三种抗阳性菌药物比较课件.ppt

1、稳可信稳可信VSVS替考拉宁及利奈唑胺替考拉宁及利奈唑胺（药物的三大特性比较）（药物的三大特性比较）l有效性l安全性l经济性稳可信的有效性稳可信的有效性l 作用机制l 耐药及敏感率l MIC：万古MIC“飘逸”而非“漂移”l 临床疗效l 指南推荐重杀菌机制重杀菌机制相对于相对于人工合成人工合成抗生素的抗生素的单一抑菌机制单一抑菌机制万古霉素万古霉素让葡萄球菌更无从抵抗让葡萄球菌更无从抵抗1.影响细菌细胞膜的通透性2.抑制细菌细胞壁的合成3.抑制细菌浆内RNA合成123MDRSP=多药耐药菌株,MRSH=溶血性葡萄球菌实用抗感染治疗学第一版 汪复、张婴元主编，第九章 多肽类抗生素：pp281,p

2、p284.稳可信上市稳可信上市 年全球仅出现年全球仅出现 株耐药株耐药1997年日本首先年日本首先报告了对万古霉素报告了对万古霉素中度敏感的金黄色中度敏感的金黄色葡萄球菌葡萄球菌(VISA)12002年年07年在北美年在北美地区先后共确定地区先后共确定9株耐株耐药的金黄色葡萄球菌药的金黄色葡萄球菌(VRSA)2我国尚无报道我国尚无报道1,Chemother JA,Hiramatsu K,Janaki H.Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibili

3、ty.1997,40:135-1362,Finks J,Wells E,Dyke TL,et al.Vancomycin Resistant Staphylococcus aureus,Michigan USA,2007.Emerging Infectiuos Diseases 2009,15(6):943-945.重杀菌机制赋予万古霉素持久不变的敏感率重杀菌机制赋予万古霉素持久不变的敏感率1.Sanches IS,Mato R,Lencastre HD,et al.Patterns of multidrug resistance among Methicillin Resistant Hos

4、pital Isolates of Coagulase-Positive and Coagulase-Negative Staphylococci Colleted in the International Muticenter Study RESIST in 1997 and 1998.Microbial Drug Resistance 2000,6(3):199-211.2.实用抗感染治疗学第一版 汪复、张婴元主编,第九章 多肽类抗生素：pp281,pp284.作用于核糖体作用于核糖体单一单一抑菌机制的利奈唑胺的耐药抑菌机制的利奈唑胺的耐药1999年年12000年年2001年年22005年

5、年3三期临床三期临床时出现时出现2株株LRE利奈唑胺上市出现出现3株株LRSA美国美国匹兹堡匹兹堡大学大学医疗中心医疗中心ICU出现出现74株株LRCNSLRE=耐利奈唑胺肠球菌,LRSA=耐利奈唑胺金葡菌,LRCNS=耐利奈唑胺凝固酶阴性葡萄球菌1.Venikata G,Gold HS.Antimicrobial resistance to Linezolid.Clinical Infectious Diseases 2004,39:1010-1015.2.Tsiodras S,Gold HS,Sakoulas G,et al.Linezolid resistance in a clinic

6、al 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 Staphylocucci.Clinical Infectious Diseases 2006,43:165-171.所有金葡菌对万古霉素仍保持所有金葡菌对万古霉素仍保持100%100%敏感率敏感率20072007年年ZAAPSZAAPS细菌耐药性监测结果细菌耐药性监测结果J

7、ones 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 Infectious Disease 2009,64:191-201.敏感率%国内葡萄球菌对万古霉素保持国内葡萄球菌对万古霉素保持 敏感率敏感率20082008年中国年中国CHINETCHINET细菌耐药性监测结果

8、细菌耐药性监测结果(n=3525)(n=2313)耐药金葡菌敏感率(%)汪复,朱德妹,胡付品等.2008年中国CHINET细菌耐药性监测.中国感染与化疗杂志 2009,9(5):321-329.国内葡萄球菌对万古霉素保持国内葡萄球菌对万古霉素保持 敏感率敏感率全国主要抗生素对葡萄球菌属敏感率监测全国主要抗生素对葡萄球菌属敏感率监测 (Mohnarin)2008(Mohnarin)2008(n=10409)(n=5981)肖永红，王 进，赵彩云等，20062007年Mohnarin细菌耐药监测,中华医院感染学杂志2008,18(8):1051-1056利奈唑胺目前的利奈唑胺目前的MICMIC分布

9、情况图分布情况图220004008001200160020000.120.250.51248利奈唑胺MIC(g/ml)株数(N)6株株4株株20072007年年ZAAPSZAAPS细菌耐药性监测结果细菌耐药性监测结果1 1万古霉素对于万古霉素对于金葡菌的金葡菌的MIC90MIC90仅为仅为1mg/L1mg/LJones RN,Kohno S,Ono Y,et al.ZAAPS International Surveillance Program(2007)for Linezolid resistance:results from 5591 Gram-Positive clinical isol

10、ates in 23 countries.Diagnostic Microbiology and Infectious Disease 2009,64:191-201.欧洲欧洲4343家医院监测结果家医院监测结果Bacteria Year Strain NoVancomycin Teicoplanin MICrMIC90MICrMIC90S.aureus20053370.25-210.12-8220062200.5-210.25-4120071310.5-210.25-412008690.25-210.25-41CoNS2005933282007810.5-220.25-842008910.2

11、5-220.12-84S.pyogenes 2005410.250.25NtNt 2006-20071460.12-0.50.250.03-40.032008540.12-0.250.250.03-112820.25-1280.25ECCMID 2009,p1620ECCMID 2009,1637万古霉素和利奈唑胺治疗院内肺炎疗效相当在利奈唑胺提交给FDA的临床报告中详细描述了治疗医院内肺炎的临床研究.该研究用万古霉素和利奈唑胺进行对照显示万古霉素可评价临床疗效为60%，利奈唑胺可评价临床疗效57%，二者疗效相当，利奈唑胺疗效并未超越万古霉素。0 01010202030304040505060

12、利奈唑胺利奈唑胺万古霉素万古霉素利奈唑胺利奈唑胺万古霉素万古霉素ZYVOX 产品说明书信息 Distributed by Pfizer Pharmacia&Upjohn Company Divison of Pfizer Inc,NY,NY10017 LAB-0319-16.0%linezolid versus Vancomycin or Teicoplanin linezolid versus Vancomycin or Teicoplanin for Nosocomial Pneumonia:A Meta-Analysis for Nosocomial Pneumonia:A Meta-A

13、nalysis AC.KALIL,M.H.MURTHY,E.HERMSEN,et al.AC.KALIL,M.H.MURTHY,E.HERMSEN,et al.Methods:Prospective,randomized trials which tested linezolid vs.Methods:Prospective,randomized trials which tested linezolid vs.vancomycin or teicoplanin for treatment of NP were included.vancomycin or teicoplanin for tr

14、eatment of NP were included.Heterogeneity was analyzed by I2 and Q statistics.Relative Risks Heterogeneity was analyzed by I2 and Q statistics.Relative Risks(RR)were based on the Mantel-Haenszel method.Outcomes analyzed(RR)were based on the Mantel-Haenszel method.Outcomes analyzed included clinical

15、cure(CC),microbiologic eradication(ME),and included clinical cure(CC),microbiologic eradication(ME),and side effects.side effects.Results:8 linezolid trials(6 vancomycin,2 teicoplanin)were Results:8 linezolid trials(6 vancomycin,2 teicoplanin)were included(N=853).The linezolid vs glycopeptide analys

16、is shows: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 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 0.97,1.23;p=0.11;I2=0%;N=597);and MRSA population

17、RR=1.14(CI 0.82,1.58;p=0.44;I2=47%;N=191).If linezolid is compared(CI 0.82,1.58;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 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

18、.73,1.47),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 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;1.29,2.86;p=0.001)and GI events(RR=1.90 CI 1.04,3.48;p=0.03)were signific

19、antly higher with linezolid,but no p=0.03)were significantly higher with linezolid,but no differences were seen for renal dysfunction(RR=0.82 CI 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;0.52,1.27;p=0.37),or all-cause deaths(RR=

20、0.95 CI 0.76,1.18;p=0.63).p=0.63).Conclusions:Conclusions:Meta-analysis did not detect Meta-analysis did not detect clinical superiority of linezolid vs.clinical superiority of linezolid vs.glycopeptides for treatment of NP.glycopeptides for treatment of NP.Compared to linezolid,vancomycin was not C

21、ompared to linezolid,vancomycin was not associated with more renal dysfunction.associated with more renal dysfunction.linezolid showed a significant increase in linezolid showed a significant increase in the risk of thrombocytopenia and GI events.the risk of thrombocytopenia and GI events.Available

22、data does not support the claim Available data does not support the claim that linezolid is superior to vancomycin that linezolid is superior to vancomycin for the treatment of NP.for the treatment of NP.万古霉素治疗万古霉素治疗MRSAMRSA感染疗效未被超越感染疗效未被超越包括菌血症、肺炎以及皮肤软组织感染包括菌血症、肺炎以及皮肤软组织感染万古霉素1g/次，每天2次7-28天(n=220),

23、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 2002,34:1481-1490.万古霉素治疗万古霉素治疗MRSAMRSA起效时间未被超越起效时间未被超越万古霉素1g q12h，7-21天(n=61),利奈唑胺600mg q12h，7-21天(n=57)

24、,*退热定义为体温完全恢复正常时间(天)P=0.2057P=0.2057P=0.1760P=0.1760P=0.6149P=0.6149Http:/www.clinicalstudyresults.org/documents/company-study_1864_0.pdf稳可信：众多权威指南推荐稳可信：众多权威指南推荐l 桑福德桑福德-抗微生物治疗指南2009-2010版l 美国胸科协会美国胸科协会(ATS)(ATS)-关于医院获得性、呼吸机相关及医疗相关肺炎治疗指南l 美国抗感染协会美国抗感染协会(IDSA)(IDSA)-关于导管相关感染治疗指南l HAPHAP亚洲工作组亚洲工作组-关于H

25、AP组首次共识l 欧洲心脏协会欧洲心脏协会(ESC)(ESC)-关于感染性心内膜炎的预防、诊断及治疗指南l 英国抗菌化疗协会英国抗菌化疗协会(BSAC)(BSAC)-关于MRSA感染预防和治疗指南万古霉素万古霉素治疗治疗MRSMRS感染的首选感染的首选稳可信的安全性稳可信的安全性l 适应症比较l 副作用比较患者，疗效安全看得见！患者，疗效安全看得见！稳可信稳可信：拥有：拥有广泛广泛的适应症的适应症适应症万古霉素万古霉素1利奈唑胺2替考拉宁3肺炎皮肤软组织感染导管相关血流感染FDA警告警告？感染性心内膜炎X？脑膜炎X肺脓肿X脓胸X腹膜炎X骨髓炎X关节炎X1.万古霉素产品说明书,2.利奈唑胺产品说

26、明书,3.替考拉宁产品说明书利奈唑胺受到美国利奈唑胺受到美国FDAFDA的警告的警告1 1利奈唑胺已被FDA批准的适应证包括：用于治疗耐万古霉素的屎肠球菌感染、医源性肺炎、社区获得性肺炎、非复杂性的皮肤及软组织感染、复杂性的皮肤和软组织感染（包括未并发骨髓炎的糖尿病足部感染）。20072007年年FDAFDA提醒医务工作者：提醒医务工作者：利奈唑胺未获批准未获批准用于导管相关性血流感染、导管 接触部位感染。相关报导：C:/Documents%20and%20Settings/Administrator/C:/Documents%20and%20Settings/Administrator/Lo

27、cal%20Settings/Temp/Rar$DI06.171/%E5%88%A9Local%20Settings/Temp/Rar$DI06.171/%E5%88%A9%E5%A5%88%E5%94%91%E8%83%BA%E9%80%82%E5%BA%9%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%4%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

28、%E9%999E%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%AF-%A9-%E5%8C%BB%E8%8D%AF%E8%B5%84%E8%AE%AF-%E4%B8%AD%E5%9B%BD%E5%8C%BB%E8%8D%AF%E7%BD%9%E4%B8%AD%E5%9B%BD%E5%8C%BB%E8%8D%AF%E7%BD%91.mht1.mht利奈唑胺适应证外用药增加死亡风险利奈唑胺适应证外用药增加死亡风险 C:/Documents%20and%20Settings/Adminis

29、trator/C:/Documents%20and%20Settings/Administrator/Local%20Settings/Temp/Rar$DI06.171/%E5%88%A9Local%20Settings/Temp/Rar$DI06.171/%E5%88%A9%E5%A5%88%E5%94%91%E8%83%BA%E5%AE%89%E5%85%A%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%8%E6%80%A7%E5%BC%95%E8%B5%B7%

30、E5%B9%BF%E6%B3%9B%E9%87%8D%E8%A7%86-9B%E9%87%8D%E8%A7%86-%E5%8C%BB%E8%8D%AF%E8%B5%84%E8%AE%AF-%E5%8C%BB%E8%8D%AF%E8%B5%84%E8%AE%AF-%E4%B8%AD%E5%9B%BD%E5%8C%BB%E8%8D%AF%E7%BD%9%E4%B8%AD%E5%9B%BD%E5%8C%BB%E8%8D%AF%E7%BD%91.mht1.mht网站相关报导检索关键词：利奈唑胺网站相关报导检索关键词：利奈唑胺1,Wilcox MH,Tack KJ,Bouza E,et al.Compl

31、icated 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 3/18/2007.万古霉素纯度提高，肾毒性发生率大大减少万古霉素纯度提高，肾毒性发生率大大减少 1.Rybak M,Lomaest o B,Rotschafer JC,et al.Therapeutic monitory o

32、f vancomycin in adult patients:A consensus review of the ASHP,IDSA and the SIDP.Am J Health-Syst Pharm 2009,66:82-98.2.林东昉、吴菊芳、张婴元等。利奈唑胺与万古霉素治疗革兰阳性菌感染的随机、双盲、对照、多中心临床试验。中国感染与化疗杂志2009,9(1):10-173.Stevens D.L.Herr D,Lampiris H,et al.Linezolid versus Vancomycin for the Treatment of Methicillin-Resistant

33、 Staphylococcus aureus Infections.Clinical Infectious Diseases 2002,34:1481904.Abad F,CalboF,Zapater P,et al.Comparative pharmacoeconomic study of vancomycin and teicoplanin in intensive care patients.International Journal of Antimicrobial Agents,2000,15:65715.Downs NJ,Robert E.Neihart,MD,Jeanette M

34、.Dolezal,et al.Mild Nephrotoxicity Associated With Vancomycin Use.6.Sorrell TC,Collignon PJ.A prospective study of adverse reactions associated with vancomycin therapy.J Antimicrob Chemother.1985 Aug,16(2):235-41.7.Farbert BF,Moellering RC,Retrospective Study of the Toxicity of Preparations of Vanco

35、mycin from 1974 to 1981,Antimicrobial agents and chemotherapy.1983,23(1):138-1418.Levine DP.Vancomycin:A History.Clinical Infectious Diseases 2006,42:S5-12稳可信稀释后静脉滴注稳可信稀释后静脉滴注药物浓度不超过药物浓度不超过 5 5毫克毫克/毫升毫升每次滴注时间应该超过每次滴注时间应该超过 60 60分钟分钟肾功能损害及年长患者应调整剂量肾功能损害及年长患者应调整剂量必要时监测血药浓度必要时监测血药浓度经常改变输注部位经常改变输注部位稳可信稳

36、可信应用准则应用准则肾功能异常病人剂量调整方法肾功能异常病人剂量调整方法肌酐值以肌酐值以mol/Lmol/L表示时，表示时，K=0.814K=0.814本公式应用于女性值，求得值需乘以本公式应用于女性值，求得值需乘以0.850.85首次负荷剂量首次负荷剂量:15mg/kg:15mg/kg()血清肌酐值年龄）肌酐清除率（-=Kkgml140min/剂量调整例子剂量调整例子某男性病人65岁，体重为70kg,血肌酐值为160mol/L该病人每日稳可信的给药总量为9.370=651mg()6.0160814.065140kmin/=-=）肌酐清除率（gml万古霉素与替考拉宁安全性比较万古霉素与替考拉宁

37、安全性比较万古霉素(n=252)替考拉宁(n=275)肾毒性意大利大样本大样本临床对照试验1血小板减少美国大样本大样本临床对照试验2发生率(%)发生率(%)P=0.68P=0.003万古霉素(n=417)替考拉宁(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 Malignan

38、cies.Anitmicrobial agents and chemotherapy,1994,38(9):2041-2046.Wilson APR,Compative safety of Teicoplanin and Vancomycin.International Journal of Antimicrobial Agents,1998,10:143-152万古霉素治疗万古霉素治疗MRSAMRSA感染副反应发生率与利奈唑胺比较感染副反应发生率与利奈唑胺比较发生率(%)P=0.006P=0.006P=0.037P=0.037P=0.139P=0.139无统计学差异无统计学差异万古霉素1g/

39、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 2002,34:1481-1490.万古霉素和利奈唑胺安全性的比较万古霉素和利奈唑胺安全性的比较由于万古霉素制剂的纯度显著提高，目前临床大量应用万古霉素，证实其肾毒性很少

40、见,包括调整剂量后用于肾功能受损的病人，同时万古霉素的肾毒性具有可逆性28。而有数据表明，利奈唑胺引起的严重不良反应血小板减少的病例高达35%,在肾功能损伤的病人应用利奈唑胺引起的血小板减少达到65%,29。高纯度的万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 Con

41、trol.1987;8(4):151-729 Yen-Hung Lin,Vin-Cent Wu High frequency of linezolid-associated thrombocytopenia Among patients with renal insufficiency.International Journal of Antimicrobial Agent 28(2006)345-351 linezolid versus Vancomycin or Teicoplanin linezolid versus Vancomycin or Teicoplanin for Nosoc

42、omial Pneumonia:A Meta-Analysis for Nosocomial Pneumonia:A Meta-Analysis AC.KALIL,M.H.MURTHY,E.HERMSEN,et al.AC.KALIL,M.H.MURTHY,E.HERMSEN,et al.Methods:Prospective,randomized trials which tested linezolid vs.Methods:Prospective,randomized trials which tested linezolid vs.vancomycin or teicoplanin f

43、or treatment of NP were included.vancomycin or teicoplanin for treatment of NP were included.Heterogeneity was analyzed by I2 and Q statistics.Relative Risks Heterogeneity was analyzed by I2 and Q statistics.Relative Risks(RR)were based on the Mantel-Haenszel method.Outcomes analyzed(RR)were based o

44、n the Mantel-Haenszel method.Outcomes analyzed included clinical cure(CC),microbiologic eradication(ME),and included clinical cure(CC),microbiologic eradication(ME),and side effects.side effects.Results:8 linezolid trials(6 vancomycin,2 teicoplanin)were Results:8 linezolid trials(6 vancomycin,2 teic

45、oplanin)were included(N=853).The linezolid vs glycopeptide analysis shows: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 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 populat

46、ion RR=1.14(CI 0.97,1.23;p=0.11;I2=0%;N=597);and MRSA population RR=1.14(CI 0.82,1.58;p=0.44;I2=47%;N=191).If linezolid is compared(CI 0.82,1.58;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 to vancomycin only,the CC RR remains 1.01(CI 0

47、.90,1.12),and ME and MRSA RRs are:1.06(CI 0.88,1.28)and 1.04(CI 0.73,1.47),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 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;1.29,2.8

48、6;p=0.001)and GI events(RR=1.90 CI 1.04,3.48;p=0.03)were significantly higher with linezolid,but no p=0.03)were significantly higher with linezolid,but no differences were seen for renal dysfunction(RR=0.82 CI differences were seen for renal dysfunction(RR=0.82 CI 0.52,1.27;p=0.37),or all-cause deat

49、hs(RR=0.95 CI 0.76,1.18;0.52,1.27;p=0.37),or all-cause deaths(RR=0.95 CI 0.76,1.18;p=0.63).p=0.63).Conclusions:Conclusions:Meta-analysis did not detect Meta-analysis did not detect clinical superiority of linezolid vs.clinical superiority of linezolid vs.glycopeptides for treatment of NP.glycopeptid

50、es for treatment of NP.Compared to linezolid,vancomycin was not Compared to linezolid,vancomycin was not associated with more renal dysfunction.associated with more renal dysfunction.linezolid showed a significant increase in linezolid showed a significant increase in the risk of thrombocytopenia an