头孢洛赞/他唑巴坦,包含抗假头孢菌素和β-内酰胺酶抑制剂的组合抗菌剂,已被批准用于治疗成人医院获得性/呼吸机相关细菌性肺炎(HABP/VABP)。ASPECT-NP试验的参与者接受头孢特洛赞/他唑巴坦(每8小时3g[2g头孢特洛赞/1g他唑巴坦])或美罗培南(每8小时1g)。与美罗培南治疗相比,在进入研究时,当前HABP/VABP发作的先前抗菌治疗失败的参与者在头孢洛赞/他唑巴坦治疗的28天全因死亡率(ACM)较低。这里,我们报告了一项事后分析,检查了这一结果。
第三阶段,随机,控制,双盲,多中心,非劣效性试验比较了头孢托赞/他唑巴坦与美罗培南治疗成人通气HABP/VABP的疗效;纳入纳入研究时,因本次HABP/VABP发作而未通过抗菌治疗的患者.主要和关键次要终点是28天ACM和治愈试验(TOC)时的临床反应,分别。先前治疗失败的参与者是一个前瞻性定义的亚组;然而,亚组分析并非设计用于非劣效性检验.将治疗差异的95%CI计算为未分层的NewcombeCI。使用多变量逻辑回归分析进行事后分析,以确定基线特征和治疗对先前抗菌治疗失败的亚组临床结局的影响。
在ASPECT-NP试验中,12.8%的参与者(93/726;头孢特洛赞/他唑巴坦,n=53;美罗培南,n=40)在进入研究时先前的抗菌治疗失败。在这个子群中,接受美罗培南治疗的参与者与头孢洛赞/他唑巴坦治疗的28天ACM较高(18/40[45.0%]vs12/53[22.6%];百分比差异[95%CI]:22.4%[3.1~40.1])。头孢洛扎/他唑巴坦在TOC时的临床反应率为26/53[49.1%],美罗培南为15/40[37.5%](百分比差异[95%CI]:11.6%[-8.6至30.2])。多变量回归分析确定,伴随使用血管加压药和美罗培南治疗是与28天ACM风险相关的重要因素。调整血管加压药的使用,头孢洛赞/他唑巴坦治疗后死亡风险约为美罗培南治疗后死亡风险的1/4.
本事后分析进一步支持先前证明的头孢洛赞/他唑巴坦与美罗培南的ACM率在先前治疗失败的参与者中较低,尽管临床治愈率缺乏显着差异。
gov注册NCT02070757。2014年2月25日注册,clinicaltrials.gov/ct2/show/NCT02070757。
Ceftolozane/tazobactam, a combination antibacterial agent comprising an anti-pseudomonal cephalosporin and β-lactamase inhibitor, is approved for the treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/
VABP) in adults. Participants in the ASPECT-NP trial received ceftolozane/tazobactam (3 g [2 g ceftolozane/1 g tazobactam] every 8 h) or meropenem (1 g every 8 h). Participants failing prior antibacterial therapy for the current HABP/
VABP episode at study entry had lower 28-day all-cause mortality (ACM) rates with ceftolozane/tazobactam versus meropenem treatment. Here, we report a post hoc analysis examining this result.
The phase 3, randomized, controlled, double-blind, multicenter, noninferiority trial compared ceftolozane/tazobactam versus meropenem for treatment of adults with ventilated HABP/
VABP; eligibility included those failing prior antibacterial therapy for the current HABP/
VABP episode at study entry. The primary and key secondary endpoints were 28-day ACM and clinical response at test of cure (TOC), respectively. Participants who were failing prior therapy were a prospectively defined subgroup; however, subgroup analyses were not designed for noninferiority testing. The 95% CIs for treatment differences were calculated as unstratified Newcombe CIs. Post hoc analyses were performed using multivariable logistic regression analysis to determine the impact of baseline characteristics and treatment on clinical outcomes in the subgroup who were failing prior antibacterial therapy.
In the ASPECT-NP trial, 12.8% of participants (93/726; ceftolozane/tazobactam, n = 53; meropenem, n = 40) were failing prior antibacterial therapy at study entry. In this subgroup, 28-day ACM was higher in participants who received meropenem versus ceftolozane/tazobactam (18/40 [45.0%] vs 12/53 [22.6%]; percentage difference [95% CI]: 22.4% [3.1 to 40.1]). Rates of clinical response at TOC were 26/53 [49.1%] for ceftolozane/tazobactam versus 15/40 [37.5%] for meropenem (percentage difference [95% CI]: 11.6% [- 8.6 to 30.2]). Multivariable regression analysis determined concomitant vasopressor use and treatment with meropenem were significant factors associated with risk of 28-day ACM. Adjusting for vasopressor use, the risk of dying after treatment with ceftolozane/tazobactam was approximately one-fourth the risk of dying after treatment with meropenem.
This post hoc analysis further supports the previously demonstrated lower ACM rate for ceftolozane/tazobactam versus meropenem among participants who were failing prior therapy, despite the lack of significant differences in clinical cure rates.
gov registration NCT02070757 . Registered February 25, 2014, clinicaltrials.gov/ct2/show/NCT02070757 .