Unité Fonctionnelle de Pharmacologie, AP-HP, Groupe Hospitalier Paris Seine Saint-Denis, F-93140 Bondy, France; Université Sorbonne Paris Nord and Université Paris Cité, Inserm, IAME, F-93000 Bobigny, France.
Université Sorbonne Paris Nord and Université Paris Cité, Inserm, IAME, F-93000 Bobigny, France; Service de Microbiologie Clinique, AP-HP, Groupe Hospitalier Paris Seine Saint-Denis, F-93000 Bobigny, France.
J Chromatogr B Analyt Technol Biomed Life Sci. 2022 Nov 15;1211:123496. doi: 10.1016/j.jchromb.2022.123496. Epub 2022 Oct 9.
Therapeutic drug monitoring (TDM) of antibiotics (ATB) in patients with serious bacterial infections allows optimization of the efficacy of the treatment while reducing the risk of toxicity. Notably, early measurement of plasma beta-lactam concentration has been shown to be associated with reduced mortality in intensive care patients. In this context, a rapid, robust, and accurate assay method is essential for daily TDM. A fully automated procedure for quantification of the plasma concentrations of ten ATB was developed. The ATB were divided into two calibration pools, with Pool 1: aztreonam, ceftobiprole, cefoxitin, avibactam, tazobactam and Pool 2: metronidazole, ceftriaxone, daptomycin, ceftolozane, moxifloxacin. Sample preparation consisting of acetonitrile plasma protein precipitation and H20 dilution was applied to all analytes. This procedure was carried out by an automated sample preparation system directly coupled to a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. Since the instrument extracts sample n while sample n-1 is in the LC-MS/MS system, the delay between obtaining the results for two samples corresponds to the analytical run time, which is less than 7 min. The method was validated according to the Food and Drug Administration guidelines. The method was sensitive (lower limit of quantification 0.1-1 mg/L, depending on the ATB), accurate (intra/inter-assay bias -14.8 to 14.2 %) and precise (intra/inter-assay CVs 1.27 to 16.3 %). Application of the TDM assay was illustrated by the report of an intensive care patient treated with the ceftazidime/aztreonam/avibactam combination. Four assays were performed in 8 days with results returned within 24 h to quickly manage the dose regimen in this patient. An automated, simple, rapid, robust LC-MS/MS analysis was developed and validated for the simultaneous quantification of plasma concentrations of 10 ATB and was applied with success to perform TDM. This method provides a shorter turnaround time than classic sample batch-based analytical methods.
抗生素治疗药物监测（TDM）可优化严重细菌感染患者的治疗效果，同时降低毒性风险。值得注意的是，早期测量血浆β-内酰胺浓度与重症监护患者死亡率降低有关。在这种情况下，快速、稳健、准确的分析方法对于日常 TDM 至关重要。本文建立了一种同时定量测定 10 种抗生素的全自动化方法。将抗生素分为两个校准池，池 1：氨曲南、头孢比罗、头孢西丁、阿维巴坦、他唑巴坦；池 2：甲硝唑、头孢曲松、达托霉素、头孢洛扎烷、莫西沙星。所有分析物均采用含乙腈的血浆蛋白沉淀和 H20 稀释的样品制备方法。该程序由自动化样品制备系统直接与液相色谱-串联质谱（LC-MS/MS）系统连接完成。由于仪器在提取样本 n 的同时，样本 n-1 正在 LC-MS/MS 系统中进行分析，因此两个样本之间获得结果的延迟时间对应于分析运行时间，不到 7 分钟。该方法按照美国食品药品监督管理局的指南进行了验证。该方法具有较高的灵敏度（取决于抗生素，最低定量下限为 0.1-1mg/L）、准确性（日内/日间偏差为-14.8%至 14.2%）和精密度（日内/日间 CV 为 1.27%至 16.3%）。该 TDM 检测方法通过对接受头孢他啶/氨曲南/阿维巴坦联合治疗的重症监护患者的报告进行了说明。在 8 天内进行了 4 次检测，结果在 24 小时内返回，以便快速管理该患者的剂量方案。本文建立了一种自动化、简单、快速、稳健的 LC-MS/MS 分析方法，用于同时定量测定 10 种抗生素的血浆浓度，并成功应用于 TDM。与经典的基于样本批量的分析方法相比，该方法提供了更短的周转时间。
