2018-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/679439摘要：達托黴素daptomycin對於萬古黴素抗藥性腸球菌有很好的殺菌效果，但是目前尚未被核可用於萬古黴素抗藥性腸球菌的治療。過去雖然有一些臨床研究想要探討達托黴素合併乙內醯胺類抗生素治療，是否能改善病患的預後，但是不論是在臨床預後或是微生物學預後上，都看不出合併使用的好處。理論上乙內醯胺類抗生素使用會減少萬古黴素抗藥性腸球菌的細胞膜上的正電位，因而加強達托黴素的殺菌效果，且許多的協同作用實驗都證實達托黴素和乙內醯胺類抗生素合併使用於萬古黴素抗藥性腸球菌有殺菌的協同作用。我們的假說是達托黴素能做為萬古黴素抗藥性腸球菌菌血症的有效治療抗生素，而達托黴素的治療效果會受到達托黴素劑量及合併乙內醯胺類抗生素的影響。 本研究主要分成兩大部份。第一個部份的研究包含協同作用的體外實驗及動物模型。在這部份，我們將先使用殺菌時間曲線試驗來證實在我們的菌株中也能觀察到達托黴素和乙內醯胺類抗生素合併使用於萬古黴素抗藥性腸球菌有殺菌的協同作用。接下來，我們會嘗試建立大鼠萬古黴素抗藥性腸球菌感染的心內膜炎模型，在模型建立後，我們將利用這個模型比較達托黴素單用或達托黴素和乙內醯胺類抗生素合併使用的治療效果。 第二個部份則是臨床的觀察研究。因為目前的萬古黴素抗藥性腸球菌菌血症建議使用高劑量達托黴素，因此所有的病患都會接受高劑量的達托黴素治療。在這個觀察研究中，我們的主要研究目的在於証實達托黴素和乙內醯胺類抗生素合併使用會較達托黴素單用來的有效。其次要研究目的在於探討不同的達托黴素最小抑菌濃度及不同的劑量是否會影響到達托黴素單用或達托黴素和乙內醯胺類抗生素合併使用的治療效果的差別。<br> Abstract: Daptomycin exerts bactericidal activity against vancomycin-resistant enterococci (VRE), but is not approved for the treatment of VRE bloodstream infection (BSI). Though, the few cohort studies that have evaluated the clinical or microbiological effects of daptomycin+BLA for treatment of VRE-BSI have been inconclusive. Beta-lactam antibiotics (BLAs) reduce the net positive bacterial surface charge of VRE, and thereby enhance the bactericidal effect of daptomycin. Several studies have found an in vitro synergistic effect between daptomycin and various BLAs. We hypothesize that daptomycin can be used as an effective antimicrobial agent in treating the VRE-BSI. Daptomycin dose and beta-lactam combinations would influence the outcome of daptomycin treated VRE-BSI. There will be two parts of the current study. The first part is the in vitro study and animal study part. We will confirm the synergy between daptomycin and BLA using in vitro time-kill analysis. In addition, we will establish a rat infective endocarditis (IE) model. We aim to compare the effectiveness between daptomycin +BLA and daptomycin alone in the treatment of VRE using the established rat IE model. The second part is the clinical study part. Since that the high dose daptomycin is suggested for VRE-BSI treatment, all enrolled patients will receive a high dose daptomycin. The primary aim of the current observational study in patients with VRE-BSIs was to determine whether daptomycin +BLA were more effective than daptomycin alone on patient survival when high dose daptomycin was used. The secondary aim was to determine the influence of the daptomycin minimum inhibitory concentration and daptomycin dose on the effect of daptomycin +BLA compared to daptomycin alone.達托黴素乙內醯胺類抗生素合併治療死亡率萬古黴素抗藥性腸球菌菌血症協同作用動物模型Daptomycinbeta-lactamscombination therapymortalityvancomycin-resistant enterococcibacteremiasynergistic effectanimal model