Extended-Spectrum-β-Lactamase-Producing Klebsiella pneumoniae Bacteremia: risk factors for mortality and clinical outcome with emphasis on antimicrobial therapy

中文摘要 目的： 評估不同抗生素對於超廣效乙內醯胺酶克雷白氏肺炎桿菌所引起之菌血症的治療結果，並辨別導致病人死亡的危險因子以供臨床治療參考。 設計： 單中心、回溯性病歷回顧分析研究 地點： 國立台灣大學醫學院附設醫院─台灣北部ㄧ家醫學中心 對象： 於西元2002年4月1日至2006年12月31日期間，感染超廣效乙內醯胺酶克雷白氏肺炎桿菌菌血症之成年病患 方法： 藉由病歷回顧的方式收集病人的基本資料與臨床相關數據。臨床資料以時間作為區分，記錄菌血症發作前、中、後病人所有的合併症、移生菌種或相關感染症、醫療處置、臨床表徵、併發症以及抗生素治療 (包含經驗療法與確切治療)等等資料，並以菌血症發作後30天的死亡率作為觀察終點，進行資料統計分析比較。統計分析包括單變數分析及多變數羅吉斯迴歸分析，尋找可能導致死亡的危險因子以及不同抗生素治療是否影響病人的預後情形。 結果： 研究期間共收入104名病人，其中99人為院內感染菌血症 (95.2%)，感染單菌種菌血症的病患有67人 (64.4%)。整體死亡率為28.8%，單菌種菌血症病患之死亡率為29.9%。分析抗生素治療的結果則發現經驗療法使用適當的抗生素治療對於死亡率具有趨於顯著的差異 (P值 0.055)，而確切治療的適當與否對於病人死亡率的影響並沒有差異 (P值0.342)。而以carbapenem與非carbapenem治療組相比較，則發現30天死亡率不具有顯著差異 (P值0.668)。然而，死亡病人與存活病人之間的比較發現其疾病嚴重程度具有顯著差異 ( APACHEⅡscore 26.6±8.3 vs. 19.8±8.5，P值0.001；Pitt bacteremia score 4.8±2.8 vs. 2.9±2.6，P值0.001)。單變數分析的結果顯示與死亡有關的因子包括有嗜中性白血球減少症 (勝算比4.73，P值0.043)、先前接受免疫抑制治療 (特別是類固醇的使用，勝算比9.20，P值0.001)、APACHEⅡscore≧17 (勝算比4.19，P值0.010)、Pitt bacteremia score≧4 (勝算比3.01，P值0.013)、可能感染來源為呼吸道 (勝算比11.38，P值0.002)、敗血性休克 (勝算比6.79，P值0.001) 以及在菌血症發作前有較長的住院時間 (P=0.024)。而多變數羅吉斯迴歸分析的結果則顯示，與病人在ESBL-KP菌血症發作後30天內死亡有關的獨立因子為敗血性休克 (勝算比11.89，P值<0.001)、可能的感染來源為呼吸道 (勝算比9.96，P值0.035)、先前使用免疫抑制治療 (勝算比9.65，P值<0.001)以及經驗療法的適當抗生素使用 (勝算比0.20，P值0.014)。單菌種菌血症病人經單變數分析所得到的結果與全部病人的分析結果相似，由多變數羅吉斯迴歸分析也顯示敗血性休克 (勝算比20.14，P值<0.001)、先前使用免疫抑制治療 (勝算比24.77，P值0.001) 以及經驗療法的適當抗生素使用 (勝算比0.09，P值0.012)等是單菌種菌血症病人死亡的獨立因子。 結論： 經驗療法使用適當抗生素治療的ESBL-KP菌血症病患有較低的死亡率，而確切治療使用的抗生素療法對於病人30天的死亡率並無顯著影響。除了治療之外，病人本身的狀況如疾病嚴重程度 (如敗血性休克) 與先前接受免疫抑制治療對病人於ESBL-KP菌血症發作後30天的死亡率也具有顯著影響。Abstract Objective: To evaluate the clinical outcome of bacteremia caused by extended-spectrum β-lactamase producing Klebsiella pneumoniae under different antibiotic regimens and to identify other risk factors for mortality. Design: A single-center, retrospective, chart-review study Setting: National Taiwan University Hospital (NTUH)─a tertiary-care university hospital in northern Taiwan Patients: All adult patients with bacteremia due to extended-spectrum β-lactamase producing Klebsiella pneumoniae between April 1, 2002 and December 31, 2006 were included. Methods: Medical records were reviewed for patient’s demographic data and clinical information. Clinical data such as underlying diseases/conditions, bacterial colonization/infection, medical interventions, clinical manifestations, comorbidities, antibiotic therapy and clinical outcome were collected according to the time before, after and at the onset of ESBL-KP bacteremia. The primary endpoint was all-cause 30 -day mortality. Univariate analysis and multivariate stepwise logistic regression analysis were used to identify the risk factors for mortality and to compare the prognosis of patients received different treatment regimens. Results: During the study period, 104 patients met criteria for inclusion and 99 (95.2%) of them were hospital-acquired bacteremia. The number of patients with monomicrobial bacteremia was 67 (64.4%). The overall 30-day mortality rate was 28.8%. Analyses of different antibiotic treatment outcomes showed that there was marginal significant difference between patients received adequate and inadequate empirical therapy (P=0.055). Whether the definite therapy was adequate or not, there was no significant influence on the mortality (P=0.342). Comparison between carbapenem and non-carbapenem treatment groups also showed no significant difference (P=0.668). There was a significant difference of the severity of illness between the mortality group and survival group (APACHEⅡscore 26.6±8.3 vs. 19.8±8.5, P<0.001; Pitt bacteremia score 4.8±2.8 vs. 2.9±2.6, P=0.001). Univariate analysis revealed that the risk factors for mortality included: neutropenia (odds ratio 4.73, P=0.043), previous immunosuppressive therapy (especially steroids, odds ratio 9.20, P=0.001), APACHEⅡ score≧17 (odds ratio 4.19, P=0.010), Pitt bacteremia score≧4 (odds ratio 3.01, P=0.013), associated site of infection as pneumonia (odds ratio11.38, P=0.002), presentation of septic shock (odds ratio 6.79, P=0.001) and longer length of hospital stay before bacteremia onset (P=0.024). Multivariate logistic regression analysis showed that septic shock (odds ratio 11.89, P<0.001), associated site of infection as pneumonia (odds ratio 9.96, P=0.035), previous immunosuppressive therapy (odds ratio 9.65, P<0.001), and adequate empirical therapy (odds ratio 0.20, P=0.014) were independent factors for all-cause 30-day mortality. Similar results were obtained from univariate and multivariate analyses of patients with monomicrobial bacteremia. Conclusions: Our study showed that adequate empirical antibiotic therapy was associated with a lower 30-day mortality for ESBL-KP bacteremia patients. Regimen of definite therapy did not show significant influence on 30-day mortality, but severity of illness at the onset of bacteremia and previous immunosuppressive therapy had a significant impact on 30-day mortality.口試委員會審定書........... ........................... i 致 謝................................................. ii 中文摘要...............................................iii Abstract...............................................v 目 錄................................................. viii 中英對照表.............................................xiv 第一章 緒論................ ............................1 第二章 文獻探討............ ............................3 2.1 細菌學................. ............................3 2.2 流行病學.......................................... 13 2.3 超廣效乙內醯胺酶克雷白氏肺炎桿菌之感染............ 14 2.4 超廣效乙內醯胺酶克雷白氏肺炎桿菌感染症之治療...... 15 2.5 超廣效乙內醯胺酶克雷白氏肺炎桿菌感染症之預後...... 21 2.6 綜論目前研究概況.................................. 24 第三章 研究目的....................................... 25 第四章 研究方法....................................... 26 4.1 研究架構.......................................... 26 4.2 研究地點與研究對象................................ 27 4.3 資料收集.......................................... 27 4.4 統計分析方法...................................... 33 第五章 研究結果....................................... 35 5.1 收案過程與病人數.................................. 35 5.2 基本資料.......................................... 35 5.3 合併症與其他易造成感染之因子...................... 36 5.4 先前抗生素使用情形................................ 37 5.5 菌血症發作時之疾病嚴重程度、臨床表徵與感染來源.... 38 5.6 抗生素治療處方.................................... 39 5.7 死亡率............................................ 40 5.8 抗生素之適當性與延遲適當治療對於死亡率的影響...... 42 5.9 Carbapenem對於ESBL-KP菌血症的治療效果............. 44 5.10 存活曲線與存活分析............................... 47 5.11 死亡之危險因子-單變數分析與羅吉斯迴歸分析........ 50 第六章 討論........................................... 58 6.1 感染ESBL-KP菌血症之危險因子....................... 58 6.2 台大醫院針對ESBL-KP菌血症之抗生素處方情形......... 59 6.3 藥物治療.......................................... 60 6.4 死亡率............................................ 62 6.5 死亡之危險因子.................................... 63 6.6 研究限制.......................................... 66 第七章 結論........................................... 69 參考文獻.............................................. 7