病原体集中,随机化,对照试验(PF-RCT)在对抗碳青霉烯类耐药(CR)革兰氏阴性感染中很重要。在各种感染的PF-RCT中研究了一些最近批准的抗生素和具有抗CR革兰氏阴性菌活性的较旧的通用抗生素。
我们搜索了Pubmed,Cochrane数据库和2005年至2020年期间PF-RCTs的国际临床试验数据库,并比较了研究设计,患者群体,感染类型,病原体,和第28天全因死亡率(ACM)。
由于感染类型的异质性,PF-RCT在定量评估和比较方面尤其具有挑战性,病原体,CR机制,纳入/排除标准,和端点。由于缺乏正式的统计分析计划和/或非劣效性设计,数据解释变得更加复杂。大多数PF-RCT的功率有限。新抗生素的研究(即plazomicin,美罗培南/vaborbactam,cefiderocol)在可行性方面排名较低,相对较小的样本量(分析:37-118)与较旧的仿制药的比较有效性研究(分析:94-406)。CR肠杆菌的ACM介于11.8%和40%之间,CR不动杆菌属为17.7%和57.4%。,CR铜绿假单胞菌分别为20.0%和30.8%。必须仔细考虑收集的信息以及研究的局限性,并且在进行直接比较试验时应谨慎行事。由于抗菌素耐药性已成为全球威胁,因此需要新的抗生素来治疗耐多药革兰氏阴性菌感染。近年来,几个病原体集中,随机化,进行了对照临床试验,以测试新的抗生素或旧的通用抗生素的组合,以对抗耐药细菌。然而,这些试验极具挑战性,其中大多数纳入的患者相对较少.这些研究在物种方面具有高度异质性,抗生素,感染部位,抗性机制,终点和患者因素。在这些试验中,在碳青霉烯耐药(CR)肠杆菌引起的感染中,新抗生素在第28天或第30天时的全因死亡率在数值上较低.然而,在调查CR不动杆菌属的试验中。感染,与粘菌素单药治疗相比,在第28天或第30天时,使用较旧的通用抗生素组合治疗的全因死亡率没有降低.关于CR铜绿假单胞菌的信息有限。更多关注病原体,随机化,需要具有更可行设计和更多患者数量的对照临床试验来证明耐药感染的临床获益.
Pathogen-focused, randomized, controlled trials (PF-RCT) are important in the fight against carbapenem-resistant (CR) Gram-negative infections. Some recently approved antibiotics and older generic antibiotics with activity against CR Gram-negative bacteria were investigated in PF-RCTs in a variety of infections.
We searched Pubmed, Cochrane database and international clinical trial databases for PF-RCTs for the period between 2005 and 2020 and compared the study designs, patient populations, infection types, pathogens, and Day-28 all-cause mortality (ACM).
PF-RCTs are particularly challenging to quantitatively assess and compare due to the heterogeneity in infection types, pathogens, CR mechanism, inclusion/exclusion criteria, and endpoints. Data interpretation is further complicated by lack of formal statistical analysis plans and/or non-inferiority design, and limited power across most PF-RCTs. The studies with new antibiotics (i.e. plazomicin, meropenem/vaborbactam, cefiderocol) ranked lower regarding feasibility, with relatively small sample sizes (analyzed: 37-118) versus the comparative effectiveness studies of older generic drugs (analyzed: 94-406). ACM ranged between 11.8% and 40% for CR Enterobacterales, 17.7% and 57.4% for CR Acinetobacter spp., and 20.0% and 30.8% for CR Pseudomonas aeruginosa. The information gathered must be considered carefully alongside the study limitations and caution should be exercised when making direct comparisons across trials.PLAIN LANGUAGE SUMMARYNew antibiotics to treat multidrug-resistant Gram-negative bacterial infections are needed because antimicrobial resistance has become a global threat. In recent years, several pathogen-focused, randomized, controlled clinical trials were conducted to test new antibiotics or combinations of older generic antibiotics in the fight against resistant bacteria. However, these trials were exceptionally challenging and most of them enrolled relatively few patients. These studies were highly heterogeneous in terms of species, antibiotics, infection site, mechanism of resistance, endpoints and patient factors. In these trials, all-cause mortality at Day 28 or Day 30 were numerically lower with the new antibiotics in infections caused by carbapenem-resistant (CR) Enterobacterales. However, in the trials which investigated CR Acinetobacter spp. infections, there was no reduction in all-cause mortality at Day 28 or Day 30 with combinations of older generic antibiotics compared with colistin monotherapy. Limited information was available for CR Pseudomonas aeruginosa. More pathogen-focused, randomized, controlled clinical trials with more feasible design and higher patient numbers are needed to demonstrate clinical benefit in drug-resistant infections.