本文選題：萬古霉素 + 臨床危重患者��； 參考：《第四軍醫(yī)大學(xué)》2016年博士論文

【摘要】：研究背景與目的萬古霉素(Vancomycin)是一種糖肽類抗生素,于1958年被批準(zhǔn)用于臨床使用,對革蘭氏陽性菌有效,尤其在治療耐甲氧西林金黃色葡萄球菌(Methicillin-Resistant Staphylococcus Aureus,MRSA)等耐藥菌株所致的嚴(yán)重感染中具有重要地位。因此,萬古霉素曾被譽為“人類對付頑固性耐藥菌株的最后一道防線”,通常情況下不推薦作為一線抗菌藥物,只在其他的常用抗菌藥物無效時才應(yīng)用。但是,隨著臨床上耐藥菌株感染的逐漸增多,萬古霉素目前已經(jīng)廣泛地用于MRSA和其他革蘭陽性耐藥菌感染的臨床治療。隨著萬古霉素的大量使用,其不良反應(yīng)時有發(fā)生,較為常見的有由于劑量過大引起的腎毒性和耳毒性。而另一方面,給藥劑量不足也會促進萬古霉素耐藥性的產(chǎn)生,已有報道發(fā)現(xiàn)對萬古霉素敏感性下降或耐藥性的細(xì)菌形成。近年來,醫(yī)院獲得性感染的致病菌中MRSA比例顯著增加,由于藥物劑量不足等不規(guī)范用藥也常導(dǎo)致治療失敗。經(jīng)PubMed文獻檢索(2015年12月),萬古霉素相關(guān)論文達到23035篇,其中藥物抵抗11410篇、腎臟毒性389篇、給藥劑量817篇、連續(xù)用藥739篇、藥物動力學(xué)1786篇,表明萬古霉素的臨床合理應(yīng)用、毒副作用、藥物抵抗等一直備受國內(nèi)、外學(xué)者的關(guān)注,其中如何規(guī)范合理地使用萬古霉素是臨床面臨的重要問題。目前,西北地區(qū)尚缺乏萬古霉素臨床應(yīng)用的管理學(xué)分析,特別是針對萬古霉素應(yīng)用的藥事管理定量研究,成為本研究關(guān)注的主要問題。因此,本課題主要對西北地區(qū)臨床危重患者應(yīng)用萬古霉素的藥物療效、肝腎毒性發(fā)生、藥事管理措施等進行分析研究,為進一步完善臨床萬古霉素的規(guī)范化合理應(yīng)用提供理論依據(jù)。研究方法1.臨床病人樣本的回顧性分析:患者的錄入與排除,萬古霉素應(yīng)用方案與分組,血液藥物濃度、藥物治療療效、肝腎毒性等檢測指標(biāo)的分析方法。2.臨床數(shù)據(jù)資料的統(tǒng)計學(xué)分析:采用spss進行樣本均數(shù)的差異比較分析。3.萬古霉素藥代學(xué)的觀察方法:實時檢測分析血液和腦脊液谷濃度與變化。4.萬古霉素的藥事管理報告:采用文獻分析、比較研究、實地訪談等方法。研究結(jié)果1.萬古霉素在西北地區(qū)臨床危重患者應(yīng)用的樣本選擇與療效分析:通過嚴(yán)格篩選獲得西北地區(qū)125例臨床危重患者應(yīng)用萬古霉素樣本,根據(jù)細(xì)菌學(xué)培養(yǎng)、實驗室檢查指標(biāo)、臨床表現(xiàn)判斷療效,分析用藥方案與血藥濃度和療效的關(guān)系。結(jié)果表明:全部125例患者中,122例顯效或痊愈(66例顯效、56例痊愈)、3例死亡,有效率達到97.4%,痊愈率44.8%。分層分析,標(biāo)準(zhǔn)化用藥兩種方案(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)的痊愈率分別為42.1%與43.8%,兩者之間無統(tǒng)計學(xué)差異。全部125例患者中,92.2%的血藥濃度谷值在理想治療范圍之內(nèi),兩種標(biāo)準(zhǔn)化方案的血藥濃度谷值分布范圍有所不同,第二種方案達到理想治療濃度的比例更高。該結(jié)果說明萬古霉素在臨床危重患者應(yīng)用的療效確切,兩種標(biāo)準(zhǔn)化用藥方案具有相似的抗菌治療效果。2.萬古霉素在西北地區(qū)125例臨床危重患者應(yīng)用的肝腎毒性分析:通過回顧性分析我院125例萬古霉素治療患者,其中標(biāo)準(zhǔn)化用藥35例、個體化體重用藥90例,研究確定萬古霉素肝腎毒性的相關(guān)風(fēng)險因素。結(jié)果表明:萬古霉素應(yīng)用的全部患者中,90%以上血藥濃度谷值在理想范圍之內(nèi)。標(biāo)準(zhǔn)化用藥與個體化體重用藥組,均未發(fā)現(xiàn)明顯肝功損傷。標(biāo)準(zhǔn)化用藥方案中,第一方案出現(xiàn)腎功損傷;個體化體重用藥組90例中14例出現(xiàn)腎功損傷,約占15.6%。用藥劑量大于38mg/kg/day(50.0%vs11.3%,P=0.004)和血藥濃度谷值大于20 mg/L(57.1%vs 12.0%,P=0.01)是萬古霉素相關(guān)腎毒性的獨立風(fēng)險因素。該結(jié)果說明萬古霉素用藥劑量和血藥濃度谷值對于腎臟毒性的發(fā)生密切相關(guān),萬古霉素用藥期間的實時檢測和及時調(diào)整是必要的。3.我院一例危重患者的萬古霉素血清與腦脊液藥物濃度初步觀察:由于血腦屏障和選擇性通透機制的存在,對于藥物中樞分布和生物效應(yīng)會產(chǎn)生影響。我們選擇一例2015年6月入院并應(yīng)用萬古霉素的臨床危重患者,對萬古霉素給藥48h期間的血液和腦脊液藥物濃度水平和變化進行了實時檢測。結(jié)果表明:在動態(tài)觀察48h內(nèi),萬古霉素血藥濃度最低為3.91μg/mL,最高64.23μg/mL,平均21.56μg/mL。腦脊液濃度最低0.13μg/mL,最高3.45μg/mL,平均1.46μg/mL。在相同的9個觀察時間點,腦脊液藥物濃度均低于血藥濃度,腦脊液藥物濃度呈現(xiàn)緩慢上升趨勢。該結(jié)果說明血腦屏障對于萬古霉素透過和組中樞織分布具有較大阻礙作用。該例患者樣本極難獲得,為進一步探索萬古霉素的中樞應(yīng)用提供了寶貴的原始病例數(shù)據(jù)。4.針對醫(yī)院萬古霉素臨床規(guī)范化應(yīng)用的實時監(jiān)管實踐與藥事管理報告:依據(jù)我國《抗菌藥物臨床應(yīng)用指導(dǎo)原則》,2014年8月下發(fā)執(zhí)行《關(guān)于加強萬古霉素臨床規(guī)范化應(yīng)用的通知》。我們制定《萬古霉素臨床監(jiān)測記錄表》,實時監(jiān)測了全院620例萬古霉素應(yīng)用過程,包括用藥指征、用藥方案、血藥檢測、用藥調(diào)整、病程轉(zhuǎn)歸等情況。結(jié)果可見:規(guī)范性用藥471例,占76.0%(471/620),不合理用藥和特殊反應(yīng)149例,約占24%(149/620)。這些監(jiān)管措施和實踐有效保證了我院萬古霉素應(yīng)用的治療效果和安全性,并提示進一步嚴(yán)格進行萬古霉素規(guī)范化用藥的必要性。研究結(jié)論通過臨床資料回顧性研究和藥事監(jiān)管過程分析,表明我國西北地區(qū)臨床危重患者應(yīng)用萬古霉素的抗菌療效是明確可靠的,但存在腎臟毒性發(fā)生的危險性。該研究結(jié)果為完善萬古霉素臨床規(guī)范化應(yīng)用和用藥管理提供了新的依據(jù)。并提示深入探索科學(xué)合理的用藥方案、規(guī)范嚴(yán)謹(jǐn)?shù)乃幨鹿芾矸椒?對于保證臨床危重患者萬古霉素應(yīng)用療效和避免毒副作用仍然是十分必要的。課題研究結(jié)果具有理論和應(yīng)用意義。
[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.

【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R459.7

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