病房抗真菌经验性治疗.ppt

EmpiricAntifungalTherapyintheICU,RamziMoufarrej,M.DChiefofCriticalCareZayedMilitaryHospital/AbuDhabi,Introduction,Invasivefungalinfectionshaveincreasedsignificantlyoverthelast2decades.agingpopulationwithlifesustainingtherapieslikerenaldialysisbroadspectrumantimicrobialtherapyandinvasivemedicaldevicesbonemarrowtransplantation(BMT)33:177186;GarberGDrugs2001;61(suppl1):112.,RiskforInvasiveMycosis,Non-Neutropenicrelatedtobarrierbreakdown,changeincolonization.Acuterenalfailure(RR4.2)Parenteralnutritionwithintralipid(RR3.6)PriorsurgeryspeciallyGI(RR7.3)Indwellingcentralline?Triplelumen(RR5.4)BroadspectrumantibioticsDiabetesBurnsMechanicalVentilationSteroidsNeutropenicrelatedtoaboveplusimmunecellsuppressionandunderlyingmalignancy.Severeimmunosuppressive:BMTorSOT,InvasiveMycosis,Candidiasis,Aspergillosis,Decreasingimmunity,SOTorBMT,MICUorSICU,Barrierimmunity,Barrierpluscellularimmunity,Oncology,PolyenesAmphotericinB(AmB)orLiposomalAmB(kidneytoxicity)AzolesFluconazole400-800mg/day(livertoxicity,CYP450)Voriconazole(livertoxicity,visualdisturbances,CYP450)Posaconazole(livertoxicity,CYP450)EchinocandinsCaspofunginiv(livertoxicity)Combinationex.AmB/Fluconazole(liver,kidneytoxicity)Choiceofagentsdependsonwhetherthepatientonpreviousazoleprophylaxis,cultureresults,localfungalsensitivity,colonization,renalorliverdisease,presenceofdrug-druginteractions,presenceofhardware,immuno-suppresion,siteofdiseaseex.urine.,TreatmentofInvasiveMycosis,SiteofActionofSelectedAnti-fungalAgents,AdaptedfromAndrioleVTJAntimicrobChemother1999;44:151162;GraybillJRetalAntimicrobAgentsChemother1997;41:17751777;GrollAH,WalshTJExpertOpinInvestDrugs2001;10(8):15451558.,CellmembranePolyenesAmB(sterols)AzolesFluconazole(CYP450),CellwallEchinocandinsCaspofungin(Glucansynthesisinhibitors),FocusonCandidiasis,InvasiveCandidainfections:4thmostcommonnosocomialbloodstreaminfectionintheUSAwithmortalityapproaching40%inlinerelatedcandidemia*,*Ina3-year(19951998)surveillancestudyof49hospitalsintheUnitedStates.AdaptedfromEdmondMBetalClinInfectDis1999;29:239244;AndrioleVTJAntimicrobChemother1999;44:151162;UzunO,AnaissieEJAnnOncol2000;11:15171521.,Coagulase-negativestaphylococci390831.9Staphylococcusaureus192815.7Enterococci135411.1Candidaspecies9347.6,PathogenNo.ofIsolatesIncidence(%),InvasiveCandidiasisintheICU,CommonintheICU(9.8/1000admissions)withhighmorbidity(increasedLOS22days)739-744.,MajorRiskFactors,Priorantibioticuse,centralvenouscatheters,totalparenteralnutrition,majorsurgerywithintheprecedingweek,steroids,dialysisandimmunosuppression.Intensivecareunitlengthofstayisanimportantriskfactor,withtherateofinfectionsrisingrapidlyafter7-10days.,DimopoulosG,etal.Candidemiainimmunocompromisedandimmunocompetentcriticallyillpatients:aprospectivecomparativestudy.EurJClinMicrobiolInfectDis.2007,RiskFactorSelection,Underlyingdisease,Antibiotics,Colonization,Fever,Selection,Skinormucosadamage,Infection,MalignancyDiabetesRenaldiseaseCTDonsteroidsMalnutritiononTPNMechanicalVentilation48hBurns,InstrumentsCVCatheterKnife,InvasiveCandidiasisAfterColonizationandBacteremia,Bacteremia,Colonization,AcuteInvasiveCandidiasis,81patients,YES35,NO46,-+14248,-+71315,100,018,53%,Guiotetal.CID.1994;18:525-32,LaboratoryDiagnosis,Microbiologymethods:RecoveryofCandidaspeciesfromsterilesites(ex.blood,peritonealfluid)isdiagnosticofICandrecoveryfrommultiplenon-sterilesitesishighlysuggestiveofICintheat-riskpatient.Bloodcultureispositiveinlessthan50%ofpatientswithautopsyprovenIC.Molecularmethods:earlyidentificationexPNAFISHSerologicalmethods:earlydiagnosisex.1,3betaDglucanassay.Histopatholgicmethods.,ClinicalDiagnosis,TheclinicalmanifestationsofICarenonspecific,butmayinclude:Feverandprogressivesepsiswithmulti-organfailuredespiteantibiotics.Invasivecandidiasis(IC)relatedcutaneouslesions.Macronodularrashfrequentlyconfusedwithdrugallergies.Abiopsyofthedeeperlayersofskinparticularlythevascularizedareasandthedermisisimportant.Ophthalmiclesions(Candidaendophthalmitis).AfundoscopicevaluationforthepresenceofCandidaendophthalmitisshouldbeperformedinpatientswithcandidemia.,TherapyofICintheICU,AdefinitivediagnosisofICmaybedelayedwhentheclinicalandlaboratorytoolsreadilyavailabletocliniciansareusedtoassesspatientsforCandidainfection.Adelayindiagnosiswillunfortunatelyresultinadelayininitiationofantifungaltherapy,whichisassociatedwithincreasedmortality*.Therefore,inthepatientwithsuspectedCandidainfection,treatmentmayneedtobeinitiatedonthebasisofindividualpatientfactorsbeforeadefinitivediagnosisismade.,*MorrelMetal.2005.AntimicrobAgentsChemother.49(9):3640-5.*GareyKetal.2006.ClinInfectDis.43:25-31.,Canwewaitforthebloodcultureresultsincandidemia?,Retrospectivecohortanalysis1/2001-12/2004:N=157patientswithcandidemia.DelayinempiricRxofcandidemiatillafterbloodculturesturnpositiveresultedinhighermortality.Startofanti-fungalRx12hrsofdrawingabloodculturethatturnspositivehadAOR=2.09formortality,p=0.018.,MorrelMetal.2005.AntimicrobAgentsChemother.49(9):3640-5,TreatmentofSuspectedInvasiveCandidiasis(Definitions),Prophylactictherapy:protectiveorpreventivetherapygiventoeveryoneinagivenclass(ex.BMTpatientswhoareatveryhighriskforIC).Preemptivetherapy:therapygiventodeterorpreventanticipatedinfection;patientsatriskaremonitoredcloselyandtherapyisinitiatedwithearlyevidencesuggestinginfection(ex.positiveCandidaculturesatnon-sterilesites,clinicalsuspicion)withthegoalofpreventingdisease.Empiricaltherapy:therapyguidedbypracticalexperienceandobservation,butwithnonspecificevidenceinagivenpatient(ex.therapyisstartedbecauseacancerpatienthasremainedfebrileafterseveraldaysofbroad-spectrumantibiotics).Directedtherapy:isbasedonaclinicalorlaboratoryfindingindicatingthataninfectionispresent(ex.positivebloodcultureforCandidaspecies).,TimingofIntervention,basicdisease,refractoryfever,aspecificsymptomearlymarkers,specificsymptom,suppressiveRx,infection,Progression,Empiric,Pre-emptive,Prophylactic,Directed,Prophylactic,PreemptiveorEmpiricUseofAnti-fungals,PROSHighMortalityDifficultyinDiagnosisUndetectedInfectionReducedsystemicmycosesandimprovedmortalitywithprophylaxis,CONSToxicityExpenseDiagnosisnotcertainToomuchtreatmentwithoutinfectionToolittletreatmentwithinfection,FluconazoleProphylaxisandColonizationofNeutropenicPatients,Winstonetal.AnnInternMed.1993;118:495-503,CandidaprophylaxisintheSurgicalICU(patientswithhighriskforcandidemia),Eggimanetal.1999.CCM27:1066-1072.Fluconazolereducedcandidaperitonitisandcolonizationin43patientswithcomplicatedGIsurgeries.Highriskpatients?Wasitpreemptivetherapy.Pelzetal.2001.AnnSurg.233:542-548.FluconazolereducedcandidainfectionincriticallyillsurgicalpatientsinSICU3days.Nomortalitybenefit.Predictorsincluded:APACHEIIscore,fungalcolonization,TPN,daystofirstdoseofprophylacticdrug.Paphitouetal.2005.MedMycol.43(3):235-43.327patientsinSICU3dayswerereviewedtoidentifypredictivefactors.CombinationofDM,HD,TPN,broad-spectrumantibioticshadaninvasivecandidiasisrateof16.6%versusa5.1%rateforpatientslackingthesecharacteristics(P=0.001).Therulecaptured78%ofpatientswithIC.,CandidaProphylaxisinMICU28:1708-17,IncidenceofIC=16%,IncidenceofIC=5.8%,Summary(CandidaProphylaxis),Prophylaxisiseffectiveinthehighestriskpatients.ProphylaxisreducestheincidenceofIC.Apositiveimpactonmortalityhasnotbeenshownexceptinseverelyimmunocompromisedhosts(neutropenia,BMT,orsolidorgantransplantation).Distinctionbetweenprophylactic28(6):625-30.,ResearchOngoing,RandomizedStudyofCaspofunginProphylaxisFollowedbyPre-EmptiveTherapyforInvasiveCandidiasisintheICU.Thestudywilltestthepossibilitythatcaspofungincansuccessfullyreducetherateofcandidainfectionsinsubjectsatrisk.Itwillalsotestifcaspofunginisusefulintreatingsubjectsforthisdiseasewhendiagnosedusinganewbloodtestthatisperformedtwiceweekly,permittingearlierdiagnosisthancurrentpracticestandards.Thisstudyiscurrentlyrecruitingparticipants.MycosesStudyGroup,August2007,ConsiderationsinSelectionofEmpiricAntifungalTherapy,High-riskhostwithhematologiccancer,orstemcelltransplantation,severeimmunosuppression,hemodynamicinstability,gutdysfunctionormedicationnoncomplianceuseIVagents.Prolongedandrecentexposuretoazolespriortocurrentepisodeorsignificantliverdysfunctionordrug-druginteractionavoidazoles.Pathogeninvitrosusceptibilitypatternisknownforaclassofagents,selectanagentthatislikelytobeeffectiveagainstthespecificpathogen.SiteofInfection:Ocularorcentralnervoussysteminfectionavoidechinocandins.CanuseliposomalamphotericinB,fluconazoleorvoriconazole.Urinaryex.cystitisselectfluconazoleor5-flucytosine.,Walshetal.NEnglJMed.2004;351:1391-1402.,Overalladjustedsuccessrate,0,10,20,30,40,33.9%,50,33.7%,2.6%,11.5%,10.3%,14.5%,Nephrotoxiceffect(p3daysandunresponsivetoantibacterialtherapyfor3days.(40%allcandidemia).Strategiescompared:Fluconazole,Caspofungin,AmBandLiposomalAmB.Estimates:RtoFluconazole=5%,costofCaspofungin=381$/day,Diflucan=135$/d,ICintargetpopulation=10%.Results:CaspofunginthemosteffectivebutFluconazolemorecost-effective.IfRtoFluconazole28%orifICprevelance=60%orifcostofcaspofungin160$/daythenCaspofunginmorecosteffective.,Golanetal.2005.AnnInternMed;143:857-869.,AlgorithmforEmpiricTherapy