三种抗阳性菌药物比较

1、稳可信VS替考拉宁及利奈唑胺（药物的三大特性比较）有效性安全性经济性稳可信的有效性 作用机制 耐药及敏感率 MIC：万古MIC“飘逸”而非“漂移” 临床疗效 指南推荐重杀菌机制相对于人工合成抗生素的单一抑菌机制万古霉素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, pp284.稳可信上市 年全球仅出现 株耐药1997年日本首先报告了对万古霉素中度敏感的金黄色葡萄球菌(VISA)12002年07年在北美地区先后

2、共确定9株耐药的金黄色葡萄球菌(VRSA)2我国尚无报道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

3、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1. 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.

4、 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.作用于核糖体单一抑菌机制的利奈唑胺的耐药1999年12000年2001年22005年3三期临床时出现2株LRE利奈唑胺上市出现3株LRSA美国匹兹堡大学医疗中心ICU出现74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.Clinic

5、al 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 Staphylocucci.Clini

6、cal Infectious Diseases 2006, 43:165-171.所有金葡菌对万古霉素仍保持100%敏感率2007年ZAAPS细菌耐药性监测结果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 Infectious Disease 2

7、009, 64:191-201.敏感率%国内葡萄球菌对万古霉素保持 敏感率2008年中国CHINET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 敏感率全国主要抗生素对葡萄球菌属敏感率监测 (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MIC分布情况图2

8、20004008001200160020001248利奈唑胺MIC (g/ml)株数 (N)6株4株2007年ZAAPS细菌耐药性监测结果1万古霉素对于金葡菌的MIC90仅为1mg/LJones 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 a

9、nd Infectious Disease 2009, 64:191-201.11欧洲43家医院监测结果Bacteria Year Strain NoVancomycin Teicoplanin MICrMIC90MICrMIC90S. aureus20053370.25-210.12-8220062200.5-210.25-4120071310.5-210.25-412008690.25-210.25-41CoNS2005933282007810.5-220.25-842008910.25-220.12-84S. pyogenes 2005410.250.25NtNt 2006-200714

10、60.12-3-40.032008540.12-3-112820.25-1280.25ECCMID 2009, p1620ECCMID 2009, 163713万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利奈唑胺万古霉素利奈唑胺万古霉素ZYVOX 产品说明书信息 Distributed by Pfi

11、zer Pharmacia&Upjohn Company Divison of Pfizer Inc,NY,NY10017 LAB-0319-16.0 % linezolid versus Vancomycin or Teicoplanin for Nosocomial Pneumonia: A Meta-Analysis AC. KALIL, M. H. MURTHY , E. HERMSEN , et al.Methods: Prospective, randomized trials which tested linezolid vs. vancomycin or teicopl

12、anin 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 teico

13、planin) 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; p=0.44; I2=47%; N=191). If linezolid is compared to vancomycin only, the CC RR

14、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) were significantly higher with linezolid, but no differences were seen for renal d

15、ysfunction (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). Conclusions: Meta-analysis did not detect clinical superiority of linezolid vs. glycopeptides for treatment of NP. Compared to linezolid, vancomycin was not associated with more renal dysfunction. linezoli

16、d 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.万古霉素治疗MRSA感染疗效未被超越包括菌血症、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),利奈唑胺600mg/次，每天2次7-28天(n=240)Stevens DL,Herr D,Lampiri

17、s 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MRSA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),*退热定义为体温完全恢复正常时间 (天)P=0.2057P=0.1760P=0.6149Http:/www.clinicalstudy

18、/documents/company-study_1864_0.pdf稳可信：众多权威指南推荐 桑福德 抗微生物治疗指南2009-2010版 美国胸科协会(ATS) 关于医院获得性、呼吸机相关及医疗相关肺炎治疗指南 美国抗感染协会(IDSA) 关于导管相关感染治疗指南 HAP亚洲工作组 关于HAP组首次共识 欧洲心脏协会(ESC) 关于感染性心内膜炎的预防、诊断及治疗指南 英国抗菌化疗协会(BSAC) 关于MRSA感染预防和治疗指南万古霉素治疗MRS感染的首选稳可信的安全性 适应症比较 副作用比较患者，疗效安全看得见！稳可信：拥有广泛的适应症适应症万古霉素1利奈唑胺2替考

19、拉宁3肺炎皮肤软组织感染导管相关血流感染FDA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. 利奈唑胺产品说明书,3. 替考拉宁产品说明书利奈唑胺受到美国FDA的警告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）。 2007年FDA提醒医务工作者： 利奈唑胺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： FDA-利奈唑胺适应证外用药增加死亡风险 SFDA网站相关报导检索关键词：利奈

20、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 3/18/2007.万古霉素纯度提高，肾毒性发生率大大减少 1.Rybak M, Lomaest o B,Rotschafer JC,et

21、 al. Therapeutic monitory of vancomycin in adult patients: A consensus review of the ASHP, IDSA and the SIDP.Am J Health-Syst Pharm 2009, 66:82-98.2.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 Tr

22、eatment of Methicillin-Resistant 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.D

23、owns NJ, Robert E. Neihart, MD, Jeanette M. 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 S

24、tudy of the Toxicity of Preparations of Vancomycin 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

25、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应用准则23肾功能异常病人剂量调整方法肌酐值以肌酐值以mol/L表示时，表示时，K=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0.85首次负荷剂量首次负荷剂量:15mg/kg()血清肌酐值年龄）肌酐清除率（-=Kkgml140min/24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

26、万古霉素 (n=252)替考拉宁 (n=275)肾毒性意大利大样本临床对照试验1血小板减少美国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 Malignancies

27、. 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MRSA感染副反应发生率与利奈唑胺比较发生率 (%)P=0.006P=0.037P=0.139无统计学差异万古霉素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)Steve

28、ns DL,Herr D,Lampiris H, et al. Linezolid versus Vancomycin for the Treatment of Methicillin Resistant Staphylococcus aureus Infections.Clinical Infectious Diseases 2002, 34:1481-1490.27 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

29、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 Control. 1987;8(4):151-729 Yen-Hung Lin, Vin-Cent Wu High f

30、requency of linezolid-associated thrombocytopenia Among patients with renal insufficiency. International Journal of Antimicrobial Agent 28(2006)345-351 linezolid versus Vancomycin or Teicoplanin for Nosocomial Pneumonia: A Meta-Analysis AC. KALIL, M. H. MURTHY , E. HERMSEN , et al.Methods: Prospecti

31、ve, 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)

32、, 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; p=0.44; I

33、2=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) were signifi

34、cantly 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). Conclusions: Meta-analysis did not detect clinical superiority of linezolid vs. glycopeptides for treatment of NP. Compared to linezoli

35、d, 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.利萘唑胺引起的血小板减少的问题 利萘唑胺关于引起血小板减少的原因可能是： 通过抑制线粒体

36、呼吸、促使成熟血小板减少； 作用于血小板生成素受体，导致血小板生成减少 利萘唑胺引起血小板减少的危害利萘唑胺引起血小板的发生率高（可达47%）,程度严重（可下降到基础值的30%-79%），近半数患者需要停药，影响预期治疗血小板下降到30%的患者的死亡率是血小板正常患者的1.54倍稳可信的经济性 进口抗耐药革兰阳性菌药物中价格最低！抗耐药阳性菌药物经济性比较药物用法用量单价(元/支)日治疗费用(元)稳可信1.0g/bid154元（0.5g/支）154*4支=616替考拉宁首日0.4g/bid维持0.4g/qd343元（0.2g/支）首日4支1372元维持343*2支=686利奈唑胺0.6g/bi

37、d482元（0.6g/袋）482*2袋=964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 Hospital Isolates of Coagulase-Positive and Coagulase-Negative Staphylococci Colleted in the International Muticenter Study RESIST in 1997 and 1998. Micro

38、bial 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.所有金葡菌对万古霉素仍保持100%敏感率2007年ZAAPS细菌耐药性监测结果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.Di

39、agnostic Microbiology and Infectious Disease 2009, 64:191-201.敏感率%国内葡萄球菌对万古霉素保持 敏感率2008年中国CHINET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):321-329.35欧洲43家医院监测结果Bacteria Year Strain NoVancomycin Teicoplanin MICrMIC90MICrMIC90S. aureus20053370.25-210.12

40、-8220062200.5-210.25-4120071310.5-210.25-412008690.25-210.25-41CoNS2005933282007810.5-220.25-842008910.25-220.12-84S. pyogenes 2005410.250.25NtNt 2006-20071460.12-3-40.032008540.12-3-112820.25-1280.25ECCMID 2009, p1620 linezolid versus Vancomycin or Teicoplanin for Nosocomial Pn

41、eumonia: A Meta-Analysis AC. KALIL, M. H. MURTHY , E. 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 (C