研究背景
萬古黴素（vancomycin）為一種醣肽類抗生素（glycopeptide antibiotics），自1950年代上市以後，被廣泛用於對其他抗生素不敏感的革蘭氏陽性菌所引起致命性感染，尤其是出現methicillin抗藥性的金黃色葡萄球菌（methicillin-resistant Staphylococcus aureus, MRSA）。
腸球菌（Enterococcus spp.）在過去被認為是低毒性、較不具高臨床意義的細菌，隨著醫療的進步、侵入性裝置的介入與多種抗生素的使用，腸球菌近年來已成為院內感染菌血症的重要致病菌之一。Ampicillin和萬古黴素為治療腸球菌感染的主要抗生素，然而隨著Enterococcus faecium對ampicillin產生高抗藥性，萬古黴素的使用日趨重要。在臨床實務上，萬古黴素對於菌血症的藥效動力學研究主要根據以針對MRSA為研究的文獻建議而訂定；亦有研究指出，當萬古黴素的血中濃度達到15-20 mg/L時，療效增加，腎毒性的發生率也會大幅上升。目前在國內少有針對萬古黴素在腸球菌所引起的菌血症治療的研究，因此本研究旨於使用過去接受萬古黴素治療腸球菌引起的菌血症之數據，建立萬古黴素在此類患者體內的藥物動力學模型並分析其治療結果。
研究目的
藉由分析過去病患使用萬古黴素治療的數據資料，建立相關的群體藥物動力學模型，進而瞭解治療腸球菌所引起的菌血症之藥效動力學，建立最適治療濃度建議。
研究方法
本研究為回溯性世代研究設計，收案期間為2013年1月至2017年12月，研究對象為國立成功大學醫學院附設醫院內曾接受過萬古黴素作為腸球菌引起的菌血症主要治療的病患，研究者蒐集病人住院期間的藥物濃度監測資料及菌種的最小抑菌濃度（minimum inhibitory concentration, MIC）等資料，建立萬古黴素的藥物動力學模型及分析其治療結果。
研究結果
納入藥物動力學模型的有158位病患並取得387個濃度點，年齡中位數為68.5歲，男性占62.1%，腎功能不全的病患偏多；進入臨床療效評估的有79位病患，其中有28位治療失敗，男性有65.8%，且大於65歲的老年人居多（60.8%）。
分布體積和清除率的族群平均估計值分別為48.7 L及2.15 L/hr。對vancomycin的分布體積有顯著影響的為年齡、心衰竭與腹水；影響清除率則為腎功能和腹水，收案病人的藥物半衰期中位數為16.6小時。臨床療效以CART分析結果顯示AUIC24h介於231至767有較高的治療成功率。於單變量分析中，治療失敗組別內AUIC24h超出範圍的人數顯著較治療成功組別多（66.7% vs 33.3%, P =0.04），而治療天數、波谷濃度及最小抑菌濃度在兩組中是沒有顯著差異的。利用多變量羅吉斯迴歸校正治療成功與失敗兩組有顯著差異的變數，AUIC24h <231或> 767亦為治療失敗的獨立危險因子（aOR=4.57, 95%CI=1.36-15.33, P=0.014）。79人當中，有14人發生急性腎衰竭，AUC24h的切點為810，且發生腎毒性族群的AUC24h和波谷濃度皆顯著高於未發生腎毒性的組別。
結論與建議
在腸球菌感染菌血症之族群中，除已知的腎功能和年齡外，亦須注意腹水、心衰竭等疾病對vancomycin藥物動力學的影響，當AUIC24h大於231時，治療成功率即顯著提升，相較於過去IDSA等臨床治療指引，對於腸球菌菌血症病患的治療上或許可不須將AUC調高至400，即可達到治療目的，也可降低急性腎衰竭發生的可能性。

Enterococci has become one of the most important nosocomial pathogens in recent years. Report of Taiwan Nosocomial Infection Surveillance system showed that E. faecium to be the fourth leading cause of healthcare-associated bacteremia in 2017, an increase from the eleventh in the 2008. Vancomycin plays an important role in antimicrobial therapy for multidrug resistant E. faecium. Current recommendations for vancomycin therapeutic concentration targets were AUC24h/MIC >400 hr and trough between 15-20 mg/L and based mainly on research from methicillin-resistant Staphylococcus aureus. However, studies also showed higher trough concentration levels were associated with increased risk of nephrotoxicity. The aim of our study is to establish a pharmacokinetic and pharmacodynamics model, and to analyze the clinical outcome of vancomycin against enterococcal bacteremia. A retrospective study was conducted at National Cheng Kung University Hospital. We included all adult patients who received vancomycin treatment for enterococcal bacteremia and had at least one vancomycin level after starting treatment between January 1st 2013 and December 31st 2017. This study was approved by the hospital’s Institutional Review Board. A total of 161 patients were included for pharmacokinetics model study. Age, congestive heart failure and ascites had a significant influence on volume of distribution, and creatinine clearance and ascites significantly influenced systemic clearance. For clinical analysis, 79 patients were enrolled. In the CART analysis, vancomycin AUC24h/MIC (AUIC24h) in a range (231-767) was associated with a higher treatment success rate (66.7% vs 33.3%, P = 0.04). In conclusion, our study found that pharmacodynamic target of vancomycin AUC24h/MIC between 231 and 767 was associated with successful treatment outcome, which differed from the target of 400 for MRSA infections. These findings warranted further exploration to elucidate the possibility to lower nephrotoxicity.

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