抗革兰阳性菌药物的研究进展-肖永红教授

抗革兰阳性菌药物

研究进展肖永红浙江大学医学院附属第一医院传染病诊治国家重点实验室2023/10/7Dr.Xiao2全国细菌耐药监测结果

北京大学临床药理研究所2023/10/7Dr.Xiao3抗菌药物的研究与开发总体处于低谷；方向:抗耐药菌为主、抗阳性菌为主；甘酰胺环素：抗MRSA、ESBL(+)菌(tigecyclin)头孢菌素：抗MRSA(ceftobiprole)碳青霉烯类：抗MRSA(cs-023)糖肽类：dalbevancin,oritavancin,telavancin恶唑烷酮类：linezolid酯肽类：datomycin链阳霉素：synercid酮内酯类：telithromycin,cethromycin奎诺酮类：sitafloxacin、DX-619,garenoxiacinPMF抑制剂：化合物我国可供应用的新药：non2023/10/7Dr.Xiao4糖肽类药物万古霉素替考拉宁DalbavacinOritavacinTelavacin2023/10/7Dr.Xiao5MGMGMGMGMGMGMG糖肽类糖肽类抗菌机制2023/10/7Dr.Xiao6万古霉素研究进展细菌SENTRYBUICP年代株数MIC50MIC90%V>8%T>8株数MIC50MIC90表葡199884822-8.4134241999103422-8.72000104522-7.6151222001115522-4.0200291412-2.011724200390612-4.19314金葡1998596611-0.198121999501111-0.12000634611<0.10.1238122001590711-0.12002704611-<0.1166122003518211-0.127811CID2006,42(s1):S132023/10/7Dr.Xiao7欧洲43家医院监测结果BacteriaYearStrainNoVancomycinTeicoplaninMICrMIC90MICrMIC90S.aureus2005337<0.25-21<0.12-8220062200.5-210.25-4120071310.5-210.25-412008690.25-210.25-41CoNS200593<0.25-420.25-1642006810.5-220.25->3282007810.5-220.25-842008910.25-220.12-84S.pyogenes2005410.250.25NtNt2006-----20071460.12-0.50.25<0.03-4<0.032008540.12-0.250.25<0.03-1<0.03Enterococci20053010.125-2562560.06-256642006-----2007720.25-220.5-20.2520081070.25->12820.25-1280.25ECCMID2009,p16202023/10/7Dr.Xiao8ECCMID2009,16372023/10/7Dr.Xiao9MICCreepforMRSA?Reynolds,etal.ICAAC2009,posterC2-1452023/10/7Dr.Xiao10关于：VISA,hVISA,VRSA定义:VISA/GISA:万古霉素MIC在4-8mg/L.Vancomycin(glycopeptides)intermediateS.aureushVISA:敏感菌中含有VISA亚群,通过万古霉素培养基(4-6mg/L)筛选获得.HeterogeneousvancomycinintermediateS.aureusVRSA:万古霉素MIC>=16mg/L.VancomycinresistantS.aureusCID2001,32:1082023/10/7Dr.Xiao11肠球菌耐药现状(Mohnarin)

全国细菌耐药监测年代药品粪肠球菌（122）屎肠球菌（104）S%I%R%S%I%R%2004-2005万古霉素99.20.80.098.11.90.0替考拉宁100.00.00.0100.00.00.02006-2007万古霉素91.86.91.395.11.83.2替考拉宁97.90.81.395.21.03.82008万古霉素91.371.794.52.43.1替考拉宁980.11.196.80.82.42023/10/7Dr.Xiao12MGMG+vanAddlvanXD-AlaD-LacpyruvatevanHvancomycinVanSVanRppVanA型耐药机制vanRvanSvanHvanAvanXvanYvanZ感知万古霉素并传递信号给其他基因以D-乳酸盐合成细胞壁前体破坏正常D-ala-D-ala前体增强对万古霉素耐性TheVanAsystem(Tn1546)2023/10/7Dr.Xiao14VANCOMYCINAUC24/MIC、Cmax/MIC、T>MICmiceS.aureusmicethighinfectionR2=90%-4-202-4-2021010010001010010001-4-202401001200206080R2=56%R2=75%FreedrugAUC24/MICFreedrugCmax/MICFreedrug%T>MICCFUchangeinLg10/thignCID2006,42(suppl1):S352023/10/7Dr.Xiao15VancomycinOutcomesvsAUICsOutcomeParametersSatisfactory UnsatisfactoryIndeterminateMIC>1.0µg/ml 1 4a 0MIC<1.0µg/ml 74 2 3AUIC<125 4 4b 0AUIC>125(76) 71 2 3TotalPatients(84) 75 6 3ap<0.001bp<0.005Hyattetal,ClinicalPharmacokinetics1995,28:1432023/10/7Dr.Xiao16细菌MIC与MRSA败血症/肺炎感染治疗WilhelmKL.2008ICAACabstractA-1905参数MIC≤1MIC>1病例数2018万古霉素谷浓度(mg/L)18.618.7AUIC503±277267±95AUIC>400(%)6011Clinicalresponse,lengthofstay,mortalityandnephrotoxicitywereequal.2023/10/7Dr.Xiao17MRSABacteremia:EffectsofVancomycinMICsonOutcomeOutcomeLowMIC(<2µg/ml)HighMIC(=2µg/ml)Pvalue30-daymortality20/107(18.7%)10/54(18.5%)0.90Infectionrelatedcomplications17/104(16.3%)11/54(20.4%)0.50Persistentbacteremia>7days9/104(8.65%)11/54(20.4%)0.03KaurI.2008ICAACabstractK-5642023/10/7Dr.Xiao18神经外科术后万古霉素脑脊液浓度SurgicalNeurology2008,69:126–1292023/10/7Dr.Xiao19其他相关研究连续静脉滴注&间歇给药;药物监测:监测的目的?万古霉素需要常规监测吗?老年肾功能不全MIC>2mg/L大剂量应用2023/10/7Dr.Xiao20万古霉素IVI&CVI治疗骨髓炎比较ParametersIVI(21)CVI(23)pvalueDailydosage(mg/kg)31.9±12.533.9±12.90.13Dosingchange(pertreatment)1.7±1.11.1±1.20.09Concentrations(mg/L)21.7±9.326.0±6.10.0001Ttotargetcon(wks)2.5±2.81.4±0.70.18Convariability(mg/L)7.95.60.001Seruminhibitingquotient14.1±8.416.5±8.60.38Meanduration(wks)9.4±12.214.4±8.40.002Patientscured7(77.8%)17(94.4%)0.25JournalofClinicalPharmacyandTherapeutics(2004)29,351–3572023/10/7Dr.Xiao21Vancomycinsafety项目FarberMellorSorrelCiminoDownsRybakGoetzSalamaElting年代198319851985198719891990199319931998设计回顾前瞻前瞻回顾前瞻前瞻前瞻前瞻前瞻例次94335481662316991747人群医疗医疗医疗肿瘤医疗医疗医疗医疗肿瘤总体肾毒%1617715171022717单独肾毒%590151351908合并AG者%35714152722241432耳毒%1125-----4静脉炎%13-37-14---3皮疹%3-6-0---11Cancer1998;83:25972023/10/7Dr.Xiao22ANTIMICROBAGENTS&CHEMOTHER,2008,52(4):1330–13362023/10/7Dr.Xiao23FinallogisticregressionmodelfortheoccurrenceofnephrotoxicityParametersAdjustedOdds95%confidentialpvalueVanco≥4g/d4.41.7-11.80.003BW≥101.4kg3.41.5-7.90.004CrCl<86.6ml/min3.71.2-11.50.020ICUstay2.21.1-4.60.045ANTIMICROBAGENTS&CHEMOTHER,2008,52(4):1330–13362023/10/7Dr.Xiao24Troughconcentration&nephrotoxicityItemsCtrough<15mg/LCtough≥15mg/LPvaluePatients(m/f)98(94/4)65(63/2)0.7Medianage58(49-67)62(56-74)0.02hypertension33%52%0.01Chronicrenaldis2%12%0.02ICUstay3%5%0.7MedianCtrough9.5(7.1-11)17.2(15.9-20.6)<0.0001Medianduration7(5-13)ds9(6-14)ds0.09LOS(days)17(9-33)22(10-49)0.3Nephrotoxicity%3%8%0.3Definition:Scrincreased0.5mg/Lor50%comparingwithbaselineMora,etalICAAC2009,posterA1-1294b2023/10/7Dr.Xiao25肾功能不全患者万古霉素的应用Patientwithnormalrenalfunction:1gq12hPatientwithrenalfailure:GFR≥50ml/min:1gq12-24hGFR10-50:1gq2-7d20-50:500mgq12-24h(UK)10-20:500mgq24-48h(UK)GFR<10:1gq7-10d/500mgq2-4d(UK)PatientwithdialysisHemodialysiswithgeneralfilm:noadjustmentHemodialysiswithhighfiltrationfilm,CAPD,CAVH:sameasGFR10-502023/10/7Dr.Xiao26万古霉素应用要点治疗耐药阳性菌感染首选药物;蛋白结合率低/特殊部位浓度低;浓度非依赖性药物,AUIC>125?300-400?金葡菌MIC>=2时(VISA/hVISA),需增大剂量;Cmin维持在15mg/L以上为宜;20-40mg/kg/d;(脑膜炎可60mg/kg)安全性良好(肾毒性低,基本没有耳毒性).ClinicalInfectiousDiseases2009;49:325–72023/10/7Dr.Xiao27万古霉素替考拉宁分子量：1486分子量：18912023/10/7Dr.Xiao28万古霉素&替考拉宁体外抗菌活性比较细菌万古霉素替考拉宁细菌万古霉素替考拉宁MSSA0.78-3.10.2-1.6猪链球10.4-0.5MRSA0.3-3.120.2-3.12草绿链球10.25-0.4MSSE1.56-6.31.56-6.3肠球菌1.56-40.2-3.1MRSE3.1-43.1-12.5李司忒菌1.60.8肺炎球菌0.25-0.80.1-0.2JK棒杆菌0.8-1.560.8-1.56化脓链球0.25-0.80.1-0.2艰难梭菌1-1.60.2-0.8无乳链球0.78-10.1-0.52023/10/7Dr.Xiao29万古霉素&替考拉宁不良反应比较不良反应病人数量(发生率%)替考拉宁(406)万古霉素(417)过敏反应49(12.1)48(11.5)发热17(4.2)12(2.9)瘙痒9(2.2)11(2.6)皮疹36(8.8)33(7.9)畏寒5(1.2)3(0.7)腹泻23(5.7)29(7)恶心/呕吐11(2.7)13(3.6)听力/平衡5(1.2)6(1.4)肝功异常5(1.2)6(1.4)肾毒性25(6.2)27(6.5)血液学异常16(3.9)5(1.2)血小板减少14(3.4)2(0.5)InternationalJournalofAntimicrobialAgents10(1998)143–1522023/10/7Dr.Xiao30万古霉素与替考拉宁比较CharactersVancomycinTeicoplaninInvitroactivityCNS活性梢强链球菌活性梢强ResistanceVanA、VanBVanAPK静脉给药、半衰期短、组织渗透性偏低、蛋白结合率中等、AUC/MIC静脉、肌肉给药、半衰期长、组织渗透性稍好，蛋白结合率高安全性与氨基糖甘类联合使用时，发生肾功能损害率稍高血小板减少稍多研究与应用经验多有限2023/10/7Dr.Xiao31糖肽类药物构效关系亲脂侧链增加对细菌细胞膜的锚定,提升抗菌活性2号环的Cl与6号环的糖基,促使相互形成二聚体,抗菌作用增强CurrentOpinioninPharmacology2004,4:471–4782023/10/7Dr.Xiao32糖肽类药物体外抗菌活性比较细菌耐药型MIC90(mg/L)vancooritatelateicodalbS.auresuMSSA1-210.51-40.06-0.125MRSA1-41-20.5-12-80.06-0.25VISA81-822GRSA>1280.52S.epidermMSSE1-220.54-80.25MRSE1-4118-160.25S.pneumPenS0.50.0060.0150.06-0.1250.03-0.06PenR0.25-0.5<0.00210.030.03EnterococVanS10.0160.5-10.12VanA>1281-40.5>32>128VanB1280.1254-8212023/10/7Dr.Xiao33新糖肽类双重作用机制MGMGMGMGMGMGMGoritavancinJ.Mol.Biol.(2008)377,281–2932023/10/7Dr.Xiao34糖肽类药物PK参数比较参数药物与剂量(mg/kg)Van(15)Ori(3)Tela(7.5)Teico(6)Dalba(15)Cmax(mg/L)20-50(63/1g)318943312Vd(L/kg)0.30.10.9-1.60.11PB(%)10-559090-939096T1/2(h)4-8360783-168149AUC(mg.h/l)26015260055027103PD折点（Af/M）20.10.50.44PD折点(Cf/M)0.310.62023/10/7Dr.Xiao35糖肽类药物总体评价优势不足研究全面深入部分组织浓度较低

(脑膜炎鞘内注射)临床应用经验丰富安全性高耐药少且不易2023/10/7Dr.Xiao36恶唑烷酮类——利奈唑烷OC3HHCNOONFONLinezolid(PNU-100766)2023/10/7Dr.Xiao37Linezolid

抗菌机制2023/10/7Dr.Xiao38Linezolid

抗菌谱Gram-positivemicroorganisms:

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Someanaerobicbacteria:2023/10/7Dr.Xiao39vancomycin/aztreonamvslinezolid/aztreonamforthetreatmentofHAPCID2001,32:4022023/10/7Dr.Xiao40LZ与VANCO治疗VAP两对照研究回顾分析p=0.070.020.060.001Kollef,IntensiveCareMedicine,2004,30:388-394问题回顾性分析,缺乏研究设计;病原菌检查缺乏定量,不能完全确定为致病菌;对照组合并糖尿病,心脏疾病多;微生物确认(血培养,胸水培养)的VAP和S.aureusVAP,两组没差异;病例数,病例特征??2023/10/7Dr.Xiao41

LinezolidversusVancomycinorTeicoplaninforNosocomialPneumonia:AMeta-AnalysisAC.KALIL,M.H.MURTHY,E.HERMSEN,etal.Methods:Prospective,randomizedtrialswhichtestedlinezolidvs.vancomycinorteicoplaninfortreatmentofNPwereincluded.HeterogeneitywasanalyzedbyI2andQstatistics.RelativeRisks(RR)werebasedontheMantel-Haenszelmethod.Outcomesanalyzedincludedclinicalcure(CC),microbiologiceradication(ME),andsideeffects.Results:8linezolidtrials(6vancomycin,2teicoplanin)wereincluded(N=853).Thelinezolidvsglycopeptideanalysisshows:CCRR=1.01(95%CI0.93,1.10,p=0.80;I2=0%;N=853);MERR=1.10(CI0.97,1.23;p=0.11;I2=0%;N=597);andMRSApopulationRR=1.14(CI0.82,1.58;p=0.44;I2=47%;N=191).Iflinezolidiscomparedtovancomycinonly,theCCRRremains1.01(CI0.90,1.12),andMEandMRSARRsare:1.06(CI0.88,1.28)and1.04(CI0.73,1.47),respectively.Theriskofthrombocytopenia(RR=1.92[CI1.29,2.86];p=0.001)andGIevents(RR=1.90[CI1.04,3.48];p=0.03)weresignificantlyhigherwithlinezolid,butnodifferenceswereseenforrenaldysfunction(RR=0.82[CI0.52,1.27];p=0.37),orall-causedeaths(RR=0.95[CI0.76,1.18];p=0.63).2008ICAACK-533Conclusions:

Meta-analysisdidnotdetectclinicalsuperiorityoflinezolidvs.glycopeptidesfortreatmentofNP.Comparedtolinezolid,vancomycinwasnotassociatedwithmorerenaldysfunction.LinezolidshowedasignificantincreaseintheriskofthrombocytopeniaandGIevents.AvailabledatadoesnotsupporttheclaimthatlinezolidissuperiortovancomycinforthetreatmentofNP.2023/10/7Dr.Xiao42荟萃分析2023/10/7Dr.Xiao43适应症:敏感革兰阳性菌如下感染CAPSSSI(复杂与非复杂)HAP万古霉素耐药屎肠球菌不良反应:一般反应:胃肠道,念珠菌病,肝功能异常特殊反应:加压素样反应:正常人使用高酪胺食物同时用Linezolid时,发生加压素样反应,需要注意;少数患者发生骨髓抑制现象,用药中需要观察血象.外周神经病,周围神经病,乳酸性酸中毒linezolid适应症/不良反应2023/10/7Dr.Xiao44注意:

耐药性抗菌机制:50S亚基中23SrRNAV区结合耐药机制:23SrRNAV区点突变,G2576T叠加性:5-6个23SrRNA基因逐步变