臺灣博碩士論文加值系統

目的:
評估Enterobacter cloacae菌血症之抗生素治療、死亡率及致死危險因子，並分析發生對第三代cephalosporins具抗藥性的E. cloacae菌血症的相對危險因子。
研究設計、地點及對象:
此研究於國立台灣大學醫學院附設醫院，位於台灣北部的ㄧ家醫學中心，以翻閱病歷的方式進行單中心、回溯性世代分析研究。主要對象為滿18歲成年人，自2007年1月1日至2007年12月31日期間確定有E. cloacae菌血症之病人。
方法:
以個案紀錄表紀錄病人於紙本及電子病歷的變項，包含病人的資本資料、合併症及其他易造成感染的因子、菌血症發作前的感染及醫療處置行為、菌血症發作時相關資料收集、抗生素治療、後續感染、治療結果。本研究的觀察終點是病人於三十天內的死亡率。另外也針對具ceftazidime及cefotaxime抗藥性的E. cloacae進行危險因子分析。
統計方法包含卡方檢定（χ2 test）、無母數檢定（Mann-Whitney U Test）、T檢定（t-test）、費雪檢定（Fisher’s exact test），另外單變項及多變項分析採用線性迴歸、羅吉斯迴歸的方法。存活曲線由Kaplan-Meier method繪製，以Log-rank test比較兩組樣本間之差異。
結果:
共有168位病人感染E. cloacae菌血症，其中107位（63.7%）病人為單一菌血症感染，61位（36.3%）為多重菌血症感染。病人之平均年齡為62.5歲，男與女的比例為1.25:1.0，有89.3 % 病人為院內感染，Charslon’s comorbidity score平均為3分，病人最多的潛在疾病為心血管疾病（55.4%）、其次為癌症（48.2%），平均住院天數為38天，菌血症發作時以敗血症的臨床表現占最多，菌血症發作時的Pitt bacteremia score平均為2分。腹內感染造成之菌血症占最多（40.5%），其次為原發性菌血症（29.8%）。菌血症發作後至接受合適抗生素的時間平均為20.5小時，三十天內的死亡率為26.2%，而單一菌血症病人之三十天內的死亡率為23.4%。單一菌血症之病人與多重菌血症之病人於三十天內的死亡率無差異。
多變項分析結果顯示病人感染抗藥性E. cloacae菌血症的危險因子相對於感染非抗藥性E. cloacae包括：菌血症發作前的住院天數（OR: 1.02; 95% confidence interval ﹝CI﹞: 1.01-1.04; p=0.008）、潛在性呼吸道疾病（OR: 4.99; 95% CI: 1.65-15.18; p=0.005）、菌血症發作前14天使用過β-lactam/β-lactamase inhibitors （OR: 3.17; 95% CI: 1.31-7.71; p=0.01）、菌血症發作前14天有使用過第三代cephalosporins（OR: 18.53; 95% CI: 4.91-69.96; p<0.0001）及菌血症發作前14天有使用過第四代cephalosporins（OR: 7.96; 95% CI: 1.35-46.84; p=0.02）；單一菌血症之病人中感染抗藥性E. cloacae的危險因子有呼吸道疾病（OR: 9.71; 95% CI: 2.62-36.02; p=0.0007）、菌血症發作前72小時有中央導管置入（OR: 4.12; 95% CI: 1.19-14.29; p=0.026）及菌血症發作前14天有使用過第三代cephalospins或是第四代cephalosporins（OR: 15.13; 95% CI: 4.32-53.06; p<0.0001）。
全體病人影響三十天內死亡率之危險因子於包括：院內感染（OR: 12.64; 95% CI: 1.07-148.83; p=0.04）、Charslon’s comorbidity score較嚴重（OR: 1.18; 95% CI: 1.002-1.39; p=0.05）、Pitt bacteremia score較嚴重（OR: 1.43；95% CI: 1.22-1.69; p<0.0001）、呼吸道感染（OR: 3.98；95% CI: 1.09-14.54; p=0.04）及腹內感染（OR: 4.27；95% CI: 1.65-11.03; p=0.003）；單一菌血症之病人死亡率之顯著危險因子包括：癌症（OR: 6.21; 95% CI: 1.92-20.16; p=0.002）、菌血症發作當時的Pitt bacteremia score較嚴重（OR: 1.48; 95% CI: 1.21-1.80; p=0.0001）。而是否為抗藥性E. cloacae、抗生素起始治療之適當性、或是否延遲適當之抗生素治療皆和死亡預後沒有相關。
結論:
感染E. cloacae菌血症的病人，三十天內的死亡率和病人本身的情況（Charslon’s comorbidity score和Pitt bacteremia score）、感染源（呼吸道感染源及腹內感染源）及院內感染有關，適當性起始抗生素治療或是抗藥性菌株並不會影響病人之預後。另外，發生對ceftazidime及cefotaxime的E. cloacae菌血症與先前使用過第三代、第四代cephalosporins及β-lactam/β-lactamase inhibitors、病人本身有呼吸道疾病、及菌血症發作前的住院天數有關。
關鍵詞: Enterobacter cloacae、菌血症、危險因子、抗藥性、死亡率、適當抗生素治療。

Objectives:
The goal of this study is to evaluate the 30-day mortality of Enterobacter cloacae bacteremia and its prognosis factors. The impact of adequate therapy on clinical outcome, and risk factors of third generation cephalosporin-resistant E. cloacae bacteremia were also assessed.
Study design and study populations:
A retrospective cohort analysis was performed by charts reviewing for all adult patients hospitalized at the National Taiwan University Hospital (NTUH), a medical center in Northern Taiwan, with E. cloacae bloodstream infection between January 1, 2007 and December 31, 2007.
Research methods:
Data were collected from medical records and computerized databases and documented in the customized case report form. The data retrieved for each patient included patients’profile, underlying diseases, comorbidities and other potential risk factors for infection; previous hospitalization, previous history of E. cloacae bloodstream infection or colonization history, antibiotics exposure before bacteremia onset, clinical presentation when bacteremia onset, antibiotics regimens during treatment period, and clinical response to antibiotic treatment. The primary endpoint was 30 day all-cause mortality. Risk factors of third generation cephalosporin- resistant E. cloacae were also analysed.
The statistical methods used included: Chi-Square test, Mann-Whitney U test , T-test, Fisher’s exact test. Risk factors and clinical outcomes were examed using univariate analysis and multivariate logistic regression analysis. Survival curves shown by Kaplan-Meier method were analyzed with Log-rank test.
Results:
One hundred sixty-eight patients with E. cloacae bacteremia were enrolled in the study, 107 (63.7%) were monomicrobial infections and 61 (36.3%) were polymicrobial infections. One hundred fifty episodes (89.3%) were classified as nosocomial infections. The age of patients ranged from 21 to 89 years (median, 62.5 years). The proportion of male to female patients was approximately 1.25:1.0 (94 v.s 74). Length of stay in hospitals ranged from 1 to 2695 days (median, 37.5 days).
Charslon’s comorbidity score ranged from 0 to 11 (median, 3). The most common underlying diseases was cardiovascular diseases (93 episodes, 55.4%), neoplastic diseases (81, 48.21%), renal diseases (56, 33.3%) and GI diseases (55, 32.7%). Intra-abdominal (40.5%) site was the major source of bacteremia of the patients belonged to primary bacteremia.
Pitt bacteremia score ranged from 0 to 14 (median, 2) and the clinical presentation at bacteremia onset was sepsis in 89 episodes (53%). Time to receipt effective antibiotic therapy was from 0 to 257.75 hours (median, 20.5 hours).
The 30 day all-cause mortality rate was 26.2% (44/168) and was 23.4% (25/107) in patients with monomicrobial bacteremia. There was no significant differences about mortality between monomicrobial and polymicrobial infections.
Multivariate analysis showed that length of stay before bacteremia (odds ratio(OR), 1.02; 95% confidence interval ﹝CI﹞, 1.01-1.04; p=0.008), respiratory diseases (OR, 4.99; 95% CI, 1.65-15.18; p=0.005), previous use β-lactam/β-lactamase inhibitors (OR, 3.17; 95% CI, 1.31-7.71; p=0.01), third-generation cephalosporins (OR, 18.53; 95% CI, 4.91-69.96; p=<0.0001）or fourth–generation cephalosporins (OR, 7.96; 95% CI, 1.35-46.84; p=0.02）used prior to E. cloacae bacteremia were significantly associated with cephalosporin-resistant E. cloacae bacteremia. Among patients with monomicrobial infection, respiratory diseases (OR, 9.71; 95% CI, 2.62-36.02; p=0.0007), indwelling catheter (OR, 4.12; 95% CI, 1.19-14.29; p=0.026) or previous usage of third-generation cephalsoporins or fourth-generation cephalosporins (OR, 15.13; 95% CI, 4.32-53.06; p<0.0001) were associated with cephalosporin-resistant E. cloacae bacteremia.
Among patients with E. cloacae bacteremia, those with nosocomial infection (OR, 12.64; 95% CI, 1.07-148.83; p=0.04) or higher Charslon’s comorbidity score (OR, 1.18; 95% CI, 1.002-1.39; p=0.05) or higher Pitt bacteremia score (OR, 1.43; 95% CI, 1.22-1.69; p=<0.0001) or respiratory tract infection source (OR, 3.98; 95% CI, 1.09-14.54; p=0.04) or intra-abdominal infection source (OR, 4.27; 95% CI, 1.65-11.03; p=0.003) had an increased risk of mortality. Among monomicrobial infections, those with malignancy (OR, 6.21; 95% CI, 1.92-20.16; p=0.002) or higher Pitt bacteremia score (OR, 1.48; 95% CI, 1.21-1.80; p=0.0001) had an increased risk of mortality. Resistance of E. cloacae, adequacy of antimicrobial treatment, and delayed adequate treatment were not associated with mortality.
Conclusions:
Nosocomial infection, Charslon’s comorbidity score, Pitt bacteremia score, respiratory tract infection source and intra-abdominal infection source were found to be associated with poor prognosis by multivariate analysis in patients with E. cloacae bacteremia.
Risk factors of third-generation cephalosporin-resistant E. cloacae bacteremia were associated with length of stay before bacteremia onset, respiratory diseases, and previous use of any β-lactam/β-lactamase inhibitors, third- or fourth-generation cephalosporins.

中文摘要 I
Abstract IV
圖目錄 X
表目錄 XI
中英對照表 XIII
第一章 緒論 1
第二章 文獻回顧 3
第1節 細菌學 3
第2節 抗藥性機轉 4
第3節 流行病學相關研究 8
2. 3.1. 各地盛行率 8
2. 3.2. 台灣盛行率 9
第4節 Enterobacter spp.體外藥物敏感性試驗 10
第5節 抗生素治療 13
2. 5.1 抗生素治療選擇 13
2. 5.2 抗生素治療之適當性 14
2. 5.3 延遲抗生素治療療法 15
第6節E. cloacae菌血症的感染 15
2. 6.1 E. cloacae菌血症感染的危險因子 15
2. 6.2 Extended-spectrum cephalosporin抗藥性E. cloacae菌血症之危險因子 16
第7節 E. cloacae感染者死亡的預後因子 18
2. 7.1 死亡率 18
2. 7.2 死亡危險因子 18
第三章 研究目的 20
第四章 研究方法 21
第1節 研究架構 21
第2節 研究地點及研究對象 22
4. 2.1 收入條件： 22
4. 2.2 排除條件: 22
第3節 資料收集 23
4. 3.1 病人基本資料 23
4. 3.2 合併症及其他易造成感染之因子 23
4. 3.3 菌血症發作前的感染及醫療處置行為 24
4. 3.4 菌血症發作時相關資料收集 24
4. 3.5 抗生素治療 25
4. 3.6 後續感染 25
4. 3.7 治療結果 26
第4節 名詞定義 26
4. 4.1 院內感染 26
4. 4.2 社區型感染 26
4. 4.3 醫療照護相關感染 26
4. 4.4 免疫抑制劑 27
4. 4.5 臨床表徵 27
4. 4.6 嗜中性白血球低下 27
4. 4.7 經驗治療與確切治療 28
4. 4.8 治療之適當性 28
第5節 統計分析方法 28
第五章 研究結果 30
第1節 描述性統計 30
5. 1.1 研究設計與病人數 30
5. 1.2 病人基本資料 31
5. 1.3 病人合併症 31
5. 1.4 造成感染的潛在因子 32
5. 1.5 先前使用的抗生素 33
5. 1.6 疾病嚴重度及臨床表徵 33
5. 1.7 感染來源 33
5. 1.8 死亡率 34
5. 1.9 E. cloacae體外試驗的抗生素敏感性試驗 37
5. 1.10 抗生素的治療處方 37
5. 1.11 抗生素治療之適當性 41
5. 1.12 抗生素治療適當與否和死亡率之關係 42
5. 1.13 確切性抗生素使用種類和死亡率之關係 44
5. 1.14 延遲使用適當抗生素和死亡率之關係 45
第2節 存活分析 48
第3節 感染抗藥性E. cloacae菌血症之危險因子 54
第4節 感染E. cloacae菌血症之死亡危險因子 65
第六章 討論 76
第1節 感染E. cloacae菌血症之病人族群 76
第2節 抗生素敏感性試驗結果 76
第3節 抗生素治療之適當性 78
第4節 延遲抗生素治療與死亡率之關係 80
第5節 抗生素治療和死亡率之關係 81
第6節 感染對於ceftazidime及cefotaxime皆呈現抗藥性之危險因子 82
第7節 死亡率分析 86
第8節 死亡之危險因子 86
第9節 研究限制 88
6. 9.1 資料收集 88
6. 9.2 研究地點及病人族群 89
6. 9.3 缺乏MIC及相關資料 89
第七章 結論 90
第八章 參考資料 91


圖目錄
圖 4-1 研究流程圖 21
圖 5-1 病人數目 30
圖 5-2 全體病人之存活曲線 49
圖 5-3 多重菌種及單一菌種的存活曲線 50
圖 5-4 全體病人抗藥組及敏感組的存活曲線 50
圖 5-5 單一菌血病人抗藥組及敏感組的存活曲線 51
圖 5-6 全體病人依Pitt bacteremia score的存活曲線 51
圖 5-7 單一菌種病人依Pitt bacteremia score的存活曲線 52
圖 5-8 全體病人依敗血性休克之存活曲線 52
圖 5-9 單一菌種病人依敗血性休克之存活曲線 53
圖 5-10 共167位病人依使用適當性經驗性抗生素治療與否的存活曲線 53
圖 5-11 單一菌血病人107位使用適當性經驗性抗生素與否的存活曲線 54
圖 6-1 使用過第三代cephalosporins及第四代cephalosporins與感染抗藥性E. cloacae的關係 85


表目錄
表 2-1 誘導及stably derepressed 的E. cloacae的MIC 5
表 2-2 抗生素敏感性試驗 12
表 2-3 感染抗藥性E. cloacae的危險因子 17
表 2-4 死亡率的比較 18
表 2-5 相關研究的死亡危險因子 19
表 5-1 病人資料 34
表 5-2 抗生素敏感性試驗 37
表 5-3 臺大醫院治療E. cloacae 菌血症之經驗性抗生素使用處方 38
表 5-4 臺大醫院治療E. cloacae 菌血症之確切性抗生素使用處方 40
表 5-5 經驗性抗生素治療之適當性 41
表 5-6 抗生素治療適當與否和D7死亡率之關係 42
表 5-7 抗生素治療適當與否和D14死亡率之關係 43
表 5-8 抗生素治療適當與否和D30死亡率之關係 43
表 5-9 適當經驗性藥品第三代、第四代抗生素及carbapenems與死亡率之關係 43
表 5-10 適當確切性藥品第三代、第四代抗生素及carbapenems與死亡率之關係 44
表 5-11 確切性抗生素和D30死亡率之關係 45
表 5-12 延遲適當抗生素治療與D7死亡率之關係 47
表 5-13 全體病人及單一菌血病人延遲適當抗生素治療時間與D7死亡率之關係 47
表 5-14 延遲適當抗生素治療與D14死亡率之關係 47
表 5-15 單一菌血病人延遲適當抗生素治療時間與D14死亡率之關係 48
表 5-16 延遲適當抗生素治療與D30死亡率之關係 48
表 5-17 全體病人感染抗藥組的E. cloacae的危險因子分析（單變項分析） 56
表 5-18 全體病人感染抗藥組相對於敏感組的E. cloacae的危險因子分析 59
表 5-19 單一菌血病人感染抗藥組的E. cloacae的危險因子分析（單變項分析） 61
表 5-20 單一菌血病人感染抗藥組相對於敏感組的E. cloacae的危險因子分析 65
表 5-21 全體病人感染E. cloacae 30天內死亡率的危險因子分析 67
表 5-22 全體病人感染E. cloacae 30天內死亡率的危險因子分析 70
表 5-23 單一菌血病人感染E. cloacae 30天內死亡率的危險因子分析 72
表 5-24 單一菌血病人感染E .cloacae 30天內死亡率的的危險因子分析 75
表 6-1 抗生素敏感性測驗結果比較 77
表 6-2 抗生素治療適當與否及預後 79
表 6-3 菌血症發作前14天使用過的第三代cephalosporins及第四代cephalosporins與感染抗藥性E. cloacae的關係 84

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