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革兰阳性球菌耐药与治疗倪语星上海交通大学医学院附属瑞金医院MDR细菌已成为全球关注的焦点•在全球范围内，“ESKAPE”耐药已成为导致患者发病及死亡的重要原因1•“ESKAPE”耐药现象日益严重，但当前新型抗菌药物的研发逐渐减缓，未来可能面临无药可用的局面3新药数量1983-19871

988-19921993-19971998-20022003-20071.RiceLBetal.TheJournalofInfectiousDiseases2008;197:1079–812.http://www.who.int/w

orld-health-day/zh/3.BoucherHWetal.ClinicalInfectiousDiseases2009;48:1–12我国主要的MDR致病菌•我国，“ESKAPE”耐药菌株检出率高检出率

(%)产ESBL大肠埃希菌MRSA产ESBL肺炎克雷伯菌属不动杆菌属*铜绿假单胞菌*耐万古霉素屎肠球菌*在G-菌中的检出率朱德妹等.中国感染与化疗杂志.2011;11(5):321-32913967株5380株431株1733株1623株呼吸道尿液粪便伤口分泌物血液克雷伯菌属15.3%大肠

埃希菌47.1%金葡菌22.7%凝(-)葡萄球菌50.2%志贺菌属80.7%金葡菌14.7%肠球菌21.0%大肠埃希菌16.7%大肠埃希菌11.5%不动杆菌12.8%克雷伯菌8.2%铜绿假单孢菌9.5%金葡菌7.7%铜绿假单胞菌11.4%凝(-)葡萄球菌5.8%

克雷伯菌8.9%克雷伯菌5.7%汪复,等.中国感染与化疗杂志.2010;10(5):325-334.各类标本中的主要病原菌？血培养排名前10位的临床致病菌细菌名称正确污染率不确定金葡87.26.46.4大肠埃希菌99.30.00.7凝固酶阴性葡萄球菌12.481.95.8肺克100.00.0

0.0肠球菌69.916.114.0绿脓96.41.81.8肺链100.00.00.0白念90.00.010.0草绿链38.049.312.7阴沟100.00.00.0一、药敏监测数据•R.N.Jonesetal.DiagnosticMicrobiologyandInfectiousDise

ase.2009;64:191–201.ZAAPS监测项目简介时间入选情况G+菌株2006年16个国家的50所医学研究中心共分离到4216株G+菌2007年23个国家的64所医学研究中心共分离到5591株G+菌R.N.Jonesetal.DiagnosticMicrobiologyandIn

fectiousDisease.2009;64:191–201.近6年ZAAPS监测共分离到G+菌34170株不同国家MRSA耐药率•加拿大：55.7%•拉丁美洲：平均为50.1%(29.0%-64.1%)•欧洲：平均为28

.2%(1.7%-56.2%)•亚太地区：平均为44.2%(25.3%-68.0%)R.N.Jonesetal.DiagnosticMicrobiologyandInfectiousDisease.2009;64:191–201.常用抗菌药物对

金黄色葡萄球菌抗菌活性金黄色葡萄球菌(3000)MIC(μg/mL)百分比(%)50%90%范围敏感/耐药利奈唑胺220.25-8>99.9/—环丙沙星0.5>40.06->464.2/34.9左氧氟沙星≤0.5>4≤

0.5->465.2/34.6克林霉素≤0.25>2≤0.25->274.3/25.6替考拉宁≤2≤2≤2-8100.0/0.0TMP-SMX≤0.5≤0.5≤0.5->293.1/6.9万古霉素110.25-2100.0/0.0R.N.Joneset

al.DiagnosticMicrobiologyandInfectiousDisease.2009;64:191–201.2007年ZAAPS项目对3000株金黄色葡萄球菌药敏监测结果常用抗菌药物对CoNS的抗菌活性CoN

S(716)MIC(μg/mL)百分比(%)50%90%范围敏感/耐药利奈唑胺11≤0.06-899.7/—青霉素>2>2≤0.25->220.4/79.6奎奴普丁-达托普丁≤0.250.5≤0.25->298.9/0.6替

考拉宁≤28≤2->1697.5/0.3万古霉素12≤0.12-899.0/0.0R.N.Jonesetal.DiagnosticMicrobiologyandInfectiousDisease.2009;

64:191–201.2007年ZAAPS项目对716株CoNS药敏监测结果2008年CHINET监测网各医院金葡菌MR菌株检出率医院金黄色葡萄球菌医院金黄色葡萄球菌MR株数/总株数（%）MR株数/总株数

（%）华山医院421/54377.5北京医院/214/279/76.7瑞金医院375/56666.3上海儿科医院/43/291/14.8协和医院221/38058.7上海儿童医院/68/353/20.4同济医

院257/41762.6重庆医大一附院/8/18/44.4浙医一附院107/21450.0甘肃省人民医院/58/112/51.8广州一附院79/12065.8新疆医大一附院/65/146/44.5总计1916/343955.7(14.8-77.5)两家儿

童医院MRSA检出率低2008年CHINET监测网各医院凝固酶(-)葡萄球菌MR菌株检出率医院凝固酶阴性葡萄球菌医院凝固酶阴性葡萄球菌MR株数/总株数（%）MR株数/总株数（%）华山医院45/5188.2北京医院12/1675.0瑞金医院90/12174.4上海儿科医院/304/503

/60.4协和医院186/22881.6上海儿童医院/302/327/92.4同济医院172/21181.5重庆医大一附院/1/1//浙医一附院560/74775.0甘肃省人民医院/20/28/71.4广州一附院36/4481.8新疆医大一附院/16/21/76.2总计17

44/229875.9(60.4-92.4)MSSA(1495株)与MRSA(1916株)的耐药率（%）00001.32.11.100010092.19171.233.154.8258893.786.283.110092.750.72

4.912.37.97.27.63.12.689.2020406080100120万古霉素替考拉宁利奈唑胺苯唑西林头孢唑啉头孢呋辛氨苄西林/舒巴坦磷霉素利福平复方磺胺甲噁唑左氧氟沙星环丙沙星庆大霉素克林霉素红霉素青霉素抗菌药物耐药率（％）MSSAMRSAMRS

A的耐药率>MSSA仍有75％，67％菌株对SMZ/TMP、磷霉素敏感MSSA对β内酰胺类、氟喹诺酮类、SMZ/TMP、利福平、磷霉素的耐药率<10％无万古、替考拉宁、利奈唑胺耐药株MSCNS(555株)和MRCNS(1723株)的耐药率（%）0001

.100010.827.534.534.838.742.744.749.365.189.810010075.5052.421.333.314.75.710.310.222.70.769.3020406080100

120万古霉素替考拉宁利奈唑胺利福平氨苄西林/舒巴坦磷霉素头孢唑啉头孢呋辛左氧氟沙星庆大霉素克林霉素复方磺胺甲噁唑环丙沙星红霉素苯唑西林青霉素抗菌药物耐药率（％）MSCNSMRCNS1.MRCNS的耐药率>MSCNS2.MRCNS耐药率<MRSA,但对SMZ/TMP耐药率

>MRSA，但仍有约90％、65％菌株对利福平、磷霉素敏感。3.无万古、替考拉宁、利奈唑胺耐药株[2006-2010年监测数据]耐万古霉素的粪肠球菌与屎肠球菌发生率极少00.51.30.40.30.61.12.13.23.23.53.6020

406080100粪肠球菌屎肠球菌细菌耐药率(%)20061CHINET(N=2621)20072CHINET(N=2634)20084CHINET(N=2859)2006-20073MOH(N=7528)20095CHINET(

N=3369)20106CHINET(N=3646)1.汪复.2006年中国CHINET细菌耐药性监测.中国感染与化疗杂志2008;8(1):1-9.2.汪复等.2007年中国CHINET细菌耐药性监测.中国感染与化疗杂志2008;8(5):325-333.3.肖永红等.2006-2007年M

ohnarin细菌耐药检测.中华医院感染学杂志2008;18(8):1051-1056.4.汪复等.2008年中国CHINET细菌耐药性监测.中国感染与化疗杂志2009;9(5):321-329.5.汪复等.2009年中国CHINET细菌耐药性监测.中国感染与化疗杂志2

010;10(5):325-334.6.朱德妹,汪复,胡付品等.2010年中国CHINET细菌耐药性监测.中国感染与化疗杂志2011;11(5):321-329.二、S.aureusandMRSA•Methicillinr

esistantS.aureus•PresenceofamecAgene•Carriedinamobilegeneticelement(SCCmec)•Mostroutinetesting–antibioticsensiti

vity(MRSAidagar)LGA251MSSACLSI药敏指南“金黄色葡萄球菌或所有凝固酶阴性葡萄球菌如对苯唑西林(或甲氧西林)耐药，则对青霉素类、头孢菌素类、碳青霉烯类和含酶抑制剂的复方制剂均应报告耐药，而

不考虑其体外药敏结果”。CefoxitinDiskTestformecA-mediatedResistanceinStaphylococciBreakpoints(mm)OrganismOldM100-S16NewM100-S17ResSuscResSuscS.aureu

sS.lugdunensis192021*22**CoNSNochange24252425*Reportasoxacillinresistant**ReportasoxacillinsusceptibleCoNS,coagulase-negativestaphylococciO

X-R=mecA=MRSA?DiscoveryofthenewMRSAstrains(LGA251)•WefoundS.aureusthatwerehighlyresistantononefarm(ST425)(OxacilinMIC=16mg/l,cefo

xitinMIC=32mg/l)•LookedformecAgene–negativeresults•Sequencedwholegenometolookforthereason•FoundadivergentmecAgene

insideanewSCCmecImportanceofthenewMRSA•Moleculartests(PCR&slideagglutinationtest)designedtodetectMRSAgiveanegativeresultwhentestedonthenews

train•ThenewMRSAismovingbetweenpeopleandcattle–OldMRSAwasnotfoundindairycows–DivergentMRSAisfoundinS.aureusstrainsthou

ghttoberestrictedtoanimals–GeographicalclusteringofhumanandcowstrainsofthenewMRSA–DivergentMRSAmecAgenehasnotbeenf

oundinhumanstrains•IsolationsofdivergentMRSAappeartobeincreasingNewMRSAisolatesbyyear0102030405060ScotlandEnglandDenmark19752002200420052006

20072008200920102011CC130CC599ST425CC1943ST1021CC49Human✓✓✓✓Cattle✓✓Sheep✓Rat✓✓Cat✓✓Dog✓✓Horse✓GPig✓Deer✓Seal✓Finch✓Rabbit✓三、对糖肽类的耐药机制VRSA–vanA

genepositive•ChangeofD-alanyl-D-alanyl-D-lactate–1000folddecreaseinaffinitytovancomycin–TypicalMIC>16mg/LtovancomycinVRSA•USA–

12cases•http://www.cdc.gov/HAI/settings/lab/vrsa_lab_search_containment.html–Firstdiscoveredin2002•8fromMichigan!•2mostreccentfromDelaware

(2010)•Iran-1case–THE-2,2005•India–6cases–Fromintensivecareunitsin2tertiaryhospitalsinHydrabad-2008VISAisolates•Notasingl

emutationoracquisitionofasinglegene•Complex!Involvesaseriesofchanges!–Increasedcellwallthickening,increasednumberoffreeD-alanyl-D-alaninres

idues,–reducedautolyticactivity,–mutationsinregulatorsofcellwallsynthesis(i.e.graRS,vraSR),–changeintranscriptionprofile–Typic

alMIC4-8mg/LhVISA•isolatessusceptiblebystandardMICtestingbuthavesubpopulationsexpressingreducedsusceptibility•Sametypesofresistancemechanism

sasVISAisolates–TypicalMIC1-2mg/LPopulationprofileofinitialisolate(6000)andafterpersistantbacteremia/vancomycintherapy(6001)Howden,AAC,

2006JKD6001JKD6000ATCC25923Mu3987654321012345678Vancomycinμg/mlLog10CFU/mlPrevalenceofVISA/hVISA•Highlyvariableprevalence’sarerepo

rtedintheliteratureincludingwithincountries–IllustratedbydatafromAustralia•Melbourne(Austin)–117MRSA•VISA2isolates(2%)–Sydney

401MRSABSI•hVISA46(11.5%)(almostallST239)•VISA2(0.5%)–Australia–general–532SAB/202MRSA•hVISA2isolates0.4%/1%•VISA0isolatesHorneAAC,20

09.ValHal,Plosone.Homes,JID2011.Summary•TheprevalenceofVRSAandVISAisolatesarestilllowinmostpartoftheworld•TheprevalanceofhVISAvariesingener

alrelativelylowbutcanlocallybeup50%ofMRSAisolates•ThereareincreasingevidencethatstrainswithMIC>1mg/Lareassociatedwit

hpooeroutcome–butlargedefinitiveprospectivestudiesisneededLinezolid-RS.aureus:Review•April–June2008•12patientswithLRSA•6VAP,3bacteremia•1predominantc

lone•cfrmediatedresistance•HealthcareworkersandenvironmentNegClinicalOutbreakofLinezolid-ResistantStaphylococcusaureusinanIn

tensiveCareUnitSanchezM,JAMA2010Linezolid-RS.aureusoutbreakK-217ClinicalandMicrobiologicalcharacteristicsofLinezolid-ResistantStaphylococcusau

reus(LRSA)April-June2008•FromJuly2001toMay2011:22publications,77patients•Mechanismofresistancewasa–RNAmutationin37–cfrgenein33–Both1–Notrepo

rted7•30ICU-patients,17patientsonhospitalwordsand18outpatients•LRSAcaused29respiratorytractinfections,mostlyVAP,bacteremiain7,andSSTIin6.Sixpa

tientswerecolonized.MdelaTorre,ICAAC,Chicagao2011MechanismsofLinezolidResistance•BindingtothePetidylTransferaseCenter(P

TC)ontheribosome•Mutationsof23SrRNA•RibosomalproteinsL3andL4•CfrmethyltransferasegeneLongKS.AAC2012.ResistancetoLin

ezolidCausedbymodificationsatItsBindingSiteontheRibosomeLR-MRSAoutbreak:Results•AllLR-MRSA(patientsandHC

W’s)weregenotypicallyidenticalbyPFGE•Thecfrgenewasdetectedinallisolates•Noneoftheisolatesshowedmutationsint

he235rRNAsubunitLR-MRSAoutbreak:LinezolidUse05101520251601401201008060402002009JanuaryFebruaryMarchAprilMayJuneJulyAugustSeptemberOctoberNovemberD

ecemberJanuaryFebruaryMarchAprilMayJuneLR-MRSAMRSADDDsLinezolidIncidencedensityNpatientsandincidencedensityMRSAinPSICUDapto-Resistance:m

echanisms•MutationsingenesessentialforMembranephospholipidbiosynthesisreducethenet-negativechargeofthecellmembrane.ElectrorepulsionofDaptomycinWholeG

enomeCharacterizationoftheMechanismsofDaptomycinResistanceinClinicalandLaboratoryDerivedIsolatesofStaphyloc

occusaureusPelegAY.PLoSone2012.Dapto-Resistance:mechanismsCorrelationbetweennonsusceptibilitytodaptomycinisduetocellwallthicken

ingPelegAY.PLoSone2012.DaptomycinMICincreaseamongpatientswithmethicillin-resistantStaphylococcusaureuspersistentbacte

raemiatreatedwithdaptomycin.Prospectivestudyin22Spanishhospitals.O.Gasch*,M.Camoez,MA.Dominguez,B.Padilla…•IncreaseinMIC’sinsequentialiso

latesbothtoDaptomycinandVancomycin.•SwitchtoanotherdrugifBC’sdonotbecomenegativeGashO.ECCMID2012.四、VRE•肠

球菌对万古霉素的耐药可分为低水平耐药（MIC，8-32mg/L）和高水平耐药（MIC，≥64mg/L）。•根据肠球菌对万古霉素和替考拉宁的不同耐药水平及耐药基因，VRE分为四个表型，分别是VanA，VanB，VanC和VanD。VRE的分型及其耐药表型类型万古霉

素（μg/ml）替考拉宁VanA64~＞100016~512VanB4~10240.25~2VanC2~320.12~2VanD16~642~4CLSIbp≤2,4-816≤8,16≥32chromIDVRE粪肠球菌屎肠球菌•VRE筛选试验阳性必须做MIC确认，并观察动力和色素鉴别菌种，以区分获

得性耐药（VanA和VanB）及某些菌种存在的固有的中介（8-16）耐药（VanC），后者在感染控制中的意义与VRE不同。肠球菌的治疗•粪肠球菌：氨苄西林加减庆大霉素重症，HLAR：万古霉素•屎肠球菌：庆大霉素•重症，HLAR：万古霉素•VRE：VanA

：替考拉宁，其他：利奈唑胺•泌尿道感染：呋喃妥因五、经验治疗以下情况高度提示革兰阳性球菌感染•血流感染，包括导管相关的血流感染，菌血症，脓毒症，细菌性心内膜炎•皮肤软组织感染，包括伤口和创面感染•手术部位感染，包括植入物感染•骨和关节感染，骨髓炎以下情况有可能革兰阳性

球菌感染•HAP（MRSA）•VAP（MRSA）•复杂UTI（MRSA，肠球菌）革兰阳性球菌感染？•葡萄球菌占革兰阳性球菌感染第一位•金黄色葡萄球菌占葡萄球菌感染第一位•MRSA占金黄色葡萄球菌50~60%以下情况考虑糖肽类治疗•脓毒症•骨、关节感染•手术部位感染•血流感染：

菌血症、心内膜炎•导管相关感染•院内肺炎•复杂性尿路感染