Department of Pharmacy Practice, Midwestern University Chicago College of Pharmacy, Downers Grove, IL, USA.
Midwestern University Chicago College of Pharmacy, Downers Grove, IL, USA.
Int J Antimicrob Agents. 2018 Feb;51(2):239-243. doi: 10.1016/j.ijantimicag.2017.08.012. Epub 2017 Aug 10.
Although the exposure-dependent efficacy thresholds of vancomycin have been probed, less is known about acute kidney injury (AKI) thresholds for this drug. Sensitive urinary biomarkers, such as kidney injury molecule 1 (KIM-1), have shown high sensitivity and specificity for vancomycin-associated AKI. The aims of the study were to determine if there were dose-response curves with urinary KIM-1, and to evaluate the impact of therapy duration and sex on observed relationships.
A systematic review was conducted via PubMed/MEDLINE. Data were compiled from preclinical studies that reported individual subject data for urinary KIM-1 concentrations, vancomycin dose (mg/kg), duration of treatment, and sex. Sigmoidal Hill-type models were fit to the individual dose-response data.
A total of 15 studies were identified, 6 of which reported vancomycin dose and KIM-1 data. Of these, three included individual animal-level data suitable for analysis. For all pooled rats, increasing total daily vancomycin doses displayed a dose-response curve with urinary KIM-1 concentrations (50% maximal toxic response=130.4 mg/kg/day). Dose-response curves were shifted left for females vs. males (P = 0.05) and for long (i.e. ≥7 days) vs. short (i.e. <4 days) duration of vancomycin therapy (P=0.02).
The collective findings demonstrate a clear dose-response relationship between vancomycin dose and AKI. As these analyses focused exclusively on dose-response relationships, additional preclinical data are needed to more clearly define vancomycin exposures that predict the onset of AKI.
尽管已经探讨了万古霉素暴露依赖性疗效阈值，但对于这种药物的急性肾损伤 (AKI) 阈值知之甚少。肾脏损伤分子 1 (KIM-1) 等敏感的尿生物标志物已显示出对万古霉素相关性 AKI 的高灵敏度和特异性。本研究旨在确定尿 KIM-1 是否存在剂量反应曲线，并评估治疗持续时间和性别对观察到的关系的影响。
通过 PubMed/MEDLINE 进行系统评价。数据来自于报告尿 KIM-1 浓度、万古霉素剂量 (mg/kg)、治疗持续时间和性别的临床前研究。将 Sigmoidal Hill 型模型拟合到个体剂量反应数据中。
共确定了 15 项研究，其中 6 项报告了万古霉素剂量和 KIM-1 数据。其中，有 3 项包括适合分析的个体动物水平数据。对于所有 pooled 大鼠，增加每日万古霉素总剂量与尿 KIM-1 浓度呈剂量反应曲线 (50%最大毒性反应=130.4mg/kg/天)。与雄性相比，雌性 (P=0.05) 和万古霉素治疗时间较长 (即≥7 天) 与较短 (即<4 天) 相比，剂量反应曲线向左移动 (P=0.02)。
这些综合发现表明万古霉素剂量与 AKI 之间存在明显的剂量反应关系。由于这些分析专门针对剂量反应关系，因此需要更多的临床前数据来更清楚地定义预测 AKI 发生的万古霉素暴露。
