MRSA抗菌治療進(jìn)展課件

MRSA的診斷及臨床治療復(fù)旦大學(xué)華山醫(yī)院抗生素研究所衛(wèi)生部抗生素臨床藥理重點(diǎn)實(shí)驗(yàn)室復(fù)旦大學(xué)附屬華山醫(yī)院感染科2OUTLINEMRSA的臨床重要性MRSA的藥物敏感性及變遷MRSA感染的抗菌治療問題1、MRSA的臨床重要性如何？耐藥革蘭陰性菌給臨床帶來的問題較革蘭陽性菌更大，如鮑曼不動(dòng)桿菌革蘭陽性菌中，MRSA的臨床重要性最大3.2millionbacterialisolatesfrom300clinicallab1998–2005acrosstheUnitedStatesStyersD,etal.AnnClinMicrobiolAntimicrob2006,5:2.StaphylococcusaureusEscherichiacoliEnterococcusspp.Coagulase-negativestaphylococciPseudomonasaeruginosaKlebsiellapneumoniaeProteusmirabilisEnterobactercloacaeSerratiamarcescensAcinetobacterbaumanniEscherichiacoliStaphylococcusaureusEnterococcusspp.PseudomonasaeruginosaCoagulase-negativestaphylococciKlebsiellapneumoniaeProteusmirabilisEnterobactercloacaeStreptococcuspneumoniaeCitrobacterfreundiiPercentageofallbacterialisolatesencounteredPercentageofallbacterialisolatesencounteredToptenpathogensamonginpatientsToptenpathogensamongoutpatients12.712.717.318.805101520253035401.01.014.938.60510152025303540S.aureusisaleadingcauseofbacterialinfections

inhospitalsandcommunityintheUS中國(guó)革蘭陽性菌菌種分布細(xì)菌株數(shù)％金葡菌600035.6腸球菌屬459327.2凝固酶陰性葡萄球菌335319.9（血液腦脊液等無菌體液）肺炎鏈球菌11246.7

-溶血性鏈球菌12297.3草綠色鏈球菌（血液及無菌體液）2081.2其他3652.2合計(jì)16872100.0CHINET2011金葡菌是臨床最常見的革蘭陽性菌MRSA可引起各類感染

骨髓炎食物中毒皮膚燙傷綜合征T中毒休克綜合征膿皰病癤肺炎眼內(nèi)炎心內(nèi)膜炎蜂窩織炎AnnualDeathRatesintheUnitedStates

SelectedInfectiousDiseasesNo.ofpatientsdiedBoucherHWandCoreyGR.ClinInfectDis2008;46:S344-9.MRSA感染的死亡病例數(shù)高于AIDS的死亡病例數(shù)8S.aureusisthemostcommonpathogenofHAP(n=656)Percentage(%)SaureusMRSAPaeruginosaEcoliKpneumoniaeEnterococcussppE.faecalisCandidasppC.albicansCoNSAcinetobactersppA.baumanniiEnterobactersppE.cloacaeS.marcescensS.maltophiliaC.freundiiOthersKimJM.AmJInfectControl2000;28:454-8.91%ofS.aureuswereMRSA9MRSAisthethirdmostcommonpathogenofHAPinChinaAmulti-centersurveyconductedin12hospitalsinChinafrom2008to2010toknowtheincidenceandcausativepathogensofHAP.LiuYN,unpublisheddatabypersonalcommunicationPercentage(%)A.baumanniiP.aeruginosaS.aureusK.pneumoniaeC.albicansS.maltophiliaE.coliE.cloacaeC.TropicalCoNSTheincidenceofHAPvariesfrom0.9-4.1%indifferenthospitalsinChinaA.fumigatusDoernGVetal:DiagnMicrobiolInfectDis1999;34:65BrookI:IntJSurg2008;6:328ChiraS,MillerLG:EpidemiolInfect2010;138:313Gram-positiveorganismspredominate(60-70%)S.aureus-48%inonestudyGroupA-hemolyticstreptococci-26%Gram-negativeorganismsinvolvedin25-35%ofinfectionsAnaerobicandfungalorganismsareuncommonPolymicrobialinfectionsareencountered:EspeciallywithdeepersofttissueinfectionsMicrobiologyinSkin/SoftTissueInfections金葡菌是皮膚軟組織感染的最常見病原菌11OUTLINEMRSA的臨床重要性MRSA的藥物敏感性及變遷MRSA感染的抗菌治療PrevalenceofMRSAandMRCNS

inShanghairegionsince1999問題2、MRSA對(duì)萬古霉素的耐藥性如何？是否存在MIC漂移（MICcreep）？MSSA(2954株)與MRSA(3033株)的耐藥率（%）CHINET2011耐藥監(jiān)測(cè)數(shù)據(jù)顯示，MRSA對(duì)萬古霉素、利奈唑胺100％敏感15TwelveVRSA(VancomycinresistantS.aureus)reportedintheUSTwelvecasesfromUSAPositiveforthevanAgeneMedianvancomycinMIC:512mg/LAllpatientshadpriorMRSAcolonizationorinfectionsAllhadsevereunderlyingfactorsAAC2009;53:4580-716FiveVRSAreportedinAsiaIndia:3strains2strains:vancomyicnMIC32or64mg/L,vanAnegativeinaddition,found6VISAstrains(TiwariHK,BMCInfectDis2006;6:156)OneVRSAvancomycinMIC≥64mg/L,vanApositive(SahaB,etal.JMedMicrobiol2008;57,72–79)Iran:2strainsOneisolatehadavancomycinMICof64mg/LOtheronehadavancomycinMICof512mg/LandvanApositive(AligholiM,etal.MedPrincPract2008;17(5):432)17異質(zhì)性萬古霉素中介金葡菌（hVISA）

在中國(guó)的發(fā)生情況1012株MRSA于2002-7年（主要為05-07）分離自14個(gè)城市檢測(cè)方法：含藥平皿及MET初篩，菌群分析策略-曲線下面積方法確認(rèn)nhVISA％血培養(yǎng)20013.1％(26/199)VISA1(萬古MIC4mg/L)非血培養(yǎng)81215.7％（128/812）2007年分離自14個(gè)城市315株MRSA，hVISA9.5％(30/315)(陳宏斌，中華檢驗(yàn)醫(yī)學(xué)雜志2009;32(11):1223-7)SunW,AAC2009;53(9):3642-9HowtodetectVISAandhVISA?19ClinicalInfectiousDiseases2007;44:1536–42VISAwasidentifiedas"S“bydiscdiffusion17mmzone“S”MIC–8ug/ml“I”Discdiffusion

andE-TestE-Test:MIC2,butdiscdiffusion:for“S”E-Test:MIC=2,butdiscdiffusion:for“S”E-Test:MIC>2,butdiscdiffusion:for“S”MIC–8ug/ml“I”17mmzone“S”MIC–8ug/ml“I”17mmzone“S”MIC–8ug/ml“I”17mmzone“S”MIC–8ug/ml“I”17mmzone“S”MIC–8ug/ml“I”VISAstrains(vancoMIC4-8)hVISA(vancoMIC1-2)CANNOTbedetectedbydiskdiffusionmethod20MICtestingisrecommendedbyCLSItodeterminevancomycinsusceptibility

forMRSAsince2009*BHI+6μg/mlvancomycin**sendtoreferencelab21ComparisonoflaboratorydetectionmethodsofhVISAMethodSensitivitySpecificityVancomycinbrothMIC11%100%BHIA+BHIA6V48h,4.5–12%48h,68–100%MHA

+MHA5T48h,65–79%48h,35–95%MHA

+MHA5T48h,98%48h,53%BHIA+Vancomycin5μg/ml，10μl

ofa0.5McFarlandstandardsuspension48h,1–20%48h,59–99%SimplifiedPAP*48h,71%48h,88%MacromethodEtest(MET)48h,69–98.5%48h,89–94%EtestGRD24h,70–77%48h,93–94%24h,98–100%48h,82–95%BenjaminP.CLINICALMICROBIOLOGYREVIEWS.2010;23:99-139.hVISAcannotbedetectedbyroutinemethodsPopulationanalysisprofile(PAP)is“goldstandard”,butitislabor-intensiveandimpracticalforclinicallab.TestingforhVISAisnotroutinelyrecommended

VancomycinMICcreep：地區(qū)差異22JournalofAntimicrobialChemotherapy(2007)60,788–79423全球九國(guó)10年（2001-2010）分離MRSA

萬古霉素MIC幾何均數(shù)在1mg/L左右(0.66~1.13)ReynoldsR,ECCMID2012,P1215VancomycinSusceptibilityinMRSAOver10Years:MICDecreaseAfteraTransientCreepVancomycinMICmg/L:n(%)Year(n)0.5-0.751.001.502.003.0-4.0Means±SDVanco.useforMRSA02-03(186)06(3.2)86(46.2)85(45.7)9(4.8)1.78±0.3995.0%05-06(184)1(0.5)2(1.1)95(51.6)70(38.0)16(8.7)1.82±0.4791.0%08-09(172)00110(64.0)61(35.5)1(0.6)1.69±0.2693.2%10-12(135)2(1.5)15(10.9)97(70.8)20(14.6)1(0.78)1.52±0.3093.5%ICAAC2012.C2-1391R.Khatib,GrossePointeWoods,MI

677isolatestested.VanMICwasstablebetween2002-3and2005-6,increasedin2008-9anddecreasedin2010-2Thereasonforthisdecreaseisuncertain.ItmaybeduetoreduceduseofVorhigherdrugconcentrations.ThetargetedVtroughlevelswereincreasedinearly2010to15-20μg/L25OUTLINEMRSA引起的常見感染MRSA的藥物敏感性及變遷MRSA感染的抗菌治療問題3、目前臨床應(yīng)用的治療MRSA感染的抗菌藥主要有哪些？各有什么優(yōu)缺點(diǎn)？抗MRSA的最主要抗菌藥物27萬古霉素Vancomycin利奈唑胺Linezolid達(dá)托霉素Daptomycin類型糖肽類噁唑烷酮類

環(huán)脂肽類抗菌類型殺菌劑（葡萄球菌）抑菌劑（腸球菌/葡萄球菌）快速殺菌劑（革蘭陽性菌）抗菌譜G(+)G(+)G(+)作用部位細(xì)胞壁核糖體RNA亞基細(xì)胞膜萬古霉素的優(yōu)點(diǎn)與缺點(diǎn)優(yōu)點(diǎn)臨床使用近50年，革蘭陽性菌對(duì)其仍高度敏感治療革蘭陽性菌感染最為經(jīng)典的藥物臨床適應(yīng)證最廣缺點(diǎn)MRSA敏感性下降問題組織濃度不良反應(yīng)萬古霉素利奈唑胺達(dá)托霉素復(fù)雜性皮膚軟組織感染√√√血流感染與自身瓣膜心內(nèi)膜炎√×√人工瓣膜心內(nèi)膜炎√(聯(lián)合慶大、利福平)××肺炎√√×骨髓炎√√(超適應(yīng)證）√(超適應(yīng)證）植入物相關(guān)骨髓炎、關(guān)節(jié)炎√√(超適應(yīng)證）√(超適應(yīng)證）腦膜炎，腦膿腫等CNS感染√√(超適應(yīng)證）×不同MRSA感染的抗菌藥物選擇LiuC,ClinInfectDis2011;52(3):2852011IDSAMRSA指南萬古霉素的臨床適應(yīng)證最廣萬古霉素治療藥物監(jiān)測(cè)（TDM）相關(guān)問題監(jiān)測(cè)血清谷濃度監(jiān)測(cè)給藥劑量最準(zhǔn)確、實(shí)用；應(yīng)在達(dá)到穩(wěn)態(tài)后采集標(biāo)本（第4-5次給藥前）；并非所有患者需要血藥濃度監(jiān)測(cè)；監(jiān)測(cè)谷濃度對(duì)象：腎功能損害；肥胖；表觀分布容積波動(dòng)；31Troughserumvancomycinconcentrationsalwaysbemaintainedat>10mg/Ltoavoidthedevelopmentofresistance(BIII)Toimproveclinicaloutcomesofhospital-acquiredpneumoniacausedbyS.aureus,troughserumvancomycinconcentrationsof15–20mg/Larerecommended(Note:muchhigherthanformerconcentrationof5-10mg/L)(BIII)Toachieverapidattainmentofthistargetconcentrationforseriouslyillpatients,aloadingdoseof25–30mg/kg)(1.5-1.8g)(basedonactualbodyweight)canbeconsidered.(BIIITroughserumvancomycinconcentrationsinthatrangeshouldachieveanAUC/MICof>400formostpatientsiftheMICis<1mg/L.RybakMJ.ClinInfectDis2009;49:325-7TherapeuticvancomycindoseadjustmentanddrugmonitoringAUC24/MIC即給藥劑量：決定去甲萬古霉素治療革蘭陽性菌感染療效的主要指標(biāo)ZhangJ,EurJClinMicrobialInfectDis2008;27:275StaphylococcalinfectionEnterococcalInfectionCured(n=25)Uncured(n=11)PCure(n=17)Uncured(n=4)PAUC24(mg.h.L-1)294±129167±590.003391±200213±510.009AUC24/MIC567±299227±800.000785±478180±500.004葡萄球菌感染AUC24/MIC>580,腸球菌感染>638，預(yù)測(cè)95％患者可達(dá)臨床有效糖肽類的耳腎毒性問題在上市之初，因純度的問題，毒性較明顯純度提高后，耳腎毒性發(fā)生率低長(zhǎng)療程用藥需注意藥物熱的出現(xiàn)可能利奈唑胺的優(yōu)點(diǎn)與缺點(diǎn)優(yōu)點(diǎn)新類別抗菌藥對(duì)VRE、VISA、hVISA等具抗菌活性臨床適應(yīng)證較廣同時(shí)有靜脈及口服制劑缺點(diǎn)抑菌劑靜脈導(dǎo)管相關(guān)血流感染療效問題耐藥性出現(xiàn)較快骨髓抑制萬古霉素利奈唑胺達(dá)托霉素復(fù)雜性皮膚軟組織感染√√√血流感染與自身瓣膜心內(nèi)膜炎√×√人工瓣膜心內(nèi)膜炎√(聯(lián)合慶大、利福平)××肺炎√√×骨髓炎√√(超適應(yīng)證）√(超適應(yīng)證）植入物相關(guān)骨髓炎、關(guān)節(jié)炎√√(超適應(yīng)證）√(超適應(yīng)證）腦膜炎，腦膿腫等CNS感染√√(超適應(yīng)證）×不同MRSA感染的抗菌藥物選擇LiuC,ClinInfectDis2011;52(3):2852011IDSAMRSA指南利奈唑胺的臨床適應(yīng)證較廣新類別抗菌藥研發(fā)困難近年開發(fā)新類別抗菌藥少利奈唑胺(linezolid)：惡唑烷酮類(oxazolidinones)達(dá)托霉素(daptomycin):脂肽類現(xiàn)有類別藥物的改進(jìn)替利霉素(telithromycin)：酮內(nèi)酯類ketolides,為大環(huán)內(nèi)酯類紅霉素A的衍生物替加環(huán)素(tigecycline)：甘氨酰環(huán)素類glycylcyclines為四環(huán)素類米諾環(huán)素的衍生物特拉萬星(telavancin)：脂糖肽類lipoglycopeptides，為萬古霉素的衍生物利奈唑胺對(duì)革蘭陽性菌具良好抗菌作用致病菌菌株數(shù)MIC90(μg/ml)MIC范圍(μg/ml)敏感率(%)金黃色葡萄球菌324020.5-4100MRSA109220.5-4100MSSA214820.5-4100凝固酶陰性葡萄球菌74820.5-499.6腸球菌86420.25->899.3VRE8620.5->897.7肺炎鏈球菌6551≤0.12-2100草綠色鏈球菌2161≤0.06-2100β-溶血性鏈球菌39810.25-2100JonesRNetal.DiagnosticMicrobiologyandInfectiousDisease.2009;65:404–413.2008年對(duì)24個(gè)國(guó)家64個(gè)醫(yī)學(xué)中心收集的6121株G+球菌進(jìn)行的耐藥監(jiān)測(cè)結(jié)果利奈唑胺不推薦用于導(dǎo)管相關(guān)血流感染2007年FDA向醫(yī)生發(fā)出警告治療導(dǎo)管相關(guān)感染的研究表明2利奈唑胺治療首次用藥后84天內(nèi)的死亡率21.5%(78/363)，而對(duì)照組為16.6%(58/363)1,WilcoxMH,TackKJ,BouzaE,etal.Complicatedskinandskin–structureinfectionsandCatheter–RelatedBloodstreamInfectionsNoninferiorityofLinezolidinPhase3Sutdy.ClinicalInfectiousDisease2009,48:203-212.2,FDAAlert[3/18/2007].[美國(guó)Leaderprogram2004-2010]

耐利奈唑胺的金葡菌發(fā)生率DiagnosticMicrobiologyandInfectiousDisease74(2012)54–61耐藥率(%)N=21642全球監(jiān)測(cè)顯示，MRSA對(duì)利奈唑胺的耐藥率低Clinicaloutbreakoflinezolid-resistantStaphylococcusaureusinanintensivecareunitinSpain(HospitalClinicoSanCarlos)SánchezGarcíaM,JAMA.2010;303(22):2260-4MechanismoflinezolidresistanceMutationsindomainVof23SrRNAMutationsinrplC(ribosomalproteinL3)andrplD(L4)MediatedbyCfrmethyltransferaseUnknownmechanism問題4、治療MRSA肺炎，利奈唑胺是否優(yōu)于萬古霉素？57.654.883.380.146.644.969.967.8020406080100PPatEOSMITTatEOSPPatEOTMITTatEOTProportionofpatientswithsuccessfulresponse(%)LinezolidVancomycin

P=0.04295%CI0.5-21.6P=

0.04995%CI0.1-19.8P=

0.002

P=

0.004n=165*n=7n=180*n=3n=186*n=2n=186

*n=38n=201*n=23n=214*n=10n=205*n=19n=174*n=2PrimaryendpointSecondaryendpoint*NumberofexcludedpatientsZephyrstudy:linezolidissuperiorthanvancomycin

inthetreatmentofMRSApneumoniaWunderinkRG,CID2012;54:621-960DaysKaplan-MeierSurvivalratesweresimilarbetweentwogroupsformITTPopulationSurvivalDistributionFunction0.8010204060Time(Days)LinezolidLinezolidCensorVancomycinVancomycinCensor***●●●10305094subjectdeaths(15.7%)inlinezolidarm100subjectdeaths(17.0%)invancomycinarmControversy:islinezolidreallybetterthanvancomycin?57.654.883.380.146.644.969.967.8020406080100PPatEOSMITTatEOSPPatEOTMITTatEOTProportionofpatientswithsuccessfulresponse(%)LinezolidVancomycin

P=0.04295%CI0.5-21.6P=

0.04995%CI0.1-19.8P=

0.002

P=

0.004n=165*n=7n=180*n=3n=186*n=2n=186

*n=38n=201*n=23n=214*n=10n=205*n=19n=174*n=2PrimaryendpointSecondaryendpoint*UnknownexcludedptsfromanalysisAlargenumberofmITTpatientsexcludedfromthestatisticpopulationControversy

:islinezolidreallybetterthanvancomycin?HigherproportionofcaseswithMRSAbacteremiaandmechanicalventilationinthevancomycinarmCharacteristicBaselineClinicalCharacteristicsVancomycinarmNo.(%)LinezolidarmNo.(%)Mechanicalventilation130(73.9)115(66.9)Bacteremia20(10.8)9(5.2)ThebaselineclinicalcharacteristicsofvancomycinarmareseemstobemorecomplicatedandsevereControversy:islinezolidreallybetterthanvancomycin?47針對(duì)MRSA醫(yī)院肺炎的薈萃分析提示

萬古霉素的臨床療效與利奈唑胺相仿WalkeyAJ,CHEST2010;DOL1378/1556.RR(95%CI)1.09(0.82-1.44)1.23(0.72-2.07)0.97(0.78-1.19)1.02(0.89-1.16)0.93(0.63-1.36)0.93(0.39-2.24)1.17(0.73-1.87)1.41(0.64-3.08)1.02(0.93-1.12)臨床成功例數(shù)/總數(shù)322/84171/20320/50114/32151/5723/4711/5119/3813/74利奈唑胺糖肽類62/19326/49111/30252/5930/576/2618/429/72304/800研究/亞組研究Rubenstein2001Stevens2002Wunderink2003Wilcox2004Cepeda2004Kohno2007Lin2007Wunderink2008異質(zhì)性X2=2.20，p=0.95，I2=0%總體療效，p=0.6350.20.512利于糖肽類利于利奈唑胺薈萃分析達(dá)托霉素的優(yōu)點(diǎn)與缺點(diǎn)優(yōu)點(diǎn)新類別抗菌藥快速殺菌作用對(duì)VRE、VISA、hVISA等具抗菌活性缺點(diǎn)無肺炎適應(yīng)證價(jià)格較高CPK升高在中國(guó)的問題：血培養(yǎng)陽性率低BacterialGrowthPhases:

達(dá)托霉素對(duì)靜止期細(xì)菌也具殺菌作用Stationary-phasebacteria:arenon-dividingandmetabolicallyarrested.Associatedwithpersistentinfections(endocarditisandosteomyelitis)Associatedwithbiofilm-relatedinfections(catheters,grafts,andforeignbodies)Themechanismofactionofmanybactericidalantibioticsrequiresongoingcelldivision(logphase)Normallybactericidalantibiotics(e.g.,beta-lactams)maydisplaylimitedactivityagainststationaryphasecellsMascioetal.,AAC2007p.4255–4260Vol.51,No.12.TissueVancomycinLinezolidDaptomycinBone7%-13%60%117%CSF0%-18%70%5-6%Lungalveolar11%-17%100%-450%10%Blisterfluid20%-30%104%70%Muscle~30%94%Peritonealfluid~20%61%40%Bloodclottissue70%DrugPenetration:%Tissue/Serum達(dá)托霉素在多數(shù)組織的濃度較高萬古霉素利奈唑胺達(dá)托霉素復(fù)雜性皮膚軟組織感染√√√血流感染與自身瓣膜心內(nèi)膜炎√×√人工瓣膜心內(nèi)膜炎√(聯(lián)合慶大、利福平)××肺炎√√×骨髓炎√√(超適應(yīng)證）√(超適應(yīng)證）植入物相關(guān)骨髓炎、關(guān)節(jié)炎√√(超適應(yīng)證）√(超適應(yīng)證）腦膜炎，腦膿腫等CNS感染√√(超適應(yīng)證）×不同MRSA感染的抗菌藥物選擇LiuC,ClinInfectDis2011;52(3):2852011IDSAMRSA指南DaptomycinOutcomesinPatientswithSevereSepsisduetoStaphylococcalBacteremiawithVancomycinMICsof≥2mg/L

SuccessbySubgroup(%)Success(%)Failure(%)Overall(n=100)8614MRSA(n=73)8812MSSA(n=8)8812CoNS(n=19)7921DAPmonotherapy(n=52)8812Priorvancomycinfailure(n=27)7822Septicshock(n=15)6733100ptswereincludedintheefficacypopulation(15ofwhichhadsepticshock)72ptsreceivedvancomycinpriortoDAP,andofthose,27(38%)failedtherapy.ICAAC2012.K-1635K.Holloway,MA克林霉素（Clindamycin)FDA批準(zhǔn)治療葡萄球菌感染；皮膚軟組織、骨骼等組織濃度高（不包括CSF）；成功治療兒童侵襲性CA-MRSA感染（骨髓炎、關(guān)節(jié)炎、肺炎等）；妊娠用藥分類