Comparative analysis of the effects of aztreonam combined with four β-lactamase inhibitors against carbapenem-resistant <i>Enterobacterales</i>

Carbapenem-resistant <i>Enterobacterales</i> (CRE) pose a global public health threat due to multidrug resistance and treatment failure. This study evaluated the effects of aztreonam combined with four β-lactamase inhibitors (avibactam, clavulanic acid, tazobactam, and sulbactam) on 77 CRE isolates from Shenzhen Children's Hospital. Among these isolates, 57.1% harbored metallo-β-lactamases (MBL) genes, and most co-harbored extended-spectrum β-lactamase (ESBL)/AmpC genes. Using microbroth dilution, checkerboard assays, and time‒kill curves, aztreonam/clavulanic acid showed potent synergy against MBL⁺/AmpC^- strains (26/27), with MIC50/MIC90 values (≤0.12/1 µg/mL) comparable to those of aztreonam/avibactam (≤0.12/0.5 µg/mL). Aztreonam/tazobactam exhibited lower synergism, while aztreonam/sulbactam had indifferent effects. Time‒kill assays confirmed the similar bactericidal activity between aztreonam/clavulanic acid and aztreonam/avibactam against MBL⁺/ESBL⁺ isolates. Although aztreonam/avibactam maintains broad efficacy, these <i>in vitro</i> studies suggest that the aztreonam/clavulanic acid combination regimen should be further explored as a potential and cost-effective alternative treatment option for MBL⁺/AmpC^- CRE, which is expected to reduce the economic burden and delay avibactam resistance. These findings support tailored β-lactamase inhibitor selection on the basis of resistance mechanisms.IMPORTANCECarbapenem-resistant <i>Enterobacterales</i> (CRE) pose significant risks for pediatric infections, with few safe and affordable therapeutic options available. This study focuses on a practical issue in current clinical research: aztreonam combined with clavulanic acid shows certain <i>in vitro</i> activity against CRE strains that carry metallo-β-lactamases gene but lack AmpC enzymes gene-a common profile among pediatric CRE isolates.Compared to the costly aztreonam/avibactam, this combination presents a potential low-cost candidate, which may help alleviate economic burdens on healthcare systems and patients if further validated. Additionally, the findings provide reference for reducing over-reliance on newer antibiotics like avibactam, supporting efforts to delay antimicrobial resistance. This work may be of practical use for regions with limited access to high-cost antimicrobials.