臺灣博碩士論文加值系統

毒理學與藥理學之間有相當之共同性，例如藥物對致病菌而言就是一種毒性物質。本研究將以探討兩抗生素混合效應在最小殺菌濃度之表現為目的。
1961年對methicillin抗藥性的金黃色葡萄球菌(MRSA)首次被發現後，MRSA已成為院內感染常見病源菌。因此本研究以MRSA為試驗物種，選擇9種抗生素，依其作用機制加以分類，進行一連串的混合效應試驗。觀察混合效應對MRSA的最小殺菌濃度（MBC）變化情形，探討MBC在混合效應模式的表現，並與Mtox 7 model加以分析比較，找出彼此的相關性。
本研究結果顯示，混合效應使MRSA的MBC下降4倍以上的類別，以Vancomycin—Gentamicin的機率較高，達87.5﹪，且大斜率抑制細胞壁合成和大斜率抑制蛋白質合成的混合類別，產生MBC下降4倍或以上的機率較高，有61.11﹪。利用Mtox7 Model分析比較，發現兩抗生素之間的混合效應模式為Response addition（RA），即λ=0、r = -1，可造成協同殺菌作用。

Infections due to Methicillin- resistant Staphylococcus aures (MRSA) continued to be a significant problem in the 1990s. Clinicians now have to face the emergence of strains with reduced susceptibility to vancomycin, i.e., so-called glycopeptide-intermediate Staphylococcus aures (GISA). Therefore, there is a clearly a need for new antibiotic regimens with strong early bactericidal activity against MRSA. In this field, an alternative to the development of new classes of agents could be the use of combinations of well-known compounds.
The aim of our study was to investigate the effect on MBC of different combination between disruption of cell wall biosynthesis antibiotics and inhibition protein biosynthesis antibiotics against clinical MRSA strains. Furthermore, to discuss the synergistic bactericidal effect with Mtox7 model.
From the results of the study, the probability of combination to enormously reduce MBC for Vancomycin—Gentamicin were 87.5﹪ and combination between large slope disruption of cell wall biosynthesis antibiotics and large slope inhibition protein biosynthesis antibiotic were 61.11﹪that could enormously reduce MBC. Comparison with Mtox7 model, the relationship of synergistic bactericidal effect was response addition（RA）.

目 錄
中文摘要………………………………………………………………Ⅰ
英文摘要………………………………………………………………Ⅱ
目錄……………………………………………………………………Ⅲ
表目錄…………………………………………………………….…...Ⅵ
圖目錄………………………………………………………………....Ⅶ
符號說明………………………………………………………………Ⅸ
第一章 緒論
1.1研究緣起………………………………………………………..1
1.2研究目的及重要性………………………………………….….3
第二章 文獻回顧
2.1 MRSA簡介……………………………………………………..5
2.1.1 MRSA 抗藥性之發展……………………………………..6
2.2混合毒性……………………………………………………….7
2.2.1混合毒性理論之發展…………………………………….. 7
2.2.2混合毒性指標…………………………………………….. 7
2.3抗生素之研究發展…………………………………………….8
2.3.1抗生素（Antibiotic）之定義.…………………………… 8
2.3.2抗生素化學治療之歷史…………………………………..8
2.3.3微生物的抗藥性………………………………………... .11
2.3.4抗生素的混合使用………………………………………12
第三章 基本理論
3.1毒性物質劑量-反應模式.…………………………………….17
3.2混合毒性理論….…………………………………………….. 18
3.2.1非交互作用混合毒性理論……………………………… 18
3.2.2交互作用混合毒性理論………………………………… 20
3.2.3 混合毒性效應與ρ，λ的關係………………………... 21
3.2.4混合毒性效應模式與最小殺菌濃度(MBC)之關係…….24
3.3 抗生素的分類及作用機制.…………………………………..27
3.3.1分類……………………………………………………….27
3.3.2作用機制…………………………………….……………27
3.4 抗微生物作用效力（Antimicrobial Activity）的測定……..30
3.5 抗生素混合併用效應模式之判定………………………….. 32
第四章 實驗設備與方法
4.1實驗材料與設備……………………………………………. 35
4.1.1實驗菌種及培養………………………………………….35
4.1.2 細菌培養基…………..…………………………………..35
4.1.3 實驗所使用的抗生素……………………………………36
4.1.4 實驗設備儀器……..……………………………………..37
4.2 實驗方法…………………………………………………….. .38
4.2.1 MRSA的培養…………………………………………...38
4.2.2 MRSA之抗生素試驗…………………………………...38
4.2.3 菌種MIC值之檢測…………………………………….46
4.3 實驗結果數據整理…………………………………………...46
4.3.1 Probit Model………………………………………….…46
4.3.2 Mtox7 Model……………………………………………46
第五章 結果與討論
5.1單一毒性試驗………………….…………………………….. ..47
5.2抗生素最小抑制濃度（MIC）和最小殺菌濃度（MBC）…53
5.3最小殺菌濃度（MBC）混合毒性試驗結果…………………56
5.4最小殺菌濃度（MBC）混合毒性效驗模式與Mtox7 model
之分析比較.……………………………………………………63
5.4.1 MBC混合毒性效應在Response addition（RA）
之表現……………………………………………………..63
5.4.2 MBC混合毒性效應在No addition（NA）之表現…….73
5.5 菌種MIC之檢測……………………………………………..76
第六章 結論與建議
6.1 結論……………………………………………………….…..77
6.2 建議……………………………………………………….…..78
參考文獻……………………………………………………………..79
附錄一 劑量-反應曲線之計算……………………………………...85
附錄二 抗生素之劑量-反應曲線圖（Biomass）…………………88
附錄三 以生長率的單一毒性結果計算混合毒性Model…..…… 101

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