隱球菌性腦膜炎抗真菌治療.ppt

AntifungalTreatmentforCryptococcalMeningitis,Li-PingZhu,Xin-HuaWengHuashanHospital,FudanUniversityShanghaiChina,ChallengeforCryptococcalMeningitis,CryptococcusneoformansisthemostcommoncauseoffungalmeningitisinHIVandnon-HIV-infectedpatientsFoundin7%-10%patientswithAIDSRemainhighmortalityrate(10%-44%),especiallyinimmunocompromisedpatients,CaseStudy,PresentHistory,A46-year-oldmanwasadmittedtoourhospitalbecauseoffeversandheadacheforover2monthsLumbarpunctureshowedaWBCcountof58106/Lwith0.94monocytes,proteinwas176mg/dL,andglucosewas1.5mmol/LFailedfortreatingwithbroadspectrumantibioticsincludingceftazidime,levofloxacin,etc.Histemperaturecontinuedtoclimbupto39C,andhisheadachedevelopedintoanintolerableone.Hewasthentransferredtoourhospital,LabExaminations,CSF:WBC28106/L，multinucleatedcells15/28，monocytes13/28，protein1169mg/L，glucose1.3mmol/LCSFsmearforfungiwasnegativeCSFculturewaspositiveforCryptococcusneoformansCSFcryptococcalantigentitres1:160,CranialMRI,PastHistoryofHepatitisB,In2019hewasdiagnosedwithdecompensatedhepatitisBcirrhosis,presentingwithfatigue,anorexiaandbloatingHBVM:HBsAg(+),HBeAg(+),HBcAB(+)HBVDNAwas2.2107copies/mL,PastHistoryofHepatitisB,HetookLamivudine100mg/d，andwitnessedareductionofviralloadto3.8103copies/mL.15monthslaterhedevelopedYMDDmutationandviralloadreboundedto1.0107copies/mLSincethenhehadseveralepisodesofjaundice,liverenzymeelevation,ascitesandspontaneousbacterialperitonitis.Symptomswererelievedeachtimeafteranti-infectiveandsupportivetherapyHBVDNAwas6.19108copies/mLinJuly2019.Adefovir10mg/dwasaddedtolamivudine,LiverCT,HowcanIinitiallytreatthispatient?,AmBL-AmBFluconazoleItraconazolePosaconazoleFlucytosine,Roadmap,Clinicalstudiesinthepre-HIVEraClinicalstudiesintheAIDSEraRecentstudiesforcryptococcalmeningitis,Clinicalstudiesinthepre-HIVEra,AmB,PriortotheavailabilityofAmB,cryptococcalmeningitiswasconsideredtobeuniformlyfatalWhenAmBbecameavailableinthelate1950s,itbecamethedrugofchoiceforcrypotococcalmeningitiswithsuccessratesofupto60%Successfultherapywasoftenlimitedbyseverenephrotoxicity,electrolyteabnormalities,andinfusion-relatedadverseevents,Landmarktherapy,Twomajorrandomizedclinicaltrialsaddressingthetreatmentofcryptococcalmeningitiswereconductedinthelate1970sandmid-1980sEstablishingthe“goldstandard”towhicheverysubsequentregimenhasbeencompared,Thefirstmilestoneclinicaltrial,AmB(0.4mg/kg.d)vs.AmB(0.3mg/kg.d)and5-FC27treatedwithAmBalonefor10wks24withacombinationofAmBand5-FCforonly6wksCombinationmoreeffectiveCure/improved(66%vs41%)Relapses(5%vs18%)SterilizationofCSF:rapidNephrotoxicity:decreased-Bennettetal.NEnglJMed.1979.301:126,Thesecondlargerandomizedtrial,AmB(0.3mg/kg.d)+5-FCfor4vs.6wks91patientsmetcriteriaforrandomizationtoeitherdiscontinuingtherapyat4wks.orcontinuingtherapyfor2additionalwksBetterefficacyfor6wks.Cure/improved:higher6wks.(85%vs.75%)Relapses:lowerfor6wks.(16%vs.27%)-Dismukesetal.NEnglJMed.1987.317:334,ClinicalstudiesintheAIDSEra,Thefirstlargerandomizedtrial,AmB(0.4-0.5mg/kg.d)vs.Fluconazole(400mg/d)for10weeksBetterefficacyforAmBSuccess(40%vs.34%)andoverallmortalityratesame(14%vs.18%)Highermortalityrateat2wksinFluconazolepatients(15%vs.8%)MorerapidsterilizationofCSFintheAmBrecipients-Saagetal.NEnglJMed.1992.326:83,Thesecondrandomized,double-blindedstudy,AmB(0.7mg/kg.d)5-FC(100mg/kg.d)for2wksfollowedbyfluconazole(400mg/kg)oritraconazole(400mg/d)for8wks.381patientsreceivedAmB0.7mg/kg/dforthefirst2weekspluseither5-FC100mg/kg/d(202patients)orplacebo(179patients)At2wks,mortality5.5%At10wks,mortality3.9%(nodifference)andrapidsterilizationofCSFwithfluconazole-VanderHorstetal.NEnglJMed.2019.337:15,MaintenancetherapyinAIDSpatient,AmB(1.0mg/kg.wk)vs.fluconazole(200mg/d)for12mos.Relapserate19%vs.2%Seriousdrug-relatedeventsmorefrequentinAmBpatients-Powderlyetal.NEnglJMed.1992.326:793Fluconazole(200mg/d)vs.itraconazole(200mg/d)for12mos.Relapserate4%vs.23%-Saagetal.ClinInfectDis.2019.28:297,ThetreatmentofcryptococcalmeningitisinpatientswithAIDS,InductionAmB+5-FCfortwowks.ConsolidationHighdosefluconazole(400mg/dfornormalhepaticandrenalfunction)canbeinitiatedMaintenanceAtthecompletionof8weeks,fluconazole(200mg/d)canbecontinuedforlong-termchronicsuppression,ThetreatmentofcryptococcalmeningitisinHIV-negativepatients,Recentstudies,Updateonmaintenance,IfthepatienthasanexcellentresponsetoHAART,thendiscontinuationofmaintenancetherapycanbeconsideredAsymptomaticRespondingtoHAARTwithasustainedincreaseintheirCD4+Tlymphocytesformorethanayeartogreaterthan100cells/L(andgreaterthan10percentCD4)Thesepatientsshouldbemonitoredclosely,andfluconazolemaintenancereinstitutediftheCD4countfallsbelow100cells/L(andbelow10percentCD4cells),Mussinietal.ClinInfectDis.2019.38:565,CryptococcalIRISinAIDSpatients,TreatmentwithHAARTduringantifungaltherapycancausecryptococcalIRIS(ImmuneReconstitutionInflammatorySyndrome)IncreasedCSFOP,increasedCSFglucoselevelsandWBCantiretroviraldrug-navepatientsHAARTincloseproximitytoOIdiagnosisRapiddeclineinHIVRNAlevels-Shelburneetal.ClinInfectDis.2019.40:1049.-Shelburneetal.AIDS.2019.19:399.,CryptococcalIRISinAIDSpatients,30%ofpatientswithcryptococcosishaveIRISIRIScommonlyoccurswithinthefirst1to2monthsafterstartingHAARTAfterstartingantifungaltherapyforcryptococcaldiseases,an8-to10-weekdelayininitiatingHAARTisgenerallyrecommendedtoreducethecomplexitiesofdealingwithIRIS-Shelburneetal.ClinInfectDis.2019.40:1049,Cryptococcosis/ImmuneSyndromeInflammatoryReconstitution/OrganTransplant,IRIS5.5%(3/54)WorseningsymptomsdespitenegativeculturesEtiology:effectiveantifungaltreatmentand/orcessationofimmunosuppresivetherapy(tacrolimus,mycophenolate,prednisone)Temporalassociationofgraftloss,SinghetalClinInfectDis.2019.40:1756SinghetalTransplantation.2019.80:1131,Fluconazoleasfirst-linetherapy?,InaSouthAfricantrial,27patientswithcryptococcalmeningitisweretreatedwithfluconazoleasfirst-linetherapyTwo-thirdsofthepatientshadaclinicalrelapseassociatedwithpositiveculturesThemajorityoftheseisolateshadreducedsusceptibilitytofluconazoleDespitethesubsequentadministrationofAmBtherapy,mortalitywashigh,Retrospectivestudyinnon-AIDSpatients,306non-HIV-infectedpatienswithcryptococcosis,amongwhom157patientshadCNSdisease90%ofpatientsreceivinganAmB-containingregimenasinitialtherpayThemediandurationoftherapywithAmBwas27daysinthispopulation,andabouttwothirdsalsoreceived5-FCforamediantimeof31daysThetotalamountofAmBgivenasantifungaltherapywasapproximately800mg,andthetotaldailydoseof5-FCwasapproximately100mg/kgFluconazolewasgivenasinitialtherapyatdosesof400to800mginonlyafewpatientsFluconazolewasgivenintwothirdsofpatientsfollowingasuccessfulinductionregimencontainingAmBThesepatientsreceivedfluconazoleatamediandoseof400mgforamediandurationof10weeksOtherinitialregimenswereuncommonandcouldnotbeadequatelyassessedPappasetal.ClinInfectDis.2019.33:690,AmBlipidformulations,LiposomalAmBthesameeffectiveasAmBLesstoxicthanAmBCSFcultureconversionsignificantlyearlierthandidpatientsgivenAmB-Leendersetal.AIDS.2019.11:1463-Hamilletal.2019.39thICAAC,SanFrancisco,Abstract1161,AmBlipidcomplex,TheuseofAmBlipidcomplexhasbeenstudiedinbothHIV-positiveandnegativepatientswithCNScryptococcosis-Sharkeyetal.ClinInfectDis.2019.22:315-Baddouretal.ClinInfectDis.2019.40:S409ComparedwithAmB,AmBlipidcomplexproduceshigherclinicalresponserates(86%vs.65%)andlesstoxicity-Sharkeyetal.ClinInfectDis.2019.22:315,CollaborativeExchangeofAntifungalResearch(CLEAR)study,83patientswithCNScryptococcosis65%forthosewithCNSdisease56%forthosewhosediseasewasrefractorytopriorantifungaltherapy-Baddouretal.ClinInfect.Dis.2019.40:S409,LipidformulationsofAmBtobeeffectiveandlesstoxic,TobeparticularlyusefulforpatientsdevelopingsignificantinfusionaltoxicitiesorrenalfailureonconventionalAmBtherapy,OthernewantifungaldrugsVoriconazole,18patientswithbothcryptococcalmeningitisandAIDSResponserate39%（7/18）10outofthe11patientsthatdidnotrespondwerestableSurvivalrateat3months90%-Perfectetal.ClinInfectDis.2019.36:1122,Posaconazole,Anopen-labelinternationalmulticenterclinicaltrial29patientswithcryptococcalmeningitisreceivedposaconazoleoralsuspension（800mg/d）MostpatientswererefractorytopriortherapyofconventionalAmB,AmBlipidformulationsorfluconazoletherapyResponserate48%（14/29）Maybesuitableasconsolidationormaintenancetherapyforcryptococcalmeningitis-Pitisuttithumetal.JAantimicrobChemother.2019.56:745,RoleofCombinationTherapy,Randomizedcontrolledtrialofinitialcombinationantifungaltherapiesfortreatmentofcryptococcalmeningitis64patientsenrolled(2-3perweek)4arms:initial2weeks:AmBalone(0.7mg/kg/d)AmB+5-FC(100mg/kg/d)AmB+fluconazole(400mg/d)AmB+5-FC+fluconazoleFluconazole400mg/d8weeksFluconazole200mg/dthereafter,Brouweretal.Lancet.2019.363:1764,Resul