隱球菌性腦膜炎抗真菌治療

隱球菌性腦膜炎抗真菌治療第1頁/共46頁ChallengeforCryptococcalMeningitisCryptococcusneoformansisthemostcommoncauseoffungalmeningitisinHIVandnon-HIV-infectedpatientsFoundin7%-10%patientswithAIDSRemainhighmortalityrate(10%-44%),especiallyinimmunocompromisedpatients第2頁/共46頁CaseStudy第3頁/共46頁P(yáng)resentHistoryA46-year-oldmanwasadmittedtoourhospitalbecauseoffeversandheadacheforover2monthsLumbarpunctureshowedaWBCcountof58×106/Lwith0.94monocytes,proteinwas176mg/dL,andglucosewas1.5mmol/LFailedfortreatingwithbroadspectrumantibioticsincludingceftazidime,levofloxacin,etc.Histemperaturecontinuedtoclimbupto39?C,andhisheadachedevelopedintoanintolerableone.Hewasthentransferredtoourhospital第4頁/共46頁LabExaminationsCSF:WBC28×106/L，multinucleatedcells15/28，monocytes13/28，protein1169mg/L，glucose1.3mmol/LCSFsmearforfungiwasnegativeCSFculturewaspositiveforCryptococcusneoformansCSFcryptococcalantigentitres1:160第5頁/共46頁CranialMRI第6頁/共46頁P(yáng)astHistoryofHepatitisBIn2002hewasdiagnosedwithdecompensatedhepatitisBcirrhosis,presentingwithfatigue,anorexiaandbloatingHBVM:HBsAg(+),HBeAg(+),HBcAB(+)HBVDNAwas2.2×107copies/mL第7頁/共46頁P(yáng)astHistoryofHepatitisBHetookLamivudine100mg/d，andwitnessedareductionofviralloadto3.8×103copies/mL.15monthslaterhedevelopedYMDDmutationandviralloadreboundedto1.0×107copies/mLSincethenhehadseveralepisodesofjaundice,liverenzymeelevation,ascitesandspontaneousbacterialperitonitis.Symptomswererelievedeachtimeafteranti-infectiveandsupportivetherapyHBVDNAwas6.19×108copies/mLinJuly2005.Adefovir10mg/dwasaddedtolamivudine第8頁/共46頁LiverCT第9頁/共46頁HowcanIinitiallytreatthispatient?AmBL-AmBFluconazoleItraconazolePosaconazoleFlucytosine第10頁/共46頁RoadmapClinicalstudiesinthepre-HIVEraClinicalstudiesintheAIDSEraRecentstudiesforcryptococcalmeningitis第11頁/共46頁Clinicalstudies

inthepre-HIVEra第12頁/共46頁AmBPriortotheavailabilityofAmB,cryptococcalmeningitiswasconsideredtobeuniformlyfatalWhenAmBbecameavailableinthelate1950s,itbecamethedrugofchoiceforcrypotococcalmeningitiswithsuccessratesofupto60%Successfultherapywasoftenlimitedbyseverenephrotoxicity,electrolyteabnormalities,andinfusion-relatedadverseevents第13頁/共46頁LandmarktherapyTwomajorrandomizedclinicaltrialsaddressingthetreatmentofcryptococcalmeningitiswereconductedinthelate1970sandmid-1980sEstablishingthe“goldstandard”towhicheverysubsequentregimenhasbeencompared第14頁/共46頁

ThefirstmilestoneclinicaltrialAmB(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

第15頁/共46頁ThesecondlargerandomizedtrialAmB(0.3mg/kg.d)+5-FCfor4vs.6wks91patientsmetcriteriaforrandomizationtoeitherdiscontinuingtherapyat4wks.orcontinuingtherapyfor2additionalwksBetterefficacyfor6wks.Cure/improved:higher6wks.(85%vs.75%)Relapses:lowerfor6wks.(16%vs.27%)

--Dismukesetal.NEnglJMed.1987.317:334第16頁/共46頁Clinicalstudies

intheAIDSEra第17頁/共46頁ThefirstlargerandomizedtrialAmB(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第18頁/共46頁Thesecondrandomized,

double-blindedstudyAmB(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.1997.337:15第19頁/共46頁

MaintenancetherapyinAIDS

patientAmB(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.1999.28:297

第20頁/共46頁第21頁/共46頁

ThetreatmentofcryptococcalmeningitisinpatientswithAIDSInductionAmB+5-FCfortwowks.ConsolidationHighdosefluconazole(400mg/dfornormalhepaticandrenalfunction)canbeinitiatedMaintenanceAtthecompletionof8weeks,fluconazole(200mg/d)canbecontinuedforlong-termchronicsuppression第22頁/共46頁ThetreatmentofcryptococcalmeningitisinHIV-negativepatients

第23頁/共46頁Recentstudies第24頁/共46頁第25頁/共46頁Updateonmaintenance

IfthepatienthasanexcellentresponsetoHAART,thendiscontinuationofmaintenancetherapycanbeconsideredAsymptomaticRespondingtoHAARTwithasustainedincreaseintheirCD4+Tlymphocytesformorethanayeartogreaterthan100cells/μL(andgreaterthan10percentCD4)Thesepatientsshouldbemonitoredclosely,andfluconazolemaintenancereinstitutediftheCD4countfallsbelow100cells/μL(andbelow10percentCD4cells)Mussinietal.ClinInfectDis.2004.38:565

第26頁/共46頁CryptococcalIRISinAIDSpatientsTreatmentwithHAARTduringantifungaltherapycancausecryptococcalIRIS(ImmuneReconstitutionInflammatorySyndrome)IncreasedCSFOP,increasedCSFglucoselevelsandWBCantiretroviraldrug-na?vepatientsHAARTincloseproximitytoOIdiagnosisRapiddeclineinHIVRNAlevels--Shelburneetal.ClinInfectDis.2005.40:1049.--Shelburneetal.AIDS.2005.19

:399.第27頁/共46頁CryptococcalIRISinAIDSpatients30%ofpatientswithcryptococcosishaveIRISIRIScommonlyoccurswithinthefirst1to2monthsafterstartingHAARTAfterstartingantifungaltherapyforcryptococcaldiseases,an8-to10-weekdelayininitiatingHAARTisgenerallyrecommendedtoreducethecomplexitiesofdealingwithIRIS

--Shelburneetal.ClinInfectDis.2005.40:1049第28頁/共46頁Cryptococcosis/ImmuneSyndromeInflammatoryReconstitution/OrganTransplantIRIS5.5%(3/54)WorseningsymptomsdespitenegativeculturesEtiology:effectiveantifungaltreatmentand/orcessationofimmunosuppresivetherapy(tacrolimus,mycophenolate,prednisone)TemporalassociationofgraftlossSinghetalClinInfectDis.2005.40:1756SinghetalTransplantation.2005.80:1131第29頁/共46頁

Fluconazoleasfirst-linetherapy?InaSouthAfricantrial,27patientswithcryptococcalmeningitisweretreatedwithfluconazoleasfirst-linetherapyTwo-thirdsofthepatientshadaclinicalrelapseassociatedwithpositiveculturesThemajorityoftheseisolateshadreducedsusceptibilitytofluconazoleDespitethesubsequentadministrationofAmBtherapy,mortalitywashigh第30頁/共46頁Retrospectivestudyinnon-AIDSpatients306non-HIV-infectedpatienswithcryptococcosis,amongwhom157patientshadCNSdisease90%ofpatientsreceivinganAmB-containingregimenasinitialtherpayThemediandurationoftherapywithAmBwas27daysinthispopulation,andabouttwothirdsalsoreceived5-FCforamediantimeof31daysThetotalamountofAmBgivenasantifungaltherapywasapproximately800mg,andthetotaldailydoseof5-FCwasapproximately100mg/kgFluconazolewasgivenasinitialtherapyatdosesof400to800mginonlyafewpatientsFluconazolewasgivenintwothirdsofpatientsfollowingasuccessfulinductionregimencontainingAmBThesepatientsreceivedfluconazoleatamediandoseof400mgforamediandurationof10weeksOtherinitialregimenswereuncommonandcouldnotbeadequatelyassessed

Pappasetal.ClinInfectDis.2001.33:690第31頁/共46頁AmBlipidformulationsLiposomalAmBthesameeffectiveasAmBLesstoxicthanAmBCSFcultureconversionsignificantlyearlierthandidpatientsgivenAmB

--Leendersetal.AIDS.1997.11:1463

--Hamilletal.1999.39thICAAC,SanFrancisco,Abstract1161第32頁/共46頁AmBlipidcomplexTheuseofAmBlipidcomplexhasbeenstudiedinbothHIV-positiveand–negativepatientswithCNScryptococcosis

--Sharkeyetal.ClinInfectDis.1996.22:315

--Baddouretal.ClinInfectDis.2005.40:S409ComparedwithAmB,AmBlipidcomplexproduceshigherclinicalresponserates(86%vs.65%)andlesstoxicity

--Sharkeyetal.ClinInfectDis.1996.22:315

第33頁/共46頁CollaborativeExchangeofAntifungalResearch(CLEAR)study83patientswithCNScryptococcosis65%forthosewithCNSdisease56%forthosewhosediseasewasrefractorytopriorantifungaltherapy--Baddouretal.ClinInfect.Dis.2005.40:S409第34頁/共46頁LipidformulationsofAmBtobeeffectiveandlesstoxicTobeparticularlyusefulforpatientsdevelopingsignificantinfusionaltoxicitiesorrenalfailureonconventionalAmBtherapy第35頁/共46頁Othernewantifungaldrugs

Voriconazole

18patientswithbothcryptococcalmeningitisandAIDSResponserate39%（7/18）10outofthe11patientsthatdidnotrespondwerestableSurvivalrateat3months>90%

--Perfectetal.ClinInfectDis.2003.36:1122第36頁/共46頁P(yáng)osaconazoleAnopen-labelinternationalmulticenterclinicaltrial29patientswithcryptococcalmeningitisreceivedposaconazoleoralsuspension（800mg/d）MostpatientswererefractorytopriortherapyofconventionalAmB,AmBlipidformulationsorfluconazoletherapyResponserate48%（14/29）Maybesuitableasconsolidationormaintenancetherapyforcryptococcalmeningitis

--Pitisuttithumetal.JAantimicrobChemother.2005.56:745第37頁/共46頁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.L