dutch working party on antibiotic policy swab guidelines

DutchWorkingPartyonAntibioticPolicy

SWABGuidelinesfortheManagementofInvasiveFungalInfections

RevisedversionReleased:14December2017

SWABInvasiveFungalInfectionsGuidelinesCommitteeProfB.J.Kullberg(chair)ProfN.M.A.Blijlevens(NetherlandsSocietyforHematology,NVvH)DrJ.J.W.M.Janssen(NetherlandsSocietyforHematology,NVvH)DrJ.F.G.Meis(NetherlandsSocietyforMedicalMicrobiology,NVMM&NetherlandsSocietyforMedicalMycology,NVMy)ProfP.E.Verweij(NetherlandsSocietyforMedicalMicrobiology,NVMM&NetherlandsSocietyforMedicalMycology,NVMy)DrA.M.L.OudeLashof(NetherlandsSocietyforInternalMedicine,NIV)DrF.L.vandeVeerdonk(NetherlandsSocietyforInternalMedicine,NIV)DrB.J.Rijnders(NetherlandsSocietyforInternalMedicine,NIV)DrR.J.M.Brüggemann(NetherlandsSocietyforHospitalPharmacy,NVZA)ProfT.S.vdWerf(NetherlandsSocietyforPulmonaryPhysicians,NVALT)dr.M.H.E.Reijers(NetherlandsSocietyforPulmonaryPhysicians,NVALT)DrA.R.H.vanZanten(NetherlandsSocietyforIntensiveCare,NVIC)DrD.W.deLange(NetherlandsSocietyforIntensiveCare,NVIC)DrT.F.W.Wolfs(NetherlandsSocietyforPediatrics,NVK)ProfA.Warris,UniversityofAberdeen(Advisor,EuropeanPaediatricMycologyNetwork)©2008-2017SWABSWABSecretariatPOBox395854ZGBergensecretariaat@swab.nlwww.swab.nl

2 SWABInvasiveFungalinfections2017

Contents

Chapter1 Introduction 31.1.Scopeandvalidityoftheguidelines 31.2.Methods 31.3.Implementation 31.4.GuidelinesandConflictsofInterest 41.5.Whatisnewcomparedtothe2008versionoftheguidelines? 51.6.SummaryofRecommendations 6Chapter2 InvasiveAspergillosis 112.1.Diagnosisandantifungalsusceptibility 112.2.Treatmentofacuteinvasivepulmonaryaspergillosiswithprovensusceptibilitytoazoles 152.3.Treatmentofacuteinvasivepulmonaryaspergillosiswithresistanceorunknownsusceptibilitytoazoles 182.4.Invasiveaspergillosisinspecialpopulations 212.5.Managementofpatientstreatedforinvasiveaspergillosis 232.6.Preemptive(Diagnostic-driven)andempiricaltherapyforinvasiveaspergillosis 272.7Aspergillussinusitisandotitis,cerebralaspergillosis,chronicpulmonaryaspergillosisandaspergilloma 282.8.Antifungalprophylaxisinpatientswithhematologicalmalignanciesorstemcellrecipients 30

Chapter3 Candidiasis 323.1.Treatmentofcandidemiaandacutedisseminatedcandidiasis 323.2.Treatmentofcandidemiaandacutedisseminatedcandidiasisofknownspeciesandsusceptibility 353.3.Managementofintravascularcatheters 363.4.Disseminatedcandidiasisandsecondarymetastaticfoci 363.5.Therapyofcandidemiaandacutedisseminatedcandidiasisinchildren 383.6.Empiricalorpre-emptivetherapyagainstinvasivecandidiasis 393.7.Ocularcandidiasis 413.8.Urinarytractcandidiasis 423.9.Abdominalcandidiasis 433.10.Esophagealcandidiasis 443.11.Antifungalprophylaxisintheintensivecareunit 443.12.Antifungalprophylaxisinpatientswithhematologicalmalignanciesorsolidorgantransplantrecipients 453.13.Antifungalprophylaxisinneonates 47Chapter4 Cryptococcosis 484.1.Cryptococcalmeningitis 484.2.Treatmentofnonmeningealcryptococcosis 504.3.Secondaryprophylaxisofcryptococcosis 51Chapter5 Mucormycosis 53

5.1.Diagnosisofmucormycosis 535.2Treatmentofinvasivemucormycosis 53Potentialconflictsofinterest 55References 55Appendix 65

SWABInvasiveFungalinfections2017 3

Chapter1 Introduction

The Dutch Study Group on Antibiotic Policy (SWAB) has been established by the Infectious Diseases Society of theNetherlands (VIZ), the Netherlands Society forMedicalMicrobiology (NVMM) and the Netherlands Society for HospitalPharmacists (NVZA). In cooperation with the National Center for Infectious Diseases Control (CIb), SWAB coordinatesactivitiesaimedatoptimizingthequalityofantibioticuse,monitoringthedevelopmentofresistance,andatreducingthecostofantibioticuseintheNetherlands.By way of evidence-based development of guidelines, the SWAB offers local hospital antibiotic guidelines committeesguidingprinciplesforthedevelopmentofantibioticpolicies.TheseguidelinesalsoformthebasisofSwabID,thenationalonlineantimicrobialguidelines(www.swab.nl).Themembersofthecommitteehavebeendelegatedbytheirrespectiveprofessionalbodies;theNetherlandsAssociationSociety Hospital Pharmacists, the Netherlands Society for Medical Microbiology, the Infectious Diseases Society of theNetherlands, including the pediatrics division, the Netherlands Society for Hematology and the Netherlands Society forIntensiveCare.

1.1.ScopeandvalidityoftheguidelinesThese guidelines cover invasive fungal infection by Candida species,Aspergillus species, Cryptococcus neoformans, andmucorales. In addition to invasive infections, the policy for oropharyngeal candidiasis is also included in the guideline.Vulvovaginal candidiasis and dermatomycoses are beyond the scope of the guideline. The guidelines are applicable toadults,childrenandneonates,andareintendedforbothintramuralandextramuraluse.SWAB intends to revise theirguidelinesevery5years.Thepotentialneed forearlier revisionswillbedeterminedby theSWABboardatannualintervals,onthebasisofanexaminationofcurrentliterature.Ifnecessary,theguidelinescommitteewillbereconvenedtodiscusspotentialchanges.Whenappropriate,thecommitteewillrecommendexpeditedrevisionoftheguidelinetotheSWABboard.

1.2.Methods

The guidelines were drafted in accordance with the recommendations on evidence-based development of guidelines(MedicalSpecialtiesGuidelines2.0,finalreport,2011)bytheNetherlandsFederationofMedicalSpecialties.Theguidelineswerederived froma systematic literature reviewbasedonessential researchquestionsabout the treatmentof invasivefungalinfections.Theconclusionsandrecommendationshavebeenprovidedwithlevelsofevidentialvalueinconformitywith the handbook of the Dutch Institute for Healthcare Improvement CBO. For the original guidelines (published,September2008),asystematicreviewwasconductedoneachoftheresearchquestionsinthePubmeddatabase(January1966 through January 2008). In addition, usewasmade of The Cochrane Library, Clinical Evidence and Sumsearch, andexploratorystudiesofexistingguidelineswereconducted.Forthepresentversion,theanadditionalsystematicreviewwasperformed, using the same sources, for January 2008 throughDecember 2016. The draft guidelineswere edited by theGuidelinesCommitteeofdelegatesfromtheprofessionalsocietiesinvolved,andsubsequentlysubmittedtothemembersof the professional societies for comment. The final versionwas approved by the SWAB executive board, consisting ofmandatedrepresentativesoftheprofessionalsocieties.

1.3.ImplementationAfterfinalapproval,theSWABguidelinesarepublishedatwww.swab.nl,andanexecutivesummaryispublishedinapeer-reviewedjournal.Thenewguidelinesformthebasisofthetreatmentrecommendationsintheonlinenationalantimicrobialguide (SWAB-ID) for theprophylaxisandtreatmentof infectiousdiseases inhospitals.SWAB-ID isupdatedat least twiceyearly, incorporating all SWAB guideline recommendations. Every hospital in the Netherlands has been offered theopportunitytoobtainacustom,localizedversionofSWAB-IDasalocalorregionalonlineantimicrobialguide.Updatesofthe national version of SWAB-ID, including new guidelines, are distributed to the localized SWAB-ID guides. Theimplementation of national and local SWAB-ID antimicrobial guidelines and adherence to the recommendations aresecuredby thenationalAntimicrobialStewardshipProgramthathasbeenestablishedbySWAB, theHealth Inspectorate(IGZ)andtheMinistryofHealth(VWS)since2013.Ineachhospital,anAntimicrobialStewardshipTeam(A-team)ischargedwith implementation and monitoring of guidelines on a daily basis. Adherence to guidelines and recommendations isreportedtotheSWABNationalStewardshipMonitor.


1.4.GuidelinesandConflictsofInterest AllmembersoftheguidelinecommitteecompliedwiththeSWABpolicyonconflictsofinterest,whichrequiresdisclosureofanyfinancialorotherinterestthatmightbeconstruedasconstitutinganactual,potential,orapparentconflict.MembersoftheguidelinecommitteewereprovidedtheSWABconflictof interestdisclosurestatementandwereaskedto identifytiestocompaniesdevelopingproductsthatmightbeaffectedbypromulgationoftheguideline.Informationwasrequestedregardingemployment,consultancies,stockownership,honoraria,researchfunding,experttestimony,andmembershiponcompanyadvisorycommittees.Thepanelmadedecisionsonacase-by-casebasisastowhetheranindividual’sroleshouldbelimitedasaresultofaconflict.Potentialconflictsarelistedatthebottomoftheguideline.Table1.1Methodologicalqualityofindividualstudiesrelatingtopreventionortreatment†

Evidencelevel DefinitionA1A2

SystematicreviewofatleasttwoindependentA2levelstudiesRandomisedcontrolledtrial(RCT)ofsufficientmethodologicalqualityandpowerorProspectivecohortstudywithsufficientpowerandwithadequateconfoundingcorrections

B

ComparativestudylackingthesamequalityasmentionedinA2(includingpatient-controlandcohortstudies)orProspectivecohortstudylackingthesamequalityasmentionedinA2,retrospectivecohortstudyorpatient-controlstudy

C

Non-comparativestudy

D

EvidencebasedontheopinionofmembersoftheGuidelinecommittee

Table1.2.Levelofevidence

Evidencelevel DefinitionLevel1 StudyoflevelA1,oratleasttwoindependentstudiesof

levelA2Level2 OnestudyoflevelA2,oratleasttwoindependent

studiesoflevelBLevel3

OnestudyoflevelBorC

Level4

Expertopinion

†Definedin:HandbookoftheDutchInstituteforHealthcareImprovementCBO


1.5.Whatisnewcomparedtothe2008versionoftheguidelines?Inviewofthetimeelapsedsincethereleaseofthepreviousversionoftheguidelines,themajorityoftheparagraphsandrecommendationshavechanged.Therefore,thisparagraphwillnotattempttosummarizeallchanges,andreadersarereferredtothespecificcontentofthepresentguidelinestocarefullyappreciateanychangesinrecommendations.Here,onlymajorchangeswillbedescribedglobally.Aspergillosis

Emergingazoleresistanceandchangingepidemiologyofinvasiveaspergillosisinnon-hematologicalpatients(e.g.,inICUpatientsandpost-influenza)havesignificantlyaffectedthetreatmentstrategiesforinvasiveaspergillosis,includingdiagnosticprocedures,andthechoiceofprimarytherapy(Chapter2).Toprovideabackgroundonepidemiology,diagnosticstrategiesandantifungalresistance,aspecificchapterhasbeenadded(Chapter2.1).SeparaterecommendationsarenowprovidedforpatientswithAspergillusisolatesproventobeazole-susceptible(Chapter2.2)andthosewithresistanceorunknownsusceptibilitytoazoles(Chapter2.3).Aseparatechapterhasbeenaddedonspecialpopulations:ICUpatients,patientswithinfluenzapneumonia,andpatientswithchronicgranulomatousdisease(CGD)(Chapter2.4).Asectionontherapeuticdrugmonitoringhasbeenadded,aswellasonoralstep-down,durationoftherapy,andadjunctiveimmunotherapy(Chapter2.5).Theparagraphsonempiricalandpreemptivetherapy(formerlyChapter4)havebeenmovedtothesectiononaspergillosis(Chapter2.4).CandidiasisTheaccumulatingevidenceontherelativeefficacyofechinocandinantifungalshasledtomajorchangesinthetherapeuticstrategyforpatientswithcandidemiaorinvasivecandidiasis(Chapters3.1–3.2and3.5).Thesectiononempiricaltherapyofinvasivecandidiasis(formerlyChapter4)hasbeenmovedtoChapter3(Chapter3.6).Finally,changingepidemiologyandnewinsightshaveledtomajorchangesintheparagraphsonprophylaxisofinvasivecandidiasisinpatientsintheICU,transplantrecipientsandneonates(Chapters3.12–3.14).Cryptococcosis

Duringthepastdecade,majorinsightshaveledtobetterdefinitionofoptimaltreatmentofcryptococcalmeningitis,includingthevalueofcombinationtherapy.Thus,treatmentrecommendationsforalltypesofcryptococcosishavechanged(Chapters4.1–4.2).Also,studiesoncorticosteroiduse,adjunctiveimmunotherapy,andinitiationofcombinationantiretroviraltherapy(cART)haveledtonewrecommendations(Chapter4.1).Finally,thechangingepidemiologyhasledtomajorchangesintheparagraphonprophylaxis(Chapter4.3).Mucormycosis

FortreatmentofMucormycosis(formerlyZygomycosis),theroleofironchelators,posaconazole,andisavuconazolehavebeenadded(Chapter5.2).


1.6.SummaryofRecommendations AspergillosisDiagnosisofinvasiveaspergillosis(IA)inpatientswithhematologicalmalignanciesRecommendation1 Forearlydiagnosis,determinationofserumAspergillusgalactomannanatleasttwiceweeklyshouldbeconsideredin

neutropenicpatientswithhematologicalmalignancyorHSCT.Recommendation2 InneutropenicpatientswithhematologicalmalignancyorHSCT,andapositiveserumAspergillusgalactomannanindex

(≥0.5)orpersistentunexplainedfever,anHR-CTlungscanshouldbeperformed,regardlessofchestradiographresults.Recommendation3 Bronchoalveolarlavage(BAL)toobtainspecimensforbothcultureandgalactomannanantigenassayshouldbeperformed

inpatientswithsuspectedinvasivepulmonaryaspergillosis

AntifungalsusceptibilityRecommendation4 Forallpatientswithsuspectedinvasiveaspergillosis,maximaleffortsshouldbemadetoobtainsamplesformycology

cultureandsusceptibilitytesting.1Recommendation5 Frompatientswithsuspectedinvasiveaspergillosis,clinicalisolatesshouldbetestedforantifungalsusceptibility.1

Recommendation6 ResistancetoazolesshouldbetestedbyMICor4-wellscreeningagarscreeningfollowedbyMICtesting.1

Recommendation7 Aspergillusisolatestestedtoberesistanttoonemould-activeazoleshouldbeconsideredpan-azoleresistant,unless

otherwiseprovenRecommendation8 Incaseofnegativefungalculturesinpatientswithinvasiveaspergillosis,Cyp51PCRforresistance-associatedgenesonBAL

fluidisstronglyrecommended1See:TechnicalNoteonfungalcultureandsusceptibilitytesting(www.nvmy.nl)

First-linetherapyforacuteinvasiveaspergillosiswithprovenvoriconazolesusceptibilityRecommendation9 Primarytreatmentwithvoriconazoleorisavuconazoleisrecommendedforpatientswithacuteinvasiveaspergillosis

causedbyisolateswithconfirmedsusceptibilitytoazoles.Recommendation10 Thecommitteerecommendsagainsttheuseofitraconazoleorc-AmBforprimarytreatmentofinvasiveaspergillosisRecommendation11 Incaseofcontraindicationstovoriconazoleorisavuconazole,L-AmB(3mg/kg/d)orposaconazolearesuitablealternatives

forpatientswithacuteinvasiveaspergillosiswithconfirmedsusceptibilitytoazoles.

First-linetherapyforaspergillosiswithunknownsusceptibilitytovoriconazoleorisavuconazoleRecommendation12 Forpatientswithinvasiveaspergillosiscausedbyisolateswithunknownsusceptibilitytoazoles,initialcombination

therapywithvoriconazole/isavuconazoleplusL-AmB,orvoriconazole/isavuconazoleplusanechinocandinisrecommended.MonotherapywithL-AmBisconsideredasasecondchoiceinthesepatients.Incaseofmixedazole-resistantandazole-susceptiblemoldinfections,orsuspectedco-infectionwithmucorales,voriconazole/isavuconazoleplusL-AmBisrecommended.

Recommendation13 IfsusceptibilityorBALCyp51resistancePCRresultsareexpectedshortly,initialmonotherapywithvoriconazolemaybe

prescribedtopatientswithinvasiveaspergillosisofunknownazolesusceptibility.SubsequentPCRresultsshouldguideescalationtoL-AmBincaseofresistance,andtocombinationtherapyifsusceptibilityresultsareunavailable.SeverelyillpatientsandpatientsintheICUshouldreceiveinitialcombinationtherapypendingsusceptibilityresults.

First-linetherapyforaspergillosiswithprovenazoleresistanceRecommendation14 Forpatientswithinvasiveaspergillosiscausedbyisolateswithconfirmedresistancetoazoles,L-AmBisrecommended.

Echinocandinmonotherapyisrecommendedasasecondchoiceinthesepatients.

InvasiveaspergillosisinICUpatients,patientswithinfluenza,andpatientswithCGDRecommendation15 ICUpatientswithapositiveAspergillusculturefromrespiratorysamples,whohavechestradiologyabnormalitiesandriskfactorsforICU-

relatedaspergillosisshouldundergoBALandserumgalactomannantesting.Apositivegalactomannanindexineithersamplepromptsforantifungaltherapy,coveringazole-resistantAspergillus,unlesstheisolatehasbeenprovensusceptible.

Recommendation16 ICUpatientswithclinicallyrelevantunexplainedchestradiologyabnormalitiesandriskfactorsforICU-relatedaspergillosiswhoarenot

Aspergillusculture-positiveshouldundergoserumandBALgalactomannantesting.Apositivegalactomannanindexineithersampleintheabsenceofotherexplanationspromptsforantifungaltherapy,coveringazole-resistantAspergillus.Patientswhohaveclinicallyimprovedafter2weeks,arestableandhaveunknownazoleresistancemaybesteppeddowntoazolemonotherapyunderstrictfollow-up.

Recommendation17 ICUpatientswithconfirmedinfluenzashouldundergosamplingforserumgalactomannan.ItisrecommendedthatICUpatientswithconfirmed

influenzaandradiologicabnormalitiesonchestX-rayshouldundergobronchoscopyandBALforgalactomannanandculture.Incaseoftracheobronchitis,apositiveserumgalactomannanorapositiveBALgalactomannan(index≥0.8),patientsshouldbetreatedwithcombinationazole+echinocandinorazole+L-AmBtherapy.MonotherapywithL-AmBisconsideredasasecondchoiceinthesepatients.IfculturesrevealnoAspergillusgrowth,galactomannan-positiveBALmaterialshouldbetestedbyPCRforthepresenceofCyp51mutations.ICUpatientswithinfluenzaandnegativeAspergillusserumandbronchoscopy/BALscreening,andnon-ICUinfluenzapatientsshouldundergo(repeat) serum and bronchoscopy/BAL diagnostics if new respiratory complications or clinical worsening occur, or if sputum/trachealAspergilluscolonizationculturesarepositive.

Recommendation18 SerumgalactomannanshouldnotbeusedtoscreenfororruleoutinvasiveaspergillosisinCGDpatients


Therapeuticdrugmonitoring(TDM)andoralstepdownRecommendation19 TDMisstronglyrecommendedforpatientsusingitraconazole.Forprophylaxis,troughlevelsof>1mg/l(itraconazole+

hydroxy-itraconazole)shouldbeachieved;fortherapy,troughlevelsshouldbe2to4mg/l.Fororaladministration,itraconazolesuspensionispreferredovertablets.

Recommendation20 TDMisrecommendedforpatientsusingvoriconazole.Troughlevelsshouldbe1.5-2to6mg/l.Concentrationsshouldbe

assessed2–3daysafterfirstadministration,andrepeatedduringtherapy,regardlessofpreviousconcentrations.Recommendation21 TDMshouldbeconsideredforpatientsusingposaconazoletabletsoriv.

Forpatientsusingposaconazolesuspension,TDMisrequired.Posaconazolesuspensionshouldonlybeusediftabletsarecontraindicated.Forprophylaxis,troughlevelsof>0.7mg/lshouldbeachieved;fortherapy,troughlevelsshouldbe>1mg/l.Concentrationsshouldbeassessed3daysafterfirstadministrationusingaloadingdose,andrepeatedduringtherapy.

Recommendation22 Pendingfurtherevidence,TDMshouldbeconsideredforpatientsusingisavuconazole.

Troughlevelsof2to4mg/lshouldbeachievedfortherapy.Usingaloadingdose,concentrationsshouldbeassessed3daysafterfirstadministration.

Recommendation23 Forchildren,TDMisstronglyrecommendedforallmould-activeazoles.Recommendation24 Patientsmaybesteppeddownfromanivtooralazole,providedthattheycantolerateoraltherapy,andwithTDMwhere

appropriate.

Streamlining,durationoftherapyandsecondaryprophylaxisforacuteinvasiveaspergillosisRecommendation25 Thedurationoftherapyforpatientswithacuteinvasivepulmonaryaspergillosisdependsontheclinicalcourseofthe

diseaseandtheevolutionofserumgalactomannanindexandCT-scanfindings.Durationoftherapyisatleast6to12weeksand,inneutropenicpatients,notlessthan2weeksafterresolutionofneutropenia.

Recommendation26 Secondaryprophylaxisisrecommendedafterrecentinvasiveaspergillosisinpatientsundergoingnewimmunosuppressive

treatment(e.g.,HSCT)orpatientswithaspecificprimaryimmunedeficiency(e.g.,CGD).Incaseofproven/probableaspergillosis,thesusceptibilitypatternshouldguidethechoiceofprophylaxis.Voriconazoleorposaconazoleareeligibleasoralprophylaxisforazole-susceptibleisolates,withappropriateTDM.

ImmunotherapyandsalvagetherapyforacuteinvasiveaspergillosisRecommendation27 TestingforIFN-γproductiondefectsbyareferencelabshouldbeconsidered,toguidethedecisiontostartrIFN-γ

immunotherapyinnon-neutropenicpatientswithinvasiveaspergillosiswithfulminantorrefractorydisease.AdjunctiveIFN-γtherapyshouldbeconsideredinallCGDpatients,andinotherpatientswithprovenorsuspectedTh1/Th17hostdefensepathwaydefectsandinvasiveaspergillosis.

Recommendation28 Onfailureofafirst-linetherapyfor(provenorsuspected)aspergillosis,thecauseofthefailureshouldbeinvestigated.In

particular,resistanceofAspergillusspeciesor(co)-infectionwithmucoralesshouldbetakenintoconsideration.Recommendation29 Onfailureofvoriconazoleorisavuconazole,thecommitteeconsidersittobeofprimaryimportancethatazoleresistanceand

aco-infectionwithmucoralesbeexcluded.Inviewofthisdifferentialdiagnosis,L-AmBisrecommended.Anechinocandinmaybeconsideredasthesecondchoiceifmucormycosishasbeenexcludedandthereisnoevidenceofcerebralaspergillosis.

Diagnostic-driven(preemptive)andempiricalantifungaltherapyinleukemia/HSCTpatientsRecommendation30 InneutropenicpatientswithhematologicalmalignanciesorHSCT,adiagnostic-drivenantifungalstrategyisrecommended,

basedonscreeningserumAspergillusgalactomannanatleasttwiceweekly.Recommendation31 InneutropenicpatientswithhematologicalmalignanciesorHSCTandapositiveserumAspergillusgalactomannanindex

(≥0.5)orpersistentunexplainedfever,anHRCTlungscanshouldbecarriedout.PreemptivetherapyagainstAspergillusshouldbegivenintheeventofxapositiveGM>0.5orfindingsconsistentwithinvasivefungalinfectionontheHRCTscan.

Recommendation32 Thecommitteerecommendstheuseofadiagnostic-drivenantifungalstrategyasopposedtosymptom-drivenempiric

strategy.Ifcircumstancesrequireanempiricstrategyinpatientswithpersistentfeverandneutropenia,L-AmBorcaspofunginmaybeused.

TherapyofotherformsofinvasiveaspergillosisRecommendation33 ForthetreatmentofinvasiveAspergillussinusitis,thecombinationofsurgeryandsystemicantifungaltherapyare

recommended,exceptforanon-invasivefungalball,whichcanberemovedsurgicallywithoutsystemicantifungals.Recommendation34 Forcerebralaspergillosis,combinationantifungaltherapywithvoriconazoleandL-AmBisrecommendedpending

confirmationofvoriconazolesusceptibility,and,iffeasible,surgicaldebridement.Recommendation35 UncomplicatedAspergillusotitisexternashouldbetreatedwithtopicalantifungalsorboricacid.Forinvasiveaspergillosis

oftheear,thecombinationofsurgeryandprolongedsystemicantifungaltherapyarerecommended.Recommendation36 Forchronicpulmonaryaspergillosis(CPA),prolongedazoletherapyisrecommended.Echinocandinsareanacceptable

alternativeifazolesarenotsuitable.Recommendation37 Surgicalresectionisrecommendedforbothsymptomaticsingleaspergillomawithbleeding.Inpatientsnoteligiblefor

surgicaltherapy,prolongedantifungaltherapyandbronchialarterialembolizationshouldbeconsideredincaseofbleeding.

Recommendation38 Forpatientswithcomplicatedcranialorpulmonaryaspergillosis,consultationwiththeNationalMycologyExpertise

Centershouldbeconsidered.


AntifungalprophylaxisininpatientswithhematologicalmalignanciesorHSCTRecommendation39 InpatientswithneutropeniafollowingchemotherapyforAML/MDSorHSCT,posaconazole(untilresolutionofthe

neutropenia,orduringtreatmentofsevereGVHD,andmonitoredbyTDMwhereappropriate)maybeconsideredforantifungalprophylaxis,dependingonthelocalincidenceofinvasivemycoses.

CandidiasisTreatmentofcandidemiaduetounidentifiedCandidaspeciesofunknownsusceptibilityRecommendation1 Foradultpatientswithcandidemiaorinvasivecandidiasis,anechinocandin(anidulafungin,caspofungin,ormicafungin)is

thepreferredinitialtherapy.Thisrecommendationappliestoallnon-neutropenicandneutropenicpatients,exceptthosewithCandidameningitis,endophthalmitis,orinvasiveurinarytractcandidiasis,andneonates.

Recommendation2 ForpatientswhohaveCandidaendophthalmitis,orinvasiveurinarytractcandidiasis,fluconazoleisrecommendedas

initialtherapy.Recommendation3 Afollow-upbloodculturesampleshouldbeobtaineddailyfrompatientswithcandidemia,untilnegative.Recommendation4 Initialechinocandintherapyshouldbecontinueduntilthepatienthasstabilized,regardlessofCandidaspecies.Recommendation5 Stablepatientsmaybesteppeddownfromanechinocandintofluconazoleafter≥5days,providedthatfollow-upblood

culturesduringtherapyarestillnegative,thepatientisclinicallyimproving,theisolatehasbeenconfirmedfluconazole-susceptible,andthepatienthasnoCandidaendocarditis,intravascularcandidiasis,unchangedvascularcatheters,orprosthesis-associatedcandidiasis.

TherapyofcandidemiawithidentifiedCandidaspeciesofknownsusceptibilityRecommendation6 ForCandidaalbicansorC.parapsilosiscandidemia/invasivecandidiasisinstabilizedpatients,step-downtofluconazoleis

preferredafterinitialechinocandintreatment,providedthatfollow-upbloodculturesduringtherapyarenegative,thepatientisclinicallyimproving,theisolatehasbeenconfirmedfluconazole-susceptible,andthepatienthasnoCandidaendocarditis,intravascularcandidiasis,unchangedvascularcatheters,orprosthesis-associatedcandidiasis.

Recommendation7 ForCandidakruseicandidemia/invasivecandidiasis,anechinocandin(anidulafungin,caspofungin,ormicafungin)is

preferred.VoriconazoleorL-AmBmaybeusedasanalternative.Recommendation8 ForCandidaglabratacandidemia/invasivecandidiasis,anechinocandin(anidulafungin,caspofungin,ormicafungin)is

preferred.L-AmBmaybeusedasanalternative.Recommendation9 Patientswithanuncomplicatedcandidemiashouldbetreatedfor14daysafterthelastpositivebloodculture.Treatment

ofacutedisseminatedcandidiasisdependsonclinicalandradiologicalfindings.Incaseofprovenmetastaticfoci,thedurationoftherapyisatleast4to8weeks.

Recommendation10 Inpatientswithcandidemia,allintravascularcatheters(central,peripheralandarterial)shouldberemovedorreplaced.

SecondarymetastaticfociincandidemiaRecommendation11 Fundoscopyshouldbeconsideredforpatientswithcandidemia,andisstronglyrecommendedforpatientswithsignsof

disseminatedinfection,ocularsymptoms,orpatientsunabletocommunicateaboutvisualsymptoms.Recommendation12 Asearchforintravascularandmetastaticfoci,usingophthalmoscopy,echocardiography(TEE)andFDGPET-CT,should

beconsideredforallpatientswithcandidemiawhohavepersistently(≥96h)positivebloodculturesduringtherapy,orsignsofdisseminatedcandidiasis,ocularsymptoms,orcardiacvalvedisease,avalveprosthesis,oranintravasculardevice,prosthesis,orthrombus.

Recommendation13 Forpatientswithchronicdisseminatedcandidiasis,prolongedtherapywitheitherL-AmBoranechinocandinis

recommended,followedbyfluconazoleorvoriconazole,untilradiographicresolutionofalllesions.Inpatientswithsignsofimmunereconstitutioninflammatorysyndrome(IRIS),corticosteroidsmaybeconsidered.

Recommendation14 Forpatientswithcomplicateddisseminatedcandidiasis,Candidameningitis,endocarditisorosteomyelitis,consultation

withtheNationalMycologyExpertiseCentershouldbeconsidered.

TreatmentofcandidemiaandacutedisseminatedcandidiasisinchildrenRecommendation15 Inneonates,treatmentofcandidemiaorinvasivecandidiasisshouldbetargetedatpotentialhematogenousCandida

meningoencephalitis.FluconazoleorL-AmBisthepreferredinitialtherapyforcandidemiaorinvasivecandidiasisinneonates.

Recommendation16 Fortreatmentofchildrenwithcandidemiaorinvasivecandidiasis,caspofunginormicafunginisthepreferredinitial

therapy.L-AmB,fluconazoleorvoriconazolearesecond-linealternatives.Recommendation17 ForchildrenwhohaveCandidameningitis,endophthalmitis,orinvasiveurinarytractcandidiasis,fluconazoleis

recommendedasinitialtherapy.Recommendation18 Recommendationsforchildrentostepdownfromechinocandintofluconazole,forcathetermanagement,treatment

duration,follow-up,andmanagementofcomplicationsaresimilartothoseforadults(sections3.1and3.2).


Empiricalorpre-emptivetherapyagainstinvasivecandidiasisRecommendation19 Thepredictivevalueofnonculturediagnostictestsisnotsufficientlyvalidatedforuseinthediagnosisofinvasive

candidiasis.Recommendation20 Theindicationofempiricaltherapyonsuspicionofcandidemiainnon-neutropenicpatientsiscontroversial.Empirical

therapymaybeconsideredinselectedindividualcases,suchaspatients>7daysintheICUandunexplainedsepsis,withacombinationofthefollowingfactors:(1)significantcolonizationwithCandidaand(2)clinicalriskfactors(e.g.,abdominalsurgery,anastomoticleakage,broadspectrumantibiotics,centralvenousline).

TreatmentofCandidaendophthalmitisandchorioretinitisRecommendation21 Candidachorioretinitisorendophthalmitisshouldbetreatedsystemicallywithanazole(fluconazoleorvoriconazolei.v.)in

caseofprovenorpresumedazolesusceptibility.Forprovenorpotentiallyazole-resistantcases,liposomalAmBcombinedwith5-FCisrecommended.Intheeventofinvasionintothevitreousbody,vitrectomyshouldbeperformedincombinationwithintravitrealvoriconazoleorc-AmB.Treatmentdurationisgenerallylengthyanddependsontheclinicalcourseoftheinfection.

TreatmentofcandiduriaRecommendation22 Inasymptomaticcandiduria,removalorreplacementofurinarycathetersmustbeconsidered.Thereisnoplacefor

antifungaltreatment,exceptinpatientswithsevereneutropenia,kidneytransplant,inlowbirthweightneonates,andpriortorenalsurgery.

Recommendation23 Symptomaticcandiduriaorinvasiverenalcandidiasisshouldbetreatedwithfluconazole(loadingdose800mg,followedby

400mgqdfor2-4weeks).Incaseoffluconazole-resistance,localirrigationwithc-AmBisasuitablealternativeforlowerurinarytractcandidiasis.Fungalballsorpersistentobstructionsrequiresurgicalintervention.

ManagementofabdominalcandidiasisRecommendation24 Forpatientswithinvasiveabdominalcandidiasis,anechinocandin(anidulafungin,caspofungin,ormicafungin)isthe

preferredinitialtherapy.L-AmBisanappropriatealternativeincaseofechinocandinresistance.Appropriatesourcecontrol,includingsurgicaldebridementanddrainageiscrucialintreatmentofabdominalcandidiasis.Thedurationoftreatmentdependsprimarilyonsurgicalandradiologicalresolutionofinfectedfoci.Stablepatientsmaybesteppeddownfromanechinocandintofluconazoleafter≥5days,providedthatallinfectedfocihavebeendrained,thepatientisclinicallyimproving,theisolatehasbeenconfirmedfluconazole-susceptible,andthepatienthasnovascularorprosthesis-associatedcandidiasis.

TreatmentofesophagealcandidiasisRecommendation25 Foresophagealcandidiasis,fluconazole(loadingdose400mg,followedby200mgqd)for2weeksisthepreferred

treatment.Incaseoffluconazoleresistance,voriconazole(basedonthesusceptibilityspectrum)iseligible,or,asasecondchoice,anechinocandin.

AntifungalprophylaxisRecommendation26 Prophylaxiswithfluconazoleinintensivecareisnotrecommended,exceptinspecificsituations,suchasrelaparotomy

followinganastomoticintestinalleakageinunitswithanunacceptablyhighlocalincidenceofinvasivecandidiasis.Recommendation27 Fluconazole(400mgqd)anti-CandidaprophylaxisisrecommendedforallogeneicHSCTrecipientsduringtheneutropenic

phasewhodonotreceiveanti-moldprophylaxis.Prolongedprophylaxisupto100daysposttransplantmaybeconsideredRecommendation28 Fluconazole(400mgqd)isonlyrecommendedforpatientsundergoinglivertransplantationwhohaveanelevatedriskof

invasivemycoses,i.e.,thosewithrenalinsufficiency,re-transplantation,choledochojejunostomy,perioperativemassivebloodtransfusion,orprovenperioperativecolonizationwithCandida.

Recommendation29 Inprematureneonateswithaverylowbirthweight,fluconazoleprophylaxis(3mg/kgtwiceweekly)shouldonlybe

consideredinsettingsinwhichthereisaprovenhighincidenceofinvasivecandidiasis.

CryptococcosisTreatmentofcryptococcalmeningitisRecommendation1 CryptococcalmeningitisshouldbetreatedwithL-AmB(3mg/kg/d)plus5-FC(100mg/kg/d)foratleast2weeks.

Thereafter,thetreatmentofstableandfavorablyrespondingpatientsmaybecontinuedwithfluconazole(loadingdose800mg,followedby400mgqd),foratotalofatleast10weeks,followedbychronicmaintenancetherapy.

Recommendation2 Forpatientswithcontraindicationsto5-FC,inductiontherapywithL-AmB(3mg/kg/d)plusfluconazole(400mgtwice

daily)foratleast2weeksisanacceptablesecondchoice.Recommendation3 AdjunctivetherapywithrIFN-γ(100µg)ondays1and3maybeconsideredforpatientswithcryptococcalmeningitis.In

patientswithaslowclinicalresponse,rIFN-γmaybecontinuedtwiceweekly.Recommendation4 ControlofCSFpressureisacriticaldeterminantofoutcome,andrepeatedtherapeuticlumbarpuncturesarerequiredfor

patientswithelevatedintracranialpressureorclinicaldeterioration.Recommendation5 Dexamethasoneadjunctivetherapyiscontraindicatedinpatientswithcryptococcalmeningitis.Recommendation6 IncART-naïveHIV-infectedinpatientswithcryptococcalmeningitis,theinitiationofcARTshouldbedeferreduntil5weeks

afterstartofantifungaltherapy.Recommendation7 InapparentlyimmunocompetentpatientswithC.gattiiinfectionauto-antibodiesagainstGM-CSFshouldbetested,to

guideinitiationofrGM-CSFimmunotherapy.


TreatmentofnonmeningealcryptococcosisRecommendation8 NonmeningealordisseminatedcryptococcosisshouldbetreatedwithL-AmB(3mg/kg/d)plus5-FC(100mg/kg/d)forat

least2weeks.Consolidationtherapyofstableandfavorablyrespondingpatientsshouldfollowwithfluconazole(loadingdose800mg,followedby400mgqd,for6to12months).

Recommendation9 Fluconazole(loadingdose800mg,followedby400mgqd,for6to12months)maybeareasonablealternativeforpatients

withmild,localized,nonmeningealinfection,andlesssevereimmunosuppression.Beforeconsideringthisoption,alumbarpunctureandbloodculturesarerequiredinallpatients,toruleoutcryptococcalmeningitis,disseminateddiseaseandcryptococcemia.

Recommendation10 AdjunctivetherapywithrIFN-γ(100µgtwiceweekly)maybeconsideredforallpatientswithseveremeningeal,pulmonary

ordisseminatedcryptococcosis,andforpatientsinwhomT-cellimmunitycannotberestoredbycARTorwithdrawalofimmunosuppressivetherapy.

SecondaryprophylaxisofcryptococcosisRecommendation11 Chronicmaintenancetherapywithfluconazole(200mgqd)isrequiredforpatientswhohavesufferedfrominvasive

cryptococcosisandcontinuetohaveanunderlyingimmunedefect.Insolidorgantransplantrecipients,maintenancetherapywithfluconazole(200-400mgqd)for6-12monthsisrecommended.

Recommendation12 Afteraminimumof1yearaftersuccessfultreatmentofcryptococcosis,chronicmaintenancetherapycanbediscontinued

insolidorgantransplantrecipients,andinHIV-positivepatientswithCD4counts≥100cells/µL,whohaveundetectableviralloadsoncARTfor>3months.

Mucormycosis

Recommendation1Directmicroscopyofclinicalspecimensfollowedbycultureisstronglyrecommendedforthediagnosisofmucormycosis.

Recommendation2 InvasivemucormycosisshouldbetreatedwithL-AmBinadosageofatleast5mg/kg/day.Recommendation3 Wherepossible,theantifungaltreatmentofinvasivemucormycosisshouldbecombinedwithsurgicaldebridementand

correctionofunderlyingriskfactors.Recommendation4 ForsalvagetreatmentofinvasivemucormycosisonfailureorintoleranceofL-AmB,posaconazoleorisavuconazolemaybe

considered.


Chapter2 InvasiveAspergillosisIntroduction

Aspergillosishasemergedasasevere invasive infection in immunocompromizedpatients. Invasiveaspergillosisgenerallyaffectsthelowerrespiratorytractorsinuses,andmaydisseminatehematogenously.Saprophytic,non-invasiveinvolvementincludespulmonaryaspergillomaandallergicbronchopulmonaryaspergillosis (ABPA). The lattermanifestation isbeyondthescopeoftheseguidelines.VariousclassesofantifungalagentsareactiveagainstAspergillusspecies.Ofthepolyenes,conventional amphotericin B deoxycholate (c-AMB) is the oldest antifungal drug. Themany side effects of c-AMB haveresultedinthedevelopmentofvariouslipidassociatedamphotericinB(LFAB)compounds,suchasliposomalamphotericinB (L-AmB) and amphotericin B lipid complex (ABLC). Of the azoles, itraconazole, voriconazole, isavuconazole andposaconazoleareactiveagainstAspergillus species.Theechinocandins (caspofungin,micafunginandanidulafungin)havefungistatic activity against Aspergillus species. In recent years, emerging resistance against azoles has become a majorprobleminEurope.Thishasledtoreconsiderationofoptimaltreatmentstrategiesinthecurrentguidelines.

2.1.DiagnosisandantifungalsusceptibilityDefinitionsTheEuropeanOrganization forResearchandTreatmentofCancer/InvasiveFungal InfectionsCooperativeGroup (EORTC)and the formerNational InstituteofAllergy and InfectiousDiseases (NIAID)Mycoses StudyGroup (Now:Mycoses StudyGroupEducationandResearchConsortium(MSGERC))havepublishedstandarddefinitionsforinvasivefungalinfectionsforclinicalandepidemiological research (1).TheseEORTC/MSGdefinitionshavebeenused inmajor trialsofantifungaldrugefficacy, in strategy trials, for the formulation of clinical practice guidelines, for validation of diagnostic tests, and forperformanceofepidemiologicstudies.Thedefinitionsassign3 levelsofprobability tothediagnosisof invasive fungal infection:proven,probable,andpossible.While proven infection requires microbiologic or histologic proof of infection, probable and possible invasive fungalinfectionshingeon3elements—namely,ahostfactorthatidentifiesthepatientsatrisk,clinicalandradiologicalsignsandsymptoms consistent with the disease, and mycological evidence including culture, microscopy or antigen detection.WhereastheEORTC/MSGdefinitionshavebeenprimarilydevelopedforclinicalstudies,theyareusedastodefinepatientpopulationsinthepresentguidelines.Diagnosisofinvasiveaspergillosis

While the EORTC/MSG definitions require a histopathologic diagnosis or a positive culture of a normally sterile site(excluding sputum or bronchoalveolar lavage (BAL)) to define proven invasive aspergillosis, this issue is challenging inclinicalpractice.Inthemajorityofpatients,adiagnosisofprobable invasiveaspergillosiswillbeestablishedbycombiningclinicalriskfactors(e.g.,immunosuppression,underlyingdisease)withclinicalandradiologicalsigns,andmycologicaldatasuchasapositiveculturefromanonsterilesite(e.g.,BAL)orantigendetection.In clinical practice, patients oftendonot fulfill the2008EORTC/MSGdefinitionof proven, probableor possible invasiveaspergillosis.Typicallytheseunclassifiablepatientsfulfillthehostaswellasthemicrobiologicalcriterionbutdonotfulfillthe radiological signs described in the EORTC/MSGdefinition (e.g. pulmonary infiltrate present but not awell-describednodulenoracavityorhalosign).PendingtheupdateoftheEORTC/MSGcriteriaaddressingthis issue,thesepatientsaretreatedinasimilarwayaspatientswhofulfilltheEORTC/MSGprobablecategory.Importantly, the diagnostic techniques described in this section have been predominantly validated in patients withhematologicalmalignancies. Inotherpatientsgroups,suchas ICUpatientsandnon-immunocompromizedhosts, thetestperformancemaybedifferent.ThosepatientsgroupsarespecificallydiscussedinChapter2.4.CultureandPCRCulture is critical for species identification and susceptibility testing. The taxonomy of Aspergillus species has changeddramatically in the past decademainly due to the use ofmolecular techniques for classification.Aspergillus fumigatus,previously classifiedon thebasisofmorphological characteristics, includesnowover55different species, referred toassiblingspecies.Identificationofthesesiblingspeciesoftenrequiressequencingofhouseholdgenessuchascalmodulinandbeta-tubulin. Species identification in the clinical microbiology laboratory is therefore a challenge, although automatedidentification by MALDITOF spectrometry is emerging as a useful tool. The Netherlands Society for Medical Mycology(NVMy)willprovideaTechnicalNoteonfungalcultureandsusceptibilitytesting(www.nvmy.nl).


NewsiblingspecieshavebeenidentifiedforotherAspergillusspeciesaswell, includingA.niger,A.flavus,A.terreus,etc.Whenphenotypicmethodsareusedforstrainidentificationoftentheterm‘speciescomplex’isaddedtohighlightthatthestrainmightbeoneofthesiblingspecies.TissueobtainedbyCT-guidedpercutaneouslungbiopsyfordirectstaining,PCRandculturehasahighdiagnosticyield(2).Incontrast,thesensitivityofAspergillusculturesfromrespiratorymaterialsislow,andanegativerespiratoryculturedoesnotexcludethediagnosisofinvasiveaspergillosis.ThespecificityofpositiveculturesfromrespiratorysamplesyieldingAspergillus islimited,asculturescannotdifferentiateinvasivediseasefromcolonization(3).Therefore,positiveculturesfromsputum,trachealaspirateorBALonlyconstituteaprobableinvasiveaspergillosiswhenfoundincombinationwithappropriateclinicalriskfactorsandclinicalorradiologicalsigns.ThesamelimitationappliestoapositiveAspergillusPCRfromrespiratorysamples.Inasystematicreviewof9studiesadherenttotheEORTC/MSGcriteria,thesensitivityofBALPCRwas62–88%,andthespecificity91to96%,resulting inapositive predictive value of 60–80% in the study populations (4). As PCR assays for Aspergillus have not yet beenstandardized,thecharacteristicsofvariousPCRassaysmayvary.SerumgalactomannanTheAspergillusgalactomannanserumantigentesthasbeenassociatedwithreasonablesensitivity(around70%)inchildrenand adults with hematological malignancies or HSCT, and the optimal cutoff has been set at ≥0.5 (5–8). In high-riskhematology patients (AML, MDS, HSCT) monitoring of serum galactomannan has been successfully used as part of adiagnostic driven (or pre-emptive) strategy, in combination with lung CT in galactomannan positive patients. Innonneutropenic patients, the sensitivity is substantially lower, and in solid organ transplant recipients or patients withchronic granulomatous disease (CGD), the galactomannan sensitivity is less than 20% (9,10). In patients receiving anti-Aspergillusprophylaxis,thesensitivityofserumgalactomannanwasreduced(11,12).However,thetestremainedusefulasdiagnostic tool in patients suspected of invasive fungal disease. False positive results have been reported due to thepresence of galactomannan in transfused blood products and certain antibiotics, e.g. piperacillin/tazobactam, althoughrecentstudiesindicatethatcurrentbatchesaregalactomannan-negative(13,14).The course of the serum galactomannan index has been found to be ameasure of response to therapy (5). In patientsenrolled ina largeprospective trial (15),aserumgalactomannan indexreductionof>35%betweenbaselineandweek1predictedaprobabilityof a favorable clinical response, andan increaseduring therapywas significantly associatedwithfailure(16).Twice-weekly galactomannan serumantigen screeninghasbeendemonstratedaneffective strategy to guidediagnostic-driventherapyinpatientshematologicalmalignanciesorHSCTatriskforinvasiveaspergillosis(11,17)(seechapter2.4).BALgalactomannanThe detection of galactomannan in BAL fluid has been shown to have a sensitivity of 70–92% in several studies,whichsignificantlyexceedsthesensitivityofcultures(50–58%)(18–21).TheoptimalthresholdforBALgalactomannanpositivityhasnotbeendetermined. Inananalysisof251consecutiveBALgalactomannantestsorderedforpatientsat risk,anODindex of ≥0.8 resulted in an optimal performance in diagnosing proven/probable invasive aspergillosis of 86.4%, and aspecificityof90.7%(20).InthepopulationtestedatLeuvenUniversityHospital,thepositivepredictivevaluewas81%andthenegativepredictivevalue93.6%at this cutoff.PatientswithanOD indexof>3.0allhadconfirmedproven/probableinvasiveaspergillosis(100%specificityandpositivepredictivevalueirrespectiveofthepretestprobability).Conversely,anODcutoffof<0.5ledtoasensitivityof93.2%,correspondingwithanegativepredictivevalueof92-97%inthepopulationtested(20).RadiologyInpatientswithhematologicalmalignanciesorHSCT,thevalueofradiologicimaginghasbeenwellestablished.High-resolution CT (HRCT) scan is more sensitive than chest radiograph to identify lesions of invasive aspergillosis.Combined screening by twice-weekly serum galactomannan and early HRCT scan in patients with positive serumgalactomannan results or feverwhile neutropenic led to early identification of invasive diagnosis and a shorter time todiagnosis(11,17,22).AhalosignasidentifiedonHRCTscanningisanearlysignofinvasiveaspergillosisandcanbeseenin61–92% of neutropenic patients. Early detection of a halo sign is associated with an improved prognosis (23,24). In aprospective study, vascular occlusion detected byCT angiographywasmore sensitive than standardHRCT evaluation inpatientswithhematologicalmalignancies(25).


Conclusions2.1.–Diagnosisofinvasiveaspergillosis(IA)inpatientswithhematologicalmalignancies

Conclusion1 Whereasnorandomizedstudiescomparingdiagnosticstrategieshavebeenperformed,determinationofserumAspergillusgalactomannan(cut-off,ODindex≥0.5)twiceweeklycanbeusedfortheearlydiagnosisofinvasiveaspergillosisinpatientswhoarenotonanti-moldprophylaxis.

Level1 Maertens,2005a(B);Maertens,2005b(B);Maertens,2007(A2);Steinbach,2007(A2),Morrissey,2013(A2);Duarte,2014(A2)

Conclusion2 ThesensitivityandspecificityofBALAspergillusgalactomannanforthediagnosisofIAexceedthoseofBALcultureandPCR.

Level1 Meersseman,2008(A2);Maertens,2009(A2);D'Haese,2012(A2)Conclusion3 Thecut-offforBALAspergillusgalactomannanforthediagnosisofIAhasnotbeenformallyestablished.AnOD

index≥0.8isassociatedwithanoptimalpredictivevalue.Level2 Guo,2010(A2),D'Haese,2012(A2)Conclusion4 ThecourseoftheAspergillusserumgalactomannanindexisameasureofresponsetotherapy.Level2 Maertens,2005(B);Chai,2012(A2)Conclusion5 HR-CTscanninghasanimportantroleintheearlydiscoveryofinvasivepulmonaryaspergillosis.Level1 Caillot,1997(B),Maertens,2005b,(B);Greene,2007(A2);Morrissey,2013(A2)Conclusion6 AhalosignonanHR-CTscanhasahighspecificityforthediagnosisofearlyinvasivepulmonaryfungalinfectionin

neutropenicpatients.Level2 Caillot,1997(B);Greene,2007(A2)RecommendationsMostdiagnosticstudieshavebeenperformedinpatientswithhematologicalmalignancies.Inotherpatientsgroups,suchas ICU patients and non-immunocompromized hosts, the test performancemay be different. For example, HR-CT scanfindings may be less specific in nonneutropenic patients, and the sensitivity of serum galactomannan in hematologypatientswithoutneutropenia(e.g.GVHD),solidorgantransplantrecipientsorpatientswithchronicCGD(seeChapter2.4)isverylow.As studies comparing the outcome benefits of various combinations of diagnostic strategies (e.g., HRCT, serumgalactomannanscreening)aresparse,thecommitteecannotmakeaformalevidence-basedrecommendationforaspecificscreening strategy. In addition, diagnostic strategies should be adapted to local policies, such as use of antifungalprophylaxis, which reduces the sensitivity of serum galactomannan. In the absence of antifungal prophylaxis, both BALgalactomannan index of <0.8 (20) and twice-weekly serum galactomannan screening (index <0.5) corresponded with anegativepredictivevalueof92-99%inthepopulationstested.Recommendation1 Forearlydiagnosis,determinationofserumAspergillusgalactomannanatleasttwiceweekly

shouldbeconsideredinneutropenicpatientswithhematologicalmalignancyorHSCT.Recommendation2 InneutropenicpatientswithhematologicalmalignancyorHSCT,andapositiveserum

Aspergillusgalactomannanindex(≥0.5)orpersistentunexplainedfever,anHR-CTlungscanshouldbeperformed,regardlessofchestradiographresults.

Recommendation3 Bronchoalveolarlavage(BAL)toobtainspecimensforbothcultureandgalactomannanantigen

assayshouldbeperformedinpatientswithsuspectedinvasivepulmonaryaspergillosisAntifungalsusceptibilityPrimaryantifungaldrugresistancemaybefoundinAspergillusspecies.A.terreusisintrinsicallyresistanttoamphotericinB,andazoletherapyisrecommended.Furthermore,siblingspeciesmightexhibitdifferentresistanceprofilescomparedwithothermembersof thespeciescomplex.For instanceA. tubingensis,which isasiblingspecieswithin theA.niger speciescomplex, is less susceptible to the triazoles compared with A. niger. As identification to the species level may not beavailableinclinicalmicrobiologylaboratories,invitrosusceptibilitytestingofclinicallyrelevantisolatesmayhelptoguideantifungaltherapyinindividualpatients.AcquiredtriazoleresistanceofA.fumigatushasbeenrapidlyrisingintheNetherlands,andhadincreasedto12.9%in2016,as reported from centers that screened unselected isolates, with local prevalences up to 35% in specific ICU andhematology departments in the Netherlands (26). Azole resistance has now been reported worldwide, in Europe, theMiddle East,Asia,Africa,Australia and,most recently,North and SouthAmerica (27). Forupdateson theprevalenceofazoleresistanceintheNetherlands,readersarereferredtotheyearlyNethMapreports(26).


Two routes of resistance development are distinguished: through long-term azole therapy in patients, and via theapplication of azole fungicides in the environment.While data from patients with aspergilloma or chronic aspergillosisindeedhaveconfirmedthatA.fumigatuscanundergomultiplegeneticchangesleadingtoazoleresistance(28),themainburdenof resistance is throughresistanceselection in theenvironment.Theuseofazole fungicides isassumedtobeanimportant factor in the selection of azole resistance in the environment, and patients are colonized by azole-resistantstrains outside the hospital, whichmay subsequently cause invasive disease once patients undergo immunomodulatingtherapies(28).Thisisinagreementwiththeobservationthattwo-thirdsofpatientswithresistantdiseasehavenoprevioushistoryofazoletherapy(29).Thus,environmentalresistanceischaracterizedbyalackofpatientriskfactors.Onlyresidencyinorvisitingofageographicareawithknownenvironmentalresistancecanbeconsideredarisk.MechanismsofazoleresistanceSurveillance studies in the Netherlands indicate that environmental mutations are responsible for over 80% of clinicalinfections with azole-resistant strains. Environmental azole resistance is caused by a limited number of resistancemechanisms associated with the Cyp51A-gene, including TR34/L98H, TR53, and TR46/Y121F/T289A (28). Mostenvironmentallyazole-resistantAspergillusisolatesareresistanttoallazoles.Hence,isolatestestedtoberesistanttooneazole should be considered pan-azole resistant, unless otherwise proven (30,31). In selected cases, an elevatedMIC toposaconazolemaystillbeamenabletohigh-doseposaconazoletherapyunderstrictTDM(trough>1.5mg/l)(28).PatientsmayhavemixedinfectionscausedbysusceptibleandresistantAspergillusstrains. In2015,azole-susceptibleandazole-resistantcoloniesinculturewerefoundin13of50patients(26%)withazole-resistantculturesfromthreecentersintheNetherlands(26,32).ScreeninganddetectionofresistanceControlled studies of the clinical implications of azole resistance have not been published, but case series havedemonstratedamortalityrateofazole-resistantinvasiveaspergillosisbetween50%and100%(33,34),whichishigherthanthemortalityrateof<30%inazole-susceptible infection.Therefore, it is importantto identifypatients infectedbyazole-resistantA.fumigatus,andtoadaptthechoiceofempiricaltherapytopotentialazole-resistantstrains.Detectionofresistancerequirescultureoftheinfectingstrains;however,Aspergillusculturesarenegativeinthemajorityofpatients.Evenwhenculturesarepositive,resistancemaybemissedduetoconcomitantpresenceofazole-susceptibleandazole-resistantcolonies.AsroutineMICtestingofmultipleA. fumigatus colonies isnot feasible,anagar-basedscreeningmethodhasbeendeveloped(30).GrowthofA.fumigatusonazole-containingagarishighlysuggestiveofresistance,andthesecoloniesshouldthenundergoMICtesting.Asthescreeningagarisnot100%sensitive,clinicallyrelevantisolatesmaybetestedforMICirrespectiveofscreeningresults.It is recommendedto test≥5separatecolonies ifpresent in theprimaryculture. IfMIC testing isnotavailable, selectedisolatesshouldbereferredtoareferencelaobratoryforMICtestingand/orsequence-basedanalysisofthecyp51Agene.For details, laboratories are referred to the NVMy Technical Note on fungal culture and susceptibility testing(www.nvmy.nl).Biomarkerssuchasgalactomannanareunabletodetectazoleresistance.However,anincreasinggalactomannanindexduringazoletherapymayindicatetreatmentfailure.Cyp51resistancePCRUnfortunately,Aspergillus culturesarenegative in themajorityofpatientswithan invasiveaspergillosis.Therefore,non-culturebasedmethodscouldhelpinthedetectionofinfectionswithanazoleresistantAspergillusfumigatusstrain.Bothin-houseandcommercialPCRshavebeendevelopedtodetectmarkersfortheTR34/L98HandTR46/Y121F/T289Aresistancemechanisms,intheabsenceofpositivecultures(27,35–37).In a recentmulticenter study such Cyp51 resistance PCRwas used on 202 BAL samples from hematology patientswithinvasive aspergillosis (34). In patientswith PCR-positive TR34/L98Hor TR46/ Y121F/T289A resistancemechanisms, azoletreatmentfailedin6of8patients,comparedto12of45patientswithoutthepresenceofresistance(P = 0.01).Mortalitywas2.7timeshigherinpatientswithresistance(50.0%versus18.6%;P = 0.07)(34).It shouldbenoted that thesePCRsdetectonly2ofat least15knownCyp51A resistancemutations. In theNetherlands,these2mutationpatternsarecurrentlybyfarthemostfrequentlyobservedmutations.Also,thesensitivityofthePCRisfarfromoptimal.Futurestudiesarethereforeneededtobetterdefinetheroleofthesenon-culturebasedresistancetests.Conclusions2.1.–Antifungalsusceptibility

Conclusion7 ResistanceofAspergillusspeciestoazoleantifungalshasbeenrapidlyrisingintheNetherlandsLevel1 SWABNethMap,2016(A1)Conclusion8 AzoleresistantAspergillusspeciesinazole-naïvepatientsoriginatefromenvironmentalsourcesLevel1 VanderLinden,2013(A2);Verweij,2015(A2)Conclusion9 PatientsmayhavemixedinfectionscausedbysusceptibleandresistantAspergillusstrains,requiringmultiple

coloniestobetestedforsusceptibilityLevel2 SWABNethMap,2016(A2);Kolwijck,2016(B);Schauwvlieghe,2017(C)


Conclusion10 AzoleresistantAspergillusspeciesisdiagnosedbyscreeningclinicalisolateson4-wellagarscreeningplates,followedbyMICand/orsequencing,orcyp51resistancegenePCRondirectmaterials

Level3 VanderLinden,2015(B);Verweij,2016(C)Conclusion11 Mostenvironmentallyazole-resistantAspergillusisolatesareresistanttoallazolesLevel3 VanderLinden,2015(B);Verweij,2016(C)Recommendation4 Forallpatientswithsuspectedinvasiveaspergillosis,maximaleffortsshouldbemadetoobtain

samplesformycologycultureandsusceptibilitytesting.1Recommendation5 Frompatientswithsuspectedinvasiveaspergillosis,clinicalisolatesshouldbetestedfor

antifungalsusceptibility.1

Recommendation6 ResistancetoazolesshouldbetestedbyMICor4-wellscreeningagarscreeningfollowedby

MICtesting.1

Recommendation7 Aspergillusisolatestestedtoberesistanttoonemould-activeazoleshouldbeconsideredpan-

azoleresistant,unlessotherwiseprovenRecommendation8 Incaseofnegativefungalculturesinpatientswithinvasiveaspergillosis,Cyp51PCRfor

resistance-associatedgenesonBALfluidisstronglyrecommended1See:TechnicalNoteonfungalcultureandsusceptibilitytesting(www.nvmy.nl)

2.2.TreatmentofacuteinvasivepulmonaryaspergillosiswithprovensusceptibilitytoazolesThepresentguidelineprovidesseparatetreatmentrecommendationsforisolateswithknownorwith(yet)unknownazolesusceptibility.The mortality associated with invasive aspergillosis remains substantial despite treatment, i.e., 28.5% in a recentpopulation-basedstudy(38).Thispromptsearlyinitiationofantifungaltherapyinpatientswithprobableorproveninvasiveaspergillosis. This chapter addresses treatmentprinciplesof azole-susceptible aspergillosis. Theapproach to aspergillosiswithunknownsusceptibilityisdiscussedinChapter2.3;empiricandpreemptivetherapyaredescribedinchapter2.5.To select appropriate therapy, infection due to Aspergillus species should be distinguished from other molds (e.g.,mucormycosis, see chapter 5), as voriconazole is not active againstmucorales. Thus, a specificmicrobiological diagnosisfollowedbyin-vitrosusceptibilitytestingiscriticaltoguidingtherapy(seechapter2.1).Intheabsenceofpositivemycologycultures, Cyp51 PCR for the TR34/L98H and TR46/Y121F/T289A resistance-associated genes on BAL fluid is stronglyrecommended. The TR34/L98H and TR46/Y121F/T289Amutations are themost prevalent resistancemechanisms in theNetherlands,accountingfor>80%ofresistantisolates.Therefore,culture-negativeinvasiveaspergillosiscaseswithawild-type for these genes in the Cyp51 resistance PCR are considered to have a low risk of bearing azole-resistance. Thecommittee considers these patients eligible for treatment with regimens as recommended for cases with provensusceptibilitytoazoles,asdescribedinthischapter.TreatmentofacuteinvasiveaspergillosiswithprovensusceptibilitytoazolesImportantly, all randomized studies of invasive aspergillosis have been conducted before the emergence of azoleresistance,andtheresultsshouldbeviewedinthelightofcurrentresistanceepidemiologyintheNetherlands.Therefore,theconclusionsandrecommendationsinthisparagrapharelimitedtopatientswithanA.fumigatusisolatethathasbeenculturedandhasconfirmedsusceptibilitytoazoles.VoriconazoleIn a pivotal randomized study (15), voriconazolewas superior to c-AmB (1.0-1.5mg/kg/d) for the treatment of invasiveaspergillosis. Voriconazole success ratewas 53% vs. 32%with c-AmB, 12-weeks survivalwas 71% vs. 58% (p=0.02) (15).Recently,subjectsenteredintothistrialwererecategorizedaccordingtothe2008EORTC/MSGcriteria,includingbaselineserumgalactomannanlevelsobtainedfromfrozensamples(39).Overallvoriconazolesuccessratewas55%vs.30%withc-AmB(p<0.0001).Survivalinprobable/provenaspergillosiscaseswas70%withvoriconazoleand55%withAmB(p=0.01).Inpatientsclassifiedaspossible invasiveaspergillosis,successrateswithvoriconazolewerealsosignificantlyhigher(66%vs39%, p<0.02) (39). This suggests that patients classified as possible invasive aspergillosis in that study actually did haveaspergillosisandrequiredantifungaltherapy.ThisalsosupportsthemorerecentrecommendationsthatBALforcultureandgalactomannantesting is strongly recommendedtodiagnose invasiveaspergillosis in thispatientgroup,especially in thecurrentsettingwithazole-resistantaspergillosis.


IsavuconazoleIn a recent randomized trial, voriconazole was compared with isavuconazole (40). All-cause mortality was 19% withisavuconazolevs.20%withvoriconazole(difference-1%,95%CI–8to6).Thus,thetrialshowednoninferiorityintermsofclinical efficacy in patientswith possible, probable, and proven invasivemold infections. Therewere fewer drug-relatedadverse effects in patientswith isavuconazole (42%) thanwith voriconazole (60%; p<0·001). Specifically, isavuconazole-treatedpatientshadfewerhepaticdisorders(9%vs.16%;p=0·016),ocularadverseevents(15%vs.27%;p=0·002),andskinadverseevents (33%vs. 42%;p=0·037).While interactionsof isavuconazolewith substratesand inducersof theCYP3A4enzyme do occur, current data suggest that these are less severe than with voriconazole. Based on these data,isavuconazolehasbeenapprovedforfirst-linetherapyofinvasiveaspergillosis.OtherazolesItraconazoleandposaconazolehavenotbeenstudiedasprimarytherapyforinvasiveaspergillosisinrandomizedtrials.Theefficacy of itraconazole has not been well established, and its use is limited by its poor bioavailability and restrictedavailabilityofthe i.v. formulation.Likewise,thebioavailabilityofposaconazoleassuspensionhasbeenvariable.Thenewdelayed-release tablet formulation has improved bioavailability and is dosed once daily, as is the new intravenousformulation inβ-cyclodextrin (41).Pendingdata fromprimary treatment trials,posaconazole is consideredanoption forpatientswhodonottoleratevoriconazoleorisavuconazole.AmphotericinBBased on the significantly greater mortality and lower success rates associated with c-AmB in the randomized trialcomparedtovoriconazole(15),c-AmBisnotconsideredappropriatetherapyforinvasiveaspergillosis.LiposomalAmB (L-AmB) has not been compared to voriconazole or c-AmB in randomized trials. In a large retrospectivecohort study on 289 patients fulfilling EORTC/MSG criteria in France, survival associatedwith L-AmB initial therapywas47%, vs. 69% with voriconazole (p<0.02) (42). In a randomized double-blind study of L-AmB at 3 mg/kg/d (L-AmB3)comparedwith10mg/kg/d(L-AmB10),therewasnodifferenceinresponse(L-AmB3,50%vs.L-AmB10,46%;p>0.05)andnodifferenceinsurvivalat12weeks(72%vs.59%;p=0.09)(43).Retrospectively,subjectsenteredintothistrialhavebeenrecategorizedaccordingtothe2008EORTC/MSGcriteria.Survivalat12weeksforprobable/provencaseswas58%withL-AmB3, vs. 50%with L-AmB10 (44).Greater toxicitywasobserved in the10mg/kg/dgroup, specificallynephrotoxicity (L-AmB314%vs.LAmB1031%;p<0.01)(43).AmB lipid complex (ABLC) has not been studied in randomized trials for invasive aspergillosis, and published data aremerelyobservational(45).AretrospectivecaseseriesonlimitednumbersofpatientswithEORTC/MSGproven/probableinvasiveaspergillosishassuggestedoutcomessimilartothosewithL-AmB,butahigherrateofnephrotoxicity(21%vs.3%,P<0.01)(46).Inaretrospectivecohortstudy,frequencyofseverenephrotoxicitywas11.5%forc-AmB,7.2%forABLC,and2.4%forL-AmB(P<0.05)(47).Inamultivariateanalysis,L-AmB,butnotABLC,wassuggestedtobeaprotectivefactorformortality(ORvsc-AmB,P=0.047)(47).EchinocandinsAll three echinocandins (caspofungin, anidulafungin, micafungin) have fungistatic activity against Aspergillus species.Caspofunginandmicafunginhavebeenapproved for salvage treatmentof invasiveaspergillosisbasedoncohort studies(48–50). Subsequent small trials on primary treatment with caspofungin have yielded less favorable outcomes. In aprospective, nonrandomized EORTC trial including 61 hematology patients with EORTC/MSG probable/proven invasiveaspergillosis,successratewithcaspofunginwas33%,and12-weekmortalitywas47%(51).InthecompanionEORTCstudyincluding 24 allogeneic HSCT recipients, success rate was 43%, and mortality 50% (52). Based on these limited data,echinocandinmonotherapyisnotrecommendedasprimarytreatmentforinvasiveaspergillosis.CombinationtherapyCombinationtherapyofanazolewithanechinocandinofinvasiveaspergillosishasinitiallybeensupportedbyhistoricallycontrolledcohorts,suggestingasurvivalbenefitinprimaryorsalvagetherapy(53–55).Arecentrandomizedtrialcomparedoutcomesofvoriconazolemonotherapy tocombination therapywithvoriconazoleandanidulafungin, in454hematologypatients with EORTC/ MSG probable/proven invasive aspergillosis (56). Mortality (6 weeks) was 20% forvoriconazole+anidulafungin vs. 28% for voriconazole monotherapy (p=0.087; 95%CI, -19 to 1.5). Thus, the primarysuperiorityendpointwasnotmet.Inapost-hocexploratoryanalysisofthelargestsubgroupof218patientswithpositiveserumgalactomannan(EORTC/MSGprobableaspergillosis),mortalitywas16%forvoriconazole+anidulafunginvs.28%forvoriconazole(p<0.05;95%CI,-23to-0.4). Itshouldbenotedthatthecombinationtherapystudyrandomizedpatientsforinitial combination therapyvs.monotherapy, regardlessof severityof illness (56).Thus, there isno informationwhetherlateradditionofcombinationtherapyindeterioratingpatientswouldbeassociatedwithsimilaroutcomes.PrimarytherapyofinvasiveaspergillosiswithprovensusceptibilitytoazolesinchildrenThe majority of studies on treatment of invasive aspergillosis have been conducted in adults or children >12 years.Therefore,treatmentrecommendationsforchildrenarebasedonefficacydataderivedfromadultstudiesincombination


withpharmacokineticandsafetydata inchildren,aswellas supportivepediatricclinicaldata.Thepharmacokineticsanddosing regimens of various antifungals differ substantially in children. Specific dosing recommendations for children aregiveninthenationalChildren’sFormulary,basedonthefollowingobservations.Voriconazole pharmacokinetics are substantially different in children. In a pooled data analysis of 138 immuno-compromizedchildrenandadolescents,aloadingdoseof9mg/kgbid,followedby8mg/kgbidmaintenanceledtosimilarAUCs as did 4 mg/kg bid iv or 200mg bid orally in adults (57). In adolescents <50 kg, body weight-based dosing wasrequiredtoachieveappropriateAUC,whileadolescents>50kgcouldbedosedasadults.Anothercohortstudyreportedsimilarresults,andfoundthatbioavailabilityoforalvoriconazolewaslowerinchildrenthaninadults(approximately60%vs.95%),requiringdedicateddosingandTDMafteriv-to-oralswitch(58).For posaconazole and isavuconazole, no dose regimens have been formally established for children yet. In mycologyexpertisecenters,experiencewithdosingforchildrenhasbeenobtained,basedonTDM.Treatmentofchildrenwiththesedrugsisnotrecommended,unlessafterconsultationwithanexpertcenter.Caspofunginataweight-basedloadingdoseof70mg/m2,followedby50mg/m2maintenance(maximum70mg/d)in39childrenandadolescentsledtoasimilarexposureasthatinadultshadafterstandarddosinginaprospectivestudy(59).Micafunginwasfoundtohaveanonlinearrelationshiptobodyweightinapopulationpharmacokineticsstudyinchildrenaged2–17years(60).Forchildren<40kg,adoseof2-4mg/kg(maximum100mg/d)wasestablished(60).Inaprospectivestudyofanidulafungininneutropenicpediatricpatientsaged2–17years,aloadingdoseof3mg/kgandamaintenanceof1.5mg/kg/dwerefoundtobeequivalenttoamaintenanceof100mg/dinadults(61).However,anidulafunginisnotlicensedforuseinchildren,anditsuseisnotrecommended.

Conclusions2.2–First-linetherapyforacuteinvasiveaspergillosiswithprovenvoriconazolesusceptibility

Conclusion12 Voriconazoleissuperiortoc-AmBinthetreatmentofinvasiveaspergillosis.Level2 Herbrecht,2002(A2);Herbrecht,2015(B);Nivoix,2008(B);Lortholary,2011(B),Perkhofer,2010(B)Conclusion13 Isavuconazoleisaseffectiveasvoriconazoleinthetreatmentofinvasiveaspergillosisandassociatedwithfewer

sideeffectsbutissubstantiallymoreexpensiveLevel2 Maertens,2016(A2)Conclusion14 Combinationtherapywithvoriconazoleandanidulafunginwassuggestedtobeassociatedwithlowermortality

ratesingalactomannanpositivepatientswithinvasiveaspergillosiscomparedtovoriconazolemonotherapyinapost-hocanalysis

Level2 Marr,2015(A2);Singh,2006(B)Conclusion15 L-AmBatadoseof3mg/kg/disaseffectiveasL-AmBat10mg/kg/dinthetreatmentofinvasiveaspergillosis,and

isassociatedwithfewersideeffectsLevel2 Cornely,2005(A2);Cornely,2011(B)Conclusion16 Caspofungintherapyofinvasiveaspergillosisleadstolowersuccessratesthanthosethathavebeenachievedwith

voriconazoleLevel2 Viscoli,2009(B);Herbrecht,2010(B)Conclusion17 Therapyofinvasiveaspergillosiswithvoriconazoleorwithvoriconazoleplusechinocandinisassociatedwithhigher

survivalratesthanprimarytherapywithL-AmBorcaspofunginLevel2 Herbrecht,2002(A2);Herbrecht,2015(B);Nivoix,2008(B);Lortholary,2011(B),Perkhofer,2010(B);Viscoli,2009

(B);Herbrecht,2010(B)

Conclusion18 Treatmentofinvasiveaspergillosisinchildreniscomparabletothatinadults.However,pharmacokineticsofazolesandechinocandinsdifferssubstantiallyfromthoseinadultsandrequirededicateddosingregimens.Isavuconazoleandanidulafunginhavenotbeenlicensedforuseinchildren.

Level3 Walsh,2005(C),Benjamin,2006(C);Hope,2007(C);Walsh,2010(C);Friberg,2012(C)Conclusion19 IntheabsenceofanAspergillusisolatesuitableforsusceptibilitytesting,thecommitteeconsidersawild-typeresult

oftheCyp51resistancePCRonBALmaterialasareasonablesurrogatemarkerforazole-susceptibilityLevel4 ExpertopinionRecommendationsFor the primary treatment of invasive aspergillosis with confirmed susceptibility to azoles, the committee considersvoriconazoleandisavuconazoleequallyeffective.Thesafetybenefitofisavuconazoleassuggestedbythecomparativetrial(40)anditsbetterpredictablepharmacokinetics(62,63)maycounterbalancethelimitedclinicalexperiencewiththedruginthecomingyears.Initialazole-echinocandincombinationtherapyforpatientswithpresumablymostlyazole-susceptiblestrainsdidnotmeettheprimary superiority endpoint in a recent comparative trial (mortality 20%, vs. 28% for azolemonotherapy (p=0.087)(56).InasecondaryanalysisofpatientswithEORTC/MSGprobableaspergillosisbasedonserumgalactomannanpositivity,mortalitywas significantly reduced in the combinationarm (16%vs.28%,p<0.05).While these subgroupdata suggestasurvivalbenefitwithprimarycombinationtherapyinpatientswithserumgalactomannan-positiveinvasiveaspergillosis,no


definite conclusions can be drawn from this post-hoc analysis. Based on these findings, the committee does notrecommendinitialazole+echinocandincombinationasafirstchoicetherapyforpatientswithconfirmedazole-susceptibleisolates.There is accumulatingevidence that the individual variations in thepharmacokineticsof voriconazole,posaconazoleanditraconazolehaveamajorinfluenceontreatmentoutcome.Recommendationsontherapeuticdrugmonitoring(TDM)areprovidedinchapter2.5.Likewise,TDMshouldbeconsideredforisavuconazole,pendingmoredata.Recommendation9 Primarytreatmentwithvoriconazoleorisavuconazoleisrecommendedforpatientswithacute

invasiveaspergillosiscausedbyisolateswithconfirmedsusceptibilitytoazoles.Recommendation10 Thecommitteerecommendsagainsttheuseofitraconazoleorc-AmBforprimarytreatmentof

invasiveaspergillosisRecommendation11 Incaseofcontraindicationstovoriconazoleorisavuconazole,L-AmB(3mg/kg/d)or

posaconazolearesuitablealternativesforpatientswithacuteinvasiveaspergillosiswithconfirmedsusceptibilitytoazoles.

ForrecommendeddrugsandstandarddosesfortreatmentofinvasiveaspergillosisseeTable2.1

2.3.Treatmentofacuteinvasivepulmonaryaspergillosiswithresistanceorunknownsusceptibilitytoazoles While no specific randomized studies have been conducted among patients with invasive aspergillosis due to azole-resistantAspergillusspecies,caseserieshavereportedamortalityratebetween50%and100%forazole-resistantinvasiveaspergillosis(33,34).Asofthereleaseofthepresentguidelines,resistanceofAspergillusspeciestoazoleantifungalshadincreased to 12.9% in the Netherlands, with local prevalences up to 35% in specific ICU and hematology departments.UpdatesontheprevalenceofazoleresistancecanbefoundintheyearlyNethMapreports(26).As expected resistance rates now generally are >10%, treatment of patients with (suspected or proven) invasiveaspergillosisofunknownsusceptibilityshouldincludecoverageforazole-resistantstrains(28).UnknownazolesusceptibilityCohort studies have suggested an approximately 15% improved survival at 12weekswith voriconazole or voriconazole-echinocandin combination treatment, compared with other intravenous therapies such as L-AmB or echinocandinmonotherapy(15,42,44,51,52,64–66).Basedonthesedata,modelingsuggeststhatcombinationtherapywithvoriconazoleandeitheranechinocandinorL-AmBisassociatedwithhighestsurvivalratesinpatientswithunknownazolesusceptibility,combiningthesuperiorefficacyofvoriconazoleagainstsusceptibleisolateswithasecondagentactiveagainstvoriconazole-resistant strains. In viewof the recent trial comparing voriconazolemonotherapy to voriconazole plus anidulafungin forazole-susceptibleisolates(56),combinationofvoriconazolewithanechinocandinisareasonablechoiceforpatientswithunknown azole susceptibility (28).No published outcomedata are available on the combination of voriconazolewith L-AmB. Assuming that the combination causes no clinically relevant antagonism or synergism, modeling suggests similarbenefitsasthosewiththevoriconazole-echinocandincombinationinsettingswith>5%voriconazoleresistance.Thevoriconazole-echinocandinandvoriconazole-L-AmBcombinationsareexpected tobeequally effectiveatprevalencerates for azole resistance of 5 to 50%.With very high (≥50%) resistance rates, the voriconazole-L-AmB combination isexpectedtobemoreeffective,inviewofthelimitedeffectivenessofechinocandinsmonotherapy.Monotherapy with L-AmB would be an acceptable alternative, although less effective than an azole in the majority ofpatientswhowillstillbeinfectedbyazole-susceptiblestrains.Therefore,expectedsurvivalrateswithL-AmBmonotherapyinasettingwith5%to50%azoleresistancearepredictedtobelessfavorablethanwitheithercombinationtherapy.Caspo-funginmonotherapyisexpectedtobeassociatedwithahighermortalitycomparedtoazole-echinocandincombinationorL-AmBmonotherapy,inviewofthelessfavorableoutcomesofthetwoprospectivecaspofunginstudies(51,52).


Conclusions2.3–First-linetherapyforaspergillosiswithunknownsusceptibilitytovoriconazoleorisavuconazole

Conclusion20 Basedonmodeling,anantifungalcombinationregimencontainingvoriconazoleandeitherL-AmBoranechinocandinisassociatedwiththelowestmortalityratesinasettingwith5–50%prevalenceofazoleresistantAspergillus

Level4 (D)Conclusion21 Insettingswith>50%azoleresistance,acombinationofvoriconazolewithL-AmBisassociatedwithlowerexpected

mortalitythanechinocandinmonotherapyorvoriconazoleplusechinocandincombinationtherapyLevel4 (D)RecommendationsGiven the high prevalence of azole-resistance in the Netherlands, maximum efforts should be made to obtain clinicalspecimenstoperforminvitrosusceptibilitytestingfromallpatientswithsuspectedinvasiveaspergillosis(seechapter2.1).Direct detection of resistance mutations by PCR on clinical specimens may help the identification of resistance in themycologyreferencelaboratory.In view of the high mortality rates associated with invasive aspergillosis, the committee recommends that azolemonotherapy should not be prescribed as standard therapy in patients with proven, probable or possible invasiveaspergillosisofunknownazoleresistance.Themajorityofthesepatientswillstillbeinfectedbyavoriconazole-susceptibleAspergillusstrain.Therefore,combinationregimens combining voriconazolewith a non-azole antifungal (L-AmBor echinocandin)will retain the efficacy benefit inthosepatientswithazole-susceptibleisolates,whilecoveringazole-resistantstrainsbythecompaniondrug.Basedonthismodeling, the committee favors an azole-echinocandin or azole-L-AmB combination for cases with unknown azolesusceptibility.Thechoicebetweenazole-echinocandinorazole-L-AmBcombinationtherapymaybeindividualized,e.g.,apreferenceforazole-echinocandinincaseofpotentialrenaltoxicity,forazole-L-AmBinsettingswithahigherthanaverageprevalenceofazoleresistance,orifmixedinfectionscausedbyazole-susceptibleandazole-resistantisolatesarepresent,orforsuspectedmucormycosis(e.g.,reversedhalosign,negativegalactomannaninBAL).ForhematologypatientsinsettingswhereBALisperformedforresistancegenePCR,thecommitteeconsidersinitialazolemonotherapyareasonablealternativeforthefirstfewdays,pendingsusceptibilitytestingorresistancegenePCRresults.Susceptibility or PCR results should subsequently guide escalation to L-AmB in case of resistance detection, and tocombinationtherapyifsusceptibilityresultsareunavailable.InviewofthehighermortalityrateamongICUpatientswithinvasive aspergillosis, the committee recommends that those patients receive initial combination therapy, even whenresistancegenePCRresultsarepending.Inaddition,closeclinicalfollow-up,withtherapeuticdrugmonitoring(TDM),sequentialgalactomannanassays,andimagingtomonitorprogress,isrequiredforpatientsinfectedbystrainsofunknownsusceptibility.Recommendation12 Forpatientswithinvasiveaspergillosiscausedbyisolateswithunknownsusceptibilityto

azoles,initialcombinationtherapywithvoriconazole/isavuconazoleplusL-AmB,orvoriconazole/isavuconazoleplusanechinocandinisrecommended.MonotherapywithL-AmBisconsideredasasecondchoiceinthesepatients.Incaseofmixedazole-resistantandazole-susceptiblemoldinfections,orsuspectedco-infectionwithmucorales,voriconazole/isavuconazoleplusL-AmBisrecommended.

Recommendation13 IfsusceptibilityorBALCyp51resistancePCRresultsareexpectedshortly,initialmonotherapy

withvoriconazolemaybeprescribedtopatientswithinvasiveaspergillosisofunknownazolesusceptibility.SubsequentPCRresultsshouldguideescalationtoL-AmBincaseofresistance,andtocombinationtherapyifsusceptibilityresultsareunavailable.SeverelyillpatientsandpatientsintheICUshouldreceiveinitialcombinationtherapypendingsusceptibilityresults.

ProvenazoleresistanceIn patients infected by isolates that underwent susceptibility testing and were confirmed to be resistant to all azoles,including voriconazole, or patients with positive Cyp51 resistance PCR results, treatment with combination therapycontainingvoriconazoleis irrational. Inthesecases,L-AmBmonotherapyisassociatedwithhigherexpectedsurvivalratesthanechinocandinmonotherapy(42,44,51,52,64–66),andechinocandinsarenotrecommendedasprimarytreatmentforinvasiveaspergillosis.ABLChasnotbeenstudied inrandomizedtrials for invasiveaspergillosis,andpublishedobservationaldataareequivocalabout both its relative effectiveness and its safety compared to L-AmB. Therefore, the committee does not make anyrecommendationsfortheuseofABLC.


Inexceptionalsituations,andonlyiftheposaconazoleMIChasbeendocumentedtobe<2,astepdownfromL-AmBtoposaconazoleincombinationmaybeconsidered,providedthattherapeuticdrugmonitoringisperformedtomaintainhighserumlevels.Consultationwithanexpertcenterbeforeastep-downtoposaconazoleisrequired.Recommendation14 Forpatientswithinvasiveaspergillosiscausedbyisolateswithconfirmedresistancetoazoles,

L-AmBisrecommended.Echinocandinmonotherapyisrecommendedasasecondchoiceinthesepatients.

Table2.1.Recommendeddrugandstandardadultdosefortreatmentofinvasiveaspergillosis†

A.Therapyforisolateswithunknownsusceptibilitytoazoles Antifungalagent Loadingdose Maintenancedose

1stchoice*Azole+Echinocandincombination:VoriconazoleORIsavuconazoleANDCaspofunginORMicafunginORAnidulafunginORAzole+L-AmBcombination:VoriconazoleORIsavuconazoleANDL-AmB

bid6mg/kgivorbid400mgpotid200mgivorpoondays1+270mg-200mgbid6mg/kgivorbid400mgpotid200mgivorpoondays1+2-

4mg/kgbidiv#or200-300mgbidpo#200mgqdivorpo50mgqd,(>80kg:70mgqd)100mgqd100mgqd4mg/kgbidiv#or200-300mgbidpo#200mgqdivorpo3mg/kg/d

2ndchoice*LiposomalAmB - 3mg/kg/d3rdchoice*Caspofungin 70mg 50mgqd,(>80kg:70mgqd)Micafungin - 100mgqdAnidulafungin 200mg 100mgqd

B.Therapyforisolateswithconfirmedsusceptibilitytoazoles Antifungalagent Loadingdose Maintenancedose

1stchoice*Voriconazole bid6mg/kgivorbid400mgpo 4mg/kgbidiv#or200mgbidpo#Isavuconazole tid200mgivorpoondays1+2 200mgqdivorpo 2ndchoice*LiposomalAmB - 3mg/kg/d3rdchoice*Voriconazole+Echinocandincombination:VoriconazoleANDCaspofunginORMicafunginORAnidulafungin

bid6mg/kgivorbid400mgpo70mg-200mg

4mg/kgbidiv#or200-300mgbidpo#50mgqd,(>80kg:70mgqd)100mgqd100mgqd

C.Therapyforisolateswithconfirmedresistancetoazoles Antifungalagent Loadingdose Maintenancedose

1stchoice*LiposomalAmB - 3mg/kg/d2ndchoice*Caspofungin 70mg 50mgqd,(>80kg:70mgqd)Micafungin - 100mgqdAnidulafungin 200mg 100mgqd

*Forspecificrecommendations,exceptions,andcontra-indications,seetext.†Thedosagesinthistablearespecificforinvasiveaspergillosis;forothermycoses,differentdosagesmayapply.#Individualdosebasedontherapeuticdrugmonitoring


2.4.Invasiveaspergillosisinspecialpopulations

AspergillosisinICUpatientsInvasive aspergillosis has been increasingly diagnosed in patients in the intensive care unit without traditional riskfactors.InretrospectiveanalysesinEuropeandtheUSA,corticosteroiduseeitherbeforeorduringICUadmission,COPDorotherstructurallungdiseases,sepsisandpost-sepsisimmunoparalysis,andH1N1influenzawereidentifiedasthemajorriskfactors(67–69).The2008EORTC/MSGcriteriaperformpoorlyinICUpatientswithoutclassicalriskfactors(1,70).In ICU patients with respiratory samples growing Aspergillus species, discrimination between colonization and invasiveaspergillosisisdifficult,whilelungbiopsytodemonstrateinvasiveinfectionisfrequentlycontraindicated.Inacaseseriesof172culture-positiveICUpatients,52%hadconfirmedcolonizationwithoutinfection,10%hadhistologicallyproveninvasiveaspergillosis,and38%hadprobableaspergillosisbasedonICU-specificriskfactorsandradiology(71).ArecentinternationalprospectivestudyinEuropeamong563ICUpatientsfoundthat47%werecolonized,17%hadprovenand36%hadputativeinvasiveaspergillosis(72).In a prospective ICU study, the sensitivity of serum galactomannan was limited to 42% in ICU patients with invasiveaspergillosis(18).GalactomannaninBALfluidhadaspecificityof87%andsensitivityof88%whichsignificantlyexceedsthesensitivityofcultures(58%)(seeChapter2.1)(18).Basedonthesedata,itisrecommendedthatICUpatientswithclinicallyrelevantunexplainedchestradiologyabnormalitieswho have a positiveAspergillus colonization culture in respiratory samples and risk factors for ICU-related aspergillosis(corticosteroids,COPD, sepsis,or classical EORTC/MSG risk factors foraspergillosis) are tested for serumgalactomannanand undergo BAL for galactomannan (70). A positive galactomannan index in either sample indicates probable invasiveaspergillosis. Likewise, ICU patients with unexplained chest radiology abnormalities and risk factors for ICU-relatedaspergillosiswhoarenotAspergillusculturepositiveshouldundergoserumandBALgalactomannantesting.ApositiveBALgalactomannan (specificity 87%) should prompt for antifungal therapy, if false-positivity and alternative etiology areconsideredunlikely.Influenza-relatedinvasiveaspergillosisisdiscussedseparatelyinthenextparagraph.In viewof the severityof illnessofpatientsadmitted to the ICU, it is recommended that initial therapy for ICUpatientscovers azole-resistant Aspergillus isolates, until susceptibility has been confirmed. For specific treatment choices, seeChapter 2.3 and Table 2.1. Patients who have clinically improved after 2 weeks, are stable and have unknown azole-resistancemaybesteppeddowntoazolemonotherapyunderstrictfollow-up.AspergillosisinpatientswithinfluenzaRecently,highratesofsecondaryinvasivepulmonaryaspergillosiscomplicatinginfluenzapneumoniahavebeenreported,inapparentlyimmunocompetentpatients(73–75).AcaseseriesfromBelgiumincluded9casesofinvasiveaspergillosisamong40criticallyillpatientswithH1N1viralinfection(23%).Corticosteroidusewasthemajorindependentriskfactorforinfluenza-relatedinvasiveaspergillosis(73).IntheNetherlands,25patientswithpost-influenzainvasiveaspergillosiswereidentifiedamong110ICUpatientswithinfluenza(23%)ina4months'periodin2016(76).Mortalitywas56%.Fiveof16isolates(31%)wereazole-resistant.BALculturewaspositivein84%,BALgalactomannanin89%,andserumgalactomannanin67%.TwopatientshadAspergillustracheobronchitisatautopsy(76).Inviewoftherecentdata,diagnosticrecommendationscannotbebasedonprospectivestudiesyet.Basedonaseriesofconsensusconferencesin2016,thecommitteehasmadethefollowingrecommendationsforICUpatients.During the influenza season, patients admitted to the ICUwith a respiratory infection should be testedbynasopharynxswab influenza PCR. All ICU patients with PCR-confirmed influenza should undergo sampling for serum galactomannan,bronchoscopytoruleouttracheobronchitis,andBALforgalactomannanandculture.Incaseoftracheobronchitis,apositiveserum galactomannan or a positive BAL galactomannan (index ≥0.8), patients should be treated as a probable invasiveaspergillosiswithcombinationazole+echinocandintherapy(oralternatives)asoutlinedinChapter2.3.IftrachealaspirateandBALculturesrevealnoAspergillusgrowthbutgalactomannanispositive,AspergillusPCRaswellasCyp51PCRforthepresenceofmutationsassociatedwithazoleresistanceshouldbeperformedonBAL.Influenza-confirmed ICU patients for whom all three diagnostic criteria (bronchoscopy, serum galactomannan and BALgalactomannan)arenegativeshouldbefollowedbystandardtrachealaspiratescreeningcultures.Oncescreeningculturesyield Aspergillus colonization or new respiratory complications occur, the diagnostic workup (bronchoscopy, serumgalactomannanandBALgalactomannan)shouldberepeated.If BAL cannot be performed, positiveAspergillus colonization cultures should guide antifungal treatment, in addition toserumgalactomannanandbronchoscopytomacro-/microscopicallyruleouttracheobronchitis.Administration of corticosteroids should be avoided in patients with proven/probable influenza-related invasiveaspergillosis. Combination azole+echinocandin therapy for probable influenza-related invasive aspergillosis of unknownazolesusceptibilityshouldbecontinuedforaminimumof2weeks.Patientswhohaveclinicallyimprovedafter2weeks,are


stableandhavewild-typecyp51PCRresultsmaybesteppeddowntoazolemonotherapyunderstrictfollow-up.Incaseofazoleresistancedetectedbyagarscreening,MICorcyp51resistancePCR,therapyshouldbechangedtoL-AmBasoutlinedinChapter2.3.For patients with confirmed influenza not admitted to the ICU, new respiratory complications, clinical worsening, or asputumculturepositive forAspergillus spp shouldprompt adiagnosticworkupasdescribed for ICUpatients. Physiciansshouldconsiderstartingantifungaltherapypendingdiagnosticresults,dependingontheclinicalstatusofthepatient.Aspergillosisinpatientswithchronicgranulomatousdisease(CGD)Patients with chronic granulomatous disease havemutations in the NADPH-oxidase complex, rendering patients highlysusceptibletoinvasivefungalinfections(77,78).Inacohortstudyof268CGDpatientsover4decades,invasiveaspergillosisoccurred in 125 (44%), and was the major determinant for mortality (79). Of these patients, 70% were on antifungalprophylaxis,mostly itraconazole.Antifungalprophylaxiswith itraconazole inCGDpatientshasdecreasedthe incidenceofIFDinCGDpatients(80).Posaconazolehasbeensuggestedtobeafavorablealternative(81).ThesensitivityofserumgalactomannaninCGDpatientswithinvasiveaspergillosisisverylow(<20%)(3,10).Duetothefactthat patientswith CGD are at risk to develop invasive fungal disease caused by awide range of differentmolds, everyattemptshouldbemadetomakeacausativediagnosis.Recombinant IFN-γ (rIFN-γ) prophylaxis in patients with chronic granulomatous disease (CGD) reduced the incidence offungalandbacterialinfectionsbyapproximately70%(82)(SeeChapter2.5).Conclusions2.4–InvasiveaspergillosisinICUpatients,patientswithinfluenza,andpatientswithCGD

Conclusion22 InvasiveaspergillosisinICUpatientsoccursinsubjectswithoutclassicalriskfactorsforaspergillosis;corticosteroidadministration,COPD,sepsis,post-sepsisimmunoparalysisarethemajordeterminants.

Level2 Meersseman,2004(C);Vandewoude,2006(B);Meersseman,2007(C);Blot,2012(C);Baddley,2013(B);Taccone,2015(B)

Conclusion23 BALgalactomannanhaspredictivevaluetodiagnoseprobableinvasiveaspergillosisinICUpatientsLevel3 Meersseman,2008(C);Blot,2012(C)Conclusion24 InvasiveaspergillosisisafrequentearlycomplicationofinfluenzapneumoniaintheICU;31%ofcasesinthe

Netherlandswerecausedbyazole-resistantisolatesLevel3 Wauters,2012(C);VandeVeerdonk,2016(C)Conclusion25 ThesensitivityofserumgalactomannantestinginCGDpatientsis<20%Level3 Verweij,2000(C);Mortensen,2011(C)Recommendation15 ICUpatientswithapositiveAspergillusculturefromrespiratorysamples,whohavechestradiology

abnormalitiesandriskfactorsforICU-relatedaspergillosisshouldundergoBALandserumgalactomannantesting.Apositivegalactomannanindexineithersamplepromptsforantifungaltherapy,coveringazole-resistantAspergillus,unlesstheisolatehasbeenprovensusceptible.

Recommendation16 ICUpatientswithclinicallyrelevantunexplainedchestradiologyabnormalitiesandriskfactorsforICU-

relatedaspergillosiswhoarenotAspergillusculture-positiveshouldundergoserumandBALgalactomannantesting.Apositivegalactomannanindexineithersampleintheabsenceofotherexplanationspromptsforantifungaltherapy,coveringazole-resistantAspergillus.Patientswhohaveclinicallyimprovedafter2weeks,arestableandhaveunknownazoleresistancemaybesteppeddowntoazolemonotherapyunderstrictfollow-up.

Recommendation17 ICU patients with confirmed influenza should undergo sampling for serum galactomannan. It is

recommended that ICU patients with confirmed influenza and radiologic abnormalities on chest X-rayshouldundergobronchoscopyandBALforgalactomannanandculture.In case of tracheobronchitis, a positive serum galactomannan or a positive BAL galactomannan (index≥0.8), patients should be treated with combination azole+echinocandin or azole+L-AmB therapy.MonotherapywithL-AmBisconsideredasasecondchoiceinthesepatients.IfculturesrevealnoAspergillusgrowth,galactomannan-positiveBALmaterialshouldbetestedbyPCRforthepresenceofCyp51mutations.ICUpatientswithinfluenzaandnegativeAspergillusserumandbronchoscopy/BALscreening,andnon-ICUinfluenza patients should undergo (repeat) serum and bronchoscopy/BAL diagnostics if new respiratorycomplications or clinical worsening occur, or if sputum/tracheal Aspergillus colonization cultures arepositive.

Recommendation18 SerumgalactomannanshouldnotbeusedtoscreenfororruleoutinvasiveaspergillosisinCGDpatients


2.5.ManagementofpatientstreatedforinvasiveaspergillosisTherapeuticdrugmonitoring(TDM)Accumulatingevidencehasidentifiedtherapeuticdrugmonitoring(TDM)ofitraconazole,posaconazoleandvoriconazoleasrequiredtooptimizetheefficacyandsafetyofthesedrugs(83,84).Bothinterindividualvariationinpharmacokineticsandthe specific concentrations required for the MIC established for the infecting strain require individual dosing andmonitoring(85).ItraconazoleItraconazoleisavailableasbothtabletsandsuspensionfororaladministration,aswellasinivformulation.Fororaluse,thesuspensionhassuperiorbioavailabilityandismoreeffectiveinprophylaxisthantablets(86).Forantifungalprophylaxis,acumulativeplasmatroughlevelof1mg/lforbothitraconazoleanditsmetabolitehydroxy-itraconazolewasfoundeffective(87,88).Forantifungaltherapy,highertroughlevelswereshowntocorrelatewithsuccessfuloutcomes(89,90).Asaresult,troughlevelsof2to4mg/l(itraconazole+hydroxy-itraconazole)arerecommended,tobeassessedwithin3-5daysafterstartoftherapy.VoriconazoleVoriconazoleisavailableastablets,suspensionandivformulation.Thetabletsandsuspensionhavesimilarbioavailability.The kinetics of voriconazole are nonlinear. In addition, concentrations are variable, not only between patients but alsointra-individually over time. In a randomized trial, voriconazole TDM resulted in similar incidence of adverse events butsignificantlybettersuccessratesamongpatientswithinvasiveaspergillosis(91).Clinical failurewasassociatedwith troughvoriconazole concentrations<1mg/l in adults and children (83,92). In severallarge cohort studiesusing troughconcentrationcutoffsof1.5,1.7or2.0mg/l, levelsabove the cutoffwere significantlyassociatedwithgreaterprobabilityofresponse(84,92,93).Inaretrospectiveanalysisof>1000patientsenrolledintrialsforinvasiveaspergillosis,atrough/MICratioof2to5wasassociatedwithnear-maximalchanceofsuccessfuloutcomes(94).Astep-downfrom4mg/kgbid iv toastandarddoseof200mg/bid (i.e.,2.5 to3mg/kgbid inmostpatients) resulted ininsufficienttroughlevelsinalargeproportionofpatients(84).Initial200–300mgivbidand300–400mgoralbidwerebest-suitedtoachieveinitialtherapeuticconcentrationsof1.5to4.5mg/l(84).Neurotoxicity,was found tobeassociatedwith concentrations>4–6mg/L,whereasa strict correlationofhepatotoxicitywithhighconcentrationwasnotestablished(83,84,93).However,intheAsianpopulation,anassociationofconcentrations>4mg/lwithhepatotoxicitywasestablished(95).Concentrations are to be assessed 2-3 days after first administration, and to be repeated once or twice weekly duringtherapyregardlessofpreviousconcentrations,inviewofthehighintra-individualvariation.PosaconazolePosaconazoleisavailableasbothtabletsandsuspensionfororaladministration,aswellasinanivformulation.Fororaluse,thesuspensionhasaninferiorandhighlyvariablebioavailabilityascomparedtotablets(96),andrecommendeddosingisdifferentfortabletsandsuspension.Forprophylacticuseofposaconazole, failuresweresignificantlyassociatedwith lowtroughconcentrations(Doltonetal.2012;Jangetal.2010).Hence,forantifungalprophylaxis,asteadystateplasmatroughlevelof>0.7mg/lisrecommended(99).Anassociationofhighermeansteadystateplasmaconcentrationswithsuccessfuloutcomeswasfoundinaprospectivestudyofposaconazolesalvagetherapyforinvasiveaspergillosis(100).Hence,atroughlevelof>1.0mg/lisrecommendedforantifungaltherapyofazole-susceptibleA.fumigatus.Inselectedcases,anelevatedMICtoposaconazolemaystillbeamenabletoposaconazoletherapyattroughconcentrations>1.5mg/lunderstrictTDM(28).Posaconazole iv formulation and tablets are dosed using a loading dose to achieve early steady state concentrations(96,101), and TDM should be initiated around day 3 of therapy. As the intra-individual variation is less than withvoriconazole,repeatTDMshouldbeperformednomorethanonceweeklyoncetargetconcentrationshavebeenreached.IsavuconazoleIsavuconazoleisavailableastabletsandivformulation.Optimaltargetconcentrationshavenotyetbeenestablished,butbasedonmodelingstudies,aimedtroughsareassumedtobe2to4mg/l(62,63).Inviewoftheclearrelationshipbetweenplasma concentrations and clinical outcomes established for the other azoles, the committee recommends TDM for allpatientsreceivingisavuconazole(e.g.,onceweeklyuntiltargethasbeenreached),pendingmorestudyresults.Intravenoustooralstepdown


Little prospective data are available to support recommendations on the step-down from intravenous to oral azoles inpatientswith acute invasive pulmonary aspergillosis. Based on pharmacokinetic data, azolesmay be switched to oral inpatientswhotolerateoraltherapy,providedthatspecificeffortsaremadetomonitortherapeuticdruglevels,asoutlinedabove.Conclusions2.5–Therapeuticdrugmonitoring(TDM)andoralstepdown

Conclusion26 Itraconazoleoralsuspensionhassuperiorbioavailabilitycomparedtotablets.Itraconazoletroughconcentrationscorrelatewithsuccessfuloutcomes.

Level2 Glasmacher,2003(B);Glasmacher1999(B);Boogaerts,1989(B);Denning1994,(A2);Lestner,2009(B)Conclusion27 Voriconazoleconcentrationsshowhighinter-andintra-individualvariation.UtilizationofTDMandmaintaining

troughconcentrations>1.5to2mg/ltroughconcentrationscorrelatewithsuccessfuloutcomes.Level2 Park,2012(A2);Pascual,2008(B);Pascual,2008(B);Troke,2011(B);Dolton,2012a(B);Pascual,2012(B);Lee,

2013(B)Conclusion28 Posaconazoletabletshassuperiorbioavailabilitycomparedtooralsuspension.Posaconazoletroughconcentrations

correlatewithsuccessfuloutcomes.Level2 Kersemaekers,2015(C);Walsh,2007(B);Jang,2010(B);Dolton,2012b(B);Dolton,2012c(B)Conclusion29 Isavuconazoletroughconcentrations>2–4mg/lareassumedtoberequiredforsuccessfuloutcomeLevel3 Kovanda,2016(C);Desai,2016(C)Recommendation19 TDMisstronglyrecommendedforpatientsusingitraconazole.Forprophylaxis,troughlevelsof

>1mg/l(itraconazole+hydroxy-itraconazole)shouldbeachieved;fortherapy,troughlevelsshouldbe2to4mg/l.Fororaladministration,itraconazolesuspensionispreferredovertablets.

Recommendation20 TDMisrecommendedforpatientsusingvoriconazole.Troughlevelsshouldbe1.5-2to6mg/l.

Concentrationsshouldbeassessed2–3daysafterfirstadministration,andrepeatedduringtherapy,regardlessofpreviousconcentrations.

Recommendation21 TDMshouldbeconsideredforpatientsusingposaconazoletabletsoriv.

Forpatientsusingposaconazolesuspension,TDMisrequired.Posaconazolesuspensionshouldonlybeusediftabletsarecontraindicated.Forprophylaxis,troughlevelsof>0.7mg/lshouldbeachieved;fortherapy,troughlevelsshouldbe>1mg/l.Concentrationsshouldbeassessed3daysafterfirstadministrationusingaloadingdose,andrepeatedduringtherapy.

Recommendation22 Pendingfurtherevidence,TDMshouldbeconsideredforpatientsusingisavuconazole.

Troughlevelsof2to4mg/lshouldbeachievedfortherapy.Usingaloadingdose,concentrationsshouldbeassessed3daysafterfirstadministration.

Recommendation23 Forchildren,TDMisstronglyrecommendedforallmould-activeazoles.

Recommendation24 Patientsmaybesteppeddownfromanivtooralazole,providedthattheycantolerateoral

therapy,andwithTDMwhereappropriate.StreamliningandDurationoftherapyIn general, primary treatment of invasive pulmonary aspergillosis is continued for 6 to 12 weeks. Patients should bemonitored serially by clinical evaluation, radiographic imaging, and course of serum galactomannan index (if positive atbaseline).Thecourseofserumgalactomannanhasbeenfoundtobeameasureofresponsetotherapyinanearlierreviewofstudies(102),aswellasinmorerecentprospectivecohortstudies(103–105).Inpatientsenrolledinalargeprospectivetrial(15),agalactomannan increasebetweenbaselineandweek1wassignificantlyassociatedwith failure,anda reductionof>35%predictedaprobabilityofafavorableclinicalresponse(16,106).However,resolutionofserumgalactomannanisnotasolecriterionfordiscontinuationofantifungaltherapy,andthedecisiontodiscontinueprimarytherapyistakenonthebasisofthe clinical response, the status of underlying disease, course of biomarkers, and the evolution of CT-scan findings. In


neutropenic patients, a similar durationof therapy is recommended; in thesepatients, therapy shouldneverbe shorterthanuntil2weeksafterresolutionoftheneutropenia(107).Forpatientsreceivinginitialcombinationtherapyforpulmonaryaspergillosisofunknownazolesusceptibility,nodataexisttorecommendaspecificstreamliningstrategy.Patients receiving combination therapy may be stepped down to azole monotherapy as soon as azole susceptibility(culture)orabsenceofCyp51mutations(BALCyp51PCR)hasbeendocumented.Incaseofazoleresistancedetectedbyagarscreening,MICorCyp51resistancePCR,therapyshouldbechangedtoL-AmBasoutlinedinChapter2.3.IntheabsenceofCyp51resultsandunknownazolesusceptibility,continuationofinitialcombinationtherapyisrationalbutdifficulttomaintainifprolongedtreatmentisrequired.Intheabsenceofevidence,someexpertsconsiderstreamlinginclinicallyimprovedpatientsafter2weeks.Dependingonthe underlying disease and immune status, step-down regimens covering potentially azole-resistant strains have beenconsideredbysomeexperts,e.g.,voriconazoleplusthriceweeklyechinocandin,orhigh-doseposaconazolemonotherapybasedonTDM(troughconcentrations>1.5mg/l),despitetheabsenceofpublishedevidence.Alternatively,steppingdownto voriconazole monotherapy despite unknown susceptibility had been considered in selected clinically stable andimmunologicallyimprovedpatients.Allstreamliningshouldbedoneunderstrictfollow-upofserumgalactomannan(twiceweekly)andrepeatedCT-scanofthelesions(e.g.,every3weeks),untilfurtherresolutionhasbeendocumented.Noneofthesepolicieshavebeensupportedbycurrentevidence,andnoformalrecommendationcanbemade.SecondaryprophylaxisAfter discontinuation of primary treatment in patients with persistent immunosuppression or those undergoing HSCT,maintenancetherapyorresumptionofantifungaltherapyatthetimeofsubsequentcoursesofimmunosuppressionmaybeconsidered.In2prospectiveopen-labeltrials,patientsundergoingallo-HSCTafterinvasiveaspergillosisreceivedsecondaryprophylaxiswithvoriconazoleorotherantifungals,leadingtoaprotectiveeffectof>90%inbothstudies(108,109).Incaseofproven/probableaspergillosis,thesusceptibilitypatternshouldguidethechoiceofsecondaryprophylaxis.Incaseofunknownsusceptibility,high-doseposaconazole,L-AmB,orechinocandinshavebeenused. Conclusions2.5–Durationoftherapyandsecondaryprophylaxisforacuteinvasiveaspergillosis

Conclusion30 Thedurationofantifungaltherapyhasnotbeeninvestigated.Ingeneral,treatmentiscontinuedfor6to12weeks,andatleast2weeksaftertheresolutionofneutropenia.

Level4 Singh,2003(D)Conclusion31 Thecourseofserumgalactomannanisanindicatorofresponsetotherapy.Level2 Micelli,2008(C);Park,2011(B);Chai,2012(B);Fisher,2013(B);Chai,2014(C);Neofytos,2015(B)Conclusion32 Secondaryprophylaxisiseffectiveinpreventingarelapseofinvasiveaspergillosisinpatientsundergoingallo-HSCTLevel3 Cordonnier,2010(B);Liu,2014(C)Recommendation25 Thedurationoftherapyforpatientswithacuteinvasivepulmonaryaspergillosisdependson

theclinicalcourseofthediseaseandtheevolutionofserumgalactomannanindexandCT-scanfindings.Durationoftherapyisatleast6to12weeksand,inneutropenicpatients,notlessthan2weeksafterresolutionofneutropenia.

Recommendation26 Secondaryprophylaxisisrecommendedafterrecentinvasiveaspergillosisinpatients

undergoingnewimmunosuppressivetreatment(e.g.,HSCT)orpatientswithaspecificprimaryimmunedeficiency(e.g.,CGD).Incaseofproven/probableaspergillosis,thesusceptibilitypatternshouldguidethechoiceofprophylaxis.Voriconazoleorposaconazoleareeligibleasoralprophylaxisforazole-susceptibleisolates,withappropriateTDM.

AdjunctiveimmunotherapyWhile the roleofprophylactic colony-stimulating factors (mainlyG-CSF) to reduce thedurationofneutropeniahasbeenestablished, their adjunctive role for the treatment of fungal infections in neutropenic patients is unclear. Whereas


preclinicalstudieshavedemonstratedabeneficialeffectofG-CSFandGM-CSFonantifungalhostdefensemechanisms,noclinicaldataareavailable,andnospecificrecommendationscanbemadeforpatientswithinvasivefungalinfections.Granulocytetransfusionshavebeenusedasadjunctivetreatmentinpersistentlyneutropenicpatientswithneutropenia.ArecentrandomizedmulticentertrialcomparedadjunctiveG-CSF-elicitedgranulocytetransfusionswithstandardtherapyin97neutropenicpatientswithseverebacterialor fungal infections (including28caseswithproven/probableaspergillosis)(110).Overall success ratewas42% for thegranulocyte transfusiongroupand43% for the controls, andsurvival curveswere similar for both treatment groups. Whereas the trial formally was underpowered to detect small treatmentdifferences,therewasnotrendtowardsimprovedoutcomesinthetotalstudygroup,norwasthereinthesubgroupwithprovenorpresumedfungalinfections(110).Interferon-γisacrucialmediatorofantifungalhostdefense.RecombinantIFN-γ(rIFN-γ)prophylaxisinpatientswithchronicgranulomatous disease (CGD) reduced the incidence of fungal and bacterial infections by approximately 70% (82). NocontrolledtrialshavebeenconductedtoinvestigateadjunctivetherapywithrIFN-γasatreatmentofinvasiveaspergillosisinpatientswithCGD.However,basedontheoreticalconsiderations,manyexpertsadvocateadjunctiverIFN-γtreatmentforCGDpatientswithinvasiveaspergillosis.RecentstudieshavereporteddefectiveIFN-γinpatientswithchronicpulmonaryaspergillosis(111),aswellasinpatientswithsevereacute invasivecandidiasisoraspergillosis (112).Patientswithoutknownimmunodeficiencyand invasiveskullbaseaspergillosiswerefoundtohaveanormalIFN-γresponsebutanimpairedTh17response,whichisalsoknowntobeimportant for fungal host defense (113). Adjunctive therapy with rIFN-γ was shown to have beneficial effects on theimmunestatus including IL-17and IL-22responses inacaseseriesofpatientswith invasivefungal infections, including3patientswithproven/probable invasiveaspergillosis(112).Functionaltestingof IFN-γproductioncapacityduring invasiveaspergillosismaybeusedtoguidethedecisiontostart immunotherapywithrIFN-γ in fulminantorrefractorycaseswithinvasiveaspergillosis.Conclusions2.5–Immunotherapyforacuteinvasiveaspergillosis

Conclusion33 Adjunctivetherapywithgranulocytetransfusionsorcolony-stimulatingfactorsforpatientswithinvasiveaspergillosishasnoprovenbenefit.

Level3 Price,2015(B);expertopinion9D)Conclusion34 PatientswithinvasiveaspergillosismayhavedefectsintheTh1/IFN-γorTh17antifungalhostdefensepathwaysLevel3 Smith,2014(C);Delsing,2014(C)Conclusion35 ProphylaxiswithIFN-γprotectsagainstinvasiveaspergillosisinCGDpatientsLevel2 InternationalCGDStudyGroup,1991(A2)Conclusion36 AdjunctivetherapywithIFN-γmayhavebeneficialeffectsinpatientswithinvasiveaspergillosisLevel3 Safdar,2005(C);Delsing,2015(C)Recommendation27 TestingforIFN-γproductiondefectsbyareferencelabshouldbeconsidered,toguidethe

decisiontostartrIFN-γimmunotherapyinnon-neutropenicpatientswithinvasiveaspergillosiswithfulminantorrefractorydisease.AdjunctiveIFN-γtherapyshouldbeconsideredinallCGDpatients,andinotherpatientswithprovenorsuspectedTh1/Th17hostdefensepathwaydefectsandinvasiveaspergillosis.

SalvagetherapySalvage therapy is defined as treatment given in the event of failure of first-line therapy, or undue toxicity of first-linetherapy.Nodouble-blindcontrolledstudieshavebeenconductedinthiscategoryofpatients.Following failure of primary antifungal therapy for invasive aspergillosis, a number of causes should be taken intoconsideration. Firstly, drug exposure may have been suboptimal, in particular to azoles that require intensive TDM.Secondly,theinfectionmayhavebeencausedbymucorales,aloneorincombinationwithAspergillusspecies.Thirdly,theinfectionmaystemfromanAspergillusspeciesthatisintrinsicallylesssusceptibletocertainantifungalagents(suchasA.terreus,which is lesssusceptibletoAmBcompounds)or isazole-resistant.Forthesereasons,theAspergillusspeciesandthesusceptibilityshouldbedeterminedintheeventoftherapyfailure.LipidformulationsofAmB,voriconazole,posaconazole, itraconazole,caspofunginandmicafunginhaveallbeendescribedassalvagetreatments.Comparisonofstudiesisdifficult,sincepatientpopulationsanddefinitionsofoutcomeconsiderablydifferbetweenstudies.Inaddition,theindicationforsalvagetherapymaybeamajorconfounder,sincepatientsintolerantforafirst-lineagenthavebetteroutcomesthanthosewithefficacyfailuresonprimarytreatment.In patients who fail initial voriconazole or isavuconazole therapy, a change of antifungal class is recommended. L-AmB(114,115), ABLC (116), caspofungin (48,49,117) andmicafungin (50) have been described as salvage options, as has the


combinationofvoriconazoleplus caspofungin (54).Thevalueofaddinga secondantifungal to the failing therapy ratherthandiscontinuingthefirstagenthasnotbeeninvestigated.Conclusions2.5–Salvagetherapyforacuteinvasiveaspergillosis

Conclusion37 Nocomparativestudieshaveassessedtherelativeefficacyofantifungalsforsalvagetreatmentofinvasiveaspergillosis.L-AmB,ABLC,caspofungin,micafungin,andvoriconazolepluscaspofunginhavebeendescribedforsalvageregimens

Level3 Ng,1995(C);Walsh,1998(C);Marr,2004(C);Maertens,2004(C);Betts,2006(C);Denning,2006(C);Hiemenz,2010(C)

Recommendation28 Onfailureofafirst-linetherapyfor(provenorsuspected)aspergillosis,thecauseofthefailure

shouldbeinvestigated.Inparticular,resistanceofAspergillusspeciesor(co)-infectionwithmucoralesshouldbetakenintoconsideration.

Recommendation29 Onfailureofvoriconazoleorisavuconazole,thecommitteeconsidersittobeofprimary

importancethatazoleresistanceandaco-infectionwithmucoralesbeexcluded.Inviewofthisdifferentialdiagnosis,L-AmBisrecommended.Anechinocandinmaybeconsideredasthesecondchoiceifmucormycosishasbeenexcludedandthereisnoevidenceofcerebralaspergillosis.

2.6.Preemptive(Diagnostic-driven)andempiricaltherapyforinvasiveaspergillosisPreemptiveordiagnostic-drivenantifungal therapy is treatmentofpatients inwhomthere isstrongevidenceof invasiveaspergillosis based on certain diagnostic tests (radiological, serological ormolecular) but inwhom the infection has notbeenhistologicallyormicrobiologicallydemonstrated. Incontrast, theclassicalconceptofempiricalantifungal therapy isdefinedas initiatingantifungaltherapyinpatients inspecificriskgroups(e.g.,neutropenia)withfever,wherethere isnospecificevidenceoffungalinfection.Diagnostic-driventherapySeveralstudieshavesupportedthevalueofdiagnostic-driven(preemptive)strategiesascomparedtoclassicalfever-driven(empirical)therapy.Recommendeddiagnostictechniques,includinggalactomannanantigenindexandHRCTchestscan,aredescribedinchapter2.1.Inafeasibilitystudy,diagnostic-driventherapybasedongalactomannanscreeningandHRCTwascompared to empirical therapy in 117 patientswith leukemia (17). Diagnostic-driven therapy led to a 78% reduction ofantifungaluse,andnocasesofinvasiveaspergillosisweremissed.Several randomized studies have compared diagnostic-driven strategies based on serum galactomannan. In a largemulticenterrandomizedstudyfromFrance,survivalwassimilarinthediagnostic-drivenandempiricaltherapygroups(118).Probable or proven invasive aspergillosis was more commonly detected in the diagnostic-driven group, but costs ofantifungal therapywere35% lower.A small study fromSingaporeyieldedcomparable results (119). Ina large trial fromAustralia,240leukemia/alloHSCTpatientswererandomizedbetweenastandardempiricalstrategyandadiagnostic-drivenstrategy based on serum galactomannan and PCR screening followed by HRCT (11). Antifungal use was lower in thediagnostic-driven group (15% vs. 32%, p=0.002). Notably, 55% of probable/possible invasive aspergillosis cases in thediagnostic-driven groupwere diagnosed in the absence of fever. No cases of invasive aspergillosis weremissed in thatgroup. The diagnosis of probable/possible aspergillosis was established a median of 4-7 days earlier with the galacto-mannan/PRC-driven strategy.Mortalitydidnotdiffer significantlybetween the groups (11). In a recent randomized trialfrom Spain, 219 leukemia/alloHSCT patients underwent a diagnostic-driven antifungal strategy based on galactomannanscreeningvs.galactomannanplusserumPCR(120).Patientsinthegalactomannan-PCRgrouphadashortermedianintervaltothediagnosisof(probable)invasiveaspergillosis(13vs20days;P<0.05).Empirictherapy

Empiric antifungal therapy in neutropenic patients with fever despite broad spectrum antibiotics has been studied inseveral large randomized trials. L-AmB was as effective as c-AmB but associated with significantly fewer provenbreakthrough infections (121). Ina randomized trialusingacompositeendpoint,voriconazole (overall success rate26%)was slightly worse than L-AmB (success rate 31%). However, significantly fewer breakthrough infections occurred withvoriconazole (p=0.02) (122). In a large randomized study, caspofungin was as effective as L-AmB but L-AmB caused


significantlymore nephrotoxicity andmore infusion-related adverse event andwasmore frequently discontinued early.Survival7daysafterdiscontinuationappearedtobebetterinthecaspofungingroup(93%vs.89%,p=0.05)(123).Conclusions2.6–Diagnostic-driven(preemptive)andempiricalantifungaltherapyinleukemia/HSCTpatients

Conclusion38 Diagnostic-drivenantifungaltherapybasedonserumgalactomannanand/orPCRscreeningandHRCTresultsinsimilarmortalityrates,earlierdiagnosisofaspergillosis,morepatientsidentifiedwithprobable/provenaspergillosis,andlessantifungalusecomparedtoafever-drivenempiricaltherapystrategy.

Level2 Maertens,2005(B);Cordonnier,2009(A2);Tan,2011(B);Morrissey,2013(A2);Conclusion39 L-AmB,voriconazoleandcaspofunginhavebeenassessedasempiricaltreatmentforneutropenicpatientswith

fever;caspofunginwasassociatedwithfewersideeffectsandbettersurvivalthanL-AmB.Level2 Walsh,1999(A2);Walsh,2002(A2);Walsh,2004(A2)RecommendationsBased on the proven safety, the higher diagnostic yield, and the reduction in unnecessary antifungal use of diagnostic-driven compared to empirical therapy, a diagnostic-driven therapy based on a minimum of twice weekly serumgalactomannanscreening,followedbyHRCTwhenpositive,shouldbeusedinallneutropenicpatientswithhematologicalmalignanciesandHSCTrecipients.Ifadiagnosisofpossible,probableorprovendiagnosis isestablished,antifungaltherapyshouldbestarted,followingtherecommendationsgiven inChapters2.2and2.3.Theuseofblood-basedPCR for screeningcannotbe recommended forroutine use in clinical practice at present, due tothe lackofstandardization and validationforcommerciallyavailableassays.Classicalfever-drivenempirictherapyisnotrecommended,anditshouldbenotedthatvoriconazoleorotherazolesarenotsuitableforempirictherapyatpresent,giventhepresentazoleresistancerateof5to35%intheNetherlands.Wheneveritwouldbenecessarytouseanempiricratherthandiagnostic-driventherapy,e.g.,insituationsweretimelygalactomannanscreeningorHRCTare(temporarily)notavailable,caspofunginorL-AmBwouldbeappropriatechoices.Recommendation30 InneutropenicpatientswithhematologicalmalignanciesorHSCT,adiagnostic-driven

antifungalstrategyisrecommended,basedonscreeningserumAspergillusgalactomannanatleasttwiceweekly.

Recommendation31 InneutropenicpatientswithhematologicalmalignanciesorHSCTandapositiveserum

Aspergillusgalactomannanindex(≥0.5)orpersistentunexplainedfever,anHRCTlungscanshouldbecarriedout.PreemptivetherapyagainstAspergillusshouldbegivenintheeventof2xapositiveGM>0.5orfindingsconsistentwithinvasivefungalinfectionontheHRCTscan.

Recommendation32 Thecommitteerecommendstheuseofadiagnostic-drivenantifungalstrategyasopposedto

symptom-drivenempiricstrategy.Ifcircumstancesrequireanempiricstrategyinpatientswithpersistentfeverandneutropenia,L-AmBorcaspofunginmaybeused.

2.7Aspergillussinusitisandotitis,cerebralaspergillosis,chronicpulmonaryaspergillosisandaspergillomaAspergillussinusitisandotitis

Animportantdistinctionmustbemadebetweeninvasiveandnon-invasiveAspergillussinusitis.InvasiveAspergillussinusitisgenerallyoccursintheimmunocompromizedpatientandpresentswithfever,nasalmucosalulceration,epistaxis,pain,andheadache.Non-invasiveAspergillussinusitismanifestsasasinusitisnonresponsivetoantibioticsinimmunocompetentpatients(124).In these cases, endoscopic removal of a fungal ball is usually curative. Local or systemic antifungals haveno role in thetreatmentofamaxillaryfungalball.InacuteaswellaschronicorgranulomatousAspergillussinusitisinimmunocompetentpatients,surgicaldebridementandsystemic antifungal therapy is recommended. The choice of antifungal agents has not been specifically studied in thispatient group. ForAspergillus sinusitis, there is no reason to deviate from the general recommendations as outlined inChapters2.2and2.3.


InvasiveAspergillusotitisisrareandoccursinimmunocompromizedpatients,incontrasttoAspergilluscolonization(otomycosis),whichiscommoninhealthypersonsandnoninvasive.MalignantotitisexternacausebyAspergillusisusuallytreatedwithlocalantimycoticagentswhenconfinedtotheexternalauditorycanal.Tissue-invasiveAspergillusotitisshouldbetreatedwithsurgicaldebridementandprolongedsystemicantifungalsasoutlinedinchapters2.2and2.3.AseriesofpatientswithinvasiveskullbaseaspergillosiswerefoundtohaveanimpairedTh17lymphocyteresponse,leadingtoaspecifichostdefensedefectforfungal.SkullbaseaspergillosisisaseverecomplicationofprogressiveAspergillusotitisorsinusitis,andusuallyrequiresrepeatedsurgicaldebridementsandprolongedantifungaltherapy(113).AseriesofthesepatientswerefoundtohaveaspecifichostdefensedefectforAspergillus,requiringadjunctiveimmunotherapy(113).Cerebralaspergillosis

Cerebral aspergillosis is a common manifestation of disseminated aspergillosis. Its prognosis was poor, with mortalityrunning toalmost100%untilvoriconazolebecameavailable. Inastudyof81patientswithcerebralaspergillosis treatedwithvoriconazole,theresponsewas35%,andaspergillosis-relatedmortalitywas46%(125).Multivariateanalysisshowedneurosurgical intervention to be associatedwith improved survival (p=0.02). Case reports also have described favorableresponses inpatientswithCNSaspergillosistreatedwithlipidformulationsofAmB(126). Itraconazole,posaconazoleandthe echinocandins do not reach appropriate levels in CSF, although brain tissue concentrations may be acceptable, ifsystematicexposureisintheacceptedrange(127).AnimalmodelshaveindicatedthatL-AmBreachedsubstantiallyhigherconcentrations in thebrainwere significantlyhighercompared toc-AmBandABLC (128).When indicated,neurosurgicalinterventionmayalsoimproveprognosis(126).Chronicpulmonaryaspergillosis

Chronicpulmonaryaspergillosis(CPA)isagenerictermforavarietyofdiseases.ThemostcommonformofCPAischroniccavitarypulmonaryaspergillosis(CCPA),definedasoneormorepulmonarycavities,withapositiveAspergillusIgGantibodytest ormicrobiological evidence implicatingAspergillus sppwith significant pulmonary or systemic symptoms and overtradiographicprogression (newcavities, increasingpericavitary infiltrates,or increasingpleural thickening)overat least3months (129,130). When untreated, CCPA may progress to chronic fibrosing pulmonary aspergillosis. Less commonmanifestationsofCPAincludeAspergillusnoduleorsingleaspergilloma.CPAusuallydevelopsinapparentlynon-immuno-compromizedpatientswithunderlyinglungdisease.Subacute invasive pulmonary aspergillosis (formerly called chronic necrotizing pulmonary aspergillosis) is amore rapidlyprogressive infection, usually found inmoderately immunocompromizedpatients,which shouldbemanaged as invasiveaspergillosis(130).The diagnosis of CPA requires CT abnormalities (fungal ball,multiple empty cavities,with ofwithout associated pleuralthickening, and pericavitary infiltrates) present for >3 months, and evidence of Aspergillus infection by culture,galactomannan,PCR,orserumAspergillus IgG(130,131).ApproximatelyhalfofpatientswithCPAhaveanincreasedtotalandAspergillus-specificIgEtiterand/oreosinophilia.PatientswithCPAoftenhaveunderlyinggeneticdefect inantifungalhostdefense,and long-termsuppressiveantifungaltherapy is often warranted. Except for single uncomplicated aspergilloma (see below), azole treatment for CPA is nowconsideredstandardofcare,leadingtosubstantialhealthimprovementinthemajorityofpatients(132).Inarandomizedtrial, CCPA patients treated with itraconazole (400 mg/d) for 6 months had significantly better overall, clinical andradiologicalresponsesthanpatientsreceivingsupportivecare(133).Intwoopen,prospectivetrials,oralvoriconazolefor6-12months)waseffectiveinapproximately60%ofpatients(134).Initialazoletherapyusuallyis6-9month;nonrespondersareswitchedtoanalternativeregimen,whilerespondersusuallyrequireindefinitesuppressivetreatment(130).Inarandomizedtrial,micafunginwasaseffectiveasi.v.voriconazolefor4weeksin107patientswithCPA(successrates60.0vs.53.2%;CI,-12.9,26.5)(135).Inasubsequentsmallrandomizedstudy,caspofunginwasaseffectiveasmicafungin(136). Case series have described successful treatment of CPA with repeated short courses of L-AmB or caspofungin(137,138).Aspergilloma

Anaspergillomausuallydevelopsinanexistingpulmonarycavity,e.g.,followingtuberculosis,orbronchiectasis.Themajorcomplication, hemoptysis, occurs in approximately 75% of the patients and is massive and life-threatening in 25%.Moreover,aspergillomamaydevelopintochronicpulmonaryaspergillosis(130).For a singleuncomplicatedaspergilloma,definedas a singlepulmonary cavity containing a fungal ball in anonimmuno-compromizedpatientwithminimalclinicalsymptomsandnoradiographicprogressionoveratleast3months,theoptimaltreatment is unknown (130). Surgical resection is indicated in case of severe bleeding (139). Peri-operative antifungaltherapymaybe considered if risk of spillage ofAspergillus during surgery exists, anddiscontinuedpostoperatively if nospillage has occurred. In patients who are not eligible for surgery, prolonged antifungal therapy to minimize recurrenthemoptysishasbeendescribed,andbronchialarteryembolizationmayberequiredincaseofhemoptysis(130).


RecommendationsDeeply invasive cranial and chronic pulmonary aspergillosis are difficult to manage, and may be associated with azoleresistanceandwithsubtlehostdefensedefectsthatrequirespecificdiagnosticexpertiseoradjuvantimmunotherapy.Forthesepatients,consultationwiththeNationalMycologyExpertiseCenterisstronglyrecommended.Conclusions2.7–Therapyofotherformsofinvasiveaspergillosis Conclusion40 InvasiveAspergillussinusitisorotitisshouldbedistinguishedfromnon-invasiveformsofotomycosisorfungalballs.

ForinvasiveAspergillussinusitisorotitis,combinationofsurgicaldebridementandsystemicantifungaltherapyisfavored.

Level3 DeShazo,1997(C)Conclusion41 Voriconazolehasfavorablepharmacokineticsandefficacyintreatmentofcerebralaspergillosis.Oftheother

antifungals,L-AmBisassumedtohavethemostfavorablepenetrationintothebrain.Level3 Schwartz,2005(C);Coleman,1995(C);Felton,2014(C)Conclusion42 Thediagnosisofchronicpulmonaryaspergillosis(CPA)requiresCTabnormalities(fungalballorcavities,withof

withoutassociatedpleuralthickening,andpericavitaryinfiltrates)presentfor>3months,andevidenceofAspergillusinfectionbypositiveculture,galactomannan,PCR,orserumAspergillusIgG.

Level3 Page,2015(C);Denning,2016(C)Conclusion43 ProlongedazoleantifungaltherapyimprovestheoutcomeofCPA.Initialechinocandintherapyhadsimilareffects

ashadvoriconazoleinCPApatients.Level2 Cadranel,2012(B);Agarwal,2013(B);Al-Shair,2013(C);Kohno,2010(B);Kohno,2013(C);Keir,2014(C);Denning,

2016(C);Newton,2016(C)Conclusion44 Forsingleaspergillomawithbleeding,surgicalresectionisconsideredtobethetreatmentofchoice.Inpatientsnot

eligibleforsurgery,prolongedantifungaltherapyand/orbronchialarteryembolizationhavebeensuggestedtoreducethechanceofbleeding.

Level3 Muniappan,2014(C);Denning,2016(C)Recommendation33 ForthetreatmentofinvasiveAspergillussinusitis,thecombinationofsurgeryandsystemic

antifungaltherapyarerecommended,exceptforanon-invasivefungalball,whichcanberemovedsurgicallywithoutsystemicantifungals.

Recommendation34 Forcerebralaspergillosis,combinationantifungaltherapywithvoriconazoleandL-AmBis

recommendedpendingconfirmationofvoriconazolesusceptibility,and,iffeasible,surgicaldebridement.

Recommendation35 UncomplicatedAspergillusotitisexternashouldbetreatedwithtopicalantifungalsorboric

acid.Forinvasiveaspergillosisoftheear,thecombinationofsurgeryandprolongedsystemicantifungaltherapyarerecommended.

Recommendation36 Forchronicpulmonaryaspergillosis(CPA),prolongedazoletherapyisrecommended.

Echinocandinsareanacceptablealternativeifazolesarenotsuitable.Recommendation37 Surgicalresectionisrecommendedforbothsymptomaticsingleaspergillomawithbleeding.In

patientsnoteligibleforsurgicaltherapy,prolongedantifungaltherapyandbronchialarterialembolizationshouldbeconsideredincaseofbleeding.

Recommendation38 Forpatientswithcomplicatedcranialorpulmonaryaspergillosis,consultationwiththe

NationalMycologyExpertiseCentershouldbeconsidered.

2.8.AntifungalprophylaxisinpatientswithhematologicalmalignanciesorstemcellrecipientsSeveral meta-analyses have evaluated antifungal prophylaxis studies in neutropenic patients with hematologicalmalignanciesorallogeneichematopoieticcelltransplantrecipients.InpatientsundergoingmyeloablativeallogeneicHSCT,the incidence of invasive mycoses is considerably higher than among patients undergoing autologous HSCT orchemotherapy (140). For this reason, antifungal prophylaxis in patients with alloHSCT is described separately in theseguidelines.


In an older meta-analysis, antifungal prophylaxis decreased all-cause mortality compared with placebo in alloHSCTrecipients (RR,0.62;95%CI,0.45to0.85),butnot inacute leukemiapatients (RR,0.88;95%CI,0.74to1.06) (141). Inamorerecentsystematicreview,comparisonsbetweendrugsyieldednonsignificantdifferencesinmortality,andtherewerenoconsistentdifferences in incidenceofproven/probable invasiveaspergillosisbetweenvariousprophylaxisregimensinalloHSCTrecipients(142).Itraconazole prophylaxis compared with fluconazole in patients undergoing alloHSCT led to a significant reduction ininvasive aspergillosis (fluconazole 12%; vs. itraconazole 5%; p=0.03) at the costs ofmore adverse events (16% vs. 36%;p<0.001)butnodifferenceinmortalityinonestudy(Marretal.2004).Inanothertrial,therewasnosignificantreductionofinvasiveaspergillosis,fungalinfection-relatedmortality,oroverallmortality(144).Voriconazole prophylaxis was compared with fluconazole (145) or itraconazole (146) in patients undergoing alloHSCT.Compared to fluconazole, therewas a trend towards fewer probable/proven aspergillosiswith voriconazole (3% vs. 6%,p=0.09),butthefungal-freesurvivalandoverallsurvivalwerenotdifferent(145).Comparedtoitraconazole,therewasnodifferenceinprobable/provenaspergillosis(0.4%vs.2%,p=0.12)orsurvival,butvoriconazolewasbettertolerated(146).Posaconazole (suspension) was randomized to fluconazole in alloHSCT patients with a severe graft-versus-host disease(GVHD) (147). There was no difference for the primary endpoint, incidence of all invasive fungal infections, butposaconazole led to fewerproven/probable aspergillosis (2.3% vs. 7.0%; 95%CI 0.13-0.75; p=0.006) (147). In the secondtrial,posaconazolewascomparedwithfluconazoleoritraconazoleoralsolutioninarandomized,non-blindedstudyduringconsecutiveneutropenicepisodesinpatientswithAMLorMDS(148).Proven/probableinvasiveaspergillosisdevelopedin1%vs. 7% (p<0.001), and100-daysmortalitywas14%vs. 21% in the control arm (p=0.04), at the costsofmore seriousadverseevents(p=0.01)(148).Inadouble-blindstudycomparingmicafunginwith fluconazoleprophylaxis inneutropenicHSCTrecipients, therewasnosignificantdifference in thenumbersof invasive fungal infections1.6%vs. 2.4%;p=0.48), invasive aspergillosis (0.2%vs.1.5%;p=0.07)ormortality(149).ChildrenOnly2RCTsonantifungalprophylaxishaveincludedchildren(145,149)buttherearenospecificstudiesavailabletoguidepediatric recommendations (150). For children undergoing allogeneic HSCT, prophylaxis until engraftment has beenrecommended. Options include fluconazole (if local incidence of aspergillosis is low), itraconazole or voriconazole.Alternatively,micafungin,L-AmBBorposaconazole(inchildren>13y)havebeenused.InthepresenceofGvHD,prophylaxishasbeenrecommendedwithposaconazole(>13y),voriconazole,oritraconazole.Alternatively,micafunginorL-AmBhavebeenused.Inchildrenwithacuteleukemia,itraconazole,posaconazole(>13y),L-AmBorfluconazoleareamongtheoptionsmostlyfavored(150).Conclusions2.8.–AntifungalprophylaxisinpatientswithhematologicalmalignanciesorHSCT

Conclusion45 AntifungalprophylaxishasbeenshowntodecreasemortalitycomparedwithplaceboinalloHSCTrecipients,butnotconvincinglyinacuteleukemiapatients

Level1 Robenshtok,2007(A1);Ziakas,2014(A1)Conclusion46 ItraconazoleandvoriconazolearesuperiortofluconazoleforthepreventionofinvasiveaspergillosisinalloHSCT

patientsLevel1 Marr,2004(A2);Winston,2003[A2);Wingard,2010(A2);Marks,2011(A2)Conclusion47 Posaconazoleissuperiortofluconazoleinthepreventionofinvasiveaspergillosisinpatientswithseveregraft-

versus-hostdiseaseandinneutropenicpatientsLevel2 Ullmann,2007(A2);Cornely,2007(A2)

RecommendationsThe incidence of invasive mycoses in patients undergoing chemotherapy for hematological malignancies or autologousHSCT is relatively low. In patients undergoing myeloablative allogeneic HSCT, or AML remission-induction therapy, theincidence of invasive mycoses is considerably higher, particularly in the group with severe GVHD and/or undergoingimmunosuppressive therapy. Meta-analyses suggest that itraconazole is more effective than fluconazole in preventinginvasive aspergillosis, as are voriconazole and posaconazole. Whether or not their use as prophylaxis is also efficient,dependsontheincidenceinthespecificpatientgroup,thecosts,adverseeffectsandinteractions.Itshouldbenotedthatallpublishedanalyseshavebeenbasedonsettingswithoutazoleresistance.Giventhepresentazoleresistancerateof5to35%intheNetherlands,theactualbenefitofazoleprophylaxismaybelower.Nevertheless,thecommitteeconsidersazoleprophylaxispotentiallyuseful,buttheindicationisstronglydependentuponthelocalincidenceofinvasiveaspergillosisandpatientpopulation.Recommendation39 InpatientswithneutropeniafollowingchemotherapyforAML/MDSorHSCT,posaconazole

(untilresolutionoftheneutropenia,orduringtreatmentofsevereGVHD,andmonitoredbyTDMwhereappropriate)maybeconsideredforantifungalprophylaxis,dependingonthelocalincidenceofinvasivemycoses.


Chapter3 Candidiasis

Introduction

Candida species cause both superficial and invasive infections. The superficial infections include oropharyngeal,oesophageal, vulvovaginal candidiasis and Candida dermatitis. This guideline is restricted to invasive candidiasis andoropharyngeal/oesophageal candidiasis. Untreated candidemiamay result in a disseminated candidiasis and has a highmortality (151). Positive blood cultures taken via an intravascular catheter are also associated with a high mortality(152,153). Patients with a positive blood culture growing Candida, therefore, must always be treated with antifungalagents.Incontrast,thereisnoevidencesupportingtherelevanceofcathetertipculturesgrowingCandidaintheabsenceofpositivebloodcultures.

3.1.TreatmentofcandidemiaandacutedisseminatedcandidiasisProspectiverandomizedstudies

Inearlierstudies,fluconazole,voriconazole,andcaspofunginwereaseffectiveasconventionalamphotericinB(c-AmB)butassociatedwithsignificantlylowertoxicityandtherapydiscontinuations(154–156).Theseresultshaveindicatedthatc-AmBisnolongerappropriatefortreatmentofinvasivecandidiasis(157).Intwosubsequentcomparativetrials,micafunginwasaseffectiveasliposomalamphotericinB(L-AmB)andascaspofungin(158,159).Inapivotalstudy,anidulafunginwascomparedwithfluconazoleinpatientswithcandidemiaandinvasivecandidiasis(160).Theoverallresponseratesweresignificantlyhigherwithanidulafungin(76%)thanfluconazole(60%;difference15.4%,95%CI:3.85-26.99,p=0.009).Remarkably,anidulafunginwasmoreeffectiveinthepatientsinfectedwithC.albicans(success,81%vs.62%,p=0.015),thaninthoseinfectedwithCandidanon-albicansspecies(71%vs.60%),despitethefactthatallC.albicansisolatesweresusceptibletofluconazoleinvitro.InferioroutcomeswithfluconazolewerealsopresentinpatientswithlowAPACHEIIscores,andthereforenotrelatedtodiseaseseverity(160).Inpost-hocmultivariateanalyses,theseoutcomedifferencescouldnotberelatedtoother,confoundingfactors(161).Inasimilarrandomizedtrial,isavuconazolewascomparedwithcaspofunginin400patientswithcandidemiaandinvasivecandidiasis(162).Theprimaryendpointofsuccessfuloverallresponsesignificantlybetterwithcaspofungin(71.1%)thanwithisavuconazole(60.3%;adjusteddifference-10.8,95%CI:-19.9,-1.8). In separatepublications, thesubgroupsofpatientswhowere in the ICUat timeof randomization into theechinocandintrialshavebeendescribed.Thesuccessrate(MITT)amongICUpatientswas68%forcaspofunginvs56%forc-AmB(163),63%formicafunginvs.66%forL-AmB(164),and69%foranidulafunginvs.46%forfluconazole(p=0.076)(165).Meta-analysis

Andesetal.conductedanindividualpatient-levelquantitativereviewofrandomizedtrials(166).Apatient-leveldatabasewasbuilton1915patientsfrom7trials,whohadbeenrandomizedtoc-AmB,fluconazole,c-AmBplusfluconazole,c-AmBfollowedbyfluconazole,voriconazole,caspofungin,micafungin,oranidulafungin(154–156,158–160,167).Mortalitywaschosenastheprimaryendpoint.Overall30-daymortalityamongpatientsintheentiredatasetwas31%,andtherateoftreatmentsuccesswas67%.Acrossthetrials,logisticregressionanalysisidentifiedtwointerventionsasindependentdeterminantsofreducedmortality:removalofacentralvenouscatheter(Oddsratio,0.50;95%CI,0.35–0.72;P=0.0001),andrandomizationtoanechinocandinantifungal(OR,0.65;95%CI,0.45–0.94;P=0.02).ThiswasalsothecaseforpatientsinfectedbyC.albicans(OR,0.55;95%CI,0.32–0.95;P=0.03).Similarfindingswereobservedfortheclinicalsuccessendpoint:inmultivariateanalysis,randomizationtoanechinocandinwasassociatedwithincreasedchanceofresolutionofcandidiasisinallpatients(OR,2.33;95%CI,1.27–4.35;P=0.01),andinpatientsinfectedbyC.albicans(OR,3.70;95%CI,1.49–9.09;P=0.005)(166).Non-randomizedstudies

The efficacy of anidulafungin in patients in the ICU and thosewith additional risk factors (renal or hepatic impairment,recent abdominal surgery, elderly, solid tumors, solid organ transplant, or neutropenia,) in Europe was studied in aprospective,non-comparativemulticentertrial(168).TheMITTsuccessratewasbetween68%and76%inallgroupsofICUpatientswith additional risk factors, except for thosewithneutropenia (6/12, 50%)or solid organ transplant (3/8, 38%)(168).Inaretrospectivecohortstudyof224patientswithsepticshockduetocandidemia,multivariatelogisticregressionanalysisshowedthatearlyappropriateantifungaltherapy,sourcecontrol(intravascularcatheterremoval),andtreatmentwithanechinocandinallwereindependentlyassociatedwithimprovedsurvival(P<0.001)(169).


WhereasthevariousCandidaspeciesslightlydiffer intheirsusceptibilitytoechinocandins,additionaldatahaveprovidedreasonablesupportfortheefficacyofechinocandinsasinitialtherapyinpatientsinfectedbyotherspeciesthanC.albicans,reportedsuccessratesrangingfrom67%to85%forallmajorCandidaspecies(170,171).Initialtherapyinneutropenicpatients

No randomized trials have been specifically conducted in neutropenic patients with candidemia or invasive candidiasis.Smallnumbersofneutropenicpatientshave,however,beenincludedinseveralstudies,butthesestudiesareinsufficientlypowered to enable evidence-based judgment on the treatment of invasive candidiasis in neutropenic patients. In thosetrials, the responseofpatientswhowereneutropenicat startof treatmentwasbetween50%and64% forcaspofungin,micafungin,anidulafunginandfluconazole,and40%forc-AmB(155,158,159,171).Onthebasisofthesedata,theoutcomesoftreatmentinneutropenicpatientsappearnottobemuchdifferentfromthoseinnon-neutropenicpatients.Stepdown

Littledataareavailabletosupportrecommendationsonthetotaldurationoftherapyorthestep-downfromechinocandinsto intravenous or oral azoles (172). In general, candidemia trials have required a minimum 10 days of parenteralechinocandintherapy,beforeallowingastepdowntooralazoles(155,158–160).ArecentPhase4studyhasdemonstratedfeasibilityofastep-downstrategytoanoralazoleasearlyas5daysafterstartofivtreatment,providedtheCandidahasbeenclearedfromthebloodstream,likelyisazole-susceptible,andthepatientisclinicallystableandcapableoftakingoraltherapy (173). Such studies were, however, not randomized to compare early step-down therapy to prolongedechinocandintherapy,andpatientstransitionedtoazoleswerelessseverelyill.Inordertoassessthetimepointofbloodculturenegativity,asrequiredformakingdecisionsonoralstepdownortotaldurationoftherapy,bloodculturesamplesshouldbeobtaineddailyuntilnegative.Conclusions3.1–TreatmentofcandidemiaduetounidentifiedCandidaspeciesofunknownsusceptibility

Conclusion1 Initialtreatmentwithanechinocandinismoreeffectivethantreatmentwithfluconazole,voriconazole,isavuconazole,orc-AmBinpatientswithinvasivecandidiasis,irrespectiveofseverityofillness.

Level1 Andes,2012(A1);Reboli,2007(A2);Kullberg,2016(A2);Kollef,2013(B)Conclusion2 L-AmB,caspofungin,micafungin,andanidulafunginhavesimilarresponseratesinnon-neutropenicpatientswith

invasivecandidiasisLevel2 Mora-Duarte,2002(A2);Kuse,2007(A2);Reboli,2007(A2);Pappas,2007(A2)Conclusion3 Therearenosignificantdifferencesinoutcomesofinitialechinocandintherapyforinvasivecandidiasisinfected

bydistinctCandidaalbicansornon-albicansspeciesLevel3 Colombo,2010(B);Kullberg,2017(B)Conclusion4 Step-downfrominitialechinocandintherapytoanoralazoleafter≥5daysissafeinpatientswithnegativefollow-

upbloodcultures,clinicalstabilization,andazole-susceptibleinvasivecandidiasisLevel3 Vazquez,2014(B)

RecommendationsRecentstudieshavesignificantlychangedthe insights intotheoptimal initial therapyof (culture-proven)candidemiaandinvasivecandidiasis.Arandomized,double-blindtrialdemonstratedthatanidulafunginwasmoreeffectivethanfluconazole(160). In the 2008 edition of these guidelines, the committee recommended an echinocandin in seriously ill orhemodynamicallyunstablepatients.Atpresent,supportforthesuperiorityofechinocandinsoverfluconazolehasaccumulatedforallpatientgroupswithcandidemia.Inthesecondrandomizedtrialcomparinganechinocandinwithanazole,i.e.,caspofunginwithisavuconazole,thesuccessrateswerehighlysimilartothosefromthefirststudy:caspofunginoutcomesweresuperiortothosewithisavuconazole(162).Inalargeindividualpatient-levelquantitativeanalysisofrandomizedtrials(166),using30-daymortalityasasolidprimaryendpoint,randomizationtoanechinocandinwasanindependentlyassociatedwithreducedmortality(OR,0.65;P=0.02).Inagreementwiththeearlierrandomizedtrial(160),thesuperiorityofechinocandinswasalsosignificantinthegroupofpatientsinfectedbyC.albicans(166).TheassociationofechinocandinswithreducedmortalitywasalsosignificantinthelowertwoAPACHEIIquartiles.Thecommitteeconsidersthesedataprovidinglevel1evidencetosupportthenotionthatinitialtherapywithanechinocandin(asopposedtoazolesorAmB)isassociatedwithareductionofmortality,regardlessofseverityofillness.Furthersupportfortherelativebenefitofechinocandinswasderivedfromthecohortstudyinseverely-illcandidemiapatientswithsepticshock,identifyingprescriptionofanechinocandinasanindependentdeterminantofreducedmortalityinmultivariateanalysis(169),andfromsubgroupanalysesandnon-randomizedprospectivestudiessuggestingfavorablesuccessratesofinitialechinocandintherapyinICUpatientswithcandidemiaorinvasivecandidiasis,irrespectiveofCandidaspecies(163–165,168,170,171,173–176).Thecommitteeconsidersthethreeechinocandinsanidulafungin,caspofunginandmicafungintobeequallyeffective.Exceptionstothepreferentialuseofechinocandinsasinitialtherapyforcandidemiaorinvasivecandidiasisaremeningitis,endophthalmitis,andurinarytractcandidiasis,asintheseconditions,echinocandinsarelimitedbytheirpharmacokinetics.


Likewise, echinocandins arenot thepreferredagents inpatientspre-exposed toechinocandins forprolongedperiodsoftime(151).ConventionalamphotericinBhasnoplace inthetreatmentofcandidemia inadults,since,basedoncomparativestudiesandmeta-analyses, thedrug is lesseffectiveandsignificantlymoretoxic thantheechinocandins (155,166,169).L-AmB isconsideredaseffectiveastheechinocandins,buthasalessfavorablesafetyprofile(158).Althoughrandomizedstudiesofstepdownfromechinocandintooralazoletherapyarelacking,accumulatingdatasupportsthe safety of step down as early as after ≥5 days (173). Patients with Candida infection of cardiac valves, thrombi, orprostheticmaterialshouldnotbeswitchedtoazoletherapy,inviewofthelimitedactivityofazolesinbiofilms(177).Basedon the superiority of initial echinocandin therapy in preventingmortality, the committee stresses that the transition toazolesshouldnotprimarilybebasedonthespeciesidentificationandazolesusceptibility,butratherontheclinicalstabilityof the patient and negative follow-up blood cultures, obtained during the first days of echinocandin therapy. Thus,transitiontoanazoleisreasonablearoundday5oftherapy,providedthatfollow-upbloodculturesobtainedatday1–2oftherapyarestillnegative,thepatienthasbeenclinicallystabilized,hasnointravascularinfectionorunchangedivcatheter,andtheisolatehasbeenprovensusceptibletoazoles.Additional therapy choices based on known identification and susceptibility of Candida species and susceptibility arediscussedbelowin3.2.Recommendation1 Foradultpatientswithcandidemiaorinvasivecandidiasis,anechinocandin(anidulafungin,

caspofungin,ormicafungin)isthepreferredinitialtherapy.Thisrecommendationappliestoallnon-neutropenicandneutropenicpatients,exceptthosewithCandidameningitis,endophthalmitis,orinvasiveurinarytractcandidiasis,andneonates.

Recommendation2 ForpatientswhohaveCandidaendophthalmitis,orinvasiveurinarytractcandidiasis,

fluconazoleisrecommendedasinitialtherapy.Recommendation3 Afollow-upbloodculturesampleshouldbeobtaineddailyfrompatientswithcandidemia,

untilnegative.Recommendation4 Initialechinocandintherapyshouldbecontinueduntilthepatienthasstabilized,regardlessof

Candidaspecies.Recommendation5 Stablepatientsmaybesteppeddownfromanechinocandintofluconazoleafter≥5days,

providedthatfollow-upbloodculturesduringtherapyarestillnegative,thepatientisclinicallyimproving,theisolatehasbeenconfirmedfluconazole-susceptible,andthepatienthasnoCandidaendocarditis,intravascularcandidiasis,unchangedvascularcatheters,orprosthesis-associatedcandidiasis.

Table3.1.Recommendeddrugandstandardadultdoseofantifungalagentsusedforcandidemia†Antifungalagent Loadingdose Maintenancedose1stchoice*Anidulafungin 200mg 100mgqdCaspofungin 70mg 50mgqd,>80kg:70mgqd

Micafungin - 100mgqd

2ndchoice*LiposomalAmB - 3mg/kg/dVoriconazole bid6mg/kgivor

bid400mgpo4mg/kgbidiv#or200mgbidpo#

Isavuconazole tid200mgivorpoondays1+2 200mgqdivorpo3rdchoice*Fluconazole 800mgiv/po 400mg/div/po*Forspecificrecommendations,exceptions,andcontra-indications,seetext.†Thedosagesinthistablearespecificforinvasivecandidiasisandcandidemia;forothermycoses,differentdosagesmayapply.#Individualdosebasedontherapeuticdrugmonitoring


3.2.TreatmentofcandidemiaandacutedisseminatedcandidiasisofknownspeciesandsusceptibilityCandidaalbicans

Basedonthemeta-analysisandstudiesdiscussed in thepreviousparagraph(161,162,166,169), thecommitteeconsidersinitialtherapywithanechinocandininpatientswithcandidemiaorinvasivecandidiasissuperiortothatwithfluconazoleorotherazoles.Asnotedabove,earlystep-downfromanechinocandintoi.v.ororalfluconazoleissuggestedtobesafe,oncethepatienthasclinicallyimprovedandfollow-upbloodculturesarenegative.Thisimpliesthat–evenforC.albicansknowntobesusceptibletofluconazole–initialtherapywithanechinocandinshouldnotbechangedtofluconazoleonthebasisofspecies identification or susceptibility results per se, but only after favorable clinical and microbiological follow-up, asdescribedin3.1.Candidaparapsilosis

C.parapsilosisisgenerallylesssusceptibletoechinocandinsthantheotherCandidastrains(178).Outcomesofafullcourseof i.v.echinocandin therapy inpatientswithC.parapsilosis candidemiaor invasivecandidiasishavebeen lessoptimal insomestudies(155,160),whereasotherstudiesreportedoutcomessimilartothoseforotherCandidaspecies(158,159,171).Aretrospectivecohortstudyincluding307patientswithC.parapsilosiscandidemiadidnotdemonstrateadifferencein30-days'mortalitybetweenpatientsreceivingechinocandins(9.9%)orfluconazole(9.5%;risk-adjustedOR,0.82,95%CI0.33–2.07)(179).Basedonthesedata,thecommitteegivespreferencetotherapywithfluconazoleforC.parapsilosisinfections,butdoesnotadviseagainsttherapywithanechinocandin.CandidakruseiandCandidaglabrata

C.kruseiisinherentlyresistanttofluconazole(180).C.glabratahasavariablesusceptibilitytofluconazole(181).Althoughthe in-vitro activity of voriconazole against C. glabrata is usually greater than that of fluconazole, C. glabrata may beresistant to voriconazole, and fluconazole and voriconazole are considered less appropriate for treating infections byC.glabrata(181,182).Thus,thecommitteegivespreferencetoanechinocandinforthetreatmentofC.glabrataandC.krusei,eveninthecaseofin-vitroazole-susceptiblestrains.Iforalazoletreatmentisdeemedpossible,voriconazoleispreferredtofluconazole. In individualpatients, fluconazolemaybeconsideredbasedonMICdata, ifstrictclinicalandmicrobiologicalmonitoringiscarriedout.Candida isolates with acquired echinocandin resistance have been reported with increasing frequency. C. glabrata isoverrepresentedamongechinocandin-resistant isolates (178,183).However, in the two largestprospectivecollectionsofpatientstreatedwithanechinocandin,thesuccessratewas78–85%forpatientswithC.glabrata,vs.77%forpatientswithC. albicans (170,171). Thus, the committee considers an echinocandin as the first choice for candidemia or invasivecandidiasisbyC.glabrata.Durationoftherapy

Forcandidemiawithoutprovenmetastaticfoci,treatmentlasting14daysafterthelastpositivebloodcultureisappropriatein non-neutropenic patients who have responded well to therapy (151,172). In patients with acute disseminatedcandidiasis,thetreatmentdependsupontheresolutionofthemetastaticfoci.Ingeneral,adurationoftreatmentfrom4to8weeksisnecessaryinthosecases.FDGPET-CTimagingmayguidetheresolutionoffocianddurationoftherapy(184,185).Conclusions3.2.TherapyofcandidemiawithidentifiedCandidaspeciesofknownsusceptibility

Conclusion5 C.kruseiisusuallyresistanttofluconazole.C.glabrataisgenerallylesssusceptibletofluconazoleandvoriconazolethantheotherCandidaspecies.

Level2 Pfaller,2010(B);Pfaller,2011(B);Arendrup,2014(C)Conclusion6 IncreasingechinocandinresistanceofC.parapsilosisandC.glabratahasbeenreportedLevel3 Alexander,2013(C);Arendrup,2014(C);Kullberg&Arendrup,2015(D)Conclusion7 Clinicalexperiencehasestablishedatreatmentdurationof14daysafterthelastpositivebloodculture,unless

thereareprovenmetastaticfoci.Level4 Rex,1994(C);Mora-Duarte,2002(C);OudeLashof,2003(C);Kullberg,2005(C);Reboli,2007(C);Pappas,2007

(C)Recommendation6 ForCandidaalbicansorC.parapsilosiscandidemia/invasivecandidiasisinstabilizedpatients,

step-downtofluconazoleispreferredafterinitialechinocandintreatment,providedthatfollow-upbloodculturesduringtherapyarenegative,thepatientisclinicallyimproving,theisolatehasbeenconfirmedfluconazole-susceptible,andthepatienthasnoCandidaendocarditis,intravascularcandidiasis,unchangedvascularcatheters,orprosthesis-associatedcandidiasis.


Recommendation7 ForCandidakruseicandidemia/invasivecandidiasis,anechinocandin(anidulafungin,caspofungin,ormicafungin)ispreferred.VoriconazoleorL-AmBmaybeusedasanalternative.

Recommendation8 ForCandidaglabratacandidemia/invasivecandidiasis,anechinocandin(anidulafungin,

caspofungin,ormicafungin)ispreferred.L-AmBmaybeusedasanalternative.Recommendation9 Patientswithanuncomplicatedcandidemiashouldbetreatedfor14daysafterthelast

positivebloodculture.Treatmentofacutedisseminatedcandidiasisdependsonclinicalandradiologicalfindings.Incaseofprovenmetastaticfoci,thedurationoftherapyisatleast4to8weeks.

3.3.ManagementofintravascularcathetersThegutisthemajorportalofentryforCandida,ratherthantheskinorintravascularcathetersbeingtheprimarysourceofcandidemia.Even ifan intravascularcatheter isnottheportalofentry, itmaybesecondarily infected,andsubsequentlylead to persistent candidemia and the formation of metastatic foci (151). This is supported by the observation thatcandidemiamaypersistuntilcathetershavebeenexchanged.Recentstudiesfoundcatheterremovalatanytimepointtobeassociatedwith lowermortalityandbetterclinical success rates (169,186,187). Inapooledpatient-levelanalysisof7randomizedtreatmenttrials,treatmentwithanechinocandinandcatheterremovalwereidentifiedasthetwomodifiablemanagementstrategiesassociatedwithbettersurvival rates (166).Anewcathetershouldbe insertedatadifferentsite;catheterexchangeattheoriginalsiteusingaguidewireisinadequate(188).

Basedontheidentificationofcatheterretentionasanindependentriskfactorformortalityinarecentmeta-analysis(166),thecommitteeconsiderstheevidencetobesocompellingthatitrecommendsremovalorreplacementofallintravascularcatheters(central,peripheralandarterial)wheneverlogisticallyfeasible.Nostudieshavebeenconductedastotheoptimalintervalbetweenremovalofanintravascularcatheterandtheinsertionofanewcatheter. Inthestudiescited,nominimalintervalwasspecified,andusually,anewcatheteris insertedwithoutcatheter-free interval (166). Inviewof thetime involvedwithbiofilmformationonanewcatheterandthe fact that thenewcatheterisinsertedduringantifungaltherapy,thereareinsufficientgroundsforobservingaminimumintervalbeforeinsertinganewcatheter(166).Conclusions3.3.–Cathetermanagement

Conclusion8 Exchangeofintravascularcathetersinpatientswithcandidemiaisassociatedwithreducedmortality.Level1 Andes,2012(A);Kollef,2012(B)Conclusion9 Replacementofanintravascularcatheteratthesamesiteandusingaguidewirehasnofavorableeffectonthe

durationofcandidemiaLevel3 Rex,1995(B)Conclusion10 Therearenogroundsfordelayingtheinsertionofanewcatheterfollowingtheremovalofanintravascular

catheter.Level3 Andes,2012(C)Recommendation10 Inpatientswithcandidemia,allintravascularcatheters(central,peripheralandarterial)should

beremovedorreplaced.

3.4.DisseminatedcandidiasisandsecondarymetastaticfociCandida species relatively frequently cause hematogenous dissemination (acute disseminated candidiasis). The mostcommonmetastatic foci areendophthalmitis and chorioretinitis. In aprospective study in370patientswith candidemiawhowere followed ophthalmologically, abnormal fundoscopic findings were noted in 16%; in 11% the anomalies wereprobablyCandida related:chorioretinitis in14.5%andendophthalmitis in1.5% (189).RetinalCandida lesionssometimesonlydevelopinthecourseof1-2weeksduringtherapy(189).Forpatientswithocularcandidiasis(chorioretinitisorendophthalmitis),alongerdurationoftherapymayberequiredthanthestandard(14days)treatmentofuncomplicatedcandidemia,andfundoscopicexaminationofisdesirablebeforethedurationoftherapyisdecidedupon.Whileechinocandinspenetratepoorlyintotheeye,comparativestudieshavenot


reportedincreasedriskofdevelopingocularcandidiasisinpatientstreatedwithechinocandins(160,162).Sincetheincidenceofendophthalmitisamongpatientstreatedforcandidemiaisaslowas1.5%(189),thecommitteenolongermakesastrongrecommendationtoperformroutineophthalmoscopiesineverypatient.Clinicalvigilanceiswarrantedtodetectsignsofocularinvolvementoranyothermetastaticfociinindividualpatients.InICUpatientsorpatientsotherwisenotabletocommunicateaboutvisualsymptoms,ophthalmoscopyisrecommended.Inviewofthepoorocularpenetrationofechinocandins,thetimingofophthalmoscopyshouldbeearlyduringechinocandintherapy.Treatmentofocularcandidiasisisdescribedinchapter3.7. Candida meningitis and central nervous system candidiasis are rare manifestations in adults and mostly related toneurosurgicalprocedures.InitialtreatmentwithL-AmBcombinedwithflucytosineismostcommonlyused,withfluconazoleas step-down treatment. Voriconazole does achieve excellent levels in CSF and may be used for fluconazole-resistantisolates.PosaconazoleandechinocandinsdonotreachadequateCSFconcentrationsandarenotrecommended.Frequently occurringmanifestations of dissemination are spondylodiscitis, osteomyelitis, pulmonarymetastatic foci andrenalabscesses(151).Intravascularfoci,suchasendocarditis,aninfectedthrombus,oramycoticaneurysmmaydevelop.Inpatientswithcandidemia,thereisaclearassociationbetweenpersistentlypositivebloodculturesandthepresenceofaninfectedintravascularcatheterorotherintravascularfoci.Thus,exchangeofallindwelling(arterial,centralandperipheral)intravascularlinesisaprerequisitetopreventhematogenousdisseminationofCandidaandassociatedmortality.A recent prospective single-center study from Spain has suggested that up to 6% of patients with candidemia developCandidaendocarditis(190).Thisriskwashighestamongpatientswithavalvularprosthesisorprolongedcandidemia.Specificdiagnosticapproachestometastaticfoci includeechography,CT,MRIorFDGPET-CT.TheFDGPET-CTscanisthemostsensitiveforthispurpose(184,185).The committee is of the opinion that persistently positive blood cultures despite antifungal therapy, or the presence ofcardiac valve disease, valve prosthesis, or an intravascular device, prosthesis, or thrombus should initiate examinationtargetedatintravascularandmetastaticfoci.Likewise,provendissemination(e.g.,spondylodiscitis)shouldpromptsearchforother foci.Whereasnosoliddataareavailable todefineacutoff forpersistentlypositivebloodcultures,≥72hafterinitiation of antifungal therapy is considered a strong indicator of dissemination and increased mortality. Diagnosticprocedures include ophthalmoscopy, transesophageal echocardiography (unless a diagnosis of endocarditis has alreadybeenestablishedbytransthoracicechocardiography),andFDGPET-CT.Severe disseminated candidiasismay be difficult tomanage, andmay be associatedwith host defense defects that arerequire specific diagnostic expertise or adjuvant immunotherapy. For these patients, consultation with the NationalMycologyExpertiseCenterisstronglyrecommended.ChronicdisseminatedcandidiasisChronicdisseminated(orhepatosplenic)candidiasisisaspecificsyndromeinhemato-oncologypatientsaftertherecoveryofneutrophilsduetopriorchemotherapy.Chronicdisseminatedcandidiasisisdiagnosedbyimaging(CTorMRI).TheroleofPET-CTmaybehelpfulbuthasnotbeen fullydefinedyet (185,191).Confirmationof thediagnosisbybiopsy remainstroublesomeas the sensitivityhistologyandcultureare low (192).Dataonoptimal treatmentaremostlybasedoncaseseries.Mortalitywithc-AmBhasbeenveryhigh (74%) (193). Initial therapywithL-AmBoranechinocandin isassociatedwith better outcomes and lower mortality rates (20-25%) (192). Therapy may be continued with fluconazole orvoriconazole, and should be given until all lesions have disappeared on repeated imaging, which is usually for severalmonths.Prematurediscontinuationof antifungal therapyoften leads to relapse. If chemotherapyorHSCT is required, itshould not be delayed because of the presence of chronic disseminated candidiasis, and antifungal therapy should becontinued throughout theperiodofhigh risk toprevent relapse. Increasingevidencesuggests that chronicdisseminatedcandidiasisisaformofimmunereconstitutioninflammatorysyndrome(194).Aretrospectivemulticenterstudyofpatientswithsymptomaticchronicdisseminatedcandidiasiswithfeverunresponsivetoantifungaltherapysuggestedthatsystemiccorticosteroids (0.5 to0.8mg/kgprednisone for 2-3weeks, followedby tapering after deferescence) can result in rapidclinical improvement. The duration of antifungal therapy and corticosteroids in symptomatic chronic disseminatedcandidiasispatientshasbeenreportedtobeaslongasseveralmonths(194). Conclusions3.4.–Secondarymetastaticfociincandidemia

Conclusion11 Inpatientswithprolongedcandidemia,apersistentintravascularfocusisoftenpresent.Level4 (D)Conclusion12 Candidaendocarditisasacomplicationofcandidemiaismostfrequentinpatientswithvalvular

prosthesesorprolongedcandidemia.Level3 Fernandez-Cruz,2015(B)Conclusion13 Chronicdisseminatedcandidiasisinhemato-oncologypatientsisdiagnosedbyCT,MRIorPET-CT,and


usuallyrequiresantifungaltherapyforseveralmonths.Persistentinflammationandfeverinthesepatientsmaybebasedinanimmunereconstitutioninflammatorysyndrome,responsivetocombinedantifungalandsystemiccorticosteroidtherapy.

Level3 Anttila,1997(C);Legrand,2008(C);DeCastro,2012(C)Recommendation11 Fundoscopyshouldbeconsideredforpatientswithcandidemia,andisstrongly

recommendedforpatientswithsignsofdisseminatedinfection,ocularsymptoms,orpatientsunabletocommunicateaboutvisualsymptoms.

Recommendation12 Asearchforintravascularandmetastaticfoci,usingophthalmoscopy,echocardiography

(TEE)andFDGPET-CT,shouldbeconsideredforallpatientswithcandidemiawhohavepersistently(≥96h)positivebloodculturesduringtherapy,orsignsofdisseminatedcandidiasis,ocularsymptoms,orcardiacvalvedisease,avalveprosthesis,oranintravasculardevice,prosthesis,orthrombus.

Recommendation13 Forpatientswithchronicdisseminatedcandidiasis,prolongedtherapywitheitherL-AmBor

anechinocandinisrecommended,followedbyfluconazoleorvoriconazole,untilradiographicresolutionofalllesions.Inpatientswithsignsofimmunereconstitutioninflammatorysyndrome(IRIS),corticosteroidsmaybeconsidered.

Recommendation14 Forpatientswithcomplicateddisseminatedcandidiasis,Candidameningitis,endocarditisor

osteomyelitis,consultationwiththeNationalMycologyExpertiseCentershouldbeconsidered.

3.5.Therapyofcandidemiaandacutedisseminatedcandidiasisinchildren

NeonatesCandidemiaandinvasivecandidiasisoccurrelativelyfrequentlyinprematureneonates.AspecificsyndromeinneonatesishematogenousCandidameningoencephalitis,with invasionofthecentralnervoussystem,associatedwithhighmortalityandlong-termsequelae.Neonateswithasmallergestationalageandlowbirthweighthaveahigherincidenceofinvasivecandidiasis(ReviewedinHopeetal.2012;Roilides2011).A neonate with candidemia or invasive candidiasis should be considered to have acute disseminated candidiasis, andtherapyshouldpotentiallyincludethecentralnervoussystem(197).For candidemia and hematogenous Candida meningoencephalitis in neonates, both c-AmB and lipid amphotericin Bformulations have beenused, specifically L-AmB (3-7mg/kg/d) andABLC (5mg/kg/d). Fluconazole has beenused at 12mg/kg/d,withaloadingdoseupto25mg/kg/d(ReviewedinHopeetal.2012).Echinocandins,inparticularmicafungin(4mg/kg/d),havebeenusedforneonatalcandidiasis.InviewofthelimitedpenetrationofmicafunginintotheCNS,adoseof10mg/kg/d is usedwhen hematogenousCandidameningoencephalitis is thought to be likely (Reviewed in Hope et al.2012).Clinicalefficacyofcaspofungin(25mg/kg/d)hasbeendescribedincasereports,whilelittledocumentedexperienceexistswithanidulafunginforthisindication.Based on this information, the committee considers L-AmB, ABLC and fluconazole appropriate choices for neonatalcandidemiaandinvasivecandidiasis,withmicafunginorc-AmBaspotentialalternativesifCandidameningoencephalitisisnotsuspected.DosagerecommendationsarelistedinthenationalChildren’sFormulary.InfantsandolderchildrenIn older children, candidemia and invasive candidiasis closely resemble the disease in adults. The recommendations forchildrenarebasedonestablishedefficacyoftheantifungaldrugsinadults,pharmacokineticdatainchildren,documentedsafety,andapediatric label fromtheEMA.OnlyoneprospectiverandomizedstudyhasbeenperformedInchildrenwithinvasivecandidiasisorcandidemia,comparingmicafungin(2mg/kg/d)toL-AmB(3mg/kg/d) in98children<16yearsold(198). Whereas the trial was not formally powered for noninferiority, the response rates at end of therapy werecomparable: 73% in the micafungin arm vs. 76% (p=0.73) in the L-AmB arm. There were significantly more treatmentdiscontinuationsduetoadverseeventsintheL-AmBarm(198).Inlinewiththerecommendationsforadults,thecommitteeconsidersechinocandinsthefirst-linetherapyforcandidemiaandinvasivecandidiasisinchildren.Pharmacokineticstudiesinchildrenhaveestablisheddosingregimensforcaspofungin(70mg/m2loadingdosefollowedby50mg/m2/dayi.v.)(59,199),andmicafungin(2–4mg/kg/dayi.v.)(60)L-AmB (3mg/kg/d) is an alternative choice for candidemia and invasive candidiasis in children (198). Clinical experiencewithABLCinchildrenhasbeenpublished,butpharmacokineticstudiesonABLCinchildrenareabsent.Whereasthetoxicity


of c-AmB in childrenmay be somewhat less than in adults, the committee considers c-AmB no longer appropriate fortherapyofcandidemiaandinvasivecandidiasisininfantsandolderchildrenbecauseofitssignificanttoxicity.Forfluconazole(8–12mg/kg/day),extensivepharmacokineticandsafetydatainchildrenexist(200,201).Inviewoftherecentdataontherelativesuperiorityofechinocandinsforcandidemiaandinvasivecandidiasis(obtainedinadults),thecommitteeconsidersfluconazolenolongerthefirstchoiceinchildren,andstronglyfavorsanechinocandin.Exceptionswherefluconazoleisstillthefirstchoiceforinvasivecandidiasisaremeningitis,endophthalmitis,andurinarytractcandidiasis,inwhichechinocandinsarelimitedbytheirpharmacokinetics,andforinvasivecandidiasiscausedbyC.parapsilosis.Voriconazolecanbeusedforcandidemiaandinvasivecandidiasisinchildren.Especiallyinchildren<4yofage,druglevelsarhighlyvariable,andTDMisindispensableforallagegroups(202).DosagerecommendationsarelistedinthenationalChildren’sFormulary,andhavebeenbasedonseveralpharmacokineticstudies(58,203,204).WhereasvoriconazolehasabroaderspectrumthanfluconazoleagainstC.kruseiandsomestrainsofC.glabrata,thecommitteedoesnotconsidervoriconazolefirst-linetherapyforcandidiasis,inviewoftherelativesuperiorityofechinocandins.

Conclusions3.5.–Treatmentofcandidemiaandacutedisseminatedcandidiasisinchildren

Conclusion14 CandidemiaorinvasivecandidiasisinneonatesisoftenassociatedwithhematogenousCandidameningo-encephalitis,andtherapyshouldincludepotentialcentralnervoussysteminfection.

Level2 Benjamin,2010(B);Roilides,2011(B)Conclusion15 Fluconazole,c-AmB,L-AmB,ABLC,micafunginandcaspofunginhavebeenreportedeffectiveincaseseries

ofcandidemiaandinvasivecandidiasisinneonates.Level3 ReviewedinHope,2012(C)Conclusion16 MicafunginisaseffectiveasL-AmBinthetreatmentofinvasivecandidiasisinchildren.Level3 Queiroz-Telles,2008(B)Conclusion17 Thetreatmentofchildrenwithcandidemiaorinvasivecandidiasisisnotdifferentfromthatinadults,

basedonestablishedefficacyoftheantifungaldrugsinadults,andpharmacokineticandsafetydatainchildren.

Level3 Walsh,2005(C);Zaoutis,2009(C);Hope,2007(C);Lee,1992(C);Novelli,1998(C);Walsh,2010(C);Driscoll,2011(C);Neely,2010(C);

Recommendation15 Inneonates,treatmentofcandidemiaorinvasivecandidiasisshouldbetargetedatpotential

hematogenousCandidameningoencephalitis.FluconazoleorL-AmBisthepreferredinitialtherapyforcandidemiaorinvasivecandidiasisinneonates.

Recommendation16 Fortreatmentofchildrenwithcandidemiaorinvasivecandidiasis,caspofunginormicafunginis

thepreferredinitialtherapy.L-AmB,fluconazoleorvoriconazolearesecond-linealternatives.Recommendation17 ForchildrenwhohaveCandidameningitis,endophthalmitis,orinvasiveurinarytract

candidiasis,fluconazoleisrecommendedasinitialtherapy.Recommendation18 Recommendationsforchildrentostepdownfromechinocandintofluconazole,forcatheter

management,treatmentduration,follow-up,andmanagementofcomplicationsaresimilartothoseforadults(sections3.1and3.2).

3.6.Empiricalorpre-emptivetherapyagainstinvasivecandidiasisInviewofthehighmortalityofcandidemia,theoptionofempiricalorpre-emptivetherapyforpatientsinintensivecareunitshouldbeconsidered.Inthiscontext,empiricaltherapyisdefinedasantifungaltherapyforpatientswithsymptoms(fever,sepsis)intheabsenceofspecificevidenceofaCandidainfection.Pre-emptivetherapyisdefinedastreatmentforpatientswithspecificsigns(e.g.,apositiveß-D-glucantest)intheabsenceofaproveninvasiveinfection.Empiricaltherapy

Retrospectiveobservationalstudiesandrecentmultivariateanalyseshaveconsistentlyidentifiedearlyappropriateantifungaltherapyandinfectionsourcecontrolasmajordeterminantsofsurvival(166,169,186).Thus,althoughitis


plausiblethatearly,presumptivetreatmentofpatientswithinvasivecandidiasisisbeneficial,only2randomizedstudiesofempiricaltherapyhasbeenconducted,whichdidnotdemonstrateasurvivalbenefit(205,206).Inarandomizedstudyofmicafunginvs.placeboin260ICUpatientswithsepsis,Candidacolonizationandorganfailure,therewasnosignificantdifferencein28-dayssurvivalbetweenmicafungin-treated(87/128,68%)andplacebo-treated(74/123,60.2%)groups(206).Likewise,anolderplacebo-controlledstudyoffluconazolein270ICUpatientsdidnotshowanybeneficialoutcomes(205).

Pre-emptivetherapyPre-emptive (or diagnostic-driven) therapy is initiated on the basis of positive markers that may indicate an invasiveCandida infection. Prediction rules have been based on clinical risk factors, Candida colonization, or serum ß-D-glucanscreening(207,208).However,todate,suchstrategieshavenotbeendemonstratedtoreducemortalityorlengthofstayinprospectivestudies.In addition, published prediction rules have been shown not to be generally applicable in other regions or settings(209,210). Application of theCandida score prediction rule developed in Spain (207,211) to an Australian cohort of ICUpatientsreducedthePPVtoonly2%(210).Theseregionaldifferencesaremainlydrivenbythelowprevalenceofinvasivecandidiasis.IntypicalICUsettingswherethepretestlikelihoodofcandidiasisis0.5–10%,bothindividualnon-culturetestsandrisk factor-basedrules,havingaspecificityof50–80%,willmerely leadtoapositivepredictivevalue(PPV)of1–30%(reviewedin148).

Biomarkersβ-D-glucanandCandidamannan/anti-mannanarethesurrogatemarkersavailableforinvasivecandidiasis(212–214).β-D-glucanisacirculatingfungalpolysaccharidethat isnotspecificforCandida.Positivetestresultrequiresconfirmationandidentificationoftheinfectingorganism(Aspergillus,PneumocystisjiroveciiorCandida)(212,214).Itsspecificityislimitedbymanypotentialsourcesforcontamination:cellulosehemodialysismembranes,humanbloodproducts(immunoglobulinsoralbumin), amoxicillin-clavulanate or piperacillin-tazobactam, surgical sponges & gauzes containing glucan, and severemucositis(213,215).Theperformanceoftheβ-D-glucantestdependsonthecutoffvalueandnumberofpositivesamplesrequired.Thesensitivityrangesfrom65%to91%,andthespecificity is31%to79%(216,217). Inuninfectedorcolonizedchildren,circulatingβ-D-glucanmaybehigher,andthetestperformancemaybelessfavorablethaninadults(218).Thenegativepredictivevalue(NPV)ofβ-D-glucanwashighinseveralstudies(217).Thishasledtothegeneralassumptionthatthemaindiagnosticbenefitofβ-D-glucanliesinexcludinginvasivecandidiasis.However,thisappliesonlytopublishedseries with a low prevalence of candidemia (i.e., screening strategies), where the NPV is mainly driven by the lowprevalence.Thelimitedsensitivityofβ-D-glucaninotherstudiesimpliesthattheNPVwillbeinsufficientinselectedhigh-prevalencegroups,suchasICUpatientsselectedbydiagnosticrules,wherethelimitedsensitivitybecomesthemajordriveroftheNPV(208,214,216).TheCandidamannanandanti-mannantestisacombinedantigen/antibodytestthatisspecificforCandidaspecies.Itssensitivityrangesfrom55%to87%,anditsspecificityfrom82%to98%(213,219).Thetesthasalsobeenappliedfordetectionofbloodculture-negativehepatospleniccandidiasisandCNScandidiasis(reviewedin213).Forclinicaluse,thesamelimitationsapplyasdescribedfortheβ-D-glucantest.CandidaPCR

Recently,twoCandidaPCRtestshavebeenmarketed,theSeptiFastand,in2015,thefullyautomatedmultiplexT2Candida(220,221).Basedonameta-analysisofpublisheddata,theSeptiFastsensitivityis48%to72%,anditsspecificity99%(220).Untilnow,theT2Candidatesthasbeentestedinasingleclinicaltrial(221).Itsreportedsensitivitywas91%,andspecificity99%.ItsuseislimitedbytheavailabilityoftheT2Candidaequipmentrequired.Conclusions3.6.–Empiricalorpre-emptivetherapyagainstinvasivecandidiasis

Conclusion18 Whileearlyappropriateantifungaltherapyforcandidemiaisassociatedwithreducedmortality,controlledtrialsshowingbenefitofempiricaltherapyarelacking.

Level2 Schuster,2008(A2);Timsit,2016(A2),Kollef,2013(B)Conclusion19 PredictionrulesbasedonCandidacolonizationorriskscoreshavelimitedreproducibility,andaverylowpositive

predictivevalueincountrieswithlowincidenceofcandidemia.Level3 Playford,2009(B);ReviewedinKullberg&Arendrup,2015(D).Conclusion20 Biomarkerssuchasβ-D-glucanandmannan/anti-mannanhavelimitedsensitivityandspecificity,andalow

predictivevalueinhigh-riskgroups.Level3 Karageorgopoulos,2011(A1);Lamoth,2012(A1);Tissot,2013(B);ReviewedinKullberg&Arendrup,2015(D).RecommendationsEarlyappropriatetreatmentofcandidemiaorinvasivecandidiasishasbeenconsistentlyidentifiedasamajordeterminantofsurvival.However,todate,strategiesbasedonempiricorpre-emptivetherapyhavenotbeendemonstratedtoreducemortalityorlengthofstayinprospectivestudies.Clinicalpredictionrulesthathavebeendevelopedinregionswithahigh


prevalenceofinvasivecandidiasisperformpoorlyinsettingssuchasintheNetherlands,withalowprevalenceofinvasivecandidiasis.EvenintypicalICUsettings,thepredictivevalueofpredictionrulesorCandidabiomarkersislow.Asanexample,basedondata collected in theUS (217), the positive predictive value of ß-D-glucanwill only be 6% in an ICUpopulationwith anincidenceofcandidemiaof1%.Thismeansthat94%ofthepositivetestswouldbefalse-positive.Evenfortheinitiationofprophylaxis (let alonepre-emptive therapy), a positive predictive valueof >10% is considereddesirable. Conversely, thelimited specificityofß-D-glucanprecludes itsuse to ruleout invasive candidiasis in selectedpatientswithahigh clinicallikelihoodofCandida infection.Thus,ratherthanbeviewedasdefinitivediagnostics,predictionrulesornonculturetestsmightbebestviewedasmarkersthathelpassessapatient'sriskofhavinginvasivecandidiasis.Inselectedcases,initiationofempiricaltherapymaybeconsideredinICUpatientswithalengthydurationofstay(>7days)andunexplainedsepsis,ifthisisbasedonacombinationofthefollowingfactors:(1)significantcolonizationwithCandidaand(2)clinicalriskfactors(e.g.,abdominalsurgery,anastomoticleakage,broadspectrumantibiotics,centralvenousline).Currently,noneofthesecriteriahasbeenadequatelyinvestigated,andthecommitteeisawareofthedilemmasurroundingthepotential benefits of early treatment of candidemia, versus overtreatment of a large groupof patients. Appropriateculturesamplesshouldalwaysbeobtainedpriortotheinitiationoftreatmentandthatempiricaltherapyisdiscontinuedifbloodculturesornonculturediagnostictestsprovenegative.Recommendation19 Thepredictivevalueofnonculturediagnostictestsisnotsufficientlyvalidatedforuseinthe

diagnosisofinvasivecandidiasis.Recommendation20 Theindicationofempiricaltherapyonsuspicionofcandidemiainnon-neutropenicpatientsis

controversial.Empiricaltherapymaybeconsideredinselectedindividualcases,suchaspatients>7daysintheICUandunexplainedsepsis,withacombinationofthefollowingfactors:(1)significantcolonizationwithCandidaand(2)clinicalriskfactors(e.g.,abdominalsurgery,anastomoticleakage,broadspectrumantibiotics,centralvenousline).

3.7.Ocularcandidiasis

Candidachorioretinitisisaninfectionofthechoroidandtheretina;Candidaendophthalmitisisamoreadvancedinfectionextending into the vitreous body, associatedwith poor visual outcome.Candida chorioretinitis occurs in around 10%ofpatientswithcandidemia(189,222).Epidemiologyandscreeningrecommendationsforocularcandidiasisaredescribedinchapter3.4.Thetreatmentofocularcandidiasisis limitedbythepoorpenetrationofsystemicamphotericinBandechinocandinsintothe vitreous body (223). These drugs are therefore not a first choice in the treatment of Candida endophthalmitis orchorioretinitis. While Candida chorioretinitis (without vitreous involvement) usually responds to standard antifungaltherapy (189), treatment of Candida endophthalmitis with involvement of the vitreous body usually comprises threecomponents:administrationofsystemicantifungaltherapy,intravitrealinjectionofantifungalagents,andearlyvitrectomy(224).WhileAmphotericinBdeoxycholate(5–10µg)hasbeenusedasintravitreousinjection, intravitrealvoriconazole(25mg/l;totaldose100µg)wasfoundtobesafeandeffectiveaspartofacombinedapproach(225).Conclusions3.7–TreatmentofCandidaendophthalmitisandchorioretinitis

Conclusion21 Echinocandinsdonotreachadequateconcentrationsinthevitreousbody.Fluconazole,voriconazoleorthecombinationofAmB+flucytosinedoreachtherapeuticconcentrationsinthevitreousbody

Level3 Rodriguez-Adrian,2003(C);OudeLashof,2005(C);Gauthier,2005(C)Conclusion22 ThetreatmentofCandidaendophthalmitisisbasedonacombinationofsystemicantifungaltherapy,

intravitrealinjectionofamphotericinBorvoriconazole,andvitrectomy.Earlyvitrectomy,within1weekaftertheoccurrenceofCandidaendophthalmitis,appearstoimprovetheprognosis.

Level3 Martinez-Vazquez,1998(C);Rodriguez-Adrian,2003(C);Riddell,2011(C)

RecommendationsWhereas the pharmacokinetics of echinocandins limits their activity in the eye, initial therapy of candidemia and acutedisseminatedcandidiasiswithechinocandinshasnot lead to increased incidenceofocular complications.Thus, standardechinocandin therapy of candidemia is assumed to prevent progression of ocular foci inmost cases. Nevertheless, thecommittee favors systemic therapywith an azolewhenever chorioretinitis or endophthalmitiswith an azole-susceptibleCandidastrainarediagnosed.Inpatientswhorequiresystemicechinocandintherapyfordisseminatedcandidiasis,anazole


shouldbeaddedincaseofocular involvement,untilclinicalstabilityallowsstep-downtoazolemonotherapy. Inpatientswithcandidiasiswithunknownazole-susceptibility,initialtherapywithliposomalAmBandflucytosineisrecommended.Depending on the clinical course of the infection, a treatment duration of 4 to 12 weeks is usually required inendophthalmitis,asdeterminedbyrepeatfundoscopies.Recommendation21 Candidachorioretinitisorendophthalmitisshouldbetreatedsystemicallywithanazole

(fluconazoleorvoriconazolei.v.)incaseofprovenorpresumedazolesusceptibility.Forprovenorpotentiallyazole-resistantcases,liposomalAmBcombinedwithflucytosineisrecommended.Intheeventofinvasionintothevitreousbody,vitrectomyshouldbeperformedincombinationwithintravitrealvoriconazoleorc-AmB.Treatmentdurationisgenerallylengthyanddependsontheclinicalcourseoftheinfection.

3.8.UrinarytractcandidiasisCandida-positive urine cultures may be an expression of Candida colonization, of Candida cystitis, of Candidapyelonephritis, or, incidentally, candidemia/disseminated candidiasis. During a prospective surveillance study in 530patients with Candida-positive urine cultures, candiduria resolved in 76% of the untreated patients, vs. 35% followingcatheterremoval,vs.50%followingantifungaltherapy.Candidemiadevelopedinonly1%ofpatients(226).Asymptomaticcandiduria

In a placebo-controlled, double-blind study in 316 patients with asymptomatic candiduria, 200 mg fluconazole wascomparedwithplacebofor14days(227).RemovaloftheurinarycatheteraloneledtoclearanceoftheCandidain20%ofthe cases.At twoweeks after endof treatment, candiduria rateswere similar between fluconazole andplacebo groups(68%vs.65%)Therewasnodifferenceinmortalityandnoneofthepatientsdevelopedcandidemia.Symptomaticcandiduriaandinvasiverenalcandidiasis

No studies have specifically addressed symptomatic Candida cystitis and pyelonephritis (228). In a large randomizedcandidemiastudy,5patients(1.4%)presentedwithaprovenCandidapyelonephritisassourceofthecandidemia,mostlyrelatedtourinarytractobstruction(156).Echinocandinsdonotachievehighurineconcentrationsandarethusnotsuitableforurinarytractcandidiasis.Somecasesthoughhavesuccessfullybeentreatedwithcaspofungin(229).Bladderirrigationwithc-AmB(50-200μg/ml)hasbeenusedwithsuccess(230).Conclusions3.8–Treatmentofcandiduria –

Conclusion23 Inpatientswithasymptomaticcandiduria,initiationofantifungaltherapyhasnomeasurableeffectontheresolutionofcandiduriaortheclinicaloutcomes.

Level3 Sobel,2000(A2);Kauffman,2000(C)Conclusion24 Symptomaticcandiduriaorinvasiverenalcandidiasis,especiallyinthepresenceofaurinarytractobstruction,can

leadtocomplicationsandshouldbetreated.Level3 Kullberg,2005(C).Conclusion25 Systemicfluconazoleandc-AmBbladderirrigationaresuitablefortreatmentofsymptomaticurinarytract

candidiasis.Echinocandinsmaybeeffectiveininfectionswithparenchymalkidneyinvolvement.Level2 Tuon,2009(A1);Sobel,2000(A2);Sobel,2007(C);Fisher,2011(C).

RecommendationsAsymptomatic candiduria is common, but not associated with clinical consequences. Prospective studies show thatasymptomatic candiduria almost never leads to invasive candidiasis, and that antifungal treatment does not lead toeradicationanymorefrequentlythandoescatheterremovalorreplacement.Treatmentofasymptomaticcandiduriamaybeconsideredinpatientswithsevereneutropenia,withakidneytransplant,inneonateswithalowbirthweightandpriortorenalsurgery.Symptomaticascendingcandidiasis intheurinarytract isrelativelyrare, isusuallyassociatedwithanobstruction,and itscourse may be complicated. No studies have been conducted with respect to the specific treatment of this condition.Echinocandinsarenotexcretedintheurineandhavebarelybeeninvestigatedforthisindication.Itisrecommendedthatsymptomatic, invasive renalcandidiasisbe treatedwith fluconazole if susceptible. Incaseof fluconazole-resistance, localirrigationwithc-AmB isasuitablealternative; lipid formulationsofAmBdonotachieveappreciable levels inthekidneys


(228).Adurationoftreatmentof2weeksfollowingremovaloftheurinarytractobstructionseemsadequate;wheretherearestonesorotherforeignbodiesorpersistentobstructions,moreprolongedtreatmentisrequired.Fungalballsshouldbesurgicallyremoved.Recommendation22 Inasymptomaticcandiduria,removalorreplacementofurinarycathetersmustbeconsidered.

Thereisnoplaceforantifungaltreatment,exceptinpatientswithsevereneutropenia,kidneytransplant,inlowbirthweightneonates,andpriortorenalsurgery.

Recommendation23 Symptomaticcandiduriaorinvasiverenalcandidiasisshouldbetreatedwithfluconazole

(loadingdose800mg,followedby400mgqdfor2-4weeks).Incaseoffluconazole-resistance,localirrigationwithc-AmBisasuitablealternativeforlowerurinarytractcandidiasis.Fungalballsorpersistentobstructionsrequiresurgicalintervention.

3.9.AbdominalcandidiasisCandida peritonitis usually occurs following abdominal surgery, perforation of the gut or anastomotic leakage, or inconjunctionwithnecrotizingpancreatitis.Deep-seated infectionsmay remain localizedor lead to secondarycandidemia.Thelimitedpublisheddatasuggestthatinvasiveabdominalcandidiasismaybesignificantlymorecommonthanrecognized(231,232).Culturesfromnonsterilesites,suchaswoundsorsurgicaldrains,arefrequentlypositive,butlackspecificityfordifferentiating infection from colonization. The gold standard for deep-seated candidiasis are sterilely collected culturesobtainedbysurgery,punctureordraininsertion(232–235).Candidaobtainedfromindwellingsurgicaldrains(inplacefor>24h)arenotsufficientfordiagnosisofdeep-seatedcandidiasis,andshouldbeconsideredasacolonization(235).Theroleof biomarkers such as β-D-glucan and Candida mannan/anti-mannan has not been sufficiently established. In a Swissprospective cohort study among patients with recurrent GI tract perforation, anastomotic leakage, or necrotizingpancreatitis, and thus, at very high risk for abdominal candidiasis, the sensitivity of 2 consecutive positive β- D-glucanresultswas65%,andthespecificity78%(208).NorandomizedtrialshavebeenconductedspecificallyontreatmentofCandidaperitonitis.Thechoiceoftheappropriateantifungal agent for invasive abdominal candidiasis is mainly supported by indirect evidence from studies on invasivecandidiasis (155,158–160). Fluconazole and isavuconazolehavebeenassociatedwithhigher failure rates comparedwithechinocandins(160,162,166).Besidesantifungaltherapy,earlysourcecontrolismandatorytoreducemortality(169).Conclusions3.9–Managementofabdominalcandidiasis

Conclusion26 Candidaculturedfromsurgicallycollecteddeepsitesorfromrecently(<24h)inserteddrainsareindicativeofinvasivecandidiasis.Samplesobtainedfromdrainagetubesorwoundswabsarenotvaluablefordiagnosingdeep-seatedinfection

Level3 Calandra,1989(B);Sandven,2002(B);Bassetti,2013(C)Conclusion27 β-D-glucanmayhaveadditionaldiagnosticvalueinhigh-riskpatientswithanastomoticleakageoracute

necrotizingpancreatitisLevel3 Tissot,2013(B);ReviewedinKullberg&Arendrup,2015(D)Conclusion28 Successfultreatmentofintraabdominalcandidiasishasbeendescribedusingcaspofungin,micafungin,

anidulafungin,andL-AmB.Successrateswithfluconazoleandisavuconazoletendedtobelower.Level3 Andes,2012(A1);Mora-Duarte,2002,(C);Kuse,2007(C);Pappas,2007(C);Reboli,2007(C);Kullberg,

2016(C)

RecommendationsOn the basis of published trials and clinical experience, the committee’s recommendations for treatment of abdominalcandidiasisfollowthoseforcandidemiaanddisseminatedcandidiasis.Echinocandinsareconsideredthefirstchoice,exceptforC.parapsilosisinfection,forwhichfluconazoleisfavored.Basedonsusceptibilitypatters,L-AmBmaybeanappropriatealternative.Appropriatesourcecontrol, includingsurgicaldebridementanddrainage iscrucial intreatmentofabdominalcandidiasis.Step-downtofluconazoleshouldbeconsideredafterinitialechinocandintreatment,providedthatinfectedfocihavebeendrained,thepatientisclinicallyimproving,theisolatehasbeenconfirmedfluconazole-susceptible,andthepatienthasno


vascularorprosthesis-associatedcandidiasis.Thetotaldurationoftreatmentdependsprimarilyonsurgicalandradiologicalresolutionof infected foci, and shouldusuallybe2 to4weeksbutmaybeprolonged in caseofundrainedabscessesorvascularinvolvement.Theroleβ-D-glucanasabiomarkerforabdominalcandidiasishasnotbeensufficientlyestablished.Inasinglecohortstudy,2consecutiveβ-D-glucanresultshadareasonablepositiveandnegativepredictivevaluearound70%amongveryhighriskpatientswithrecurrentGItractperforation,anastomoticleakage,ornecrotizingpancreatitis(208).Whilethisapproach may be helpful in settings where β-D-glucan testing is available on a regular basis, the committee does notconsiderthesedatasufficientforageneralrecommendationonβ-D-glucanuseforthesepatientgroups.Recommendation24 Forpatientswithinvasiveabdominalcandidiasis,anechinocandin(anidulafungin,caspofungin,

ormicafungin)isthepreferredinitialtherapy.L-AmBisanappropriatealternativeincaseofechinocandinresistance.Appropriatesourcecontrol,includingsurgicaldebridementanddrainageiscrucialintreatmentofabdominalcandidiasis.Thedurationoftreatmentdependsprimarilyonsurgicalandradiologicalresolutionofinfectedfoci.Stablepatientsmaybesteppeddownfromanechinocandintofluconazoleafter≥5days,providedthatallinfectedfocihavebeendrained,thepatientisclinicallyimproving,theisolatehasbeenconfirmedfluconazole-susceptible,andthepatienthasnovascularorprosthesis-associatedcandidiasis.

3.10.Esophagealcandidiasis

The treatment ofCandida esophagitis has been investigated in various double-blind randomized studies, in particular inHIV-positive patients (236–240). In these studies, response rates with fluconazole, voriconazole, or isavuconazole were>95%. Conventional AmBwas inferior to echinocandins (238). Responseswith voriconazole, isavuconazole, caspofungin,micafungin, or anidulafunginwere not significantly different from the fluconazole comparator at or shortly after end oftreatment (236–240). However, the relapse rate 2 to 4 weeks after end of treatment was higher in the echinocandingroups.Acombinedanalysisof theabovestudiesbythecommitteesuggestsasignificantlyhigherpercentageofrelapsefollowing treatment with echinocandins compared to fluconazole (24 % vs. 10%; p<0.001). Posaconazole has not beeninvestigated for esophageal candidiasis in randomized studies. Two open-label studies suggested reasonable efficacy opposaconazolesuspension,butthetabletformulationhasnotbeeninvestigated(241,242).TheoptimaldoseanddurationoftreatmentinCandidaesophagitishavenotbeeninvestigated.Treatmentwithaminimumfluconazoledoseof200mgqd(loadingdose,400mg)foratleast2weeksisrecommended.Thisdurationcanbeprolongedonthebasisoftheclinicalandendoscopiccourse(whereavailable).Conclusions3.10–Treatmentofesophagealcandidiasis

Conclusion29 Echinocandinsaremoreeffectivethanc-AmB,andaseffectiveasfluconazoleforthetreatmentofCandidaesophagitisinimmunocompromizedpatients,butmoreoftenleadtorelapse

Level2 Villanueva,2001(B);Villanueva,2002(A2);DeWet,2004(A2);Ally,2001(A2);Krause,2004(A2);Viljoen,2015(A2)

Recommendation25 Foresophagealcandidiasis,fluconazole(loadingdose400mg,followedby200mgqd)for2

weeksisthepreferredtreatment.Incaseoffluconazoleresistance,voriconazole(basedonthesusceptibilityspectrum)iseligible,or,asasecondchoice,anechinocandin.

3.11.Antifungalprophylaxisintheintensivecareunit

Antifungalprophylaxisintheintensivecareunithasbeeninvestigatedinsubgroupsof(usuallysurgical)ICUpatientswithahigh riskof invasivecandidiasis. Inpatientswith recentabdominal surgeryand recurrentgastrointestinalperforationsoranastomotic leakages, fluconazoleprophylaxis (400mgqd)waseffective inaplacebo-controlledstudy, inasettingwitha


veryhighincidenceofCandidaperitonitisinthecontrolgroup(35%)(243).InotherselectedpatientgroupsintheICU,e.g.high-risk surgical patients with an estimated ICU stay >3 days, randomized, placebo-controlled studies have shown areductionofthe incidenceof invasivecandidiasisbyat least50%,butthestrategydidnot improvesurvival inanyofthestudies(244,245).Twometa-analysessuggestthatprophylaxiswithazolesisassociatedwithareductionofinvasivecandidiasis(fluconazole,RR0.21,95%CI0.06-0.72,p=0.01),butnotofmortality(246,247).Thevalueofthesemeta-analyses is limitedbythefactthat the studies included are heterogeneous (aimed at patients with a prolonged ICU stay, patients with anastomoticleakage, patientswith gut perforation or patientswith pancreatitis). Also, the dosage and duration of administration offluconazole(singledoseor100–400mgqd)variedwidely.A recent randomized study utilized targeted caspofungin prophylaxis in high-risk ICU patients, selected by a clinicalprediction rule (248). In this study, both serum ß-glucan and cultureswere used to define invasive candidiasis. Overall,therewerenosignificantdifferencesinincidenceofcandidemia,allcausemortality,antifungaldruguse,orlengthofstaybetweenthetwostudyarms(248).Clinicalpredictionrulesforprophylaxis

Defining a subgroup of ICU patients with a high risk of invasive candidiasis, for whom antifungal prophylaxis may beefficient,hasfailedtodate.IntheUS,predictionrulesforpatientswithahighriskofcandidemiaidentifiedasubgroupwitha10.1%incidenceofinvasivecandidiasis(249,250).However,theruleidentifiedonly50%ofallpatientswithcandidemiaafter day 4. Applying the prediction rule, therefore, will fail to identify the majority of the patients who developcandidemia.Moreover,theclinicalutilityofpredictionrulesisshapedbythelowprevalenceofinvasivecandidiasis(151).IntypicalICUsettingsintheNetherlands,wherethepretestlikelihoodofcandidiasisis0.5–1%,riskfactor-basedruleswithaspecificityofaround80%willmerelyleadtoapositivepredictivevalue(PPV)of1.5to3%,andanumberneededtotreatof70to140.Conclusions3.11–Antifungalprophylaxisinpatientsintheintensivecaresetting

Conclusion30 Fluconazoleprophylaxis(400mgqd)iseffectiveinpreventingintra-abdominalcandidiasisinpatientsundergoingrelaparotomyforanastomoticintestinalleakageincircumstancescharacterizedbyahighincidenceofcandidiasis,andreducestheincidenceofinvasivecandidiasisinapredefinedcategoryofhigh-riskICUpatients.CaspofunginprophylaxishasnotbeenshowntoreducetheincidenceofinvasivecandidiasisintheICU.

Level1 Eggimann,1999(B);Pelz,2001(A2);Garbino,2002(A2);Ostrosky-Zeichner,2014(A2)Conclusion31 Theuseofclinicalpredictionrulestoselectpatientsforantifungalprophylaxisintheintensivecarehasnotleadto

improvedclinicaloutcomesorsurvivalinpublishedstudies.Level2 Ostrosky-Zeichner,2011(C);;Ostrosky-Zeichner,2014(A2)

RecommendationsAntifungalprophylaxisinICUpatientsisnotsupportedbyclinicalstudies,fromwhichresultshavebeennegative,oratmostmodest.Themajorchallengeistoselectindividualpatientsorsubgroupswhowillbenefitmostfromprophylaxis,inordertolimitthenumberneededtotreat.IntheNetherlands,wheretheincidenceofinvasivecandidiasishastraditionallybeen<1% in the ICU, trial results and algorithmspublished fromhigh-incidence settings donot apply. In addition, the use ofselectivedecontamination(SD),containingnon-resorbablec-AmBornystatin,hasbeensuggestedtobeassociatedwithafurther declining incidenceof candidemia. The committee considers prophylaxiswith fluconazole to be effective in veryselected high-risk situations, such as those involving patients undergoing relaparotomy following anastomotic intestinalleakageinunitswithaveryhighincidenceofinvasivecandidiasis,aswellasforpancreas,smallbowel,andselectedhigh-risklivertransplantrecipients(seechapter3.13).Recommendation26 Prophylaxiswithfluconazoleinintensivecareisnotrecommended,exceptinspecific

situations,suchasrelaparotomyfollowinganastomoticintestinalleakageinunitswithanunacceptablyhighlocalincidenceofinvasivecandidiasis.

3.12.Antifungalprophylaxisinpatientswithhematologicalmalignanciesorsolidorgantransplantrecipients

Hemato-oncologypatients

GastrointestinaltractcolonizationwithCandidaspp.isrecognizedasariskfactorfordisseminatedcandidiasisinneutropenichematologypatients,especiallyHSCTrecipients.Inthe1990s,tworandomizedstudieshavedemonstratedthe


benefitoforalfluconazole(400mg/dupto75daysposttransplant)asantifungalprophylaxisafterHSCT(251,252).Moreover,long-termfollow-uphasshownanimprovedlong-termsurvivalbenefitofprophylaxis(253,254).However,recentchangesintransplantationpractices,includingtheuseofperipheralbloodstemcells(PBSC),reducedintensityconditioning(RIC)regimenswithbetterpreservationoftheintestinalbarrierandfeweroralmucositismightchallengethevalueoffluconazoleprophylaxis.Ingeneral,autologousHSCTisnotconsideredahigh-risksituationforinvasivecandidiasis,becauseoftheshortneutropenicphase.Anti-CandidaprophylaxishasremainedrecommendedforallogeneicHSCTduringtheneutropenicphaseaftermyeloablativeregimens,andisusuallycontinueduntil100dayspost-HSCT.

Conclusions3.12–Anti-Candidaprophylaxisinhemato-oncologypatients

Conclusion32 FluconazoleprotectsagainstinvasivecandidiasisinpatientsundergoingallogeneicHSCT.Level1 Goodman,1992(B);Slavin,1995(B);Marr,2000(B)Recommendation27 Fluconazole(400mgqd)anti-CandidaprophylaxisisrecommendedforallogeneicHSCT

recipientsduringtheneutropenicphasewhodonotreceiveanti-moldprophylaxis.Prolongedprophylaxisupto100daysposttransplantmaybeconsidered

Lungtransplants

Several studies have assessed the use of fluconazole, voriconazole, or aerosolized conventional or lipidAmB as primaryprophylaxisinlungtransplantrecipients(255–259).Studiesofantifungalprophylaxiswithanti-moldazolesorinhaledAmBformulationsoveralldemonstrateddecreasedratesofinvasivefungalinfectionascomparedwithhistoricalcontrols,butasmoststudieswerenotprospectivelydesignedandrandomized,noconclusioncanbedrawnabouttheoptimalchoice.Livertransplants

Prophylaxis against invasive mycoses in liver transplant patients has been studied using L-AmB (260–262), ABLC (263),fluconazole(264),anidulafungin(265),ormicafungin(266).Inthelatterstudy,344high-riskpatientsreceivedmicafunginorcenter-specificstandardcareposttransplant.Clinicalsuccesswas96.5%formicafunginand93.6%forstandardcare(Δ-2.9%[-8.0%to1.9%]).Inanearliermeta-analysisofantifungalprophylaxis in livertransplantpatients(267), fluconazoleresulted inasignificantreductionofinvasivemycoses,butwithouteffectonmortality.Inarecentmeta-analysisincluding14randomizedstudies(268),antifungalprophylaxisreducedtherateofproveninvasivefungalinfections(OR0.37,95%CI0.19–0.72,p=0.003),andmortalityduetofungalinfections(OR0.32,95%CI0.10–0.83,p=0.02)whencomparedtoplacebo.Anequivalentreductionintherateoffungalinfectionswasseenspecificallywithfluconazole(OR0.21,CI0.06–0.57)andL-AmB(OR0.21,CI0.05–0.71)(268).Factors associatedwith an increased risk of invasivemycoses in liver transplant patients include renal insufficiency, re-transplantation,choledochojejunostomy,perioperativemassivebloodtransfusion,orfungalcolonizationaroundthedayoftransplantation,andinabsenceoftheseriskfactors,theriskofinvasivefungalinfectionisverylow(267,269).Othersolidorgantransplants

Theincidenceofinvasivemycosesinpatientsundergoingkidney,kidney-pancreas,orhearttransplantationislow(270),andstudiesofthepossibleeffectofantifungalprophylaxishavenotbeenconductedinthesepatientgroups.Conclusions3.12–Antifungalprophylaxisinsolidorgantransplantation

Conclusion33 Inlivertransplantpatientswithoutspecificriskfactors,theincidenceofinvasivemycosesisverylow.Fluconazole,L-AmB,anidulafungin,andmicafunginareeffectiveinthepreventionofinvasivemycosesinhigh-risklivertransplantpatients.

Level1 Playford,2006(A1);Evans,2014(A1);Pappas,2006(B);Winston,2014(B)Conclusion34 Theincidenceofinvasivemycosesinpatientsundergoingkidney,kidney-pancreas,orhearttransplantationislow,

andafavorableeffectofantifungalprophylaxishasnotbeendemonstratedinthesegroups.Level3 Pappas,2010(B)Recommendation28 Fluconazole(400mgqd)isonlyrecommendedforpatientsundergoinglivertransplantation

whohaveanelevatedriskofinvasivemycoses,i.e.,thosewithrenalinsufficiency,re-transplantation,choledochojejunostomy,perioperativemassivebloodtransfusion,orprovenperioperativecolonizationwithCandida.


3.13.Antifungalprophylaxisinneonates

Prophylaxiswithfluconazolewasinvestigatedintenplacebo-controlledstudiesinprematureneonateswithverylowbirthweight(definedas<1500,<1000,or<750g)(271).InaCochranemeta-analysis(272),fluconazolesignificantlyreducedtheincidenceofinvasivecandidiasis,butnottheriskofdeathpriortohospitaldischarge.Inthemostrecentstudyamong362infants<750g,theprimarycompositeendpointofdeathorinvasivecandidiasiswasnotsignificantlydifferentbetweenthestudyarms(273).Fluconazolehadnoeffectonneurodevelopmentaloutcomesat18-22months.Theincidenceofinvasivecandidiasis among neonates has been decreasing, and it is questionable whether prophylaxis of invasive candidiasistranslatesintosubstantialimprovementsintheoutcomesofprematurity(273).Conclusions3.14–Antifungalprophylaxisinprematureneonates

Conclusion35 Fluconazoleprophylaxisreducestheincidenceofinvasivecandidiasisinprematureneonateswithaverylowbirthweight,butisnotassociatedwithanimprovedsurvivalorneurodevelopmentaloutcomes.

Level2 Cleminson,2015(A1);Benjamin,2014(A2)Recommendation29 Inprematureneonateswithaverylowbirthweight,fluconazoleprophylaxis(3mg/kgtwice

weekly)shouldonlybeconsideredinsettingsinwhichthereisaprovenhighincidenceofinvasivecandidiasis.


Chapter4 Cryptococcosis

4.1.CryptococcalmeningitisImmunocompromized patients, e.g., HIV/AIDS patients or organ transplant recipients, have an increased risk ofcryptococcalinfection.Themajorityofpatientspresentwithsubacutemeningitisormeningoencephalitis.Theprincipleofrapid fungicidalactivityshouldbetheprimary focusofany inductionstrategy (274),andsterilizationof theCSFwithin2weeks is significantly associated with favorable outcome (275). This was underlined in a recent study (276), wherefluconazole-basedinductiontreatmentandslowclearanceofCSFinfectionwereindependentlyassociatedwithincreasedmortality. Other determinants of mortality were: altered mental status (OR, 3.1), high cerebrospinal fluid (CSF) fungalburden(OR,1.4perlog10cfu/mLincrease),olderage(>50years;OR,3.9),andhighperipheralwhitebloodcellcount(>10×109/L;OR,8.7)(276).Inavarietyofrandomizedtrials,afungicidalinductionstrategyusingcombinationtherapyofc-AmBwithflucytosine(5-FC)yieldedbetteroutcomesthanc-AmBmonotherapy(274,275,277–279).Fluconazolemonotherapyhasbeenassociatedwithhigher mortality and poorer outcomes in comparative trials (276,280,281). Combination therapy consisting offluconazole+5-FCwasmorefungicidalthanfluconazolemonotherapy,andassociatedwithsignificantlyfewerdeaths(282).Severaltrialshavefurtherdefinedtheimportanceofrapidfungicidalactivity.InarandomizedstudyamongpatientswithcryptococcalmeningitisinThailand,fourtreatmentstrategieswerecompared:c-AmB,c-AmB+5-FC,c-AmB/fluconazole,orc-AmB+5-FC+fluconazole,allfor2weeks(274).TheprimaryendpointwastherateofreductioninCSFcryptococcalcolony-forming units (CFUs) from repeated CSF cultures. Combination therapywith c-AmB and 5-FCwas themost effective insterilizingtheCSFcomparedwithmonotherapyc-AmB(p<0.001),c-AmB+fluconazole(p=0.02)andc-AmB+5-FC+fluconazole(p=0.02). Ina subsequent, large, randomized trial inVietnam,c-AmBmonotherapywascompared toc-AmB+5-FCandc-AmB+fluconazole (at a dose of 400mg twice daily) (279). Mortality was lower among patients receiving c-AmB+5-FCcompared to c-AmBalone (HR, 0.61; 95%CI, 0.39, 0.97; P = 0.04). Combination therapywith c-AmB+fluconazole yieldedintermediate results (comparedwith c-AmBmonotherapy, HR 0.71; 95%CI, 0.45, 1.11; P=0.13). In a smaller 4-arm trial(278), c-AmB+5-FC, c-AmB+fluconazole (800 mg daily), AmB+fluconazole (600 mg daily), and AmB+voriconazole werecompared.TherewerenostatisticallysignificantdifferencesinmortalityortherateofCFSclearanceofcryptococcalCFUamong the 4 treatment groups, suggesting that AmB plus fluconazole or voriconazole is an effective alternativecombinationtoc-AmB+5-FC,ifthelatterisunavailable(278).Differentdosagesofc-AmB(0.7vs1.0mg/kgperday)plusflucytosinehavebeencompared,andthehigherdosagewasmorefungicidal,althoughnodifferenceinmortalitywasobserved(283).Severaltrialshavecomparedc-AmBtoL-AmBforthetreatmentofcryptococcalmeningitis.Intwosmallpilotstudies,monotherapywithL-AmByieldedsimilaroutcomesasc-AmB monotherapy (284,285). Monotherapy with c-AmB was compared to L-AmB (3mg/kg/d) and L-AmB (6mg/kg/d)(286).Efficacywassimilaramongall3treatmentgroups.The2-weekmycologicalsuccessofL-AmB3mg/kg(64%)and6mg/kg (54%)was similar.The lowerdoseof L-AmBwasaccompaniedby significantly feweradverseeffects, inparticularnephrotoxicity(286).Adjunctivetherapy

There is ample evidence that endogenous interferon-γ (IFN-γ) production is associated with the rate of clearance ofcryptococci from CSF (287,288). In a double-blind, placebo-controlled pilot study (289), adjuvant immunotherapy withrecombinant IFN-γ (100µg vs. 200µg 3 x per week) was compared to placebo in patients with cryptococcal meningitisreceiving standard therapy (c-AmB+5-FC). CSF sterilization after 2 weeks tended to be greater with rIFN-γ (p=0.064),compared to standard therapy (289). In a larger controlled trial (290), patients receiving standard therapy (c-AmB+5-FC)wererandomizedtoreceivenoadjunctivetherapy,rIFN-γ(100µg)ondays1and3(rIFN-γtwodoses),orondays1,3,5,8,10and12(rIFN-γsixdoses).PrimaryoutcomewasrateofclearanceofCryptococcusfromtheCSF(earlyfungicidalactivity,EFA),previouslyshowntobeindependentlyassociatedwithsurvival.RateoffungalclearancewassignificantlyfasterintherIFN-γgroupsthanwithstandardtreatment.MeanEFA[logcolonyformingunit(CFU)/mlperday]was-0.49withstandardtreatment,-0.64withrIFN-γtwodoses,and-0.64withrIFN-γsixdoses(P<0.02).Mortalitywas16%at2weeksand31%at10weeks,withnosignificantdifferencebetweengroups.Alltreatmentswerewelltolerated(290).The use of adjuvant corticosteroids in patients with cryptococcal meningitis has been supported by preclinical andobservationaldata.However,dexamethasonewasshowntobedeleteriousinarecentrandomizedtrial(291).Inthisstudy,inpatientswithcryptococcalmeningitiswererandomizedtoreceiveeitherdexamethasoneorplacebofor6weeks,alongwithcombinationantifungaltherapywithAmBandfluconazole.Thetrialwasstoppedforsafetyreasonsafterenrollmentof451 patients. Fungal clearance in CSF was significantly slower in the dexamethasone group. The endpoint of death ordisabilityat10weekswashigherinthedexamethasonegroup(ORforgoodoutcome,0.42;95%CI,0.25to0.69;P<0.001).


Adverse events were more common in the dexamethasone group (P=0.01), with significantly more patients in havingsecondary infection, renal events, or cardiac events. In addition, there was no reduction in paradoxical IRIS (immunereconstitution)reactionswithdexamethasone.Auto-antibodies againstGM-CSFhavebeen reported in apparently immunocompetentpatients infectedbyCryptococcusgattii. These autoantibodies can be functionally tested and also determined in serum. The presence of these auto-antibodiesmayguideinitiationofimmunotherapywithhigh-doserGM-CSF,inadditiontoantifungaltherapy(292). Elevationofintracranialpressureincryptococcalmeningitis

Elevated intracranial pressure in patients with cryptococcal meningitis is associated with a less favorable prognosis(275,293).However,earlierstudieshavenotclearlydemonstratedanassociationbetweenbaselineopeningpressureand2-weekmortality.Inarecentstudy(294),patientsunderwentanLPtodiagnosecryptococcalmeningitis,andsubsequenttherapeutic LPswere recommended forelevated intracranialpressure (>25cmH2O)ornewsymptoms.Allpatientsweretreated with combination antifungal therapy with AmB and fluconazole. Therapeutic LPs were associated with a 69%relativeimprovementinsurvival,regardlessofinitialintracranialpressure.Theadjustedrelativeriskofmortalitywas0.31(95%CI,0.12to0.82)(294).Antiretroviraltherapy Earlystartofcombinationantiretroviraltherapy(cART)hasbeenassociatedwithbetteroutcomesofseveralAIDS-defininginfectiousdiseases.Inasmallrandomizedstudy,earlycARTwasassociatedwithatrendtowardshighermortality(295).Inalarge, sufficiently powered trial (296), HIV-infected patients with cryptococcal meningitis and no previous cART wererandomized to initiate early cART (1-2 weeks after diagnosis) or deferred cART (after 5 weeks). All patients receivedcombination antifungal therapy with c-AmB and fluconazole. The 26-week mortality with earlier cART initiation wassignificantlyhigherthanwithdeferredcARTinitiation(45%vs.30%;HRfordeath,1.73;95%CI,1.06to2.82;P=0.03).TheexcessdeathsassociatedwithearliercARTinitiationoccurred2to5weeksafterdiagnosis(P=0.007),particularlyinpatientswithlowCSFleukocytecounts(<5/mm3)atbaseline.TheincidenceofcryptococcalIRISdidnotdiffersignificantlybetweenthegroups(296).

Conclusions4.1–Treatmentofcryptococcalmeningitis

Conclusion1 CombinationtherapywithAmBplus5-FCleadstomorerapidsterilizationofCSFandbettersurvivalthanmonotherapywithAmB.

Level1 Bennett,1979(A2);vanderHorst,1997(A2);Brouwer,2004(A2);Loyse,2012(A2);Day,2013(A2)Conclusion2 FluconazoleinductiontherapyresultsinslowerclearanceofCSFinfectionandincreasedmortalitycomparedto

AmBofAmBplus5-FC.Level1 Saag,1992(A2);Brouwer,2004(A2);Larsen,1990(B);Jarvis,2014(B)Conclusion3 ThecombinationofAmBplusfluconazole(800mg/d)resultsinareasonablerateofCSFclearance.Level1 Brouwer,2004(A2);Loyse,2012(A2);Day,2013(A2)Conclusion4 L-AmB(3mg/kg/d)hassimilarefficacyasc-AmBincryptococcalmeningitisandisassociatedwithsignificantlyless

nephrotoxicityandothersideeffects.Level2 Hamill,2010(A2)Conclusion5 AdjunctivetherapywithrIFN-γ(100µg)ondays1and3ofantifungaltherapyleadstomorerapidclearanceofCSF

infection.Level1 Pappas,2004(A2);Jarvis,2012(A2)Conclusion6 Adjunctivetherapywithdexamethasoneisassociatedwithmoreadverseeventsanddisability,andhighermortality

inpatientswithHIV-associatedcryptococcalmeningitis.Level2 Beardsley,2016(A2)Conclusion7 Auto-antibodiesagainstGM-CSFmaybeassociatedwithcryptococcosisinapparentlyimmunocompetentpatients.Level3 Saijo,2014(C)Conclusion8 Inpatientswithelevated(>25cmH2O)intracranialpressureornewevents,repeatedtherapeuticlumbarpunctures

areassociatedimprovementinsurvival,regardlessofinitialintracranialpressure.Level3 Rolfes,2014(B)Conclusion9 DeferringcARTfor5weeksafterthediagnosisofcryptococcalmeningitisisassociatedwithsignificantlyimproved

survival,ascomparedwithinitiatingcARTat1to2weeksLevel2 Bisson,2013(B);Boulware,2014(A2)

RecommendationsRecent randomized trials havedemonstrated the importanceof rapid sterilizationof theCSF as amajor determinantofpatient survival in the treatment cryptococcalmeningitis (274,276,278,279). Induction therapywith the combination of


AmBand5-FCisassociatedwithrapidCSFclearanceandbettersurvivalcomparedtootherinductionregimens.Inviewoftheseveretoxicityofc-AmBandtheextensiveclinicalexperiencewithL-AmBfortreatmentofcryptococcalmeningitis,thecommittee considers c-AmB no longer indicated. This policy is in agreement with the treatment recommendations foraspergillosis,candidiasisandmucormycosisinthisguideline,aswellaswithinternationalexpertopiniononcryptococcosis(297).Therefore, L-AmB (3mg/kg/d)combinedwith5-FC (100mg/kg/d;with therapeuticdrugmonitoring) forat least2weeksisthepreferredinductiontherapyforallpatientswithcryptococcalmeningitis.ItmustbeemphasizedthatcontrolofCSFpressureisacriticaldeterminantofoutcome,andantifungaltherapyshouldbecombinedwithoptimalpressuremanagement.Repeatedtherapeuticlumbarpuncturesmayberequiredforpatientswithelevatedintracranialpressureorclinicaldeterioration(294).If5-FCiscontraindicated,thecombinationofL-AmBplusfluconazole(800mg/d)isareasonablealternative,althoughtheCSFclearanceandsurvivalratewiththisregimenwerelessfavorablethanthosewithAmB+5FCinthelargesttrial(279).In patients who have responded favorably, induction therapy should be followed by fluconazole (loading dose 800mg,followedby400mgqd)foratotalofatleast10weeks(298).Subsequently,fluconazolemaintenancetherapy(orsecondaryprophylaxis)shouldbeprescribed(seeparagraph4.3).Adjunctivetherapywithdexamethasonehasbeendemonstrateddeleterious inpatientswithcryptococcalmeningitisandshouldnotbegiven(291).Incontrast,rIFN-γadministrationwasassociatedwithasignificantlygreaterrateofclearanceofCryptococcus fromtheCSF (early fungicidalactivity,EFA) in tworandomizedtrials (289,290).While thesetrialswerenotpowered to demonstrate a survival benefit, the EFA is known to be an important determinant of outcome and survival(274,276).AstwodosesofrIFN-γ(100µg)ondays1and3wereaseffectiveassixdosesinthecomparativetrial(290),itissuggestedthat2dosessufficeinrespondingpatients,whilerIFN-γmaybecontinuedtwiceweekly inpatientswitha lessfavorable clinical response.As the trialswerenotdesigned todemonstratea survivalbenefitofadjunctive therapywithrIFN-γ,thecommitteeconsidersthepresentdatanotstrongenoughtorecommendrIFN-γasstandardadjunctivetherapyinallpatientswithseverecryptococcosis.Recommendation1 CryptococcalmeningitisshouldbetreatedwithL-AmB(3mg/kg/d)plus5-FC(100mg/kg/d)for

atleast2weeks.Thereafter,thetreatmentofstableandfavorablyrespondingpatientsmaybecontinuedwithfluconazole(loadingdose800mg,followedby400mgqd),foratotalofatleast10weeks,followedbychronicmaintenancetherapy.

Recommendation2 Forpatientswithcontraindicationsto5-FC,inductiontherapywithL-AmB(3mg/kg/d)plus

fluconazole(400mgtwicedaily)foratleast2weeksisanacceptablesecondchoice.

Recommendation3 AdjunctivetherapywithrIFN-γ(100µg)ondays1and3maybeconsideredforpatientswithcryptococcalmeningitis.Inpatientswithaslowclinicalresponse,rIFN-γmaybecontinuedtwiceweekly.

Recommendation4 ControlofCSFpressureisacriticaldeterminantofoutcome,andrepeatedtherapeuticlumbarpuncturesarerequiredforpatientswithelevatedintracranialpressureorclinicaldeterioration.

Recommendation5 Dexamethasoneadjunctivetherapyiscontraindicatedinpatientswithcryptococcalmeningitis.

Recommendation6 IncART-naïveHIV-infectedinpatientswithcryptococcalmeningitis,theinitiationofcARTshouldbedeferreduntil5weeksafterstartofantifungaltherapy.

Recommendation7 InapparentlyimmunocompetentpatientswithC.gattiiinfectionauto-antibodiesagainstGM-

CSFshouldbetested,toguideinitiationofrGM-CSFimmunotherapy.

4.2.TreatmentofnonmeningealcryptococcosisExtrameningealcryptococcal infectionoccursmainly inpatientsnot infectedwithHIV.Pulmonarycryptococcosis includesclinicalpresentationsrangingfromasymptomaticpneumoniatodiffuseinterstitialpneumoniaandssevereARDS.Therearenoprospectivestudiesthatspecificallyaddressthemanagementofpulmonarycryptococcosisoranyothernonmeningealmanifestations.Case serieshavedescribed treatmentof suchpatientsmostlywith L-AmBwithorwithout5-FC,while c-AmB and fluconazole were alternative regimens. (299–302). In a large case series including 208 HIV-positive and HIV-negative patients presenting with or without meningitis, combination therapy for ≥14 days of AmB plus 5-FC wasindependentlyassociatedwithimprovedoutcomesinamultivariateanalysis(302).Non-HIVpatientswithcryptococcosisasacomplicationofT-celldeficitsreportedlybenefitfromadjunctiveimmunotherapywithrIFN-γ(112,303).


Conclusion4.2–Treatmentofnonmeningealcryptococcosis

Conclusion10 Althoughrandomizedstudiesspecificallyaddressingpatientswithnonmeningealcryptococcosisarelacking,cohortstudiessuggestthatcombinationtherapywithAmBplus5-FCleadstomorerapidsterilizationofCSFandbettersurvivalthanalternativeinductionregimens.

Level3 Dromer,2009(B).Conclusion11 AdjunctivetherapywithrIFN-γ(100µgtwiceweekly)restoresanti-cryptococcalhostdefensesinpatientswith

functionalT-celldefectsandinvasivecryptococcosis.Level3 Netea,2004(C);Delsing,2014(C)

RecommendationsNo studies of sufficient quality havebeen conducted in patientswith extrameningeal cryptococcosis. The available datasuggestthattheearlyfungicidalactivity(EFA)associatedwithcombinationtherapywithAmBplus5-FCisalsoimportantinnonmeningealcryptococcosis,especiallyinimmunocompromizedpatients(300–302).Therefore,thecommitteeconsidersL-AmBplus5-FCthetherapyofchoiceforallpatientswithcryptococcosis.Fluconazolemaybeareasonablealternativeforpatientswithmild,localized,nonmeningealinfection,andlesssevereimmunosuppression.Whenconsideringthisoption,itis important to exclude cryptococcal meningitis, disseminated disease and cryptococcemia. This requires that a lumbarpunctureandbloodculturesshouldbeperformed.Basedon the functionalT-celldefectsgenerallyunderlying invasiveordisseminatedcryptococcosis (112,303),adjunctiveimmunotherapy with rIFN-γ may be considered for all patients with severe meningeal, pulmonary or disseminatedcryptococcosis, and those in whom T-cell immunity cannot be restored by cART or withdrawal of immunosuppressivetherapy.The duration of antifungal therapy in non-meningeal cryptococcosis has not been investigated, but lengthy treatment(usually≥6months)isassumedtobenecessary.Recommendation8 NonmeningealordisseminatedcryptococcosisshouldbetreatedwithL-AmB(3mg/kg/d)plus

5-FC(100mg/kg/d)foratleast2weeks.Consolidationtherapyofstableandfavorablyrespondingpatientsshouldfollowwithfluconazole(loadingdose800mg,followedby400mgqd,for6to12months).

Recommendation9 Fluconazole(loadingdose800mg,followedby400mgqd,for6to12months)maybeareasonablealternativeforpatientswithmild,localized,nonmeningealinfection,andlesssevereimmunosuppression.Beforeconsideringthisoption,alumbarpunctureandbloodculturesarerequiredinallpatients,toruleoutcryptococcalmeningitis,disseminateddiseaseandcryptococcemia.

Recommendation10 AdjunctivetherapywithrIFN-γ(100µgtwiceweekly)maybeconsideredforallpatientswithseveremeningeal,pulmonaryordisseminatedcryptococcosis,andforpatientsinwhomT-cellimmunitycannotberestoredbycARTorwithdrawalofimmunosuppressivetherapy.

4.3.SecondaryprophylaxisofcryptococcosisWiththeintroductionofearlycARTforallHIV-infectedpatientswithlowCD4+cellcounts,primaryantifungalprophylaxisforcryptococcosisisnolongerrequiredforHIV-infectedpatientsintheUnitedStatesandEurope.Despiteexistingevidencesuggestingthatmostcryptococcaldiseaseintransplantrecipientslikelyresultsfromreactivationof a subclinical infection, there are no data suggesting that routine primary prophylaxis for cryptococcosis in transplantrecipientswouldbebeneficial.Secondaryprophylaxisisrequiredforpatientswhohavesufferedfrominvasivecryptococcosis,inviewoftheirunderlyingimmunedefect. For thepreventionof cryptococcalmeningitis relapse inHIV-infectedpatients, several randomized trialshavedemonstratedthesuperiorityoffluconazoleoverplacebo,c-AmB,oritraconazole(304–306).

Severalstudieshavedemonstratedthatdiscontinuationofsecondarycryptococcalprophylaxis (fluconazole200mgqd) inpatients with a CD4 count of >100/µl and an undetectable HIV RNA during cART is safe and does not lead to relapses(307,308). Therefore, it is recommended to discontinue antifungal maintenance therapy for cryptococcosis in patientswhoseCD4cellcountsare≥100cells/µL,whohaveundetectableviralloadsoncARTfor>3months,andwhohavereceivedaminimumof1yearofmaintenancetherapyaftersuccessfultreatmentofcryptococcosis(309).Insolidorgantransplantrecipientswhoreceivelong-termimmunosuppressivemedicationanddidnotreceivesecondaryprophylaxis,relapsesofcryptococcosisfrequentlyoccurredwithin6months,andinallcaseswithin1yearaftercessationofantifungaltherapy(300,301).Thus,continuationofmaintenanceantifungaltherapywithfluconazole200-400mg/dayinsolid-organtransplantrecipientsforatleast6andupto12monthsisrational.


Conclusions4.3–Secondaryprophylaxisofcryptococcosis

Conclusion12 Fluconazole(200mgqd)iseffectiveinthepreventionofcryptococcosisrelapsepatientswithpersistenthostdefensedeficits.

Level1 Bozzette,1991(A2);Powderly,1992(A2);Saag,1999(A2);Singh,2005(C)Conclusion13 SecondaryantifungalprophylaxisinpatientshavinghadcryptococcalmeningitiscanbediscontinuedinHIV-positive

patientswhohaveafavorableimmunologicalandvirologicalresponsetocART(CD4>100cells/µlandHIVload<50copies/ml,for>3months),andafter6to12monthsafterresolutionofcryptococcosisinsolidorgantransplantrecipients.

Level2 Vibhagool,2003(A2);Mussini,2004(B);Singh,2005(C);Singh,2009(D).Recommendation11 Chronicmaintenancetherapywithfluconazole(200mgqd)isrequiredforpatientswhohave

sufferedfrominvasivecryptococcosisandcontinuetohaveanunderlyingimmunedefect.Insolidorgantransplantrecipients,maintenancetherapywithfluconazole(200-400mgqd)for6-12monthsisrecommended.

Recommendation12 Afteraminimumof1yearaftersuccessfultreatmentofcryptococcosis,chronicmaintenancetherapycanbediscontinuedinsolidorgantransplantrecipients,andinHIV-positivepatientswithCD4counts≥100cells/µL,whohaveundetectableviralloadsoncARTfor>3months.


Chapter5 MucormycosisIntroduction

Mucormycosis,alsoknownasZygomycosis,isaninfectioncausedbyfungibelongingtotheorderMucorales.ThegeneraofmucoralescausingdiseaseareRhizopus,Mucor,Lichtheimia,Cuninghamella,Rhizomucor,SaksenaeaandApophysomyces.Rhizopusarrhizus(Rhizopusoryzae)isthemostfrequentlyisolatedpathogeninmucormycosis(310–312).Mucormycosisisoften a severe and fatal infection and themost common sites ofmucormycosis are the paranasal sinuses and adjacentareas (rhinocerebral, sino-orbitalandsinopulmonarymucormycosis), the lungs, theskin,andthebrain (311). Inchildren,mucormycosismayoccurinthegastro-intestinaltract(313).The incidence of invasive mucormycosis appears to be rising (from 0.09% to 0.17%) in recent years, especially inhematological patients (314), which has been related to the increasing use of voriconazole (315). The conduct ofprospective, randomized studies of the treatment of mucormycosis is difficult due to its low incidence. Data on thetreatmentofmucormycosisarethereforepredominantlybasedonclinicalexperienceandretrospectiveanalyses.

5.1.DiagnosisofmucormycosisSimilartoaspergillosis,mucormycosisisdiagnosedasproven,probableorpossibleaccordingtoEORTC/MSGcriteria.DirectmicroscopycanbeusefulindistinguishingMucoralesfrommorecommonfilamentousfungisuchasAspergillusorFusarium,sinceMucoraleshavebroadnon-septatehyphaewithirregularribbon-likeappearance(316).Histologyfrompatientswithmucormycosispredominantlyshowsneutrophilicinflammatoryresponsesandinvasivediseasewascharacterizedbyinfarctionandangioinvasion;angioinvasionismoreprominentinneutropenicpatients(316,317).SinceMucoralesdonotcontainsignificantgalactomannanandb-glucanintheircellwall,diagnostictestssuchasgalactomannanandb-D-glucanassaysarenothelpful(318).Thus,anegativeGMindexinBALintheclinicalcontextofsuspectedpulmonaryinvasivefungaldiseaseshouldraisesuspicionformucormycosis(17,319).Radiologicalsignsarenotveryspecific,althoughareversedhalosign,whichisarimofconsolidationsurroundingacenterofgroundglassopacityonCT,mightindicatepulmonarymucormycosis(320,321).Inastudyinvestigatingradiologicimagingin189patientswithprovenorprobablepulmonaryinvasivefungalinfectionareversehalosignwaspresentin19%ofpatientsdiagnosedwithmucormycosiscomparedto<1%forotherfungalinfections(321).Mucoralesgrowrapidly,howevernegativeculturesofmucoraleshavebeenassociatedwithaggressivehandlingofthespecimenbeforeplating,suchasgrinding(322).Conclusions5.1.–Diagnosisofmucormycosis

Conclusion1 Directmicroscopyisusefulindistinguishingmucormycosisfromotherinvasivefungalinfectionsandseptation,width,branchingangleandmorphologyshouldbeevaluated.Aggressiveprocessingofthespecimensisassociatedwithnegativecultures.

Level3 Ribes,2000(C);Frater,2001(C)Conclusion2 AnegativeGMindexinserumandBALintheclinicalcontextofsuspectedpulmonaryinvasivefungaldisease

increasethelikelihoodofmucormycosis.Level3 Maertens,2005(C);Pang,2012(C)Conclusion3 AreversehalosignonCTisanindicatorofmucormycosis.Level3 Wahba,2008(C);Juan,2014(C)

Recommendation1Directmicroscopyofclinicalspecimensfollowedbycultureisstronglyrecommendedforthediagnosisofmucormycosis.

5.2TreatmentofinvasivemucormycosisMostexperienceinthetreatmentofinvasivemucormycosishasbeengainedwithc-AmB(323).Retrospectiveanalysesofprimary and salvage therapy with ABLC (116,324) and ABCD (325) have suggested response rates of 50 to 75%. In aretrospectivestudy in58patientswithhematologicalmalignanciesandmucormycosis,multivariateanalysis showedthattheonly factorassociatedwithcurewastreatmentwith liposomalamphotericinB (326).Similarly,L-AmB(averagedose,5mg/kg)wasassociatedwithabetterclinicaloutcomeandsurvivalinaninternationalregistry(327).AphaseIIstudyinvestigatedtheefficacyandtoxicityofhigh-doseL-AmB(10mg/kg)asfirst-linetherapyformucormycosis.Response rate at 12 weeks was 45% and renal toxicity was frequently observed (40%) (328). Anecdotal reports have


suggestedabenefitofthecombinationofABLCandcaspofungin(329).However,arecentretrospectivestudyamong101patientswithmucormycosisdidnotfindasurvivalbenefitafterintroductionofL-AmB-echinocandincombinationtherapy(330).Isavuconazolewas evaluated as first-line therapy in an open-label non-comparative trial in 37 patientswith proven andprobablemucormycosis(VITALstudy)(331).Themostcommonsitesofinfectionwerethelung(59%)andsinuses(43%).Byday42,11%hadapartialresponse,43%hadstabledisease,3%hadprogression,and35%haddied.Inamatchedcohortcomparison,patientsfromtheVITALstudywerecomparedwithpatientswhoreceivedprimaryAmB-basedtreatmentfromthe international FungiScope registry. At day 42 all-cause mortality (isavuconazole study 33%; AmB registry 32%) wassimilarinbothgroups(331).Althoughisavuconazolehasnotbeeninvestigatedinarandomized,comparativetrialforthisindication, and comparison of a prospective open-label study with a retrospective observational cohort has seriouslimitations (332), the FDA has approved the drug for first line therapy in the treatment ofmucormycosis; the EMAhasapprovedisavuconazoleastreatmentoptioninmucormycosiswhenamphotericinBisclinicallyinappropriate.Posaconazolesuspension(800mgqd)assalvagetherapyhasbeeninvestigatedretrospectivelyinthreecohorts,with60to79% response rates, mostly partial responses (327,333,334). Primary therapy with posaconazole has been sporadicallydocumented,withdisappointingoutcomes(327,335).AdjunctivetreatmentregimensSurgicaldebridementwasassociatedwithbetteroutcomesandincreasedsurvivalintworetrospectiveanalyses(312,336)andinamultivariateanalysisbasedonaECMMregistry(335).Particularlyforrhino-cerebralmucormycosis,survivalwithsurgery(100%)wassuggestedtobesuperiortoconservativetherapy(25%)(336).Ironchelatorshavebeeninvestigatedinthesettingofmucormycosis,sinceironoverloadisariskfactorformucormycosis(337).AphaseIItrialwith8patientswithmucormycosisdemonstratedthatdeferasiroxwassafe inpatientswithprovenmucormycosis(338).However,inarandomizedprospectivedoubleblindplacebocontrolledtrial(DEFEATstudy)including20patientswithprobableandprovenmucormycosis,82%of11patientswithdeferasiroxhaddiedat3months,comparedto22%of9patientswithoutdeferasirox(339).RecommendationsTheabsenceofrandomizedcomparativestudiesonthetreatmentofinvasivemucormycosishasresultedinthechoiceoftherapybeingbasedonretrospectiveanalysesandexpertopinion.Resultswithc-AmBhavebeenverypoor,andL-AmBinadailydosageofatleast5mg/kghasbeenassociatedwithbestclinicaloutcomesandsurvivalratesinobservationalcohortstudies. Theexperiencewithposaconazole is still limited; thisdrughasonlybeen investigatedas second line therapy inpatientswithrefractoryinfectionsandappearstohavereasonableefficacyinthesecircumstances.Whereasisavuconazolewasassociatedwithreasonableresponseratesin37patientsundergoingprimarytreatmentofinvasivemucormycosis,thecommitteeconsiderstheevidencenotsufficienttorecommendisavuconazoleasprimarychoiceforthisindication.Inviewofthepoorprognosisofinvasivemucormycosisdespiteantifungaltreatment,surgicaldebridementandcorrectionofunderlyingriskfactors(e.g.immunosuppression,ketoacidosis)isofgreatimportance.Conclusions5.2–Treatmentofinvasivemucormycosis

Conclusion4 L-AmBiseffectiveforthetreatmentofinvasivemucormycosisLevel3 Pagano,2004(C);Rüping,2010(C);Skiada,2011(C);Lanternier,2015(C)Conclusion5 Antifungaltreatmentofinvasivemucormycosiscombinedwithsurgicaldebridementleadstoabetterresponse

thanantifungaltherapyonly.Level3 Skiada,2011(C);Vironneau,2014(C);Lanternier,2015(C)Conclusion6 AdjunctivetherapyofmucormycosiswithdeferasiroxwasnotdemonstratedtobebeneficialLevel2 Spellberg,2012(B)Conclusion7 PosaconazoleappearstobeeffectiveasasalvagetherapyinrefractoryinvasivemucormycosisLevel3 VanBurik,2006(C);Greenberg,2006(C)Conclusion8 IsavuconazoleappearstobeeffectiveininvasivemucormycosisLevel3 Marty,2016(C)Recommendation2 InvasivemucormycosisshouldbetreatedwithL-AmBinadosageofatleast5mg/kg/day.Recommendation3 Wherepossible,theantifungaltreatmentofinvasivemucormycosisshouldbecombinedwith

surgicaldebridementandcorrectionofunderlyingriskfactors.Recommendation4 ForsalvagetreatmentofinvasivemucormycosisonfailureorintoleranceofL-AmB,

posaconazoleorisavuconazolemaybeconsidered.


PotentialconflictsofinterestThe SWAB employs strict guidelines with regard to potential conflicts of interests as described in the SWAB Format for GuidelineDevelopment(www.swab.nl).Membersofthepreparatorycommitteereportedthefollowingpotentialconflictsofinterest:Prof.Dr.N.M.A.Blijlevens:sheorherdepartmentreceivedcontributionsforscientificresearchoreducationfromNovartis,BMS,Pfizer,Ariad,MSD,Astellas,Xenikos,Celgene,JanssenCilag.Dr.R.Brüggemann:hisdepartmentreceivedcontributionsforscientificresearchandconsultancyservicesfromAstellas,F2G,Gilead,MSD,andPfizer.DrJ.J.W.M.Janssen:participatedinCMEwithsupportfromPfizerandAriad;hereceivendcontributionsforscientificresearchfromNovartisandBMS,andforconsultancyservicesfromNovartisandPfizer.ProfDrB.J.Kullberg:participatedinCMEwithsupportfromPfizerandGilead;heorhisdepartmentreceivedcontributionsforconsultancyservicesforAmplyx,Astellas,Basilea,Cidara,andScynexis.DrD.W.deLange:receivedresearchfeesfromThermoFisher.DrJ.F.G.Meis:participatedinCMEwithsupportfromGileadandUnitedMedical;heorhisdepartmentreceivedcontributionsforscientificresearchandconsultancyservicesfromAstellas,Basilea,F2GandMerck.Dr.M.H.E.Reijers:nothingtodisclose.DrA.M.L.OudeLashof:participatedinCMEwithsupportfromGSKandJanssen.DrB.J.Rijnders receivedcontributions for scientific research fromGileadandcontributions for travel,CMEorconsultancy fromAbbvie,BMS,Gilead,MSD,PfizerandViivHealthcare.ProfDrP.E.Verweij:participatedinCMEwithsupportfromMSDandGileadSciences;heorhisdepartmentreceivedcontributionsforscientificresearchandconsultancyservicesfromAstellas,Basilea,GileadSciences,MSD,F2GandScynexis.Dr.F.L.vandeVeerdonk:participatedinCMEwithsupportfromAstellas,MSDandGileadSciences.ProfDrA.Warris:participatedinCMEwithsupportfromGileadandPfizer;receivedsupportforconferenceattendancefromBasilea;sheorherdepartmentreceivedcontributionsforscientificresearchorconsultancyservicesfromBasilea,GileadandPfizer.ProfT.S.vanderWerf:heorhisdepartmentreceivedcontributionsforscientificresearchfromNovartis,Pfizer,Astellas,andJanssenCilagDrT.Wolfs:participatedinCMEwithsupportfromAbbvie;receivedsupportforconferenceattendancefromGilead.DrA.R.H.vanZanten:receivedhonorariaforadvisoryboardmeetings,lectures,andtravelexpensesfromAbbott,Astellas,Baxter,Danone,FreseniusKabi,MSD,Nestle,Novartis,NutriciaandPfizer.FeesforstudieswerepaidtothelocalICUresearchfoundationatGelderseValleiHospital.

References1. DePauwB,WalshTJ,DonnellyJP,StevensDa,EdwardsJE,CalandraT,etal.ReviseddefinitionsofinvasivefungaldiseasefromtheEuropean

OrganizationforResearchandTreatmentofCancer/InvasiveFungalInfectionsCooperativeGroupandtheNationalInstituteofAllergyandInfectiousDiseasesMycosesStudyGroup(EORTC/MSG)C.ClinInfectDis.2008Jun;8(12):321–4.

2. Lass-FlorlC,ReschG,NachbaurD,MayrA,GastlG,AubergerJ,etal.TheValueofComputedTomography-GuidedPercutaneousLungBiopsyforDiagnosisofInvasiveFungalInfectioninImmunocompromisedPatients.ClinInfectDis.2007Oct1;45(7):e101–4.

3. MortensenKL,JohansenHK,FuurstedK,KnudsenJD,Gahrn-HansenB,JensenRH,etal.AprospectivesurveyofAspergillusspp.inrespiratorytractsamples:prevalence,clinicalimpactandantifungalsusceptibility.EurJClinMicrobiolInfectDis.2011;30:1355–63.

4. AvniT,LevyI,SprecherH,YahavD,LeiboviciL,PaulM.DiagnosticaccuracyofPCRalonecomparedtogalactomannaninbronchoalveolarlavagefluidfordiagnosisofinvasivepulmonaryaspergillosis:asystematicreview.JClinMicrobiol.2012Nov;50(11):3652–8.

5. MaertensJ,GlasmacherA,SelleslagD,NgaiA,RyanD,LaytonM,etal.Evaluationofserumsandwichenzyme-linkedimmunosorbentassayforcirculatinggalactomannanduringcaspofungintherapy:resultsfromthecaspofungininvasiveaspergillosisstudy.ClinInfectDis.2005Jul1;41(1):e9-14.

6. MaertensJA,KlontR,MassonC,TheunissenK,MeerssemanW,LagrouK,etal.OptimizationofthecutoffvaluefortheAspergillusdouble-sandwichenzymeimmunoassay.ClinInfectDis.2007May15;44(10):1329–36.

7. SteinbachWJ,AddisonRM,McLaughlinL,GerraldQ,MartinPL,DriscollT,etal.ProspectiveAspergillusgalactomannanantigentestinginpediatrichematopoieticstemcelltransplantrecipients.PediatrInfectDisJ.2007Jul;26(7):558–64.

8. LehrnbecherT,RobinsonPD,FisherBT,CastagnolaE,GrollAH,SteinbachWJ,etal.Galactomannan,β-D-Glucan,andPolymeraseChainReaction-BasedAssaysfortheDiagnosisofInvasiveFungalDiseaseinPediatricCancerandHematopoieticStemCellTransplantation:ASystematicReviewandMeta-Analysis.Vol.63,ClinicalInfectiousDiseases.2016.p.1340–8.

9. KuNS,HanSH,ChoiJY,KimSB,KimH-W,JeongSJ,etal.Diagnosticvalueoftheserumgalactomannanassayforinvasiveaspergillosis:Itislessusefulinnon-haematologicalpatients.ScandJInfectDis.2012Aug;44(8):600–4.

10. VerweijPE,WeemaesCM,CurfsJHAJ,BretagneS,MeisJFGM.FailuretodetectcirculatingAspergillusmarkersinapatientwithchronicgranulomatousdiseaseandinvasiveaspergillosis.JClinMicrobiol.2000Oct;38(10):3900–1.

11. MorrisseyCO,ChenSC-A,SorrellTC,MillikenS,BardyPG,BradstockKF,etal.GalactomannanandPCRversuscultureandhistologyfordirectinguseofantifungaltreatmentforinvasiveaspergillosisinhigh-riskhaematologypatients:arandomisedcontrolledtrial.LancetInfectDis.2013Jun;13(6):519–28.

12. DuarteRF,Sánchez-OrtegaI,CuestaI,ArnanM,PatiñoB,FernándezdeSevillaA,etal.Serumgalactomannan-basedearlydetectionofinvasiveaspergillosisinhematologypatientsreceivingeffectiveantimoldprophylaxis.ClinInfectDis.2014Dec15;59(12):1696–702.

13. ViscoliC,MachettiM,CappellanoP,BucciB,BruzziP,VanLintMT,etal.False-positivegalactomannanplateliaAspergillustestresultsforpatientsreceivingpiperacillin-tazobactam.ClinInfectDis.2004Mar15;38(6):913–6.

14. Martín-RabadánP,GijonP,FernandezRA,BallesterosM,AnguitaJ,BouzaE.False-positiveaspergillusantigenemiaduetobloodproductconditioningfluids.ClinInfectDis.2012Aug;55(4):e22-7.

15. HerbrechtR,DenningDW,PattersonTF,BennettJE,GreeneRE,OestmannJ-W,etal.VoriconazoleversusamphotericinBforprimarytherapyofinvasiveaspergillosis.NEnglJMed.2002Aug8;347(6):408–15.

16. ChaiLYa,KullbergBJ,JohnsonEM,TeerenstraS,KhinLW,VonkAG,etal.Earlyserumgalactomannantrendasapredictorofoutcomeofinvasiveaspergillosis.JClinMicrobiol.2012;50:2330–6.

17. MaertensJ,TheunissenK,VerhoefG,VerschakelenJ,LagrouK,VerbekenE,etal.Galactomannanandcomputedtomography-basedpreemptiveantifungaltherapyinneutropenicpatientsathighriskforinvasivefungalinfection:aprospectivefeasibilitystudy.ClinInfectDis.2005;41:1242–50.


18. MeerssemanW,LagrouK,MaertensJ,WilmerA,HermansG,VanderschuerenS,etal.Galactomannaninbronchoalveolarlavagefluid:atoolfordiagnosingaspergillosisinintensivecareunitpatients.AmJRespirCritCareMed.2008Jan1;177(1):27–34.

19. MaertensJ,MaertensV,TheunissenK,MeerssemanW,MeerssemanP,MeersS,etal.Bronchoalveolarlavagefluidgalactomannanforthediagnosisofinvasivepulmonaryaspergillosisinpatientswithhematologicdiseases.ClinInfectDis.2009Dec1;49(11):1688–93.

20. D’HaeseJ,TheunissenK,VermeulenE,SchoemansH,DeVliegerG,LammertijnL,etal.Detectionofgalactomannaninbronchoalveolarlavagefluidsamplesofpatientsatriskforinvasivepulmonaryaspergillosis:analyticalandclinicalvalidity.JClinMicrobiol.2012Apr;50(4):1258–63.

21. GuoYL,ChenYQ,WangK,QinSM,WuC,KongJL.AccuracyofBALgalactomannanindiagnosinginvasiveaspergillosis:Abivariatemetaanalysisandsystematicreview.Chest.2010;138:817–24.

22. CaillotD,CasasnovasO,BernardA,CouaillierJF,DurandC,CuisenierB,etal.Improvedmanagementofinvasivepulmonaryaspergillosisinneutropenicpatientsusingearlythoraciccomputedtomographicscanandsurgery.JClinOncol.1997Jan;15(1):139–47.

23. CaillotD,CouaillierJF,BernardA,CasasnovasO,DenningDW,MannoneL,etal.Increasingvolumeandchangingcharacteristicsofinvasivepulmonaryaspergillosisonsequentialthoraciccomputedtomographyscansinpatientswithneutropenia.JClinOncol.2001Jan1;19(1):253–9.

24. GreeneRE,SchlammHT,OestmannJ-W,StarkP,DurandC,LortholaryO,etal.Imagingfindingsinacuteinvasivepulmonaryaspergillosis:clinicalsignificanceofthehalosign.ClinInfectDis.2007;44:373–9.

25. StanzaniM,SassiC,LewisRE,TolomelliG,BazzocchiA,CavoM,etal.HighResolutionComputedTomographyAngiographyImprovestheRadiographicDiagnosisofInvasiveMoldDiseaseinPatientsWithHematologicalMalignancies.ClinInfectDis.2015Jun1;60(11):1603–10.

26. SWAB/RIVM.NethMap2017.ConsumptionofantimicrobialagentsandantimicrobialresistanceamongmedicallyimportantbacteriainTheNetherlandsin2016.

27. VerweijPE,ChowdharyA,MelchersWJG,MeisJF.AzoleResistanceinAspergillusfumigatus:CanWeRetaintheClinicalUseofMold-ActiveAntifungalAzoles?ClinInfectDis.2016Feb1;62(3):362–8.

28. VerweijPE,Ananda-RajahM,AndesD,ArendrupMC,BrüggemannRJ,ChowdharyA,etal.Internationalexpertopiniononthemanagementofinfectioncausedbyazole-resistantAspergillusfumigatus.DrugResistUpdat.2015Aug;21–22:30–40.

29. VanDerLindenJWM,CampsSMT,KampingaGa.,ArendsJPa,Debets-OssenkoppYJ,HaasPJa,etal.AspergillosisduetovoriconazolehighlyresistantAspergillusfumigatusandrecoveryofgeneticallyrelatedresistantisolatesfromdomiciles.ClinInfectDis.2013;57:513–20.

30. vanderLindenJWM,ArendrupMC,WarrisA,LagrouK,PellouxH,HauserPM,etal.ProspectivemulticenterinternationalsurveillanceofazoleresistanceinAspergillusfumigatus.EmergInfectDis.2015Jun;21(6):1041–4.

31. VerweijPE,ChowdharyA,MelchersWJG,MeisJF.AzoleResistanceinAspergillusfumigatus:CanWeRetaintheClinicalUseofMold-ActiveAntifungalAzoles?ClinInfectDis.2016Feb1;62(3):362–8.

32. KolwijckE,vanderHoevenH,deSévauxRGL,TenOeverJ,RijstenbergLL,vanderLeeHAL,etal.Voriconazole-SusceptibleandVoriconazole-ResistantAspergillusfumigatusCoinfection.AmJRespirCritCareMed.2016Apr15;193(8):927–9.

33. vanderLindenJWM,SneldersE,KampingaGa.,RijndersBJa,MattssonE,Debets-OssenkoppYJ,etal.ClinicalimplicationsofazoleresistanceinAspergillusfumigatus,TheNetherlands,2007-2009.EmergInfectDis.2011;17(10):1846–54.

34. ChongGM,vanderBeekMT,vondemBornePA,BoelensJ,SteelE,KampingaGA,etal.PCR-baseddetectionofAspergillusfumigatusCyp51Amutationsonbronchoalveolarlavage:amulticentrevalidationoftheAsperGeniusassayin201patientswithhaematologicaldiseasesuspectedforinvasiveaspergillosis.JAntimicrobChemother.2016Dec;71(12):3528–35.

35. VanDerLindenJWM,SneldersE,ArendsJP,DaenenSM,MelchersWJG,VerweijPE.Rapiddiagnosisofazole-resistantaspergillosisbydirectPCRusingtissuespecimens.JClinMicrobiol.2010Apr;48(4):1478–80.

36. ChongG-LM,vandeSandeWWJ,DingemansGJH,GaajetaanGR,VonkAG,HayetteM-P,etal.ValidationofanewAspergillusreal-timePCRassayfordirectdetectionofAspergillusandazoleresistanceofAspergillusfumigatusonbronchoalveolarlavagefluid.JClinMicrobiol.2015;53(3):868–74.

37. SchauwvliegheAFAD,VonkAG,BuddinghEP,HoekRAS,DalmVA,KlaassenCHW,etal.Detectionofazole-susceptibleandazole-resistantAspergilluscoinfectionbycyp51APCRampliconmeltingcurveanalysis.JAntimicrobChemother.OxfordUniversityPress;2017Nov1;72(11):3047–50.

38. BitarD,LortholaryO,LeStratY,NicolauJ,CoignardB,TattevinP,etal.Population-basedanalysisofinvasivefungalinfections,France,2001-2010.EmergInfectDis.2014Jul;20(7):1149–55.

39. HerbrechtR,PattersonTF,SlavinMA,MarchettiO,MaertensJ,JohnsonEM,etal.Applicationofthe2008definitionsforinvasivefungaldiseasestothetrialcomparingvoriconazoleversusamphotericinBfortherapyofinvasiveaspergillosis:acollaborativestudyoftheMycosesStudyGroup(MSG05)andtheEuropeanOrganizationforR.ClinInfectDis.2015Mar1;60(5):713–20.

40. MaertensJA,RaadII,MarrKA,PattersonTF,KontoyiannisDP,CornelyOA,etal.IsavuconazoleversusvoriconazoleforprimarytreatmentofinvasivemoulddiseasecausedbyAspergillusandotherfilamentousfungi(SECURE):aphase3,randomised-controlled,non-inferioritytrial.Lancet.2016Feb20;387(10020):760–9.

41. CumpstonA,CaddellR,ShillingburgA,LuX,WenS,HamadaniM,etal.SuperiorSerumConcentrationswithPosaconazoleDelayed-ReleaseTabletsComparedtoSuspensionFormulationinHematologicalMalignancies.AntimicrobAgentsChemother.2015Aug;59(8):4424–8.

42. NivoixY,VeltenM,Letscher-BruV,MoghaddamA,Natarajan-AméS,FohrerC,etal.Factorsassociatedwithoverallandattributablemortalityininvasiveaspergillosis.ClinInfectDis.2008;47:1176–84.

43. CornelyOA,MaertensJ,BresnikM,EbrahimiR,UllmannAJ,BouzaE,etal.LiposomalamphotericinBasinitialtherapyforinvasivemoldinfection:arandomizedtrialcomparingahigh-loadingdoseregimenwithstandarddosing(AmBiLoadtrial).ClinInfectDis.2007;44(10):1289–97.

44. CornelyOA,MaertensJ,BresnikM,EbrahimiR,DellowE,HerbrechtR,etal.EfficacyoutcomesinarandomisedtrialofliposomalamphotericinBbasedonrevisedEORTC/MSG2008definitionsofinvasivemoulddisease.Mycoses.2011Sep;54(5):e449-55.

45. ChandrasekarPH,ItoJI.AmphotericinBlipidcomplexinthemanagementofinvasiveaspergillosisinimmunocompromisedpatients.ClinInfectDis.2005May1;40Suppl6:S392-400.

46. HachemRY,BoktourMR,HannaHA,HusniRN,TorresHA,AfifC,etal.AmphotericinBlipidcomplexversusliposomalamphotericinBmonotherapyforinvasiveaspergillosisinpatientswithhematologicmalignancy.Cancer.2008Mar15;112(6):1282–7.

47. FalciDR,daRosaFB,PasqualottoAC.ComparisonofnephrotoxicityassociatedtodifferentlipidformulationsofamphotericinB:areal-lifestudy.Mycoses.2015Feb;58(2):104–12.

48. MaertensJ,RaadI,PetrikkosG,BoogaertsM,SelleslagD,PetersenFB,etal.Efficacyandsafetyofcaspofunginfortreatmentofinvasiveaspergillosisinpatientsrefractorytoorintolerantofconventionalantifungaltherapy.ClinInfectDis.2004;39:1563–71.

49. BettsR,GlasmacherA,MaertensJ,MaschmeyerG,VazquezJA,TepplerH,etal.EfficacyofcaspofunginagainstinvasiveCandidaorinvasiveAspergillusinfectionsinneutropenicpatients.Cancer.2006Jan15;106(2):466–73.

50. DenningDW,MarrKA,LauWM,FacklamDP,RatanatharathornV,BeckerC,etal.Micafungin(FK463),aloneorincombinationwithothersystemicantifungalagents,forthetreatmentofacuteinvasiveaspergillosis.JInfect.2006Nov;53(5):337–49.

51. ViscoliC,HerbrechtR,AkanH,BailaL,Soneta.,GallaminiA,etal.AnEORTCphaseIIstudyofcaspofunginasfirst-linetherapyofinvasiveaspergillosisinhaematologicalpatients.JAntimicrobChemother.2009;64(October):1274–81.

52. HerbrechtR,MaertensJ,BailaL,AounM,HeinzW,MartinoR,etal.Caspofunginfirst-linetherapyforinvasiveaspergillosisinallogeneichematopoieticstemcelltransplantpatients:anEuropeanOrganisationforResearchandTreatmentofCancerstudy.BoneMarrowTransplant.2010;45(October2009):1227–33.

53. SinghN,LimayeAP,ForrestG,SafdarN,MuñozP,PursellK,etal.Combinationofvoriconazoleandcaspofunginasprimarytherapyforinvasiveaspergillosisinsolidorgantransplantrecipients:aprospective,multicenter,observationalstudy.Transplantation.2006Feb15;81(3):320–6.

54. MarrKA,BoeckhM,CarterRA,KimHW,CoreyL.CombinationAntifungalTherapyforInvasiveAspergillosis.ClinInfectDis.2004Sep15;39(6):797–802.

55. Martín-PeñaA,Aguilar-GuisadoM,EspigadoI,CisnerosJM.Antifungalcombinationtherapyforinvasiveaspergillosis.ClinInfectDis.2014Nov15;59(10):1437–45.


56. MarrKA,SchlammHT,HerbrechtR,RottinghausST,BowEJ,CornelyOA,etal.CombinationAntifungalTherapyforInvasiveAspergillosis.AnnInternMed.2015Jan20;162(2):81.

57. FribergLE,RavvaP,KarlssonMO,LiuP.Integratedpopulationpharmacokineticanalysisofvoriconazoleinchildren,adolescents,andadults.AntimicrobAgentsChemother.2012Jun;56(6):3032–42.

58. WalshTJ,DriscollT,MilliganPa.,WoodND,SchlammH,GrollAH,etal.Pharmacokinetics,safety,andtolerabilityofvoriconazoleinimmunocompromisedchildren.AntimicrobAgentsChemother.2010;54(10):4116–23.

59. WalshTJ,AdamsonPC,SeibelNL,FlynnPM,NeelyMN,SchwartzC,etal.Pharmacokinetics,safety,andtolerabilityofcaspofungininchildrenandadolescents.AntimicrobAgentsChemother.2005;49:4536–45.

60. HopeWW,SeibelNL,SchwartzCL,ArrietaA,FlynnP,ShadA,etal.Populationpharmacokineticsofmicafungininpediatricpatientsandimplicationsforantifungaldosing.AntimicrobAgentsChemother.2007;51(10):3714–9.

61. BenjaminDK,DriscollT,SeibelNL,GonzalezCE,RodenMM,KilaruR,etal.Safetyandpharmacokineticsofintravenousanidulafungininchildrenwithneutropeniaathighriskforinvasivefungalinfections.AntimicrobAgentsChemother.2006Feb;50(2):632–8.

62. DesaiA,KovandaL,KowalskiD,LuQ,TownsendR,BonatePL.PopulationPharmacokineticsofIsavuconazolefromPhase1andPhase3(SECURE)TrialsinAdultsandTargetAttainmentinPatientswithInvasiveInfectionsDuetoAspergillusandOtherFilamentousFungi.AntimicrobAgentsChemother.2016;60(9):5483–91.

63. KovandaLL,DesaiAV,LuQ,TownsendRW,AkhtarS,BonateP,etal.IsavuconazolePopulationPharmacokineticAnalysisUsingNonparametricEstimationinPatientswithInvasiveFungalDisease(ResultsfromtheVITALStudy).AntimicrobAgentsChemother.2016;60(8):4568–76.

64. UptonA,KirbyKA,CarpenterP,BoeckhM,MarrKA.Invasiveaspergillosisfollowinghematopoieticcelltransplantation:outcomesandprognosticfactorsassociatedwithmortality.ClinInfectDis.2007Feb15;44(4):531–40.

65. LortholaryO,GangneuxJ-P,SitbonK,LebeauB,deMonbrisonF,LeStratY,etal.EpidemiologicaltrendsininvasiveaspergillosisinFrance:theSAIFnetwork(2005-2007).ClinMicrobiolInfect.2011Dec;17(12):1882–9.

66. PerkhoferS,Lass-FlörlC,HellM,RussG,KrauseR,HöniglM,etal.TheNationwideAustrianAspergillusRegistry:Aprospectivedatacollectiononepidemiology,therapyandoutcomeofinvasivemouldinfectionsinimmunocompromisedand/orimmunosuppressedpatients.IntJAntimicrobAgents.2010;36(6):531–6.

67. MeerssemanW,VandecasteeleSJ,WilmerA,VerbekenE,PeetermansWE,VanWijngaerdertE.Invasiveaspergillosisincriticallyillpatientswithoutmalignancy.AmJRespirCritCareMed.2004;170(3):621–5.

68. MeerssemanW,LagrouK,MaertensJ,VanWijngaerdenE.Invasiveaspergillosisintheintensivecareunit.ClinInfectDis.2007;45:205–16.69. BaddleyJW,StephensJM,JiX,GaoX,SchlammHT,TaralloM.AspergillosisinIntensiveCareUnit(ICU)patients:epidemiologyandeconomic

outcomes.BMCInfectDis.BMCInfectiousDiseases;2013;13(1):29.70. BlotSI,TacconeFS,VanDenAbeeleAM,BulpaP,MeerssemanW,BrusselaersN,etal.AClinicalAlgorithmtoDiagnoseInvasivePulmonary

AspergillosisinCriticallyIllPatients.AmJRespirCritCareMed.2012;186:56–64.71. VandewoudeKH,BlotSI,DepuydtP,BenoitD,TemmermanW,ColardynF,etal.ClinicalrelevanceofAspergillusisolationfromrespiratorytract

samplesincriticallyillpatients.CritCare.2006;10(1):R31.72. TacconeFS,VandenAbeeleA-M,BulpaP,MissetB,MeerssemanW,CardosoT,etal.Epidemiologyofinvasiveaspergillosisincriticallyillpatients:

clinicalpresentation,underlyingconditions,andoutcomes.CritCare.2015;19(1).73. WautersJ,BaarI,MeerssemanP,MeerssemanW,DamsK,DePaepR,etal.Invasivepulmonaryaspergillosisisafrequentcomplicationofcritically

illH1N1patients:Aretrospectivestudy.IntensiveCareMed.2012;38:1761–8.74. LatA,BhadeliaN,MikoB,FuruyaEY,ThompsonGR.Invasiveaspergillosisafterpandemic(H1N1)2009.EmergInfectDis.2010Jun;16(6):971–3.75. Martin-LoechesI,JSchultzM,VincentJ-L,Alvarez-LermaF,BosLD,Solé-ViolánJ,etal.Increasedincidenceofco-infectionincriticallyillpatients

withinfluenza.IntensiveCareMed.2017;43(1):48–58.76. vandeVeerdonkFL,KolwijckE,LestradePPA,HodiamontCJ,RijndersBJA,vanPaassenJ,etal.Influenza-AssociatedAspergillosisinCriticallyIll

Patients.AmJRespirCritCareMed.2017Apr7;rccm.201612-2540LE.77. HenrietS,VerweijPE,HollandSM,WarrisA.Invasivefungalinfectionsinpatientswithchronicgranulomatousdisease.AdvExpMedBiol.

2013;764:27–55.78. KingJ,HenrietS,WarrisA.AspergillosisinChronicGranulomatousDisease.JFungi.2016;2(2):15.79. MarcianoBE,SpaldingC,FitzgeraldA,MannD,BrownT,OsgoodS,etal.Commonsevereinfectionsinchronicgranulomatousdisease.ClinInfect

Dis.2015Apr15;60(8):1176–83.80. GallinJI,AllingDW,MalechHL,WesleyR,KoziolD,MarcianoB,etal.ItraconazoletoPreventFungalInfectionsinChronicGranulomatousDisease.N

EnglJMed.2003;348(24):2416–22.81. WelzenMEB,BrüggemannRJM,VanDenBergJM,VoogtHW,GilissenJH,PajkrtD,etal.ATwiceDailyPosaconazoleDosingAlgorithmforChildren

WithChronicGranulomatousDisease.PediatrInfectDisJ.2011Sep;30(9):794–7.82. TheInternationalChronicGranulomatousDiseaseCooperativeStudyGoup.Acontrolledtrialofinterferongammatopreventinfectioninchronic

granulomatousdisease.NEnglJMed.1991Feb21;324(8):509–16.83. PascualA,CalandraT,BolayS,BuclinT,BilleJ,MarchettiO.Voriconazoletherapeuticdrugmonitoringinpatientswithinvasivemycosesimproves

efficacyandsafetyoutcomes.ClinInfectDis.2008;46:201–11.84. PascualA,CsajkaC,BuclinT,BolayS,BilleJ,CalandraT,etal.Challengingrecommendedoralandintravenousvoriconazoledosesforimproved

efficacyandsafety:populationpharmacokinetics-basedanalysisofadultpatientswithinvasivefungalinfections.ClinInfectDis.2012Aug;55(3):381–90.

85. SeyedmousaviS,MoutonJW,MelchersWJG,BrüggemannRJM,VerweijPE.Theroleofazolesinthemanagementofazole-resistantaspergillosis:fromthebenchtothebedside.DrugResistUpdat.2014Jul;17(3):37–50.

86. GlasmacherA,PrenticeA,GorschlüterM,EngelhartS,HahnC,DjulbegovicB,etal.Itraconazolepreventsinvasivefungalinfectionsinneutropenicpatientstreatedforhematologicmalignancies:evidencefromameta-analysisof3,597patients.JClinOncol.2003Dec15;21(24):4615–26.

87. GlasmacherA,HahnC,MolitorE,MarkleinG,SauerbruchT,Schmidt-WolfIGH.Itraconazoletroughconcentrationsinantifungalprophylaxiswithsixdifferentdosingregimensusinghydroxypropyl-beta-cyclodextrinoralsolutionorcoated-pelletcapsules.Mycoses.1999;42(11–12):591–600.

88. BoogaertsMA,VerhoefGE,ZacheeP,DemuynckH,VerbistL,DeBeuleK.AntifungalProphylaxiswithItraconazoleinProlongedNeutropenia:CorrelationwithPlasmaLevels.Mycoses.1989;32(s1):103–8.

89. DenningDW,LeeJY,HostetlerJS,PappasP,KauffmanCA,DewsnupDH,etal.NIAIDmycosesstudygroupmulticentertrialoforalitraconazoletherapyforinvasiveaspergillosis.AmJMed.1994Aug;97(2):135–44.

90. LestnerJM,RobertsSA,MooreCB,HowardSJ,DenningDW,HopeWW.Toxicodynamicsofitraconazole:implicationsfortherapeuticdrugmonitoring.ClinInfectDis.2009Sep15;49(6):928–30.

91. ParkWB,KimN-H,KimK-H,LeeSH,NamW-S,YoonSH,etal.Theeffectoftherapeuticdrugmonitoringonsafetyandefficacyofvoriconazoleininvasivefungalinfections:arandomizedcontrolledtrial.ClinInfectDis.2012Oct;55(8):1080–7.

92. LeeY-J,LeeS-O,ChoiS-H,KimYS,WooJH,ChunS,etal.Initialvoriconazoletroughbloodlevelsandclinicaloutcomesofinvasiveaspergillosisinpatientswithhematologicmalignancies.MedMycol.2013Apr;51(3):324–30.

93. DoltonMJ,RayJE,ChenSC-A,NgK,PontLG,McLachlanAJ.Multicenterstudyofvoriconazolepharmacokineticsandtherapeuticdrugmonitoring.AntimicrobAgentsChemother.2012;56(9):4793–9.

94. TrokePF,HockeyHP,HopeWW.Observationalstudyoftheclinicalefficacyofvoriconazoleanditsrelationshiptoplasmaconcentrationsinpatients.AntimicrobAgentsChemother.2011;55(10):4782–8.

95. SuzukiY,TokimatsuI,SatoY,KawasakiK,SatoY,GotoT,etal.Associationofsustainedhighplasmatroughconcentrationofvoriconazolewiththeincidenceofhepatotoxicity.ClinChimActa.2013;424:119–22.

96. KersemaekersWM,DogteromP,XuJ,MarcantonioEE,deGreefR,WaskinH,etal.Effectofahigh-fatmealonthepharmacokineticsof300-


milligramposaconazoleinasolidoraltabletformulation.AntimicrobAgentsChemother.2015;59(6):3385–9.97. DoltonMJ,RayJE,ChenSC-A,NgK,PontL,McLachlanAJ.Multicenterstudyofposaconazoletherapeuticdrugmonitoring:exposure-response

relationshipandfactorsaffectingconcentration.AntimicrobAgentsChemother.2012;56(11):5503–10.98. JangSH,ColangeloPM,GobburuJVS.Exposure–ResponseofPosaconazoleUsedforProphylaxisAgainstInvasiveFungalInfections:Evaluatingthe

NeedtoAdjustDosesBasedonDrugConcentrationsinPlasma.ClinPharmacolTher.2010Jul26;88(1):115–9.99. DoltonMJ,RayJE,MarriottD,McLachlanAJ.Posaconazoleexposure-responserelationship:evaluatingtheutilityoftherapeuticdrugmonitoring.

AntimicrobAgentsChemother.2012;56(6):2806–13.100. WalshTJ,RaadI,PattersonTF,ChandrasekarP,DonowitzGR,GraybillR,etal.Treatmentofinvasiveaspergillosiswithposaconazoleinpatientswho

arerefractorytoorintolerantofconventionaltherapy:anexternallycontrolledtrial.ClinInfectDis.2007;44:2–12.101. KersemaekersWM,vanIerselT,NassanderU,O’MaraE,WaskinH,CaceresM,etal.Pharmacokineticsandsafetystudyofposaconazole

intravenoussolutionadministeredperipherallytohealthysubjects.AntimicrobAgentsChemother.2015;59(2):1246–51.102. MiceliMH,GrazziuttiML,WoodsG,ZhaoW,KocogluMH,BarlogieB,etal.StrongCorrelationbetweenSerumAspergillusGalactomannanIndexand

OutcomeofAspergillosisinPatientswithHematologicalCancer:ClinicalandResearchImplications.ClinInfectDis.2008May1;46(9):1412–22.103. ParkSH,ChoiSM,LeeDG,ChoiJH,KimSH,KwonJC,etal.Serumgalactomannanstronglycorrelateswithoutcomeofinvasiveaspergillosisinacute

leukaemiapatients.Mycoses.2011Nov;54(6):523–30.104. FisherCE,StevensAM,LeisenringW,PergamSA,BoeckhM,HohlTM.Theserumgalactomannanindexpredictsmortalityinhematopoieticstem

celltransplantrecipientswithinvasiveaspergillosis.ClinInfectDis.2013Oct;57(7):1001–4.105. NeofytosD,RailkarR,MullaneKM,FredricksDN,GranwehrB,MarrKA,etal.CorrelationbetweenCirculatingFungalBiomarkersandClinical

OutcomeinInvasiveAspergillosis.PLoSOne.2015Jan;10(6):e0129022.106. ChaiLYA,KullbergBJ,EarnestA,JohnsonEM,TeerenstraS,VonkAG,etal.VoriconazoleoramphotericinBasprimarytherapyyieldsdistinctearly

serumgalactomannantrendsrelatedtooutcomesininvasiveaspergillosis.PLoSOne.2014Jan;9(2):1–5.107. SinghN.Treatmentofopportunisticmycoses:Howlongislongenough?Vol.3,LancetInfectiousDiseases.2003.p.703–8.108. CordonnierC,RoviraM,MaertensJ,OlavarriaE,FaucherC,BilgerK,etal.Voriconazoleforsecondaryprophylaxisofinvasivefungalinfectionsin

allogeneicstemcelltransplantrecipients:resultsoftheVOSIFIstudy.Haematologica.2010Oct;95(10):1762–8.109. LiuQ,LinR,SunJ,XiaoY,NieD,ZhangY,etal.AntifungalAgentsforSecondaryProphylaxisBasedonResponsetoInitialAntifungalTherapyin

AllogeneicHematopoieticStemCellTransplantRecipientswithPriorPulmonaryAspergillosis.BiolBloodMarrowTransplant.2014Aug;20(8):1198–203.

110. PriceTH,BoeckhM,HarrisonRW,McCulloughJ,NessPM,StraussRG,etal.EfficacyoftransfusionwithgranulocytesfromG-CSF/dexamethasone-treateddonorsinneutropenicpatientswithinfection.Blood.2015Oct29;126(18):2153–61.

111. SmithNLD,DenningDW.Clinicalimplicationsofinterferon-γgeneticandepigeneticvariants.Immunology.2014Dec;143(4):499–511.112. DelsingCE,GresnigtMS,LeentjensJ,PreijersF,FragerFA,KoxM,etal.Interferon-gammaasadjunctiveimmunotherapyforinvasivefungal

infections:acaseseries.BMCInfectDis.2014;14:166.113. DelsingCE,BeckerKL,SimonA,KullbergBJ,Bleeker-RoversCP,vandeVeerdonkFL,etal.Th17cytokinedeficiencyinpatientswithAspergillusskull

baseosteomyelitis.BMCInfectDis.2015Mar21;15(1):140.114. NgTT,DenningDW.LiposomalamphotericinB(AmBisome)therapyininvasivefungalinfections.EvaluationofUnitedKingdomcompassionateuse

data.ArchInternMed.1995May22;155(10):1093–8.115. CornelyOa.,MaertensJ,BresnikM,Ullmanna.J,EbrahimiR,HerbrechtR.Treatmentoutcomeofinvasivemoulddiseaseaftersequentialexposure

toazolesandliposomalamphotericinB.JAntimicrobChemother.2009;65(November2009):114–7.116. WalshTJ,HiemenzJW,SeibelNL,PerfectJR,HorwithG,LeeL,etal.AmphotericinBlipidcomplexforinvasivefungalinfections:analysisofsafety

andefficacyin556cases.ClinInfectDis.1998Jun;26(6):1383–96.117. HiemenzJW,RaadII,MaertensJa.,HachemRY,Saaha.J,SableCa.,etal.Efficacyofcaspofunginassalvagetherapyforinvasiveaspergillosis

comparedtostandardtherapyinahistoricalcohort.EurJClinMicrobiolInfectDis.2010;29:1387–94.118. CordonnierC,PautasC,MauryS,VekhoffA,FarhatH,SuarezF,etal.Empiricalversuspreemptiveantifungaltherapyforhigh-risk,febrile,

neutropenicpatients:arandomized,controlledtrial.ClinInfectDis.2009Apr15;48(8):1042–51.119. TanBH,LowJGH,ChlebickaNL,KurupA,CheahFK,LinRTP,etal.Galactomannan-guidedpreemptivevs.empiricalantifungalsinthepersistently

febrileneutropenicpatient:Aprospectiverandomizedstudy.IntJInfectDis.2011May;15(5):e350-6.120. AguadoJM,VázquezL,Fernández-RuizM,VillaescusaT,Ruiz-CampsI,BarbaP,etal.Serumgalactomannanversusacombinationofgalactomannan

andpolymerasechainreaction-basedAspergillusDNAdetectionforearlytherapyofinvasiveaspergillosisinhigh-riskhematologicalpatients:arandomizedcontrolledtrial.ClinInfectDis.2015Feb1;60(3):405–14.

121. WalshTJ,FinbergRW,ArndtC,HiemenzJ,SchwartzC,BodensteinerD,etal.LiposomalamphotericinBforempiricaltherapyinpatientswithpersistentfeverandneutropenia.NEnglJMed.1999Mar11;340(10):764–71.

122. WalshTJ,PappasP,WinstonDJ,LazarusHM,PetersenF,RaffalliJ,etal.VoriconazolecomparedwithliposomalamphotericinBforempiricalantifungaltherapyinpatientswithneutropeniaandpersistentfever.NEnglJMed.2002Jan24;346(4):225–34.

123. WalshTJ,TepplerH,DonowitzGR,MaertensJA,BadenLR,DmoszynskaA,etal.CaspofunginversusliposomalamphotericinBforempiricalantifungaltherapyinpatientswithpersistentfeverandneutropenia.NEnglJMed.2004Sep30;351(14):1391–402.

124. deShazoRD,ChapinK,SwainRE.Fungalsinusitis.NEnglJMed.1997;337(4):254–9.125. SchwartzS,RuhnkeM,RibaudP,CoreyL,DriscollT,CornelyOA,etal.Improvedoutcomeincentralnervoussystemaspergillosis,usingvoriconazole

treatment.Blood.2005;106(8):2641–5.126. ColemanJM,HoggGG,RosenfeldJV,WatersKD.Invasivecentralnervoussystemaspergillosis:curewithliposomalamphotericinB,itraconazole,

andradicalsurgery--casereportandreviewoftheliterature.Neurosurgery.1995;36(4):858–63.127. FeltonT,TrokePF,HopeWW.Tissuepenetrationofantifungalagents.ClinMicrobiolRev.2014Jan;27(1):68–88.128. GrollAH,GiriN,PetraitisV,PetraitieneR,CandelarioM,BacherJS,etal.Comparativeefficacyanddistributionoflipidformulationsofamphotericin

BinexperimentalCandidaalbicansinfectionofthecentralnervoussystem.JInfectDis.2000Jul;182(1):274–82.129. DenningDW,RiniotisK,DobrashianR,SambatakouH.Chroniccavitaryandfibrosingpulmonaryandpleuralaspergillosis:caseseries,proposed

nomenclaturechange,andreview.ClinInfectDis.2003;37(Suppl3):S265–80.130. DenningDW,CadranelJ,Beigelman-AubryC,AderF,ChakrabartiA,BlotS,etal.Chronicpulmonaryaspergillosis:rationaleandclinicalguidelines

fordiagnosisandmanagement.EurRespirJ.2016Jan;47(1):45–68.131. PageID,RichardsonM,DenningDW.Antibodytestinginaspergillosis--quovadis?MedMycol.2015;53(5):417–39.132. Al-ShairK,AthertonGT,HarrisC,RatcliffeL,NewtonPJ,DenningDW.Long-termantifungaltreatmentimproveshealthstatusinpatientswith

chronicpulmonaryaspergillosis:alongitudinalanalysis.ClinInfectDis.2013Sep;57(6):828–35.133. AgarwalR,VishwanathG,AggarwalAN,GargM,GuptaD,ChakrabartiA.Itraconazoleinchroniccavitarypulmonaryaspergillosis:Arandomised

controlledtrialandsystematicreviewofliterature.Mycoses.2013;56:559–70.134. CadranelJ,PhilippeB,HennequinC,BergeronA,BergotE,BourdinA,etal.Voriconazoleforchronicpulmonaryaspergillosis:aprospective

multicentertrial.EurJClinMicrobiolInfectDis.2012Nov;31(11):3231–9.135. KohnoS,IzumikawaK,OgawaK,KurashimaA,OkimotoN,AmitaniR,etal.Intravenousmicafunginversusvoriconazoleforchronicpulmonary

aspergillosis:amulticentertrialinJapan.JInfect.2010Nov;61(5):410–8.136. KohnoS,IzumikawaK,YoshidaM,TakesueY,OkaS,KameiK,etal.Adouble-blindcomparativestudyofthesafetyandefficacyofcaspofungin

versusmicafungininthetreatmentofcandidiasisandaspergillosis.EurJClinMicrobiolInfectDis.2013Mar;32(3):387–97.137. NewtonPJ,HarrisC,MorrisJ,DenningDW.ImpactofliposomalamphotericinBtherapyonchronicpulmonaryaspergillosis.JInfect.2016Jun

29;73(5):485–95.138. KeirGJ,GarfieldB,HansellDM,LoebingerMR,WilsonR,RenzoniEA,etal.Cyclicalcaspofunginforchronicpulmonaryaspergillosisinsarcoidosis.


Thorax.2014Mar;69(3):287–8.139. MuniappanA,TapiasLF,ButalaP,WainJC,WrightCD,DonahueDM,etal.Surgicaltherapyofpulmonaryaspergillomas:a30-yearNorthAmerican

experience.AnnThoracSurg.2014Feb;97(2):432–8.140. GoodrichJM,ReedEC,MoriM,FisherLD,SkerrettS,DandlikerPS,etal.Clinicalfeaturesandanalysisofriskfactorsforinvasivecandidalinfection

aftermarrowtransplantation.JInfectDis.1991Oct;164(4):731–40.141. RobenshtokE,Gafter-GviliA,GoldbergE,WeinbergerM,YeshurunM,LeiboviciL,etal.Antifungalprophylaxisincancerpatientsafter

chemotherapyorhematopoieticstem-celltransplantation:systematicreviewandmeta-analysis.JClinOncol.2007Dec1;25(34):5471–89.142. ZiakasPD,KourbetiIS,MylonakisE.Systemicantifungalprophylaxisafterhematopoieticstemcelltransplantation:ameta-analysis.ClinTher.2014

Feb1;36(2):292–306.e1.143. MarrKA,CrippaF,LeisenringW,HoyleM,BoeckhM,BalajeeSA,etal.Itraconazoleversusfluconazoleforpreventionoffungalinfectionsinpatients

receivingallogeneicstemcelltransplants.Blood.2004Feb15;103(4):1527–33.144. WinstonDJ,MaziarzRT,ChandrasekarPH,LazarusHM,GoldmanM,BlumerJL,etal.Intravenousandoralitraconazoleversusintravenousandoral

fluconazoleforlong-termantifungalprophylaxisinallogeneichematopoieticstem-celltransplantrecipients.Amulticenter,randomizedtrial.AnnInternMed.2003May6;138(9):705–13.

145. WingardJR,CarterSL,WalshTJ,KurtzbergJ,SmallTN,LindseyR,etal.PreventionofinvasivefungalinfectionafterallogeneichematopoieticcelltransplantationRandomized,double-blindtrialoffluconazoleversusvoriconazoleforpreventionofinvasivefungalinfectionafterallogeneichematopoieticcelltransplantation.Blood.2010;116(24):5111–8.

146. MarksDI,PagliucaA,KibblerCC,GlasmacherA,HeusselCP,KanteckiM,etal.Voriconazoleversusitraconazoleforantifungalprophylaxisfollowingallogeneichaematopoieticstem-celltransplantation.BrJHaematol.2011;155(August):318–27.

147. UllmannAJ,LiptonJH,VesoleDH,ChandrasekarP,LangstonA,TarantoloSR,etal.Posaconazoleorfluconazoleforprophylaxisinseveregraft-versus-hostdisease.NEnglJMed.2007Jan25;356(4):335–47.

148. CornelyOA,MaertensJ,WinstonDJ,PerfectJ,UllmannAJ,WalshTJ,etal.Posaconazolevs.fluconazoleoritraconazoleprophylaxisinpatientswithneutropenia.NEnglJMed.2007;356:348–59.

149. vanBurikJH,RatanatharathornV,StepanDE,MillerCB,LiptonJH,VesoleDH,etal.Micafunginversusfluconazoleforprophylaxisagainstinvasivefungalinfectionsduringneutropeniainpatientsundergoinghematopoieticstemcelltransplantation.ClinInfectDis.2004;39:1407–16.

150. GrollAH,CastagnolaE,CesaroS,DalleJ-H,EngelhardD,HopeW,etal.FourthEuropeanConferenceonInfectionsinLeukaemia(ECIL-4):guidelinesfordiagnosis,prevention,andtreatmentofinvasivefungaldiseasesinpaediatricpatientswithcancerorallogeneichaemopoieticstem-celltransplantation.LancetOncol.2014;15(8):e327–40.

151. KullbergBJ,ArendrupMC.InvasiveCandidiasis.NEnglJMed.2015Oct8;373(15):1445–56.152. LeccionesJA,LeeJW,NavarroEE,WitebskyFG,MarshallD,SteinbergSM,etal.VascularCatheter-AssociatedFungemiainPatientswithCancer:

Analysisof155Episodes.ClinInfectDis.1992Apr;14(4):875–83.153. KullbergB,RexJ,RuhnkeM,SobelJ,PappasP.Candidaemiasecondarytointravascularcathetercolonisation?Lancet.2006;367:729.154. RexJH,BennettJE,SugaraM,PappasPG,vanderHorstCM,EdwardsJE,etal.ArandomizedtrialcomparingfluconazolewithamphotericinBfor

thetreatmentofcandidemiainpatientswithoutneutropenia.NEnglJMed.1994;331:1325–30.155. Mora-DuarteJ,BettsR,RotsteinC,ColomboAL,Thompson-MoyaL,SmietanaJ,etal.ComparisonofcaspofunginandamphotericinBforinvasive

candidiasis.NEnglJMed.2002Dec19;347(25):2020–9.156. KullbergBJ,SobelJD,RuhnkeM,PappasPG,ViscoliC,RexJH,etal.VoriconazoleversusaregimenofamphotericinBfollowedbyfluconazolefor

candidaemiainnon-neutropenicpatients:Arandomisednon-inferioritytrial.Lancet.2005;366:1435–42.157. PappasPG,KauffmanCA,AndesD,BenjaminDK,CalandraTF,EdwardsJE,etal.Clinicalpracticeguidelinesforthemanagementofcandidiasis:2009

updatebytheInfectiousDiseasesSocietyofAmerica.ClinInfectDis.2009;48:503–35.158. KuseER,ChetchotisakdP,daCunhaCA,RuhnkeM,BarriosC,RaghunadharaoD,etal.MicafunginversusliposomalamphotericinBforcandidaemia

andinvasivecandidosis:aphaseIIIrandomiseddouble-blindtrial.Lancet.2007;369:1519–27.159. PappasPG,RotsteinCMF,BettsRF,NucciM,TalwarD,DeWaeleJJ,etal.Micafunginversuscaspofunginfortreatmentofcandidemiaandother

formsofinvasivecandidiasis.ClinInfectDis.2007;45:883–93.160. ReboliAC,RotsteinC,PappasPG,ChapmanSW,KettDH,KumarD,etal.Anidulafunginversusfluconazoleforinvasivecandidiasis.NEnglJMed.

2007;356:2472–82.161. ReboliAC,ShorrAF,RotsteinC,PappasPG,KettDH,SchlammHT,etal.Anidulafungincomparedwithfluconazolefortreatmentofcandidemiaand

otherformsofinvasivecandidiasiscausedbyCandidaalbicans:amultivariateanalysisoffactorsassociatedwithimprovedoutcome.BMCInfectDis.2011;11:261.

162. KullbergBJ,ThompsonG,PappasP,VazquezJ,ViscoliC,Ostrosky–ZeichnerL,etal.IsavuconazoleversuscaspofungininthetreatmentofcandidaemiaandotherinvasiveCandidainfections:theACTIVEtrial.In:EuropeanCongressofClinicalMicrobiologyandInfectiousDiseases(ECCMID).2016.p.#O423.

163. DiNubileMJ,LupinacciRJ,StrohmaierKM,SableCa.,KartsonisNa.Invasivecandidiasistreatedintheintensivecareunit:Observationsfromarandomizedclinicaltrial.JCritCare.2007;22:237–44.

164. DupontBF,LortholaryO,Ostrosky-ZeichnerL,StuckerF,YeldandiV.Treatmentofcandidemiaandinvasivecandidiasisintheintensivecareunit:posthocanalysisofarandomized,controlledtrialcomparingmicafunginandliposomalamphotericinB.CritCare.2009;13(5):R159.

165. KettDH,CubillosGF.Anidulafungininthetreatmentofpatientswithinvasivecandidiasis.IntJAntimicrobAgents.ElsevierBV;2008;32(S2):S99–102.

166. AndesDR,SafdarN,BaddleyJW,PlayfordG,ReboliAC,RexJH,etal.Impactoftreatmentstrategyonoutcomesinpatientswithcandidemiaandotherformsofinvasivecandidiasis:Apatient-levelquantitativereviewofrandomizedtrials.ClinInfectDis.2012;54:1110–22.

167. RexJH,PappasPG,KarchmerAW,SobelJ,EdwardsJE,HadleyS,etal.Arandomizedandblindedmulticentertrialofhigh-dosefluconazoleplusplaceboversusfluconazoleplusamphotericinBastherapyforcandidemiaanditsconsequencesinnonneutropenicsubjects.ClinInfectDis.2003;36:1221–8.

168. RuhnkeM,PaivaJA,MeerssemanW,PachlJ,GrigorasI,SgangaG,etal.Anidulafunginforthetreatmentofcandidaemia/invasivecandidiasisinselectedcriticallyillpatients.ClinMicrobiolInfect.2012Jul;18(7):680–7.

169. KollefM,MicekS,HamptonN,DohertyJa.,KumarA.SepticshockattributedtoCandidainfection:Importanceofempirictherapyandsourcecontrol.ClinInfectDis.2012;54(1):1739–46.

170. ColomboAL,NgaiAL,BourqueM,BradshawSK,StrohmaierKM,TaylorAF,etal.Caspofunginuseinpatientswithinvasivecandidiasiscausedbycommonnon-albicansCandidaspecies:Reviewofthecaspofungindatabase.AntimicrobAgentsChemother.2010;54(5):1864–71.

171. KullbergBJ,VasquezJ,MootsikapunP,NucciM,PaivaJ-A,GarbinoJ,etal.Efficacyofanidulafunginin539patientswithinvasivecandidiasis:apatient-levelpooledanalysisofsixclinicaltrials.JAntimicrobChemother.2017Apr28;72(8):2368–77.

172. OudeLashofAML,DonnellyJP,MeisJFGM,VanderMeerJWM,KullbergBJ.Durationofantifungaltreatmentanddevelopmentofdelayedcomplicationsinpatientswithcandidaemia.EurJClinMicrobiolInfectDis.2003;22:43–8.

173. VazquezJ,ReboliAC,PappasPG,PattersonTF,ReinhardtJ,Chin-HongP,etal.Evaluationofanearlystep-downstrategyfromintravenousanidulafungintooralazoletherapyforthetreatmentofcandidemiaandotherformsofinvasivecandidiasis:resultsfromanopen-labeltrial.BMCInfectDis.2014Jan;14:97.

174. EschenauerGA,CarverPL,LinSW,KlinkerKP,ChenYC,PotoskiBA,etal.FluconazoleversusanechinocandinforCandidaglabratafungaemia:Aretrospectivecohortstudy.JAntimicrobChemother.2013;68:922–6.

175. NucciM,ColomboAL,PettiM,MaganaM,AbreuP,SchlammHT,etal.Anopen-labelstudyofanidulafunginforthetreatmentofcandidaemia/invasivecandidiasisinLatinAmerica.Mycoses.2014;57:12–8.

176. MootsikapunP,HsuehP,TalwarD,CoVM,RajadhyakshaV,OngM.Intravenousanidulafunginfollowedoptionallybyoralvoriconazoleforthe


treatmentofcandidemiainAsianpatients :resultsfromanopen-labelPhaseIIItrial.BMCInfectDis.2013;13(1):1.177. NwezeEI,GhannoumA,ChandraJ,GhannoumMA,MukherjeePK.Developmentofa96-wellcatheter-basedmicrodilutionmethodtotest

antifungalsusceptibilityofCandidabiofilms.JAntimicrobChemother.2012Jan;67(1):149–53.178. ArendrupMC,PerlinDS.Echinocandinresistance:anemergingclinicalproblem?CurrOpinInfectDis.2014;27(6):484–92.179. ChiotosK,VendettiN,ZaoutisTE,BaddleyJ,Ostrosky-ZeichnerL,PappasP,etal.Comparativeeffectivenessofechinocandinsversusfluconazole

therapyforthetreatmentofadultcandidaemiaduetoCandidaparapsilosis :aretrospectiveobservationalcohortstudyoftheMycosesStudyGroup(MSG-12).JAntimicrobChemother.2016Dec;71(12):3536–9.

180. PfallerMA,DiekemaDJ,GibbsDL,NewellVa.,EllisD,TullioV,etal.Resultsfromtheartemisdiskglobalantifungalsurveillancestudy,1997to2007:A10.5-yearanalysisofsusceptibilitiesofcandidaspeciestofluconazoleandvoriconazoleasdeterminedbyCLSIstandardizeddiskdiffusion.JClinMicrobiol.2010;48(12):1366–77.

181. ArendrupMC,Cuenca-EstrellaM,Lass-FlörlC,HopeWW,Arikan-AkdagliS,BarchiesiF,etal.EUCASTTechnicalNoteonCandidaandmicafungin,anidulafunginandfluconazole.Mycoses.2014;57(6):377–9.

182. PfallerMA,AndesD,ArendrupMC,DiekemaDJ,Espinel-IngroffA,AlexanderBD,etal.ClinicalbreakpointsforvoriconazoleandCandidaspp.revisited:reviewofmicrobiologic,molecular,pharmacodynamic,andclinicaldataastheypertaintothedevelopmentofspecies-specificinterpretivecriteria.DiagnMicrobiolInfectDis.2011Jul;70(3):330–43.

183. AlexanderBD,JohnsonMD,PfeifferCD,Jiménez-OrtigosaC,CataniaJ,BookerR,etal.IncreasingechinocandinresistanceinCandidaglabrata:clinicalfailurecorrelateswithpresenceofFKSmutationsandelevatedminimuminhibitoryconcentrations.ClinInfectDis.2013Jun;56(12):1724–32.

184. Bleeker-RoversCP,WarrisA,DrenthJPH,CorstensFHM,OyenWJG,KullbergB-J.DiagnosisofCandidalungabscessesby18F-fluorodeoxyglucosepositronemissiontomography.ClinMicrobiolInfect.2005Jun;11(6):493–5.

185. SharmaP,MukherjeeA,KarunanithiS,BalC,KumarR.Potentialroleof18F-FDGPET/CTinpatientswithfungalinfections.AJRAmJRoentgenol.2014Jul;203(1):180–9.

186. Puig-AsensioM,PemánJ,ZaragozaR,Garnacho-MonteroJ,Martín-MazuelosE,Cuenca-EstrellaM,etal.ImpactoftherapeuticstrategiesontheprognosisofcandidemiaintheICU.CritCareMed.2014;42(c):1423–32.

187. HornDL,Ostrosky-ZeichnerL,MorrisMI,Ullmanna.J,WuC,BuellDN,etal.Factorsrelatedtosurvivalandtreatmentsuccessininvasivecandidiasisorcandidemia:Apooledanalysisoftwolarge,prospective,micafungintrials.EurJClinMicrobiolInfectDis.2010;29:223–9.

188. RexJH,BennettJE,SugarAM,PappasPG,SerodyJ,EdwardsJE,etal.Intravascularcatheterexchangeanddurationofcandidemia.ClinInfectDis.1995Oct;21(4):994–6.

189. OudeLashofAML,RothovaA,SobelJD,RuhnkeM,PappasPG,ViscoliC,etal.Ocularmanifestationsofcandidemia.ClinInfectDis.2011;53:262–8.190. Fernández-CruzA,CruzMenárguezM,MuñozP,PedromingoM,PeláezT,SolísJ,etal.Thesearchforendocarditisinpatientswithcandidemia:a

systematicrecommendationforechocardiography?Aprospectivecohort.EurJClinMicrobiolInfectDis.2015May13;34(8):1543–9.191. VosFJ,DonnellyJP,OyenWJG,KullbergB-J,Bleeker-RoversCP,BlijlevensNMA.18F-FDGPET/CTfordiagnosinginfectiouscomplicationsinpatients

withsevereneutropeniaafterintensivechemotherapyforhaematologicalmalignancyorstemcelltransplantation.EurJNuclMedMolImaging.2012;39(1):120–8.

192. DeCastroN,MazoyerE,PorcherR,RaffouxE,SuarezF,RibaudP,etal.Hepatospleniccandidiasisintheeraofnewantifungaldrugs:AstudyinParis2000-2007.ClinMicrobiolInfect.2012;18:1–3.

193. AnttilaVJ,ElonenE,NordlingS,SivonenA,RuutuT,RuutuP.Hepatospleniccandidiasisinpatientswithacuteleukemia:incidenceandprognosticimplications.ClinInfectDis.1997Mar;24(3):375–80.

194. LegrandF,LecuitM,DupontB,BellatonE,HuerreM,RohrlichP-S,etal.Adjuvantcorticosteroidtherapyforchronicdisseminatedcandidiasis.ClinInfectDis.2008;46:696–702.

195. HopeWW,CastagnolaE,Grolla.H,RoilidesE,AkovaM,ArendrupMC,etal.ESCMIDguidelineforthediagnosisandmanagementofCandidadiseases2012:PreventionandmanagementofinvasiveinfectionsinneonatesandchildrencausedbyCandidaspp.ClinMicrobiolInfect.2012;18:38–52.

196. RoilidesE.Invasivecandidiasisinneonatesandchildren.EarlyHumDev.2011Mar;87Suppl1:S75-6.197. BenjaminDK,StollBJ,GantzMG,WalshMC,SánchezPJ,DasA,etal.Neonatalcandidiasis:epidemiology,riskfactors,andclinicaljudgment.

Pediatrics.2010Oct;126(4):e865-73.198. Queiroz-TellesF,BerezinE,LevergerG,FreireA,vanderVyverA,ChotpitayasunondhT,etal.MicafunginversusliposomalamphotericinBfor

pediatricpatientswithinvasivecandidiasis:substudyofarandomizeddouble-blindtrial.PediatrInfectDisJ.2008;27(9):820–6.199. ZaoutisT,LehrnbecherT,GrollAH,SteinbachWJ,JafriHS,MaertensJ,etal.Safetyexperiencewithcaspofungininpediatricpatients.PediatrInfect

DisJ.2009;28(12):1132–5.200. LeeJW,SeibelNL,AmanteaM,WhitcombP,PizzoPA,WalshTJ.Safetyandpharmacokineticsoffluconazoleinchildrenwithneoplasticdiseases.J

Pediatr.1992;120(6):987–93.201. NovelliV,HolzelH.Safetyandtolerabilityoffluconazoleinchildren.AntimicrobAgentsChemother.1999;43(8):1955–60.202. BartelinkIH,WolfsT,JonkerM,deWaalM,EgbertsTCG,VerversTT,etal.Highlyvariableplasmaconcentrationsofvoriconazoleinpediatric

hematopoieticstemcelltransplantationpatients.AntimicrobAgentsChemother[Internet].AmericanSocietyforMicrobiology(ASM);2013Jan[cited2017Jul26];57(1):235–40.Availablefrom:http://www.ncbi.nlm.nih.gov/pubmed/23114771

203. DriscollTA,FrangoulH,NemecekER,MurpheyDK,YuLC,BlumerJ,etal.Comparisonofpharmacokineticsandsafetyofvoriconazoleintravenous-to-oralswitchinimmunocompromisedadolescentsandhealthyadults.AntimicrobAgentsChemother.2011;55(12):5780–9.

204. NeelyM,RushingT,KovacsA,JelliffeR,HoffmanJ.Voriconazolepharmacokineticsandpharmacodynamicsinchildren.ClinInfectDis.2010Jan1;50(1):27–36.

205. SchusterMG,SchusterMG,JrJEE,JrJEE,SobelJD,SobelJD,etal.EmpiricalFluconazoleversusPlaceboforIntensiveCareUnitPatients.AnnInternMed.2008;

206. TimsitJ-F,AzoulayE,SchwebelC,CharlesPE,CornetM,SouweineB,etal.EmpiricalMicafunginTreatmentandSurvivalWithoutInvasiveFungalInfectioninAdultsWithICU-AcquiredSepsis,CandidaColonization,andMultipleOrganFailure.JAMA.2016;316(15):1555.

207. LeónC,Ruiz-SantanaS,SaavedraP,GalvánB,BlancoA,CastroC,etal.Usefulnessofthe“Candidascore”fordiscriminatingbetweenCandidacolonizationandinvasivecandidiasisinnon-neutropeniccriticallyillpatients:aprospectivemulticenterstudy.CritCareMed.2009;37(5):1624–33.

208. TissotF,LamothF,HauserPM,OraschC,FlückigerU,SiegemundM,etal.Β-Glucanantigenemiaanticipatesdiagnosisofbloodculture-negativeintraabdominalcandidiasis.AmJRespirCritCareMed.2013;188:1100–9.

209. BruyèreR,QuenotJ,PrinS.Empiricalantifungaltherapywithanechinocandinincritically-illpatients:prospectiveevaluationofapragmaticCandidascore-basedstrategyinonemedicalICU.BMCInfectDis.2014Jan;14:385.

210. PlayfordEG,LipmanJ,KabirM,McBrydeES,NimmoGR,LauA,etal.AssessmentofclinicalriskpredictiverulesforinvasivecandidiasisinaprospectivemulticentrecohortofICUpatients.IntensiveCareMed.2009;35:2141–5.

211. LeónC,Ruiz-SantanaS,SaavedraP,AlmiranteB,Nolla-SalasJ,Alvarez-LermaF,etal.Abedsidescoringsystem(“Candidascore”)forearlyantifungaltreatmentinnonneutropeniccriticallyillpatientswithCandidacolonization.CritCareMed.2006;34(3):730–7.

212. Cuenca-EstrellaM,VerweijPE,ArendrupMC,Arikan-AkdagliS,BilleJ,DonnellyJP,etal.ESCMID*guidelineforthediagnosisandmanagementofCandidadiseases2012:diagnosticprocedures.ClinMicrobiolInfect.2012Dec;18Suppl7:9–18.

213. MikulskaM,CalandraT,SanguinettiM,PoulainD,ViscoliC.Theuseofmannanantigenandanti-mannanantibodiesinthediagnosisofinvasivecandidiasis:recommendationsfromtheThirdEuropeanConferenceonInfectionsinLeukemia.CritCare.2010Jan;14(6):R222.

214. LamothF,CrucianiM,MengoliC,CastagnolaE,LortholaryO,RichardsonM,etal.β-Glucanantigenemiaassayforthediagnosisofinvasivefungalinfectionsinpatientswithhematologicalmalignancies:asystematicreviewandmeta-analysisofcohortstudiesfromtheThirdEuropeanConferenceonInfectionsinLeukemia(ECIL-3).ClinInfectDis.2012Mar;54(5):633–43.

215. PoissyJ,SendidB,DamiensS,IchiIshibashiK,FrançoisN,KauvM,etal.PresenceofCandidacellwallderivedpolysaccharidesintheseraof


intensivecareunitpatients:relationwithcandidaemiaandCandidacolonisation.CritCare.2014Jan;18(3):R135.216. KarageorgopoulosDE,VouloumanouEK,NtzioraF,MichalopoulosA,RafailidisPI,FalagasME.ß-D-glucanassayforthediagnosisofinvasivefungal

infections:Ameta-analysis.ClinInfectDis.2011;52:750–70.217. Ostrosky-ZeichnerL,AlexanderBD,KettDH,VazquezJ,PappasPG,SaekiF,etal.Multicenterclinicalevaluationofthe(1-3)beta-D-glucanassayas

anaidtodiagnosisoffungalinfectionsinhumans.ClinInfectDis.2005;41:654–9.218. WarrisA,LehrnbecherT.ProgressintheDiagnosisofInvasiveFungalDiseaseinChildren.CurrFungalInfectRep[Internet].Springer;2017[cited

2017Jul26];11(2):35–44.Availablefrom:http://www.ncbi.nlm.nih.gov/pubmed/28680525219. SendidB,PoirotJL,TabouretM,BonninA,ÃãDC,CamusD,etal.Combineddetectionofmannanaemiaandanti-mannanantibodiesasastrategy

forthediagnosisofsystemicinfectioncausedbypathogenicCandidaspecies.JMedMicrobiol.2002;51:433–42.220. ChangS-S,HsiehW-H,LiuT-S,LeeS-H,WangC-H,ChouH-C,etal.MultiplexPCRsystemforrapiddetectionofpathogensinpatientswithpresumed

sepsis-asystemicreviewandmeta-analysis.PLoSOne.2013;8(5):e62323.221. MylonakisE,ClancyCJ,Ostrosky-ZeichnerL,GareyKW,AlangadenGJ,VazquezJA,etal.T2magneticresonanceassayfortherapiddiagnosisof

candidemiainwholeblood:aclinicaltrial.ClinInfectDis.2015Mar15;60(6):892–9.222. Rodríguez-AdriánLJ,KingRT,Tamayo-DeratLG,MillerJW,GarciaCa,RexJH.Retinallesionsascluestodisseminatedbacterialandcandidal

infections:frequency,naturalhistory,andetiology.Medicine(Baltimore).2003;82(3):187–202.223. GauthierGM,NorkTM,PrinceR,AndesD.SubtherapeuticocularpenetrationofcaspofunginandassociatedtreatmentfailureinCandidaalbicans

endophthalmitis.ClinInfectDis.2005Aug1;41(3):e27-8.224. Martínez-VázquezC,Fernández-UlloaJ,BordónJ,SopeñaB,delaFuenteJ,OcampoA,etal.Candidaalbicansendophthalmitisinbrownheroin

addicts:responsetoearlyvitrectomyprecededandfollowedbyantifungaltherapy.ClinInfectDis.1998Nov;27(5):1130–3.225. RiddellIVJ,ComerGM,KauffmanCa.Treatmentofendogenousfungalendophthalmitis:Focusonnewantifungalagents.ClinInfectDis.

2011;52:648–53.226. KauffmanCa,VazquezA,SobelJD,GallisHa,MckinseyDS,KarchmeraW,etal.ProspectiveMulticenterSurveillanceStudyofFunguriain

HospitalizedPatients.ClinInfectDis.2000Jan;48105(1):14–8.227. SobelJD,KauffmanCa,MckinseyD,ZervosM,VazquezJa,KarchmeraW,etal.Candiduria:arandomized,double-blindstudyoftreatmentwith

fluconazoleandplacebo.ClinInfectDis.2000;30:19–24.228. FisherJF,SobelJD,KauffmanCa.,NewmanCa.Candidaurinarytractinfections-Treatment.ClinInfectDis.2011;52(Suppl6):457–66.229. SobelJD,BradshawSK,LipkaCJ,KartsonisNa.Caspofungininthetreatmentofsymptomaticcandiduria.ClinInfectDis.2007;44:e46–9.230. TuonFF,AmatoVS,PenteadoFilhoSR.BladderirrigationwithamphotericinBandfungalurinarytractinfection--systematicreviewwithmeta-

analysis.IntJInfectDis.Elsevier;2009Nov11;13(6):701–6.231. LeroyO,GangneuxJ-P,MontraversP,MiraJ-P,GouinF,SolletJ-P,etal.Epidemiology,management,andriskfactorsfordeathofinvasiveCandida

infectionsincriticalcare:amulticenter,prospective,observationalstudyinFrance(2005-2006).CritCareMed.2009;37(5):1612–8.232. ClancyCJ,NguyenMH.Findingthemissing50%ofinvasivecandidiasis:Hownonculturediagnosticswillimproveunderstandingofdiseasespectrum

andtransformpatientcare.ClinInfectDis.2013;56:1284–92.233. CalandraT,BilleJ,SchneiderR,MosimannF,FrancioliP.ClinicalsignificanceofCandidaisolatedfromperitoneuminsurgicalpatients.Lancet.

1989;2(8677):1437–40.234. SandvenP,BevangerL,DigranesA,GaustadP,HauklandHH,SteinbakkM.Constantlowrateoffungemiainnorway,1991to1996.TheNorwegian

YeastStudyGroup.JClinMicrobiol.1998Dec;36(12):3455–9.235. BassettiM,MarchettiM,ChakrabartiA,ColizzaS,Garnacho-MonteroJ,KettDH,etal.Aresearchagendaonthemanagementofintra-abdominal

candidiasis:Resultsfromaconsensusofmultinationalexperts.IntensiveCareMed.2013;39:2092–106.236. AllyR,SchürmannD,KreiselW,CarosiG,AguirrebengoaK,DupontB,etal.Arandomized,double-blind,double-dummy,multicentertrialof

voriconazoleandfluconazoleinthetreatmentofesophagealcandidiasisinimmunocompromisedpatients.ClinInfectDis.2001;33:1447–54.237. VillanuevaA,GotuzzoE,ArathoonEG,NoriegaLM,KartsonisNa.,LupinacciRJ,etal.Arandomizeddouble-blindstudyofcaspofunginversus

fluconazoleforthetreatmentofesophagealcandidiasis.AmJMed.2002;113:294–9.238. VillanuevaA,ArathoonEG,GotuzzoE,BermanRS,DiNubileMJ,SableCa.Arandomizeddouble-blindstudyofcaspofunginversusamphotericinfor

thetreatmentofcandidalesophagitis.ClinInfectDis.2001;33:1529–35.239. KrauseDS,SimjeeaE,vanRensburgC,ViljoenJ,WalshTJ,GoldsteinBP,etal.Arandomized,double-blindtrialofanidulafunginversusfluconazole

forthetreatmentofesophagealcandidiasis.ClinInfectDis.2004;39(August):770–5.240. ViljoenJ,AzieN,Schmitt-HoffmannA-H,GhannoumM.Aphase2,randomized,double-blind,multicentertrialtoevaluatethesafetyandefficacyof

threedosingregimensofisavuconazolecomparedwithfluconazoleinpatientswithuncomplicatedesophagealcandidiasis.AntimicrobAgentsChemother.2015Mar;59(3):1671–9.

241. SkiestDJ,VazquezJA,AnsteadGM,GraybillJR,ReynesJ,WardD,etal.Posaconazoleforthetreatmentofazole-refractoryoropharyngealandesophagealcandidiasisinsubjectswithHIVinfection.ClinInfectDis.2007Feb15;44(4):607–14.

242. VazquezJA,SkiestDJ,Tissot-DupontH,LennoxJL,BoparaiN,IsaacsR.Safetyandefficacyofposaconazoleinthelong-termtreatmentofazole-refractoryoropharyngealandesophagealcandidiasisinpatientswithHIVinfection.HIVClinTrials.2007Jan;8(2):86–97.

243. EggimannP,FrancioliP,BilleJ,SchneiderR,WuMM,ChapuisG,etal.Fluconazoleprophylaxispreventsintra-abdominalcandidiasisinhigh-risksurgicalpatients.CritCareMed.1999;27(June):1066–72.

244. PelzRK,HendrixCW,SwobodaSM,Diener-WestM,MerzWG,HammondJ,etal.Double-blindplacebo-controlledtrialoffluconazoletopreventcandidalinfectionsincriticallyillsurgicalpatients.AnnSurg.2001;233(4):542–8.

245. GarbinoJ,LewDP,Jacques-A.Romand,HugonnetS,AuckenthalerR,PittetD.PreventionofsevereCandidainfectionsinnonneutropenic,high-risk,criticallyillpatients:Arandomized,double-blind,placebo-controlledtrialinpatientstreatedbyselectivedigestivedecontamination.IntensiveCareMed.2002;28:1708–17.

246. VardakasKZ,SamonisG,MichalopoulosA,SoteriadesES,FalagasME.Antifungalprophylaxiswithazolesinhigh-risk,surgicalintensivecareunitpatients:ameta-analysisofrandomized,placebo-controlledtrials.CritCareMed.2006Apr;34(4):1216–24.

247. AguilarG,DelgadoC,CorralesI,IzquierdoA,GraciaE,MorenoT,etal.Theuseofprophylacticfluconazoleinimmunocompetenthigh-risksurgicalpatients:ameta-analysis.ClinInfectDis.2006;9(1):R710-7.

248. Ostrosky-ZeichnerL,ShohamS,VazquezJ,ReboliA,BettsR,BarronMa.,etal.MSG-01:Arandomized,double-blind,placebo-controlledtrialofcaspofunginprophylaxisfollowedbypreemptivetherapyforinvasivecandidiasisinhigh-riskadultsinthecriticalcaresetting.ClinInfectDis.2014;58:1219–26.

249. Ostrosky-ZeichnerL,SableC,SobelJ,AlexanderBD,DonowitzG,KanV,etal.Multicenterretrospectivedevelopmentandvalidationofaclinicalpredictionrulefornosocomialinvasivecandidiasisintheintensivecaresetting.EurJClinMicrobiolInfectDis.2007;26:271–6.

250. Ostrosky-ZeichnerL,PappasPG,ShohamS,ReboliA,BarronMA,SimsC,etal.Improvementofaclinicalpredictionruleforclinicaltrialsonprophylaxisforinvasivecandidiasisintheintensivecareunit.Mycoses.2011Jan;54(1):46–51.

251. SlavinMA,OsborneB,AdamsR,LevensteinMJ,SchochHG,FeldmanAR,etal.Efficacyandsafetyoffluconazoleprophylaxisforfungalinfectionsaftermarrowtransplantation--aprospective,randomized,double-blindstudy.JInfectDis.1995Jun;171(6):1545–52.

252. GoodmanJL,WinstonDJ,GreenfieldRA,ChandrasekarPH,FoxB,KaizerH,etal.AControlledTrialofFluconazoletoPreventFungalInfectionsinPatientsUndergoingBoneMarrowTransplantation.NEnglJMed.1992Mar26;326(13):845–51.

253. MaertensJ,MarchettiO,HerbrechtR,CornelyOa,FlückigerU,FrêreP,etal.Europeanguidelinesforantifungalmanagementinleukemiaandhematopoieticstemcelltransplantrecipients:summaryoftheECIL3--2009update.BoneMarrowTransplant.2011;46(July2010):709–18.

254. MarrKA,SeidelK,SlavinMA,BowdenRA,SchochHG,FlowersME,etal.Prolongedfluconazoleprophylaxisisassociatedwithpersistentprotectionagainstcandidiasis-relateddeathinallogeneicmarrowtransplantrecipients:long-termfollow-upofarandomized,placebo-controlledtrial.Blood.2000;96(6):2055–61.


255. DrewRH,DoddsAshleyE,BenjaminDK,DuaneDavisR,PalmerSM,PerfectJR.ComparativesafetyofamphotericinBlipidcomplexandamphotericinBdeoxycholateasaerosolizedantifungalprophylaxisinlung-transplantrecipients.Transplantation.2004Jan27;77(2):232–7.

256. MonforteV,UssettiP,GavaldàJ,BravoC,LaportaR,LenO,etal.Feasibility,tolerability,andoutcomesofnebulizedliposomalamphotericinBforAspergillusinfectionpreventioninlungtransplantation.JHearlungTransplant.2010May;29(5):523–30.

257. MitsaniD,NguyenMH,ShieldsRK,ToyodaY,KwakEJ,SilveiraFP,etal.Prospective,observationalstudyofvoriconazoletherapeuticdrugmonitoringamonglungtransplantrecipientsreceivingprophylaxis:factorsimpactinglevelsofandassociationsbetweenserumtroughs,efficacy,andtoxicity.AntimicrobAgentsChemother.2012May;56(5):2371–7.

258. TofteN,JensenC,TvedeM,AndersenCB,CarlsenJ,IversenM.UseofprophylacticvoriconazoleforthreemonthsafterlungtransplantationdoesnotreduceinfectionwithAspergillus:aretrospectivestudyof147patients.ScandJInfectDis.2012Nov;44(11):835–41.

259. SchaenmanJM.Isuniversalantifungalprophylaxismandatoryinlungtransplantpatients?CurrOpinInfectDis.2013Aug;26(4):317–25.260. TollemarJ,HöckerstedtK,EriczonBG,JalankoH,RingdénO.LiposomalamphotericinBpreventsinvasivefungalinfectionsinlivertransplant

recipients.Arandomized,placebo-controlledstudy.Transplantation.1995Jan15;59(1):45–50.261. HadleyS,HuckabeeC,PappasPG,DalyJ,RabkinJ,KauffmanCa.,etal.Outcomesofantifungalprophylaxisinhigh-risklivertransplantrecipients.

TransplInfectDis.2009;11:40–8.262. PerrellaA,EspositoC,PisanielloD,D’AlessioL,PerrellaO,MarcosA,etal.RoleofliposomalAmphotericinBprophylaxisafterlivertransplantation

comparedwithfluconazoleforhigh-riskpatients.Impactoninfectionsandmortalitywithinoneyear.In:TransplantationProceedings.2012.p.1977–81.

263. HellingerWC,BonattiH,YaoJD,AlvarezS,BrumbleLM,KeatingMR,etal.Riskstratificationandtargetedantifungalprophylaxisforpreventionofaspergillosisandotherinvasivemoldinfectionsafterlivertransplantation.LiverTransplant.2005Jun;11(6):656–62.

264. WinstonDJ,PakrasiA,BusuttilRW.Prophylacticfluconazoleinlivertransplantrecipients.Arandomized,double-blind,placebo-controlledtrial.AnnInternMed.1999Nov16;131(10):729–37.

265. WinstonDJ,LimayeAP,PelletierS,SafdarN,MorrisMI,MenesesK,etal.Randomized,Double-BlindTrialofAnidulafunginVersusFluconazoleforProphylaxisofInvasiveFungalInfectionsinHigh-RiskLiverTransplantRecipients.AmJTransplant.2014Dec;14(12):2758–64.

266. SalibaF,PascherA,CointaultO,LaterreP-F,CerveraC,DeWaeleJJ,etal.Randomizedtrialofmicafunginforthepreventionofinvasivefungalinfectioninhigh-risklivertransplantrecipients.ClinInfectDis.2015Apr1;60(7):997–1006.

267. PlayfordEG,WebsteraC,SorrellTC,CraigJC.Systematicreviewandmeta-analysisofantifungalagentsforpreventingfungalinfectionsinlivertransplantrecipients.EurJClinMicrobiolInfectDis.2006;25:549–61.

268. EvansJDW,MorrisPJ,KnightSR.Antifungalprophylaxisinlivertransplantation:asystematicreviewandnetworkmeta-analysis.AmJTransplant.2014Dec;14(12):2765–76.

269. PappasPG,AndesD,SchusterM,HadleyS,RabkinJ,MerionRM,etal.Invasivefungalinfectionsinlow-risklivertransplantrecipients:Amulti-centerprospectiveobservationalstudy.AmJTransplant.2006;6(October2005):386–91.

270. PappasPG,AlexanderBD,AndesDR,HadleyS,KauffmanCA,FreifeldA,etal.Invasivefungalinfectionsamongorgantransplantrecipients:resultsoftheTransplant-AssociatedInfectionSurveillanceNetwork(TRANSNET).ClinInfectDis.2010Apr15;50(8):1101–11.

271. KaufmanD,BoyleR,HazenKC,PatrieJT,RobinsonM,GrossmanLB,etal.TwiceweeklyfluconazoleprophylaxisforpreventionofinvasiveCandidainfectioninhigh-riskinfantsof.JPediatr.2005Aug;147(2):172–9.

272. CleminsonJ,AustinN,McGuireW.Prophylacticsystemicantifungalagentstopreventmortalityandmorbidityinverylowbirthweightinfants.CochranedatabaseSystRev.2015;(10):CD003850.

273. BenjaminDK,HudakML,DuaraS,RandolphDA,BidegainM,MundakelGT,etal.Effectoffluconazoleprophylaxisoncandidiasisandmortalityinprematureinfants:arandomizedclinicaltrial.JAMA.2014May7;311(17):1742–9.

274. BrouwerAE,RajanuwongA,ChierakulW,GriffinGE,LarsenRa.,WhiteNJ,etal.CombinationantifungaltherapiesforHIV-associatedcryptococcalmeningitis:Arandomisedtrial.Lancet.2004;363:1764–7.

275. vanderHorstCM,SaagMS,CloudGA,HamillRJ,GraybillJR,SobelJD,etal.Treatmentofcryptococcalmeningitisassociatedwiththeacquiredimmunodeficiencysyndrome.NEnglJMed.1997Jul3;337(1):15–21.

276. JarvisJN,BicanicT,LoyseA,NamarikaD,JacksonA,NussbaumJC,etal.Determinantsofmortalityinacombinedcohortof501patientswithHIV-associatedcryptococcalmeningitis:Implicationsforimprovingoutcomes.ClinInfectDis.2014Mar;58(5):736–45.

277. BennettJE,DismukesWE,DumaRJ,MedoffG,SandeMA,GallisH,etal.AcomparisonofamphotericinBaloneandcombinedwithflucytosineinthetreatmentofcryptoccalmeningitis.NEnglJMed.1979Jul19;301(3):126–31.

278. LoyseA,WilsonD,MeintjesG,JarvisJN,BicanicT,BishopL,etal.Comparisonoftheearlyfungicidalactivityofhigh-dosefluconazole,voriconazole,andflucytosineassecond-linedrugsgivenincombinationwithamphotericinBforthetreatmentofHIV-associatedcryptococcalmeningitis.ClinInfectDis.2012;54:121–8.

279. DayJN,ChauTTH,WolbersM,MaiPP,DungNT,MaiNH,etal.Combinationantifungaltherapyforcryptococcalmeningitis.NEnglJMed.2013;368:1291–302.

280. SaagMS,PowderlyWG,CloudGA,RobinsonP,GriecoMH,SharkeyPK,etal.ComparisonofamphotericinBwithfluconazoleinthetreatmentofacuteAIDS-associatedcryptococcalmeningitis.NEnglJMed.1992Jan9;326(2):83–9.

281. LarsenRA,LealMAE,ChanLS.FluconazolecomparedwithamphotericinBplusflucytosineforcryptococcalmeningitisinAIDS.Arandomizedtrial.AnnInternMed.1990Aug1;113(3):183–7.

282. NussbaumJC,JacksonA,NamarikaD,PhulusaJ,KenalaJ,KanyembaC,etal.Combinationflucytosineandhigh-dosefluconazolecomparedwithfluconazolemonotherapyforthetreatmentofcryptococcalmeningitis:arandomizedtrialinMalawi.ClinInfectDis.2010Feb1;50(3):338–44.

283. BicanicT,WoodR,MeintjesG,RebeK,BrouwerA,LoyseA,etal.High-doseamphotericinBwithflucytosineforthetreatmentofcryptococcalmeningitisinHIV-infectedpatients:arandomizedtrial.ClinInfectDis.2008;47(April2007):123–30.

284. LeendersAC,ReissP,PortegiesP,ClezyK,HopWC,HoyJ,etal.LiposomalamphotericinB(AmBisome)comparedwithamphotericinBbothfollowedbyoralfluconazoleinthetreatmentofAIDS-associatedcryptococcalmeningitis.AIDS.1997Oct;11(12):1463–71.

285. JadhavMP,BambaA,ShindeVM,GogtayN,KshirsagarNA,BichileLS,etal.LiposomalamphotericinB(Fungisone)forthetreatmentofcryptococcalmeningitisinHIV/AIDSpatientsinIndia:amulticentric,randomizedcontrolledtrial.JPostgradMed.2010;56(2):71–5.

286. HamillRJ,SobelJD,El-SadrW,JohnsonPC,GraybillJR,JavalyK,etal.Comparisonof2dosesofliposomalamphotericinBandconventionalamphotericinBdeoxycholatefortreatmentofAIDS-associatedacutecryptococcalmeningitis:arandomized,double-blindclinicaltrialofefficacyandsafety.ClinInfectDis.2010;51(2):225–32.

287. NeteaMG,SutmullerR,HermannC,VanderGraafCaa,VanderMeerJWM,vanKriekenJH,etal.Toll-likereceptor2suppressesimmunityagainstCandidaalbicansthroughinductionofIL-10andregulatoryTcells.JImmunol.2004;172(541):3712–8.

288. SiddiquiAa,BrouwerAE,WuthiekanunV,JaffarS,ShattockR,IrvingD,etal.IFN-gammaatthesiteofinfectiondeterminesrateofclearanceofinfectionincryptococcalmeningitis.JImmunol.2005;174(3):1746–50.

289. PappasPG,BustamanteB,TiconaE,HamillRJ,JohnsonPC,ReboliA,etal.Recombinantinterferon-gamma1basadjunctivetherapyforAIDS-relatedacutecryptococcalmeningitis.JInfectDis.2004;189:2185–91.

290. JarvisJN,MeintjesG,RebeK,WilliamsGN,BicanicT,WilliamsA,etal.Adjunctiveinterferon-γimmunotherapyforthetreatmentofHIV-associatedcryptococcalmeningitis:arandomizedcontrolledtrial.AIDS.2012;26(9):1105–13.

291. BeardsleyJ,WolbersM,KibengoFM,GgayiA-BM,KamaliA,CucNTK,etal.AdjunctiveDexamethasoneinHIV-AssociatedCryptococcalMeningitis.NEnglJMed.2016Feb11;374(6):542–54.

292. SaijoT,ChenJ,ChenSC-A,RosenLB,YiJ,SorrellTC,etal.Anti-granulocyte-macrophagecolony-stimulatingfactorautoantibodiesareariskfactorforcentralnervoussysteminfectionbyCryptococcusgattiiinotherwiseimmunocompetentpatients.MBio.2014Mar18;5(2):e00912-14.

293. GraybillJR,SobelJ,SaagM,vanDerHorstC,PowderlyW,CloudG,etal.DiagnosisandmanagementofincreasedintracranialpressureinpatientswithAIDSandcryptococcalmeningitis.ClinInfectDis.2000;30:47–54.


294. RolfesMA,HullsiekKH,RheinJ,NabetaHW,TaseeraK,SchutzC,etal.Theeffectoftherapeuticlumbarpuncturesonacutemortalityfromcryptococcalmeningitis.ClinInfectDis.2014Dec1;59(11):1607–14.

295. BissonGP,MolefiM,BellamyS,ThakurR,SteenhoffA,TamuhlaN,etal.EarlyversusdelayedantiretroviraltherapyandcerebrospinalfluidfungalclearanceinadultswithHIVandcryptococcalmeningitis.ClinInfectDis.2013Apr;56(8):1165–73.

296. BoulwareDR,MeyaDB,MuzooraC,RolfesMA,HupplerHullsiekK,MusubireA,etal.Timingofantiretroviraltherapyafterdiagnosisofcryptococcalmeningitis.NEnglJMed.2014Jun26;370(26):2487–98.

297. PerfectJR,DismukesWE,DromerF,GoldmanDL,GraybillJR,HamillRJ,etal.Clinicalpracticeguidelinesforthemanagementofcryptococcaldisease:2010updatebytheinfectiousdiseasessocietyofamerica.ClinInfectDis.2010Feb1;50(3):291–322.

298. DismukesWE,CloudG,GallisHA,KerkeringTM,MedoffG,CravenPC,etal.TreatmentofcryptococcalmeningitiswithcombinationamphotericinBandflucytosineforfourascomparedwithsixweeks.NEnglJMed.1987Aug6;317(6):334–41.

299. DromerF,MathoulinS,DupontB,BrugiereO,LetenneurL.ComparisonoftheefficacyofamphotericinBandfluconazoleinthetreatmentofcryptococcosisinhumanimmunodeficiencyvirus-negativepatients:retrospectiveanalysisof83cases.FrenchCryptococcosisStudyGroup.ClinInfectDis.1996May;22Suppl2:S154-60.

300. SinghN,LortholaryO,AlexanderBD,GuptaKL,JohnGT,PursellKJ,etal.Antifungalmanagementpracticesandevolutionofinfectioninorgantransplantrecipientswithcryptococcusneoformansinfection.Transplantation.2005Oct27;80(8):1033–9.

301. SinghN,ForrestG,ASTInfectiousDiseasesCommunityofPractice.Cryptococcosisinsolidorgantransplantrecipients.AmJTransplant.2009Dec;9Suppl4:S192-8.

302. DromerF,Bernede-BauduinC,GuillemotD,LortholaryO,FrenchCryptococcosisStudyGroup.MajorroleforamphotericinB-flucytosinecombinationinseverecryptococcosis.PLoSOne.2008;3(8):e2870.

303. NeteaMG,BrouwerAE,HoogendoornEH,MeerJWMVanDer,KoolenM,VerweijPE,etal.TwoPatientswithCryptococcalMeningitisandIdiopathicCD4Lymphopenia :DefectiveCytokineProductionandReversalbyRecombinantInterferon-gTherapy.ClinInfectDis.2004;39(October):83–7.

304. BozzetteSA,LarsenRA,ChiuJ,LealMA,JacobsenJ,RothmanP,etal.Aplacebo-controlledtrialofmaintenancetherapywithfluconazoleaftertreatmentofcryptococcalmeningitisintheacquiredimmunodeficiencysyndrome.NEnglJMed.1991Feb28;324(9):580–4.

305. PowderlyWG,SaagMS,CloudGA,RobinsonP,MeyerRD,JacobsonJM,etal.AcontrolledtrialoffluconazoleoramphotericinBtopreventrelapseofcryptococcalmeningitisinpatientswiththeacquiredimmunodeficiencysyndrome.TheNIAIDAIDSClinicalTrialsGroupandMycosesStudyGroup.NEnglJMed.1992Mar19;326(12):793–8.

306. SaagMS,CloudGA,GraybillJR,SobelJD,TuazonCU,JohnsonPC,etal.AcomparisonofitraconazoleversusfluconazoleasmaintenancetherapyforAIDS-associatedcryptococcalmeningitis.ClinInfectDis.1999Feb;28(2):291–6.

307. VibhagoolA,SungkanuparphS,MootsikapunP,ChetchotisakdP,TansuphaswaswadikulS,BowonwatanuwongC,etal.Discontinuationofsecondaryprophylaxisforcryptococcalmeningitisinhumanimmunodeficiencyvirus-infectedpatientstreatedwithhighlyactiveantiretroviraltherapy:aprospective,multicenter,randomizedstudy.ClinInfectDis.2003May15;36(10):1329–31.

308. MussiniC,PezzottiP,MiróJM,MartinezE,deQuirosJCLB,CinqueP,etal.DiscontinuationofmaintenancetherapyforcryptococcalmeningitisinpatientswithAIDStreatedwithhighlyactiveantiretroviraltherapy:aninternationalobservationalstudy.ClinInfectDis.2004Feb15;38(4):565–71.

309. CDC/NIH/IDSAPanelonOpportunisticInfectionsinHIV-InfectedAdultsandAdolescents.GuidelinesforthepreventionandtreatmentofopportunisticinfectionsinHIV-infectedadultsandadolescents:recommendationsfromtheCentersforDiseaseControlandPrevention,theNationalInstitutesofHealth,andtheHIVMedicineAssociation.2016.

310. BalaK,ChanderJ,HandaU,PuniaRS,AttriAK.AprospectivestudyofmucormycosisinnorthIndia:experiencefromatertiarycarehospital.MedMycol.2015Apr1;53(3):248–57.

311. RodenMM,ZaoutisTE,BuchananWL,KnudsenTA,SarkisovaTA,SchaufeleRL,etal.EpidemiologyandOutcomeofZygomycosis:AReviewof929ReportedCases.ClinInfectDis.2005Sep1;41(5):634–53.

312. LanternierF,DannaouiE,MorizotG,ElieC,Garcia-HermosoD,HuerreM,etal.AglobalanalysisofmucormycosisinFrance:TheRetroZygostudy(2005-2007).ClinInfectDis.2012;54(Suppl1):35–43.

313. ZaoutisTE,RoilidesE,ChiouCC,BuchananWL,KnudsenTA,SarkisovaTA,etal.ZygomycosisinChildren:ASystematicReviewandAnalysisofReportedCases.PediatrInfectDisJ.2007Aug;26(8):723–7.

314. KontoyiannisDP,LionakisMS,LewisRE,ChamilosG,HealyM,PeregoC,etal.ZygomycosisinaTertiary-CareCancerCenterintheEraofAspergillus-ActiveAntifungalTherapy:ACase-ControlObservationalStudyof27RecentCases.JInfectDis.2005Apr15;191(8):1350–60.

315. ParkBJ,PappasPG,WannemuehlerKA,AlexanderBD,AnaissieEJ,AndesDR,etal.Invasivenon-Aspergillusmoldinfectionsintransplantrecipients,UnitedStates,2001-2006.EmergInfectDis.2011Oct;17(10):1855–64.

316. FraterJL,HallGS,ProcopGW.Histologicfeaturesofzygomycosis:emphasisonperineuralinvasionandfungalmorphology.ArchPatholLabMed.2001Mar;125(3):375–8.

317. Ben-AmiR,LunaM,LewisRE,WalshTJ,KontoyiannisDP.Aclinicopathologicalstudyofpulmonarymucormycosisincancerpatients:extensiveangioinvasionbutlimitedinflammatoryresponse.JInfect.2009Aug;59(2):134–8.

318. OdabasiZ,PaetznickVL,RodriguezJR,ChenE,McGinnisMR,Ostrosky-ZeichnerL.Differencesinbeta-glucanlevelsinculturesupernatantsofavarietyoffungi.MedMycol.2006Jan;44(3):267–72.

319. PhaiPangKA,GodetC,FekkarA,SchollerJ,NivoixY,Letscher-BruV,etal.Breakthroughinvasivemouldinfectionsinpatientstreatedwithcaspofungin.JInfect.2012;64:424–9.

320. WahbaH,TruongMT,LeiX,KontoyiannisDP,MaromEM.ReversedHaloSigninInvasivePulmonaryFungalInfections.ClinInfectDis.2008Jun;46(11):1733–7.

321. JuanY-H,SabooSS,LinY-C,ConnerJR,JacobsonFL,KhandelwalA.Reversehalosigninpulmonarymucormyosis.QJM.2014Sep1;107(9):777–8.322. RibesJA,Vanover-SamsCL,BakerDJ.Zygomycetesinhumandisease.ClinMicrobiolRev.2000Apr;13(2):236–301.323. ChayakulkeereeM,GhannoumMa.,PerfectJR.Zygomycosis:There-emergingfungalinfection.EurJClinMicrobiolInfectDis.2006;25:215–29.324. PerfectJR.TreatmentofNon-AspergillusMouldsinImmunocompromisedPatients,withAmphotericinBLipidComplex.ClinInfectDis.2005

May;40(S6):S401–8.325. HerbrechtR,Letscher-BruV,BowdenRA,KusneS,AnaissieEJ,GraybillJR,etal.Treatmentof21casesofinvasivemucormycosiswithamphotericin

Bcolloidaldispersion.EurJClinMicrobiolInfectDis.2001Jul;20(7):460–6.326. PaganoL,OffidaniM,FianchiL,NosariA,CandoniA,PicardiM,etal.Mucormycosisinhematologicpatients.Haematologica.2004Feb;89(2):207–

14.327. RupingMJGT,HeinzWJ,KindoAJ,RickertsV,Lass-FlorlC,BeiselC,etal.Forty-onerecentcasesofinvasivezygomycosisfromaglobalclinical

registry.JAntimicrobChemother.2010Feb1;65(2):296–302.328. LanternierF,PoireeS,ElieC,Garcia-HermosoD,BakouboulaP,SitbonK,etal.Prospectivepilotstudyofhigh-dose(10mg/kg/day)liposomal

amphotericinB(L-AMB)fortheinitialtreatmentofmucormycosis.JAntimicrobChemother.2015Aug27;70(11):3116–23.329. ReedC,BryantR,IbrahimAS,EdwardsJ,FillerSG,GoldbergR,etal.Combinationpolyene-caspofungintreatmentofrhino-orbital-cerebral

mucormycosis.ClinInfectDis.2008;47:364–71.330. AbidiMZ,SohailMR,CumminsN,WilhelmM,WengenackN,BrumbleL,etal.Stabilityinthecumulativeincidence,severityandmortalityof101

casesofinvasivemucormycosisinhigh-riskpatientsfrom1995to2011:acomparisonoferasimmediatelybeforeandaftertheavailabilityofvoriconazoleandechinocandin-amphotericinc.Mycoses.2014Nov;57(11):687–98.

331. MartyFM,Ostrosky-ZeichnerL,CornelyOA,MullaneKM,PerfectJR,ThompsonGR,etal.Isavuconazoletreatmentformucormycosis:asingle-armopen-labeltrialandcase-controlanalysis.LancetInfectDis.2016Mar8;16(7):828–37.

332. SpellbergB,BrassE,Chin-HongP,Al.E,Al.E.TheVITALstudy:casecontrolstudiesarehypothesis-generating.LancetInfectDis.2016Aug;16(8):886.333. vanBurikJ-AH,HareRS,SolomonHF,CorradoML,KontoyiannisDP.Posaconazoleiseffectiveassalvagetherapyinzygomycosis:aretrospective


summaryof91cases.ClinInfectDis.2006;42:e61–5.334. GreenbergRN,MullaneK,vanBurikJ-AH,RaadI,AbzugMJ,AnsteadG,etal.Posaconazoleassalvagetherapyforzygomycosis.AntimicrobAgents

Chemother.2006Jan;50(1):126–33.335. SkiadaA,PaganoL,GrollA,ZimmerliS,DupontB,LagrouK,etal.ZygomycosisinEurope:analysisof230casesaccruedbytheregistryofthe

EuropeanConfederationofMedicalMycology(ECMM)WorkingGrouponZygomycosisbetween2005and2007.ClinMicrobiolInfect.2011Dec;17(12):1859–67.

336. VironneauP,KaniaR,MorizotG,ElieC,Garcia-HermosoD,HermanP,etal.Localcontrolofrhino-orbito-cerebralmucormycosisdramaticallyimpactssurvival.ClinMicrobiolInfect.Elsevier;2014May;20(5):O336-9.

337. IbrahimAS,GebermariamT,FuY,LinL,HusseinyMI,FrenchSW,etal.Theironchelatordeferasiroxprotectsmicefrommucormycosisthroughironstarvation.JClinInvest.2007Sep;117(9):2649–57.

338. SpellbergB,AndesD,PerezM,AnglimA,BonillaH,MathisenGE,etal.Safetyandoutcomesofopen-labeldeferasiroxironchelationtherapyformucormycosis.AntimicrobAgentsChemother.2009;53(7):3122–5.

339. SpellbergB,IbrahimAS,Chin-HongPV.,KontoyiannisDP,MorrisMI,PerfectJR,etal.Thedeferasirox-AmBisometherapyformucormycosis(DefeatMucor)study:Arandomized,double-blinded,placebo-controlledtrial.JAntimicrobChemother.2012;67(September2011):715–22.

AppendixSpecificconsiderationsfordosingofantifungalsinchildrenTableS1.Recommendeddosesofantifungalagentsforchildren†

Antifungalagent Loadingdose MaintenancedoseAzolesVoriconazole 2-14yearsand<50kg:

bid9mg/kg12-14yearsand>50kg;and15-17years:bid6mg/kgivorbid400mgpo≥18yearsrefertoadultrecommendations

8mg/kgbidiv#or9mg/kgbidpo#4mg/kgbidiv#or200mgbidpo#

Isavuconazole * Posaconazole * EchinocandinsAnidulafungin notlicensedforchildren Caspofungin 12monthsto17years:

70mg/m2/d(maximum70mg)3to11months:50mg/m2/dNeonates/<3months:25mg/m2/d

12monthsto17years:50mg/m2/d(maximum70mg)3to11months:50mg/m2/dNeonates/<3months:25mg/m2/d

Micafungin - 4months–16yearsand<40kg:2mg/kg/d(maximum4mg/kg/d)4months–16yearsand≥40kg:100mg/d(maximum200mg/d)Neonates/<4months4mg/kg/d(maximum10mg/kg/d)

AmphotericinBLiposomalAmB 3mg/kg/d 3mg/kg/d

†Thedosagesinthistablearespecificforinvasiveaspergillosis.Forothermycoses,differentdosagesmayapply.Forspecificrecommendations,exceptions,andcontra-indications,seetextandTable2.1.*Fordosing,consultwithexperts#Individualdosebasedontherapeuticdrugmonitoring

TableS2.Recommendeddosesofantifungalagentsfortreatmentofinvasivecandidiasisinneonates

Antifungalagent Loadingdose Maintenancedose

Azoles

Fluconazole Consider25mg/kg 12mg/kg/d

Echinocandins

Caspofungin 25mg/m2/d

Micafungin 4–10mg/kg/d

AmphotericinB

AmphotericinBdeoxycholate 1mg/kg/d

LiposomalAmB 3mg/kg/d†Thedosagesinthistablearespecificforinvasivecandidiasis.Forothermycoses,differentdosagesmayapply.Forspecificrecommendations,exceptions,andcontra-indications,seetext.


TableS3.Recommendeddosesofantifungalagentsfortreatmentofinvasivecandidiasisinchildren

Antifungalagent Loadingdose Maintenancedose

Azoles

Fluconazole 8-12mg/kg/d

Voriconazole 2-14yearsand<50kg:bid9mg/kg12-14yearsand>50kg;and15-17years:bid6mg/kgivorbid400mgpo

8mg/kgbidiv#or9mg/kgbidpo#

4mg/kgbidiv#or200mgbidpo#

Echinocandins

Caspofungin 12monthsto17years:

70mg/m2/d(maximum70mg)

3to11months:

50mg/m2/d

12monthsto17years:

50mg/m2/d(maximum70mg)

3to11months:

50mg/m2/d

Micafungin - 4months–16yearsand<40kg:

2mg/kg/d(maximum4mg/kg/d)

4months–16yearsand≥40kg:

100mg/d(maximum200mg/d)

AmphotericinB

LiposomalAmB 3mg/kg/d†Thedosagesinthistablearespecificforinvasivecandidiasis.Forothermycoses,differentdosagesmayapply.Forspecificrecommendations,exceptions,andcontra-indications,seetext.#Individualdosebasedontherapeuticdrugmonitoring

dutch working party on antibiotic policy swab guidelines

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