1、穩可信的有效性作用機制耐藥及敏感率MIC：萬古MIC“飄逸”而非“漂移”臨床療效指南推薦第一頁，共二十七頁。重殺菌機制3相對于人工合成抗生素的單一抑菌機制萬古霉素讓葡萄球菌更無從抵抗1. 影響細菌細胞膜的通透性2. 抑制細菌細胞壁的合成3. 抑制細菌漿內RNA合成123MDRSP=多藥耐藥菌株,MRSH=溶血性葡萄球菌實用抗感染治療學第一版 汪復、張嬰元主編，第九章 多肽類抗生素：pp281, pp284.第二頁，共二十七頁。穩可信上市 年全球僅出現 株耐藥91997年日本首先報告了對萬古霉素中度敏感的金黃色葡萄球菌(VISA)12002年07年在北美地區先后共確定9株耐藥的金黃色葡萄球菌(V

2、RSA)2我國尚無報道50+1, Chemother JA, Hiramatsu K, Janaki H. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility.1997,40:135-1362, Finks J, Wells E, Dyke TL,et al. Vancomycin Resistant Staphylococcus aureus ,Michigan USA,2007.Emerging Infectiuos Diseases 2009,

3、 15(6):943-945.第三頁，共二十七頁。重殺菌機制賦予萬古霉素持久不變的敏感率31. Sanches IS ,Mato R,Lencastre HD, et al. Patterns of multidrug resistance among Methicillin Resistant Hospital Isolates of Coagulase-Positive and Coagulase-Negative Staphylococci Colleted in the International Muticenter Study RESIST in 1997 and 1998. Mi

4、crobial Drug Resistance 2000,6(3):199-211.2. 實用抗感染治療學第一版 汪復、張嬰元主編,第九章 多肽類抗生素：pp281, pp284.第四頁，共二十七頁。作用于核糖體單一抑菌機制的利奈唑胺的耐藥1999年12000年2001年22005年3三期臨床時出現2株LRE利奈唑胺上市出現3株LRSA美國匹茲堡大學醫療中心ICU出現74株LRCNSLRE=耐利奈唑胺腸球菌,LRSA=耐利奈唑胺金葡菌,LRCNS=耐利奈唑胺凝固酶陰性葡萄球菌1. Venikata G,Gold HS. Antimicrobial resistance to Linezolid

5、.Clinical Infectious Diseases 2004, 39:1010-1015.2. Tsiodras S, Gold HS,Sakoulas G,et al.Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 2001, 358:207-208.3. Poloski BA, Adams J,Clarke L,et al. Epidemiological Profile of Linezolid-Resistant Coagulase-Negative Staphylocucc

6、i.Clinical Infectious Diseases 2006, 43:165-171.第五頁，共二十七頁。所有金葡菌對萬古霉素仍保持100%敏感率2007年ZAAPS細菌耐藥性監測結果Jones RN ,Kohno S, Ono Y, et al. ZAAPS International Surveillance Program(2007) for Linezolid resistance: results from 5591 Gram-Positive clinical isolates in 23 countries.Diagnostic Microbiology and Inf

7、ectious Disease 2009, 64:191-201.敏感率%第六頁，共二十七頁。國內葡萄球菌對萬古霉素保持 敏感率100%2008年中國CHINET細菌耐藥性監測結果(n=3525)(n=2313)耐藥金葡菌敏感率 (%)汪復,朱德妹,胡付品等. 2008年中國CHINET細菌耐藥性監測.中國感染與化療雜志 2009, 9(5):321-329.第七頁，共二十七頁。國內葡萄球菌對萬古霉素保持 敏感率100%全國主要抗生素對葡萄球菌屬敏感率監測 (Mohnarin) 2008(n=10409)(n=5981)肖永紅，王 進，趙彩云等，20062007年Mohnarin細菌耐藥監測,

8、中華醫院感染學雜志2008,18(8):1051-1056第八頁，共二十七頁。利奈唑胺目前的MIC分布情況圖220004008001200160020001248利奈唑胺MIC (g/ml)株數 (N)6株4株2007年ZAAPS細菌耐藥性監測結果1萬古霉素對于金葡菌的MIC90僅為1mg/LJones RN ,Kohno S, Ono Y, et al. ZAAPS International Surveillance Program(2007) for Linezolid resistance: results from 5591 Gram-Positive clin

9、ical isolates in 23 countries.Diagnostic Microbiology and Infectious Disease 2009, 64:191-201.第九頁，共二十七頁。歐洲43家醫院監測結果Bacteria Year Strain NoVancomycin Teicoplanin MICrMIC90MICrMIC90S. aureus20053370.25-210.12-8220062200.5-210.25-4120071310.5-210.25-412008690.25-210.25-41CoNS2005933282007810.5-220.25-8

10、42008910.25-220.12-84S. pyogenes 2005410.250.25NtNt 2006-20071460.12-3-40.032008540.12-3-112820.25-1280.25ECCMID 2009, p1620第十頁，共二十七頁。ECCMID 2009, 1637第十一頁，共二十七頁。萬古霉素和利奈唑胺治療院內肺炎療效相當在利奈唑胺提交給FDA的臨床報告中詳細描述了治療醫院內肺炎的臨床研究.該研究用萬古霉素和利奈唑胺進行對照顯示萬古霉素可評價臨床療效為60%，利奈唑胺可評價臨床療效57%，二者療效相當，利奈唑胺療效

11、并未超越萬古霉素。0102030405060利奈唑胺萬古霉素利奈唑胺萬古霉素ZYVOX 產品說明書信息 Distributed by Pfizer Pharmacia&Upjohn Company Divison of Pfizer Inc,NY,NY10017 LAB-0319-16.0 %12第十二頁，共二十七頁。 linezolid versus Vancomycin or Teicoplanin for Nosocomial Pneumonia: A Meta-Analysis AC. KALIL, M. H. MURTHY , E. HERMSEN , et al.Methods:

12、Prospective, randomized trials which tested linezolid vs. vancomycin or teicoplanin for treatment of NP were included. Heterogeneity was analyzed by I2 and Q statistics. Relative Risks (RR) were based on the Mantel-Haenszel method. Outcomes analyzed included clinical cure (CC), microbiologic eradica

13、tion (ME), and side effects. Results: 8 linezolid trials (6 vancomycin, 2 teicoplanin) were included (N=853). The linezolid vs glycopeptide analysis shows: CC RR=1.01(95% CI 0.93,1.10, p=0.80; I2=0%; N=853); ME RR=1.10 (CI 0.97,1.23; p=0.11; I2=0%; N=597); and MRSA population RR=1.14 (CI 0.82,1.58;

14、p=0.44; I2=47%; N=191). If linezolid is compared to vancomycin only, the CC RR remains 1.01(CI 0.90,1.12), and ME and MRSA RRs are: 1.06 (CI 0.88,1.28) and 1.04 (CI 0.73,1.47), respectively. The risk of thrombocytopenia (RR=1.92 CI 1.29,2.86; p=0.001) and GI events (RR=1.90 CI 1.04,3.48; p=0.03) wer

15、e significantly higher with linezolid, but no differences were seen for renal dysfunction (RR=0.82 CI 0.52,1.27; p=0.37), or all-cause deaths (RR=0.95 CI 0.76,1.18; p=0.63). 2008 ICAAC K-533Conclusions: Meta-analysis did not detect clinical superiority of linezolid vs. glycopeptides for treatment of

16、 NP. Compared to linezolid, vancomycin was not associated with more renal dysfunction. linezolid showed a significant increase in the risk of thrombocytopenia and GI events. Available data does not support the claim that linezolid is superior to vancomycin for the treatment of NP.第十三頁，共二十七頁。萬古霉素治療MR

17、SA感染療效未被超越包括菌血癥、肺炎以及皮膚軟組織感染萬古霉素1g/次，每天2次7-28天(n=220),利奈唑胺600mg/次，每天2次7-28天(n=240)Stevens DL,Herr D,Lampiris H, et al. Linezolid versus Vancomycin for the Treatment of Methicillin Resistant Staphylococcus aureus Infections.Clinical Infectious Diseases 2002, 34:1481-1490.第十四頁，共二十七頁。萬古霉素治療MRSA起效時間未被超越萬

18、古霉素1g q12h，7-21天(n=61),利奈唑胺600mg q12h，7-21天(n=57),*退熱定義為體溫完全恢復正常時間 (天)P=0.2057P=0.1760P=0.6149第十五頁，共二十七頁。穩可信：眾多權威指南推薦桑福德抗微生物治療指南2009-2010版美國胸科協會(ATS)關于醫院獲得性、呼吸機相關及醫療相關肺炎治療指南美國抗感染協會(IDSA)關于導管相關感染治療指南HAP亞洲工作組關于HAP組首次共識歐洲心臟協會(ESC)關于感染性心內膜炎的預防、診斷及治療指南英國抗菌化療協會(BSAC)關于MRSA感染預防和治療指南萬古霉素治療MRS感染的首選第十六頁，共二十七頁

19、。穩可信的安全性適應癥比較副作用比較第十七頁，共二十七頁?；颊?，療效安全看得見！1億穩可信：擁有廣泛的適應癥適應癥萬古霉素1利奈唑胺2替考拉寧3肺炎皮膚軟組織感染導管相關血流感染FDA警告？感染性心內膜炎X？腦膜炎X肺膿腫X膿胸X腹膜炎X骨髓炎X關節炎X1. 萬古霉素產品說明書,2. 利奈唑胺產品說明書,3. 替考拉寧產品說明書第十八頁，共二十七頁。利奈唑胺受到美國FDA的警告1利奈唑胺已被FDA批準的適應證包括： 用于治療耐萬古霉素的屎腸球菌感染、醫源性肺炎、社區獲得性肺炎、非復雜性的皮膚及軟組織感染、復雜性的皮膚和軟組織感染（包括未并發骨髓炎的糖尿病足部感染）。 2007年FDA提醒醫務工

20、作者： 利奈唑胺未獲批準用于導管相關性血流感染、導管 接觸部位感染。 相關報導： C:/Documents%20and%20Settings/Administrator/Local%20Settings/Temp/Rar$DI06.171/%E5%88%A9%E5%A5%88%E5%94%91%E8%83%BA%E9%80%82%E5%BA%94%E8%AF%81%E5%A4%96%E7%94%A8%E8%8D%AF%E5%A2%9E%E5%8A%A0%E6%AD%BB%E4%BA%A1%E9%A3%8E%E9%99%A9-%E5%8C%BB%E8%8D%AF%E8%B5%84%E8%AE%A

21、F-%E4%B8%AD%E5%9B%BD%E5%8C%BB%E8%8D%AF%E7%BD%91.mht利奈唑胺適應證外用藥增加死亡風險 C:/Documents%20and%20Settings/Administrator/Local%20Settings/Temp/Rar$DI06.171/%E5%88%A9%E5%A5%88%E5%94%91%E8%83%BA%E5%AE%89%E5%85%A8%E6%80%A7%E5%BC%95%E8%B5%B7%E5%B9%BF%E6%B3%9B%E9%87%8D%E8%A7%86-%E5%8C%BB%E8%8D%AF%E8%B5%84%E8%AE%A

22、F-%E4%B8%AD%E5%9B%BD%E5%8C%BB%E8%8D%AF%E7%BD%91.mht網站相關報導檢索關鍵詞：利奈唑胺1,Wilcox MH, Tack KJ,Bouza E,et al. Complicated skin and skin structure infections and Catheter Related Bloodstream Infections Noninferiority of Linezolid in Phase 3 Sutdy.Clinical Infectious Disease 2009, 48:203-212.2,FDA Alert 3/18

23、/2007.第十九頁，共二十七頁。萬古霉素純度提高，腎毒性發生率大大減少 Rybak M, Lomaest o B,Rotschafer JC,et al. Therapeutic monitory of vancomycin in adult patients: A consensus review of the ASHP, IDSA and the SIDP.Am J Health-Syst Pharm 2009, 66:82-98.林東昉、吳菊芳、張嬰元等。利奈唑胺與萬古霉素治療革蘭陽性菌感染的隨機、雙盲、對照、多中心臨床試驗。中國感染與化療雜志2009,9(1):10-17Steven

24、s D.L. Herr D, Lampiris H,et al.Linezolid versus Vancomycin for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections. Clinical Infectious Diseases 2002, 34:148190Abad F, CalboF, Zapater P,et al. Comparative pharmacoeconomic study of vancomycin and teicoplanin in intensive care pat

25、ients.International Journal of Antimicrobial Agents ,2000,15:6571Downs NJ, Robert E. Neihart, MD, Jeanette M. Dolezal,et al.Mild Nephrotoxicity Associated With Vancomycin Use.Sorrell TC, Collignon PJ.A prospective study of adverse reactions associated with vancomycin therapy.J Antimicrob Chemother.

26、1985 Aug,16(2):235-41.Farbert BF,Moellering RC,Retrospective Study of the Toxicity of Preparations of Vancomycin from 1974 to 1981, Antimicrobial agents and chemotherapy. 1983,23(1):138-141Levine DP. Vancomycin:A History. Clinical Infectious Diseases 2006, 42:S5-12第二十頁，共二十七頁。穩可信稀釋后靜脈滴注藥物濃度不超過 5毫克/毫升

27、每次滴注時間應該超過 60分鐘腎功能損害及年長患者應調整劑量必要時監測血藥濃度經常改變輸注部位穩可信 應用準則第二十一頁，共二十七頁。腎功能異常病人劑量調整方法肌酐值以mol/L表示時，K=0.814本公式應用于女性值，求得值需乘以0.85首次負荷劑量:15mg/kg()血清肌酐值年齡）肌酐清除率（-=Kkgml140min/第二十二頁，共二十七頁。劑量調整例子某男性病人65歲，體重為70kg,血肌酐值為160mol/L該病人每日穩可信的給藥總量為9.370=651mg()6.0160814.065140kmin/=-=）肌酐清除率（gml23第二十三頁，共二十七頁。萬古霉素與替考拉寧安全性比

28、較萬古霉素 (n=252)替考拉寧 (n=275)腎毒性意大利大樣本臨床對照試驗1血小板減少美國大樣本臨床對照試驗2發生率 (%)發生率 (%)P=0.68P=0.003萬古霉素 (n=417)替考拉寧 (n=406)Menichetiti F, Martino B,Bucaneve G,et al.Effects of Teicoplanin and Those of Vancomycin in Initial Emperical Antibiotic Regimen for Febrile Neutropenic Patients with Heamatologic Malignancie

29、s. Anitmicrobial agents and chemotherapy,1994, 38(9):2041-2046.Wilson APR,Compative safety of Teicoplanin and Vancomycin.International Journal of Antimicrobial Agents,1998, 10:143-152第二十四頁，共二十七頁。萬古霉素治療MRSA感染副反應發生率與利奈唑胺比較發生率 (%)P=0.006P=0.037P=0.139無統計學差異萬古霉素1g/次，每天2次7-28天(n=220),利奈唑胺600mg/次，每天2次7-28

30、天(n=240)Stevens DL,Herr D,Lampiris H, et al. Linezolid versus Vancomycin for the Treatment of Methicillin Resistant Staphylococcus aureus Infections.Clinical Infectious Diseases 2002, 34:1481-1490.第二十五頁，共二十七頁。 萬古霉素和利奈唑胺安全性的比較由于萬古霉素制劑的純度顯著提高，目前臨床大量應用萬古霉素，證實其腎毒性很少見,包括調整劑量后用于腎功能受損的病人，同時萬古霉素的腎毒性具有可逆性28。

31、而有數據表明，利奈唑胺引起的嚴重不良反應血小板減少的病例高達35%,在腎功能損傷的病人應用利奈唑胺引起的血小板減少達到65%,29。高純度的萬古霉素具有良好的安全性28 Wakefield DS, Pfaller M, Massanari RM, Hammons GT. Variation in methicillin-resistant Staphylococcus aureus occurrence by geographic location and hospital characteristics. Infect Control. 1987;8(4):151-729 Yen-Hung

32、Lin, Vin-Cent Wu High frequency of linezolid-associated thrombocytopenia Among patients with renal insufficiency. International Journal of Antimicrobial Agent 28(2006)345-351 第二十六頁，共二十七頁。 linezolid versus Vancomycin or Teicoplanin for Nosocomial Pneumonia: A Meta-Analysis AC. KALIL, M. H. MURTHY , E

33、. HERMSEN , et al.Methods: Prospective, randomized trials which tested linezolid vs. vancomycin or teicoplanin for treatment of NP were included. Heterogeneity was analyzed by I2 and Q statistics. Relative Risks (RR) were based on the Mantel-Haenszel method. Outcomes analyzed included clinical cure (CC), microbiologic eradication (ME), and side effects. Results: 8 linezolid trials (6 vancomycin, 2 teicopl