真菌感染的诊疗和抗真菌药物应用培训课件

真菌感染的诊疗和抗真菌药物应用真菌感染医院真菌感染的病原体以念珠菌居多，各临床科室发病率有所不同PfallerMAetal.CritRevMicrobiol.

2010;36(1):1-53.普通病房血液恶性肿瘤骨髓移植HIV新生儿监护病房实体器官移植实体肿瘤外科(非移植)合计(n=3,640)(n=1,010)(n=377)(n=263)(n=54)(n=886)(n=863)(n=1,906)(n=6031)念珠菌属81.742.631.632.796.357.289.291.275隐球菌属4.02.10.048.70.04.5其它酵母菌*3.40.01.0曲霉属8.333.826.04.93.412.3接合菌0.00.61.4其它霉*1.50.02.7地方性真菌1.60.01.62004-2008年间美国IFD病原体在各临床科室的分布(%)*其它酵母包括6例马拉色菌属，26例肺孢子菌，12例红酵母，21例啤酒酵母和6例毛孢子菌*其它霉菌包括2例支顶孢菌,9例交链孢霉,3例双极孢菌，53例镰刀霉，10例拟青霉菌,13例赛多孢子菌，6例足分枝霉菌和1例白色簇孢霉

院内深部真菌感染最主要病原体内容常见真菌感染常用抗真菌感染治疗药物治疗策略

CHINET2012年菌种分布总株数：1619株，其中9株未完成鉴定；已鉴定共37种念珠菌病遍及各组织器官(一)皮肤粘膜念珠菌病皮肤念珠菌病粘膜念珠菌病(口腔、食道、胃肠道、阴道)(二)深部组织念珠菌病念珠菌血症、心内膜炎、化脓性血栓性静脉炎、其他心血管念珠菌病中枢神经系统：脑膜炎、脑脓肿骨髓炎、关节炎、肋软骨炎、肌炎腹膜、肝、脾、胆囊念珠菌感染尿路感染：膀胱炎、肾盂肾炎呼吸道感染：肺炎、肺脓肿、支气管炎、喉炎、会厌炎眼内炎播散性念珠菌病侵袭性念珠菌感染病死率Tortoranoetal.,EJCMID2004;23:317%各种念珠菌感染均具有很高的死亡率白念珠菌(n=1090)光滑念珠菌(n=269)近平滑念珠菌(n=263)热带念珠菌(n=140)死亡率(%)*ECMM:TheEuropeanConfederationofMedicalMycology3.TortoranoMAetal.EurJClinMicrobiolInfectDis.2004;23:317-22.ECMM*对各种念珠菌血流感染患者死亡率的监测结果欧洲7国自1997年9月至1999年12月进行的一项前瞻性研究，分析欧洲念珠菌血症的流行现状，同时评估监测30天时患者的粗计死亡率状况。静脉高营养中心静脉导管粒细胞缺乏广谱抗菌药肾脏替代治疗免疫抑制剂治疗ClinicalPracticeGuidelinesfortheManagementofCandidiasis:2009UpdatebytheIDSA.CID2009;48:503-35.

侵袭性念珠菌感染危险因素人工装置侵袭性念珠菌病的菌种分布

ARTEMIS1997-2007(n=197,619)%Totalnumberofcases*ARTEMISDISKGlobalAntifungalSurveillance41国家142中心.JClinMicrobial2010,48(4)1366-7720306株酵母菌的分布（％）

(ARTEMIS中国2001～2009)百分比（％）239207株酵母菌的分布（％）

(ARTEMISGlobal

2001～2008)百分比（％）与全球ARTEMIS酵母菌监测结果的比较(%)

两者均以白念珠菌的比例占首位，其次是光滑念珠菌和热带念珠菌占临床分离酵母菌的比例(%)2001年-2008年期间，中国4大城市5所医院的念珠菌监测结果我国白念珠菌的临床分离率持续居高不下2001年至2008年期间，我国5所医院对15281株酵母菌菌株的监测结果。并按CLSI/NCCLS推荐的纸片扩散法进行氟康唑和伏立康唑的药敏试验。念珠菌病：体外抗菌活性结果念珠菌种类氟康唑伊曲康唑伏立康唑泊沙康唑氟胞嘧啶两性霉素B棘白菌素白念珠菌SSSSSSS热带念珠菌SSSSSSS近平滑念珠菌SSSSSSStoRa光滑念珠菌S-DDtoRS-DDtoRS-DDtoRS-DDtoRSStoIS克柔念珠菌RS-DDtoRSSItoRStoIS葡萄牙念珠菌SSSSSStoRS

S：susceptible敏感；I：intermediatelysusceptible中度敏感

R：resistant耐药；S-DD：susceptibledose-dependent剂量依赖性敏感；

a：近平滑念珠菌对棘白菌素类耐药不常见ClinicalInfectiousDisease2009;48:503～535AllergicaspergillosisAllergicaspergillussinusitisAllergicbronchopulmonaryAspergillosisInvasiveaspergillosisInvasivepulmonaryaspergillosisInvasivesinusaspergillosisTracheobronchialaspergillosisChronicnecrotizingpulmonaryaspergillosisAspergillosisoftheCNSAspergillusinfectionsoftheheartAspergillusosteomyelitisandsepticarthritisAspergillusinfectionsoftheeyeCutaneousaspergillosisAspergillusperitonitisChronic(andsaprophytic)formsofaspergillosisAspergillomaChroniccavitarypulmonaryaspergillosisg曲霉病

RelativeriskofAspergillusinfection

Aspergillusasapathogeninman-

Patientswhoseimmunesystemisalreadyweakenedaremostsusceptible.Thosemostatriskincludesomecancerandleukaemiapatients,thoseonchemotherapyandtransplantpatients.ImmunemalfunctionFrequency

of

aspergillosisImmunehyper-reactivityFrequency

of

aspergillosisAcuteinvasive

aspergillosis

AspergillomaAllergicaspergillosisAllergicsinusitisNormal

immunefunctionTracheobronchitisFungusballChroniccavitaryChronicfibrosingSubacuteIAAspergillusspp.IsolatesSubmittedtoSanAntonioFungusTestingLaboratory918Isolates;Jan.2001-July2004SuttonDetal,AdvancesAgainstAspergillus2004(Abstract16)A.nidulans3% AmBMLC>16A.fumigatus24% AmBMIC>2A.terreus90%A.flavus51%A.ustus 50%

隐球菌–流行病学有免疫缺陷疾病的患者比例上升HIV/AIDSAccountsforupto50%cryptococcalinfectionsCD

4<200IncidencehasdeclinedsinceadventHAARTProlongedsteroidtherapyOrgantransplantationMalignancySarcoidosis隐球菌病存在于空气、鸟粪等，人自呼吸道吸入，免疫功能低下者致病肺部：病变轻,少数呈肉芽肿样,X线浸润性病变或粟粒脑膜炎：颅底病变者，1/3患者颅N累及（视、动眼、外展），脑刺激征，颅N受损皮肤粘膜损害：10-15%丘疹、结节、脓肿病原检查：墨汁涂片阳性率早期≥85%（透明厚壁），直接涂片易漏诊骨关节眼…脑隐球菌病的易感因素众多

慢性消耗性疾病

-肝硬化

-糖尿病

-慢性肾脏疾病

-实体肿瘤、恶性血液病

-系统性红斑狼疮

-肺结核等使用皮质类固醇激素自身免疫性疾病使用免疫抑制剂器官移植其他：头颅外伤史、脾切除、特发性CD4+淋巴细胞减少症等LuCH,etal.JHospInfect.1999Aug;42(4):313-20.ZhuLP,etal.MedMycol.2010Jun;48(4):570-9.诊断

CultureWhitemucoidcolonieswithin48hoursBloodculturesoften(+)inimmunosuppressedpatients2/3rdswithmeningitisTissueSilverormucicarminestainIndiaInkforCSFCryptococcalantigenSerumandCSFare99%sensitiveinAIDSpatientsSerumislesssensitiveinnormalhosts曲霉-半乳甘露聚糖（GM试验）曲霉细胞壁上一种多聚糖抗原标本：血清、脑脊、胸水、BALFFDA批准:用于造血干细胞移植受者和血液系统恶性疾病患者侵袭性曲霉病的诊断敏感性80.7％，特异性89.2％假阳性见于：新生儿或儿科患者、异体骨髓移植者、菌血症者、自身抗体阳性者、使用PIP/TAZ、AM/CL者PerformanceofGMdetectioninpublishedstudiesspecificitysensitivity酵母菌、丝状真菌细胞壁成分可检测除隐球菌和接合菌以外的侵袭性真菌标本：血液、BAL、CSF适用于血液系统恶性肿瘤患者深部真菌病和真菌血症的诊断敏感性67%～100%，特异性90％假阳性见于：输注白蛋白或球蛋白、血液透析、输注抗肿瘤的多糖类药物、外科手术后早期、标本接触某些纱布等G试验并未在儿科和实体器官移植患者进行评价1,3--D-葡聚糖（G试验）两种试验敏感性、特异性相当都可以在早期诊断侵袭性曲霉病，但是－D－葡聚糖可能出现更早两者结合，可以互补弥补GM假阴性可能同样在粒细胞缺乏患者用的多，其他患者有待研究半乳甘露聚糖(GM)与－D－葡聚糖的比较隐球菌抗原检测隐球菌荚膜抗原乳胶凝集试验特异性接近100%，敏感性约为95%与菌体计数具有平行性，对于预后判断有帮助CTScansHalosignAircrescentsignKuhlman1987Chest92:95-99;Caillot2001JClinOncol19:253-9曲霉病肺部病变影像学的动态变化

晕轮征--atypical--新月征时间Day0714CAILLOTetal.JClinOncol2001;19:253影像学检查注意事项可表现为晕轮征和其他与侵袭性曲霉相似的影像学特征接合菌、镰孢菌、赛多孢菌等血管侵袭性真菌感染铜绿假单胞菌、诺卡菌等呼吸道分泌物检出念珠菌属的临床意义呼吸道分泌物分离到的念珠菌很少提示侵袭性念珠菌感染，不需要抗真菌治疗（A-III）。气道分泌物中分离出曲霉的意义免疫功能正常：定植76例曲霉培养阳性非粒细胞缺乏患者48例定植，19例曲霉球，慢性坏死性肺曲霉病7例，2例曲霉支气管炎，无1例急性侵袭性肺曲霉病粒细胞缺乏/白血病：阳性预测值80－90％中低危患者：广谱抗生素治疗、营养不良、肾移植、HIV感染者、实体器官移植、长期糖皮质激素治疗：阳性预测值10－30％结合胸部影象学、血清抗原检测，以及气道分泌物直接镜检PerfectJR.ClinInfectDis2001,33:1824-1833侵袭性真菌病修订定义

EORTC/MSG确诊ProveninvasivefungalinfectionsTissueBloodculturehistologycultureMycology拟诊ProbableinvasivefungalinfetionsHostfactorClinicalfeaturesMycology++InvasiveFungalInfectionsCooperativeGroup疑似Possibleinvasive

fungaldiseaseHostfactorClinicalfeatures+InvasiveFungalInfectionsCooperativeGroup修订定义的不足之处修订IFD定义是为了促进临床试验和流行病学研究修订后的定义适用于免疫功能缺陷患者，并不适用于重症监护室中将有可能发展成为疑似和拟诊IFD的危重患者不能满足IFD的诊断标准并不意味着不存在IFD，只是无足够的证据支持诊断这正是不能将本定义用于日常临床实践的最主要原因定义II-宿主因素宿主因素粒细胞缺乏发热>4日，经广谱抗菌药治疗无效GVHD激素>3周粒细胞缺乏激素>3周T细胞免疫抑制治疗遗传性严重免疫功能不全造血敢细胞移植受者<36°C或>38°C先前真菌病AIDS免疫抑制药物粒细胞缺乏>10日定义II–临床特征Clinicalfeature下呼吸道感染鼻窦感染CNS感染慢性播散性念珠菌病不分主要次要标准CT特异性改变光晕征空气新月征空洞影响学显示鼻窦炎＋以下至少一项:急性局部疼痛(包括疼痛放射至眼)鼻部溃疡,黑痂自鼻窦延伸穿越骨屏障，包括进入眼眶至少以下一项:-影像学局灶损害MRI或CT显示脑膜增厚肝和/或脾周边、微小、靶样脓肿(牛眼征)气管支气管炎支气管镜检见气管支气管溃疡、结节、假膜、斑点、或结痂*EORTC/MSG共识组：CID2008,46:1813-21定义II–真菌学真菌学血,BAL.CSF抗原阳性组织、吸取物、BAL或痰液培养霉阳性鼻窦吸取物霉阳性无菌组织或体液真菌阳性BAL.CSF或血G试验阳性PCRtodetectnucleicacidNotuntilaPCRsystemisdevelopedthathasbeenexternallyvalidatedforblood,tissue,orBALfluidMedicalMycology:

TheLast50YearsNystatinAmphotericinB(1958)Griseofulvin5-FCMiconazoleKetoconazoleFluconazoleItraconazoleL-AmBABCDABLCTerbinafineVoriconPosaconSordarinsCaspofunginMicafunRavuconAnidulafungin#ofdrugs抗真菌药物多烯类两性霉素B及含脂制剂制霉菌素脂质体（Liposomalnystatin）吡咯类（azole）(三唑类,triazole）氟康唑伊曲康唑伏立康唑泊沙康唑(Posaconazole)棘白菌素类（Echinocandins）卡泊芬净米卡芬净(Micafungin,)阿尼芬净(Anidulafungin)5-FCThreePatternsofAntifungalActivityDrugclassTimeCourseofActivityPharmacodynamicParameterKillingPAETypeMagnitudePolyeneCidalLongPeak/MIC4EchinocandinCidalLongPeak/MIC3TriazoleStaticLongAUC/MIC25FlucytosineStaticShortT>MIC25AndesD.AAC2003;47:1179-1186MembraneFunctionPolyenes:

AmphotericinB AmBlipidformulations

(ABLC,ABCD,LAmB) Nystatin

LiposomalnystatinErgosterolSynthesisAzoles:

Fluconazole Itraconazole Voriconazole Posaconazole

Ravuconazole

CellWallSynthesisEchinocandins:

Caspofungin Micafungin AnidulafunginNucleicAcidSynthesis5-fluorocytosineAntifungalTherapyTargetsofFungalCell两性霉素BPolyenegroup–affectsfungalcytoplasmicmembraneBroadspectrumCoversalmostallCandida,Aspergillus,Blastomyces,Histoplasma,Cryptococcus,Cocciodiodes,ZygomycesetcLimitationsNephrotoxicityAcutereactionsduringadministrationManyotheradverseeffects两性霉素BPro’s:fungicidalbroadspectrumclinicalexperienceminimaldrug-druginteractionsCon’s:Nephrotoxicityinfusion-relatedreactionsonlyIVformulationNoactivityagainstFusariumspp.andScedosporiumspp.两性霉素BNotabsorbedfromgut,skinormmIV-highlyproteinbound–91%~95％GoodpenetrationintoserouscavitiesPoorCSFpenetrationLowbloodlevelCrossesplacentaHalflife24hoursSlowrenalexcretion–2%~5％/d,40%/w两性霉素BIVinfusion–chills,fever,vomitingFlushing,muscle,jointpainsAvoidothernephrotoxicdrugsSteroidsworsenhypokalemiaPotentiatesactivityofFlucytosinePremediation-veryimportantforpatientdiscomfort-duetoreleaseofcytokinesadequatehydration,smallamountofsteroid.两性霉素BDose0.5–1.5mg/kg/dayIVDuration–usually14daysContraindicatedifpreviousallergicreactiontothedrugMonitoringDailyU,E,Cr.Cr^,hypokalemiaFBCweeklyEnsureadequatehydrationandNaintake两性霉素BFDAApprovedIndicationsEmpiricanti-fungaltherapyCandidaspp.Aspergillusspp.CryptococcosisMucormycosisEndemicmycosesBlastomycosis,HistoplasmosisCoccidioidomycosis,ParacoccidioidomycosisPenicilliosis,SporotrichosisLeishmaniasis1.Ostrosky-Zeichneretal.ClinInfectDis.2003;37:415-425.2.Batesetal.ClinInfectDis.2001;32:686-693.ConventionalAmBIsNoLongerthe“GoldStandard”forTreatmentApprovedin1958withnorandomizedstudiesBecametreatmentofchoiceduetobroad-spectrumefficacyandlowrateofresistance1NephrotoxicitywasinitiallyunderestimatedCurrently,AmBtreatmentresultsin30%incidenceofacuterenalfailure,resultingin2:IncreasedmortalityIncreasedhospitalstayLipidAmphotericinBFormulationsRibbon-likeparticlesCarrierlipids:DMPC,DMPGParticlesize(µm):1.6-11 Abelcet®ABLCAmphotec®ABCDAmbisome®L-AMBDisk-likeparticlesCarrierlipids:CholesterylsulfateParticlesize(µm):0.12-0.14 Unilaminar

liposomeCarrierlipids:HSPC,DSPG,cholesterolParticlesize(µm):0.08 DMPC-DimyristoylphospitidylcholineDMPG-DimyristoylphospitidylcglycerolHSPC-HydrogenatedsoyphosphatidylcholineDSPG-DistearoylphosphitidylcholineLipidAMBFormulationsIndicationsnotindicateasinitialtherapyformostpatientswiththevariouscandidasyndromes,cryptococcosisandtheendemicmycosesindicationsPreexistingrenaldysfunction(serumCr>2.5-3mg/dL)RefractorytoorintolerateofamphotericinBorazoletherapyLife-threatening,progressivedisease(e.g.,aspergillosisorzygomycosis)L-AmBFebrileneutropenicpatientswithsuspectedfungalinfections氟胞嘧啶IVororalNarrowspectrum–mainlycandidaandcryptococcusNotusedassoledrug–usedalongwithamphoBOralabsorptiongood–80%,lowproteinbindingT½~3-6hoursPenetratesintoCNSExcretedinurine-80%unchanged氟胞嘧啶PrecautionsMonitorFBC,LFTandrenalfunctionMonitorpeaklevels–40～60mg/LUsualsideeffectsNausea,vomiting,diarrhoeaTransientrashesbonemarrowsuppressionThrombocytopeniaAlopeciadecreasedliverfunction

Indicationsseriousinfectionscausedbysusceptiblestrainsofcandidaand/orcryptococcusCandidasepticemia,endocaarditis,urinarytractinfectionsandpulmanaryinfectionsCryptococcusmeningitis,pulmanaryinfections,septicemia,urinarytractinfections氟胞嘧啶Azoles:ImidazolesandTriazolesforSystemicUseImidazolesImiconazoleKetoconazoleTriazolesFluconazoleItraconazoleVoriconazolePosaconazoleRavuconazole氟康唑Azole–IV,oralsuspension,capsuleSpectrumUsefulagainstcryptococcusandC.albicansIneffectiveagainstsomeCandidaspeciessuchasC.kruseiandC.glabrataIneffectiveagainstAspergillusspeciesUsedtotreatskin,mmandsystemiccandidalinfectionsandcryptococcalinfectionAlsousedorallyinprophylaxisofabove氟康唑IdealpharmacokineticsGoodbioavailabilityafteroralandIVOralbioavailiability≥90%Lowproteinbinding,12%GoodserumconcentrationsGooddistributiontoalltissuesGetsintoCSFwell.Only9%hepaticmetabolism.t½-25–30hours氟康唑Largetherapeuticindex-dosesupto1200mg/daywelltolerated.ResistancebeginningtobeaproblemforbothCandidaalbicansandnon-albicansisolates.IdealsideeffectprofileWelltolerated,nausea,headache,abdominalpain,Rarehepatictoxicity.Elevatedliverenzymes,skinrash-discontinueDosemustbeadjustedinrenalfailure.氟康唑FewsignificantdruginteractionsAllazolesinteractwithawidevarietyofdrugsincludingantiretrovirals–henceimportanttolookintheformularytobecomeawareofpossibleinteractionsinaparticularpatient氟康唑IndicationsCryptococcalmeningitisSystemicinfectionscausedbyCandidasp.Vaginalcandidiasis-single150mgdose.Oralpharyngeal/esophagealcandidiasisProphylaxis-BMTandchemotherapypatientstodecreasetheincidenceofcandidiasis.伊曲康唑Azole–IV,oralsolution,capsulesVerybroadspectrum–coversaspergillus,candida,cryptococcusandothersUsesAlternativetoamphobininvasiveaspergillusProphylaxisagainstaspergillusandcandidaTreatsuperficialskinmmfungalinfectionsPreventrelapseofcryptococcalinfectioninHIV伊曲康唑Pharmacokinetics–notidealOralabsorptionnotgood－33％and55%LiquidtastesbadVeryhighlyproteinboundNeedsrepeateddosingbeforeoptimalconcentrationsareachievedPoorCSFconcentrations,reasonabletissueconcentrations伊曲康唑-AdverseEffectsNauseaandvomitingHeadacheanddizzinessLiverdysfunctionHypokelemia,hypokalemia,impotenceAllergicskinreactionsHypertriglyceridemiaDrug-druginteractions,similiartoketoconazolebuttolesserdegree伊曲康唑PrecautionsLiverenzymes–contraindicatedinsevereliverimpairmentIVpreparationcontraindicatedinsevererenalimpairment(cyclodextrinpresentisexcretedbykidney)BP,HypoK+,nausea,rash伊曲康唑IndicationsforcapsulesBlastomycoses-pulmonaryandextrapulmonaryHistoplasmosis-pulmonaryanddisseminatedAspergillosis-pulmonaryandextrapulmonaryOnychomycosisduetodermatophytesofthetoenailsandfingernails.伊曲康唑IndicationsfororalsolutionFebrileneutropenicpatientswithsuspectedfungalinfectionsOralpharyngeal/esophagealcandidiasisIndicationsforintravenousFebrileneutropenicpatientswithsuspectedfungalinfectionsBlastomycoses-pulmonaryandextrapulmonaryHistoplasmosis-pulmonaryanddisseminatedAspergillosis-pulmonaryandextrapulmonaryTriazoleAntifungals:Voriconazole,PosaconazoleSpectrumofActivityCandidaspp.Aspergillusspp.Blastomycesspp.Histoplasmaspp.Cryptococcusspp.Cocciodiodesspp.Fusariumspp.ScedosporiumTriazoleAntifungals:Voriconazole,PosaconazolePro’s:IncreasedspectrumofactivityminimaladverseeffectsexcellentbioavailabilityIV(VOR,POS)andPO(VOR,POS,RAV)Con’s:fungistaticdrug-druginteractions(CYP3A4and2C19)visualdisturbancesnon-linearpharmacokineticsNoactivityagainstChrysosporiumspp.,ZygomycesVoriconazole

SummaryofPharmacokineticsRapidandconsistentabsorptionwithhighoralbioavailability(96%)Largevolumeofdistribution(4.6L/kg)Plasmaproteinbinding58%Non-lineareliminationHepaticmetabolismbyCYP2C19,2C9and3A4isoenzymesVoriconazole

TissueDistributioninAnimalsConcentrationsofradioactivityinmalerattissueat5minutespostinfusionCerebrospinalfluid/plasmaconcentration

ratio=0.8inguineapigsatsteadystateaftermultipledosing**Jezequeletal.1995,ICAACAdverseEventsHepaticOverallrateof13%.~2-foldmorethanFluVisualNotedby~30%.Asenseofalteredlightperception,blurring,orphotophobiaEXHAUSTIVELYstudied.Noapparentconsequences.MiscellaneousPhotosensitivity(~1%)?Avoidstrongsunlight.SaboAnnPharmacother34:1032,’00;Voriconazolepackageinsert,May2002;VoriconazoleFDAAdvisoryCmte,‘01伏立康唑适应症侵袭性曲霉病念珠菌病非粒缺患者念珠菌血症念珠菌所致播散性皮肤感染、腹部、肾脏、膀胱壁及伤口感染食道念珠菌病不能耐受其他药物或其他药物无效的赛多孢菌和镰孢菌，包括腐皮镰孢菌所致的严重真菌感染KartsonisNA.Presentedatthe12thEuropeanCongressofClinicalMicrobiologyandInfectiousDiseases.

April24-27,2002.Milan,Italy.棘白菌素类:NewClassofDrugNucleosideAnalogs-(1,3)-D-glucanErgosterolPolyenesAzolesPhospholipidbilayer

ofthefungalcellmembraneFungal

cellwall-(1,6)-glucan-(1,3)-D-glucansynthaseGlucanSynthesisInhibitornucleusBreakthroughMechanismofAction:TargetsthePathogen,NotthePatientTheEchinocandinsOHHHHOOHHNHONHHHOH2NHOONHH3CHOHHONHHHOOHHHNHNHOCH3OHHHONOHOHHEchinocandin“backbone”Cycliclipopeptidesthatnon-competitivelyinhibitof1,3-b-Dglucansynthase210kDaintegralmembraneheterodimericprotein?ResponsibleforexportofglucanpolymerThreeechinocandinsCancidas®(caspofungin)Micafungin(FK463)Anidulafungin(VER002)Echinocandins:CaspofunginandMicafunginSpectrumofActivity:Candidaspp.Aspergillusspp.Histoplasmaspp.Blastomycesspp.Pneumocystisspp.Caspofungin:BroadSpectrumofActivityDataonfile,MSD;BartizalK,GillCJ,AbruzzoGKetalAntimicrobAgentsChemother1997;41:2326-2332.C.albicansC.glabrataCANDIDAALBICANSC.parapsilosisC.tropicalisC.kruseiC.guilliermondiiC.lipolyticaC.dubliniensisC.kefyrC.lusitaniaeC.rugosaA.flavusA.fumigatusA.terreusA.nigerA.nidulansCANDIDA

NON-ALBICANSASPERGILLUSExpandedSpectrumofInVitroActivityC.pseudotropicalisEchinocandins:CaspofunginandMicafunginPro’s:fungicidal(Candidaspp.)minimaldrug-druginteractionsminimaladverseeffectsCon’s:NoactivityagainstCryptococcusspp.,Fusariumspp.,orScedosporiumspp.onlyIVformulationsSummaryandConclusionCaspofunginBecauseofitsnovelmechanismofaction,caspofunginmayprovidethedesiredeffects

ofantifungaltherapyInhibitionoffungalcell-wallbiosynthesisPotencycomparabletoamphotericinB*TolerabilitysuperiortoamphotericinB*** Asshowninpreclinicaldata.**Basedonexperienceinclinicalstudies.AndrioleVT.JAntimicrobChemother1999;44:151-162;GrollAHetal.AdvPharmacol1998;44:343-500;

GraybillJRetal.AntimicrobAgentsChemother1997;41:1775-1777.卡泊芬净的适应症粒缺发热经验治疗念珠菌血症和下列念珠菌感染：腹腔脓肿、腹膜炎和胸腔感染食道念珠菌病难治性或不能耐受其他治疗（即AmB、AmBLF和/或伊曲康唑）的侵袭性曲霉病米卡芬净Micafungin棘白菌素类，抗菌谱与卡泊芬净相仿蛋白结合率高（>99％），t1/2ß10-15h主要经肝脏代谢，少部分由肾脏排出2002年日本上市，2005年美国上市FDA批准适应证及给药方案食道念珠菌病的治疗，150mg/d静滴造血干细胞移植患者预防念珠菌感染，50mg/d静滴主要不良反应：恶心、呕吐、血胆红素升高及肝功能异常阿尼芬净Anidulafungin抗菌活性对念珠菌属作用强，对近平滑和季列蒙念珠菌的作用稍差对曲霉及卡氏肺孢菌有作用对新型隐球菌、皮炎芽生菌，申克孢子丝菌、毛孢子菌、镰刀菌属等作用差t1/2ß25.6h2006.2美国批准上市，适应证及用法念珠菌血症、其他念珠菌感染（腹腔脓肿、腹膜炎）：首剂200mg，继100mgqd静滴食管念珠菌病：首剂100mg，继以50mgqd静滴不良反应：静脉炎、头痛、恶心、呕吐Combinationtherapy

IssuesClinicaltrialssupportingcombinationtherapyaresparseNoconcensusregardingwhichcombinationsaresynergisticorantagnosticPredictingwhethersynergyorantagonismwillpredominateinvivoisextraordinarilydifficultExtrapolationfrominvitrooranimalstudiesis,atbest,tenuous.Antagnosticinteractionscanbebasedonmechanismsofaction,butnotsynergy.Lewis&KontoyiannisPharmacotherapy2001;21:149S-164SConclusionsAmphotericin+Azoles:CombinationtherapymaylackantagonismEnhancedefficacyagainstCandidaspp.andAspergillusspp.ThesequenceofadministrationisimportantinestablishingtherapeuticefficacyAmphotericin+Echinocandins:NoantagonismEnhancedefficacyagainsttoA.fumigatusEchinocandins+Azoles:NoantagonismEnhancedefficacyagainstCandidaspp.andAspergillusspp.治疗策略治疗免疫抑制0363738394041体温培养+T组织+-7071421283542495663-140.1110粒缺时间粒细胞经验治疗疑似预防治疗无目标治疗确诊先发治疗拟诊治疗策略预防性治疗对尚无真菌感染的高危病人给予抗真菌药，可减少侵袭性真菌感染并减少抗真菌药的全身应用，降低与真菌感染相关的病死率和某些粒缺和器官移植患者的总病死率What’stheindicationforprophylaxis?实体器官移植受者HSCT受者粒缺患者侵袭性念珠菌病高发的ICU中的高危患者侵袭性真菌病高发的婴儿室，且新生儿出生体重<1000gClinicalInfectiousDiseases2009;48:503–35预防性抗真菌治疗预防性抗真菌治疗实体器官移植受者推荐氟康唑或LAmB治疗至少7-14天作为肝脏(A-I)、胰腺(B-II)及小肠(B-II)移植术后念珠菌病高危患者的预防性抗真菌治疗ICU住院患者推荐氟康唑用于侵袭性念珠菌病发病率较高的成人病房内的高危患者(B-I)化疗后的中性粒细胞减少患者推荐在诱导化疗期间使用氟康唑(A-I)、泊沙康唑(A-I)或卡泊芬净(B-II)口服伊曲康唑也有效，但与其它抗真菌药物相比无明显优势且耐受性不佳中性粒细胞减少干细胞移植受者推荐在中性粒细胞减少的危险时期使用氟康唑、泊沙康唑或米卡芬净(A-I)侵袭性曲霉病的预防在具有侵袭性曲霉病高危因素的HSCT受者（同时发生GVHD）、急性髓性白血病以及骨髓增生异常综合征患者推荐泊沙康唑预防应用伊曲康唑可能有效，但因耐受性差应用受限（B-I）治疗策略-2经验治疗临床研究已证实，对粒缺发热患者经广谱抗菌药治疗无效者采用AmB可减少真菌感染的发生率和病死率在经验性治疗中药物的选择不仅要考虑药物的确切疗效，更应考虑药物的安全性ClinicalInfectiousDisease2009;48:503～535非粒缺患者念珠菌血症的经验性治疗对于存在侵袭性念珠菌病危险因素、且出现不明原因发热的重症患者，应考虑采用经验性抗真菌治疗治疗基于侵袭性念珠菌病的危险因素临床评估、血清学标志物和/或非无菌部位培养结果研究证据汇总：侵袭性念珠菌病的早期诊断仍是一个难题；G试验、PCR等为早期诊断提供了新视角，但仍需大量不断改进研究显示：早期使用氟康唑可有效降低念珠菌病的发生率氟康唑抢先治疗使外科ICU中部分念珠菌定植患者的念珠菌病发生率下降对胃肠道手术患者早期给予氟康唑治疗可在一定程度上改善发热症状、减少念珠菌血症的发病率、ICU入住时间及死亡率首选备选备注氟康唑首日800mg(12mg/kg)，此后每日400mg(6mg/kg)或棘白菌素类药物(B-III)LFAmB每日3-5mg/kg或AmB-d每日0.5-1mg/kg或(B-III)中重度感染以及近期使用过唑类药物的患者，首选棘白菌素类药物。疗程尚未确定，一旦培养和/或血清学检查结果转阴应停止治疗ClinicalInfectiousDisease2009;48:503～535粒缺患者念珠菌血症的经验性治疗首选备选备注LFAmB每日3-5mg/kg；卡泊芬净首日70mg，此后每日50mg(A-I)，或伏立康唑首日400mg(6mg/kg)bid，此后200mg(3mg/kg)bid(B-I)氟康唑首日800mg(12mg/kg)，此后400mg(6mg/kg)；或伊曲康唑200mg(3mg/kg)bid(B-I)绝大部分中性粒细胞减少患者，若抗生素治疗4天后仍持续发热则可开始经验性抗真菌治疗；此前接受唑类预防性治疗的患者不再使用唑类药物ClinicalInfectiousDisease2009;48:503～535氟康唑首剂负荷剂量AUC更高，抗菌活性更强真菌症フォーラム学術集会プログラム抄録集：27，2003(L20030303006)负荷剂量及常规给药方式氟康唑的比较治疗策略先发治疗（pre-emptivetherapy）Preemptiveantifungaltherapyisalogicalextensionofempirical

antifungaltherapy,inthatitdefinesahigh-riskpatient

populationonthebasisofmorethanpersistentfeverandneutropenia

(i.e.,withasurrogatemarkerofinfection,suchas

abnormalCTfindingsorapositiveresultofassayforAspergillus

antigen).ClinInfectDis2008;46:327–60先发治疗重要意义在于尽可能降低经验性治疗所导致的抗真菌药物的过度使用及其所致不良反应降低真菌耐药的可能性降低医疗费用可有效治疗经替代指标诊断的深部真菌病患者治疗策略-4目标治疗对已获病原真菌的侵袭性真菌病患者，采用针对性抗真菌治疗非中性粒细胞减少患者

念珠菌血症的治疗首选备选备注氟康唑首日800mg(12mg/kg)，此后每日400mg(6mg/kg)或棘白菌素类药物(A-I)LFAmB每日3-5mg/kg或AmB每日0.5-1mg/kg或伏立康唑首日400mg(6mg/kg)bid，此后200mg(3mg/kg)bid(A-I)中重度感染以及近期使用过唑类药物的患者，予以棘白菌素类药物(A-III)。在患者首次血培养转阴、念珠菌血症关头和体征消失后继续治疗14天分离株可能对氟康唑敏感(如白色念珠菌)且临床病情稳定的患者，建议将棘白菌素类药物换为氟康唑(A-II)光滑念珠菌首选棘白菌素类药物(B-II)氟康唑或伏立康唑初始治疗改善且血培养转阴的患者继续使用三唑类完成治疗(B-III)分离菌株可能对氟康唑敏感(如白色念珠菌)且临床病情稳定者建议将LFAmB或AmB-d换为氟康唑(A-I)采用氟康唑治疗近平滑念珠菌感染(B-III)无明显转移性并发症的念珠菌血症，在血培养转阴、相关症状缓解后继续治疗2周(A-III)强烈建议拨除非中性粒细胞减少念珠菌血症患者的静脉内导管(A-II)中性粒细胞减少患者

念珠菌血症的治疗首选备选备注棘白菌素类药物或LFAmB每日3-5mg/kg(A-II)氟康唑首日800mg(12mg/kg)，此后400mg(6mg/kg)；或伏立康唑首日400mg(6mg/kg)bid，此后200mg(3mg/kg)bid(B-II)近期未使用唑类药物且病情不太严重的患者，推荐使用氟康唑；若需覆盖霉菌，推荐使用伏立康唑。建议拨除血管内导管，但尚存在争议病情不太严重且近期未使用三唑类药物的患者氟康唑是一种合理的治疗选择(B-III)已接受氟康唑或伏立康唑初始治疗，临床症状改善且血培养随访转阴的患者继续使用三唑类完成治疗(B-III)氟康唑或LFAmB是近平滑念珠菌感染初始治疗的首选药物(B-III)无持续性真菌血症及转移性并发症的念珠