftazidime–avibactam, meropenem–vaborbactam, imipenem–relebactam and the aminoglycosides exhibited limited activity against these organisms. Aztreonam–avibactam and cefiderocol were active against 97.8% and 84.4% of DTR metallo-β-lactamase (MBL) producers, respectively. The most common carbapenemase genes identified among DTR isolates were blaKPC (57.7% of isolates) and blaNDM (29.9%). An MBL gene was observed in 31.7% of DTR and 25.1% of CRE isolates.ConclusionsAztreonam–avibactam retained potent activity against DTR Enterobacterales from US medical centres, and its activity was not adversely affected by clinically relevant carbapenemases or resistance to agents used to treat multidrug-resistant Enterobacterales. The activities of other β-lactam/β-lactamase inhibitor combinations and cefiderocol were compromised by the increased occurrence of MBL producers.