發生抗藥性Enterobacter cloacae菌血症之危險因子及Enterobacter cloacae菌血症之死亡預後因子分析:著重於藥物治療效果

Risk factors of cephalosporin-resistant Enterobacter cloacae bacteremia and prognosis of patients with Enterobacter cloacae bacteremia with emphasis on antimicrobial regimen

郭立芬(Li-Fen Kuo)

指導教授 ： 張上淳

共同指導教授 ： 林淑文(Shu-Wen Lin)

國立臺灣大學/醫學院/臨床藥學研究所/碩士(2009年)

https://doi.org/10.6342/NTU.2009.00754

摘要

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。

關鍵字

菌血症 ； 危險因子 ； 抗藥性 ； 死亡率 ； 適當抗生素治療

並列摘要

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.

並列關鍵字

Enterobacter cloacae ； bacteremia ； risk factors ； resistance ； mortality ； adequate antaimicrobial therapy

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