背景
腸球菌（Enterococcus spp.）隨著抗生素廣泛使用、侵入性裝置的介入，近年來已成為院內感染的主要致病菌之一，其中以Enterococcus faecalis和Enterococcus faecium最為常見。根據2017年衛生福利部疾病管制署統計，自2010年開始，腸球菌在院內引發的感染症，以血流感染最多，占40%。近年E. faecium的抗藥性逐漸升高，根據成大醫院感染管制中心統計，2019年1-6月E. faecium對vancomycin的抗藥性比率已高達五成以上，具抗藥基因之病患有較高的死亡率，因此及時給予適當的抗生素治療成為日趨重要的議題。目前文獻多排除院外感染及免疫低下的病人，血流感染之適當抗生素治療的時間切點，對於這群患者仍有待研究確認。

目的
本研究目的將分析腸球菌血流感染病人接受適當抗生素治療的時間切點與30天死亡率之相關性；並探討腸球菌血流感染之病人，若是延遲適當的抗生素治療，對於後續治療成效的影響。

方法
本研究為單中心回溯性世代研究，以病歷回顧方式納入2014年10月1日至2019年5月31日於成大醫院採檢為腸球菌血流感染之病人。採檢時為年齡20歲以上並接受適當抗生素治療的住院病人，若多次腸球菌血流感染事件，則只納入第一次為指標日期。排除轉院來已在其他醫院記錄腸球菌血流感染、HIV患者、指標日期前已接受適當抗生素治療、或30天內失去追蹤者等，且根據病人臨床特徵區分為院內感染型（指入院48小時後發生腸球菌血流感染之患者）及社區型感染（指入院48小時內發生腸球菌血流感染之患者；包含社區醫療機構相關感染及社區感染）；絕對嗜中性白血球低下（absolute neutrophil count<500 cells/µL）；接受腎臟替代治療；多重菌種感染等。指標時間（index time）為血液培養呈腸球菌陽性的採檢時間，接受適當抗生素治療時間定義為自指標時間至病人使用到細菌培養藥敏試驗中，具感受性的藥物。同時使用Charlson comorbidity index評估共病症，感染嚴重度會根據Pitt bacteremia score、SOFA score評估。本研究分析方式採用分類和回歸樹（classification and regression tree, CART）分析確立適當治療的時間切點，以及使用ROC曲線呈現30天死亡率與時間切點之預測性。多變量分析則利用羅吉斯迴歸模型（logistic regression model）分析延遲治療對30天死亡率和延遲治療預測因子的獨立關聯。

結果
本研究共納入673位病人，其中211位病人於指標日期30天內發生死亡，30天死亡率為31.4%。結果發現指標日期30天內死亡的病人，其平均接受適當抗生素治療的時間明顯晚於存活者（死亡組 vs 存活組： 54.7小時；37.5小時）p值<0.0001。由CART分析與30天死亡率的時間切點為26.1小時，並使用ROC曲線證實CART之預測數值。26.1小時前接受適當抗生素的病人分為及早治療組，而26.1小時以後接受適當抗生素的病人則為延遲治療組。及早治療組與延遲治療組分別為258人、415人。在羅吉斯多因子迴歸分析中，具萬古黴素抗藥性在校正可能的干擾因素後，aOR為5.67（95% CI, 3.02-10.64）。延遲治療≥26.1小時相對及早治療組有兩倍左右的死亡風險（aOR, 1.92 [95% CI, 1.22-3.01]），及早治療組與延遲治療組30天死亡率分別為17.8%與39.8%，p值<0.0001。透過CART次族群分析發現在不同程度的疾病嚴重度下，與30天死亡率最相關之時間切點會隨之變化，較輕症的病人（如： 社區醫療機構相關感染或社區感染）可以延長至48小時以上，而疾病嚴重度高者（SOFA分數≥13）接受適當治療的時間段縮短，需在6至12小時內接受適當抗生素治療，且有更高的死亡率。VRE血流感染、免疫不全的病人同樣須及早接受適當治療。在敏感性與次族群分析中，研究結果的方向性與主要結果相同。 

結論
對於患有腸球菌血流感染的患者，在開始的26小時內接受適當的治療可降低死亡率。感染症嚴重程度較高的病人，更突顯及時接受適當抗生素治療的重要性。嚴重程度較輕微，如：社區感染和免疫正常患者，由於死亡風險相對較低，可以忍受更長的時間才接受適當的治療。造成延遲治療的重要因素為抗藥性菌株的出現，尤其為VRE菌株。

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