万古霉素用于临床危重患者的规范化用药管理研究

发布时间：2018-05-07 10:12

本文选题：万古霉素 + 临床危重患者　；参考：《第四军医大学》2016年博士论文

【摘要】：研究背景与目的万古霉素(Vancomycin)是一种糖肽类抗生素,于1958年被批准用于临床使用,对革兰氏阳性菌有效,尤其在治疗耐甲氧西林金黄色葡萄球菌(Methicillin-Resistant Staphylococcus Aureus,MRSA)等耐药菌株所致的严重感染中具有重要地位。因此,万古霉素曾被誉为“人类对付顽固性耐药菌株的最后一道防线”,通常情况下不推荐作为一线抗菌药物,只在其他的常用抗菌药物无效时才应用。但是,随着临床上耐药菌株感染的逐渐增多,万古霉素目前已经广泛地用于MRSA和其他革兰阳性耐药菌感染的临床治疗。随着万古霉素的大量使用,其不良反应时有发生,较为常见的有由于剂量过大引起的肾毒性和耳毒性。而另一方面,给药剂量不足也会促进万古霉素耐药性的产生,已有报道发现对万古霉素敏感性下降或耐药性的细菌形成。近年来,医院获得性感染的致病菌中MRSA比例显著增加,由于药物剂量不足等不规范用药也常导致治疗失败。经PubMed文献检索(2015年12月),万古霉素相关论文达到23035篇,其中药物抵抗11410篇、肾脏毒性389篇、给药剂量817篇、连续用药739篇、药物动力学1786篇,表明万古霉素的临床合理应用、毒副作用、药物抵抗等一直备受国内、外学者的关注,其中如何规范合理地使用万古霉素是临床面临的重要问题。目前,西北地区尚缺乏万古霉素临床应用的管理学分析,特别是针对万古霉素应用的药事管理定量研究,成为本研究关注的主要问题。因此,本课题主要对西北地区临床危重患者应用万古霉素的药物疗效、肝肾毒性发生、药事管理措施等进行分析研究,为进一步完善临床万古霉素的规范化合理应用提供理论依据。研究方法1.临床病人样本的回顾性分析:患者的录入与排除,万古霉素应用方案与分组,血液药物浓度、药物治疗疗效、肝肾毒性等检测指标的分析方法。2.临床数据资料的统计学分析:采用spss进行样本均数的差异比较分析。3.万古霉素药代学的观察方法:实时检测分析血液和脑脊液谷浓度与变化。4.万古霉素的药事管理报告:采用文献分析、比较研究、实地访谈等方法。研究结果1.万古霉素在西北地区临床危重患者应用的样本选择与疗效分析:通过严格筛选获得西北地区125例临床危重患者应用万古霉素样本,根据细菌学培养、实验室检查指标、临床表现判断疗效,分析用药方案与血药浓度和疗效的关系。结果表明:全部125例患者中,122例显效或痊愈(66例显效、56例痊愈)、3例死亡,有效率达到97.4%,痊愈率44.8%。分层分析,标准化用药两种方案(方案一19例,每日2次,每次1克;方案二16例,每日3次,每次0.5克)的痊愈率分别为42.1%与43.8%,两者之间无统计学差异。全部125例患者中,92.2%的血药浓度谷值在理想治疗范围之内,两种标准化方案的血药浓度谷值分布范围有所不同,第二种方案达到理想治疗浓度的比例更高。该结果说明万古霉素在临床危重患者应用的疗效确切,两种标准化用药方案具有相似的抗菌治疗效果。2.万古霉素在西北地区125例临床危重患者应用的肝肾毒性分析:通过回顾性分析我院125例万古霉素治疗患者,其中标准化用药35例、个体化体重用药90例,研究确定万古霉素肝肾毒性的相关风险因素。结果表明:万古霉素应用的全部患者中,90%以上血药浓度谷值在理想范围之内。标准化用药与个体化体重用药组,均未发现明显肝功损伤。标准化用药方案中,第一方案出现肾功损伤;个体化体重用药组90例中14例出现肾功损伤,约占15.6%。用药剂量大于38mg/kg/day(50.0%vs11.3%,P=0.004)和血药浓度谷值大于20 mg/L(57.1%vs 12.0%,P=0.01)是万古霉素相关肾毒性的独立风险因素。该结果说明万古霉素用药剂量和血药浓度谷值对于肾脏毒性的发生密切相关,万古霉素用药期间的实时检测和及时调整是必要的。3.我院一例危重患者的万古霉素血清与脑脊液药物浓度初步观察:由于血脑屏障和选择性通透机制的存在,对于药物中枢分布和生物效应会产生影响。我们选择一例2015年6月入院并应用万古霉素的临床危重患者,对万古霉素给药48h期间的血液和脑脊液药物浓度水平和变化进行了实时检测。结果表明:在动态观察48h内,万古霉素血药浓度最低为3.91μg/mL,最高64.23μg/mL,平均21.56μg/mL。脑脊液浓度最低0.13μg/mL,最高3.45μg/mL,平均1.46μg/mL。在相同的9个观察时间点,脑脊液药物浓度均低于血药浓度,脑脊液药物浓度呈现缓慢上升趋势。该结果说明血脑屏障对于万古霉素透过和组中枢织分布具有较大阻碍作用。该例患者样本极难获得,为进一步探索万古霉素的中枢应用提供了宝贵的原始病例数据。4.针对医院万古霉素临床规范化应用的实时监管实践与药事管理报告:依据我国《抗菌药物临床应用指导原则》,2014年8月下发执行《关于加强万古霉素临床规范化应用的通知》。我们制定《万古霉素临床监测记录表》,实时监测了全院620例万古霉素应用过程,包括用药指征、用药方案、血药检测、用药调整、病程转归等情况。结果可见:规范性用药471例,占76.0%(471/620),不合理用药和特殊反应149例,约占24%(149/620)。这些监管措施和实践有效保证了我院万古霉素应用的治疗效果和安全性,并提示进一步严格进行万古霉素规范化用药的必要性。研究结论通过临床资料回顾性研究和药事监管过程分析,表明我国西北地区临床危重患者应用万古霉素的抗菌疗效是明确可靠的,但存在肾脏毒性发生的危险性。该研究结果为完善万古霉素临床规范化应用和用药管理提供了新的依据。并提示深入探索科学合理的用药方案、规范严谨的药事管理方法,对于保证临床危重患者万古霉素应用疗效和避免毒副作用仍然是十分必要的。课题研究结果具有理论和应用意义。
[Abstract]:Background and objective vancomycin (Vancomycin) is a glycopeptide antibiotic, which was approved for clinical use in 1958. It is effective for Gram-positive bacteria, especially in the treatment of severe infections caused by Methicillin-Resistant Staphylococcus Aureus (MRSA) resistant strains of methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin, therefore, has been known as "the last line of defense against refractory resistant strains", usually not recommended as a first-line antibiotic, only when other commonly used antibiotics are ineffective. However, vancomycin is now widely used in MRSA and it is now widely used as the infection of clinically resistant strains gradually increases. The clinical treatment of gram positive bacteria infection. With the extensive use of vancomycin, its adverse reactions occur, more common are nephrotoxicity and ototoxicity caused by excessive dose, and on the other hand, the lack of dose will also promote the birth of vancomycin resistance. It has been reported to be sensitive to vancomycin. The formation of descending or drug-resistant bacteria. In recent years, the proportion of MRSA in the pathogenic bacteria of hospital acquired infection has increased significantly. The drug dose insufficiency and other non standardized drugs often lead to the failure of the treatment. Through the PubMed literature search (December 2015), the vancomycin related papers have reached 23035, including 11410 drug resistance and 389 nephrotoxicity. 817 articles, 739 continuous drugs and 1786 pharmacokinetics showed that vancomycin's clinical rational use, toxic side effects and drug resistance have always been concerned by domestic and foreign scholars. How to standardize the use of vancomycin is an important problem in clinical practice. At present, the management of vancomycin in clinical application is still lacking in Northwest China. The analysis, especially the quantitative research on the application of vancomycin, has become the main concern of this study. Therefore, this subject is mainly to analyze the therapeutic effect of vancomycin, the occurrence of hepatorenal toxicity and the management measures for the clinical critical patients in Northwest China, in order to further improve the standard of clinical vancomycin. A retrospective analysis of 1. clinical patients: a retrospective analysis of clinical patient samples: Patients' entry and exclusion, vancomycin application and grouping, blood drug concentration, drug treatment effect, hepatorenal toxicity and other indicators of analysis of.2. clinical data: the difference between the number of samples with SPSS Comparative analysis of the observation methods of.3. vancomycin pharmacokinetics: real-time detection and analysis of blood and cerebrospinal fluid Valley concentration and change of.4. vancomycin drug management report: using literature analysis, comparative study, field interview and other methods. The sample selection and efficacy analysis of 1. vancomycin in the clinical critical patients in Northwest China were analyzed: Through strict screening, 125 cases of clinical critical patients in Northwest China were selected to use vancomycin samples. According to bacteriological culture, laboratory examination indexes and clinical manifestations, the relationship between drug concentration and curative effect was analyzed. The results showed that in all 125 cases, 122 cases were markedly effective or recovered (66 cases, 56 cases, 56 cases) and 3 deaths. The efficiency reached 97.4%, the recovery rate 44.8%. stratification analysis, the standardized medication two schemes (19 cases, 2 times a day, 1 grams per time, two 16 cases, 3 times a day, 0.5 grams per day) were 42.1% and 43.8% respectively, and there was no statistical difference between the two. All 125 patients were within the ideal range of blood concentration within the ideal treatment range. The range of the distribution of blood concentration valleys in the standardized regimen was different, and the ratio of the second schemes to the ideal treatment concentration was higher. The results showed that vancomycin was effective in the clinical critical patients, and the two standardized regimens had similar antibiosis effect.2. vancomycin in 125 cases of clinical critical illness in the northwest region. Hepatorenal toxicity analysis: a retrospective analysis of 125 cases of vancomycin in our hospital, including 35 cases of standardized medication and 90 cases of individualized weight, was used to determine the risk factors of hepatorenal toxicity of vancomycin. The results showed that among all the patients with vancomycin, more than 90% of the blood concentration valleys were within the ideal range. The standardized medication and the individual body weight group had no obvious liver damage. In the standardized regimen, the first scheme had renal function damage; 14 cases of 90 cases of individualized weight taking group had renal function injury, about 15.6%. dosage was greater than 38mg/kg/day (50.0%vs11.3%, P =0.004) and the valley value of blood drug concentration was greater than 20 mg/L (57.1%vs 12%,) P=0.01) is an independent risk factor for vancomycin related nephrotoxicity. The results show that the dose of vancomycin and the value of the blood concentration valley are closely related to the occurrence of nephrotoxicity. Real-time detection and timely adjustment of vancomycin during the use of vancomycin are necessary for the concentration of vancomycin serum and cerebrospinal fluid in a critically ill patient in.3. hospital. Preliminary observation: the presence of the blood-brain barrier and selective permeability mechanism will affect the distribution and biological effects of the drug center. We chose a clinical critical patient who was admitted to hospital in June 2015 and used vancomycin. The level and changes of the concentration and change of the blood and cerebrospinal fluid (CSF) during the 48H period of vancomycin administration were detected. The results showed that in dynamic observation of 48h, the lowest concentration of vancomycin was 3.91 mu g/mL, the highest was 64.23 mu g/mL, the mean 21.56 u g/mL. cerebrospinal fluid concentration was the lowest 0.13 mu g/mL, the highest 3.45 mu g/mL, the average 1.46 mu g/mL. at the same 9 observation time points, the concentration of cerebrospinal fluid was lower than the blood concentration, and the drug concentration in cerebrospinal fluid showed a slow rise. The results show that the blood brain barrier has a great hindrance to the transmission of vancomycin and the distribution of the central fabric. The sample of this case is very difficult to obtain. It provides valuable original case data for the further exploration of the central application of vancomycin, the real time regulatory practice and drug management of the clinical standardized application of vancomycin in hospital,.4.. Report: according to the guiding principles of clinical application of antibacterial drugs in China, the notification of the implementation of the clinical standardized application of vancomycin in 8 month of 2014 was more than. We formulated the vancomycin clinical monitoring record table, and monitored the application process of 620 cases of vancomycin in real time, including drug indication, medication plan, blood test, medication adjustment, and disease. The results showed that 471 cases of standardized drug use, 76% (471/620), 149 cases of irrational drug use and special reaction, accounting for about 24% (149/620). These regulatory measures and practices effectively guaranteed the therapeutic effect and safety of vancomycin application in our hospital, and suggested the necessity of strictly carrying out the standardized use of vancomycin. Conclusion through the retrospective study of clinical data and the analysis of drug regulatory process, it is shown that the antibacterial effect of vancomycin in the clinical critical patients in Northwest China is clear and reliable, but the risk of nephrotoxicity exists. The results provide a new basis for the improvement of the standardized application and administration of vancomycin. It is necessary to explore the scientific and rational drug use scheme and standardize the strict medicine management method. It is still necessary for the application of vancomycin to ensure the clinical critical patients and to avoid toxic and side effects. The results of the study are of theoretical and practical significance.

【学位授予单位】：第四军医大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R459.7

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