臺灣博碩士論文加值系統

研究背景
不動桿菌屬 (Acinetobacter species) 是一廣泛存在於土壤及水中的革蘭氏陰性菌，亦存在於人體的皮膚、黏膜及分泌物中，為近年來造成院內感染之重要病原菌，以 A. baumannii、A. nosocomialis、A. pitti 三菌種與臨床感染最密切相關，其中又以 A. baumannii 與 A. nosocomialis 所占臨床感染比例最高。不動桿菌可長時間在環境中存活之特性為導致院內群聚感染的重要原因之一，並經常在重症及免疫功能不足的病患身上造成感染，不僅使病患臨床症狀加劇、住院時間增長，亦會造成病患死亡風險上升。
菌血症 (bloodstream infection) 以及肺炎為不動桿菌臨床上最常見之表現，其次為導管相關之菌血症 (catheter-related blood stream infection)，前者已被廣泛討論，然而，目前尚未有進一步研究探討導管相關之不動桿菌菌血症其臨床預後與相關結果。

研究目的
本研究欲闡明導管相關之不動桿菌菌血症病患其存活預後之相關影響因子，以及移除導管與否與病患預後之關係。並深入分析該菌引起之各類感染的危險因子、症狀、抗藥性、細菌學特性、生物膜之形成分佈、各類導管之治療結果與預後評估等，用以預測導管相關之不動桿菌菌血症病患之病情，提供該類病患之適當治療建議與感染控制。

研究方法
本試驗自2012年起，由三軍總醫院、台北馬偕醫院、台北榮民總醫院、彰化基督教醫院、國防醫學院及國家衛生研究院共同建立之不動桿菌菌血症多中心線上資料庫所實行，為一多中心回溯型研究 (multicentric retrospective study)。納入自2012至2014年，二十歲以上感染導管相關之不動桿菌菌血症病患，臨床資料由醫師記錄，研究人員不介入病人診斷與治療。使用multiplex PCR 確認其菌種，利用 pulsed-field gel electrophoresis 分型。使用瓊脂稀釋法確認最小抑菌濃度。使用 SPSS 22.0軟體進行統計分析處理：類別變項使用 Pearson chi-square 或 Fisher’s exact test分析；連續變項使用 two-sample t-test或 Mann-Whitney U test分析；死亡相關危險因子使用 Logistic regression 進行單變項及多變項分析；使用配對病例對照分析方法，探討移除導管與否與病患預後之相關；使用 Kaplan-Meier curve 與 log-rank test 進行病患存活之預後分析。本研究分析之結果以雙尾檢定 p 值小於0.05訂為達統計上顯著意義。

研究結果
本研究研究期間共有874位個案接受評估，共納入119位導管相關之不動桿菌菌血症病患。其中以感染 A. nosocomialis 者佔最大宗為51.3%，其次為 A. baumannii 佔41.2%、A. pittii 佔6.7%、A. soli 佔0.8%。A. baumannii 產生抗藥性之情形最為嚴重。病患感染各菌株之30天存活率以 A. baumannii 最差 (40.8%)、A. nosocomialis (32.8%) 次之，其餘菌株則為11.1% (p = 0.119)。
使用中央靜脈導管 (central venous catheters) 之病患，其14天 (35.4% vs. 6.9%, p < 0.001) 及 30天死亡率 (45.6% vs. 12.5%, p < 0.001) 之預後皆較使用內植式輸液導管 (port catheters) 顯著來的差。導管相關之不動桿菌菌血症病患其生物膜之形成以 A. nosocomialis 所佔之比例較 A. baumannii 為高；形成生物膜之病患其14天 (21.6% vs. 47.6%, p = 0.016) 及30天死亡率 (33.4% vs. 57.1%, p = 0.022)，皆較未形成生物膜之病患顯著來的低。於使用中央靜脈導管之病患，其14天 (21.6% vs. 47.6%, p = 0.016) 及30天死亡率 (33.4% vs. 57.1%, p = 0.022) 亦有類似之情形。
本分析結果發現：疾病嚴重程度較高 (Acute Physiologic and Chronic Health Evaluation, APACHE II scores, odds ratio [OR] = 1.12; 95% confidence interval [CI]: 1.02-1.23)、住院時間較長 (OR = 1.04; 95% CI: 1.00-1.08) 及有休克 (shock, OR = 6.43; 95% CI: 1.28-32.33) 之病患，其30天死亡率之風險為顯著較高。然而，於導管相關菌血症發生48小時內移除其導管與否，與病患死亡之風險並未有統計上顯著關係。

結論
於本研究119位導管相關之不動桿菌菌血症病患中，以感染 A. nosocomialis 者佔最多，其次為 A. baumannii。A. baumannii 產生抗藥性之情形最為嚴重，病患感染該菌株之30天存活率亦最差。A. nosocomialis 產生生物膜之比例最多，死亡風險較低。使用中央靜脈導管之病患其及預後較使用內植式輸液導管顯著來的差。導管相關菌血症發生48小時內移除其導管與否，與本研究族群之病患死亡風險並未有統計上顯著關係。感染導管相關之不動桿菌菌血症之病患，其疾病嚴重程度較高、住院時間較長及休克等因素為增加該族群之亡風險之重要因子。以上研究發現仍建議未來以完整之前瞻性研究 (prospective study)，詳細證明其因果時序性及確立完備之因果關係。

Background
Acinetobacter species are strictly aerobic, gram-negative, non-fermenting, oxidase-negative, catalase-positive, and non-motile coccobacilli, which have been increasingly reported as being associated with nosocomial infections. Acinetobacter spp. infections not only prolong the length of hospital stays but also results in high attributable mortality.
Previous reports primarily focused on deaths from bacteremia and pneumonia; therefore, the risk of mortality from catheter-related bloodstream infections (CRBSIs) caused by Acinetobacter spp. remains obscure. The prevalence of CRBSIs caused by Acinetobacter spp. is increasing. The management of intravascular catheters in patients with bloodstream infections is affected by several factors, including the characteristics of the causative pathogens. However, because there have been limited studies elucidating the risk of mortality for CRBSIs caused by Acinetobacter spp., the outcome of patient health with early catheter removal in CRBSIs caused by Acinetobacter spp. remains unclear.

Objectives
Our study aimed to delineate the epidemiology and microbiological characteristics of bacteremia caused by Acinetobacter spp. These include risk factors, clinical and microbiological characteristics, antimicrobial resistances, formation of biofilm, treatment modality, and outcomes in multi-center setting. Second, to examine the risk of mortality and the effect of early catheter removal on survival of patients with CRBSIs caused by Acinetobacter spp.

Materials and Methods
This retrospective study was conducted at multiple centers in Taiwan including (alphabetically) Changhua Christian Hospital, Mackay Memorial Hospital, National Defense Medical Center, National Health Research Institute, Taichung Veterans General Hospital, Taipei Veterans General Hospital, and Tri-Service General Hospital from 2012-2014. Patients with at least one positive blood culture and one positive catheter culture for the same Acinetobacter spp. and who showed symptoms and signs of CRBSIs were included (n = 119). Risk factors for 30-day mortality were analyzed using a logistic regression model. The characteristics of patients with early catheter removal (within 48 hours after CRBSI diagnosis) were compared with those without catheter removal matching for age, sex, and disease severity.

Results
In this study, A. nosocomialis (51.3%) was found to be predominant, followed by A. baumannii (41.2%), A. pittii (6.7%) and A. soli (0.8%). A. baumannii was more resistant than the other species to most of the antimicrobial agents resulting in a higher multi-drug resistance rate. The 30-day mortality rate was highest in A. baumannii, followed by A. nosocomialis and the other Acinetobacter spp. (40.8%, 32.8%, 11.1%, respectively, p = 0.119).
The 14-day mortality (35.4% vs. 6.9%, p < 0.001) and 30-day mortality (45.6% vs. 12.5%, p < 0.001) rates were significantly higher in CRBSI patients with CVCs (central venous catheters) than those with port or other catheter types. The 14-day mortality rate of CRBSI patients was significantly lower in patients infected with biofilm-forming isolates than in the patients infected with the biofilm-negative isolates (16.4% vs. 34.5%, p = 0.019). The proportion of A. baumannii was higher in the group of biofilm-negative CRBSI patients than in the biofilm-positive patients, while the proportion of A. nosocomialis was higher in the group of biofilm-positive CRBSI patients than in the biofilm-negative patients. The 14-day (21.6% vs. 47.6%, p = 0.016) and 30-day (33.4% vs. 57.1%, p = 0.022) mortality rates were significantly lower in the CRBSI patients with CVCs infected with biofilm-positive isolates than the patients infected with biofilm-negative isolates.
There were no significant differences in 30-day mortality with regard to causative Acinetobacter spp., catheter type, catheter site, or appropriateness of antimicrobial therapy. Patients with higher Acute Physiologic and Chronic Health Evaluation APACHE II scores (odds ratio [OR] = 1.12; 95% confidence interval [CI]: 1.02-1.23), shock (OR = 6.43; 95% CI: 1.28-32.33), and longer hospitalization before CRBSI (OR = 1.04; 95% CI: 1.00-1.08) had a significantly higher 30-day mortality rate. Early removal of catheters after CRBSI diagnosis was not associated with better survival outcomes.

Conclusion
Higher disease severity, shock, and longer hospitalization before bacteremia were independently associated with a higher 30-day patient mortality rate in CRBSIs caused by Acinetobacter spp. The current results do not find that early removal of catheters improved survival outcome. Further well-controlled prospective studies are needed to clarify the outcomes of infections caused by Acinetobacter spp.

Table of Contents I
List of Examples IV
List of Tables V
List of Figures VIII
摘要 1
Abstract 4
Section I. 不動桿菌菌血症多中心線上資料庫之建立與構思 7
第一章、不動桿菌菌血症多中心線上資料庫之背景與介紹 8
第二章、不動桿菌菌血症多中心線上資料庫之變項定義 11
第一節、基本資料各變項之定義 12
第二節、菌血症菌株基本變項之定義 15
第三節、Charlson score 變項註記之定義 18
第四節、病患住院期間 Procedure I and II 之定義 21
第五節、菌株藥物敏感性之變項定義 24
第六節、其他相關感染之變項定義 26
第七節、病患使用抗生素藥物註記之定義 29
第八節、APACHE II score 變項註記之定義 32
第九節、SOFA score 變項註記之定義 39
第三章、不動桿菌菌血症多中心線上資料庫之研究方向 43

Section II. 不動桿菌菌血症多中心線上資料庫之應用與分析：
Clinical characteristics and risk of mortality of catheter-related bloodstream infections caused by Acinetobacter species: A multi-center study 46
Chapter 1. Introduction 47
1-1. Microbiology and epidemiology of Acinetobacter species 48
1-2. Epidemiology of Acinetobacter species 48
1-3. Bloodstream and catheter-related infections of Acinetobacter species 50
1-4. Biofilm formation of Acinetobacter species 51
1-5. Catheters: Central venous catheters and port catheters 52
1-6. Purpose of the Study 54
Chapter 2. Material and Methods 55
2-1. Study population and data collection 56
2-2. Definitions of variables 56
2-3. Species identification 59
2-4. Antimicrobial susceptibilities 60
2-5. Biofilm formation 60
2-6. Matched case-control study 62
2-7. Statistical methods 62
2-8. Study flow-chart 63
Chapter 3. Results 64
3-1. Distribution of the Acinetobacter species in CRBSI patients 65
3-2. Analysis of the 14-day mortality in CRBSI patients 70
3-3. Analysis of the 30-day mortality in CRBSI patients 76
3-4. Impact of the removal or retention of catheters in CRBSI patients 84
3-5. Analysis of patients with central venous catheters 94
3-6. Biofilm distribution in the patients of CRBSIs 101
Chapter 4. Discussion 106
4-1. Species distribution in patients with CRBSIs 107
4-2. Risk factors of mortality in patients with CRBSIs 107
4-3. Correlation between the removal of catheters and prognosis 108
4-4. Character of biofilm formation in CRBSI patients 110
Chapter 5. Conclusion 112
Chapter 6. References 114
Appendix 121

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