Objectives

In vitro models showing synergism between polymyxins and carbapenems support combination treatment for carbapenem-resistant Gram-negative (CRGN) infections. We tested the association between the presence of in vitro synergism and clinical outcomes in patients treated with colistin plus meropenem.

Methods

This was a secondary analysis of AIDA, a randomized controlled trial comparing colistin with colistin–meropenem for severe CRGN infections. We tested in vitro synergism using a checkerboard assay. Based on the fractional inhibitory concentration (ΣFIC) index for each colistin–meropenem combination, we categorized results as synergistic, antagonistic or additive/indifferent. The primary outcome was clinical failure at 14 days. Secondary outcomes were 14- and 28-day mortality and microbiological failure.

Results

The sample included 171 patients with infections caused by carbapenem-resistant Acinetobacter baumannii (n = 131), Enterobacteriaceae (n = 37) and Pseudomonas aeuruginosa (n = 3). In vitro testing showed synergism for 73 isolates, antagonism for 20 and additivism/indifference for 78. In patients who received any colistin plus meropenem, clinical failure at 14 days was 59/78 (75.6%) in the additivism/indifference group (reference category), 54/73 (74.0%) in the synergism group (adjusted odds ratio (aOR) 0.76, 95% CI 0.31–1.83), and 11/20 (55%) in the antagonism group (aOR 0.77, 95% CI 0.22–2.73). There was no significant difference between groups for any secondary outcome. Comparing the synergism group to patients treated with colistin monotherapy, synergism was not protective against 14-day clinical failure (aOR 0.52, 95% CI 0.26–1.04) or 14-day mortality (aOR1.09, 95% CI 0.60–1.96).

Discussion

In vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit.

中文翻译：

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Colistin加美罗培南用于抗碳青霉烯的革兰氏阴性感染：体外协同作用与更好的临床结果无关。

目标

显示多粘菌素和碳青霉烯类之间协同作用的体外模型支持抗碳青霉烯类革兰氏阴性（CRGN）感染的联合治疗。我们测试了大肠菌素加美罗培南治疗的患者中体外协同作用与临床结果之间的关联。

方法

这是对AIDA的二次分析，它是对大肠CRGN感染进行大肠菌素和大肠菌素-美罗培南比较的随机对照试验。我们使用棋盘试验测试了体外协同作用。根据每种大肠菌素-美罗培南组合的抑制分数浓度（ΣFIC）指数，我们将结果分类为协同，拮抗或加和/无关。主要结局是14天临床失败。次要结果为14天和28天死亡率和微生物衰竭。

结果

该样本包括171例因耐碳青霉烯类鲍曼不动杆菌（n  = 131），肠杆菌科（n  = 37）和铜绿假单胞菌（n  = 3）引起的感染。体外测试显示73株分离菌具有协同作用，20株具有拮抗作用，78株具有补充/抑制作用。在添加大肠粘菌素和美罗培南的患者中，14 d的临床失败率为59/78（75.6％），见表3。协同组54/73（74.0％）（调整比值比（aOR）0.76，95％CI 0.31-1.83）和拮抗组11/20（55％）（aOR 0.77，95％CI 0.22-2.73） ）。两组之间的任何次要结局均无显着差异。将增效组与接受粘菌素单药治疗的患者进行比较，增效对14天临床失败（aOR 0.52，95％CI 0.26–1.04）或14天死亡率（aOR1.09，95％CI 0.60–1.96）没有保护作用。

讨论区

大肠菌素和美罗培南之间通过棋盘法的体外协同作用未转化为临床益处。