最新ICU病房抗真菌经验性治疗课件

ICU病房抗真菌经验性治疗NationalEpidemiologyofMycosisSurvey(NEMIS)wasaprospective,multicenterstudyconductedat6USsitesfrom1993–1995toexamineratesofriskfactorsforthedevelopmentofcandidalbloodstreaminfections(CBSIs)amongpatientsinsurgicalandneonatalintensivecareunits>48hours.Among4276patients,42CBSIsoccurred.AdaptedfromBlumbergHMetal,andtheNEMISStudyGroupClinInfectDis2001;33:177–186;GarberGDrugs2001;

61(suppl1):1–12.RiskforInvasiveMycosisNon-Neutropenicrelatedtobarrierbreakdown,changeincolonization.Acuterenalfailure(RR4.2)Parenteralnutritionwithintralipid(RR3.6)PriorsurgeryspeciallyGI (RR7.3)Indwellingcentralline?Triplelumen(RR5.4)Broadspectrumantibiotics DiabetesBurnsMechanicalVentilationSteroidsNeutropenicrelatedtoaboveplusimmunecellsuppressionandunderlyingmalignancy.Severeimmunosuppressive:BMTorSOTInvasiveMycosisCandidiasisAspergillosisDecreasingimmunitySOTorBMTMICUorSICUBarrierimmunityBarrierpluscellularimmunityOncologyPolyenesAmphotericinB(AmB)orLiposomalAmB(kidneytoxicity)AzolesFluconazole400-800mg/day(livertoxicity,CYP450)Voriconazole(livertoxicity,visualdisturbances,CYP450)Posaconazole(livertoxicity,CYP450)Echinocandins

Caspofunginiv(livertoxicity)Combinationex.AmB/Fluconazole(liver,kidneytoxicity) Choiceofagentsdependsonwhetherthepatientonpreviousazoleprophylaxis,cultureresults,localfungalsensitivity,colonization,renalorliverdisease,presenceofdrug-druginteractions,presenceofhardware,immuno-suppresion,siteofdiseaseex.urine.TreatmentofInvasiveMycosis

SiteofActionofSelectedAnti-fungalAgentsAdaptedfromAndrioleVTJAntimicrobChemother1999;44:151–162;GraybillJRetalAntimicrobAgentsChemother1997;41:1775–1777;GrollAH,WalshTJExpertOpinInvestDrugs2001;10(8):1545–1558.Cellmembrane PolyenesAmB (sterols) AzolesFluconazole (CYP450)Cellwall Echinocandins Caspofungin(Glucan synthesisinhibitors)FocusonCandidiasisInvasiveCandidainfections:4thmostcommonnosocomialbloodstreaminfectionintheUSAwithmortalityapproaching40%inlinerelatedcandidemia**Ina3-year(1995–1998)surveillancestudyof49hospitalsintheUnitedStates.AdaptedfromEdmondMBetalClinInfectDis1999;29:239–244;AndrioleVTJ

AntimicrobChemother1999;44:151–162;

UzunO,AnaissieEJAnnOncol2000;11:1517–1521.Coagulase-negativestaphylococci 3908 31.9Staphylococcusaureus 1928 15.7Enterococci 1354 11.1Candidaspecies 934 7.6 Pathogen No.ofIsolates Incidence(%)C.

glabrata16%C.albicans54%C.

parapsilosis15%C.

tropicalis8%C.krusei2%otherCandidaspp

5%AdaptedfromPfallerMAetalandTheSENTRYParticipantGroupAntimicrobAgentsChemother2000;44:747–751.SpeciesofCandidaMostCommonlyIsolatedinBloodstreamInfectionsInaninternationalsurveillancestudy1997-1998:SincethenincreaseinCandidaspp.withhigherincidenceoffluconazoleresistance.SnydmanDR.2003.Chest123(Suppl5):500S-503S).GarbinoJ.etal.2002.Medicine;81:425-433.InvasiveCandidiasisintheICU

CommonintheICU(9.8/1000admissions)withhighmorbidity(increasedLOS~22days)&mortality(~30-40%)resultinginincreasedcost(~$44,000/episode).Difficulttodiagnose(culturespositiveinonly~50%).WecandefineICUriskfactorsforcandidiasisandtargetthepopulationathighestriskwithempiricRx.RecentincreaseinCandidaspp.resistanttoDiflucan.Advancesinantifungaltherapyhaveresultedinagents,likeechinocandinsandtriazoles,withhighactivity,abroadspectrum,andlowtoxicityidealforempirictherapyandcombinationtherapyoptions.Prophylaxisandtreatmentofinvasivecandidiasisintheintensivecaresetting.EurJClinMicrobiolInfectDis.2004:23;739-744.MajorRiskFactorsPriorantibioticuse,centralvenouscatheters,totalparenteralnutrition,majorsurgerywithintheprecedingweek,steroids,dialysisandimmunosuppression.Intensivecareunitlengthofstayisanimportantriskfactor,withtherateofinfectionsrisingrapidlyafter7-10days.DimopoulosG,etal.Candidemiainimmunocompromisedandimmunocompetentcriticallyillpatients:aprospectivecomparativestudy.EurJClinMicrobiolInfectDis.2007

RiskFactorSelectionUnderlyingdiseaseAntibioticsColonizationFeverSelectionSkinormucosadamageInfectionMalignancyDiabetesRenaldiseaseCTDonsteroidsMalnutritiononTPNMechanicalVentilation>48hBurnsInstrumentsCVCatheterKnifeInvasiveCandidiasisAfterColonizationandBacteremiaBacteremiaColonizationAcuteInvasiveCandidiasis81patientsYES35NO46-++++14248-++++713151 0 00 1 853%Guiotetal.CID.1994;18:525-32LaboratoryDiagnosisMicrobiologymethods:

RecoveryofCandidaspeciesfromsterilesites(ex.blood,peritonealfluid)isdiagnosticofICandrecoveryfrommultiplenon-sterilesitesishighlysuggestiveofICintheat-riskpatient.Bloodcultureispositiveinlessthan50%ofpatientswithautopsyprovenIC.Molecularmethods:earlyidentificationexPNAFISHSerologicalmethods:earlydiagnosisex.1,3betaDglucanassay.Histopatholgicmethods.ClinicalDiagnosisTheclinicalmanifestationsofICarenonspecific,butmayinclude:Feverandprogressivesepsiswithmulti-organfailuredespiteantibiotics.Invasivecandidiasis(IC)relatedcutaneouslesions.Macronodularrashfrequentlyconfusedwithdrugallergies.Abiopsyofthedeeperlayersofskinparticularlythevascularizedareasandthedermisisimportant.Ophthalmiclesions(Candidaendophthalmitis).AfundoscopicevaluationforthepresenceofCandidaendophthalmitisshouldbeperformedinpatientswithcandidemia.TherapyofICintheICUAdefinitivediagnosisofICmaybedelayedwhentheclinicalandlaboratorytoolsreadilyavailabletocliniciansareusedtoassesspatientsforCandidainfection.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-fungalRx>12hrsofdrawingabloodculturethatturnspositivehadAOR=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).TimingofInterventionbasicdiseaserefractoryfeveraspecificsymptom±earlymarkersspecificsymptomsuppressiveRxinfectionProgression

EmpiricPre-emptiveProphylacticDirectedProphylactic,PreemptiveorEmpiricUseofAnti-fungalsPROSHighMortalityDifficultyinDiagnosisUndetectedInfectionReducedsystemicmycosesandimprovedmortalitywithprophylaxisCONSToxicityExpenseDiagnosisnotcertainToomuchtreatmentwithoutinfectionToolittletreatmentwithinfectionFluconazoleProphylaxisandColonizationofNeutropenicPatientsWinstonetal.AnnInternMed.1993;118:495-503CandidaprophylaxisintheSurgicalICU

(patientswithhighriskforcandidemia)Eggimanetal.1999.CCM27:1066-1072.Fluconazolereducedcandidaperitonitisandcolonizationin43patientswithcomplicatedGIsurgeries.Highriskpatients?Wasitpreemptivetherapy.Pelzetal.2001.AnnSurg.233:542-548.FluconazolereducedcandidainfectionincriticallyillsurgicalpatientsinSICU>3days.Nomortalitybenefit.Predictorsincluded:APACHEIIscore,fungalcolonization,TPN,daystofirstdoseofprophylacticdrug.Paphitouetal.2005.MedMycol.43(3):235-43.

327patientsinSICU>3dayswerereviewedtoidentifypredictivefactors.CombinationofDM,HD,TPN,broad-spectrumantibioticshadaninvasivecandidiasisrateof16.6%versusa5.1%rateforpatientslackingthesecharacteristics(P=0.001).Therulecaptured78%ofpatientswithIC.CandidaProphylaxisinMICU&SICU

(MV>48h&expectedLOS>72h)Garbinoetal.IntensiveCareMed.2002;28:1708-17IncidenceofIC=16%IncidenceofIC=5.8%Summary(CandidaProphylaxis)

Prophylaxisiseffectiveinthehighestriskpatients.ProphylaxisreducestheincidenceofIC.Apositiveimpactonmortalityhasnotbeenshownexceptinseverelyimmunocompromisedhosts(neutropenia,BMT,orsolidorgantransplantation).Distinctionbetweenprophylactic&preemptivetherapyneededspeciallyinICU.Risk?Dose?.AssessmentofPreemptiveTreatmenttopreventseverecandidiasisinSICUBefore/afterinterventionstudy(2yearsprospective&historical)

SystematicmycologicalscreeningonallpatientsadmittedtotheSICU≥5days,immediatelyatadmittanceandthenweeklyuntildischarge.Patientswithcolonizationindex≥0.4(usedtoassessintensityofmucosalcolonization)receivedearlypreemptiveantifungalRx(fluconazoleIV800mg,then400mg/dayfor2wks).

Candidainfectionsoccurredmorefrequentlyinthecontrolcohort(7%vs.3.8%;p=.03).IncidenceofSICU-acquiredprovencandidiasissignificantlydecreasedfrom2.2%to0%(p<.001).Noemergenceofazole-resistantCandidaspecieswasnotedduringtheprospectiveperiod.Piarroux,etal..CritCareMed.2004Dec;32(12):2443-9.ArchSurgery.2001;136:1401-1409TemporalAssessmentofCandidaRiskFactorsintheSICUPearlsofthestudy

ChangeinCandidariskfactorsovertimeisclinicallyrelevant.Earlyriskfactorsatday1,timeofSICUadmission.Morethan8riskfactorsatanytimeRapidincreaseinriskfactors(clinicaldeterioration)APACHEIIscore>18day3or4Earlyriskfactormaybeevidentfromday1&maybeusedwithprogressionofriskfactorsasfever,durationofantibiotics&mechanicalventilationtoassessrisk.?moreaggressivesurveillanceculturesvs.preemptiveorempirictherapy.SerologicalMethods?earlyaidinempirictherapydecisionmakingPlasmabeta-D-glucan,acellwallconstituentoffungi,wasmeasuredbeforestartingantifungaltherapyempiricallyonpostoperativepatients,colonizedwithcandida&havingriskfactorsforcandidainfection.47%ofthosewithpositivetestrespondedtoRxbut9%ofthosenegativeresponded(p<.01)(OR=13).Numberofsitescolonizedwithcandidaalsopredictedresponse.Colonizationat≥3sitesvs.1site(p=0.03)(OR=7.57).Inpostoperativepatientscolonizedwithcandida,&withfeverdespiteantibioticsabeta-D-glucanassaywasusefulfordecidingwhethertostartempirictherapy.TakesueYetal.WorldJSurg.2004;28(6):625-30.ResearchOngoingRandomizedStudyofCaspofunginProphylaxisFollowedbyPre-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.Overalladjustedsuccessrate01020304033.9%5033.7%2.6%11.5%10.3%14.5%Nephrotoxiceffect(p<0.001)Discontinuedthestudyprematurely(p=0.03)CaspofunginLiposomalAmBEmpiricCaspofungininPatientswithNeutropeniaandPersistentfeverPercentofPatientsCaspofunginhadsignificantlyfewer:Drug-relatedclinicalorlabadverseevents,anddiscontinuationsduetoseriousdrug-relatedclinicalorlabAEs.

**EmpiricCaspofunginvs.liposomalAmBinpersistentFeverandNeutropeniaPercentsurvivalCaspofungin(n=556)L-AmB(n=539)Studydayp=0.044212835637145649420901008070605010203040Superiorinpreventingoverallmortalitywithlesstoxicity.Walshetal.NEnglJMed.2004;351:1391-1402CandidemiainNon-neutropenicICUPatients.RiskFactorsforNon-albicansCandidaSpp.

NationwideAustralianprospectivecohortstudy.PatientswithICU-acquiredcandidemiaover3yr.Measuredclinicalriskfactorsoccurringupto30daysprecedingcandidemia.Calbicans62%,Cglabrata18%,Cparasilopsis8%,Ctropicalis6%,Ckrusei4%,OtherCandidaspp.2%IndependentriskfactorsforNCAorpotentiallyfluconazole-resistantspecies:age(OR1.3),recentGIsurgery(OR2.9),priorexposuretosystemicantifungalagents(OR4.6)especiallyfluconazole(OR5.7).EGPlayfordetal.Crit.CareMed.2008;36(7):2034-2039.EmpiricAnti-CandidaTherapy:Cost-EffectivenessTarget:PatientsintheICU>3daysandunresponsivetoantibacterialtherapyfor>3days.(~40%allcandidemia).Strategiescompared:Fluconazole,Caspofungin,AmBandLiposomalAmB.Estimates:RtoFluconazole=5%,costofCaspofungin=381$/day,Diflucan=135$/d,ICintargetpopulation=10%.Results:CaspofunginthemosteffectivebutFluconazolemorecost-effective.IfRtoFluconazole>28%orifICprevelance=60%orifcostofcaspofungin<160$/daythenCaspofunginmorecosteffective.Golanetal.2005.AnnInternMed;143:857-869.AlgorithmforEmpiricTherapyEmpirictreatmentforinvasivecandidiasisbasedonthehemodynamicstatusofthepatient.Unstablepatients:broad-spectrumantifungalagents,whichcanbenarrowedoncethepatienthasstabilized&theidentityoftheinfectingspeciesisestablished.Instablepatients:fluconazole,providedthatthepatientisnotcolonizedwithfluconazoleresistantstrainsortherehasbeenrecentpastexposuretoanazole(<30

days).Incontrast,pre-emptivetherapyisbasedonthepresenceofsurrogatemarkersexcolonizationindex.Spellbergetal.(2006).ClinInfectDis42:244–251

Summary(EmpiricTherapy)Inthepatientwithsepticshockriskfactorsforcandidemiashouldbeevaluated.IfCandidainfectionissuspected,treatmentwillneedtobeinitiatedempiricallywithoutdelayonthebasisofindividualpatientfactorsbeforeadefinitivediagnosisismade*.Choiceofagentwillrelyonlocalresistancepatterns,microbiologydata,priorazoletherapy,recentGIsurgery,neutropenia,hemodynamicstability,&otherhostfactors.Azolesareeffectiveunlesshighratesofresistance,orneutropeniainwhichcaseechinocandinsortriazolesshouldbeused.*SurvivingSepsisCampaign:InternationalGuidelinesforManagementofSevereSepsisandSepticShock:CCM2008DirectedTherapyAzoles:FluconazoleisthemostcommonagentusedtotreatclinicalCandidainfections.However,fluconazolehaslimitedactivityagainstCglabrataandCkrusei.Theevolutionofresistanceandtrendstowardmorenon-albicansspecies,maylimititsroleinthefuture.TriazoleshavearoleinNCAandimmunesuppr