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系統識別號 U0026-2408201008515100
論文名稱(中文) 南台灣某醫學中心ertapenem非敏感性克雷白氏肺炎桿菌之抗藥性分析
論文名稱(英文) Characterization of Ertapenem-non-Susceptible Klebsiella pneumoniae Isolates in a University Hospital in Southern Taiwan
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 98
學期 2
出版年 99
研究生(中文) 王梨容
研究生(英文) Li-Rong Wang
學號 t3696409
學位類別 碩士
語文別 中文
論文頁數 91頁
口試委員 召集委員-吳俊忠
口試委員-柯文謙
口試委員-張長泉
指導教授-顏經洲
中文關鍵字 克雷白氏桿菌  抗藥性 
英文關鍵字 Klebsiella pneumoniae  Ertapenem 
學科別分類
中文摘要 Carbapenems (包括ertapenem, imipenem及meropenem)為治療由AmpC-或超廣效β-內醯胺酶 (extended-spectrum β-lactamase, ESBL)多重抗藥性腸內桿菌科細菌所造成感染之選擇用藥;然而對carbapenem抗藥性問題的增加也逐漸造成了對病人在治療上的威脅,但對ertapenem抗藥性之菌株有可能仍對imipenem及meropenem具敏感性。本研究乃欲探討南台灣一醫學中心對ertapenem不具敏感性 (ETP-R) K. pneumoniae分離菌株的盛行率及其特性。 研究方法以抗生素敏感性試驗進行pump inhibitors的探討、以聚合酶連鎖反應與核酸定序進行抗藥性基因及porin基因的探討、以PFGE進行基因分型探討、以SDS-PAGE進行外膜蛋白之探討。結果在血流分離菌株中對ETP-NS的盛行率由2001年的0%上升到2008年的13.6%。針對2008年82株來自不同病人且無重複性之ETP-R分離菌株進行研究,其中74株(90.2%)單獨或同時帶有ESBL酵素 (包括CTX-M- 與 SHV-type)、AmpC酵素 (DHA-1與CMY-2)以及IMP-8 metallo-β-lactamase;這些菌株也同時具有fluoroquinolone抗藥性的高盛行率 (95.1%)以及高比例 (90.2%)的plasmid-mediated quinolone resistance determinants (qnrS, qnrB and aac(6′)-Ib-cr)。以2008年18株ETP-R但對imipenem具敏感性並帶有基因變異性菌株,與2008年以前18株對imipenem不具敏感性菌株進行比較,結果所有36株菌株中除2株IPM不具敏感性菌株外均出現OmpK35及/或OmpK36的表現降低,但這兩類族群在此2種porin蛋白表現降低與基因崩解之分離菌株數上之差異並不具有意義性。協同實驗結果無法證明排出作用對carbapenem抗藥性有所影響,但可能phenylalanine-arginine-β- naphthylamide-sensitive pumps的存在參與了菌株同時對fluoroquinolones及tigecycline的抗藥性。本研究結果顯示,過去八年來對ertapenem不具敏感性K. pneumoniae菌株之盛行率有明顯的增加,而對imipenem 抗藥性的產生,除了大部分是由於產生β-lactamase以及porin表現的喪失或減少外,可能還有其他未知機轉的存在。
英文摘要 Carbapenems (ertapenem, imipenem and meropenem) are the drugs of choice for the treatment of severe infections caused by multidrug-resistant AmpC- or extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae isolates, and the emergence of carbapenem resistance is a growing threat to patients. Bacteria resistant to ertapenem may appear susceptible to imipenem and meropenem in routine susceptibility tests. This study was conducted to investigate the prevalence and characteristics of ertapenem-nonsusceptible (ETP-R) Klebsiella pneumoniae isolates at a Taiwanese hospital. Antimicrobial susceptibility testing with and without pump inhibitors, PCR and nucleotide sequencing of resistance genes and porins genes, genotyping with PFGE and SDS-PAGE of outer membrane proteins were performed. The prevalence of ertapenem nonsusceptibility among bloodstream isolates increased from 0% in 2001 to 13.6% in 2008. Eighty-two nonduplicate ETP-R isolates recovered from various specimens in 2008 were examined. Seventy-four (90.2%) isolates of them had extended-spectrum β-lactamases (CTX-M- and SHV-type), AmpC enzymes (DHA-1 and CMY-2) and IMP-8 metallo-β-lactamase alone or in combination, and a high prevalence (95.1%) of fluoroquinolone resistance accompanied by a high rate (90.2%) of plasmid-mediated quinolone resistance determinants (qnrS, qnrB and aac(6′)-Ib-cr) was observed. Eighteen ETP-R but imipenem-susceptible isolates with genetic diversity were compared with 18 imipenem-nonsusceptible isolates collected before 2008. All 36 isolates except 2 imipenem-nonsusceptible isolates showed decreased expression of OmpK35 and/or OmpK36, and there was no significant difference in the numbers of isolates with decreased expression and genetic disruptions of both porins between the two groups. Synergy experiments revealed no evidence of efflux action contributing to carbapenem resistance but suggest the existence of phenylalanine-arginine-β-naphthylamide-sensitive pumps conferring coresistance to fluoroquinolones and tigecycline. This study revealed a marked increase in the prevalence of ertapenem nonsusceptibility in K. pneumoniae over an 8-year period and suggests that imipenem resistance was mostly caused by unidentified resistance mechanisms in addition to β-lactamase production and decreased porin expression.
論文目次 中文摘要 I
英文摘要 II
誌謝 III
目錄 IV
表目錄 VI
圖目錄 VII
緒論 1
一、克雷白氏肺炎桿菌 (Klebsiella pneumoniae) 1
二、抗微生物製劑 1
三、Klebsiella pneumoniae感染治療用藥 4
A. β-內醯胺類(β-lactam) 5
B. Quinolone類 8
四、細菌的抗藥性 9
A. 抗藥性機制 10
B. 抗藥性基因之傳遞 24
C. 抗藥性的偵測 25
五、研究目的 25
材料與方法 27
一、本研究各實驗之藥品、溶液配方及儀器 27
二、菌株來源、培養與保存 27
三、菌株抗生素敏感性測試 28
四、β-Lactamase特性試驗 29
五、藥物排出系統活性之試驗 31
六、Porin表現型分析 32
七、核酸技術 34
結果 40
一、對ertapenem不具敏感性K. Pneumoniae之盛行率分析 40
二、對ertapenem不具敏感性K. pneumoniae 之藥物敏感性試驗 40
三、β-lactamases之檢測與分析 41
四、PMQRs盛行率的測定 42
五、IPM-S與IPM-NS 兩族群菌株之分析 42
A. β-lactamases特性 42
B. 菌株親源性分析 42
C. 外膜蛋白基因型與表現型之分析 43
D. EPIs之協同實驗 44
討論 45
一、K. pneumoniae抗藥性 45
二、外膜蛋白表現對抗藥性之影響 46
三、efflux pumps系統與抗藥性之關係 47
四、2010年6月CLSI guideline判讀標準更新之影響 48
結論 50
參考文獻 51
表 68
圖 77
附錄 84
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