氨基糖苷类抗生素和万古霉素治疗药物监测分析方法的建立及临床应用

发布时间：2018-01-19 08:12

本文关键词： 氨基糖苷类抗生素万古霉素治疗药物浓度监测 LC-MS/MS CMIA HPLC-UV　出处：《上海师范大学》2017年硕士论文　论文类型：学位论文

【摘要】：氨基糖苷类抗生素如阿米卡星、异帕米星、妥布霉素是治疗耐药革兰阴性菌感染的的重要抗生素之一,糖肽类抗生素万古霉素是抗耐甲氧西林金黄色葡萄球菌(MRSA)等耐药革兰阳性菌感染的首选抗生素,近年来CHINET耐药监测网结果显示,该些抗生素仍然对耐药革兰阴性菌或耐药革兰阳性菌保持良好的敏感率,推荐单药或联合用于耐药菌引起的严重感染。然而该些抗生素主要从肾脏排泄,并有耳肾毒性,药物疗效、毒性均与血药浓度浓度相关。为提高临床疗效和安全性,国内外的指南均推荐对氨基糖苷类抗生素和万古霉素进行治疗药物浓度监测(Therapeutic Drug Monitoring,TDM)。临床医生可根据监测的血药浓度,结合病人病情等进行个体化给药剂量的调整,提高该类药物疗效,减少毒副反应的发生。因而,准确、灵敏的定量分析方法测定该些抗生素在血清(血浆)中的药物浓度很有必要。目前,氨基糖苷类抗生素和万古霉素治疗药物浓度监测的分析方法主要为免疫分析法。阿米卡星、妥布霉素、异帕米星在国外已有商品化的免疫试剂盒用于其血药浓度监测,但在中国尚未进行临床注册,不能在临床使用,使得该类药物在国内临床TDM的开展受到了限制。万古霉素在国内有免疫方法、高效液相法和液质联用法等测定患者血样中万古霉素浓度,近期国外文献报道不同厂家生产的仪器、相同厂家生产的仪器的定量下限、测得药物浓度均存在一定差异。此将对万古霉素的TDM方法准确性带来挑战。大样本数据量下不同分析方法间的检测差异及对临床医生调整给药方案判断的影响,目前国内尚无相关报道。本课题研究将分成两部分:第一部分:氨基糖苷类抗生素阿米卡星、异帕米星、妥布霉素LC-MS/MS法建立及临床样本监测本课题建立了用于三种氨基糖苷类抗生素治疗药物浓度监测分析的LC-MS/MS法,对方法的特异性、精密度与准确度、基质效应与回收率、标准曲线与定量下限、样品放置稳定性、自动进样器稳定性、进样重复性、残留效应、交互作用等进行了考察。收集、测定了接受阿米卡星治疗的革兰阴性菌感染患者的样本,首次了解中国患者用药后的血药谷浓度、峰浓度水平,为开展中国患者革兰阴性菌感染患者阿米卡星治疗药物浓度监测临床观察研究提供了参考。第二部分:三种万古霉素血药浓度检测方法的比较及对临床TDM结果影响的分析本课题基于以前的实验基础,考察了大样本数据量下常见的三种万古霉素血药浓度分析方法测定结果的相关性及差异,并分析了不同检测方法下临床给药方案调整判断的差异,为TDM分析方法的选择提供参考,进一步保障万古霉素TDM分析结果的准确性。
[Abstract]:Aminoglycoside antibiotics such as amikacin, isopamicin and tobramycin are one of the important antibiotics for the treatment of drug-resistant gram-negative bacteria. Vancomycin, a glycopeptide antibiotic, is the first choice of antibiotics for resistant gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). In recent years, the results of CHINET resistance monitoring network show that vancomycin is the first choice of antibiotics. These antibiotics remain highly sensitive to the resistant or resistant gram-positive bacteria and are recommended for single or combined use in severe infections caused by drug-resistant bacteria. However, these antibiotics are mainly excreted from the kidneys. The otorenal toxicity, drug efficacy and toxicity were all related to the concentration of blood drug. In order to improve the clinical efficacy and safety. Both domestic and foreign guidelines recommend therapeutic concentration monitoring of aminoglycoside antibiotics and vancomycin for Therapeutic Drug Monitoring. The clinicians can adjust the dosage of individualized medicine according to the concentration of blood drug and the patient's condition, improve the curative effect of this kind of drug, and reduce the occurrence of side effects. Therefore, it is accurate. A sensitive quantitative method is necessary to determine the concentration of these antibiotics in serum (plasma). Aminoglycoside antibiotics and vancomycin treatment drug concentration monitoring methods are mainly immunoassay. Amikacin, tobramycin. Isoparmicin has been commercially available in foreign countries for monitoring its blood concentration, but it has not been registered clinically in China and cannot be used in clinical use. Vancomycin has been used in China to determine the concentration of vancomycin in blood samples by high performance liquid chromatography (HPLC) and liquid / mass spectrometry (HPLC). It is reported in recent foreign literature that the quantitative lower limit of the instruments produced by different manufacturers and the instruments produced by the same manufacturers. This will challenge the veracity of vancomycin TDM method. The difference between different analytical methods in large sample data and its influence on clinicians' judgment of adjusting drug delivery plan. Ring. At present, there are no related reports in China. This research will be divided into two parts: the first part: aminoglycoside antibiotics amikacin, isopamicin. Establishment of tobramycin LC-MS/MS method and clinical sample monitoring the LC-MS/MS method for monitoring the concentration of three aminoglycoside antibiotics was established. Precision and accuracy, matrix effect and recovery, standard curve and lower limit of quantification, stability of sample placement, stability of automatic sampler, repeatability of injection, residual effect and interaction were investigated. Samples of patients with Gram-negative bacilli infection treated with amikacin were measured, and the serum concentration and peak concentration of Gram-negative bacteria in Chinese patients were investigated for the first time. It provides a reference for clinical observation and study on the concentration monitoring of amikacin in Chinese patients with Gram-negative bacilli infection. Part two:. Comparison of three methods for determination of vancomycin concentration and analysis of the effect on clinical TDM results this subject is based on the previous experimental basis. The correlation and difference of three common methods for determination of vancomycin concentration in large sample data were investigated, and the differences of the adjustment and judgment of clinical administration schemes under different detection methods were analyzed. To provide a reference for the selection of TDM analysis methods and to further ensure the accuracy of vancomycin TDM analysis results.
【学位授予单位】：上海师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R969

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