2016年美国感染病学会(IDSA)念珠菌病治疗指南

ClinicalInfectiousDiseasesIDSAGUIDELINEClinicalPracticeGuidelinefortheManagementofCandidiasis:2016UpdatebytheInfectiousDiseasesSocietyofAmericaPeterG.Pappas,1CarolA.Kauffman,2DavidR.Andes,3CorneliusJ.Clancy,4KierenA.Marr,5LuisOstrosky-Zeichner,6AnnetteC.Reboli,7MindyG.Schuster,8JoseA.Vazquez,9ThomasJ.Walsh,10TheoklisE.Zaoutis,11andJackD.Sobel121UniversityofAlabamaatBirmingham;2VeteransAffairsAnnArborHealthcareSystemandUniversityofMichiganMedicalSchool,AnnArbor;3UniversityofWisconsin,Madison;4UniversityofPittsburgh,Pennsylvania;5JohnsHopkinsUniversitySchoolofMedicine,Baltimore,Maryland;6UniversityofTexasHealthScienceCenter,Houston;7CooperMedicalSchoolofRowanUniversity,Camden,NewJersey;8UniversityofPennsylvania,Philadelphia;9GeorgiaRegentsUniversity,Augusta;10WeillCornellMedicalCenterandCornellUniversity,NewYork,NewYork;11Children’sHospitalofPennsylvania,Philadelphia;and12HarperUniversityHospitalandWayneStateUniversity,Detroit,MichiganItisimportanttorealizethatguidelinescannotalwaysaccountforindividualvariationamongpatients.Theyarenotintendedtosupplantphysicianjudgmentwithrespecttoparticularpatientsorspecialclinicalsituations.IDSAconsidersadherencetotheseguidelinestobevoluntary,withtheultimatedeterminationregardingtheirapplicationtobemadebythephysicianinthelightofeachpatient’sindividualcircumstances.Keywords.candidemia;invasivecandidiasis;fungaldiagnostics;azoles;echinocandins.EXECUTIVESUMMARYBackgroundInvasiveinfectionduetoCandidaspeciesislargelyaconditionas-sociatedwithmedicalprogress,andiswidelyrecognizedasamajorcauseofmorbidityandmortalityinthehealthcareenvironment.Thereareatleast15distinctCandidaspeciesthatcausehumandis-ease,but>90%ofinvasivediseaseiscausedbythe5mostcommonpathogens,C.albicans,C.glabrata,C.tropicalis,C.parapsilosis,andC.krusei.Eachoftheseorganismshasuniquevirulencepo-tential,antifungalsusceptibility,andepidemiology,buttakenasawhole,significantinfectionsduetotheseorganismsaregen-erallyreferredtoasinvasivecandidiasis.MucosalCandidainfections—especiallythoseinvolvingtheoropharynx,esopha-gus,andvagina—arenotconsideredtobeclassicallyinvasivedisease,buttheyareincludedintheseguidelines.Sincethelastiterationoftheseguidelinesin2009[1],therehavebeennewdatapertainingtodiagnosis,prevention,andtreatmentforprovenorsuspectedinvasivecandidiasis,leadingtosignifi-cantmodificationsinourtreatmentrecommendations.Summarizedbelowarethe2016revisedrecommendationsforthemanagementofcandidiasis.Duetotheguideline’srele-vancetopediatrics,theguidelinehasbeenreviewedanden-dorsedbytheAmericanAcademyofPediatrics(AAP)andthePediatricInfectiousDiseasesSociety(PIDS).TheMycosesStudyGroup(MSG)hasalsoendorsedtheseguidelines.ThepanelfollowedaguidelinedevelopmentprocessthathasbeenadoptedbytheInfectiousDiseasesSocietyofAmerica(IDSA),whichincludesasystematicmethodofgradingboththequalityofevidence(verylow,low,moderate,andhigh)andthestrengthoftherecommendation(weakorstrong)[2](Figure1).[3]Theguidelinesarenotintendedtoreplaceclin-icaljudgmentinthemanagementofindividualpatients.Ade-taileddescriptionofthemethods,background,andevidencesummariesthatsupporteachrecommendationcanbefoundinthefulltextoftheguideline.I.WhatIstheTreatmentforCandidemiainNonneutropenicPatients?Recommendations1.Anechinocandin(caspofungin:loadingdose70mg,then50mgdaily;micafungin:100mgdaily;anidulafungin:load-ingdose200mg,then100mgdaily)isrecommendedasini-tialtherapy(strongrecommendation;high-qualityevidence).2.Fluconazole,intravenousororal,800-mg(12mg/kg)load-ingdose,then400mg(6mg/kg)dailyisanacceptablealter-nativetoanechinocandinasinitialtherapyinselectedpatients,includingthosewhoarenotcriticallyillandwhoareconsideredunlikelytohaveafluconazole-resistantCan-didaspecies(strongrecommendation;high-qualityevidence).3.Testingforazolesusceptibilityisrecommendedforallblood-streamandotherclinicallyrelevantCandidaisolates.Testingforechinocandinsusceptibilityshouldbeconsideredinpa-tientswhohavehadpriortreatmentwithanechinocandinandamongthosewhohaveinfectionwithC.glabrataorC.parapsilosis(strongrecommendation;low-qualityevidence).Received28October2015;accepted2November2015.Correspondence:P.G.Pappas,UniversityofAlabamaatBirmingham,DivisionofInfectiousDisease,229TinsleyHarrisonTower,1900UniversityBlvd,Birmingham,AL35294-0006(pappas@uab.edu).ClinicalInfectiousDiseases®2016;62(4):409–17©TheAuthor2016.PublishedbyOxfordUniversityPressfortheInfectiousDiseasesSocietyofAmerica.Allrightsreserved.Forpermissions,e-mailjournals.permissions@oup.com.DOI:10.1093/cid/civ1194ClinicalPracticeGuidelinefortheManagementofCandidiasis•CID2016:62(15February)•4094.Transitionfromanechinocandintofluconazole(usuallywithin5–7days)isrecommendedforpatientswhoareclin-icallystable,haveisolatesthataresusceptibletofluconazole(eg,C.albicans),andhavenegativerepeatbloodculturesfol-lowinginitiationofantifungaltherapy(strongrecommenda-tion;moderate-qualityevidence).5.ForinfectionduetoC.glabrata,transitiontohigher-dosefluconazole800mg(12mg/kg)dailyorvoriconazole200–300(3–4mg/kg)twicedailyshouldonlybeconsideredamongpatientswithfluconazole-susceptibleorvoricona-zole-susceptibleisolates(strongrecommendation;low-qualityevidence).6.LipidformulationamphotericinB(AmB)(3–5mg/kgdaily)isareasonablealternativeifthereisintolerance,limitedavailability,orresistancetootherantifungalagents(strongrecommendation;high-qualityevidence).7.TransitionfromAmBtofluconazoleisrecommendedafter5–7daysamongpatientswhohaveisolatesthataresuscepti-bletofluconazole,whoareclinicallystable,andinwhomrepeatculturesonantifungaltherapyarenegative(strongrec-ommendation;high-qualityevidence).8.Amongpatientswithsuspectedazole-andechinocandin-resistantCandidainfections,lipidformulationAmB(3–5mg/kgdaily)isrecommended(strongrecommendation;low-qualityevidence).9.Voriconazole400mg(6mg/kg)twicedailyfor2doses,then200mg(3mg/kg)twicedailyiseffectiveforcandidemia,butofferslittleadvantageoverfluconazoleasinitialtherapy(strongrecommendation;moderate-qualityevidence).Vorico-nazoleisrecommendedasstep-downoraltherapyforselectedcasesofcandidemiaduetoC.krusei(strongrecommendation;low-qualityevidence).10.Allnonneutropenicpatientswithcandidemiashouldhaveadilatedophthalmologicalexamination,preferablyper-formedbyanophthalmologist,withinthefirstweekafterdiagnosis(strongrecommendation;low-qualityevidence).11.Follow-upbloodculturesshouldbeperformedeverydayoreveryotherdaytoestablishthetimepointatwhichFigure1.ApproachandimplicationstoratingthequalityofevidenceandstrengthofrecommendationsusingtheGradingofRecommendationsAssessment,DevelopmentandEvaluation(GRADE)methodology(unrestricteduseofthefiguregrantedbytheUSGRADENetwork)[3].410•CID2016:62(15February)•Pappasetalcandidemiahasbeencleared(strongrecommendation;low-qualityevidence).12.Recommendeddurationoftherapyforcandidemiawithoutobviousmetastaticcomplicationsisfor2weeksafterdocu-mentedclearanceofCandidaspeciesfromthebloodstreamandresolutionofsymptomsattributabletocandidemia(strongrecommendation;moderate-qualityevidence).II.ShouldCentralVenousCathetersBeRemovedinNonneutropenicPatientsWithCandidemia?Recommendation13.Centralvenouscatheters(CVCs)shouldberemovedasearlyaspossibleinthecourseofcandidemiawhenthesourceispresumedtobetheCVCandthecathetercanberemovedsafely;thisdecisionshouldbeindividualizedforeachpatient(strongrecommendation;moderate-qualityevidence).III.WhatIstheTreatmentforCandidemiainNeutropenicPatients?Recommendations14.Anechinocandin(caspofungin:loadingdose70mg,then50mgdaily;micafungin:100mgdaily;anidulafungin:loadingdose200mg,then100mgdaily)isrecommendedasinitialtherapy(strongrecommendation;moderate-qualityevidence).15.LipidformulationAmB,3–5mg/kgdaily,isaneffectivebutlessattractivealternativebecauseofthepotentialfortoxicity(strongrecommendation;moderate-qualityevidence).16.Fluconazole,800-mg(12mg/kg)loadingdose,then400mg(6mg/kg)daily,isanalternativeforpatientswhoarenotcriticallyillandhavehadnopriorazoleexposure(weakrecommendation;low-qualityevidence).17.Fluconazole,400mg(6mg/kg)daily,canbeusedforstep-downtherapyduringpersistentneutropeniainclinicallysta-blepatientswhohavesusceptibleisolatesanddocumentedbloodstreamclearance(weakrecommendation;low-qualityevidence).18.Voriconazole,400mg(6mg/kg)twicedailyfor2doses,then200–300mg(3–4mg/kg)twicedaily,canbeusedinsit-uationsinwhichadditionalmoldcoverageisdesired(weakrecommendation;low-qualityevidence).Voriconazolecanalsobeusedasstep-downtherapyduringneutropeniainclinicallystablepatientswhohavehaddocumentedblood-streamclearanceandisolatesthataresusceptibletovoricona-zole(weakrecommendation;low-qualityevidence).19.ForinfectionsduetoC.krusei,anechinocandin,lipidformulationAmB,orvoriconazoleisrecommended(strongrecommendation;low-qualityevidence).20.Recommendedminimumdurationoftherapyforcan-didemiawithoutmetastaticcomplicationsis2weeksafterdocumentedclearanceofCandidafromthebloodstream,providedneutropeniaandsymptomsattributabletocandide-miahaveresolved(strongrecommendation;low-qualityevidence).21.Ophthalmologicalfindingsofchoroidalandvitrealinfec-tionareminimaluntilrecoveryfromneutropenia;therefore,dilatedfunduscopicexaminationsshouldbeperformedwith-inthefirstweekafterrecoveryfromneutropenia(strongrec-ommendation;low-qualityevidence).22.Intheneutropenicpatient,sourcesofcandidiasisotherthanaCVC(eg,gastrointestinaltract)predominate.Catheterremovalshouldbeconsideredonanindividualbasis(strongrecommendation;low-qualityevidence).23.Granulocytecolony-stimulatingfactor(G-CSF)–mobilizedgranulocytetransfusionscanbeconsideredincasesofpersis-tentcandidemiawithanticipatedprotractedneutropenia(weakrecommendation;low-qualityevidence).IV.WhatIstheTreatmentforChronicDisseminated(Hepatosplenic)Candidiasis?Recommendations24.InitialtherapywithlipidformulationAmB,3–5mg/kgdailyORanechinocandin(micafungin:100mgdaily;caspofungin:70-mgloadingdose,then50mgdaily;oranidulafungin:200-mgloadingdose,then100mgdaily),forseveralweeksisrec-ommended,followedbyoralfluconazole,400mg(6mg/kg)daily,forpatientswhoareunlikelytohaveafluconazole-resistantisolate(strongrecommendation;low-qualityevidence).25.Therapyshouldcontinueuntillesionsresolveonrepeatimaging,whichisusuallyseveralmonths.Prematurediscon-tinuationofantifungaltherapycanleadtorelapse(strongrecommendation;low-qualityevidence).26.Ifchemotherapyorhematopoieticcelltransplantationisrequired,itshouldnotbedelayedbecauseofthepresenceofchronicdisseminatedcandidiasis,andantifungaltherapyshouldbecontinuedthroughouttheperiodofhighrisktopre-ventrelapse(strongrecommendation;low-qualityevidence).27.Forpatientswhohavedebilitatingpersistentfevers,short-term(1–2weeks)treatmentwithnonsteroidalanti-inflammatorydrugsorcorticosteroidscanbeconsidered(weakrecommendation;low-qualityevidence).V.WhatIstheRoleofEmpiricTreatmentforSuspectedInvasiveCandidiasisinNonneutropenicPatientsintheIntensiveCareUnit?Recommendations28.Empiricantifungaltherapyshouldbeconsideredincriticallyillpatientswithriskfactorsforinvasivecandidiasisandnootherknowncauseoffeverandshouldbebasedonclinicalassessmentofriskfactors,surrogatemarkersforinvasivecan-didiasis,and/orculturedatafromnonsterilesites(strongrec-ommendation;moderate-qualityevidence).Empiricantifungaltherapyshouldbestartedassoonaspossibleinpatientswhohavetheaboveriskfactorsandwhohaveclinicalsignsofsep-ticshock(strongrecommendation;moderate-qualityevidence).29.Preferredempirictherapyforsuspectedcandidiasisinnonneutropenicpatientsintheintensivecareunit(ICU)isClinicalPracticeGuidelinefortheManagementofCandidiasis•CID2016:62(15February)•411anechinocandin(caspofungin:loadingdoseof70mg,then50mgdaily;micafungin:100mgdaily;anidulafungin:load-ingdoseof200mg,then100mgdaily)(strongrecommenda-tion;moderate-qualityevidence).30.Fluconazole,800-mg(12mg/kg)loadingdose,then400mg(6mg/kg)daily,isanacceptablealternativeforpatientswhohavehadnorecentazoleexposureandarenotcolonizedwithazole-resistantCandidaspecies(strongrecommenda-tion;moderate-qualityevidence).31.LipidformulationAmB,3–5mg/kgdaily,isanalternativeifthereisintolerancetootherantifungalagents(strongrec-ommendation;low-qualityevidence).32.Recommendeddurationofempirictherapyforsuspectedinvasivecandidiasisinthosepatientswhoimproveis2weeks,thesameasfortreatmentofdocumentedcandidemia(weakrecommendation;low-qualityevidence).33.Forpatientswhohavenoclinicalresponsetoempirican-tifungaltherapyat4–5daysandwhodonothavesubsequentevidenceofinvasivecandidiasisafterthestartofempirictherapyorhaveanegativenon-culture-baseddiagnosticassaywithahighnegativepredictivevalue,considerationshouldbegiventostoppingantifungaltherapy(strongrec-ommendation;low-qualityevidence).VI.ShouldProphylaxisBeUsedtoPreventInvasiveCandidiasisintheIntensiveCareUnitSetting?Recommendations34.Fluconazole,800-mg(12mg/kg)loadingdose,then400mg(6mg/kg)daily,couldbeusedinhigh-riskpatientsinadultICUswithahighrate(>5%)ofinvasivecandidiasis(weakrecommendation;moderate-qualityevidence).35.Analternativeistogiveanechinocandin(caspofungin:70-mgloadingdose,then50mgdaily;anidulafungin:200-mgloadingdoseandthen100mgdaily;ormicafun-gin:100mgdaily)(weakrecommendation;low-qualityevidence).36.DailybathingofICUpatientswithchlorhexidine,whichhasbeenshowntodecreasetheincidenceofbloodstreamin-fectionsincludingcandidemia,couldbeconsidered(weakrecommendation;moderate-qualityevidence).VII.WhatIstheTreatmentforNeonatalCandidiasis,IncludingCentralNervousSystemInfection?WhatIstheTreatmentforInvasiveCandidiasisandCandidemia?Recommendations37.AmBdeoxycholate,1mg/kgdaily,isrecommendedforneonateswithdisseminatedcandidiasis(strongrecommenda-tion;moderate-qualityevidence).38.Fluconazole,12mg/kgintravenousororaldaily,isarea-sonablealternativeinpatientswhohavenotbeenonflucon-azoleprophylaxis(strongrecommendation;moderate-qualityevidence).39.LipidformulationAmB,3–5mg/kgdaily,isanalternative,butshouldbeusedwithcaution,particularlyinthepresenceofurinarytractinvolvement(weakrecommendation;low-qualityevidence).40.EchinocandinsshouldbeusedwithcautionandgenerallylimitedtosalvagetherapyortosituationsinwhichresistanceortoxicityprecludetheuseofAmBdeoxycholateorflucon-azole(weakrecommendation;low-qualityevidence).41.AlumbarpunctureandadilatedretinalexaminationarerecommendedinneonateswithculturespositiveforCandidaspeciesfrombloodand/orurine(strongrecommendation;low-qualityevidence).42.Computedtomographicorultrasoundimagingofthegen-itourinarytract,liver,andspleenshouldbeperformedifbloodculturesarepersistentlypositiveforCandidaspecies(strongrecommendation;low-qualityevidence).43.CVCremovalisstronglyrecommended(strongrecommen-dation;moderate-qualityevidence).44.Therecommendeddurationoftherapyforcandidemiawithoutobviousmetastaticcomplicationsisfor2weeksafterdocumentedclearanceofCandidaspeciesfromthebloodstreamandresolutionofsignsattributabletocandide-mia(strongrecommendation;low-qualityevidence).WhatIstheTreatmentforCentralNervousSystemInfectionsinNeonates?Recommendations45.Forinitialtreatment,AmBdeoxycholate,1mg/kgintrave-nousdaily,isrecommended(strongrecommendation;low-qualityevidence).46.AnalternativeregimenisliposomalAmB,5mg/kgdaily(strongrecommendation;low-qualityevidence).47.Theadditionofflucytosine,25mg/kg4timesdaily,maybeconsideredassalvagetherapyinpatientswhohavenothadaclinicalresponsetoinitialAmBtherapy,butadverseeffectsarefrequent(weakrecommendation;low-qualityevidence).48.Forstep-downtreatmentafterthepatienthasrespondedtoinitialtreatment,fluconazole,12mg/kgdaily,isrecommend-edforisolatesthataresusceptibletofluconazole(strongrec-ommendation;low-qualityevidence).49.Therapyshouldcontinueuntilallsigns,symptoms,andcere-brospinalfluid(CSF)andradiologicalabnormalities,ifpresent,haveresolved(strongrecommendation;low-qualityevidence).50.Infectedcentralnervoussystem(CNS)devices,includingventriculostomydrainsandshunts,shouldberemovedifatallpossible(strongrecommendation;low-qualityevidence).WhatAretheRecommendationsforProphylaxisintheNeonatalIntensiveCareUnitSetting?Recommendations51.Innurserieswithhighrates(>10%)ofinvasivecandidiasis,intravenousororalfluconazoleprophylaxis,3–6mg/kgtwice412•CID2016:62(15February)•Pappasetalweeklyfor6weeks,inneonateswithbirthweights<1000gisrecommended(strongrecommendation;high-qualityevidence).52.Oralnystatin,100000units3timesdailyfor6weeks,isanalternativetofluconazoleinneonateswithbirthweights<1500ginsituationsinwhichavailabilityorresistanceprecludetheuseoffluconazole(weakrecommendation;moderate-qualityevidence).53.Oralbovinelactoferrin(100mg/day)maybeeffectiveinneonates<1500gbutisnotcurrentlyavailableinUShospi-tals(weakrecommendation;moderate-qualityevidence).VIII.WhatIstheTreatmentforIntra-abdominalCandidiasis?Recommendations54.Empiricantifungaltherapyshouldbeconsideredforpa-tientswithclinicalevidenceofintra-abdominalinfectionandsignificantriskfactorsforcandidiasis,includingrecentabdominalsurgery,anastomoticleaks,ornecrotizingpancre-atitis(strongrecommendation;moderate-qualityevidence).55.Treatmentofintra-abdominalcandidiasisshouldincludesourcecontrol,withappropriatedrainageand/ordebride-ment(strongrecommendation;moderate-qualityevidence).56.Thechoiceofantifungaltherapyisthesameasforthetreatmentofcandidemiaorempirictherapyfornonneutro-penicpatientsintheICU(SeesectionsIandV)(strongrec-ommendation;moderate-qualityevidence).57.Thedurationoftherapyshouldbedeterminedbyadequacyofsourcecontrolandclinicalresponse(strongrecommenda-tion;low-qualityevidence).IX.DoestheIsolationofCandidaSpeciesFromtheRespiratoryTractRequireAntifungalTherapy?Recommendation58.GrowthofCandidafromrespiratorysecretionsusuallyindi-catescolonizationandrarelyrequirestreatmentwithantifungaltherapy(strongrecommendation;moderate-qualityevidence).X.WhatIstheTreatmentforCandidaIntravascularInfections,IncludingEndocarditisandInfectionsofImplantableCardiacDevices?WhatIstheTreatmentforCandidaEndocarditis?Recommendations59.Fornativevalveendocarditis,lipidformulationAmB,3–5mg/kgdaily,withorwithoutflucytosine,25mg/kg4timesdaily,ORhigh-doseechinocandin(caspofungin150mgdaily,micafungin150mgdaily,oranidulafungin200mgdaily)isrecommendedforinitialtherapy(strongrecommen-dation;low-qualityevidence).60.Step-downtherapytofluconazole,400–800mg(6–12mg/kg)daily,isrecommendedforpatientswhohavesusceptibleCandidaisolates,havedemonstratedclinicalstability,andhaveclearedCandidafromthebloodstream(strongrecom-mendation;low-qualityevidence).61.Oralvoriconazole,200–300mg(3–4mg/kg)twicedaily,orposaconazoletablets,300mgdaily,canbeusedasstep-downtherapyforisolatesthataresusceptibletothoseagentsbutnotsusceptibletofluconazole(weakrecommendation;verylow-qualityevidence).62.Valvereplacementisrecommended;treatmentshouldcon-tinueforatleast6weeksaftersurgeryandforalongerdurationinpatientswithperivalvularabscessesandothercomplications(strongrecommendation;low-qualityevidence).63.Forpatientswhocannotundergovalvereplacement,long-termsuppressionwithfluconazole,400–800mg(6–12mg/kg)daily,iftheisolateissusceptible,isrecommended(strongrecommendation;low-qualityevidence).64.Forprostheticvalveendocarditis,thesameantifungalreg-imenssuggestedfornativevalveendocarditisarerecom-mended(strongrecommendation;low-qualityevidence).Chronicsuppressiveantifungaltherapywithfluconazole,400–800mg(6–12mg/kg)daily,isrecommendedtopre-ventrecurrence(strongrecommendation;low-qualityevidence).WhatIstheTreatmentforCandidaInfectionofImplantableCardiacDevices?Recommendations65.Forpacemakerandimplantablecardiacdefibrillatorinfec-tions,theentiredeviceshouldberemoved(strongrecommen-dation;moderate-qualityevidence).66.Antifungaltherapyisthesameasthatrecommendedfornativevalveendocarditis(strongrecommendation;low-qualityevidence).67.Forinfectionslimitedtogeneratorpockets,4weeksofan-tifungaltherapyafterremovalofthedeviceisrecommended(strongrecommendation;low-qualityevidence).68.Forinfectionsinvolvingthewires,atleast6weeksofanti-fungaltherapyafterwireremovalisrecommended(strongrecommendation;low-qualityevidence).69.Forventricularassistdevicesthatcannotberemoved,thean-tifungalregimenisthesameasth