头孢他啶/阿维巴坦治疗产β-内酰胺酶革兰氏阴性病原菌感染患者的疗效和安全性：来自 3 期临床试验项目的汇总分析。
Efficacy and safety of ceftazidime/avibactam in patients with infections caused by β-lactamase-producing Gram-negative pathogens: a pooled analysis from the Phase 3 clinical trial programme.
机构信息
Servei de Pneumologia, Hospital Clinic, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain.
Pfizer, Collegeville, PA, USA.
出版信息
J Antimicrob Chemother. 2023 Nov 6;78(11):2672-2682. doi: 10.1093/jac/dkad280.
OBJECTIVES
This post hoc pooled analysis evaluated clinical and microbiological outcomes and safety in patients with infections caused by β-lactamase-producing Gram-negative pathogens across five Phase 3, randomized, controlled, multicentre trials of ceftazidime/avibactam in adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI)/pyelonephritis and nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP).
METHODS
In each trial, RECLAIM/RECLAIM 3 (cIAI), REPRISE (cIAI/cUTI), RECAPTURE (cUTI) and REPROVE (NP, including VAP) patients were randomized 1:1 to IV ceftazidime/avibactam (plus metronidazole for patients with cIAI) or comparators (carbapenems in >97% patients) for 5-21 days. Clinical and microbiological responses at the test-of-cure visit were assessed for patients with ESBLs, and/or plasmidic and/or overexpression of chromosomal AmpC, and/or serine carbapenemases without MBLs identified in baseline Gram-negative isolates by phenotypic screening and molecular characterization in the pooled microbiological modified ITT (mMITT) population.
RESULTS
In total, 813 patients (ceftazidime/avibactam, n = 389; comparator, n = 424) had ≥1 β-lactamase-producing baseline pathogen identified, amongst whom 792 patients (ceftazidime/avibactam, n = 379; comparator, n = 413) had no MBLs. The most frequent β-lactamase-producing pathogens across treatment groups were Escherichia coli (n = 381), Klebsiella pneumoniae (n = 261) and Pseudomonas aeruginosa (n = 53). Clinical cure rates in the pooled non-MBL β-lactamase-producing mMITT population were 88.1% (334/379) for ceftazidime/avibactam and 88.1% (364/413) for comparators; favourable microbiological response rates were 76.5% (290/379) and 68.8% (284/413), respectively. The safety profile of ceftazidime/avibactam was consistent with previous observations.
CONCLUSIONS
This analysis provides supportive evidence of the efficacy and safety of ceftazidime/avibactam in patients with infections caused by ESBLs, AmpC and serine carbapenemase-producing Gram-negative pathogens.
TRIAL REGISTRATION
NCT01499290; NCT01726023; NCT01644643; NCT01595438/NCT01599806; NCT01808092.
目的
本事后分析评估了在五项头孢他啶/阿维巴坦治疗成人复杂性腹腔感染（cIAI）、复杂性尿路感染（cUTI）/肾盂肾炎和医院获得性肺炎（NP）（包括呼吸机相关性肺炎[VAP]）的 3 期随机对照多中心试验中，由产β-内酰胺酶的革兰氏阴性病原体引起的感染患者的临床和微生物学结局以及安全性，这些试验包括 RECLAIM/RECLAIM 3（cIAI）、REPRISE（cIAI/cUTI）、RECAPTURE（cUTI）和 REPROVE（NP，包括 VAP）。
方法
在每个试验中，RECLAIM/RECLAIM 3（cIAI）、REPRISE（cIAI/cUTI）、RECAPTURE（cUTI）和 REPROVE（NP，包括 VAP）患者按 1:1 随机分配接受 IV 头孢他啶/阿维巴坦（cIAI 患者加用甲硝唑）或对照药物（>97%患者用碳青霉烯类药物）治疗 5-21 天。在治愈期评估试验中，对产 ESBLs、和/或产质粒和/或染色体 AmpC 过表达、和/或无 MBL 的丝氨酸碳青霉酶的革兰氏阴性分离物进行表型筛选和分子特征分析，以确定研究人群的改良意向治疗人群（mMITT）中符合条件的患者的临床和微生物学应答。
结果
共有 813 名患者（头孢他啶/阿维巴坦，n=389；对照组，n=424）至少有 1 种产β-内酰胺酶的基线病原体被鉴定，其中 792 名患者（头孢他啶/阿维巴坦，n=379；对照组，n=413）无 MBL。在治疗组中最常见的产β-内酰胺酶病原体是大肠埃希菌（n=381）、肺炎克雷伯菌（n=261）和铜绿假单胞菌（n=53）。在非 MBL 产β-内酰胺酶的 mMITT 人群中，头孢他啶/阿维巴坦的临床治愈率为 88.1%（334/379），对照组为 88.1%（364/413）；有利的微生物学应答率分别为 76.5%（290/379）和 68.8%（284/413）。头孢他啶/阿维巴坦的安全性特征与以往观察结果一致。
结论
本分析提供了支持头孢他啶/阿维巴坦在治疗产 ESBLs、AmpC 和丝氨酸碳青霉酶的革兰氏阴性病原体引起的感染患者中的疗效和安全性的证据。
试验注册
NCT01499290；NCT01726023；NCT01644643；NCT01595438/NCT01599806；NCT01808092。
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