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在线固相萃取-高效液相色谱-串联质谱法同时测定人血浆中头孢洛林、达托霉素、利奈唑胺和利福平的浓度

Simultaneous determination of ceftaroline, daptomycin, linezolid and rifampicin concentrations in human plasma by on-line solid phase extraction coupled to high-performance liquid chromatography-tandem mass spectrometry.

作者信息

Grégoire M, Leroy A G, Bouquié R, Malandain D, Dailly E, Boutoille D, Renaud C, Jolliet P, Caillon J, Deslandes G

机构信息

Clinical Pharmacology Department, University Hospital of Nantes, Nantes, France; EA 3826Clinical and Experimental Therapy of Infectious Diseases, University of Nantes, France.

Bacteriology Department, University Hospital of Nantes, Nantes, France.

出版信息

J Pharm Biomed Anal. 2016 Jan 25;118:17-26. doi: 10.1016/j.jpba.2015.10.008. Epub 2015 Oct 26.

Abstract

Methicillin-resistant Staphylococcus aureus infection is a serious clinical problem worldwide. Ceftaroline, daptomycin, linezolid in combination with rifampicin are particularly used in this indication. To allow monitoring of these antibiotics, an on-line solid phase extraction coupled to high-performance liquid chromatography-tandem mass spectrometry assay requiring a 100 μL aliquot of human plasma has been developed. Besides, significance of 25-O-desacetylrifampicin concentrations was evaluated. Sample pre-treatment is limited to protein precipitation with methanol. After centrifugation 10 μL of supernatant are injected into the chromatographic system, which consists of an on-line solid phase extraction followed by a separation on a phenyl-hexyl column and detected by a tandem mass spectrometer. Plasma drug concentrations were determined by multiple reaction monitoring in positive ion mode, and assay performance was evaluated. 25-O-Desacetylrifampicin activity, was compared to rifampicin using a microbiological method. Sample preparation using methanol precipitation followed by solid-phase extraction yielded good recovery and ionization efficiency, with chromatographic separation achieved within 3 min per sample. Within-run and between-run precisions ranged respectively from 1.22% to 9.35% and from 1.61% to 9.36%. Lower limits of quantification were 0.04 mg/L for linezolid, 0.1mg/L for rifampicin, 0.2mg/L for ceftaroline and 0.5mg/L for daptomycin. It appears that 25-O-desacetylrifampicin displays a substantial intrinsic bactericidal activity against S. aureus. This assay provides simple, rapid, sensitive and accurate quantification of the four antibiotic drugs and one metabolite and can be routinely used to monitor drug concentration in methicillin-resistant S. aureus infected patients.

摘要

耐甲氧西林金黄色葡萄球菌感染是一个全球性的严重临床问题。头孢托罗、达托霉素、利奈唑胺联合利福平尤其用于此适应症。为了监测这些抗生素,已开发出一种在线固相萃取结合高效液相色谱 - 串联质谱分析法,该方法需要100μL人血浆等分试样。此外,还评估了25 - O - 去乙酰利福平浓度的意义。样品预处理仅限于用甲醇进行蛋白沉淀。离心后,将10μL上清液注入色谱系统,该系统由在线固相萃取、随后在苯基己基柱上分离并由串联质谱仪检测组成。血浆药物浓度通过正离子模式下的多反应监测来测定,并对分析性能进行了评估。使用微生物学方法将25 - O - 去乙酰利福平的活性与利福平进行了比较。使用甲醇沉淀后进行固相萃取的样品制备方法具有良好的回收率和电离效率,每个样品的色谱分离在3分钟内完成。批内和批间精密度分别为1.22%至9.35%和1.61%至9.36%。利奈唑胺的定量下限为0.04mg/L,利福平为0.1mg/L,头孢托罗为0.2mg/L,达托霉素为0.5mg/L。看来25 - O - 去乙酰利福平对金黄色葡萄球菌显示出相当大的内在杀菌活性。该分析方法提供了对四种抗生素药物和一种代谢物的简单、快速、灵敏和准确的定量,可常规用于监测耐甲氧西林金黄色葡萄球菌感染患者的药物浓度。

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