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系統識別號 U0026-2208201214505200
論文名稱(中文) Quinolone非敏感性沙門氏菌之抗藥性分析
論文名稱(英文) Characterization of quinolone-non-susceptible Salmonellae isolates from an 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 100
學期 2
出版年 101
研究生(中文) 陳俊安
研究生(英文) Chun-An Chen
學號 T36991040
學位類別 碩士
語文別 中文
論文頁數 77頁
口試委員 指導教授-吳俊忠
口試委員-顏經洲
口試委員-柯文謙
口試委員-楊采菱
中文關鍵字 沙門氏菌  氟喹諾酮類  廣效性頭芽孢菌素  質體媒介之quinolone抗藥機轉 
英文關鍵字 Salmonella enterica  Fluoroquinolones  Extended spectrum cephalosporins  Plasmid-mediated quinolone resistance mechanisms 
學科別分類
中文摘要 Fluoroquinolones (FQ) 和廣效性cephalosporins (ESCs) 類抗生素常被用於治療沙門氏菌引起的相關疾病。一般而言,造成quinolone抗藥性之機制有DNA拓樸異構酶胺基酸序列置換,有時則會合併有活性輸出幫浦高度表現與外膜蛋白缺失等機制。而近年研究提出質體媒介之quinolone抗藥機制,其包含有抗quinolone蛋白 (quinolone resistance protein, Qnr)、活性輸出幫浦相關基因 (如qepA和oqxAB) 及氨基糖苷類氟喹諾酮類修飾酶 (如AAC(6’)-Ib-cr) 等。本研究之目的是為探討quinolone非敏感性沙門氏菌在南台灣之盛行率及其抗藥機制為何。從成大醫院收集1999年至2008年1416之沙門氏菌臨床菌株中,根據紙錠擴散法資料進一步篩選出對FQs、ESCs或cefoxition為非敏感性之76株菌株進行後續研究。最小抑菌濃度 (MIC) 結果顯示76株菌株中,分別有65.8%、43.4%與11.8%為對FQs、ESCs與兩者為非敏感性之菌株。根據聚合酶鏈鎖反應及核酸定序結果分別得到3株qnrS1陽性、2株qnrD陽性、1株aac(6’)-Ib-cr陽性與10株oqxAB陽性菌株。南方點墨法確認qnrS1與qnrD分別位在一個10.2 kb與4.2 kb之質體上,且qnrD和aac(6’)-Ib-cr並不位在同一個質體。進一步利用電穿孔轉型作用將帶有qnrD的質體送入DH5α中發現MIC會有12倍的提升 (MIC自0.016 提升至 0.19 μg/ml) 。 此外,以接合作用 (conjugation) 方式將帶有oqxAB之質體送入大腸桿菌C600 中發現FQ之MIC會自0.023上升至0.5 μg/ml,若將oqxAB之質體送入沙門氏菌ATCC14028標準菌株,其對ciprofloxacin之MIC由0.008 上升至 0.064 μg/ml。在35株對FQ類藥物屬於高度抗藥性之菌株中分別帶有不同GyrA之胺基酸置換型態與數目,Ser83Phe/Asp87Asn (27株)、Ser83Phe/Asp87Gly (7株)、Ser83Ser/Asp87Asp (1株) 。此外,使用活性輸出幫浦抑制劑比較前後MIC的差異發現35株對FQ類藥物屬於高度抗藥性之菌株中有8株對PAβN 抑制劑,其MIC至少會有4倍的差異。總結,本研究發現FQ非敏感性的菌株在1999年至2008年有上升的趨勢,而其中GyrA胺基酸置換對quinolone非敏感性菌株之抗藥機制中扮演著重要的角色,而質體媒介之quinolone抗藥機制在本研究中也扮演某種程度的角色。本研究是台灣第一個在沙門氏菌上發現有qnrD與oqxAB基因之存在。
英文摘要 Fluoroquinolones (FQ) and extended spectrum cephalosporins (ESCs) are commonly used antibiotics to treat salmonellosis. Generally, quinolone resistance mechanisms are associated with amino acid substitution of DNA gyrase, sometimes combining with efflux pump over expression and outer membrane proteins (OMPs) lost. Recent studies have shown that Plasmid-Mediated Quinolone Resistance (PMQR) mechanisms are involved including quinolone-resistance protein (Qnr), efflux pump-associated gene (ex. qepA, oqxAB) and aminoglycoside acetyltransferase (ex. AAC(6’)-Ib-cr). The objectives of this study were to characterize the prevalence and quinolone resistance mechanisms of quinolone-non-susceptible salmonellae in southern Taiwan. A total of 76 salmonellae isolates were collected for further analysis by the disk diffusion data that were non-susceptible to FQs, ESCs or cefoxitin from 1,416 clinical isolates in National Cheng Kung University Hospital between 1999 and 2008. The minimum inhibitory concentration (MIC) of 76 quinolone-non-susceptible isolates showed that 65.8%, 43.4% and 11.8% were non-susceptible to FQs, ESCs and both, respectively. According to PCR and nucleotide sequencing of PMQR genes revealed the presence of qnrS1, qnrD and aac(6’)-Ib-cr, oqxAB in 3, 2, 1 and 10 isolates, respectively. Southern blot analysis confirmed that qnrS1, qnrD were located in a 10.1 kb and 4.2 kb plasmid, respectively and aac(6’)-Ib-cr was not co-localized with qnrD in the same plasmid. Further, transformation of the qnrD-containing plasmid into DH5α cells conferred a 12-fold-increase in the MIC of FQs (0.016 to 0.19 μg/ml). The oqxAB-containing plasmid was transfered into E.coli C600 by conjugation increased the MIC of FQs from 0.023 to 0.5 μg/ml, whereas Salmonella ATCC14028 only increased the MIC of ciprofloxacin from 0.008 to 0.064 μg/ml. Among 35 strains with highly resistance to FQs, the amino acid sequences of GyrA showed that 35 isolates carried amino acid substitutions of Ser83Phe/Asp87Asn (27 isolates), Ser83Phe/Asp87Gly (7 isolates) and Ser83Ser/Asp87Asp (1 isolate). Moreover, comparing the MIC of FQs with efflux pump inhibitors, 8 of 35 strains with highly resistance to FQs revealed the over expression of efflux pump as 4-fold-decreased with PAβN inhibitor. In conclusion, the prevalence of FQ-non-susceptible salmonellae had increased from 1999 to 2008 and amino acid substitution of GyrA played the most important role to cause quinolone non-susceptible salmonellae in this study. However, several PMQR mechanisms were also involved in quinolone resistance. This study is the first finding of the qnrD and oqxAB genes in salmonellae isolates in Taiwan.
論文目次 目錄
中文摘要 i
英文摘要 ii
致謝 iii
目錄 iv
表目錄 ix
圖目錄 x
符號與縮寫 xi
第一章 緒論 1
1.1 沙門氏菌 1
1.1.1沙門氏菌簡介 1
1.1.2沙門氏菌之臨床重要性 1
1.1.3 台灣沙門氏菌之抗藥性現況 2
1.2 沙門氏菌血清型分型 3
1.2.1 表現型分型法 3
1.2.1.1傳統血清凝集分型法 3
1.2.2 分子分型法 3
1.2.2.1脈衝式電泳分型法 3
1.3 抗微生物製劑及抗生素 4
1.3.1 喹諾酮類抗生素 4
1.3.2 乙內醯胺類抗生素 5
1.3.2.1 廣效性頭芽孢菌素類抗生素 5
1.4 抗藥性機制 6
1.4.1 喹諾酮類藥物之抗藥性 6
1.4.1.1 DNA拓樸異構酶胺基酸序列置換 6
1.4.1.2 活性輸出幫浦高度表現 7
1.4.1.3 細胞膜之通透性改變 7
1.4.1.4 質體媒介之quinolone類藥物抗藥機制 7
1.4.1.4.1 Quinolone resistance protein 8
1.4.1.4.2 氨基糖苷類氟喹諾酮類修飾酶 8
1.4.1.4.3 Efflux pump associated gene 9
1.4.1.4.3.1 qepA 9
1.4.1.4.3.2 oqxAB 9
1.4.2 Cephalosporin類藥物之抗藥性 10
1.4.2.1 廣效性乙內醯胺酶 10
1.4.2.1.1 CTX-M 10
1.4.2.2 AmpC乙內醯胺酶 11
1.4.2.2.1 CMY 11
1.5 研究目的 12
第二章 材料與方法 13
2.1 菌株來源、培養及保存 13
2.2 抗生素感受性測試 13
2.2.1 紙錠擴散法 13
2.2.2 最小抑菌濃度 14
2.2.2.1 瓊脂稀釋法 14
2.2.2.2 E test 14
2.2.3 活性輸出幫浦抑制測試 15
2.3 廣效性乙內醯胺酶檢測 15
2.3.1 紙錠擴散確認試驗 15
2.3.2 雙紙錠協同試驗 16
2.4 DNA相關實驗操作 16
2.4.1 沙門氏菌DNA粗萃取 16
2.4.2 沙門氏菌染色體DNA萃取 16
2.4.3 沙門氏菌質體DNA之抽取 17
2.4.4 大腸桿菌質體DNA之抽取 17
2.4.5 聚合酶鏈鎖反應 17
2.4.6 洋菜膠體電泳 18
2.5 電穿孔轉型 18
2.5.1 勝任細胞製備 18
2.5.1.1 大腸桿菌勝任細胞的製備 18
2.5.1.2 沙門氏菌勝任細胞的製備 18
2.5.2 大腸桿菌電穿孔轉型 19
2.5.3 沙門氏菌電穿孔轉型 19
2.6 南方點墨雜交法 19
2.6.1 探針的製備 19
2.6.2 質體DNA之限制酶切割 20
2.6.3 DNA轉漬 20
2.6.3.1 轉漬前處理 20
2.6.3.2 DNA轉漬 20
2.6.3.3 雜交作用 21
2.6.3.4 清洗和呈色作用 21
2.7 接合實驗 21
2.8 RNA相關實驗 21
2.8.1 沙門氏菌RNA之萃取 21
2.8.2 Reverse transcriptase PCR 22
2.9 蛋白質實驗操作 23
2.9.1 沙門氏菌細胞外膜蛋白質萃取 23
2.9.2 蛋白質定量 23
2.9.3 蛋白質膠體電泳 24
2.10 沙門氏菌臨床菌株之血清型分型 24
2.10.1 脈衝式電泳法 24
2.10.2 沙門氏菌菌株之包埋 24
2.10.3 破菌與膠塊清洗 24
2.10.4 限制酶切割 25
2.10.5 脈衝式電泳分析 25
2.10.6 圖譜判讀與分析 25
第三章 結果 26
3.1 沙門氏菌流行病學之相關分析 26
3.1.1 沙門氏菌之抗生素感受性測試 26
3.1.2 沙門氏菌血清型分析 26
3.2 Quinolone類藥物非敏感性之沙門氏菌抗藥機制之探討 27
3.2.1 質體媒介之quinolone類藥物抗藥機轉 27
3.2.1.1 Qnr 27
3.2.1.1.1 qnr相關基因之PCR偵測 27
3.2.1.1.2 qnrS與qnrD質體特性分析 28
3.2.1.1.3 探討qnrD對細菌MIC提升之影響 28
3.2.1.2 Aminoglycoside acetyltransferase 29
3.2.1.2.1 Aminoglycoside acetyltransferase gene質體特性分析29
3.2.1.3 Efflux pump-assocaited gene 29
3.2.1.3.1 Efflux pump-assocaited gene之PCR偵測 29
3.2.1.3.2 oqxAB 質體特性分析 29
3.2.1.3.3 探討oqxAB對細菌MIC之影響 30
3.2.2 DNA拓樸異構酶胺基酸置換 30
3.2.3 活性輸出幫浦高度表現 31
3.2.3.1 探討acrB基因之表現量 31
3.3 Cephalosporin類藥物非敏感性之沙門氏菌抗藥機制之探討 32
3.3.1 乙內醯胺酶之特性分析 32
第四章 討論 33
4.1 台灣與全球對fluoroquinolone抗藥性沙門氏菌之盛行趨勢 33
4.2 沙門氏菌血清型與抗藥性之關係 34
4.3 沙門氏菌血清型分析 34
4.4 Fluoroquinolone非敏感性沙門氏菌與質體媒介之quinolone抗藥機制35
4.5 DNA 拓樸酶胺基酸置換 36
4.6 成大醫院沙門氏菌對quinolone抗藥機制探討 37
4.7 成大醫院沙門氏菌對廣效性cephalosporin抗藥機制探討 37
4.8 CLSI guideline對MIC判讀標準之變更 38
4.9 總結 39
第五章 參考文獻 40
第六章 Tables 49
第七章 Figures 59
第八章 Appendix 68
8.1 Classification of antibiotics and their structures in this study 68
8.2 Antibiotic, solvent and diluent used in this study 70
8.3 The qnrS plasmid map used to predict the enzyme digestion profiles in this study 71
8.4 The qnrD plasmid map used to predict the enzyme digestion profiles in this study 72
8.5 Comparison of the pros and cons of some Salmonella serotyping methods 73
8.6 CLSI criteria of antimicrobial agents used in this study 74
8.7 Chemicals and reagents 75
8.8 Culture medium and solutions 76

表目錄
Table 1. Salmonellae strains used for characterizing plasmid-mediated quinolone resistance mechanisms in this study 49
Table 2. The primers for screening quinolone or cephalosporin resistance-associated genes in this study 50
Table 3. Cephalosporin and quinolone susceptibility test among 76 salmonellae isolates from NCKUH 52
Table 4. Antimicrobial susceptibility tests for qnrD clinical isolate and transformants 53
Table 5. Antimicrobial susceptibility tests of oqxAB clinical isolate, transconjugants and transformants 54
Table 6. The correlation between the MICs and drug resistance mechanisms of the 76 salmonella clinical isolates 55

圖目錄
Figure 1. The disk diffusion methods of extended spectrum β-lactamase-producing salmonellae isolates 59
Figure 2. The distribution of Salmonellae serotypes among 76 Salmonellae isolates from 1999 to 2008 in NCKUH 60
Figure 3. The correlation among PFGE patterns, salmonellae serotypes and drug resistance patterns of 76 salmonellae isolates 61
Figure 4. The qnrS gene is present in the plasmid of clinical isolates 62
Figure 5. The qnrD gene is present in the plasmid of clinical isolates 63
Figure 6. The aac (6’)-Ib-cr gene is present in the plasmid of clinical isolates but not in qnrD transformants 64
Figure 7. Detection of the oqxA gene in clinical isolates 65
Figure 8. Detection of the oqxA gene in clinical isolates 66
Figure 9. Expression of acrB in salmonellae clinical isolates. 67
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