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1、常用抗菌药物在 MRSA HAP的临床应用,HAP的流行病学,HAP发病率为0.5%1.0%，居院内感染第二位，占所有院内感染的15%20%。在ICU，HAP发病率高达18%60%。,Chest,2002,122:2115-2121.,肺炎患病危险每日增加1%,在美国，HAP病死率达30%50%，入住ICU者HAP病死率超过50%（有报道达70%），为院内感染首要的死亡原因。,不同人群HAP发病率,88篇论文总计8705例HAP的meta分析,VAP的病原体:NNIS database,86%的医院内肺炎和机械通气相关革兰阳性金黄色葡萄球菌非常常见,Richards et al.Crit Ca
2、re Med 1999;27:887892,5,引起ICU内HAP的病原体NNIS（19862003年）,Clinical Infectious Diseases 2005;41:84854,MRSA引起的感染（2004-2005 美国）,JAMA.2007;298(15):1763-1771,ICU内耐药菌的增加(NNIS,2002 vs 19972001),Resistance(%),0,10,20,30,40,50,60,70,80,90,万古霉素/肠球菌甲氧西林/金葡菌甲氧西林/CNS3rd Ceph/E.coli3rd Ceph/K.pneumoniaeImipenem/P.aeru
3、ginosaQuinolone/P.aeruginosa3rd Ceph/P.aeruginosa3rd Ceph/Enterobacter spp.,+11+13+1+142+32+27+225,Change in resistance(%),JanDec 2002,19972001(sd),Ceph=cephalosporin;NNIS=National Nosocomial Infections Surveillance System;CNS=coagulase-negative staphylococci,NNIS.Am J Infect Control 2003;31:48198,I
4、CU病人与MRSA,CDC.Available at:http:/www.cdc.gov/ncidod/hip/ARESIST/ICU_RESTrend1995-2004.pdf.Accessed August 30,2005.Lowy FD.J Clin Invest.2003;111:1265-1273.,63%,MRSA 在中国,不同时期甲氧西林耐药葡萄球菌的检出率,检出率（%）,中国CHINET（2006）,Prevalence of MRSA in China,798 isolates,2005,12 Cities,China,%,Wang H et al.Int J Antimic
5、rob Agents 2008;(online),S.aureus Pathogenic Mechanisms,Cell wallPeptidoglycanTeichoic acidsProtein AEnzymesCatalaseCoagulaseClumping factor,Toxins-toxin-toxin/-toxin/-toxinLeukocidinSuper antigensToxic Shock SyndromeEnterotoxinsExfoliative,HA-MRSA主要感染住院病人，几乎都是通过接触传播，通常感染年纪大、病情较严重、皮肤有伤口（例如褥疮）或有导管（如导
6、尿管）的人，健康人很少会感染CA-MRSA能够感染健康人拥挤的监狱中颇为流行近年在美国各地的城镇社区（包括洛杉矶、旧金山、纽约、波士顿、迈阿密等大城市）也出现了多次小规模爆发,CA-MRSA：现状,美国弗吉尼亚州贝德福德一名17岁高中生就因感染MRSA而死亡，21所学校停课 美国每年有逾9万人感染MRSA；每年致死人数可能超过艾滋病,阿什顿邦兹，07年10月4日感到身体一侧疼痛，就到当地一家医院就诊。10月17日死亡。,Zeller JL,et al.JAMA patient page.MRSA infectionsJAMA.2007 Oct 17;298(15):1826.,CA-MRSA,
7、CA-MRSA,全球范围内社区获得性MRSA的发病率呈上升趋势社区获得性MRSA可从以下情况中隐匿获得 医疗保健 日常生活 过去一年中住院超过5天 社区获得性MRSA，表达Panton-Valentine leukocidin(p-v)潘顿-瓦伦丁杀白细胞素,JAC 2004;53:4749.Infect Control Hosp Epidemiol 2003;24:40914.Emerg Infect Dis 2003;9:97884.,Emerg Infect Dis 2003;9:97884 Infect Control Hosp Epidemiol 2003;24:4515Clin I
8、nfect Dis 2003;36:1319.,PVL Positive S.aureusCommunity-acquired PneumoniaGillet et al,Clin Infect Disease,2007,50 cases over 9 years from 39 hospitals in 9 countriesSelection biasOnly 12%MRSA casesInfluenza-like illness 67%,confirmed in 4/924%concomitant skin infectionsPleural effusion 53%,multiloba
9、r infil 79%Mech vent 78%,ARDS 51%Mortality 56%,all due to pneumonia,Community-acquired MRSA Pneumonia,Survey of IDSA Emerging Infection Network After 06-07 influenza season30%reported a case of hospitalized S.aureus CAPCharacteristics 440 adults,117 children72%MRSA49%mechanical ventilation13%mortali
10、ty43%bacteremiaInfluenza suspected 26%,CA-MRSA Pneumonia,CA-MRSA CAP will be an increasing problemMay correlate more with skin colonization than nasalPVL is necessary but not sufficient to define high risk pathogenCavitary/necrotizing pneumonia+/-effusionCombination with influenza appears to be part
11、icularly lethal,even if MSSAMassive hemoptysis,neutropeniaToxin suppression appears to be an important component of effective treatmeant,HAP的病原体构成主要影响因素,住院的时间 早发 晚发肺炎本身的严重程度：重症 非重症基础疾病 先前的治疗（抗生素、免疫抑制）,住院时间与HAP致病菌的关系,早发性HAP和晚发性HAP的病原菌,Infect Control Hosp Epidemiol 2007;28:825-831,Etiology of HAP In A
12、sian Countries,*Philippines:VAP data,Asian HAP Working Group.Am J Infect Control 2008;36:S83-92.,Adapted from Kollef MH et al.Chest.1999;115:462-474.ATS/IDSA.Am J Respir Crit Care Med.2005;171:388-416.,“selection of initial appropriate antibiotic therapy(ie,getting the antibiotic treatment right the
13、 first time)is an important aspect of care for hospitalized patients with serious infections.”ATS/IDSA Guidelines,A Study by Kollef and Colleagues Evaluating the Impact of Inadequate Antimicrobial Therapy on Mortality,不充分的抗生素治疗(n=169),充分的抗生素治疗(n=486),0,10,20,30,40,50,60,总死亡率,感染相关死亡率,24,42*,18,住院死亡率(
14、%),52*,*P.001,充分起始抗生素治疗降低ICU内肺炎死亡率,1.Ibrahim EH,et al.Chest.2000;118:146-155.2.Valles J,et al.Chest.2003;123:1615-1624.3.Khatib R,et al.Eur J Clin Microbiol Infect Dis.2006;25:181-185.4.Teixeira PJZ,et al.J Hosp Infect.2007;65:361-367.5.The American Thoracic Society and the Infectious Diseases Socie
15、ty of America.Am J Respir Crit Care Med.2005;171:388-416.,0,10,20,30,40,50,60,70,80,菌血症,社区获得性-,菌血症,金葡菌,菌血症,呼吸机相关,肺炎,病死率(患者%),正确的抗菌治疗,不恰当的抗菌治疗,P,.001,1a,3,P,.05,P,=.02,2,4a,P=,.02,不充分的初始经验性抗菌治疗的影响,不充分初始治疗使死亡率上升研究显示，不充分治疗是病死率高的重要独立危险因素1-4,不充分初始治疗定义为：分离到的病原菌对所使用的药物不敏感5,选择初始适当治疗应考虑的因素*,患者有无危险因素严重程度HAP或V
16、AP发生时间（住院时间）既往抗生素使用区域微生物学和细菌耐药模式 药物代动力学和药效学*正确的抗生素剂量和疗程获取最佳疗效的给药间隔应用可穿透感染部位的制剂联合治疗的必要性预期的临床转归,*Karam,George H,et al.Crit Care Med 2003;31（2）:648650*Schentag JJ,et al.Clin Infect Dis 1998,26:1204-1214.Young RJ,et al.J Antimicrob Chemother 1997,40:269-273,怀疑HAP、VAP或HCAP,晚发(5 days)HAP或 MDR病原体的危险因素,否,是,
17、窄谱抗菌药物,广谱抗菌药物针对MDR病原体,HAP初始经验性抗菌药物治疗的流程图,ATS.Am J Respir Crit Care Med 2005;171:388-416,Risk Factors for Multidrug-Resistant Pathogens(MDRP)HAP,VAP,HCAP,Antimicrobial therapy in preceding 90 daysCurrent hospitalization of 5 days or moreHigh frequency of antibiotic resistance in the community or in t
18、he specific hospital unitPresence of risk factor for HCAPHospitalization for 2 days or more in preceding 90 daysResidence in a nursing home or extended care facilityHome infusion therapy(including antibiotics)Chronic dialysis within 30 daysHome wound careFamily member with MDRPImmunosuppressive dise
19、ase and/or therapy,Bonten MJ et al.Am J Respir Crit Care Med 2005;171:388-416.,经验性治疗:晚期发病或存在MDR病原菌感染,2006年亚洲HAP工作组抗生素选择策略特殊耐药菌感染的抗生素方案,Jae-Hoon Song,and the Asian HAP Working Group.Am J Infect Control 2008;36:S83-92.,金葡肺炎：女，26岁，宫腔术后,金葡菌,Nosocomial Pneumonia due to MRSA,Sputum and blood:MRSA,Better 1
20、st-line Anti-MRSA Agents,Glycopeptide orLinezolid?,万古霉素、利奈唑胺和替考拉宁分子结构比较,万古霉素是微生物发酵产生的天然抗生素,属糖肽类抗生素利奈唑胺是人工合成的抗菌药,属于噁唑烷酮类抗菌药物替考拉宁是微生物发酵产生的抗生素,属于糖肽类抗生素,万古霉素、利奈唑胺和替考拉宁 抗菌谱比较,万古霉素、替考拉宁和利奈唑胺的抗菌谱相似，都是窄谱抗生素，治疗革兰阳性菌感染 金葡菌，包括MRSA 肺炎链球菌，包括PRSP 凝固酶阴性葡萄球菌，包括MRCNS 肠球菌，有少数耐药菌株,万古霉素、利奈唑胺和替考拉宁 适应证的比较,35、稳可信、他格适和斯沃产品
21、说明书,万古霉素抗菌素作用机制,万古霉素属快效杀菌剂具有三重作用机制1.抑制细菌细胞壁的合成抑制细菌细胞壁粘肽链合成的第二步 与五肽末端氨基酸分子结合，阻断转肽交叉连接 转糖作用发生障碍2.影响细菌细胞膜的通透性3.抑制细菌孢浆中RNA的合成,糖肽类,糖肽类抗菌机制,Vancomycin,It is not obsoleteIt works mostlyResistance is rareIt is cheap,It is obsoleteTissue concentrationProtein bindingNeed high trough concentrationsMIC creepPoo
22、r target attainment when MICs1VISA and hVISA hVanco,S.aureus with reduced vancomycin susceptibility,2000(n=945),2001(n=1026),2002(n=1317),2003(n=1297),2004(n=1418),万古霉素对金葡菌的MIC值呈逐年上升趋势,Wang G et al.J Clin Microbiol.2006;44:3883-3886,*一项自2000年1月至2004年12月UCLA医学中心对6003例临床分离金黄色葡萄球菌菌株进行的分析监测结果,近年来，万古霉素对7
23、0%金黄色葡萄球菌的MIC值1g/mL*,分离菌株的百分比(%),Implications of decreasing susceptibility to vancomycin,Gradual reductions in vancomycin susceptibility in S aureus1,2Vancomycin-intermediate S aureus(VISA)strains have emergedTreatment failure in MRSA bacteremia may occur within the susceptible vancomycin MIC range2
24、,1.Wang G,et al.J Clin Microbiol.2006;44:3883-3886.2.Sakoulas G,et al.J Clin Microbiol.2004;42:2398-2402.,CLSI MIC breakpoints:2 mg/mLSusceptible4-8 mg/mLIntermediate 16 mg/mL Resistant,CLSI=Clinical and Laboratory Standards Institute.,万古霉素PK与PD,PK/PD分类：兼具时间依赖性与浓度依赖性双重特征万古霉素血药浓度要求峰浓20-40ug/ml谷浓10-15
25、ug/ml最佳杀菌效应应为MIC3-5倍单次给药间隔TMIC或T3MIC以上时间应40%,万古霉素PK与PD,以t1/2 6hr 1g 滴注 1hr 滴注结束，即刻峰浓60ug/ml；2hr后峰浓 25ug/ml计,用药剂量：1.0g q12h,万古霉素PK与PD,以t1/2 6hr 0.5g 滴注 30分滴注,结束即刻峰浓33ug/ml;6hr后峰浓 2.8ug/ml计,用药剂量：0.5g q8h,万古霉素小鼠 S.aureus 腿感染PK/PD(AUC24/MIC、Cmax/MIC、TMIC),R2=90%,-4,-2,0,2,-4,-2,0,2,10,100,1000,10,100,10
26、00,1,-4,-2,0,2,40,100,120,0,20,60,80,R2=56%,R2=75%,Free drug AUC24/MIC,Free drug Cmax/MIC,Free drug%TMIC,CFU change in Lg10/thign,CID 2006,42(suppl 1):S35,万古霉素疗效与 AUICs,OutcomeParameters Satisfactory Unsatisfactory IndeterminateMIC 1.0 g/ml 1 4a 0MIC 125(76)71 2 3Total Patients(84)75 6 3,a p 0.001 b
27、 p 0.005,Hyatt et al,Clinical Pharmacokinetics 1995,28:143,万古霉素MIC与MRSA败血症/肺炎感染治疗,Wilhelm KL.2008 ICAAC abstract A-1905,万古霉素MIC与MRSA 败血症疗效,Kaur I.2008 ICAAC abstract K-564,国内葡萄球菌对万古霉素始终保持100%敏感率,1998-2006全国细菌耐药监测结果,1、李家泰,Allan J Weinstein,杨敏等.中国细菌耐药监测研究.中华医学杂志 2001;81(1):8-162-7.国家细菌耐药性监测中心监测数据总结,RE
28、SIST研究中3100株耐甲氧西林葡萄球菌对12种抗生素的耐药率,RESIST研究中207株甲氧西林敏感葡萄球菌对12种抗生素的耐药率,RESIST研究的结论,3307株葡萄球菌中：除一株MRCNS，所有菌株对万古霉素保持100%敏感无论对甲氧西林耐药还是对甲氧西林敏感的葡萄球菌对替考拉宁存在不同程度耐药，尤其是凝固酶阴性葡萄球菌MRCNS对替考拉宁的耐药性高，其中耐甲氧西林溶血性葡萄球菌(MRSH)对替考拉宁的耐药率高达48.2%对甲氧西林敏感的溶血性葡萄球菌(MSSH)对替考拉宁的耐药率达38.5%,2009年CLSI最新指南：,葡萄球菌：,万古霉素与同为糖肽类替考拉宁相比：万古霉素对葡萄
29、球菌和肠球菌的MIC值比较中，万古霉素仍然有明显的优势,肠球菌：,万古霉素在肺组织的浓度,在一项30例行肺叶次全切除术的患者研究中，静脉给予万古霉素1 g 之后，组织药物浓度范围为0-12.2 mg/kg，平均组织浓度为2.8 mg/kg，组织穿透率为41%,Penetration of vancomycin into human lung tissueM.Cruciani,G.Gattr*,L.Lazzarini,G.Furlan,G.Broccali,M.Malena,C.Franchini and Ercole Concia,万古霉素的肺组织浓度,健康志愿者给予万古霉素1 g q12h
30、给药后，12 h肺组织浓度为2.4 mg/kg，总体穿透率为52%。,Program and abstracts of the 14th European Congress of Clinical Microbiology and Infectious Diseases(Prague).Basel:European Society of Clinical Microbiology and Infectious Diseases,2004:4431 MichaelJ.Rybak The Pharmacokinetic and Pharmacodynamic Properties of Vanco
31、mycin.Clinical Infectious Diseases 2006;42(Suppl 1):S35S39,不同时间血浆和肺组织中万古霉素的浓度1,万古霉素治疗金葡菌菌血症和心内膜炎的临床疗效,9 Ann Int Med 115:674 10 JAMA 238:1756 11 J Antimicrob Chemo 14:Suppl D:73 12 J Infect Dis 147:137 13 NEJM 262:49-55 14 Ann Int Med 97:330-338 15 Antimicro Agents and Chemo 23:36 16 Ann Int Med 97:3
32、44,替考拉宁治疗重症感染的疗效,17 J Infect Dis 1987;155(2):187-91 18 Int J Antimicrob Agents 1994;4(Suppl 1):S1-S30 19 Clin Drug Invest 1996;12:80-7,替考拉宁治疗金葡菌心内膜炎的疗效,20 J Antimicro Chemo 27(Suppl B):43 21 Antimicrob Agents S1 24 ICC 1993,Abstract 1223,万古霉素和替考拉宁的疗效比较,同属于糖肽类抗生素，具有相似的化学结构和抗菌谱 金葡菌和凝固酶阴性葡萄球菌对替考拉宁易产生耐药
33、 替考拉宁较高的蛋白结合率（90-97%),使感染部位无法达到有效 的药物浓度，导致对严重感染疗效不确切，需加大剂量 替考拉宁常规剂量临床疗效不理想（尤其在心内膜炎），加大剂 量往往导致副反应增加 研究表明，稳可信与替考拉宁在引起皮疹，肾功能障碍等副反应 方面无统计学差异；但替考拉宁引起的血小板减少症的发生率显 著高于稳可信,利奈唑胺抗菌机制,利奈唑胺抗菌谱,Gram-positive microorganisms:屎肠球菌(包括VRE)金黄色葡萄球菌(包括MRSA)肺炎链球菌(包括PRSP)无乳链球菌化脓性链球菌粪肠球菌(包括VRE)表皮葡萄球菌(包括MRSE)溶血葡萄球菌草绿色链球菌Som
34、e anaerobic bacteria:,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,治疗医院内肺炎的临床研究.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%,0,10,20,30,40,50,60,利奈唑胺,万古霉素,利奈唑胺,25 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
35、TeicoplaninFor Nosocomial Pneumonia:A Meta-AnalysisAC.KALIL,M.H.MURTHY,E.HERMSEN,et al.Methods:Prospective,randomized trails which tested linezolid vs.vancomycin or teicoplanin of NP were included.Heterogenneity was analyzed by I2 and Q statistics.Relative Risks(RR)were base on the Mantel-Haenszel m
36、ethod.Outcomes analysed included clinical cure(CC),microbiologic eradication(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
37、%;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 remains 1.01(CI 0,73,1.47),respectively.The risk of thrombocytopenia(RR=1.92CI 1.29,2.86;p=0.001)and GI event(RR=1.90CI 1.04,3.48;p=0.03)were significantly higher with linezol
38、id,but no differences were seen for renal dysfunction(RR=0.82CI 0.52,1.27;p=0.37,or all cause deaths(RR=0.95CI 0.76,1.18;P=0.63).,2008 ICAAC K-533,Conclusions:Meta-analysis did not detect clinical superiority of linezolid vs.glycopeptides for treatment of NP.Compared to linezolid,Vancomycin was not
39、associated with more renal dysfunction.Linezolid shows a significant increase in the risk of thrombocytopenia an GI events.Available data dose not support the claim that linezolid is superior to vancomycin for the treatment of NP.,利奈唑胺耐药性,抗菌机制:50S亚基中23S rRNA V区结合耐药机制:23S rRNA V区点突变,G2576T叠加性:5-6个23S
40、 rRNA 基因逐步变异交叉耐药:氯霉素,链阳霉素,林可霉素Enterocccus,Staphylococcus临床菌株已有报道实验室筛选,万古霉素和替考拉宁安全性的比较,26、a p=0.007,Fishers test27、Source:Wilson,Grunberg,Neu,Int.J.Antimicrob Agents,Suppl 1:S1(1994),万古霉素和利奈唑胺安全性比较,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减少的病例
41、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 frequency o
42、f linezolid-associated thrombocytopenia Among patients with renal insufficiency.International Journal of Antimicrobial Agent 28(2006)345-351,Antibiotic regimens against specificantibiotic-resistant pathogens Pathogen Rank Antibiotic regimen MRSA 1 Vancomycin or teicoplanin 2 Linezolid or tigecycline
43、 MDR P.aer 1 Piperacillin/tazobactam or carbapenems aminoglycosides or fluoroquinolones(cipro)2 Polymyxin B or colistin ciprofloxacin MDR Acinetobacter 1 Cefoperazone/sulbactam and/or tigecycline 2 Polymyxin B or colistin ESBL1 K.pn 1 Carbapenems or tigecycline 2 Piperacillin/tazobactam ESBL1 E.coli
44、 1 Carbapenems or tigecycline 2 Piperacillin/tazobactam,Treatment recommendations of hospital-acquired pneumonia in Asian countries:first consensus report by the Asian HAP Working Group,Copyright a 2008 by the Association for Professionals in InfectionControl and Epidemiology,Inc.doi:10.1016/j.ajic.
45、2007.01.015 S83,万古霉素治疗MRS感染的一线方案,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 1,美国感染协会(IDSA)关于肿瘤病人中性粒细胞减少治疗指南 2,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 3,美国感染协会(IDSA)关于导管相关感染治疗指南 4,桑福德抗微生物治疗指南2008版 5,万古霉素-治疗MRS感染的首选,小结,MRSA出现万古霉素耐药值得重视，目前VRSA、VISA很少hVISA的临床意义和检测仍有待更深入的研究：药敏与临床结果的关系及其他可以作为评价的指标、可靠和可行的检测技术、优化临床治疗的剂量方案万古霉素仍然治疗MRSA感染的标杆，新药临床实验均以其作对照，虽然某些新药在某些方面显示有点，但总体上还没有全面超优万古霉素的新药。万古霉素另有一个重要优点，即没有药物相互作用。即使存在hVISA，但其发生率不高。因此，认为万古霉素“过时”是没有依据的,万古霉素临床应用50年，国内应用10多年变化的是耐药细菌有不断增多的趋势不变的是万古霉素对革兰阳性菌强大的抗菌活性国内葡萄球菌中未见耐药菌株肺炎球菌中未见耐药菌株国内临床分离的肠球菌对万古霉素耐药少见对于怀疑耐甲氧西林葡萄球菌感染的患者，应首选万古霉素等糖肽类抗生素，对于肾功能损害的患者，应根据肌酐清除率调整用药方案，监测肾功能,小结,
