Background The advocated pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin, AUC/MIC ≥ 400 mg·h/L, may not be reached with a conventional fixed starting dose of 1000 mg in critically ill patients, but increasing the dose may cause nephrotoxicity. Objectives To evaluate the effect of a weight-based loading dose of 25 mg/kg vancomycin on PK/PD target attainment in the first 24 h (AUC0–24) in critically ill patients and to evaluate whether this increases the risk of acute kidney injury (AKI). Patients and methods A prospective observational before/after study was performed in ICU patients, comparing the percentage of vancomycin courses with AUC0–24 ≥ 400 mg·h/L and the incidence of AKI, defined as worsening of the risk, injury, failure, loss of kidney function and end-stage kidney disease (RIFLE) score. The conventional dose group received 1000 mg of vancomycin as initial dose; the loading dose group received a weight-based loading dose of 25 mg/kg. A population PK model developed using non-linear mixed-effects modelling was used to estimate AUC0–24 in all patients. Results One hundred and four courses from 82 patients were included. With a loading dose, the percentage of courses achieving AUC0–24 ≥ 400 mg·h/L increased significantly from 53.8% to 88.0% (P = 0.0006). The percentage of patients with new-onset AKI was not significantly higher when receiving a 25 mg/kg loading dose (28.6% versus 37.8%; P = 0.48). However, the risk of AKI was significantly higher in patients achieving AUC0–24 > 400 mg·h/L compared with patients achieving AUC < 400 mg·h/L (39.0% versus 14.8%; P = 0.031). Conclusions A weight-based loading dose of 25 mg/kg vancomycin led to significantly more patients achieving AUC0–24 ≥ 400 mg·h/L without increased risk of AKI. However, some harm cannot be ruled out since higher exposure was associated with increased risk of AKI.

中文翻译：

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万古霉素负荷剂量对在最初 24 小时内达到目标万古霉素暴露量以及危重患者伴随的肾毒性风险的影响

背景 万古霉素提倡的药代动力学/药效学 (PK/PD) 目标，即 AUC/MIC ≥ 400 mg·h/L，在危重患者中使用 1000 mg 的常规固定起始剂量可能无法达到，但增加剂量可能会导致肾毒性。目的 评估基于体重的负荷剂量 25 mg/kg 万古霉素对危重患者前 24 小时内 PK/PD 目标达到（AUC0-24）的影响，并评估这是否会增加急性肾损伤的风险（AKI）。患者和方法 在 ICU 患者中进行了一项前/后的前瞻性观察性研究，比较了 AUC0-24 ≥ 400 mg·h/L 的万古霉素疗程百分比和 AKI 的发生率，定义为风险恶化、损伤、失败、肾功能丧失和终末期肾病（RIFLE）评分。常规剂量组初始剂量为万古霉素1000mg；负荷剂量组接受基于体重的负荷剂量 25 mg/kg。使用非线性混合效应模型开发的群体 PK 模型用于估计所有患者的 AUC0-24。结果 纳入了 82 名患者的 104 个疗程。在负荷剂量下，达到 AUC0-24 ≥ 400 mg·h/L 的疗程百分比从 53.8% 显着增加至 88.0% (P = 0.0006)。接受 25 mg/kg 负荷剂量时，新发 AKI 患者的百分比没有显着增加（28.6% 对 37.8%；P = 0.48）。然而，达到 AUC0-24 > 的患者发生 AKI 的风险显着更高。与达到 AUC < 400 mg·h/L 的患者相比 400 mg·h/L（39.0% 对 14.8%；P = 0.031）。结论 基于体重的 25 mg/kg 万古霉素负荷剂量可使更多患者达到 AUC0-24 ≥ 400 mg·h/L，而不会增加 AKI 的风险。然而，不能排除某些危害，因为较高的暴露与 AKI 风险增加有关。