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研究生:黃于珊
研究生(外文):Yu-ShanHuang
論文名稱:以晶片檢測陽性液態培養中結核桿菌群對 rifampin 及 isoniazid 之抗藥性
論文名稱(外文):Rapid detection of rifampin and isoniazid resistance of Mycobacterium tuberculosis complex in positive liquid cultures by an oligonucleotide array
指導教授:張長泉張長泉引用關係
指導教授(外文):Tsung-Chain Chang
學位類別:碩士
校院名稱:國立成功大學
系所名稱:醫學檢驗生物技術學系碩博士班
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:74
中文關鍵詞:結核分枝桿菌群結核病抗藥性異質抗藥性
外文關鍵詞:Mycobacterium tuberculosis complex (MTBC)Tuberculosis (TB)ResistanceHeteroresistanceRifampin (RIF)Isoniazid (INH)Mycobacteria Growth Indicator Tube (MGIT)
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結核病是由結核分枝桿菌群所引起的一種傳染性疾病,主要藉由飛沫傳染,為世界三大傳染病之一。根據世界衛生組織資料,2010年全球有八百八十萬個結核病新病例,並且有一百四十萬人死於結核病。由於抗藥性MTBC的出現,造成結核病治療更為困難,病患至少同時對第一線抗生素rifampin (RIF)和isoniazid (INH)具有抗藥性稱為多重抗藥性結核病。由於傳統的藥物感受性試驗需三週時間,若有快速檢測RIF與INH抗藥性的方法將具有其臨床應用價值。MTBC的抗藥性與數個基因的點突變有關,RIF抗藥性和rpoB基因突變有關,而INH與katG以及inhA上游基因等之突變有關。本論文利用之前已建構之寡核苷酸晶片,修改並增添部分探針,以檢測生長及抗酸性染色陽性之MGIT (Mycobacteria Growth Indicator Tube)檢體,及抗酸性染色陽性之直接檢體中MTBC之抗藥性。以多套式聚合酶連鎖反應擴增上述和抗藥性有關基因,將PCR產物與尼龍膜之探針進行雜合反應,比較野生型和突變型探針反應訊號強弱,以檢測這些基因是否突變。晶片和傳統藥物感受性試驗結果不一致時,以GenoType MTBDRplus及基因定序法進一步確認結果。檢體主要由高雄醫學大學附設中和醫院取得,在高醫1578個陽性MGIT培養檢體中,晶片及培養方法檢測到603個含有MTBC。晶片檢測RIF抗藥性之靈敏度、特異性、陽性預測值及陰性預測值分別為100%、99.8%、95%、及100%,而檢測INH抗藥性之靈敏度、特異性、陽性預測值及陰性預測值分別為84.7%、99.6%、96.8%、及98.0%。晶片檢測到2個MGIT檢體具有異質抗藥性(heteroresistance)的現象,而傳統方法並沒有檢測到。此外,400個直接檢體中,晶片及培養方法檢測到154個含有MTBC。以晶片檢測RIF抗藥性,其靈敏度、特異性、陽性預測值及陰性預測值均為100%。而晶片檢測INH 抗藥性之靈敏度、特異性、陽性預測值及陰性預測值分別為60%、100%、100%、及95.9%。其中晶片檢測到6個直接檢體具有異質抗藥性的現象,而傳統方法並未檢測到。依上述結果顯示,本研究之晶片可有效檢測陽性MGIT培養液中之MTBC及對RIF與 INH之抗藥性,該測試可在一個工作天內完成,並且有效縮短檢測藥物感受性時間。
Tuberculosis (TB) is an important infectious disease worldwide. The disease is caused by Mycobacterium tuberculosis complex (MTBC). According to the data of WHO, there were 8.8 million new cases of TB and 1.4 million people died from TB in 2010. Due to the emergence of drug-resistant MTBC, the treatment of TB is becoming more challenging. Therefore, it is necessary to develop molecular methods for rapid detection of drug resistance in MTBC. Multidrug-resistant tuberculosis (MDR-TB) is defined as TB that is resistant to the most effective first-line antibiotics rifampin (RIF) and isoniazid (INH). Antibiotic resistance in MTBC is known to be caused by point mutations in several genes, including rpoB for RIF, katG and the promoter of inhA for INH resistance. The conventional proportional methods for drug susceptibility testing normally take three weeks, resulting in the delay for TB treatment. The purpose of this study was to evaluate an oligonucleotide array to detect MTBC and its drug resistance to RIF and INH in positive Mycobacteria Growth Indicator Tube (MGIT) cultures and in clinical specimens. The method was consisted of multiplex PCR amplification of rpoB, katG and the promoter of inhA, followed by hybridization of the PCR products to oligonucleotide probes immobilized on nylon membrane. Most clinical samples were from Kaohsiung Medical University Hospital (KMUH, Kaohsiung, Taiwan). A total of 1578 positive MGIT cultures from KMUH were analyzed and 603 cultures were found to contain MTBC by both of the array and culture. For detection of RIF resistance, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the array were 100%, 99.8%, 95%, and 100%, respectively, while the corresponding values for detection of INH resistance were 84.7%, 99.6%, 96.8% and 98.0%, respectively.
The array was also used for clinical detection of RIF and INH resistance in clinical specimens. A total of 400 clinical specimens from KMUH were analyzed and 154 specimens were found to contain MTBC by both of the array and culture. For detection of RIF resistance, the sensitivity, specificity, PPV, and NPV of the array were all 100%, while the corresponding values were 60%, 100%, 100%, and 95.9%, respectively, for detection of INH resistance. Two MGIT cultures and six clinical specimens were found to contain heteroresistant MTBC, but heteroresistance was not found by culture. In conclusion, the array can effectively detect RIF and INH resistance of MTBC in positive MGIT cultures. The current method can provide results within a working day.

中文摘要 I
Abstract III
誌謝 V
目錄 VI
表目錄 IX
圖目錄 XI
緒論 1
結核菌群(Mycobacterium tuberculosis complex, MTBC) 1
結核病之流行病學 1
實驗室診斷 3
抗藥性結核菌之分子機轉 4
抗藥性之分子檢測方法 5
研究目的 6
研究架構 6
材料與方法 8
陽性MGIT培養檢體之收集 8
抗酸性染色陽性直接檢體之收集 8
陽性MGIT培養檢體之DNA萃取 8
抗酸性染色陽性直接檢體之DNA萃取 9
以定點突變(site-directed mutation)建構含特定單一核苷酸變異(SNP)之DNA片段 9
特異性探針(specific probes)設計與修改 11
內部增幅對照組(internal amplification control, IAC) DNA 12
結核菌群抗藥性寡核苷酸晶片製備 13
抗藥性基因之增幅及多重聚合酶鏈反應(multiplex PCR) 14
晶片雜合反應(array hybridization) 14
晶片判讀儀(reader)閾質(cutoff value)設定 15
晶片雜合反應之結果判讀 16
偵測極限(detection limit)之決定 16
GenoType® Mycobacterium CM 以及GenoType® MTBDRplus套組 17
分子選殖(molecular cloning)及基因定序 18
靈敏度(sensitivity)、特異性(specificity)、陽性預測值(positive predictive value, PPV)、陰性預測值(negative predictive value, NPV)以及偵測極限(detection limit)之定義 20
統計分析(statistical analysis) 21
結果 22
MTBC之檢測 22
RIF及INH之抗藥性檢測 23
晶片之偵測極限(detection limit) 25
討論 27
晶片鑑定MTBC之能力 27
晶片檢測RIF和INH之抗藥性 28
RIF抗藥性和rpoB基因之突變位置 30
INH抗藥性和katG及inhA上游基因之突變位置 30
抗藥性晶片與商業化套組比較 31
晶片對結核菌群異質抗藥性(heteroresistance)之檢測 31
結論 34
參考文獻 35
附錄一 73
結核病治療 73

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