社區感染多重抗藥性大腸桿菌與克雷伯氏肺炎桿菌菌血症：危險因子及死亡預後因子分析

Risk Factors and Clinical Outcomes of Community-Onset Bacteremia Caused by Multidrug-Resistant Escherichia coli and Klebsiella pneumoniae

曾文斌(Wen-Pin Tseng)

指導教授 ： 方啟泰

國立臺灣大學/公共衛生學院/流行病學與預防醫學研究所/碩士(2016年)

https://doi.org/10.6342/NTU201600851

摘要

前言
抗生素抗藥性的快速增加是一個嚴重的全球性公共衛生議題。院內感染多重抗藥性細菌會導致住院病人接受不適當的經驗性抗生素、較長的住院天數、更多的醫療支出與死亡率增加。近年社區感染多重抗藥性格蘭氏陰性桿菌菌血症病例數亦漸增加，但其盛行率、對臨床預後之影響以及危險因子則尚無相關研究。

目的
釐清社區感染多重抗藥性大腸桿菌與克雷伯氏肺炎桿菌菌血症之盛行率的時間趨勢與對臨床預後之影響；同時經由找出感染多重抗藥性細菌的危險因子來發展出簡單使用之預測模型，以提供臨床醫師在治療疑似社區感染格蘭氏陰性菌菌血症時經驗性抗生素選擇之參考。

材料與方法
本研究為一回溯性世代研究，分別自西元2001、2006與2011年共三年的時間於某醫院之急診收集大腸桿菌與克雷伯氏肺炎桿菌菌血症之成人病患的臨床資料。多重抗藥性的定義為對三種以上之抗生素具有抗藥性。我們分別比較多重抗藥性組與非多重抗藥性組臨床特徵與臨床結果、分析抗藥性細菌菌血症盛行率的時間趨勢、使用Cox比例風險模式來分析與30天內死亡有關之預後因子。在預測模型方面，我們以隨機分派的方式將所有病患之五分之四列入導出組(derivation set)，五分之一列入驗證組(validation set)後使用邏輯斯回歸模型來分析導出組感染多重抗藥性菌血症之獨立危險因子來建立預測模型。另外，亦利用參考變項係數之整數化給分法(Coefficient-base scoring method)來簡化預測模型以幫助臨床預測抗藥性感染。

結果
研究期間共收集1770位菌血症病患(其中大腸桿菌1243位，克雷伯氏肺炎桿菌527位)。多重抗藥性菌血症之盛行率由2001年之4.0%，增加至2006年之7.6%，至2011年為10.1% (p < 0.001)。社區感染多重抗藥性大腸桿菌與克雷伯氏肺炎桿菌菌血症之病患有較高比率發生敗血性休克(27.6% vs. 11.9%, p < 0.001)、較易接受不適當之經驗性抗生素(70.2% vs. 10.5%, p < 0.001)、較高之30天內死亡率(19.8% vs. 13.5%, p = 0.047)與較長之住院天數(19.9 ± 23.7天vs. 15.6 ± 17.1天, p = 0.042)。在非敗血性休克的病患中，多重抗藥性感染(adjusted HR, 1.92; 95% CI, 1.06-3.45)、惡性腫瘤(adjusted HR, 3.95; 95% CI, 2.74-5.71)、肝硬化(adjusted HR, 1.84; 95% CI, 1.17-2.90)、由克雷伯氏肺炎桿菌所造成之菌血症(adjusted HR, 2.10; 95% CI, 1.45-3.06)與泌尿道感染(adjusted HR, 0.47; 95% CI, 0.30-0.74)為與30天內死亡相關之獨立預後因子；在敗血性休克的病患中，惡性腫瘤(adjusted HR, 2.30; 95% CI, 1.56-3.40)與泌尿道感染(adjusted HR, 0.44; 95% CI, 0.26-0.75)為與30天內死亡相關之獨立預後因子。在預測模型方面，安養院住民(adjusted OR, 11.14; 95% CI, 5.57-22.31)、過去30天內於門診接受侵入性治療(adjusted OR, 1.86; 1.05-3.29)、過去90天內有住院病史(adjusted OR, 3.53; 95% CI, 2.30-5.42)、鬱血性心衰竭(adjusted OR, 2.87; 1.39-5.94)與腦中風(adjusted OR, 1.90; 1.10-3.28)為與多重抗藥性菌血症感染之獨立危險因子。以上述因子所建立之臨床風險分數模型來預測多重抗藥性感染，其使用者操作特徵曲線(Receiver Operating Curve; ROC curve)下面積為0.75 (95% CI, 0.70-0.80)，若臨床風險分數大或等於4分時，可以成功預測多重抗藥性感染的比例為30.0%至38.8%。

結論
社區感染多重抗藥性大腸桿菌與克雷伯氏肺炎桿菌菌血症盛行率逐年增加。對臨床的影響包括有較高比率發生敗血性休克、較易接受不適當之經驗性抗生素、較高的30天內死亡率與較長之住院天數，同時與非敗血症病患之30天內死亡率獨立相關。根據預測模型來做風險分層有助於提升病人照護與抗生素管理。

關鍵字

大腸桿菌 ； 克雷伯氏肺炎桿菌 ； 多重抗藥性 ； 危險因子 ； 預後因子 ； 社區感染 ； 菌血症

並列摘要

Background
The rapid emergence of antibiotics resistance is a major global health threat. Multidrug-resistant (MDR) organisms are associated with receiving ineffective empirical antibiotics, longer hospital stays, higher medical costs and increased mortality in hospital settings. However, the prevalence, impact on outcomes and risk factors of common MDR gram-negative organisms causing bacteremia among community patients has seldom been elucidated.

Objective
To clarify the temporal trend of prevalence and impact on outcomes of community-onset bacteremia caused by MDR Escherichia coli and Klebsiella pneumoniae and develop an easy-to-use predictive rule by identifying the risk factors to assist physicians in empirical antibiotics selection.

Methods
This retrospective cohort study enrolled all emergency department adult patients with E. coli and K. pneumoniae bacteremia in three study years: 2001, 2006, and 2011. MDR isolate was defined as resistance to at least 3 of different antimicrobial classes. Baseline demographic, clinical characteristics and treatment outcomes were compared. Temporal trend of MDR isolates were analyzed and prognostic factors associated with 30-day mortality were determined by Cox proportional hazard regression model. For prediction model, four-fifths of patients were randomly allocated to a derivation set and the others to a validation set for model training and testing. Independent risk factors determined by logistic regression model were included for model construction. A simplified coefficient-base scoring model was also established for the ease of clinical application.

Results
A total of 1770 bacteremia episodes (E. coli: 1243, K. pneumoniae: 527) were enrolled. Increasing in prevalence of MDR isolates was observed (year 2001: 4.0%, year 2006: 7.6%, year 2011: 10.1%, p < 0.001 by test for trend). Patients with community-onset bacteremia caused by MDR E. coli and K. pneumoniae were significantly higher risk of septic shock (27.6% vs. 11.9%, p < 0.001), more likely to receive inappropriate empirical antibiotics (70.2% vs. 10.5%, p < 0.001), increased 30-day mortality (19.8% vs. 13.5%, p = 0.047) and longer length of hospital stay (19.9 ± 23.7 days vs. 15.6 ± 17.1 days, p = 0.042). MDR isolates (adjusted HR, 1.92; 95% CI, 1.06-3.45), malignancy (adjusted HR, 3.95; 95% CI, 2.74-5.71), liver cirrhosis (adjusted HR, 1.84; 95% CI, 1.17-2.90), bacteremia due to K. pneumoniae (adjusted HR, 2.10; 95% CI, 1.45-3.06) and urinary tract infection (adjusted HR, 0.47; 95% CI, 0.30-0.74) are the independent prognostic factors associated with 30-day mortality in patients without septic shock. Malignancy (adjusted HR, 2.30; 95% CI, 1.56-3.40) and urinary tract infection (adjusted HR, 0.44; 95% CI, 0.26-0.75) are the independent prognostic factors associated with 30-day mortality in patients with septic shock. For prediction model, the independent risk factors of bacteremia due to MDR E. coli and K. pneumoniae identified from derivation set were nursing home residence (adjusted OR, 11.14; 95% CI, 5.57-22.31), OPD invasive procedure in the past 30 days (adjusted OR, 1.86; 1.05-3.29), prior hospitalization in the past 90 days (adjusted OR, 3.53; 95% CI, 2.30-5.42), congestive heart failure (adjusted OR, 2.87; 95% CI, 1.39-5.94) and cerebrovascular accident (adjusted OR, 1.90; 95% CI, 1.10-3.28) (CI, confidence interval). A clinical risk score was derived and the area under receiver operating characteristic(ROC) curve was 0.75 (95% CI, 0.70-0.80). The prediction model successfully identified 30.0% to 38.8% of patients with MDR infection in high clinical risk score ≥ 4 points.

Conclusions
MDR E. coli and K. pneumoniae causing community-onset bacteremia is alarming, and prevalence has been increasing over time. Impact of community-onset bacteremia caused by MDR E. coli and K. pneumoniae include higher risk of septic shock, more likely received inappropriate empirical antibiotics, increased 30-day mortality, longer hospital length of stay, and independently associated with increased 30-day mortality in patients without septic shock. Risk stratification by simple clinical decision rule is important for optimizing patient care and antibiotics stewardship.

並列關鍵字

Escherichia coli ； Klebsiella pneumoniae ； multidrug-resistant ； risk factor ； prognostic factor ； community-onset ； bacteremia

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