EmpiricAntifungalTherapyintheICURamziMoufarrej,M.DChiefofCriticalCareZayedMilitaryHospital/AbuDhabiIntroduction?Invasivefungalinfectionshaveincreasedsignificantlyoverthelast2decades.–agingpopulationwithlifesustainingtherapieslikerenaldialysis–broadspectrumantimicrobialtherapyandinvasivemedicaldevices–bonemarrowtransplantation(BMT)&solidorgantransplantation(SOT)–intensivechemotherapyformalignancies–HIV/AIDSepidemic.

NationalEpidemiologyofMycosisSurvey(NEMIS)wasaprospective,multicenterstudyconductedat6USsitesfrom1993–2019toexamineratesofriskfactorsforthedevelopmentofcandidalbloodstreaminfections(CBSIs)amongpatientsinsurgicalandneonatalintensivecareunits>48hours.Among4276patients,42CBSIsoccurred.AdaptedfromBlumbergHMetal,andtheNEMISStudyGroupClinInfectDis2019;33:177–186;GarberGDrugs2019;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:BMTorSOTInvasiveMycosisCandidiasisAspergillosisDecreasingimmunitySOTorBMTMICUorSICU

BarrierimmunityBarrierpluscellularimmunityOncology?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.TreatmentofInvasiveMycosis

SiteofActionofSelectedAnti-fungalAgentsAdaptedfromAndrioleVTJAntimicrobChemother2019;44:151–162;GraybillJRetalAntimicrobAgentsChemother2019;41:1775–1777;GrollAH,WalshTJExpertOpinInvestDrugs2019;10(8):1545–1558.Cellmembrane

PolyenesAmB

(sterols)

AzolesFluconazole

(CYP450)Cellwall

Echinocandins

Caspofungin(Glucan

synthesisinhibitors)

FocusonCandidiasis?InvasiveCandidainfections:–4thmostcommonnosocomialbloodstreaminfectionintheUSAwithmortalityapproaching40%inlinerelatedcandidemia**Ina3-year(2019–2019)surveillancestudyof49hospitalsintheUnitedStates.AdaptedfromEdmondMBetalClinInfectDis2019;29:239–244;AndrioleVTJ

AntimicrobChemother2019;44:151–162;UzunO,AnaissieEJAnnOncol2000;11:1517–1521.

Coagulase-negativestaphylococci390831.9Staphylococcusaureus

192815.7Enterococci135411.1Candidaspecies9347.6

PathogenNo.ofIsolatesIncidence(%)C.

glabrata16%C.albicans54%C.

parapsilosis15%C.

tropicalis8%C.krusei2%otherCandidaspp5%AdaptedfromPfallerMAetalandTheSENTRYParticipantGroupAntimicrobAgentsChemother2000;44:747–751.SpeciesofCandidaMostCommonlyIsolatedinBloodstreamInfectionsInaninternationalsurveillancestudy2019-2019:SincethenincreaseinCandidaspp.withhigherincidenceoffluconazoleresistance.SnydmanDR.2019.Chest123(Suppl5):500S-503S).GarbinoJ.etal.2019.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.2019:23;739-744.MajorRiskFactors?Priorantibioticuse,centralvenouscatheters,totalparenteralnutrition,majorsurgerywithintheprecedingweek,steroids,dialysisandimmunosuppression.?Intensivecareunitlengthofstayisanimportantriskfactor,withtherateofinfectionsrisingrapidlyafter7-10days.DimopoulosG,etal.Candidemiainimmunocompromisedandimmunocompetentcriticallyillpatients:aprospectivecomparativestudy.EurJClinMicrobiolInfectDis.2019

RiskFactorSelectionUnderlyingdiseaseAntibioticsColonizationFeverSelectionSkinormucosadamageInfectionMalignancyDiabetesRenaldiseaseCTDonsteroidsMalnutritiononTPNMechanicalVentilation>48hBurnsInstrumentsCVCatheterKnifeInvasiveCandidiasisAfterColonizationandBacteremiaBacteremiaColonizationAcuteInvasiveCandidiasis81patientsYES35NO46-++++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.

ClinicalDiagnosisTheclinicalmanifestationsofICarenonspecific,butmayinclude:

?Feverandprogressivesepsiswithmulti-organfailuredespiteantibiotics.?Invasivecandidiasis(IC)relatedcutaneouslesions.–Macronodularrashfrequentlyconfusedwithdrugallergies.Abiopsyofthedeeperlayersofskinparticularlythevascularizedareasandthedermisisimportant.?Ophthalmiclesions(Candidaendophthalmitis).–AfundoscopicevaluationforthepresenceofCandida

endophthalmitisshouldbeperformedinpatientswithcandidemia.TherapyofICintheICU?AdefinitivediagnosisofICmaybedelayedwhentheclinicalandlaboratorytoolsreadilyavailabletocliniciansareusedtoassesspatientsforCandida

infection.?Adelayindiagnosiswillunfortunatelyresultinadelayininitiationofantifungaltherapy,whichisassociatedwithincreasedmortality*.?Therefore,inthepatientwithsuspectedCandida

infection,treatmentmayneedtobeinitiatedonthebasisofindividualpatientfactorsbeforeadefinitivediagnosisismade.*MorrelMetal.2019.AntimicrobAgentsChemother.49(9):3640-5.*GareyKetal.2019.ClinInfectDis.43:25-31.Canwewaitforthebloodcultureresultsincandidemia??Retrospectivecohortanalysis1/2019-12/2019:N=157patientswithcandidemia.?DelayinempiricRxofcandidemiatillafterbloodculturesturnpositiveresultedinhighermortality.?Startofanti-fungalRx>12hrsofdrawingabloodculturethatturnspositivehadAOR=2.09formortality,p=0.018.MorrelMetal.2019.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-fungals?PROS–HighMortality

–DifficultyinDiagnosis

–UndetectedInfection

–Reducedsystemicmycosesandimprovedmortalitywithprophylaxis

?CONS–Toxicity

–Expense

–Diagnosisnotcertain?Toomuchtreatmentwithoutinfection?ToolittletreatmentwithinfectionFluconazoleProphylaxisandColonizationofNeutropenicPatientsWinstonetal.AnnInternMed.1993;118:495-503CandidaprophylaxisintheSurgicalICU(patientswithhighriskforcandidemia)?Eggimanetal.2019.CCM27:1066-1072.–Fluconazolereducedcandidaperitonitisandcolonizationin43patientswithcomplicatedGIsurgeries.Highriskpatients?Wasitpreemptivetherapy.?Pelzetal.2019.AnnSurg.233:542-548.–FluconazolereducedcandidainfectionincriticallyillsurgicalpatientsinSICU>3days.Nomortalitybenefit.–Predictorsincluded:APACHEIIscore,fungalcolonization,TPN,daystofirstdoseofprophylacticdrug.?Paphitouetal.2019.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.2019;28:1708-17IncidenceofIC=16%IncidenceofIC=5.8%Summary(CandidaProphylaxis)

?Prophylaxisiseffectiveinthehighestriskpatients.?ProphylaxisreducestheincidenceofIC.?Apositiveimpactonmortalityhasnotbeenshownexceptinseverelyimmunocompromisedhosts(neutropenia,BMT,orsolidorgantransplantation).?Distinctionbetweenprophylactic&preemptivetherapyneededspeciallyinICU.Risk?Dose?.AssessmentofPreemptiveTreatmenttopreventseverecandidiasisinSICU

?Before/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.2019Dec;32(12):2443-9.

ArchSurgery.2019;136:1401-1409TemporalAssessmentofCandidaRiskFactorsintheSICUPearlsofthestudy

?ChangeinCandidariskfactorsovertimeisclinicallyrelevant.–Earlyriskfactorsatday1,timeofSICUadmission.–Morethan8riskfactorsatanytime–Rapidincreaseinriskfactors(clinicaldeterioration)–APACHEIIscore>18day3or4?Earlyriskfactormaybeevidentfromday1&maybeusedwithprogressionofriskfactorsasfever,durationofantibiotics&mechanicalventilationtoassessrisk.??moreaggressivesurveillanceculturesvs.preemptiveorempirictherapy.SerologicalMethods?earlyaidinempirictherapydecisionmaking?Plasmabeta-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.2019;28(6):625-30.ResearchOngoing?RandomizedStudyofCaspofunginProphylaxisFollowedbyPre-EmptiveTherapyforInvasiveCandidiasisintheICU.

?Thestudywilltestthepossibilitythatcaspofungincansuccessfullyreducetherateofcandidainfectionsinsubjectsatrisk.Itwillalsotestifcaspofunginisusefulintreatingsubjectsforthisdiseasewhendiagnosedusinganewbloodtestthatisperformedtwiceweekly,permittingearlierdiagnosisthancurrentpracticestandards.

?Thisstudyiscurrentlyrecruitingparticipants.MycosesStudyGroup,August2019

ConsiderationsinSelectionofEmpiricAntifungalTherapy

High-riskhostwithhematologiccancer,orstemcelltransplantation,severeimmunosuppression,hemodynamicinstability,gutdysfunctionormedicationnoncomplianceuseIVagents.Prolongedandrecentexposuretoazolespriortocurrentepisodeorsignificantliverdysfunctionordrug-druginteractionavoidazoles.Pathogeninvitrosusceptibilitypatternisknownforaclassofagents,selectanagentthatislikelytobeeffectiveagainstthespecificpathogen.SiteofInfection:?Ocularorcentralnervoussysteminfectionavoidechinocandins.CanuseliposomalamphotericinB,fluconazoleorvoriconazole.?Urinaryex.cystitisselectfluconazoleor5-flucytosine.Walshetal.NEnglJMed.2019;351:1391-1402.Overalladjustedsuccessrate01020304033.9%5033.7%2.6%

11.5%

10.3%

14.5%

Nephrotoxiceffect(p<0.001)Discontinuedthestudyprematurely(p=0.03)EmpiricCaspofungininPatientswithNeutropeniaandPersistentfeverPercent

of

Patients

Caspofunginhadsignificantlyfewer:Drug-relatedclinicalorlabadverseevents,anddiscontinuationsduetoseriousdrug-relatedclinicalorlabAEs.

**EmpiricCaspofunginvs.liposomalAmBinpersistentFeverandNeutropeniaPercent

survival

Caspofungin(n=556)L-AmB(n=539)Studydayp=0.044212835637145649420901008070605010203040Superiorinpreventingoverallmortalitywithlesstoxicity.Walshetal.NEnglJMed.2019;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.2019;36(7):2034-2039.EmpiricAnti-CandidaTherapy:Cost-Effectiveness?Target: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.2019.AnnInternMed;143:857-869.AlgorithmforEmpiricTherapy?Empirictreatmentforinvasivecandidiasisbasedonthehemodynamicstatusofthepatient.?Unstablepatients:broad-spectrumantifungalagents,whichcanbenarrowedoncethepatienthasstabilized&theidentityoftheinfectingspeciesisestablished.?Instablepatients:fluconazole,providedthatthepatientisnotcolonizedwithfluconazoleresistantstrainsortherehasbeenrecentpastexposuretoanazole(<30days).?Incontrast,pre-emptivetherapyisbasedonthepresenceofsurrogatemarkersexcolonizationindex.Spellbergetal.(2019).ClinInfectDis42:244–251Summary(EmpiricTherapy)?Inthepatientwithsepticshockriskfactorsforcandidemiashouldbeevaluated.?IfCandidainfectionissuspected,treatmentwillneedtobeinitiatedempiricallywithoutdelayonthebasisofindividualpatientfactorsbeforeadefinitivediagnosisismade*.?Choiceofagentwillrelyonlocalresistancepatterns,microbiologydata,priorazoletherapy,recentGIsurgery,neutropenia,hemodynamicstability,&otherhostfactors.?Azolesareeffectiveunlesshighratesofresistance,orneutropeniainwhichcaseechinocandinsortriazolesshouldbeused.

*SurvivingSepsisCampaign:InternationalGuidelinesforManagementofSevereSepsisandSepticShock:CCM2019

DirectedTherapy?Azoles:FluconazoleisthemostcommonagentusedtotreatclinicalCandidainfections.However,fluconazolehaslimitedactivityagainstCglabrataandCkrusei.Theevolutionofresistanceandtrendstowardmorenon-albican