To the Editor: We read with great interest the paper published in the Journal on November 19, 2019, by Abe et al. [1]. The authors reported not to retrieve any association between earlier antibiotic administration and reduction in inhospital mortality of severe sepsis. First of all, the authors must be congratulated for their interesting work aiming to clarify the real impact of earlier antibiotic administration in septic shock, one of the key elements of care highlighted by the Surviving Sepsis Campaign (SSC) [2]. Nevertheless, to our opinion, some methodological issues deserve their results interpretation. From a statistical point of view, the categorization of the variable “time-toantibiotic therapy” induces an information loss. Despite facilitating results interpretation, such categorization implies two consequences. First, it assumes that the treatment effect of antibiotic administration, from the 1st minute, if practically possible, to the 59th minute after diagnosis, is equivalent. Second, it would imply that the antibiotic therapy treatment effect is equivalent in all predefined categories, from 0–60 to 361–1440min, which does not correspond to the reality, because the relationship between antibiotic therapy and mortality is not linear [3, 4]. In the present study, the negativity of the association between time to antibiotics (continuous variable) and mortality (OR = 0.999 [0.997–1.000]; p = 0.152) reflects this lack of linearity of the antibiotic therapy treatment effect. Furthermore, from a practical point of view, it is quite rare that the antibiotic therapy treatment effect is maximum since the first hour after administration. Beyond this, to reach infected tissues, antibiotics need the restoration of a sufficient tissue perfusion pressure [5]. In their study, the authors [1] take into account the compliance rate to the first line of hemodynamic optimization (fluid expansion completed within 3 h) as a potential cofounder in their multivariate analysis but do not inform about the mean blood pressure (the reflect of tissue perfusion pressure) reached [2]. We fully agree with the authors that the impact of earlier antibiotic therapy is greater for most severe septic patients, but as reminded in the SSC, the outcome of these patients is not only dependent on a sole therapy but more from a bundle of care [2]. More than the completion of guideline principles, we believe that impact on outcome is strongly affected by achievement of objectives, especially when the gravity is higher. Among the objectives to be achieved, we think that early hemodynamic optimization and antibiotic administration are the two utmost treatments allowing to reduce septic shock mortality.

中文翻译：

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日本对严重脓毒症和感染性休克患者实施早期抗生素治疗：抗生素作用需要时间和组织灌注才能达到目标

致编辑：我们饶有兴趣地阅读了 Abe 等人于 2019 年 11 月 19 日发表在期刊上的论文。[1]。作者报告称，没有发现早期使用抗生素与严重脓毒症住院死亡率降低之间存在任何关联。首先，必须祝贺作者的有趣工作，旨在阐明早期抗生素给药对脓毒症休克的真正影响，脓毒症生存运动 (SSC) [2] 强调了护理的关键要素之一。然而，在我们看来，一些方法论问题值得他们的结果解释。从统计的角度来看，变量“抗生素治疗时间”的分类会导致信息丢失。尽管有助于结果解释，但这种分类意味着两个后果。第一的，它假设从第 1 分钟（如果可能的话）到诊断后的第 59 分钟，抗生素给药的治疗效果是等效的。其次，这意味着抗生素治疗的治疗效果在所有预定义的类别中是等效的，从 0-60 到 361-1440 分钟，这与现实不符，因为抗生素治疗与死亡率之间的关系不是线性的 [3, 4 ]。在本研究中，抗生素治疗时间（连续变量）与死亡率（OR = 0.999 [0.997–1.000]；p = 0.152）之间的相关性为负值，反映了抗生素治疗效果缺乏线性。此外，从实用的角度来看，抗生素治疗的治疗效果从给药后的第一个小时开始就达到最大是非常罕见的。超出此，为了到达受感染的组织，抗生素需要恢复足够的组织灌注压 [5]。在他们的研究中，作者 [1] 在他们的多变量分析中考虑了对一线血流动力学优化（3 小时内完成液体扩张）的依从率作为潜在的联合创始人，但没有告知平均血压（反映组织灌注压）达到 [2]。我们完全同意作者的观点，即早期抗生素治疗对大多数严重脓毒症患者的影响更大，但正如 SSC 所提醒的那样，这些患者的结果不仅取决于单一治疗，而且更多来自综合治疗 [2] ]。不仅仅是完成指导原则，我们认为对结果的影响受到目标实现的强烈影响，尤其是当重要性更高时。