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研究生:林梅芳
研究生(外文):Mei-Fang Lin
論文名稱:綠膿桿菌感染之治療-文獻回顧
論文名稱(外文):Antimicrobial Therapy for Pseudomonas aeruginosa Infections -Review of Literature
指導教授:高雅慧高雅慧引用關係柯文謙柯文謙引用關係
指導教授(外文):Yea-Huei KaoWen-Chien Ko
學位類別:碩士
校院名稱:國立成功大學
系所名稱:臨床藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:126
中文關鍵詞:綠膿桿菌單一治療合併治療
外文關鍵詞:Pseudomonas aeruginosamonotherapycombination
相關次數:
  • 被引用被引用:7
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  • 評分評分:
  • 下載下載:151
  • 收藏至我的研究室書目清單書目收藏:3
研究背景
綠膿桿菌是造成院內感染的主要致病菌之一,由於其可在潮濕的環境生存且適應力強,因此常藉由許多媒介物引起院內感染群突發事件。由於具有較強的侵入性及毒性,對於產生全身性感染所導致的死亡率居高不下。而另一個讓人隱憂的問題是細菌的抗藥性與日俱增,儼然成為臨床治療一個棘手的問題。抗生素的合併治療,廣為臨床應用,其優點包括增加抗菌範圍,減少抗藥性發生機率以及達到協同作用等;但是合併治療仍存在負面的影響包括副作用及費用增加等。

研究目的
基於實證醫學研究基礎之下,藉由文獻回顧,收集其不同層次的試驗結果,建立完整的證據,以提供臨床對於綠膿桿菌治療用藥選擇之依據。

研究方法
利用MEDLINE、PudMed及EMBASE資料庫搜尋相關之文獻,關鍵字包括 Pseudomonas aeruginosa及個別治療藥物名稱等,另外亦包括文獻引用之相關參考資料。
研究結果
單一藥物治療比較在臨床試驗的結果,由數篇前瞻性研究結果,發現不論是臨床的反應、細菌學的反應、副作用的發生及抗藥性的產生,大部分彼此之間並無顯著差異性,僅有2篇研究結果具有統計學上的差異性。其中以院內感染肺炎的病患,使用ceftazidime或piperacillin/tazobactam 與imipenem 相比較之下,皆以imipenem的治療呈現較差的結果,並且在4篇的研究當中,發現使用imipenem治療之後發生抗藥性的機率皆比對照組高。
合併治療方面具有臨床試驗證據,僅有aminoglycoside合併antipseudomonal penicillin,應用在血流感染或本身有癌症的病患,證實合併治療優於單一治療。具有動物實驗以aminoglycoside合併antipseudomonal penicillin或ceftazidime具有正面且較多證據的組合;其他組合皆具有體外試驗,其中以aminoglycoside合併antipseudomonal penicillin具有最佳的協同效果。
結論
目前對於綠膿桿菌的感染,合併療法僅有aminoglycoside併用antipseudomonal penicillin具有臨床證據,其他的組合仍須更進一步研究。
Background
Pseudomonas aeruginosa is one of the principal pathogen associated with nosocomial infections and is frequently responsible for institutional outbreak. Mortality due to P. aeruginosa bacteremia remains ominously high. Furthermore, resistance to antipseudomonal antibiotics is an increasing problem and emergence of antibiotic resistance during therapy occurs with relatively high frequency. Appropriate use of antibiotics therapy and prevent the spread of antibiotics resistant microorganism are clinically important issues. Combination therapy has an intuitive appeal for clinicians. The advantages include broader spectrum of coverage, theoretical possibility of minimizing emergence of antimicrobial resistance and potentially synergistic interaction. On the other hand, combination therapy has some disadvantages, including increased toxicity, especially if aminoglycoside is used and more expensive.

Objectives
To review the efficacy of various therapeutic regimens and in order to provide useful suggestions regarding antibiotic selection.

Methods
MEDLINE, PudMed, EMBASE and reference lists of relevant articles to search the references. The key words for the initial search strategy were Pseudomonas aeruginosa and the names of individual drugs.
Results
Numerous prospective clinical studies demonstrated that various monotherapy regimens were not different in clinical outcomes, bacteriologic eradication and development of resistance. However, in two studies comparing imipenem to either ceftazidime or piperacillin-tazobactam, imipenem was less effective in P. aeruginosa nosocomial pneumonia . In four studies showed that imipenem has a increasing risk of emergence of antimicrobial resistance, when compared with ciprofloxacin, piperacillin-tazobactam and ceftazidime.
In vitro-in vivo synergy with antipseudomonal penicillin plus an aminoglycoside and development of resistance with monotherapy prompted combination therapy for serious infections. Aminoglycoside plus ceftazidime were significantly better than monotherapy in animal models. However, other combination regimens lacked solid in vitro or clinical evidences.
Conclusion
Only combination of antipseudomonal penicillin plus aminoglycoside has been proved to be superior to the monotherapy in patients with P. aeruginosa bacteremia. Other combination regimens merit further studies before their routine use in clinical practice.
目錄 頁數
中文摘要------------------------------------------------------------------------------ Ⅰ
英文摘要------------------------------------------------------------------------------ Ⅲ
誌謝------------------------------------------------------------------------------------Ⅴ
縮寫表--------------------------------------------------------------------------------- Ⅵ
目錄------------------------------------------------------------------------------------ Ⅸ
表目錄--------------------------------------------------------------------------------- IIX
圖目錄------------------------------------------------------------------------------ XⅤ
第一章 研究背景-------------------------------------------------------------------- 1
第一節 引言---------------------------------------------------------------------- 1
第二節 流行病學---------------------------------------------------------------- 4
第三節 院內感染群突發事件------------------------------------------------- 8
第四節 抗生素之敏感性------------------------------------------------------ 10
第五節 多重抗藥性之流行病學--------------------------------------------- 17
第二章 研究目的 ------------------------------------------------------------------ 20
第三章 研究設計與方法 --------------------------------------------------------- 21
第四章 研究結果 ------------------------------------------------------------------ 23
第一節 單一藥物治療--------------------------------------------------------- 23
第一項 前言---------------------------------------------------------------- 23
第二項 Beta-lactam 抗生素單一藥物治療比較--------------------- 25
第三項 Quinolone單一藥物治療比較--------------------------------- 28
第四項 Carbapenem單一藥物治療比較------------------------------ 30
第五項 其他---------------------------------------------------------------- 33
第六項 結論---------------------------------------------------------------- 37
第二節 合併治療--------------------------------------------------------------- 39
第一項 合併治療的理由------------------------------------------------- 39
第二項 合併治療的缺點------------------------------------------------- 41
第三項 體外試驗合併治療之研究方法------------------------------- 44
第四項 Aminoglycoside合併APPCN--------------------------------- 50
第五項 Aminoglycoside合併ceftazidime----------------------------- 58
第六項 Double beta-lactam----------------------------------------------- 62
第七項 Aminoglycoside合併quinolone------------------------------- 66
第八項 Quinolone合併APPCN---------------------------------------- 69
第九項 Quinolone合併cephalosporin--------------------------------- 72
第十項 Quinolone合併carbapenem------------------------------------ 74
第十一項 結論----------------------------------------------------------- 76
第三節 多重抗藥性感染之治療--------------------------------------------- 81
第一項 Polymyxin類抗生素-------------------------------------------- 81
第二項 合併治療 --------------------------------------------------------- 84
第五章 討論 ------------------------------------------------------------------------ 87
第六章 結論 ------------------------------------------------------------------------ 91
參考文獻------------------------------------------------------------------------------- 94
附錄一:臨床藥事服務------------------------------------------------------------ 112
附錄二:專題寫作------------------------------------------------------------------ 121
附錄三:成大醫院臨床藥事服務個案記錄表--------------------------------- 123
附錄四:成大醫院臨床藥事服務工作記錄表--------------------------------- 124
附錄五:臨床藥事服務工作記錄表--------------------------------------------- 125
自述----------------------------------------------------------------------------------- 126


表 目 錄
表1. 血流綠膿桿菌感染之死亡率------------------------------------------------- 3
表2. 綠膿桿菌於世界各國家或地區之盛行率---------------------------------- 6
表3. 綠膿桿菌於世界各國家或地區之盛行率---------------------------------- 7
表4. 綠膿桿菌院內感染群突發事件---------------------------------------------- 9
表5. 美國國家臨床實驗標準對於綠膿桿菌訂立之規範-------------------- 12
表6. 綠膿桿菌於世界各國或地區之敏感性----------------------------------- 15
表7. 綠膿桿菌於世界各國或地區之敏感性----------------------------------- 16
表8. 綠膿桿菌產生多重抗藥性之機轉---------------------------- 19
表9. 綠膿桿菌產生多重抗藥性的比例---------------------------- 19
表10. Beta-lactam抗生素單一藥物治療比較----------------------------------- 27
表11. Quinolone單一藥物治療比較---------------------------------------------- 29
表12. Carbapenem單一藥物治療比較------------------------------------------- 32
表13. 不同類藥物合併同一種aminoglycoside之比較----------------------- 36
表14. 目前成大醫院針對綠膿桿菌感染治療之藥品品項暨依健保給付之價格計算其每日藥價------------------------------------------------------- 38
表15. 體外試驗aminoglycoside合併APPCN---------------------------------- 55
表16. 動物試驗aminoglycoside合併APPCN---------------------------------- 56
表17. 臨床試驗aminoglycoside合併APPCN---------------------------------- 57
表18. 體外試驗aminoglycoside合併ceftazidime------------------------------ 60
表19. 動物試驗aminoglycoside合併ceftazidime------------------------------ 61
表20. 體外試驗double beta-lactam----------------------------------------------- 64
表21. 動物試驗double beta-lactam---------------------------------------------- 65
表22. 體外試驗aminoglycoside合併quinolone------------------------------- 68
表23. 體外試驗quinolone 合併APPCN---------------------------------------- 71
表24. 體外試驗quinolone 合併cephalosporin-------------------------------- 73
表25. 體外試驗quinolone 合併carbapenem----------------------------------- 75
表26. 合併治療應用於綠膿桿菌感染之試驗證據---------------------------- 79
表27. 於感染科研習期間與藥物相關之問題--------------------------------- 115
表28. 根據tracer agents報表評估藥物不良反應之紀錄------------------- 119
表29. 成大醫院臨床藥事服務完成個案記錄表----------------------------- 120




圖目錄
圖1. 成大醫院院內感染之主要致病菌1990-1995年及1996-2001年------ 5
圖2. NNIS加護病房院內感染1999年1月至12月與1994-1998年
抗生素抗藥性之改變比例-------------------------------------------------- 13
圖3. 美國舊金山13所醫院血流綠膿桿菌感染之抗藥性趨勢------------- 14
圖4. 成大醫院院內血流綠膿桿菌感染之抗藥性趨勢----------------------- 14
圖5. Checkerboard method---------------------------------------------------------- 47
圖6. Bacterial time killing curve method----------------------------------------- 48
圖7. Disc diffusion method--------------------------------------------------------- 49
圖8. Tobramycin合併ciprofloxacin動物實驗模式之累積死亡率----------- 67
圖9. 各種藥物合併使用以checkerboard研究達到協同作用之比例------ 80
圖10. Polymyxin E及polymyxin B化學結構---------------------------------- 83
圖11. Polymyxin作用機轉--------------------------------------------------------- 83
圖12. 體外試驗time-killing curve研究不同藥物併用之協同作用--------- 86
圖13. 體外試驗time-killing curve研究amikacin合併cefepime之協同作用---------------------------------------------------------------------------------- 86
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