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研究生:陳志銘
研究生(外文):Chih-Ming Chen
論文名稱:抗第三代頭孢子素大腸桿菌:菌血症的危險因子與分子流行病學研究
論文名稱(外文):Third Generation Cephalosporin-Resistant (TGCR) Escherichia coli: Molecular Epidemiology and Risk Factors for Bacteremia
指導教授:張照勤張照勤引用關係
口試委員:張伯俊盧敏吉賴志河邱乾順
口試日期:2015-07-02
學位類別:博士
校院名稱:國立中興大學
系所名稱:微生物暨公共衛生學研究所
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:143
中文關鍵詞:抗第三代頭孢子素大腸桿菌菌血症危險因子分子流行病學
外文關鍵詞:Third-generation cephalosporin-resistantEscherichia colirisk factorbacteremiamolecular epidemiology
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Escherichia coli是臨床上引起泌尿道感染及腸胃道感染最重要的致病菌,而第三代頭孢子素則為現今廣泛用來治療E. coli引起的嚴重感染。近年來E. coli對第三代頭孢子素的抗藥性快速上升,嚴重影響病人的治療及預後。本研究因此進行探討第三代頭孢子素抗藥性上升的原因及病人獲得抗第三代頭孢子素 (third generation cephalosporin resistant;TGCR) E. coli菌血症的危險因子。
本研究於2006年到2014年間,由中部某大型區域醫院收集各類靜脈注射抗生素的用量及各年血液分離TGCR E. coli比率,進行抗生素用量與抗藥性百分比相關性長期趨勢分析。為了探討獲得TGCR E. coli菌血症的危險因子,以2010年到2012年間血液培養出E. coli及其他腸道桿菌的病例進行配對病例對照研究,以TGCR E. coli為個案組,與兩個背景來源不同的對照組進行分析:分別是不具第三代頭孢子素抗藥性E. coli感染者對照組及非E. coli其他腸道桿菌感染者對照組,個案組及對照組進行年齡及性別的配對後,收集個案流行病學特徵因子進行分析,包括菌血症採集單位、當次住院是否住過加護病房、當次住院是否曾接受手術、住院天數、菌血症來源、菌血症發生90天內是否曾經分離出TGCR E. coli、侵入性導管置放情形、慢性全身性疾病、及菌血症發生前180天抗生素暴露情形。此外,為瞭解2009年TGCR E. coli增加原因,回溯收集檢體庫保存之2007到2009年血液分離對第三代頭孢子素感受度降低 (reduced susceptibility) 之菌株進行抗藥性基因、與不同基因分型法之分子流行病學研究。
研究結果顯示,從2006到2014年間,各類針劑抗生素用量與血液分離E. coli對第三代頭孢子素的抗藥性均無顯著相關。危險因子分析發現,只有呼吸器的使用與曾經有TGCR E. coli的移生或感染兩因子,在多變項因子分析後仍與TGCR E. coli菌血症有統計學上的顯著相關。在2007到2009年間,這些抗藥性E. coli主要在呼吸照護病房的病人間傳播,分子流行病學結果顯示這長期流行菌株具有相似的同源分子型別,菌株抗第三代頭孢子素的抗藥性基因主要是blaCTX-M-14及blaCMY-2,且在長期流行的過程中,可能也因此獲得了額外的抗藥基因。
根據以上研究結果,獲得TGCR E. coli菌血症最主要的危險因子是呼吸器使用與之前的TGCR E. coli移生/感染,而這些TGCR E. coli 主要在住過RCW病人間散播,此結果警示慢性照護單位的感染管制措施的落實,以及抗藥性菌株收集並進行系統性分子流行病學分析的重要性。此外,本研究中TGCR E. coli 多屬於ST68,而非國際及台灣其他區域中常見之ST131,這是否為台灣中部特有流行菌株則值得未來進一步探究。
Escherichia coli is the most common pathogen causing urinary and gastrointestinal tract infections. Third-generation cephalosporins (TGC) are widely used to treat E. coli serious infections. In recent years, the increasing resistance to TGC in E. coli seriously impacts treatment and prognosis of the infections. This study was conducted to study the causes of increasing TGC resistance of E. coli, and to identify the risk factors associated with third-generation cephalosporin resistant (TGCR) E. coli bacteremia.
From 2006 to 2014, the amount of intravenous use of antibiotics and ratio of TGCR E. coli in clinical patients were annually analyzed using a hospital database. A age- and sex- matched case-control study was conducted to identify risk factors associated with TGCR E. coli bacteremia. The case group recruited patients with TGCR E. coli bacteremia during 2010 and 2012. Two control groups respectively recruited patients with TGC susceptible E. coli bacteremia (the control group I) and with other Enterobacteriaceae bacteremia (the control group II) during the same period. The historical information of the studied individuals collected for epidemiological analysis included: wards where blood cultures were taken, history of intensive care unit stay and surgery during that hospitalization, length of hospitalization, sources of bacteremia, colonization or infection of TGCR E. coli within 90 days before bacteremia, invasive catheter implantation, chronic systemic diseases, and history of antibiotic use within 180 days before bacteremia. Furthermore, using stock blood isolates of TGCR E. coli, a molecular epidemiological study was conducted to analyze major antimicrobial resistance genes and genotypes during the period from 2007 to 2009.
The results showed that there was no significant correlation between use of specific antibiotics and ratio of TGCR E. coli from 2006 to 2014. The matched case-control study indicated that only receiving mechanical ventilation and colonized or infected with TGCR E. coli within 90 days before bacteremia were significantly associated with TGCR E. coli bacteremia. The molecular epidemiology also documented the clonal spread of TGCR E. coli in patients who had stayed in the respiratory care ward (RCW) in the hospital. The spreading TGCR E. coli strains belonged to ST68 clone, which included the PFGE clusters A and B. blaCTX-M-14 and blaCMY-2 were the predominant antimicrobial resistance genes in the outbreak strains.
The findings of study highlight the importance of implementation of nosocomial infection control strategies and systematical collection and analysis of multidrug-resistant bacteria in long-term care facilities. The TGCR E. coli strains belonged to ST68, but not ST131 that was commonly observed in other countries including Taiwan. Therefore, it is of urgent need to further study whether the ST68 clone is unique and locally transmitted in central Taiwan.
致謝 i
中文摘要 ii
Abstract iv
目錄 vi
圖目錄 viii
表目錄 ix
第一章 前言 1
第一節 大腸桿菌簡介 1
第二節 抗第三代頭孢子素的大腸桿菌之流行病學 13
第三節 第三代頭孢子素的抗藥機轉 16
第四節 第三代頭孢子素抗藥性及抗藥性基因之偵測 27
第五節 獲得抗第三代頭孢子素之大腸桿菌菌血症之危險因子 29
第六節 抗生素使用史對大腸桿菌抗藥性生成之影響 30
第七節 研究目的 31
第二章 材料與方法 33
第一節 研究樣本及資料來源 33
第二節 血液分離大腸桿菌對第三代頭孢子素之抗藥性趨勢 35
第三節 抗生素耗用情形 36
第四節 獲得抗第三代頭孢子素大腸桿菌菌血症之危險因子 36
第五節 抗第三代頭孢子素之大腸桿菌菌株收集 37
第六節 大腸桿菌抗第三代頭孢子素之抗藥性及抗藥性基因偵測 38
第七節 抗第三代頭孢子素大腸桿菌的基因分型 40
第八節 統計學檢定分析 44
第九節 研究材料 45
第三章 結果 46
第一節 血液分離大腸桿菌之第三代頭孢子素抗藥性趨勢 46
第二節 抗生素耗用情形 46
第三節 以配對病例對照研究法進行抗第三代頭孢子素大腸桿菌菌血症之危險因子分析 47
第四節 抗第三代頭孢子素大腸桿菌菌株分子流行病學研究 51
第五節 感染管制措施及成效 53
第四章 討論 55
第一節 大腸桿菌對第三代頭孢子素的抗藥性趨勢 55
第二節 抗生素耗用量 56
第三節 抗第三代頭孢子素大腸桿菌菌血症之危險因子 57
第四節 抗第三代頭孢子素大腸桿菌的分子流行病學 64
第五節 感染管制措施及成效 68
第六節 研究限制 69
第五章 結論 72
參考文獻 74
圖 110
表 117
附錄 139
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