抗生素RP59500 對金黃色葡萄菌及抗methicillin 金黃色葡萄菌

Abstract

I 摘要 過去研究曾以大腸桿菌和螢光菌為實驗菌種，針對有機毒物做混合毒 性研究，依有機毒物之致毒機制以及劑量-反應曲線的斜率作為主要分類工 具，歸納出一個結論，就是當劑量-反應曲線斜率為小斜率時，傾向毒性加 強（synergism），而是大斜率時則出現拮抗作用，在本篇實驗也發現到在 不同機制抗生素混合且在小斜率下，出現協同效應大大增加。 在目前對格蘭式陽性菌對抗生素已日漸增加且是一警訊，特別是抗美 錫息林金黃色葡萄球菌(Methicillin-resistant Staphylococcus aures, MRSA)本 研究是以金黃色葡萄球菌和抗美錫息林金黃色葡萄球菌為試驗菌種，選擇 了6 種抗生素，依其對細菌抑制作用的機制將其分為4 大類，利用分類後 的結果，進行Time-kill cure 混合毒性試驗，觀察其對金黃色葡萄球菌和抗 美錫息林金黃色葡萄球菌之生長抑制情形，探討混合毒性模式之預測方法 Mtox7 模式，並與過去以混濁度法所做的有機毒物試驗結果相比較，是否 不同物種、不同毒性物質間，其預測準則之可應用性，並以Time-kill curve 方法做試驗，與平板法所得的結果相比較。 由本研究之實驗結果顯示，由兩種作用機制不同，且其劑量-反應曲線 斜率小於一的抗生素混合併用下，產生協同作用（synergism）。同時以Mtox7 模式和Time-kill curve 兩種試驗方法所做混合抗生素之試驗結果。我們也 發現預測模式Mtox7 和Time-kill curve 所得結果符合度達87.2%。這表示 由劑量反應曲線所得斜率的混合能有效預測抗生素的混合效應Time-kill curve 則可讓我們瞭解菌種實際的抑制情形。而與混濁度法的一致性，可 證明毒理學應用於藥理學之可行性。

III Over the past years, E. coli and P. phosphorium were used as laboratory bacterium to conduct mixture toxicity research of organic toxins developed to study the toxicity of organic toxicants in our group. The study was found, when toxicants have a small slope tend to act synergistically while have a large slope may produce antagonistic effect. From the results of this study, it was found that the proportion of synergism was likely to be observed high when the combination of antibiotics which were different mechanism and small dose-response curve slopes. The emergence and escalation of antimicrobial resistance in the Gram-positive cocci (including enterococci and staphylococci) has been observed, especially Methicillin- resistant Staphylococcus aures (MRSA). This research used MSSA and MRSA as the test bacterium, chose six types of antibiotic, and divided into four categories based on its bacteria-suppressing mechanism. The post-categorized results were used to proceed mixture toxicity testing of the Time-kill curve, and to observe its growth-suppression situation of the MRSA and MSSA, as well as discussing prediction method Mtox7 Model of the mixture toxicity model and to make comparison with previous test results done on organic toxic materials using turbidity method, together with checking the applicability of Time-kill curve between different objects and different toxic materials, in addition to comparing test results. From the results of the study, we were found that synergism was produced with the combination of antibiotics which were different mechanism and small dose-response curve slopes. Comparison with two different method, Mtox7 model predicted the combined effect and time-kill curve was in defining the effects of antibiotics combination in treatment, we also can get most the same result and the possibility of the same result about 87.2%. This shows that the parameter as the slope of dose-response curve is good at application on predicting the combined therapeutic effects of mixtures of antibiotics. Time-kill curve allowed us to understand the actual suppression situation of the bacterium, and was consistent with the turbidity method, able to substantiate the feasibility of applying toxicology to pharmacology.