Journal of Critical Care：头孢他啶-阿维巴坦联合氨曲南治疗重症患者广泛耐药革兰阴性菌感染

Abstract

Background: Extensively drug-resistant (XDR) gram-negative pathogens represent a critical therapeutic challenge in intensive care units, with mortality rates exceeding 50 %. The synergistic combination of ceftazidime-avibactam with aztreonam offers a novel therapeutic approach, particularly in carbapenemase-producing Enterobacterales.广泛耐药（XDR）革兰阴性菌感染是重症监护病房面临的重大治疗挑战，其病死率超过50%。头孢他啶-阿维巴坦与氨曲南的协同组合为产碳青霉烯酶肠杆菌目细菌感染提供了新型治疗方案。

Methods: This prospective observational study analysed 24 critically ill adult ICU patients with confirmed XDR gram-negative infections from October 2024 to April 2025. Comprehensive antimicrobial susceptibility testing, carbapenemase detection, and E- strip based synergy testing of ceftazidime-avibactam (CZA) with aztreonam (ATM), cefepime-enmetazobactam (FEP-ENM) testing were performed. Primary outcomes included clinical response, microbiological clearance, and 30-day mortality. Statistical analysis included descriptive statistics, Fisher’s exact test, Mann-Whitney U test, logistic regression analysis and Kaplan-Meier survival analysis.本前瞻性观察研究纳入2024年10月至2025年4月确诊XDR革兰阴性菌感染的24例重症成人ICU患者。研究内容包括全面药敏试验、碳青霉烯酶检测，以及头孢他啶-阿维巴坦（CZA）与氨曲南（ATM）、头孢吡肟-恩美唑巴坦（FEP-ENM）的协同药敏试验（E-test条法）。主要结局指标包括临床应答、微生物学清除和30天病死率。统计分析采用描述性统计、Fisher精确检验、Mann-Whitney U检验、逻辑回归分析和Kaplan-Meier生存分析。

Results: Twenty-four XDR isolates were analysed: Klebsiella pneumoniae (n = 18, 75 %) and Escherichia coli (n = 6, 25 %). All demonstrated resistance to individual agents (CZA; MIC >16 μg/ml), (ATM; MIC >256 μg/mL) and FEP-ENM (zone size <6 mm). Carbapenemase detection revealed NDM in 91.7 % (22/24), with NDM + OXA-48 co- production in 66.7 % (16/24). Synergy was demonstrated in 62.5 % (15/24) cases with significant MIC reduction (median 0.5 μg/mL, IQR 0.25-1.0). Clinical improvement occurred in 31.3 % (5/16) of synergy-positive versus 12.5 % (1/8) of synergy-negative cases (p = 0.631). Microbiological clearance was achieved exclusively in synergy- positive cases (18.8 % vs 0 %, p = 0.534). Independent predictors of mortality included septic shock presentation (OR 3.5, 95 % CI 0.7-17.8, p = 0.134).24株XDR菌株中：肺炎克雷伯菌（18株，75%）和大肠埃希菌（6株，25%）。所有菌株对单药耐药（CZA MIC>16μg/ml；ATM MIC>256μg/mL；FEP-ENM抑菌圈直径<6mm）。碳青霉烯酶检测显示NDM阳性率91.7%（22/24），其中NDM+OXA-48共产率66.7%（16/24）。62.5%（15/24）菌株显示协同效应，MIC显著降低（中位数0.5μg/mL，四分位距0.25-1.0）。临床改善率在协同阳性组为31.3%（5/16），协同阴性组12.5%（1/8）（p=0.631）。微生物学清除仅见于协同阳性组（18.8% vs 0%，p=0.534）。脓毒症休克是病死率的独立预测因素（OR 3.5，95%CI 0.7-17.8，p=0.134）。

Conclusion: Ceftazidime-avibactam plus aztreonam combination demonstrated significant in vitro synergy against XDR pathogens with promising trends toward improved clinical outcomes in critically ill patients, representing a crucial salvage therapy option warranting larger randomized controlled trials. 头孢他啶-阿维巴坦联合氨曲南对XDR病原体展现出显著体外协同效应，在改善重症患者临床结局方面呈现积极趋势，是值得通过大规模随机对照试验验证的关键挽救治疗方案。