To perform a systematic review with meta-analysis with the dual intent of assessing the impact of attaining aggressive vs. conservative beta-lactams PK/PD target on the clinical efficacy for treating Gram-negative infections in critical patients, and of identifying predictive factors of failure in attaining aggressive PK/PD targets. Two authors independently searched PubMed-MEDLINE and Scopus database from inception to 23rd December 2023, to retrieve studies comparing the impact of attaining aggressive vs. conservative PK/PD targets on clinical efficacy of beta-lactams. Independent predictive factors of failure in attaining aggressive PK/PD targets were also assessed. Aggressive PK/PD target was considered a100%fT>4xMIC, and clinical cure rate was selected as primary outcome. Meta-analysis was performed by pooling odds ratios (ORs) extrapolated from studies providing adjustment for confounders using a random-effects model with inverse variance method. A total of 20,364 articles were screened, and 21 observational studies were included in the meta-analysis (N = 4833; 2193 aggressive vs. 2640 conservative PK/PD target). Attaining aggressive PK/PD target was significantly associated with higher clinical cure rate (OR 1.69; 95% CI 1.15–2.49) and lower risk of beta-lactam resistance development (OR 0.06; 95% CI 0.01–0.29). Male gender, body mass index > 30 kg/m2, augmented renal clearance and MIC above the clinical breakpoint emerged as significant independent predictors of failure in attaining aggressive PK/PD targets, whereas prolonged/continuous infusion administration of beta-lactams resulted as protective factor. The risk of bias was moderate in 19 studies and severe in the other 2. Attaining aggressive beta-lactams PK/PD targets provided significant clinical benefits in critical patients. Our analysis could be useful to stratify patients at high-risk of failure in attaining aggressive PK/PD targets.

中文翻译：

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达到积极与保守 PK/PD 目标对 β-内酰胺治疗危重患者革兰氏阴性感染临床疗效的影响：系统评价和荟萃分析

通过荟萃分析进行系统评价，其双重目的是评估实现积极与保守 β-内酰胺 PK/PD 目标对治疗危重患者革兰氏阴性感染的临床疗效的影响，并确定以下因素的预测因素：未能实现积极的 PK/PD 目标。两位作者独立检索了 PubMed-MEDLINE 和 Scopus 数据库，从最初到 2023 年 12 月 23 日，检索比较实现积极与保守 PK/PD 目标对 β-内酰胺临床疗效的影响的研究。还评估了未能达到积极的 PK/PD 目标的独立预测因素。积极的 PK/PD 目标被认为是 100%fT>4xMIC，并选择临床治愈率作为主要结局。荟萃分析是通过汇集从研究中推断出的比值比 (OR) 来进行的，这些研究使用逆方差法的随机效应模型对混杂因素进行了调整。总共筛选了 20,364 篇文章，荟萃分析中纳入了 21 项观察性研究（N = 4833；2193 项积极的 PK/PD 目标与 2640 项保守的 PK/PD 目标）。达到积极的 PK/PD 目标与较高的临床治愈率（OR 1.69；95% CI 1.15–2.49）和较低的 β-内酰胺耐药性发展风险（OR 0.06；95% CI 0.01–0.29）显着相关。男性、体重指数 > 30 kg/m2、肾清除率增强和高于临床断点的 MIC 是无法实现积极 PK/PD 目标的重要独立预测因素，而长期/连续输注 β-内酰胺则成为保护因素。 19 项研究的偏倚风险为中等，另外 2 项研究的偏倚风险为严重。实现积极的 β-内酰胺 PK/PD 目标为危重患者提供了显着的临床益处。我们的分析可能有助于对未能实现积极 PK/PD 目标的高风险患者进行分层。