臺灣博碩士論文加值系統

超廣效乙內醯胺酶（extended-spectrum β-lactase，ESBL）是一種由突變基因（bla），所媒介的新一類乙內醯胺酶（β-lactamase） ，一般位於質體（plasmid）上。這些酵素可經由一個或多個氨基酸的改變，就能水解更多cephalosporin類抗生素，所以這些能製造ESBLs的細菌就可以抵抗更多抗生素，包括較新的第三代cephalosporin、penicillin以及aztreonam。ESBLs常見於克雷白氏肺炎菌（Klebsiella pneumoniae）、大腸桿菌（Escherichia coli，E. coli）等腸道菌，可水解carbapenem以外的β-lactam類抗生素，使得臨床上的治療倍受挑戰。由於ESBL的抗藥性基因一般位於質體中，故此抗藥性基因可在細菌間相互轉移、傳遞，進一步造成抗藥性的擴散。
在另一方面，ESBL類抗藥性菌株已不僅只限制於Klebsiella pneumoniae以及E. coli，在其他細菌如沙門氏菌（Salmonella enterica）、綠膿桿菌（Pseudomonas aeruginosa）、黏質沙雷氏桿菌（Serratia marcescens）等也都相當常見。大部分的革蘭氏陰性菌（Gram negative）都會產生ESBL，並對我們現今所用的大部分抗生素產生抗藥性。當細菌產生這類ESBL的酵素時，像是cefotaxime，ceftazidime以及ceftriaxone等第三代頭孢菌素(3rd generation cephalosporins)，對於細菌就無法產生抑制作用，因此也使得在現今臨床醫療上遭遇到很大的困難。
除此之外，整合子（integron）是近年來被認為繼抗藥性質體（plasmid）和轉位子（transposon）外，另一個與細菌獲得新抗藥性基因及抗藥性基因散佈有關的機制。基因卡匣（gene cassettes）上帶有抗藥基因，許多不同的抗藥性基因是位於一基因卡匣內，細菌之質體或是genomic DNA的基因序列能夠透過integron主導基因卡匣透過進行特定部位重組作用的方式嵌入或移出integron，達到基因卡匣的整合，此種特定部位重組作用造成integron 所攜帶之抗藥性基因的改變和抗藥性基因的散佈，因此integron 和基因卡匣在臨床菌株抗藥性中扮演著重要角色。
E. coli及Klebsiella pneumoniae為ESBL中常見的菌種，其盛行率在國內有越來越高的趨勢。近年來在台灣，一些革蘭氏陰性菌，都陸續出現抗藥性的問題，對於目前所使用的抗生素均已有抗藥性的產生。在本實驗中，我們將全國各主要醫學中心及北醫附設醫院所收集的ESBL檢體，利用ERIC以及REP-PCR分子指紋圖譜分型技術（molecular fingerprinting），針對E. coli及Klebsiella pneumoniae來做基因多樣性之分析鑑定。結果證實這兩種分型法可以對台灣地區之E coli以及Klebsiella pneumoniae臨床分離菌株提供良好的區分能力，在分子流行病學上比對出菌株種源相關性，進而希望能發展出一套能夠提供臨床進行快速準確的菌種鑑別的系統平台。此外，我們更針對integron來探討細菌具有哪些抗藥性基因，進而釐清細菌抗藥性之機制。

Infections caused by multidrug-resistant bacteria expressing extended -spectrum -lactamases (ESBLs) pose serious challenges to clinicians. Extended-spectrum -lactamases (ESBLs) are plasmid-mediated bacterial enzymes that confer resistance to a broad range of -lactams. Most ESBLs have evolved by genetic mutation from native -lactamases, such as TEM-1, TEM-2, and SHV-1. These parent enzymes are commonly found in Gram-negative bacteria, particularly enterobacteriaceae; they are highly active against penicillins and modestly active against early-generation cephalosporins.
The prevalence of infections caused by extended-spectrum -lactamase (ESBL)–producing Enterobacteriaceae is increasing worldwide. Because ESBL-producing strains are resistant to a wide variety of commonly used antimicrobials, their proliferation poses a serious global health concern that has complicated treatment strategies for a growing number of hospitalized patients. Although ESBLs have been reported most frequently in Escherichia coli and Klebsiella species , they have been found in other bacterial species as well, including Salmonella enterica, Pseudomonas aeruginosa, and Serratia marcescens .
Bacterial resistance to an increasing number of antimicrobial agents is a well-established problem. In recent years, a novel group of DNA elements able to incorporate antibiotic resistance genes by a site-specific recombination have been identified in Gram-negative bacteria. These elements have been termed integrons. Gene transfer into small genomes and into plasmids is via site-specific recombination. Integron act as reporters of antibiotic resistance cassettes. As such, integron-driven gene capture is likely to be an important factor in the more general process of horizontal gene transfer in the evolution of bacterial genomes.
An increase in the number of cases of ESBL has been observed over the past few years in the hospital of major medical center in Taiwan, and will be the great challenge to overcome this threatens. There are total 323 drug-resistant ESBL have collected, in which 223 clinical isolates are from the Taipei Medical University Hospital. Other 100 samples were kindly provided by Dr. P. R. Hsueh (NTU, School of Medicine) which collected from the major medical centers in Taiwan including north, central, south, and east regions. The objectives of this proposed project are (i) to investigate the molecular epidemiology of ESBL colonization and infection in the hospital, (ii) to evaluate the diffusion of integron types among clinical isolates of ESBL in Taiwan and to carry out a molecular characterization of their gene cassette arrays, (iii) to study the molecular epidemiology of ESBL antimicrobial resistance, (iv) to evaluate the contribution of integrons and efflux pump to the multiple antibiotic resistance and nosocomial spread of ESBL strains, and (v) to identify clinical and therapeutic factors contributing to the selection of multidrug-resistant ESBL in the hospital environment.

封面內頁

章節目錄 ----------------------------------------------------------------------------- i
圖表目次 ----------------------------------------------------------------------------- v
附錄目次 ----------------------------------------------------------------------------- vi
致謝 ----------------------------------------------------------------------------------- vii
縮寫表 -------------------------------------------------------------------------------- viii
中文摘要 ----------------------------------------------------------------------------- xi
英文摘要 ----------------------------------------------------------------------------- xiii

第一章 緒論 ------------------------------------------------------------------------ 1
1.1 抗生素的種類與功能 -------------------------------------------------------- 3
1.2 乙內醯胺酶的分類 ----------------------------------------------------------- 4
1.3 乙內醯胺酶的結構 ----------------------------------------------------------- 5
1.4 腸道桿菌科細菌 -------------------------------------------------------------- 5
1.4.1 大腸桿菌 ------------------------------------------------------------------ 6
1.4.2 克雷白氏肺炎桿菌 ------------------------------------------------------ 7
1.5 ESBL的緣起 ------------------------------------------------------------------- 8
1.5.1 ESBL種類 ---------------------------------------------------------------- 9
1.5.2 ESBL菌株的鑑定 ------------------------------------------------------- 9
1.5.3 表現型測試ESBLs ------------------------------------------------------- 10
1.6 以分子生物方法進行菌種鑑別 -------------------------------------------- 10
1.6.1 脈衝式膠質電泳分析 --------------------------------------------------- 11
1.6.2 RAPD ----------------------------------------------------------------------- 12
1.6.3 Repetitive element sequence-based PCR fingerprinting ------------- 13
1.6.3.1 ERIC-PCR ------------------------------------------------------------- 13
1.6.3.2 REP-PCR -------------------------------------------------------------- 14
1.7 Integron --------------------------------------------------------------------------- 14
1.7.1 Integron之構造以及基因卡匣嵌入DNA之機制 ----------------- 15
1.7.2 Integron種類及integrase之角色 ------------------------------------- 16
1.7.3 Integron與基因卡匣之表現 ------------------------------------------- 17

第二章 研究目的及實驗設計 --------------------------------------------------- 19
2.1 研究目的 ----------------------------------------------------------------------- 19
2.2 實驗設計 ----------------------------------------------------------------------- 19
2.2.1 ERIC及REP-PCR之分子定型 --------------------------------------- 19
2.2.2 Class 1 integron偵測 ---------------------------------------------------- 20

第三章 實驗材料與方法 --------------------------------------------------------- 21
3.1 實驗菌株之來源與鑑定 ----------------------------------------------------- 21
3.2 MIC檢測ESBLs之方法 ----------------------------------------------------- 21
3.3 TSB保存液及TB培養液之配法 ------------------------------------------ 22
3.3.1 TSB保存液 --------------------------------------------------------------- 22
3.3.2 TB培養液 ---------------------------------------------------------------- 22
3.4 檢體接種與培養 -------------------------------------------------------------- 22
3.5 Genomic DNA之純化 -------------------------------------------------------- 22
3.5.1.1 DNA純化之材料配方 -------------------------------------------------- 22
3.5.2 DNA純化步驟 ----------------------------------------------------------- 23
3.6 ESBL 檢體之分子分型 ------------------------------------------------------ 23
3.6.1 ERIC-PCR ----------------------------------------------------------------- 23
3.6.2.2 REP-PCR ------------------------------------------------------------------- 24
3.6.3.3 Agarose gel electrophoresis --------------------------------------------- 24
3.7 Integron-PCR Analysis --------------------------------------------------------- 25
3.8利用RsaI對integron-PCR產物進行限制切割分析---------------------- 25
3.9 各種PCR產物之電腦分析 -------------------------------------------------- 26

第四章 結果 ------------------------------------------------------------------------ 27
4.1 ESBLs genomic DNA----------------------------------------------------------- 27
4.2 ESBLs利用ERIC-PCR做分子定型之結果-------------------------------- 27
4.2.1 ERIC-PCR指紋圖譜之探討與分析 ---------------------------------- 27
4.2.2 從ERIC-PCR看E. coli之親源關係 --------------------------------- 28
4.2.3 從ERIC-PCR看K.P.之親源關係 ------------------------------------- 28
4.3 ESBLs利用REP-PCR做分子定型之結果 -------------------------------- 29
4.3.1 REP-PCR指紋圖譜之探討與分析 ----------------------------------- 29
4.3.2 從REP-PCR看E. coli之親源關係 ---------------------------------- 29
4.3.3 從REP-PCR看K.P.之親源關係 -------------------------------------- 30
4.4 ESBLs質體DNA存在class 1 Integron之比較--------------------------- 31
4.4.1 Class 1 integron於E. coli菌株中之存在情形 ---------------------- 31
4.4.2 Class 1 integron於K.P.菌株中之存在情形 ------------------------- 31
4.4.3 從Integron看ESBLs之親緣關係 ------------------------------------ 32
4.5 利用PCR-RFLP做半定序來探討integron之差異 --------------------- 33

第五章 討論 ------------------------------------------------------------------------ 35
5.1 ERIC與REP-PCR指紋圖譜多樣性之探討 ------------------------------ 35
5.2 ERIC-PCR ----------------------------------------------------------------------- 36
5.3 REP-PCR ------------------------------------------------------------------------- 37
5.4 ERIC與REP-PCR地區性之分子分型比較-------------------------------- 37
5.5 ERIC與REP-PCR分子分型之比較----------------------------------------- 38
5.6 Integron --------------------------------------------------------------------------- 40
5.6.1 Integron中所帶有之基因片匣與ESBL菌之相關性 -------------- 41
5.6.2 比對探討Integron可能含有之抗藥性基因 ------------------------- 42
5.7 Integron分類與ERIC及REP-PCR分子分型之探討 ------------------- 43

第六章 結論 ------------------------------------------------------------------------ 45

第七章 未來實驗方向與展望 --------------------------------------------------- 46
7.1建立菌種DNA指紋資料庫並完成細菌及抗藥菌株快速檢測晶片--- 46
7.2細菌抗藥性之追蹤與預測 --------------------------------------------------- 46
7.3 總結 ----------------------------------------------------------------------------- 47

第八章 參考文獻 ------------------------------------------------------------------ 48

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