抗真菌药临床应用进展.ppt

抗真菌药临床应用进展,真菌可感染人体各部位,深部真菌感染呈持续增多趋势,ReesJRetal.CID1998;27:113847,念珠菌血症:罹患率及病死率1992-1999NNIS,Edmond,ClinInfectDis1999,感染性疾病致死人数排序:美国,真菌感染病死率,Thereisadramaticincreaseinmortalityduetoallmycoses3.4foldincreasefrom1980to1997(0.7to2.4death/100,000population),McNeiletal.Clin.Infect.Dis.(2001)33:641-647,深部真菌感染的病原条件致病真菌,念珠菌属曲霉属隐球菌属镰孢菌属赛多孢菌接合菌（毛霉、根霉、根毛霉）,70%80%,念珠菌血流感染的菌种分布US(1998-2000),Hajjehetal.(2004)J.Clin.Microbiol.42(4):1519-1527,.,定义侵袭性真菌感染EORTC-IFICG37:415-425.2.Batesetal.ClinInfectDis.2001;32:686-693.,ConventionalAmBIsNoLongerthe“GoldStandard”forTreatment,Approvedin1958withnorandomizedstudiesBecametreatmentofchoiceduetobroad-spectrumefficacyandlowrateofresistance1NephrotoxicitywasinitiallyunderestimatedCurrently,AmBtreatmentresultsin30%incidenceofacuterenalfailure,resultingin2:IncreasedmortalityIncreasedhospitalstay,LipidAmphotericinBFormulations,Ribbon-likeparticlesCarrierlipids:DMPC,DMPGParticlesize(m):1.6-11,AbelcetABLC,AmphotecABCD,AmbisomeL-AMB,Disk-likeparticlesCarrierlipids:CholesterylsulfateParticlesize(m):0.12-0.14,UnilaminarliposomeCarrierlipids:HSPC,DSPG,cholesterolParticlesize(m):0.08,DMPC-DimyristoylphospitidylcholineDMPG-Dimyristoylphospitidylcglycerol,HSPC-HydrogenatedsoyphosphatidylcholineDSPG-Distearoylphosphitidylcholine,KeyBiopharmaceuticalDifferencesoftheAmphotericinBFormulations,Groll,PiscetelliandWalshAdv.Pharmacol1998;44:343-500.,LipidAMBFormulations-Summary,EfficacyLipidformulationAMB-deoxyNephrotoxicityL-AMBABLCABCDAMB-deoxy,LipidAMBFormulations,Indicationsnotindicateasinitialtherapyformostpatientswiththevariouscandidasyndromes,cryptococcosisandtheendemicmycosesindicationsPreexistingrenaldysfunction(serumCr2.5-3mg/dL)RefractorytoorintolerateofamphotericinBorazoletherapyL-AmBFebrileneutropenicpatientswithsuspectedfungalinfections,Flucytosine,PyrimidineIVororalNarrowspectrummainlycandidaandcryptococcusNotusedassoledrugusedalongwithamphoBOralabsorptiongood80%,lowproteinbinding,Indicationsseriousinfectionscausedbysusceptiblestrainsofcandidaand/orcryptococcusCandidasepticemia,endocaarditis,urinarytractinfectionsandpulmanaryinfectionsCryptococcusmeningitis,pulmanaryinfections,septicemia,urinarytractinfections,Flucytosine,TheAzoles,TriazolesFluconazoleItraconazoleVoriconazolePosaconazoleRavuconazole,Fluconazole,AzoleIV,oralsuspension,capsuleSpectrumUsefulagainstcryptococcusandC.albicansIneffectiveagainstsomeCandidaspeciessuchasC.kruseiandC.glabrataIneffectiveagainstAspergillusspecies,Fluconazole,IndicationsCryptococcalmeningitisSystemicinfectionscausedbyCandidasp.Vaginalcandidiasis-single150mgdose.Oralpharyngeal/esophagealcandidiasisProphylaxis-BMTandchemotherapypatientstodecreasetheincidenceofcandidiasis.,Itraconazole,AzoleIV,oralsolution,capsulesVerybroadspectrumcoversaspergillus,candida,cryptococcus,blastomyces,histoplasmaandothers,Itraconazole,PharmacokineticsnotidealOralabsorptionnotgood33and55%LiquidtastesbadVeryhighlyproteinboundNeedsrepeateddosingbeforeoptimalconcentrationsareachievedPoorCSFconcentrations,reasonabletissueconcentrations,Itraconazole,IndicationsforcapsulesBlastomycoses-pulmonaryandextrapulmonaryHistoplasmosis-pulmonaryanddisseminatedAspergillosis-pulmonaryandextrapulmonaryOnychomycosisduetodermatophytesofthetoenailsandfingernails.,Itraconazole,IndicationsfororalsolutionFebrileneutropenicpatientswithsuspectedfungalinfectionsOralpharyngeal/esophagealcandidiasisIndicationsforintravenousFebrileneutropenicpatientswithsuspectedfungalinfectionsBlastomycoses-pulmonaryandextrapulmonaryHistoplasmosis-pulmonaryanddisseminatedAspergillosis-pulmonaryandextrapulmonary,TriazoleAntifungals:Voriconazole,Posaconazole,Ravuconazole,SpectrumofActivityCandidaspp.Aspergillusspp.Blastomycesspp.Histoplasmaspp.Cryptococcusspp.Cocciodiodesspp.Fusariumspp.Scedosporium,VoriconazoleSummaryofPharmacokinetics,Rapidandconsistentabsorptionwithhighoralbioavailability(96%)Largevolumeofdistribution(4.6L/kg)Non-lineareliminationHepaticmetabolismbyCYP2C19,2C9and3A4isoenzymes,AdverseEvents,HepaticOverallrateof13%.2-foldmorethanFluVisualNotedby30%.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,泊沙康唑(Posaconazole),第二代三唑类抗真菌药广谱抗真菌药，对念珠菌属、新型隐球菌、曲霉、根霉、皮炎芽生菌、球孢子菌属、组织胞浆菌、皮肤真菌、暗色孢科菌均有良好作用对光滑念珠菌，克柔念珠菌及对Flu,Itr耐药的念珠菌作用差对念珠菌属为抑菌剂，但对新型隐球菌和曲霉具杀菌作用，作用优于棘白菌素类组织分布广，终末期半衰期为2531h不良反应胃肠道反应、皮疹、视力障碍、肝功能异常、低血钾、白细胞、血小板减少、QT延长等,2006.9美国FDA批准上市，适应症预防侵袭性曲霉病和念珠菌病感染预防对象为13岁及以上高危的严重免疫缺陷患者，如造血干细胞移植受者发生GVHD或血液系统恶性肿瘤化疗后长期粒细胞缺乏成人剂量200mg(5mL)tid口咽部念珠菌病，包括伊曲康唑和/或氟康唑治疗无效者首日100mg(2.5mL)bid，继以100mg(2.5mL)qd13日用于伊曲康唑和/或氟康唑治疗无效者剂量为400mg(10mL)bid,泊沙康唑(Posaconazole),KartsonisNA.Presentedatthe12thEuropeanCongressofClinicalMicrobiologyandInfectiousDiseases.April24-27,2002.Milan,Italy.,Echinocandins:NewClassofDrug,NucleosideAnalogs,-(1,3)-D-glucan,ErgosterolPolyenesAzoles,Phospholipidbilayerofthefungalcellmembrane,Fungalcellwall,-(1,6)-glucan,-(1,3)-D-glucansynthaseGlucanSynthesisInhibitor,nucleus,BreakthroughMechanismofAction:TargetsthePathogen,NotthePatient,Echinocandins:CaspofunginandMicafungin,SpectrumofActivity:Candidaspp.Aspergillusspp.Histoplasmaspp.Blastomycesspp.Pneumocystisspp.,Echinocandins:CaspofunginandMicafungin,Pros:fungicidal(Candidaspp.)minimaldrug-druginteractionsminimaladverseeffectsCons:NoactivityagainstCryptococcusspp.,Fusariumspp.,orScedosporiumspp.onlyIVformulations,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