臺灣博碩士論文加值系統

Synercid是一個在1999年於美國食品藥物管制局所核准，用來治療臨床上抗萬古黴素尿腸球菌的有效新藥，在台灣則尚未被核准使用於臨床上，但在2000年時有報告指出，台灣地區臨床所分離出的抗萬古黴素尿腸球菌對Synercid具極高比例的抗藥性，針對這樣的現象，我們進行了對Synecid具抗藥性的抗萬古黴素尿腸球菌的株源分析，並試著從對Synercid已知的相關抗藥基因中進行篩選，希望可以藉由臨床株源及抗藥基因的分析，找出可能的抗藥原因，以做為臨床上監控Synercid抗藥性傳播的重要參考。
我們針對1999年至2004年於台大醫院細菌室所分離出來的115株臨床尿腸球菌，三株在傳統市場鷄隻身上所分離出的尿腸球菌，一株ATCC尿腸球菌標準菌株進行研究，所有的菌株皆來自不同的臨床病人或動物，在經由分子檢驗之方式，確認所有菌株確為尿腸球菌之後，對這些菌株進行Synercid及萬古黴素這兩種藥物的最小抑菌濃度分析，並進ㄧ步對所有具萬古黴素抗藥性之尿腸球菌，以多樣性聚合酶連鎖反應進行van基因的篩選，結果皆為vanA型抗萬古黴素尿腸球菌。
隨後進行脈衝式電泳，藉由unweighted-pair-group method using arithmetic averages (UPGMA)方法，利用Gel-compar II軟體進行株源群落分析，考慮尿腸球菌株之DNA線條完全吻合或差異在6條以內者視為同一群落，本實驗以80%相似度作為群落分型之切點，共計可區分出17群的分型，以A群為主要型別。在A群中所有的菌株均為抗萬古黴素尿腸球菌，此型應為這段期間中，抗萬古黴素尿腸球菌傳遞的主要型別。在呈現100％相似度的DNA片段線條影像之菌株中，考慮收集時間及收集部門後發現，抗萬古黴素尿腸球菌及抗Synercid尿腸球菌菌株中，可能有零星的院內感染發生。三株動物菌株與臨床菌株之DNA片段線條影像比較後，分別所呈現的相似度並不高，且分屬於3種不同之型別。
另一方面，我們以聚合酶連鎖反應，對實驗菌株進行鏈陽黴素的相關抗藥基因篩檢，包括了erm(B), msr(C), vgb(A), vat(D)及vat(E)等相關基因，以評估鏈陽黴素相關抗藥基因的盛行率。共有98.3%的尿腸球菌篩選出erm(B)基因，47.1％篩出msr(C)基因，vgb(A)、vat(D)及vat(E)基因均未在任何的尿腸球菌株中被發現。利用卡方試驗(Chi-Square test)發現，抗藥基因的表現與Synercid的表現型並無顯著關連。
以上的結果說明了，在此批臨床檢體中的E. faecium對於Synercid具有一定比例的抗藥性，在抗萬古黴素尿腸球菌中，發現了抗藥菌株經由1個最主要的PFGE 群別加以擴散的現象，在萬古黴素尿腸球菌及抗Synercid尿腸球菌菌株中，可能有零星的院內感染發生，而尿腸球菌對Synercid可能的抗藥機轉仍無法在此次的研究中明確交代。

While the antibiotic streptogramin Synercid hadn’t been approved for clinical use, prevalence of resistance to Synercid was demonstrated among 51% of vancomycin-resistant Enterococcus faecium (VREF) isolates in the year 2000 in Taiwan. These observations led to essentiality of investigation of clonal relationships and the molecular determinants among these isolates.
A total of 119 E. faecium strains were subjected for study, including 115 clinical isolates from National Taiwan University Hospital between 1999 to 2004, 3 chicken isolates from traditional markets and 1 ATCC strain. Molecular identification confirmed E. faecium strains before determination of MICs against vancomycin and Synercid. Results of Multiplex PCR assay showed all VREF strains were vanA type.
Clonality analysis by PFGE under unweighted-pair-group and arithmetic averages (UPGMA) methods and Gel-compar II software was performed. Isolates having identical or similar profiles, differing by six or fewer bands were assigned to the same cluster and defined the cluster similarity cut-off as 80%. The 119 E. faecium isolates were grouped into 17 clusters, each containing 1 to 56 related isolates. Cluster A strains which was the predominant PFGE type were VREF and showed main clonality spreading during the period studied. Sparse nosocomial infections among VREF and Synercid-resiatant E. faecium (SREF) were observed. In comparison, the three animal isolates showed low similarity to clinical E. faecium isolates. PCR screening for the streptogramin resistance determinants erm(B), msr(C), vgb(A), vat(D), and vat(E) basically could not account for streptogramin resistance. The erm(B) and msr(C) were identified among 98.3% and 47.1% of test isolates whereas vgb(A) or vat(D) and vat(E) were not detected. Chi-square analysis showed erm(B) and msr(C) genes are not significantly related with Synercid phenotypes. The current results showed SREF strains are commonly identified among clinical isolates. Most of the isolates formed clusters. Only sparse nosocomial SREF and VREF disseminations were observed. The potential mechanism of Synecid resistance remains largely uncharacterized in these isolates.

總目次-i
圖目次-iii
表目次-iv
中文摘要- v
Abstract-vii
第一章 研究緣起-1
第二章 文獻探討-3
腸球菌的簡介-3
臨床的腸球菌抗生素抗藥性-4
腸球菌的臨床重要性 -9
藥物（Synercid；quinupristin-dalfopristin）簡介9
抗Synercid的抗萬古黴素尿腸球菌盛行率 11
細菌的流行病學分型-11
鏈陽黴素的抗藥性及抗藥基因-12
鏈陽黴素抗藥基因的盛行率-14
實驗設計架構-16
第三章 材料與方法-17
第一階段實驗-17
(一)菌株來源、培養及保存-17
(二)菌種確認-17
(三)以瓊脂稀釋法測MIC-20
(四)抗萬古黴素尿腸球菌株抗藥基因型之確認-21
(五)脈衝式凝膠電泳(pulsed field gel electrophoresis)-22
(六)統計學分析及判讀-25
第二階段實驗:-27
(一)鏈陽黴素相關抗藥基因之偵測-27
第四章 結果-30
菌種確認-30
以瓊脂稀釋法測定MIC-30
抗萬古黴素尿腸球菌株抗藥基因型之確認-31
PFGE電泳圖比對、分析-31
鏈陽黴素相關抗藥基因之偵測-33
基因與抗藥性關連之分析-34
第五章 討論-35
抗Synercid尿腸球菌在台灣的現況-35
抗萬古黴素尿腸球菌的確認及基因型分佈-37
脈衝式凝膠電泳分析結果討論-37
VREF的株源分佈及傳播-39
鏈陽黴素相關抗藥基因分佈與抗藥性之關聯-40
細菌的抗藥性偵測及監控-42
抗生素使用與抗藥盛行率-43
總結-43
參考文獻-74
圖目次
圖1：鏈陽黴素相關抗藥基因作用機轉簡圖-45
圖2：E. faecium菌種確認之電泳圖(列舉)-46
圖3：偵測抗萬古黴素尿腸球菌株抗藥基因型之電泳圖(列舉)-46
圖4：脈衝式電泳影像彙整圖-47
圖5：脈衝式電泳群落分型及數目關係-48
圖6：菌株收集年份分佈、數目關係圖-49
圖7：菌株群落分佈及菌株來源、數目關係圖-50
圖8：對萬古黴素具抗藥及非抗藥之尿腸球菌群落分型及菌株源、 數目關係圖-51
圖9：對Synercid具抗藥及非抗藥之尿腸球菌群落分型及菌株來源、數目關係圖-52
圖10：全部菌株基因相似度分析圖（119株）-53
圖11：對Synercid具非敏感性之尿腸球菌株基因相似度分析圖（37株）-54
圖12：對Synercid具敏感性之尿腸球菌株基因相似度分析圖（82株）-55
圖13：偵測vat(D)抗藥基因之電泳圖(列舉)-56
圖14：偵測vat(E)抗藥基因之電泳圖(列舉)-56
圖15：偵測erm(B)抗藥基因之電泳圖(列舉)-57
圖16：偵測msr(C)抗藥基因之電泳圖(列舉)-57
圖17：偵測vgb(A)抗藥基因之電泳圖(列舉)-58
圖18：尿腸球菌之生化鑑定-59

表目次
表1：實驗菌株結果總表-60
表2：萬古黴素及Synercidy抗菌敏感性試驗判標準-70
表3-1：115株臨床菌株之最小抑菌濃度分佈-70
表3-2：3株雞隻菌株之最小抑菌濃度分佈-70
表4：Msr(C)基因對不同Synercid 最小抑菌濃度之表型分佈（第一型）-71
表5：msr(C)基因對不同Synercid 最小抑菌濃度之表型分佈（第二型）-71
表6：erm(B)基因對不同Synercid 最小抑菌濃度之表型分佈（第一型）-72
表7：erm(B)基因對不同Synercid最小抑菌濃度之表型分佈（第二型）-72
表8：腸球菌對萬古黴素抗藥性的基因型及表型分佈-73

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