干血斑技术用于重症感染患者美罗培南精准给药的评价研究

Evaluation of Dried Blood Spot Sampling for Guiding Precision Dosing of Meropenem in Critically Ill Patients

关键词:  干血斑  美罗培南  治疗药物监测  高效液相色谱法  精准用药

Key words:  Dried blood spot  Meropenem  Therapeutic drug monitoring  High performance liquid chromatography  Precision dosing

摘要:

目的 建立一种基于干血斑（Dried Blood Spot, DBS）技术的美罗培南血药浓度检测方法，并探讨其在重症感染患者精准用药中的应用价值。 方法 采用高效液相色谱法（High Performance Liquid Chromatography, HPLC）测定干血斑中美罗培南的浓度，优化样品前处理流程和色谱条件，进行完整的方法学验证（包括特异性、线性、准确度、精密度、提取回收率、基质效应和稳定性），并与传统静脉血浆样本进行一致性比较（Bland-Altman法和Passing-Bablok回归法），检测重症感染患者样本检验临床实用性。 结果 所建立的DBS-HPLC法在1~100 μg/mL范围内线性良好（R2 > 0.999），定量下限为1 μg/mL。特异性、准确度、精密度、提取回收率、基质效应和稳定性均符合生物样本分析要求，干血斑技术在常温、4℃和-20℃条件下均能使美罗培南保持72小时的稳定性，且在常温下的稳定性优于血浆样本。干血斑采样与传统静脉全血采样测得的美罗培南血药浓度结果具有良好的一致性。临床浓度监测显示，98%的患者血药浓度达标。 结论 干血斑技术结合HPLC法可用于美罗培南血药浓度的快速、微创监测，为重症感染患者的个体化给药提供可靠支持。

Abstract:

OBJECTIVE To develop an assay for determining meropenem concentrations using dried blood spot (DBS) sampling and to evaluate its potential application in guiding precision dosing for critically ill patients. METHODS Meropenem levels in DBS samples were quantified using high-performance liquid chromatography (HPLC). The sample pretreatment procedure and chromatographic conditions were optimized, followed by a full method validation including specificity, linearity, accuracy, precision, extraction recovery, matrix effects, and stability. The agreement between meropenem concentrations measured in DBS and paired conventional plasma samples was assessed using Bland-Altman and Passing-Bablok regression analyses. Evaluate the clinical utility of testing samples from critically ill patients. RESULTS The established DBS-HPLC method demonstrated excellent linearity over the concentration range of 1-100 μg/mL (R2> 0.999), with a lower limit of quantification of 1 μg/mL. The specificity, accuracy, precision, extraction recovery, matrix effects, and stability all met the acceptance criteria for bioanalytical method validation. DBS technology maintains the stability of meropenem for 72 hours under ambient temperature, 4℃, and -20℃ conditions, with superior stability at ambient temperature compared to plasma samples. Meropenem blood concentration results obtained from DBS sampling demonstrate good consistency with those from traditional venous plasma sampling. Clinical monitoring showed that 98% of patients achieved target concentrations. CONCLUSION The combination of DBS sampling with HPLC provides a rapid and minimally invasive approach for monitoring meropenem blood concentrations, offering reliable support for personalized antimicrobial therapy in critically ill patients.