Tigecycline在感染症之臨床治療成效及副作用

Abstract

研究背景： Tigecycline目前已被美國食物藥品管理局認可在複雜性腹腔內感染、複雜性皮膚及皮膚結構感染的治療及社區型肺炎的治療；在許多體外試驗發現，tigecycline對許多抗藥性細菌具有敏感性，因此在臨床上常拿來作為對抗抗藥性細菌的藥品，但美國食物藥品管理局在2010年發布警訊，使用tigecycline的病人比對照組藥品有死亡率上升之趨勢，特別是在院內感染肺炎，治療失敗率及發生敗血性休克的人數較多，所以不建議在感染較嚴重的病人使用。 研究目的： 評估在使用tigecycline病人的臨床治療成效及死亡率，並分析單純肺炎感染病人的臨床治療成效及死亡率，此外分析治療失敗之危險因子及使用之菌種分布，統計使用此藥品常見之副作用。 研究方法： 本研究為回溯性研究，研究之病人群為2010年1月至2011年6月曾於某醫學中心，有使用tigecycline之病人，且有感染症相關診斷者，排除年齡小於20歲及資料不全者；以電子病歷及紙本病歷收集資料，其主要內容包含病人基本資料、潛在疾病、疾病嚴重度、使用tigecycline時的臨床表徵及相關檢驗數值、使用前後的菌種培養及續發性感染之菌種分布、臨床治療成果以及治療期間發生之不良反應；不同病人的臨床治療反應以卡方檢定分析，使用羅吉斯迴歸分析所有病人以及單純肺炎感染病人治療失敗的獨立危險因子。 研究結果： 本研究共收入137人，多重感染者有61人（44.5%），其中60人（43.8%） 感染肺炎；單一感染症者有76人（55.5%），單純感染肺炎者有71人（51.8%），複雜性腹腔內感染者有11人（8%），複雜性皮膚及皮膚結構感染者5人（3.6%）；潛在疾病以呼吸系統疾病（80%）、腎臟疾病（71%）及心臟疾病（61%）最多；治療之菌種最常見為Multidrug-resistant Acinetobacter baumannii（MDRAB）71%，其次是Stenotrophomonas maltophilia 7%，大多菌種為多重抗藥性之細菌，此外MDRAB的tigecycline敏感性在本研究為67%。 治療結果整體看來有50%的臨床治療反應成功率，在單純肺炎的病人與複雜性腹腔內感染及複雜性皮膚及皮膚結構感染相比有較低的臨床治療成功率（pneumonia: 45% vs cIAIs:100%和cSSSIs:64%），在單一菌種感染也比多重菌種感染臨床治療反應好（59% vs 39%, P值0.0241），tigecycline敏感性之菌種有較好之臨床治療反應（54% vs 32%, P值0.0414）；此外本研究發生續發性感染的機率為37%，最常見之續發性感染菌種為Pseudomonas aeruginosa約有10%。 在全體病人中，治療時之血糖大於180 mg/dL（OR 3.28, P=0.0395）、在使用tigecycline時發生敗血性休克（OR 3.34, P=0.002）、在使用tigecycline時發生急性腎衰竭（OR 2.40, P=0.0416）為造成治療失敗的獨立危險因子；在單純肺炎感染之病人，使用tigecycline時發生敗血性休克（OR 5.04, P=0.0078）為tigecycline治療失敗之獨立危險因子。 本研究常見之副作用為腸胃道副作用（35%），腸胃道副作用中以腹瀉最多（21%），噁心及嘔吐的副作用各4%。 結論： 不管是全體病人或單純肺炎感染的獨立危險因子分析，均發現疾病嚴重程度以及血糖值與治療失敗有相關，因此疾病嚴重程度越高，血糖控制越差者，治療越容易失敗；不過在死亡率則和文獻顯示相近，並無較高之死亡率；在副作用方面以腸胃道副作用最多，腸胃道副作用中最常發生之副作用為腹瀉，噁心及嘔吐發生的比例較之前研究低。

Background: Tigecycline is approved by the USA Food and Drug Administration（FDA） for the treatment of complicated intra-abdominal infections（cIAIs）, complicated skin and skin structure infections（cSSSIs）, and community acquired pneumonia（CAP）. Tigecycline is active against many resistant pathogens in in-vivo study, and it can be used for the antibiotic-resistant bacterial infections. However, FDA imposed a black box warning on tigecycline in 2010. Concerning the increasing mortality rate of tigecycline, especially in the treatment of hospital-acquired pneumonia, in clinical trials and retrospective studies. In addition, patients treated by tigecycline have significant more treatment failure and septic shock. Therefore, tigecycline is not recommended in critically ill patients. Objective: The goal of this study is to evaluate the clinical response and mortality of patients receiving tigecycline treatment in Taiwan. The clinical response and mortality of patients with pneumonia only are analyzed in sub-group analysis, identifying the risk factors for treatment failure and the indicated pathogens assessed. We also evaluate the adverse drug reactions of tigecycline. Methods: This retrospective study included patients hospitalized in a 2500-bed medical center with infection-related diagnosis and received tigecycline between January 2010 and June 2011. Patients younger than 20 years old or with incomplete data are excluded. We reviewed the medical records including baseline characteristics, comorbidities, disease severity, clinical presentations, laboratory data, culture results, pathogens of secondary infection, clinical response, and adverse drug reactions of tigecycline. Treatment outcomes in different groups were analyzed by chi-square test. We also identified the risk factors for treatment failure in all patients and in patients with pneumonia only by logistic regression. Results: Among 137 patients, 61（44.5%）patients had multiple-site infection, 71（51.8%） patients had pneumonia with other infections, 76（55.5%）patients had mono-site infection, 60 patients had pneumonia only, 11（8%） patients had cIAIs, and 5（3.6%） patients had cSSSIs. Most patients had comorbid respiratory diseases（80%）, renal diseases（71%）, and cardiovascular diseases（61%）. The most common indicated pathogens were multidrug-resistant Acinetobacter baumannii（MDRAB）（71%）, and Stenotrophomonas maltophilia（7%）. The susceptibility of MDRAB was approximately 67% in this study. Overall clinical response was 50%. Clinical response in patients with pneumonia only was 45%, which is lower than patient with cIAIs or cSSSIs only（100% and 64%, respectively）.Patients with mono-microbial infection had higher clinical response than those with poly-microbial infection（59% vs 39%, P=0.0241）. Besides, the susceptible pathogens also had better clinical response（54% vs 32%, P=0.0414）. Fifty-one patients（37%） had secondary infections in total, and the most common pathogen was Pseudomonas aeruginosa（10%）. In total patients, blood sugar higher than 180 mg/dL during tigecycline treatment（OR 3.28, P=0.0395）, septic shock at the first day of tigecycline used（OR 3.34, P=0.002）, and acute kidney injury at the first day of tigecycline used（OR 2.40, P=0.0416） were independent risk factors for treatment failure. In patients with pneumonia only, the independent risk factors were septic shock at the first day of tigecycline used（OR 5.04, P=0.0078）. In this study, the most common side effects were gastrointestinal（GI） side effects（35%）, and diarrhea（21%） is the most frequently. In contrast to previous studies, nausea and vomiting were reported both only 4%in this study. Conclusion: Patients’ disease severity is correlated with treatment outcomes, regardless in all patients or in patients with pneumonia only. There would be more treatment failure in patients with severe disease status and in patients with hyperglycemia. However, the mortality rate is similar with other studies. The most adverse drug reactions of tigecycline are gastrointestinal tract side effects. Among gastrointestinal tract side effects, diarrhea is the most common side effects. Percentage of nausea and vomiting is less than prior studies.