Activity of Aztreonam-Avibactam and Comparators against Difficult-To-Treat Resistant (DTR) Enterobacterales from European Medical Centres Stratified by Infection Type and Country (2021– 2025)

Abstract Background: Difficult-to-treat resistant (DTR) isolates, defined as bacterial isolates expressing nonsusceptibility to all first-line agents, is a major problem worldwide. We evaluated the activity of aztreonam-avibactam and comparators against DTR Enterobacterales from European medical centres. Methods: 30,345 Enterobacterales isolates were consecutively collected from 41 European medical centres in 19 countries in 2021–2025. Isolates were susceptibility tested by broth microdilution and MIC interpreted according to EUCAST breakpoints. The collection included 1113 DTR isolates, defined as a carbapenem-resistant isolate (MIC ≥4 mg/L for meropenem and/or imipenem) not susceptible to fluoroquinolones. All DTR isolates were screened for β-lactamase genes by whole genome sequencing. Results were stratified by infection type and country. Results: Aztreonam-avibactam was active against 99.6% of DTR (MIC50/90, 0.25/0.5 mg/L), and exhibited consistent activity against DTR isolates from all infection types. Cefiderocol was active against 78.8% of DTR isolates; ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, and the aminoglycosides exhibited limited activity against these organisms. The frequency of DTR was higher among isolates from pneumonia (6.6%) compared to other infection types (2.3–3.4%) and varied from 0.0% (Switzerland) to 19.7% (Poland) among countries. DTR susceptibility to aztreonam-avibactam ranged from 94.4% (France) to 100.0% (14 countries). Aztreonam-avibactam retained potent activity against DTR isolates nonsusceptible to ceftazidime-avibactam (99.2% susceptible), meropenem-vaborbactam (99.6% susceptible), and/or cefiderocol (97.8% susceptible). The most common carbapenemase identified among DTR isolates was NDM (41.2% of DTR), followed by OXA-48–like (38.2%), and KPC (34.3%). Moreover, 99.6% of metallo-β-lactamase (MBL) producers were susceptible to aztreonam-avibactam and 68.2% were susceptible to cefiderocol. Conclusions: Aztreonam-avibactam retained potent activity against DTR Enterobacterales from European medical centres and its activity was not adversely affected by clinically relevant carbapenemases or resistance to agents currently used to treat multidrug-resistant Enterobacterales. The activities of other β-lactamase inhibitor combinations and cefiderocol were compromised by the increased occurrence of MBL producers.