比較不同抗生素對治療革蘭氏陽性菌感染的腎毒性及治療效力-系統性回顧與網絡統合分析研究

Comparative Nephrotoxicity and Efficacy of antibiotics for the treatment of Gram-Positive Bacterial Infections -- A systematic review and network meta-analysis

張晟瑜(Cheng-Yu Chang)

指導教授 ： 賴美淑

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(2012年)

https://doi.org/10.6342/NTU.2012.01511

摘要

細菌的抗藥性在最近這幾十年中不斷的上升，尤其是在革蘭氏陽性菌的抗藥性上的改變造成了醫院內敗血症病人的增加。在美國，革蘭氏陽性菌在加護病房中有高達百分之六十為抗藥性金黃色葡萄球菌。而在台灣，根據2008年全國院內感染偵測系統的報告指出，在醫學中心的加護病房中革蘭氏陽性菌已經有高達百分之八十為抗藥性金黃色葡萄球菌。萬古黴素(Vancomycin)是標準的治療抗藥性金黃色葡萄球菌的藥物，但它的副作用所造成的腎臟毒性卻為人所詬病。隨著藥物發展的日新月異，有多種治療抗藥性金黃色葡萄球菌的抗生素陸續問世，臨床上常使用的藥物包括vancomycin，teicoplanin，linezolid，tigecycline以及telavancin。經過文獻回顧後，我們發現之前的研究多著重於一對一藥物配對分析。然而，對於臨床決策而言，我們更希望知道這些藥物的臨床治療效力及副作用上，彼此之間的差異性。於是，我們設計了這個研究來針對革蘭氏陽性菌感染的病人，使用不同的抗生素，所造成的腎毒性及治療效力的網路統合分析。

研究方法：
我們搜尋了Medline，Cochrane Library，Pubmed資料庫中與vancomycin，teicoplanin，linezolid，teicoplanin，tigecycline以及telavancin所有相關用來治療革蘭氏陽性菌感染的臨床試驗及統合性分析。收錄的研究時間從1988年1月起到2011年12月為止。除此之外，我們也從美國衛生研究院的臨床研究註冊系統中找尋與這些藥相關的研究結果並加入我們的系統性回顧中。從這些研究內容裡面，我們收集了作者，研究設計，性別，平均年齡，病人數，感染部位，藥物的種類及用量，臨床治療成功率，微生物清除率，藥物副作用及腎毒性。我們以腎毒性作為藥物安全性的評估，以臨床治療成功率及微生物清除率作為藥物療效的評估，把收錄到的研究，進行直接與間接統合性分析。

研究結果：
根據系統性文獻搜尋，我們找出390篇相關研究，符合納入條件後共有26篇隨機臨床試驗，共計8094位參加者。在直接比較的統合性分析結果方面，teicoplanin比起vancomycin所造成的腎毒性來的低(勝算比為0.37, 95%信頼區間為0.19-0.70)。但在臨床治癒率上，這些藥物皆無統計學的差異。而在微生物清除率上，linezolid 比起vancomycin有更好的效果(勝算比為1.29, 95%信頼區間為1.02-1.63)。
經過間接的網路統合分析發現，在這些抗生素中，telavancin造成腎毒性的風險最高。Telavancin比起teicoplanin (勝算比為8.63, 95%信頼區間為2.26-66.47)跟linezolid (勝算比為6.88, 95%信頼區間為1.50-58.15)的腎毒性都來的高出許多。而這五種抗生素之中，teicoplanin是腎毒性最低的藥物，不管是間接比較或直接比較法都支持這樣的結果。而linezolid不只在臨床療效上優於vancomycin(勝算比為1.4, 95%信頼區間為1.01-1.93)，在微生物清除率上也比起傳統的vancomycin有更好的表現(勝算比為1.32, 95%信頼區間為1.03-1.7)。

結論：
本研究發現在藥物安全性上，telavancin造成腎毒性的風險最高，teicoplanin造成腎毒性的風險最低。在療效上，linezolid有最佳的臨床治療效果與微生物清除率。

關鍵字

革蘭氏陽性菌 ； 抗藥性金黃色葡萄球菌 ； 腎毒性 ； 臨床治癒率 ； 微生物清除率 ； 網路統合分析研究

並列摘要

Background：Bacterial resistance has risen dramatically during the last few decades and infections caused by Gram-positive organisms constituting nowadays the main cause of sepsis in in-hospital patients. In the United States, more than 60% of the Gram-positive organisms isolates in intensive care units are methicillin resistance Staphylococcus aureus now (MRSA). In Taiwan nosocomial surveillance system reports, the prevalence of MRSA in Gram-positive organisms is up to 80% in medical centers. There is uncertainty as to whether vancomycin in cause permanent or temporary kidney damage. Many studies have shown an increased risk of kidney failure after vancomycin treatment. At least five agents of antibiotics, including vancomycin, teicoplanin, linezolid, tigecycline and telavancin can against MRSA infection. The efficacies and nephrotoxicity of different antibiotics have been studies by traditional meta-analysis method. However, for clinical decisions, we need to know the safety and effective of each possible in comparison with all relevant alternatives, not just one. We conducted a network meta-analysis study of comparative nephrotoxicity and efficacy of antibiotics for the treatment of Gram-positive bacterial infections.

Method： We searched the Medline, Cochrane Library, PubMed databases to identify published clinical trials in which vancomycin, linezolid, telavancin, teicoplanin and tigecycline were used to treat Gram positive infection from January 1988 to December 2011. We also searched trials in “clnicaltrials.gov” which is a service of clinical trial registry in U.S. National institutes of Health. Among included articles, the following variables were abstracted and collected in a standardized form: authors; year of publication ; study design; gender; mean age; number of patients ; site of infection; antimicrobial agents and dosages used ; microorganism species and susceptibility; clinical cure outcome; microbiological eradication; survival; adverse events; and serious adverse events. The safety outcome is nephrotoxicity and efficacy outcomes are clinical cure and microbiological eradication. We analyzed direct and indirect comparisons of different treatments using Bayesian network meta-analysis.

Results：Literature searching and systematic review identified 390 non-duplicate citations, of which 26 trials comprising 8094 participants were included. In direct comparison, lower risk of nephrotoxicity in teicoplanin compared with vancomycin (OR: 0.37, 95% C.I: 0.19-0.70). There was no statistical difference in clinical cure between these antibiotic agents. In microbiological eradication, linezolid is significant more effective than vancomycin (OR: 1.29, 95%C.I: 1.02-1.63). In indirect comparison, telavancin was the antibiotics of most high risk nephrotoxicity than others, compare with teicoplanin (OR: 8.63, 95% credible interval (CrI): 2.26-66.47) and linezolid (OR: 6.88, 95%CrI: 1.50-58.15). The lower risk of nephrotoxicity with teicoplanin was observed. Compared with vancomycin, teicoplanin showed significant decrease the risk of nephrotoxicity (OR: 0.29, 95%CrI: 0.11-0.67). Linezolid was superior to vancomycin in clinical cure (OR: 1.4, 95%CrI: 1.01-1.93) and microbiological eradication (OR: 1.32, 95%CrI: 1.03-1.7).

Conclusion：Telavancin is associated with a greater risk of renal toxicity than other comparators. It is a novel concept in traditional and network meta-analysis study. Teicoplanin appear the lower risk of nephrotoxicity in treatment of Gram positive bacterial infection. Linezolid showed a significant superior efficacy in clinical cure and microbiological eradication than others. Better performed randomized trials on antibiotic treatment of Gram-positive infection are needed to build a more robust network meta-analysis.

並列關鍵字

Gram-positive bacilli ； methicillin-resistance Staphylococcus aureus (MRSA) ； nephrotoxicity ； clinical cure ； microbiological eradication ； network meta-analysis

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