抗真菌药临床应用进展

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真菌病每年每百万人发病率1970年1976年1980-1982年1992-1993年组织胞浆菌病19.723.013.97.1球孢子菌病10.317.911.215.3曲霉病1.94.88.412.4隐球菌病1.32.34.065.5念珠菌病1.81.82.672.8孢子丝菌病0.90.22.4<1芽生菌病0.60.50.60ReesJRetal.CID1998;27:1138–47念珠菌血症:罹患率及病死率1992-1999NNIS百分比(%)病死率(%)凝固酶阴性葡萄球菌3221金黄色葡萄球菌1625肠球菌属1132念珠菌属840大肠埃希菌624克雷伯菌属527肠杆菌属528假单胞菌属433沙雷菌属126草绿色链球菌123Edmond,ClinInfectDis1999感染性疾病致死人数排序:美国1980年1997年排序感染种类死亡数感染种类死亡数1呼吸道56,966呼吸道87,1812菌血症9,438菌血症22,3963肾脏/泌尿系8,006HIV/AIDS16,5244心脏2,486肾脏/泌尿系13,4135结核2,333心脏5,5776细菌性脑膜炎1,402肝脏胆道4,5967胃肠道1,377真菌2,3708肝脏胆道1,277结核1,2599围产期1,035胃肠道1,05310真菌828围产期820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.Other1.12%lusitaneae1.02%krusei2.04%tropicalis12.23%parapsilosis13.25%glabrata24.46%albicans45.87%定义侵袭性真菌感染

EORTC-IFICG&NIAID-MSG确诊ProveninvasivefungalinfectionsTissueBloodculturehistologycultureMycology拟诊ProbableinvasivefungalinfetionsHostfactorClinicalfeaturesMycology++InvasiveFungalInfectionsCooperativeGroup疑似PossibleinvasivefungalinfectionsHostfactorClinicalfeaturesMycology+ORInvasiveFungalInfectionsCooperativeGroupGOALOFADAPTINGDEFINITIONSprovenprobablepossiblepresentprovenprobablepossiblefutureTreatmentDiseaseLikelihood0363738394041Temperature(°C)Culture+Tissue+-7071421283542495663-140.1110DaysofNeutropeniaGranulocytesEmpiricalPossibleProphylaxisRemoteSpecificProvenPre-emptiveProbable

DiseaseTherapeuticStrategiesCourtesyofBenDePauw,MD,EORTC.治疗策略-1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药物：氟康唑、伊曲康唑、两性霉素B及含脂制剂、米卡芬净、泊沙康唑适用于急性白血病诱导期采用细胞毒药物者同种异体造血干细胞移植受者及自身骨髓移植患者采用增强免疫抑制剂者AIDS患者肝移植受者术后早期治疗策略-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经验治疗可选用两性霉素B、两性霉素B脂质体（AmBisome）、氟康唑、伊曲康唑、伏立康唑、卡泊芬净治疗策略-1先发治疗（pre-emptivetherapy）对高危病人有深部真菌感染迹象时，在出现临床症状前采取先发制抗真菌治疗，可能有益问题是尚缺少合适的替代指标提示真菌感染迹象如GM试验、G试验、PCR检测等，在病程中需多次检测实验指标或CT检查等尚须更多临床研究资料以确定先发制抗真菌治疗的适应证及有效性治疗策略-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MedicalMycology:

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（Liposomal

nystatin）吡咯类（azole）(三唑类,triazole）氟康唑伊曲康唑伏立康唑泊沙康唑(Posaconazole)雷夫康唑(Ravuconazole)棘白菌素类（Echinocandins）卡泊芬净米卡芬净(Micafungin,)阿尼芬净(Anidulafungin)氟胞嘧啶AmphotericinBPolyenegroup–affectsfungalcytoplasmicmembraneBroadspectrumCoversalmostallcandida,aspergillus,Cryptococcosis,Mucormycosis,EndemicmycosesIVAmphotericinBNotabsorbedfromgut,skinormmIV-highlyproteinbound–91%~95％GoodpenetrationintoserouscavitiesPoorCSFpenetrationLowbloodlevelCrossesplacentaHalflife24hoursSlowrenalexcretion–2%~5％/d,40%/wAmphotericinBIVinfusion–chills,fever,vomitingFlushing,muscle,jointpainsAvoidothernephrotoxicdrugsSteroidsworsenhypokalemiaPotentiatesactivityofFlucytosineAmphotericinBFDAApprovedIndicationsEmpiricanti-fungaltherapyCandidaspp.Aspergillusspp.Cryptococcosis

MucormycosisEndemicmycosesBlastomycosis,Histoplasmosis

Coccidioidomycosis,Paracoccidioidomycosis

Penicilliosis,SporotrichosisLeishmaniasis

1.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-DistearoylphosphitidylcholineKeyBiopharmaceuticalDifferencesoftheAmphotericinBFormulationsAmB-dFungizone®

L-AmBAmBisome®ABLCAbelcet®ABCDAmphotec®Mol%AmB34%10%35%50%LipidConfig.MicellesSUVsRibbon-likeDisklikeDiameter(µm)<0.40.081.6-11.00.12-0.14Dosage0.5-1mg/kg3-5mg/kg5mg/kg3-4mg/kgCmax(vs.AmB-d)-IncreasedDecreasedDecreasedAUC(vs.AmB-d)-IncreasedDecreasedDecreasedVd(vs.AmB-d)-DecreasedSimilarIncreasedCl(vs.AmB-d)-DecreasedIncreasedSimilarElimination-DecreasedIncreasedIncreasedNephrotox.+++

+

+

+InfusionTox.HighMildModerateModerateGroll,PiscetelliandWalshAdv.Pharmacol1998;44:343-500.LipidAMBFormulations-SummaryEfficacyLipidformulation>AMB-deoxyNephrotoxicityL-AMB<ABLC<ABCD<<AMB-deoxyInfusionrelatedtoxicityL-AMB<ABLC<ABCD<AMB-deoxyProductcost(AWP)L-AMB>ABLC>ABCD>AMB-deoxyLipidAMBFormulationsIndicationsnotindicateasinitialtherapyformostpatientswiththevariouscandidasyndromes,cryptococcosisandtheendemicmycosesindicationsPreexistingrenaldysfunction(serumCr>2.5-3mg/dL)RefractorytoorintolerateofamphotericinBorazoletherapyL-AmBFebrileneutropenicpatientswithsuspectedfungalinfectionsFlucytosinePyrimidine–IVororalNarrowspectrum–mainlycandidaandcryptococcusNotusedassoledrug–usedalongwithampho–BOralabsorptiongood–80%

,lowproteinbindingIndicationsseriousinfectionscausedbysusceptiblestrainsofcandidaand/orcryptococcusCandidasepticemia,endocaardit