ICU病房抗真菌经验性治疗

EmpiricAntifungalTherapyintheICURamziMoufarrej,M.DChiefofCriticalCareZayedMilitaryHospital/AbuDhabiIntroduction•Invasivefungalinfectionshaveincreasedsignificantlyoverthelast2decades.–agingpopulationwithlifesustainingtherapieslikerenaldialysis–broadspectrumantimicrobialtherapyandinvasivemedicaldevices–bonemarrowtransplantation(BMT)&solidorgantransplantation(SOT)–intensivechemotherapyformalignancies–HIV/AIDSepidemic.NationalEpidemiologyofMycosisSurvey(NEMIS)wasaprospective,multicenterstudyconductedat6USsitesfrom1993–1995toexamineratesofriskfactorsforthedevelopmentofcandidalbloodstreaminfections(CBSIs)amongpatientsinsurgicalandneonatalintensivecareunits48hours.Among4276patients,42CBSIsoccurred.AdaptedfromBlumbergHMetal,andtheNEMISStudyGroupClinInfectDis2001;33:177–186;GarberGDrugs2001;61(suppl1):1–12.RiskforInvasiveMycosis•Non-Neutropenicrelatedtobarrierbreakdown,changeincolonization.–Acuterenalfailure(RR4.2)–Parenteralnutritionwithintralipid(RR3.6)–PriorsurgeryspeciallyGI(RR7.3)–Indwellingcentralline?Triplelumen(RR5.4)–Broadspectrumantibiotics–Diabetes–Burns–MechanicalVentilation–Steroids•Neutropenicrelatedtoaboveplusimmunecellsuppressionandunderlyingmalignancy.•Severeimmunosuppressive:BMTorSOTInvasiveMycosisCandidiasisAspergillosisDecreasingimmunitySOTorBMTMICUorSICUBarrierimmunityBarrierpluscellularimmunityOncology•Polyenes–AmphotericinB(AmB)orLiposomalAmB(kidneytoxicity)•Azoles–Fluconazole400-800mg/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.TreatmentofInvasiveMycosisSiteofActionofSelectedAnti-fungalAgentsAdaptedfromAndrioleVTJAntimicrobChemother1999;44:151–162;GraybillJRetalAntimicrobAgentsChemother1997;41:1775–1777;GrollAH,WalshTJExpertOpinInvestDrugs2001;10(8):1545–1558.CellmembranePolyenesAmB(sterols)AzolesFluconazole(CYP450)CellwallEchinocandinsCaspofungin(Glucansynthesisinhibitors)FocusonCandidiasis•InvasiveCandidainfections:–4thmostcommonnosocomialbloodstreaminfectionintheUSAwithmortalityapproaching40%inlinerelatedcandidemia**Ina3-year(1995–1998)surveillancestudyof49hospitalsintheUnitedStates.AdaptedfromEdmondMBetalClinInfectDis1999;29:239–244;AndrioleVTJAntimicrobChemother1999;44:151–162;UzunO,AnaissieEJAnnOncol2000;11:1517–1521.Coagulase-negativestaphylococci390831.9Staphylococcusaureus192815.7Enterococci135411.1Candidaspecies9347.6PathogenNo.ofIsolatesIncidence(%)C.glabrata16%C.albicans54%C.parapsilosis15%C.tropicalis8%C.krusei2%otherCandidaspp5%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.MajorRiskFactors•Priorantibioticuse,centralvenouscatheters,totalparenteralnutrition,majorsurgerywithintheprecedingweek,steroids,dialysisandimmunosuppression.•Intensivecareunitlengthofstayisanimportantriskfactor,withtherateofinfectionsrisingrapidlyafter7-10days.DimopoulosG,etal.Candidemiainimmunocompromisedandimmunocompetentcriticallyillpatients:aprospectivecomparativestudy.EurJClinMicrobiolInfectDis.2007RiskFactorSelectionUnderlyingdiseaseAntibioticsColonizationFeverSelectionSkinormucosadamageInfectionMalignancyDiabetesRenaldiseaseCTDonsteroidsMalnutritiononTPNMechanicalVentilation48hBurnsInstrumentsCVCatheterKnifeInvasiveCandidiasisAfterColonizationandBacteremiaBacteremiaColonizationAcuteInvasiveCandidiasis81patientsYES35NO46-++++14248-++++7131510001853%Guiotetal.CID.1994;18:525-32LaboratoryDiagnosis•Microbiologymethods:–RecoveryofCandidaspeciesfromsterilesites(ex.blood,peritonealfluid)isdiagnosticofICandrecoveryfrommultiplenon-sterilesitesishighlysuggestiveofICintheat-riskpatient.–Bloodcultureispositiveinlessthan50%ofpatientswithautopsyprovenIC.•Molecularmethods:–earlyidentificationexPNAFISH•Serologicalmethods:–earlydiagnosisex.1,3betaDglucanassay.•Histopatholgicmethods.ClinicalDiagnosisTheclinic