真菌--胡亮钉讲稿.ppt

全军造血干细胞移植中心,侵袭性真菌感染(IFI)的预防和治疗,3,CAUSESOFDEATHAFTERUNRELATEDDONORTRANSPLANTS1994-1999,SUM02_41.ppt,%OFDEATHS,100,0,20,40,60,80,PrimaryDisease,GVHD,IPn,Infection,OrganFailure,Other,100%,50%,ChangeofTherapyat72hours,ResponsetoInitialregimen,Noresponse,Responsetochangeofantibacterialdrugs,7%,18%,Responsetogranulocytetransfusion,Furtherchangeoftherapyat4-6days,Responsetoantifungaltherapy,5%,50%,25%,Noresponse:died,10%,Neutrophilrecovery,5%,Responsetoantiviralagents(orsurgery),5%,0,2,4,6,8,10+,Day,Fever,Noresponse,Persistentfeverduringfirst3-5daysoftreatment:noetiology,Reassesspatientondays3-5,Changeantibiotics,Antifungaldrugwithorwithoutantibioticchange,Ifprogressivediseaseifcriteriaforvancomycinaremet,Iffebriledays5-7andresolutionofneutropeniaisnotimminent,MortalityDuetoInvasiveMycoses,McNeilMM,etal.ClinInfectDis2001;33:641-7,UnitedStates,1980-1997,NosocomialCandidemia:Epidemiology,PappasPGetal,ClinInfectDis2003;37:634-43,N=1593,InvasiveAspergillosisMortalityReviewofLiteratureafter1995,Reviewof1941Patientsfrom50Studies,LinS-Jetal,ClinInfectDis2001;32:358-66,PrimaryDiagnosisinPatientswithInvasiveAspergillosis,(595patients),PattersonTF,etal.Medicine,2000;79:250-60,EpidemiologyofInvasiveAspergillosisinHematopoieticStemCellTransplantation,WaldA,etal.JInfectDis1997;175:1459-66,DaysfromTransplanttoDiagnosisofInvasiveAspergillosis,Only31%neutropenic96%increasedincidence,真菌感染存在的问题,1真菌感染诊断？2那些是侵袭性真菌感染的高危因素？3实验室检查？4临床常见的真菌检测结果的判断？5怎样合理使用抗真菌药物？6抗真菌感染疗效评价？,真菌感染的诊断,1确诊（Proveninvasivefungalinfections)2可能（Probableinvasivefungalinfections)3可疑（Possibleinvasivefungalinfections),真菌感染的高危因素,低：自体BMTPBSC儿童急淋（卡肺除外）中低：粒缺100-500小于3W老年患者或导管中高：定植大于1个部位或1个部位多次急非淋或TBI异基因同胞间相合BMT高：粒缺小于100大于5W定植（热念）无关移植GVHD激素大于1mg/kg和粒缺小于100大于1W激素大于2mg/kg大于2W大剂量AraC、Fludarabine,粒缺或器官移植患者肺部感染检查,呼吸道症状和体症疾病状态粒缺/BMT肺X-ray/CT器官移植DSBAL肺X-rayFLneedle/biopsyDSBALCAresectionFLCTbiopsy,实验室检查,霉菌：痰涂片、BAL、活检物镜检呼吸道分泌物和活检物培养GM检测（FDA）-1，3-D-glucanPCR,实验室检查,念珠菌：体液和组织活检血和体液培养呼吸道分泌物培养PCR-1，3-D-glucanprecipitinCandidamannanby-ELISAanti-CandidamannanbyELISA,实验室检查,血清学检查：半乳甘露聚糖Galactomannan）抗原检测是FDA批准的检测曲霉菌特异的、敏感的方法。半乳甘露聚糖快速从循环以免疫复合物形式中被清除或被肝脏Kupffers细胞吞噬，故在高危患者至少每周检测2次半乳甘露聚糖抗原检测有许多优势：1无创2方法简单3定量4特异,实验室,1-3-beta-D-葡聚糖抗原检测是一种新的、有前景的检测所有真菌感染方法，包括酵母菌和霉菌，目前未被FDA批准。PCR是检测各种组织曲霉菌核酸的一种敏感的方法，目前尚无商品化的产品、价格昂贵及假阳性率高。,放射学诊断评估,X光诊断不可靠，30%的患者死亡前一周肺部X光正常高分辨肺部CT和筛窦CT对高危患者诊断有帮助，肺部曲霉菌感染包括：1光晕症伴有曲霉菌血管侵润性出血性结节（粒缺期）2空气新月症（造血恢复期）,脑曲霉菌感染,UtilityofGalactomannanDetectioninBALSamples,GMdetectioninCT-basedbronchio-alveolarlavage(BAL)fluidhashighutilityfordiagnosinginvasivepulmonaryaspergillosisearlyinuntreatedpatients,Beckeretal.BrJHaematol2003;121:448,检测方法比较,Kawazu(2004)96pts(11proven/probIA):galactomannan(GM)vsPCRvs-glucanGMmoresensitivethanPCR(100%vs55%)EarlierdetectionwithGMat0.6cutoff(median10dayssooner)Pazos(2005)40pts(9proven/probIA):GMvs-glucanIdenticalsensitivity(87.5%),specificity(89.6%)-glucanpositiveearlierCombinationimprovedspecificity(100%),Kawazuetal,JClinMicro2004;42:2733-41;Pazosetal,JClinMicro2005;43:299-305,抗真菌治疗疗效评价,完全（Completeresponse)部分(Partialresponse)稳定(Stableresponse)失败(Failure),抗真菌药物,抗真菌药物(1),二性霉素BCAmBAmBisomeAmphotecAbelcet,二性霉素B,对粒缺患者疗效减低避免与盐水输注低钾造血抑制,AmBisome,治疗严重的真菌感染可作为经验性治疗粒缺伴发热的患者在二性霉素中副作用最少3-5mg/kg/d累积剂量2-3g(3-4W),Amphotec和Abelcet,Amphotec3-4mg/kg最大6mg/kg最大累积剂量30gAbelcet5mg/kg最少2W文献报告对毛霉菌有效AmBisomeAbelcetAmphotecCAmB,抗真菌药物(2),CaspofunginMicafungin,Echinocandins,CharacteristicsRapidlyfungicidalforyeastIntravenousadministrationMinimalrenaltoxicityActivityYeasts(C.albicans;non-albicans)Moulds(Aspergillus;notZygomycetes)Others(Endemicmycoses;notCryptococcus),Cycliclipopeptideantifungalsthatinhibit-1,3-glucansynthaseCaspofunginMicafunginAnidulafungin,Caspofungin,Ckrusei和CParapsilosis不敏感新生隐球菌、分支菌属、镰刀菌和接合菌无效播散性念珠菌和侵袭性曲霉菌有效卡肺有效不作为治疗曲霉菌一线药物可与其他类抗真菌药联合应用(二性霉素B或唑类),抗真菌药物(3),FluconazoleItraconazoleVoriconazolePosaconazole,Fluconazole,治疗非粒缺患者侵袭性真菌感染光滑念珠菌敏感性低和克柔念珠菌无效预防念珠菌病在高危人群粒细胞恢复前或粒细胞恢复后1W,Itraconazole,治疗组织胞浆菌一线药物镰刀菌疗效差,接合菌无效偶有白念和烟曲霉菌耐药治疗曲霉菌、念珠菌二线药物曲霉菌或念珠菌的预防心功能不全者慎用,Voriconazole,广谱抗真菌药物侵袭性曲霉菌治疗一线药物(USapproved)有效率53%对Flu75%(CKrusei),Itra63%耐药的念珠菌对Itra和二性霉素B耐药的曲霉菌治疗严重的真菌感染(免疫功能低下的患者)对镰刀菌43%和丝状真菌(USforsalvage),接合菌无效,抗真菌治疗,真菌感染预防经验性治疗联合治疗,DetermineRiskCategory,High,NoProphylaxisRoutineclinicalevaluation,Low,Clinicalsignsandsymptomsconsistentwithfungalinfection,Intermediate+,PersistentfeverNoSwhenavailablefungalantigenemiaorPCRshouldbeused.+Surveillancemaybeconsideredforintermediate-riskpatients.ThisdashedlinePersistendfeverinseverelyneutropenicpatientswithsignsandsymptomssuggestiveoffungalinfectionS50mg/dayNon-albicansyeasts;neutropenicAmphotericinB0.7mg/kg/d;Fluat800/d;CaspoSequentialtherapySusceptibleorganismposaconazole,micafungin,anidulafungin(investigational),PappasPG,etal.ClinInfectDis2004;38:161-89,抗真菌感染的经验性治疗,粒缺伴发热的经验性治疗(推荐Guidline)1持续发热72-96h2广谱抗菌素无效3无明确的诊断CAmB1mg/kg/dAmBisome1-3mg/kg,联合治疗,粒缺患者危及生命的真菌感染棘白霉素类与多稀类棘白霉素类与唑类,CombinationTherapyinInvasiveAspergillosis,InvitroMostinteractionsshowsynergy/additiveeffects(Perea,2002)Poorinvivo/invitrocorrelation(Johnson,2004)ExperimentalinfectionsCandinplusAmB(Kohno,