MRSA抗菌治疗进展PPT课件.ppt

MRSA的诊断及临床治疗,2,OUTLINE,MRSA的临床重要性MRSA的药物敏感性及变迁MRSA感染的抗菌治疗,问题1、MRSA的临床重要性如何？,耐药革兰阴性菌给临床带来的问题较革兰阳性菌更大，如鲍曼不动杆菌革兰阳性菌中，MRSA的临床重要性最大,3.2millionbacterialisolatesfrom300clinicallab19982005acrosstheUnitedStates,StyersD,etal.AnnClinMicrobiolAntimicrob2006,5:2.,StaphylococcusaureusEscherichiacoliEnterococcusspp.Coagulase-negativestaphylococciPseudomonasaeruginosaKlebsiellapneumoniaeProteusmirabilisEnterobactercloacaeSerratiamarcescensAcinetobacterbaumanni,EscherichiacoliStaphylococcusaureusEnterococcusspp.PseudomonasaeruginosaCoagulase-negativestaphylococciKlebsiellapneumoniaeProteusmirabilisEnterobactercloacaeStreptococcuspneumoniaeCitrobacterfreundii,Percentageofallbacterialisolatesencountered,Percentageofallbacterialisolatesencountered,Toptenpathogensamonginpatients,Toptenpathogensamongoutpatients,1.5,1.6,2.9,3.1,6.1,10.3,12.7,12.7,17.3,18.8,0,5,10,15,20,25,30,35,40,1.0,1.0,1.5,4.2,6.2,6.3,6.5,8.8,14.9,38.6,0,5,10,15,20,25,30,35,40,S.aureusisaleadingcauseofbacterialinfectionsinhospitalsandcommunityintheUS,中国革兰阳性菌菌种分布,CHINET2011,金葡菌是临床最常见的革兰阳性菌,MRSA可引起各类感染,骨髓炎,食物中毒,皮肤烫伤综合征,T中毒休克综合征,脓疱病,疖,肺炎,眼内炎,心内膜炎,蜂窝织炎,AnnualDeathRatesintheUnitedStatesSelectedInfectiousDiseases,No.ofpatientsdied,BoucherHWandCoreyGR.ClinInfectDis2008;46:S344-9.,MRSA感染的死亡病例数高于AIDS的死亡病例数,8,S.aureusisthemostcommonpathogenofHAP(n=656),KimJM.AmJInfectControl2000;28:454-8.,91%ofS.aureuswereMRSA,9,MRSAisthethirdmostcommonpathogenofHAPinChina,Amulti-centersurveyconductedin12hospitalsinChinafrom2008to2010toknowtheincidenceandcausativepathogensofHAP.,LiuYN,unpublisheddatabypersonalcommunication,DoernGVetal:DiagnMicrobiolInfectDis1999;34:65BrookI:IntJSurg2008;6:328ChiraS,MillerLG:EpidemiolInfect2010;138:313,Gram-positiveorganismspredominate(60-70%)S.aureus-48%inonestudyGroupA-hemolyticstreptococci-26%Gram-negativeorganismsinvolvedin25-35%ofinfectionsAnaerobicandfungalorganismsareuncommonPolymicrobialinfectionsareencountered:Especiallywithdeepersofttissueinfections,MicrobiologyinSkin/SoftTissueInfections,金葡菌是皮肤软组织感染的最常见病原菌,11,OUTLINE,MRSA的临床重要性MRSA的药物敏感性及变迁MRSA感染的抗菌治疗,PrevalenceofMRSAandMRCNSinShanghairegionsince1999,问题2、MRSA对万古霉素的耐药性如何？是否存在MIC漂移（MICcreep）？,MSSA(2954株)与MRSA(3033株)的耐药率（%）,CHINET2011,耐药监测数据显示，MRSA对万古霉素、利奈唑胺100敏感,15,TwelveVRSA(VancomycinresistantS.aureus)reportedintheUS,TwelvecasesfromUSAPositiveforthevanAgeneMedianvancomycinMIC:512mg/LAllpatientshadpriorMRSAcolonizationorinfectionsAllhadsevereunderlyingfactorsAAC2009;53:4580-7,16,FiveVRSAreportedinAsia,India:3strains2strains:vancomyicnMIC32or64mg/L,vanAnegativeinaddition,found6VISAstrains(TiwariHK,BMCInfectDis2006;6:156)OneVRSAvancomycinMIC64mg/L,vanApositive(SahaB,etal.JMedMicrobiol2008;57,7279)Iran:2strainsOneisolatehadavancomycinMICof64mg/LOtheronehadavancomycinMICof512mg/LandvanApositive(AligholiM,etal.MedPrincPract2008;17(5):432),17,异质性万古霉素中介金葡菌（hVISA）在中国的发生情况,1012株MRSA于2002-7年（主要为05-07）分离自14个城市检测方法：含药平皿及MET初筛，菌群分析策略-曲线下面积方法确认,2007年分离自14个城市315株MRSA，hVISA9.5(30/315)(陈宏斌，中华检验医学杂志2009;32(11):1223-7),SunW,AAC2009;53(9):3642-9,HowtodetectVISAandhVISA?,19,ClinicalInfectiousDiseases2007;44:153642,VISAstrains(vancoMIC4-8)hVISA(vancoMIC1-2)CANNOTbedetectedbydiskdiffusionmethod,20,MICtestingisrecommendedbyCLSItodeterminevancomycinsusceptibilityforMRSAsince2009,*BHI+6g/mlvancomycin*sendtoreferencelab,21,ComparisonoflaboratorydetectionmethodsofhVISA,BenjaminP.CLINICALMICROBIOLOGYREVIEWS.2010;23:99-139.,hVISAcannotbedetectedbyroutinemethods,Populationanalysisprofile(PAP)is“goldstandard”,butitislabor-intensiveandimpracticalforclinicallab.TestingforhVISAisnotroutinelyrecommended,VancomycinMICcreep：地区差异,22,JournalofAntimicrobialChemotherapy(2007)60,788794,23,全球九国10年（2001-2010）分离MRSA万古霉素MIC几何均数在1mg/L左右(0.661.13),ReynoldsR,ECCMID2012,P1215,VancomycinSusceptibilityinMRSAOver10Years:MICDecreaseAfteraTransientCreep,ICAAC2012.C2-1391R.Khatib,GrossePointeWoods,MI,677isolatestested.VanMICwasstablebetween2002-3and2005-6,increasedin2008-9anddecreasedin2010-2Thereasonforthisdecreaseisuncertain.ItmaybeduetoreduceduseofVorhigherdrugconcentrations.ThetargetedVtroughlevelswereincreasedinearly2010to15-20g/L,25,OUTLINE,MRSA引起的常见感染MRSA的药物敏感性及变迁MRSA感染的抗菌治疗,问题3、目前临床应用的治疗MRSA感染的抗菌药主要有哪些？各有什么优缺点？,抗MRSA的最主要抗菌药物,27,万古霉素的优点与缺点,优点临床使用近50年，革兰阳性菌对其仍高度敏感治疗革兰阳性菌感染最为经典的药物临床适应证最广,缺点MRSA敏感性下降问题组织浓度不良反应,不同MRSA感染的抗菌药物选择,LiuC,ClinInfectDis2011;52(3):285,2011IDSAMRSA指南,万古霉素的临床适应证最广,万古霉素治疗药物监测（TDM）相关问题,监测血清谷浓度监测给药剂量最准确、实用；应在达到稳态后采集标本（第4-5次给药前）；并非所有患者需要血药浓度监测；监测谷浓度对象：肾功能损害；肥胖；表观分布容积波动；,31,Troughserumvancomycinconcentrationsalwaysbemaintainedat10mg/Ltoavoidthedevelopmentofresistance(BIII)Toimproveclinicaloutcomesofhospital-acquiredpneumoniacausedbyS.aureus,troughserumvancomycinconcentrationsof1520mg/Larerecommended(Note:muchhigherthanformerconcentrationof5-10mg/L)(BIII)Toachieverapidattainmentofthistargetconcentrationforseriouslyillpatients,aloadingdoseof2530mg/kg)(1.5-1.8g)(basedonactualbodyweight)canbeconsidered.(BIIITroughserumvancomycinconcentrationsinthatrangeshouldachieveanAUC/MICof400formostpatientsiftheMICis580,肠球菌感染638，预测95患者可达临床有效,糖肽类的耳肾毒性问题,在上市之初，因纯度的问题，毒性较明显纯度提高后，耳肾毒性发生率低长疗程用药需注意药物热的出现可能,利奈唑胺的优点与缺点,优点新类别抗菌药对VRE、VISA、hVISA等具抗菌活性临床适应证较广同时有静脉及口服制剂,缺点抑菌剂静脉导管相关血流感染疗效问题耐药性出现较快骨髓抑制,不同MRSA感染的抗菌药物选择,LiuC,ClinInfectDis2011;52(3):285,2011IDSAMRSA指南,利奈唑胺的临床适应证较广,新类别抗菌药研发困难,近年开发新类别抗菌药少利奈唑胺(linezolid)：恶唑烷酮类(oxazolidinones)达托霉素(daptomycin):脂肽类现有类别药物的改进替利霉素(telithromycin)：酮内酯类ketolides,为大环内酯类红霉素A的衍生物替加环素(tigecycline)：甘氨酰环素类glycylcyclines为四环素类米诺环素的衍生物特拉万星(telavancin)：脂糖肽类lipoglycopeptides，为万古霉素的衍生物,利奈唑胺对革兰阳性菌具良好抗菌作用,JonesRNetal.DiagnosticMicrobiologyandInfectiousDisease.2009;65:404413.,2008年对24个国家64个医学中心收集的6121株G+球菌进行的耐药监测结果,利奈唑胺不推荐用于导管相关血流感染,2007年FDA向医生发出警告治疗导管相关感染的研究表明2利奈唑胺治疗首次用药后84天内的死亡率21.5%(78/363)，而对照组为16.6%(58/363),1,WilcoxMH,TackKJ,BouzaE,etal.ComplicatedskinandskinstructureinfectionsandCatheterRelatedBloodstreamInfectionsNoninferiorityofLinezolidinPhase3Sutdy.ClinicalInfectiousDisease2009,48:203-212.2,FDAAlert3/18/2007.,美国Leaderprogram2004-2010耐利奈唑胺的金葡菌发生率,DiagnosticMicrobiologyandInfectiousDisease74(2012)5461,全球监测显示，MRSA对利奈唑胺的耐药率低,Clinicaloutbreakoflinezolid-resistantStaphylococcusaureusinanintensivecareunitinSpain(HospitalClinicoSanCarlos),SnchezGarcaM,JAMA.2010;303(22):2260-4,Mechanismoflinezolidresistance,MutationsindomainVof23SrRNAMutationsinrplC(ribosomalproteinL3)andrplD(L4)MediatedbyCfrmethyltransferaseUnknownmechanism,问题4、治疗MRSA肺炎，利奈唑胺是否优于万古霉素？,57.6,54.8,83.3,80.1,46.6,44.9,69.9,67.8,0,20,40,60,80,100,PPatEOS,MITTatEOS,PPatEOT,MITTatEOT,Proportionofpatientswithsuccessfulresponse(%),Linezolid,Vancomycin,P=0.04295%CI0.5-21.6,P=0.04995%CI0.1-19.8,P=0.002,P=0.004,n=165*n=7,n=180*n=3,n=186*n=2,n=186*n=38,n=201*n=23,n=214*n=10,n=205*n=19,n=174*n=2,Primaryendpoint,Secondaryendpoint,*Numberofexcludedpatients,Zephyrstudy:linezolidissuperiorthanvancomycininthetreatmentofMRSApneumonia,WunderinkRG,CID2012;54:621-9,60DaysKaplan-MeierSurvivalratesweresimilarbetweentwogroupsformITTPopulation,94subjectdeaths(15.7%)inlinezolidarm100subjectdeaths(17.0%)invancomycinarm,Controversy:islinezolidreallybetterthanvancomycin?,57.6,54.8,83.3,80.1,46.6,44.9,69.9,67.8,0,20,40,60,80,100,PPatEOS,MITTatEOS,PPatEOT,MITTatEOT,Proportionofpatientswithsuccessfulresponse(%),Linezolid,Vancomycin,P=0.04295%CI0.5-21.6,P=0.04995%CI0.1-19.8,P=0.002,P=0.004,n=165*n=7,n=180*n=3,n=186*n=2,n=186*n=38,n=201*n=23,n=214*n=10,n=205*n=19,n=174*n=2,Primaryendpoint,Secondaryendpoint,*Unknownexcludedptsfromanalysis,AlargenumberofmITTpatientsexcludedfromthestatisticpopulation,Controversy:islinezolidreallybetterthanvancomycin?,HigherproportionofcaseswithMRSAbacteremiaandmechanicalventilationinthevancomycinarm,Thebaselineclinicalcharacteristicsofvancomycinarmareseemstobemorecomplicatedandsevere,Controversy:islinezolidreallybetterthanvancomycin?,47,针对MRSA医院肺炎的荟萃分析提示万古霉素的临床疗效与利奈唑胺相仿,WalkeyAJ,CHEST2010;DOL1378/1556.,达托霉素的优点与缺点,优点新类别抗菌药快速杀菌作用对VRE、VISA、hVISA等具抗菌活性,缺点无肺炎适应证价格较高CPK升高在中国的问题：血培养阳性率低,BacterialGrowthPhases:达托霉素对静止期细菌也具杀菌作用,Stationary-phasebacteria:arenon-dividingandmetabolicallyarrested.Associatedwithpersistentinfections(endocarditisandosteomyelitis)Associatedwithbiofilm-relatedinfections(catheters,grafts,andforeignbodies)Themechanismofactionofmanybactericidalantibioticsrequiresongoingcelldivision(logphase)Normallybactericidalantibiotics(e.g.,beta-lactams)maydisplaylimitedactivityagainststationaryphasecells,Mascioetal.,AAC2007p.42554260Vol.51,No.12.,DrugPenetration:%Tissue/Serum,达托霉素在多数组织的浓度较高,不同MRSA感染的抗菌药物选择,LiuC,ClinInfectDis2011;52(3):285,2011IDSAMRSA指南,DaptomycinOutcomesinPatientswithSevereSepsisduetoStaphylococcalBacteremiawithVancomycinMICsof2mg/L,100ptswereincludedintheefficacypopulation(15ofwhichhadsepticshock)72ptsreceivedvancomycinpriortoDAP,andofthose,27(38%)failedtherapy.,ICAAC2012.K-1635K.Holloway,MA,克林霉素（Clindamycin),FDA批准治疗葡萄球菌感染；皮肤软组织、骨骼等组织浓度高（不包括CSF）；成功治疗儿童侵袭性CA-MRSA感染（骨髓炎、关节炎、肺炎等）；妊娠用药分类B；抑菌剂，不用于血管内感染（BSI、IE）；诱导耐药，HA-MRSA敏感性？腹泻多见；,54,MRSApneumoniaantimicrobialtherapyregimensrecommendedbyIDS