食源性疾病 (foodborne disease) 指的食用被汙染的食物或飲水等所致的疾病，俗稱食物中毒，其中最常見的食源性病原菌為腸炎弧菌 (Vibrio parahaemolyticus)，其致病型態屬於感染型，且常見的致病因子為熱穩定溶血素 (Thermostable direct hemolysin, TDH ) 及類熱穩定溶血素 (TDH-related hemolysin, TRH)。抗生素的使用成為了預防和治療細菌性疾病的重要工具，但近期卻發現，過度的使用抗生素會造成抗藥性細菌，甚至產生多重抗藥性 (multidrug-resistant, MDR)，且生物膜的形成也可能對抗藥性產生影響。本實驗選用抗生素殘留嚴重之午仔魚作為樣品來監測臺灣市場之午仔魚中腸炎弧菌之發生、致病因子、抗藥性監測與鑑定及生物膜之生成能力。結果顯示，腸炎弧菌的發生比例為傳統市場大於食品供應商，且分離出的腸炎弧菌分離株均無檢測到具有溶血素 TDH 及 TRH 的基因表現與生化表現。針對抗敏性結果則是對兩種胺基糖苷類 (amikacin 與 gentamicin) 及青黴素類的 ampicillin 和頭孢菌素類的 cefuroxime 具有明顯的抗藥性，且對碳青黴烯類的 imipenem 與 meropenem 及青黴素類的 piperacillin、頭孢菌素類的 cefepime 和四環黴素類的 doxycycline 具有明顯的敏感性。而在所有的分離株中 MDR 腸炎弧菌分離株之菌株比例比非 MDR 腸炎弧菌分離株來的高。此外，分離株之生物膜生成能力強度較弱，且生物膜生成能力越強並無提高抗藥性的結果。最後透過蛋白質體分析結果發現，即使皆為腸炎弧菌分離株，但可能因菌株為環境分離株而造成蛋白質表現量有較大的個體差異。另外發現在兩株腸炎弧菌分離株中添加頭孢菌素類藥物時，可能會降低糖代謝途徑及核甘酸代謝。藉由本次實驗之結過，除了瞭解臺灣市場午仔魚中腸炎弧菌分離株的發生、致病、抗藥性及生物膜結果外，也提供了腸炎弧菌抗藥性分離株在抗生素存在對其蛋白體之影響。

Food-borne diseases refer to the diseases caused by ingestion of contaminated food or water. Vibrio parahaemolyticus, one of the most common food-borne pathogens, could possess virulence factors thermostable hemolysin (TDH) and thermostable hemolysin-like (TRH) and normally cause illnesses via food infection. Antibiotics have been used for the prevention and treatment of bacterial diseases, but it has recently been found that excessive use of antibiotics can lead to the development of drug-resistant bacteria. In this study, threadfins on Taiwan's markets were screened for V. parahaemolyticus isolates, and their pathogenic factors, drug resistance profiles, and biofilm formation ability were investigated. 19 V. parahaemolyticus strains were isolated from 50 threadfin samples, and the incidence of V. parahaemolyticus in the samples from traditional markets was greater than those from food processing companies; in addition, and the tdh and trh genes were not detected by using PCR among the V. parahaemolyticus isolates, which as well showed no signs of Kangawa phenomenon and urease activity. Drug susceptibility tests indicated that most V. parahaemolyticus isolates showed drug resistance against amikacin/gentamicin (aminoglycosides), penicillin (penicillins), and cefuroxime (cephalosporins) and showed drug susceptibility for piperacillin (penicillins) and imipenem/meropenem (carbapenems), cefepime (cephalosporins), and doxycycline (Tetracyclins); moreover, most drug-resistant strains were multidrug drug resistant. As for the biofilms, the V. parahaemolyticus isolates showed no, weak, or intermediate biofilm formation, ability, and no signs for the relation of biofilm-forming ability and antibiotic resistance. Intriguingly, it was observed in the proteosome analysis that drug resistant V. parahaemolyticus could exhibit different patterns of gene expression in the presence of cephalosporins, suggesting different strategies for the isolates to combat antibiotics. In this study we provided the occurrence, pathogenicity, drug resistance and biofilm results of V. parahaemolyticus isolates in threadfins on Taiwan market, and the proteomics data revealed the expression strategies of the drug-resistant V. parahaemolyticu isolates in the presence of antibiotics.

謝致 I
摘要 II
Abstract III
目錄 IV
表目錄 VI
圖目錄 VII
縮寫表 VIII
壹、 前言 1
貳、 文獻整理 3
2.1 食源性病原菌：弧菌屬 3
2.1.1 食源性病原菌之介紹 3
2.1.2 腸炎弧菌 (Vibrio parahaemolyticus) 3
2.1.3 創傷弧菌 (Vibrio vulnificus) 3
2.1.4 霍亂弧菌 (Vibrio cholerae) 4
2.2 腸炎弧菌致病因子 (V. parahaemolyticus virulence factors) 4
2.2.1 致病因子之介紹 4
2.2.2 致病因子的測定 4
2.3 抗生素 (antibiotic) 5
2.3.1 抗生素之介紹 5
2.3.2 抗生素之種類 6
2.4 抗生素抗藥性腸炎弧菌 (antibiotic resistant V. parahaemolyticus) 8
2.4.1 抗生素抗藥性細菌之介紹與產生 8
2.4.2 多重抗藥性細菌 (multidrug-resistant bacteria) 9
2.4.3 抗藥性細菌之監測方式 9
2.4.4 各國腸炎弧菌之抗藥性監測與我國現今狀況 11
2.5 水產食品傳遞鏈 12
2.5.1 食品傳遞鏈之介紹 12
2.5.2 海鮮食品 13
2.5.3 午仔魚 13
2.5.4 抗生素與午仔魚的關聯 14
2.6 生物膜 (biofilm) 15
2.6.1 生物膜之介紹 15
2.6.2 生物膜的形成 15
2.6.3 生物膜的測定 17
2.6.4 生物膜對水產加工產業及抗藥性微生物的影響 18
參、 實驗設計 20
肆、 實驗材料與方法 21
4.1 實驗材料 21
4.1.1 午仔魚樣品 21
4.1.2 標準菌株 21
4.1.3 培養基 21
4.1.4 抗生素 24
4.1.5 化學藥品 24
4.1.6 實驗儀器與耗材 25
4.2 實驗方法 26
4.2.1 菌株活化 26
4.2.2 生長曲線 26
4.2.3 樣品採樣 27
4.2.4 菌叢分析 27
4.2.5 腸炎弧菌分離及菌株保存 27
4.2.6 DNA 萃取 (DNA extraction) 27
4.2.7 腸炎弧菌分離菌株鑑定及致病基因鑑定 28
4.2.8 抗生素敏感性測試 (antibiotic susceptibility testing) 29
4.2.9 生物膜生成能力測試 29
4.2.10 致病因子生化試驗 30
4.2.11. 抗藥性細菌之蛋白質體學分析 30
4.2.12 統計分析 32
伍、 結果與討論 33
5.1 午仔魚中腸炎弧菌分離株的發生比例及午仔魚之菌叢分析 33
5.2 午仔魚中腸炎弧菌分離株之致病因子 34
5.3 午仔魚中腸炎弧菌分離株之抗生素敏感性試驗及多重抗藥性 35
5.3.1 午仔魚中腸炎弧菌分離株之抗生素敏感性試驗 35
5.3.2 午仔魚中腸炎弧菌分離株之多重抗藥性結果 37
5.4 午仔魚中腸炎弧菌分離株之生物膜生成能力試驗 37
5.5 午仔魚中抗藥性腸炎弧菌分離株之蛋白質體學分析 38
陸、 結論 44
柒、 參考文獻 45
捌、 圖表 59
玖、 附錄 77

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