本文選題：耐甲氧西林金黃色葡萄球菌 + 耐藥機(jī)制��； 參考：《中國(guó)人民解放軍軍事醫(yī)學(xué)科學(xué)院》2017年博士論文

【摘要】：[背景]耐甲氧西林金黃色葡萄球菌(Methicillin-resistant Staphylococcus aureus,MRSA)是醫(yī)院內(nèi)感染最常見(jiàn)的致病菌之一,由其引起的社區(qū)感染也正日益增多。金黃色葡萄球菌能引起包括皮膚與軟組織感染、菌血癥、骨髓炎、感染性心內(nèi)膜炎及壞死性肺炎在內(nèi)的一系列疾病。自1960年以來(lái),耐甲氧西林金黃色葡萄球菌在全世界范圍內(nèi)的許多醫(yī)院和衛(wèi)生機(jī)構(gòu)流行性傳播開(kāi)來(lái),其高耐藥率成為了臨床醫(yī)生面臨的棘手問(wèn)題,威脅著患者的健康和生命。正因如此,對(duì)耐甲氧西林金黃色葡萄球菌進(jìn)行流行病學(xué)監(jiān)測(cè),為預(yù)防和治療耐甲氧西林金黃色葡萄球菌提供有力依據(jù),具有重要的臨床意義和社會(huì)效益。分子分型技術(shù)通常用來(lái)研究金黃色葡萄球菌的進(jìn)化和流行病學(xué)特征,目前,國(guó)際上最常用的金黃色葡萄球菌分子分型方法包括:葡萄球菌蛋白A分型(staphylococcal protein A,spa typing)、葡萄球菌染色體盒mec分型(staphylococcal cassette chromosome mec typing,SCCmec typing)、多位點(diǎn)序列分型(multilocus sequence typing,MLST)、脈沖場(chǎng)凝膠電泳(pulsed-field gel electrophoresis,PFGE)和多位點(diǎn)可變串聯(lián)重復(fù)序列分型(multiple-locus variable-number tandem repeat analysis,MLVA)。金黃色葡萄球菌能產(chǎn)生大量毒素,這些毒素在細(xì)菌致病過(guò)程中具有重要的作用。大約20%的金黃色葡萄球菌分離株具有編碼毒性休克綜合征毒素-1(toxic shock syndrome toxin 1,TSST-1)的基因,毒性休克綜合征毒素-1的結(jié)構(gòu)與外毒素結(jié)構(gòu)相似,可引起毒素綜合征。Panton-Valentine殺白細(xì)胞素(Panton-Valentine leukocidin,PVL)是白細(xì)胞溶解毒素,流行病學(xué)上與嚴(yán)重的皮膚感染有關(guān)。在我國(guó),耐甲氧西林金黃色葡萄球菌SCCmec III-ST239菌株分布范圍非常廣,某些全國(guó)性的研究結(jié)果顯示,該型菌株占所有耐甲氧西林金黃色葡萄球菌的75%以上。耐甲氧西林金黃色葡萄球菌的流行病學(xué)一直在不斷變化,這導(dǎo)致了不同大陸、不同國(guó)家和不同地區(qū)之間會(huì)出現(xiàn)不同的耐藥譜,具體到局部地區(qū),耐甲氧西林金黃色葡萄球菌是否具有自身獨(dú)特的流行趨勢(shì)和臨床感染特征是一個(gè)具有現(xiàn)實(shí)指導(dǎo)意義的科學(xué)問(wèn)題�；谝陨涎芯勘尘暗恼{(diào)研,本研究對(duì)收集自2012年02月至2013年05蘇州市一家三甲醫(yī)院的150株耐甲氧西林金黃色葡萄球菌進(jìn)行了分子流行病學(xué)研究,同時(shí)收集樣本對(duì)應(yīng)的患者資料,對(duì)其臨床感染特征進(jìn)行了分析。[目的](1)探討本地區(qū)耐甲氧西林金黃色葡萄球菌的耐藥情況。(2)探尋本地區(qū)耐甲氧西林金黃色葡萄球菌的分子流行病學(xué)現(xiàn)狀,從分子水平闡釋耐藥機(jī)制。(3)探討本地區(qū)耐甲氧西林金黃色葡萄球菌的臨床感染特征,為臨床防治耐甲氧西林金黃色葡萄球菌提供實(shí)驗(yàn)依據(jù)。[方法](1)利用自動(dòng)化肉湯微量稀釋法及mec A基因擴(kuò)增分析本地區(qū)耐甲氧西林金黃色葡萄球菌的耐藥情況。(2)綜合運(yùn)用spa分型技術(shù)、SCCmec分型技術(shù)、MLST分型技術(shù)、PFGE分型技術(shù)和MLVA分型技術(shù)研究本地區(qū)耐甲氧西林金黃色葡萄球菌的分子流行病學(xué)現(xiàn)狀。(3)通過(guò)擴(kuò)增pvl和tst-1基因,研究本地區(qū)耐甲氧西林金黃色葡萄球菌攜帶毒力基因的現(xiàn)狀。(4)收集感染耐甲氧西林金黃色葡萄球菌患者的臨床信息,利用多因素Logistic回歸分析研究本地區(qū)耐甲氧西林金黃色葡萄球菌的臨床感染特征。[結(jié)果](1)150株耐甲氧西林金黃色葡萄球菌均擴(kuò)增出mec A基因。所有菌株均對(duì)萬(wàn)古霉素和利奈唑胺敏感。150株實(shí)驗(yàn)菌株均對(duì)青霉素和苯唑西林耐藥,對(duì)頭孢西丁、哌拉西林-他唑巴坦、氨芐西林-舒巴坦、環(huán)丙沙星、呋喃妥因、紅霉素、克林霉素、復(fù)方新諾明和利福平的耐藥率分別為94.0%(141/150),98.0%(147/150),66.0%(99/150),64.0%(96/150),60.0%(90/150),74.0%(111/150),50.0%(75/150),72.0%(108/150)和12.7%(19/150)。(2)分子分型結(jié)果顯示,150株耐甲氧西林金黃色葡萄球菌共有11個(gè)克隆型和28個(gè)spa型別,其中CC5-spa t002(29.3%)和CC239-spa t037(14.7%)最為盛行。SCCmec II,III,IV和V型的比例分別占所有菌株的33.3%,21.3%,23.3%和21.3%。PVL基因(luk F/S-PV)在所有150株耐甲氧西林金黃色葡萄球中的檢出率為11.3%,分屬于6個(gè)不同的克隆群(5,8,59,88,239,398)。TSST-1基因(tst)的總體檢出率為18.0%,主要為CC5克隆群(96.3%)。本研究中,所有tst-1陽(yáng)性CC5克隆群的耐甲氧西林金黃色葡萄球菌菌株均為spa t002型。(3)本研究中的150株耐甲氧西林金黃色葡萄球菌,其中71株分離自?xún)?nèi)科病房(71/150,47.3%),48株分離自外科病房(48/150,32.0%),31株分離自重癥監(jiān)護(hù)病房(31/150,20.7%)。本研究中的菌株均分離自住院患者的標(biāo)本,60%分離自60歲以上患者,平均年齡為63歲,并且74%(111/150)為男性患者。本研究中的菌株大部分分離自痰樣本(90/150,60.0%),其次為引流液樣本(17/150,11.3%),傷口樣本(12/150,8.0%),另外,4株分離自血液樣本,5株分離自尿液樣本,22株分離自其他部位樣本。(4)本研究中,18位患者在住院30天內(nèi)死亡,病死率為12.0%(18/150)。本研究在三個(gè)主要的克隆群內(nèi)(CC5、CC239和CC59)比較了患者的預(yù)后、臨床特征和耐甲氧西林金黃色葡萄球菌分離株的基因分型特征。與感染CC239或CC59克隆群菌株的患者相比,感染CC5克隆群菌株的患者30天住院病死率明顯較高(P0.05)。另外,CC5克隆群菌株具有更高的機(jī)率為SCCmec II型菌株和攜帶tst-1基因(P0.01),并且具有更高的機(jī)率為分離自重癥監(jiān)護(hù)病房的患者(P0.05)。本研究也比較了預(yù)后不同的患者(生存vs.死亡)所感染的耐甲氧西林金黃色葡萄球菌的臨床和分子特征。在單因素分析中,以下因素與患者30天住院病死率相關(guān):年齡、腫瘤、紅霉素耐受、感染菌株屬于CC5克隆群、分子分型為SCCmec II spa t002以及菌株攜帶tst-1基因(P0.05)。另外,收入重癥監(jiān)護(hù)病房這個(gè)因素經(jīng)統(tǒng)計(jì)學(xué)分析,與患者30天住院病死率相關(guān)性位于臨界線(P=0.06)。值得注意的是,本研究觀察到感染了tst-1陽(yáng)性耐甲氧西林金黃色葡萄球菌的患者30天住院病死率明顯高于感染tst-1陰性耐甲氧西林金黃色葡萄球菌的患者(51.9%vs.3.3%,P0.001)。然而,感染了PVL陽(yáng)性耐甲氧西林金黃色葡萄球菌的患者與感染PVL陰性耐甲氧西林金黃色葡萄球菌的患者30天住院病死率無(wú)明顯差異(0.0%vs.13.5%,P=0.13)。多因素回歸分析發(fā)現(xiàn),與患者30天住院病死率相關(guān)的獨(dú)立危險(xiǎn)因素包括患者年齡大于60歲(odds ratio[OR]=7.2,95%confidence interval[95%CI]=1.26-41.6,P=0.026)、患有腫瘤基礎(chǔ)疾病(OR=9.6,95%CI=1.4-65.7,P=0.02)以及感染tst-1陽(yáng)性耐甲氧西林金黃色葡萄球菌(OR=62.5,95%CI=12.0-325.2,P0.001)。[結(jié)論](1)所研究地區(qū)耐甲氧西林金黃色葡萄球菌整體耐藥率較高,但尚未出現(xiàn)對(duì)萬(wàn)古霉素和利奈唑胺耐藥的菌株。(2)本研究的研究結(jié)果揭示了,與我國(guó)其他地區(qū)相比較,所研究地區(qū)具有獨(dú)特的耐甲氧西林金黃色葡萄球菌的流行譜。首先,CC5克隆群是所研究地區(qū)耐甲氧西林金黃色葡萄球菌主要的流行克隆群,主要的基因型為SCCmec II-ST002而非SCCmec III-ST239。另外,spa t037型在所研究地區(qū)流行程度勝于spat030型,這一流行趨勢(shì)與之前的其他研究結(jié)果提示的spa t037型已被spa t030型取代也不一樣。因此,本研究的研究結(jié)果提示了中國(guó)耐甲氧西林金黃色葡萄球菌在不同醫(yī)院、不同地區(qū)之間的流行具有地域差異。。(3)所研究地區(qū)耐甲氧西林金黃色葡萄球菌CC5分離株為優(yōu)勢(shì)菌株,其中tst-1陽(yáng)性的CC5-MRSA-II,spa t002菌株的比例很高。多因素分析結(jié)果顯示,耐甲氧西林金黃色葡萄球菌tst-1陽(yáng)性CC5克隆群菌株感染是患者30天住院死亡的獨(dú)立危險(xiǎn)因素,警示醫(yī)院需要采取嚴(yán)格的感染防控措施阻止這類(lèi)細(xì)菌該地區(qū)進(jìn)一步擴(kuò)散。
[Abstract]:[background] methicillin resistant Staphylococcus aureus (Methicillin-resistant Staphylococcus aureus, MRSA) is one of the most common pathogenic bacteria in hospital infection, and the community infection is increasing. Staphylococcus aureus can cause skin and soft tissue infection, bacteremia, osteomyelitis, infective endocarditis and necrosis. A series of diseases, including pneumonitis. Since 1960, methicillin resistant Staphylococcus aureus has spread widely in many hospitals and health institutions around the world. The high drug resistance rate has become a difficult problem for clinicians, threatening the health and life of the patients. The epidemiological monitoring of cocci provides a powerful basis for the prevention and treatment of methicillin resistant Staphylococcus aureus. It has important clinical significance and social benefits. Molecular typing is usually used to study the evolutionary and epidemiological characteristics of Staphylococcus aureus. At present, the most commonly used molecular typing side of Staphylococcus aureus at the international level The methods include: staphylococcal protein A typing (staphylococcal protein A, spa typing), staphylococcal chromosome box MEC typing (staphylococcal cassette chromosome mec typing), multiple point sequence typing, pulsed field gel electrophoresis, and multiple sites Multiple-locus variable-number tandem repeat analysis, MLVA). Staphylococcus aureus can produce a large number of toxins, which play an important role in the bacterial pathogenesis. About 20% of the Staphylococcus aureus isolates have toxic shock syndrome toxin -1 (toxic shock syndrome toxin). 1, TSST-1) gene, the structure of the toxic shock syndrome toxin -1 is similar to the structure of the exotoxin, which causes the toxin syndrome,.Panton-Valentine, Panton-Valentine leukocidin, PVL, is leucocyte lysis toxin, and is closely related to severe skin infection. In China, methicillin resistant Staphylococcus aureus SCCmec III The distribution of -ST239 strains is very wide. Some national studies show that the strain accounts for more than 75% of all methicillin resistant Staphylococcus aureus. The epidemiology of methicillin resistant Staphylococcus aureus has been constantly changing, which leads to different resistance spectrum between different continents, different countries and different regions. In specific areas, whether or not methicillin resistant Staphylococcus aureus has its own unique epidemic trend and clinical infection characteristics is a practical scientific problem. Based on the research background above, this study collected 150 methicillin resistant strains of methicillin in a three a hospital in Suzhou from 02 to 2013 2012. The molecular epidemiology study of Staphylococcus aureus was carried out, and the corresponding patient data were collected and the clinical infection characteristics were analyzed. [Objective] (1) to explore the resistance of methicillin resistant Staphylococcus aureus in the local area. (2) to explore the molecular epidemiology of Staphylococcus aureus in local methicillin resistant Staphylococcus aureus, and to explore the molecular epidemiology of methicillin resistant Staphylococcus aureus. Molecular level interpretation of drug resistance mechanism. (3) to explore the clinical infection characteristics of methicillin resistant Staphylococcus aureus in local area, provide experimental basis for clinical prevention and control of methicillin resistant Staphylococcus aureus. [method] (1) the analysis of methicillin resistant Staphylococcus aureus in local methicillin-resistant region by automated broth microdilution and mec A gene amplification (2) the molecular epidemiology of methicillin-resistant Staphylococcus aureus in the local area was studied by spa typing, SCCmec typing, MLST typing, PFGE typing and MLVA typing. (3) by amplifying PVL and tst-1 genes, the virulence genes in methicillin resistant Staphylococcus aureus in the region were studied. (4) the clinical information of Staphylococcus aureus patients infected with methicillin resistant Staphylococcus aureus was collected and the clinical infection characteristics of methicillin resistant Staphylococcus aureus were analyzed by multiple factor Logistic regression analysis. [results] 150 strains of methicillin resistant Staphylococcus aureus all amplified MEC A gene. All strains were all vancomycin and vancomycin. Linezolid sensitive strain.150 strains were resistant to penicillin and zoxicillin, and the resistance rates for cefoxitin, piperacillin - tazobactam, ampicillin - sulbactam, ciprofloxacin, furadyrin, erythromycin, clindamycin, compound sulfamethamine and rifampin were 94% (141/150), 98% (147/150), 66% (99/150), 64% (96/150), 60%, respectively. (90/150), 74% (111/150), 50% (75/150), 72% (108/150) and 12.7% (19/150). (2) molecular typing results showed that 150 strains of methicillin resistant Staphylococcus aureus had 11 clones and 28 spa types, of which CC5-spa T002 (29.3%) and CC239-spa T037 (14.7%) were most prevalent.SCCmec II, respectively, and accounted for 33.3 of all strains, respectively. The detection rate of%, 21.3%, 23.3% and 21.3%.PVL gene (Luk F/S-PV) in all 150 methicillin resistant golden yellow grapevine balls was 11.3%, and the total physical examination rate of 6 different clones (5,8,59,88239398).TSST-1 gene (TST) was 18%, mainly CC5 clone group (96.3%). In this study, all tst-1 positive CC5 clones were in methicillin resistant group. Staphylococcus aureus strains were spa T002 type. (3) 150 strains of methicillin resistant Staphylococcus aureus, of which 71 were isolated from the internal medicine ward (71/150,47.3%), 48 isolated from the surgical ward (48/150,32.0%), and 31 isolated from the intensive care unit (31/ 150,20.7%). The strains in this study were isolated from the hospitalized patients, 60% The average age of 60 years old was 63 years old and 74% (111/150) was male. The strains in this study were mostly isolated from sputum samples (90/150,60.0%), followed by drainage samples (17/150,11.3%), wound samples (12/150,8.0%), and 4 isolated from blood samples, 5 isolated from urine samples and 22 isolated from other sites. (4) in this study, 18 patients died within 30 days of hospitalization and the fatality rate was 12% (18/150). This study compared patients' prognosis in three major clones (CC5, CC239, and CC59), the clinical features and genotyping of methicillin resistant Staphylococcus aureus isolates. Compared to patients infected with CC239 or CC59 cloned strains, Patients infected with CC5 clones were significantly higher in hospital mortality in 30 days (P0.05). In addition, the CC5 clone strain had a higher probability of SCCmec II strain and tst-1 gene (P0.01), and had a higher probability of being separated from the intensive care unit (P0.05). The study also compared patients with different prognosis (survival vs. death). Clinical and molecular characteristics of methicillin resistant Staphylococcus aureus resistant Staphylococcus aureus. In a single factor analysis, the following factors are related to the mortality of 30 days in patients: age, tumor, erythromycin tolerance, infected strains of CC5 clones, molecular typing SCCmec II spa T002 and tst-1 gene (P0.05). In addition, income severe The factor of the guardianship was statistically analyzed and the correlation with the mortality rate of 30 days of hospitalization was on the critical line (P=0.06). It is worth noting that in this study, patients infected with tst-1 positive methicillin resistant Staphylococcus aureus were significantly higher in hospital mortality than those infected with tst-1 negative methicillin resistant Staphylococcus aureus. 51.9%vs.3.3% (P0.001). However, there was no significant difference in mortality between patients infected with PVL positive methicillin resistant Staphylococcus aureus and patients infected with PVL negative methicillin resistant Staphylococcus aureus (0.0%vs.13.5%, P=0.13) at 30 days. Independent risk factors associated with the mortality rate of 30 days hospitalization in patients with multiple factor regression analysis. The patients were older than 60 years old (odds ratio[OR]=7.2,95%confidence interval[95%CI]=1.26-41.6, P=0.026), with basic tumor disease (OR=9.6,95%CI=1.4-65.7, P=0.02), and tst-1 positive methicillin resistant Staphylococcus aureus (OR=62.5,95%CI=12.0-325.2, P0.001). [Conclusion] (1) the study area of methicillin resistant Staphylococcus aureus The overall resistance rate of Staphylococcus was high, but there was no strain resistant to vancomycin and linezolid. (2) the results of this study revealed that compared with other regions of our country, the study area has a unique epidemic spectrum of methicillin resistant Staphylococcus aureus. First, the CC5 clone is the golden yellow resistance of methicillin resistant region in the study area. The main epidemic clones of Staphylococcus aureus are SCCmec II-ST002 and not SCCmec III-ST239.. The prevalence of spa T037 in the area studied is better than that of the spat030 type. The epidemic trend is not the same as the spa T037 type of the previous research results suggested by spa t030 type. Therefore, the results of this study The prevalence of Staphylococcus aureus in methicillin resistant Staphylococcus aureus in different hospitals in China has regional differences. (3) methicillin resistant Staphylococcus aureus CC5 isolates are the dominant strains in the study area, and the proportion of tst-1 positive CC5-MRSA-II and Spa T002 strains is very high. The results of multifactor analysis show that methoxy resistant strains are resistant to methicillin. The infection of the tst-1 positive CC5 clone strain of Staphylococcus aureus is an independent risk factor for the patient's death in hospital for 30 days, warning the hospital to take strict control measures to prevent the further spread of the bacteria in the area.

【學(xué)位授予單位】：中國(guó)人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R446.5;R515

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