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Title: | 經驗性抗生素治療與抗菌譜對於敗血症患者的影響 Empiric antibiotic treatment based on hospital cumulative antibiograms in sepsis patients |
Authors: | 張家銘 Chia-Ming Chang |
Advisor: | 陳保中 Pau-Chung Chen |
Keyword: | 抗菌譜,菌血症,經驗性抗生素治療,急診,敗血症,血液培養,總基因體次世代定序, Antibiogram,Bacteremia,Empiric antibiotic treatment,Emergency department,Sepsis,Blood culture,Metagenomic next-generation sequencing, |
Publication Year : | 2023 |
Degree: | 博士 |
Abstract: | 研究背景:
敗血症(Sepsis)係因感染症引起之系統性失調的免疫反應,若未即時介入處置,將造成不良預後,尤其在高齡、糖尿病、肝臟疾病、腎臟疾病或惡性腫瘤等患者,更有增加敗血症死亡率之跡象,能正確識別敗血症並治療之,是臨床醫師刻正面臨之難題。美國重症醫學會及歐洲加護醫學會於2016年聯合發表敗血症(Sepsis-3)定義,取代既往使用之標準,因此對於符合Sepsis-3的定義族群,仍有待進行深入之研究和探討,敗血症研究也在世界各地,正如火如荼的進行。首先,以診斷而言,及早發現,避免疾病進入不可收拾之狀態,目前的研究也著重於開發、挖掘新興生物標誌(biomarker),進而發展臨床相關即時檢測之工具,另一方面,針對治療,像是過往早期目標導向治療(early goal-directed therapy),乃至於倡立盡速施以抗生素治療,無一不透露「時間」在敗血症有著舉足輕重、甚而扭轉病程的角色。有鑑於敗血症之嚴重性,且感染症又為急診病患之大宗,在急診盡早識別敗血症,依據不同病患族群,預測不同預後,給予適切處置,方能維繫敗血症病患的生命之鏈。承續前人研究成果,本研究將著重於探討影響急診敗血症病患之預後因子,利用新興的檢測方法,俾利後續建構預測模型及臨床治療改善敗血症病人預後。 研究目的: 本研究旨在探討急診敗血症病患不良預後因子,例如:到院時生命徵象、不同類型感染症、共病症、病原體等,建立預後預測模型。分析急診敗血症病患使用抗生素之類別和劑量、時間等因素是否影響其預後,利用新興的檢測方法,作為臨床治療之參考。 第一部份:根據醫院累積抗菌譜評估不同程度的經驗性抗生素對急診 (ED) 敗血症患者的菌血症(Bacteremia)的影響。第二部分:利用總基因體次世代定序(Metagenomic next-generation sequencing, mNGS)的方法,來做敗血症病患的病原體鑑定,利用一個新型的過濾器來捕獲白血球並消除宿主脱氧核醣核酸(deoxyribonucleic acid, DNA)背景,對比上使用抗生素前後的血液培養結果以及未經宿主去除的定序結果,分析不同的檢驗方法對於致病菌的鑑定力。 病人與方法: 第一部份為:回顧性研究,收錄2016年2月至2018年12月期間,於臺北榮民總醫院急診部就醫的成年敗血症患者,且患者血液培養報告為陽性。根據患者分離的細菌病原體和患者在急診接受的經驗性抗生素治療,並使用醫院累積抗生素抗菌譜,以這次急診入院前6個月中的醫院累積抗菌素敏感性(overall antimicrobial susceptibility, OAS) 70%作為切點,將這些患者分為兩組。進行多變量回歸分析和敏感度分析。 第二部分為:前瞻性研究,此部分研究執行於2021-2022年間,在一間台灣北部的醫學中心。我們收錄了急診就醫的成人敗血症患者。在病患給予抗生素之前,抽取了一份血液樣本進行血液培養(Blood culture, BC)定義為BC1。在病患給予抗生素後,再採集一份血液樣本並樣本分成三部分,其中一部分用於進行第二次血液培養且我們定義為BC2。其餘部分的血液檢體分別進行mNGS檢測,其中一部分先經過特殊膜(Devin™ fraction filter)的過濾處理再進行mNGS檢測,另一部分未經過膜的過濾處理,直接進行mNGS檢測,分析評估過濾器對宿主去除的效果並對比上使用抗生素前後血液培養的結果。 結果: 第一部份:總共納入1055名急診敗血症患者。利用多變量回歸模型,校正年齡、性別、合併症、感染部位、器官功能障礙和敗血性休克等因素。使用70%以上OAS的經驗性抗生素的患者住院死亡率降低(調整後勝算比 adjusted odds ratio [aOR] 0.46,95%信賴區間[CI] 0.28 — 0.77)和30天死亡率降低(aOR 0.53,95%CI 0.33 — 0.86)有關。這群患者更有可以縮短加護病房(intensive care unit, ICU)的住院時間1.60天(95%CI -3.00 — -0.20)。 第二部份:共有45名敗血症患者的有完整的四項檢測結果。血液培養(BC1)的陽性率為51.1%(23/45),而BC2的陽性率為24.4%(11/45)。與BC1結果相比,mNGS有用過濾器的陽性菌種檢測結果與血液培養結果的相關率顯示,陽性一致率為73.9%(17/23),而相對於對比上BC2的結果,陽性一致率為81.8%(9/11)。mNGS未經過濾器的陽性菌種檢測結果與血液培養結果的相關率顯示,相對於BC1結果,陽性一致率為47.8%(11/23),而相對於BC2的結果,陽性一致率率為63.6%(7/11)。mNGS有用過濾器的陽性菌種檢測結果與BC1和BC2結的果相比。mNGS經過濾器處理檢驗結果與BC1結果相比發現一致性為中度一致性(Kappa = 0.466,P = 0.002),與BC2結果相比的一致性為低度一致性(Kappa = 0.297, P =0.019)。mNGS檢測到的細菌陽性結果率顯著高於血液培養(BC2)的陽性結果,同時檢測結果與BC1相近。血液樣本有經過濾膜和未經過濾膜的整體相關性(R2 = 0.96)證實,血液樣本有無經濾過器並不會影響樣本中的微生物基因組成的檢驗結果。 結論: 利用醫院累積抗生素譜敏感性(OAS) 70%以上的經驗性抗生素來治療急診菌血症的敗血症患者,可明顯降低患者住院中或是三十天的死亡率,同時可縮短加護病房住院天數。若是使用OAS 90%以上的經驗性抗生素,患者死亡率可降得更低。使用過濾器的mNGS檢測結果顯示其對病原體的識別與使用抗生素前的血液培養結果相比並無不會較差。此外,mNGS的檢測結果能比用抗生素後的血液培養報告提供更多關於病原體的訊息。 透過以上這些研究結果,能提供一些資料佐證給臨床醫師作為治療敗血症患者的參考,未來仍需要進一步的研究,了解mNGS檢測在臨床應用中的效果。 Objects:The initial stage of the study involves evaluating the impact of different levels of empirical antibiotics on the presence of bacteria in the bloodstream of sepsis patients in the emergency department. This assessment will be based on the hospital's cumulative antibiogram. The subsequent phase of the research involves the conventional method of identifying pathogenic bacteria in septic patients through blood culture reports. However, there is a suggestion to utilize metagenomic next-generation sequencing (mNGS) as a rapid, efficient, and unbiased alternative method. The aim is to assess the effectiveness of the mNGS assay, with or without a new filter, compared to blood culture results before and after administering empirical antibiotic treatment for identifying pathogens. Methods: The initial phase of the study involved a retrospective analysis of adult sepsis patients who sought treatment at Taipei Veterans General Hospital's emergency department between February 2016 and December 2018. The inclusion criteria for this analysis were patients with positive blood culture reports. The study focused on the bacterial pathogens identified in these patients and the empirical antibiotic treatment they received in the ED. The hospital's cumulative antibiogram was utilized to categorize the patients, with a cutoff of 70% overall antimicrobial susceptibility (OAS) in the six months before emergency department admission. Multivariate regression analysis and sensitivity analysis were conducted. The subsequent phase of the study was a prospective investigation conducted at a tertiary medical center in northern Taiwan from 2021 to 2022. Adult sepsis patients who presented to the ED were included in this phase. Before administering antibiotics, a blood sample was collected for the first blood culture (defined to BC1). After administering antibiotics, another blood sample was obtained and divided into three portions. One portion was used for the second blood culture (defined to BC2), while the other two were subjected to metagenomic next-generation sequencing (mNGS) analysis. One of the mNGS samples was processed with a filter, while the other was processed without filtering to evaluate the efficacy of host depletion by the filter. Results: We included 1055 sepsis patients from the ED in our study. After adjusting for various factors such as age, gender, comorbidities, site of infection, organ dysfunction, and septic shock, we found that patients who received empirical antibiotics with more than 70% overall antimicrobial susceptibility (OAS) had a lower in-hospital mortality rate (adjusted odds ratio [aOR] 0.46, 95% confidence interval [CI] 0.28-0.77) and 30-day mortality rate (aOR 0.53, 95% CI 0.33-0.86). Additionally, these patients had a shorter stay in the intensive care unit (ICU) by an average of 1.60 days (95% CI -3.00 to -0.20). The second part, forty-five patients completed all the laboratory examinations. The positive rate of BC1 was 51.1%, and BC2 was 24.4%. When comparing the results of mNGS with the filter to the BC reports, we found a correlation rate of 73.9% for BC1 results and 81.8% for BC2 results. On the other hand, the correlation rate between mNGS without filter and BC reports was 47.8% for BC1 results and 63.6% for BC2 results. The concordance of findings was moderate agreement between mNGS with filter compared to BC1 results (Kappa =0.466) and fair agreement compared to BC2 results (Kappa = 0.297). The positive result rates of bacteria detected by mNGS are significantly higher than those by blood culture (BC2) and similar to BC1. The overall correlation between blood samples with and without filtration (R2 = 0.96) confirmed that filtration does not affect the microbial composition in a sample. Conclusion: Administering empiric antibiotic treatment with an OAS of 70% or higher, guided by cumulative hospital antibiograms, is linked to reduced mortality rates and shorter stays in the ICU for sepsis patients with bacteremia in the ED. The metagenomic next-generation sequencing (mNGS) results with the filter demonstrated comparable pathogen identification to blood culture (BC) results obtained before antibiotic treatment. Moreover, mNGS results can provide more comprehensive bacterial information than BC reports following antibiotic treatment. Nevertheless, further research is necessary to determine the clinical usefulness of these findings. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89804 |
DOI: | 10.6342/NTU202302866 |
Fulltext Rights: | 同意授權(限校園內公開) |
Appears in Collections: | 環境與職業健康科學研究所 |
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