<i>In vitro</i> activity of aztreonam–avibactam and distribution of carbapenemase genes in ceftazidime–avibactam-resistant carbapenem-resistant Enterobacterales: data from the global Antimicrobial Testing Leadership and Surveillance, 2019–2023

Carbapenem-resistant Enterobacterales (CRE) pose significant treatment challenges. While ceftazidime-avibactam (CZA) is commonly used, resistance rates have been increasing. Aztreonam-avibactam (ATM-AVI) may represent a promising alternative. A total of 109,603 Enterobacterales isolates were collected from 307 sites across 63 countries between 2019 and 2023 as part of the Antimicrobial Testing Leadership and Surveillance (ATLAS) program. CRE were defined as isolates with a meropenem minimal inhibitory concentration (MIC) ≥2 mg/L. Susceptibility testing was conducted according to the Clinical and Laboratory Standards Institute (CLSI) 2025 guidelines, and β-lactamase genes were identified by multiplex PCR and sequencing. Of the total Enterobacterales isolates, 7,520 (7.6%) were identified as CRE, with <i>Klebsiella</i> species accounting for the majority (76.3%, 5,735/7,520). CZA susceptibility was 49.1% (3,696/7,520), with a significant increase in resistance from 42.1% (540/1,283) in 2019 to 61.0% (875/1,435) in 2023 (<i>P</i> < 0.05). Although CRE prevalence was highest in Asia (12.2%, 2,850/23,295), the highest rate of CZA resistance was observed in Africa/Middle East (73.9%, 557/754). In contrast, ATM-AVI demonstrated the highest <i>in vitro</i> activity, with 97.4% (7,324/7,520) of CRE isolates exhibiting MICs ≤4 mg/L. This activity remained strong against carbapenemase-producing strains, including metallo-β-lactamase (MBL) producers. However, reduced susceptibility was observed in <i>Escherichia</i> (80.2%, 556/693) and <i>Proteus</i> (88.9%, 56/63) species. Notably, resistance to ATM-AVI among carbapenem-resistant <i>Escherichia</i> species was geographically clustered in India, where 9.9% (36/364) of isolates were resistant. In conclusion, ATM-AVI exhibits potent activity against global CRE, including MBL producers, and outperforms other β-lactam/β-lactamase inhibitor combinations. However, emerging resistance in <i>Escherichia</i> and <i>Proteus</i> species-particularly with regional clustering-highlights the importance of continued global surveillance.