Title of Guideline (must include the word Guideline (not

protocol, policy, procedure etc)

Clinical Guideline for the prophylaxis and
treatment of fungal infections in
Haematology patients
Contact Name and J ob Title (author)
Dr J L Byrne, Consultant Haematologist

Directorate & Speciality Clinical Haematology, CAS

Date of submission
7/8/2013
Date on which guideline must be reviewed (this should be one to
three years)

7/8/2014
Explicit definition of patient group to which it applies (e.g.
inclusion and exclusion criteria, diagnosis)

Clinical haematology patients

Changes from previous guideline
Abstract
Key Words
Antifungal drugs, Haematology

Statement of the evidence base of the guideline has the
guideline been peer reviewed by colleagues?

Evidence base: (1-5)
1a meta analysis of randomised controlled trials
1b at least one randomised controlled trial
2a at least one well-designed controlled study without
randomisation
2b at least one other type of well-designed quasi-
experimental study
3 well designed non-experimental descriptive studies
(ie comparative / correlation and case studies)
4 expert committee reports or opinions and / or clinical
experiences of respected authorities
5 recommended best practise based on the clinical
experience of the guideline developer
4
Consultation Process
Haematology Consultants. Pharmacists, Senior
Haematology nurses

Target audience
FY1/2, CT1/2 and Haematology ST3-ST7
doctors


This guideline has been registered with the trust. However,
clinical guidelines are guidelines only. The interpretation
and application of clinical guidelines will remain the
responsibility of the individual clinician. If in doubt contact a
senior colleague or expert. Caution is advised when using
guidelines after the review date.

Clinical guideline - Review date Aug 2014
2 7/8/13
Clinical Guideline for the Prophylaxis and Treatment of Fungal
Infections
Introduction
Patientswithprolongedneutropeniaareatriskofdevelopingbothlocalizedfungalinfections,mainly
involvingmucocutaneousCandidaspecies.Theyarealsoatriskofinvasivefungalinfectionsmainlywith
AspergillusandMucorspecies,usuallyofthesinusesandrespiratorysystems.Prophylaxiswithazoleanti
fungalagentscancertainlyreducetheriskofCandidainfectionsandsomeofthenewerthirdgeneration
azoledrugsalsohaveabroaderspectrumofantifungalactivityincludingAspergillus.
PatientsatriskofinvasivefungalinfectionsshouldhaveCXRsdoneregularlyforallpatientswith
neutropenicfever.HighresolutionCTscanningshouldbeperformedifthereisCXRshadowingsuspicious
offungalinfectionorifthereisunremittingfeverwithnoobviouscauseandahighCRP>200.
AntifungalProphylaxisaccordingtoRiskofInvasiveFungalInfections
Haematologypatientscanbestratifiedintothosewithahighriskofinvasivefungalinfectionandthose
withastandardorlowriskoffungalinfectiondependingontheintensityoftreatmenttheyarereceiving
andlikelydurationofneutropeniaandwhetherornottheyhavehadapreviousepisodeofprobableor
confirmedinvasivefungalinfection

HighRisk PatientsreceivingALLinductionchemotherapywhichincludes
dexamethasoneandwhoarelikelytohaveprolongedperiodof
neutropeniaandwhocannothaveazolesduetovicristinedrug
interactions
Patientswhohavehadpreviouslydocumentedconfirmedorhighly
probableinvasivefungalinfectionsandwhoareundergoingfurther
intensivechemotherapylikelytoresultinaprolongedperiodof
neutropenia>10daysegAMLinductionchemotherapyorallogeneicor
autologoustransplantprocedure
Patientsundergoingautologous/allogeneicSCT
PrescribelowdoseAbelcetorAmBisome100mgx3perweekIVD+1
untilANC>0.5
StandardRisk PatientsundergoingintensiveAML/NHLchemotherapy(Noteazolesmust
notbegiventopatientsreceivingMyelotargorAC220)
Patientsreceiving>10mgprednisoloneforGVHD
Oralposaconazole200mgtds

LowRisk Patientsundergoingoutpatientchemotherapy,egCHOP,VADorany
regimenthatincludesvincaalkaloids
Prescribefluconazole50mgodpo
TreatmentofInvasiveFungalInfectionsinNeutropenicPatients
ItisimportanttotryandprovethatthereisafungalinfectionbyBAL,highresolutionCTscanningor
galactomannanbloodtestspriortotheinitiationofantifungalagents.Thepreferredantifungalagent
forthetreatmentofpresumedinvasivefungalinfectiondependsonthelikelihoodofsuchaninfection
Clinical guideline - Review date Aug 2014
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beingpresentandthestrengthoftheevidenceforthis.Whilstpatientsarereceivingtreatmentwith
intravenousantifungalagentstheirusualazoleprophylaxisshouldbediscontinued.
1. EmpiricTherapyforUnremittingFever
Afungalinfectionmaybepresumedinneutropenicpatientswithanunremittingpyrexiawhich
hasnotresolvedwithin4872hoursdespitebroadspectrumantibiotics
ItisimportanttotryandprovethatthereisafungalinfectionbyeitherBAL,highresolutionCT
scanning(galactomannanbloodtestsaresometimesusefiul)butantifungalagentsshouldbe
initiateanywaywhilstwaitingfortheseresultstocomeback
AmphotericinlipidBcomplex(Abelcet)isacomplexofAmphotericinBwith2phospholipids
whichhasefficacyagainstAspergillusandCandidaspecies.
Abelcet1mg/kgistheinitialdrugofchoiceinHaematologypatientswithneutropenicfever
unresponsivetobroadspectrumantibioticsandwithnormalrenalfunctionandnootherrisk
factorsfornephrotoxicity.
DoseofAbelcetis1mg/kgroundedtonearest100mgvial
Doseis100mg/dayifweightisupto100kg(i.e.1mg/kgroundedtonearest100mgvial)
Doseis150mg/dayifweightis.>100kg(i.e.1mg.kgroundedtonearest100mgvial)
AbelcetisadministeredasanIVinfusionoveratleast3hoursatarateof2.5mg/kg/houraftera
testdoseof1mgover15minutesthenobservepatientfor30minutesbeforegivingtherestof
theinfusionwithoutchlorpheniramineandhydrocortisonecover.Themostcommonsideeffects
arefever,nausea,chillsandvomiting.Ifreactionsoccurchlorpheniramine10mgIVand
paracetamoligpocanbegivenaspremedication.Somepatientsmayrequirepremedicationwith
pethidine.
Renalfunctionshouldbemonitoreddailyandifthecreatinineincreasesby50%thenconsider
switchingtoanalternativeantifungalagent
Aleakofpotassiumandmagnesiummayoccurandlevelsshouldbemonitoredcloselyand
replacementgivenIVifnecessary
AbelcetcanalsocauseabnormalLFTswhichshouldalsobemonitoreddaily
IfreactionsoccurduringtheinfusionofAbelcet(egrigors/itchingetc)givehydrocortisoneand
chlorpheniramineIVandconsiderswitchingtoanalternativeantifungalagent.
Ifreactionsaresevereorifrenalimpairmentisdeveloping(i.e.thereisadoublingofthebaseline
creatinine)andtheantifungalagentneedstobecontinuedthenconsiderswitchingto
AmBisomeorIVVoriconazoleorCaspofungin
2. PreemptiveTreatmentofProbableFungalInfection
LowdosesofAbelcet(1mg/kg)havebeenshowntobeeffectiveinpatientswithpersisting
neutropenicfeverbuthigherdosesof3mg/kgarerequiredforthetreatmentofconfirmed
invasivefungalinfection.Thesedosesaremorelikelytocauserenalproblems
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ThereforepatientswithevidenceofinvasivefungalinfectionsuchasCXRchanges,highresolution
CTscanabnormalitiesorpositivegalactomannantestmayhavetheirAbelcetdoseincreasedto
3mg/kgor,ifrenaldysfunction/sideeffects,beswitchedfromAbelcettoAmBisome3mg/kgor
IVVoriconazole
RenalfunctionandLFTsmustbemonitoreddailywithbothofthesedrugs.Dosereductionsmight
beneededforIVVoriconazoleandlevelscanbesent.Forpatientswithsevererenalimpairment
Caspofunginshouldbeconsidered
3. TreatmentofSevereProven(orStronglySuspected)FungalInfectionAmBisome
/IVVoriconazole/Posaconazole/Caspofungin

AmBisome
Liposomalamphotericin(AmBisome)shouldONLYbeprescribedafterdiscussionwiththe
patientsconsultantandtheuseofthisdrugshouldberevieweddailybytheconsultant
UsuallyAmBisomeisreservedforpatientswithasevereconfirmedorhighlysuspectedinvasive
fungalinfectionandforprovencasesofMucorinfectionwhichisresistanttomostotheranti
fungalagents(AlternativeisPosaconazolewhichisgivenorallyasaliquidwithatreatmentdose
of400mgbdandwhichcanonlybeprescribedwithauthorisationofaConsultant))
DoserecommendationsforAmBisomeareasfollows
ForpatientswhereanAspergillusinfectionissuspectedbutnotproven,whohavenotshowna
responsetoAbelcet,orwhohaveintoleranceorrenaltoxicity,giveAmBisomeat1mg/kg/day
initiallyroundtonearest50mgvial
Forpatientswithprovenprogressivepulmonaryaspergillosis,orifthereisevidenceof
progression,increasethedoseofAmBisometo3mg/kg/day
Dosesof510mg/kgmayoccasionallybeusedinseverecases(D/WConsultant)
Althoughthisdrughaslowerrenaltoxicity,itisstillnecessarytomonitortheU&Edaily
PatientswithimpairedrenalfunctionmaybeswitchedtoIVVoriconazole(butnoteIV
voriconazoleshouldbeavoidedinthosewithaCrCl<50ml/minduetoaccumulationofthe
vehicle.)oralternativelyoralposaconazoleorIVcaspofungin

Voriconazole
AnalternativetoAmBisomeisIVVoriconazoleforpatientswithprobableorprovenfungal
infections(discusswithConsultant)
Loadingdosesshouldbeusedinordertorapidlyachievetherapeuticconcentrationsofthedrug.
Forseriousinfections,intravenousloadingwith2dosesof6mg/kgIVfollowedby4mg/kgIVbd
for7to10daysshouldbegivenbeforeconvertingtooraltherapy.
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Theoralcontinuationdoseisusuallyeither200mgbdor300mgbd.Patientswhorapidly
metabolisevoriconazolewilllikelyhavesubtherapeuticlevelswith200mgbddosingand
converselythosewhoareslowmetabolisersrisktoxicitywith300mgbd.
Patientswithlesssevereinfectionscanbeconsideredfororaltreatmentfromtheoutset.
However,loadingshouldbeperformedwith400mgPObdonday1followedby200mgbd.
Dosageescalationto300mgbdmayberequireddependingonlevels(seebelow).
Levelsshouldbetakentoguidetreatmentanddeterminetheneedfordosageescalationduring
theoralphaseanddosesshouldgenerallyNOTbewithheldpendinglevelresultsunlessovert
voriconazoletoxicityissuspected.
Onlypredose(trough)levelsarerequired.
Afirstlevelshouldbetaken34daysintoIVtherapy.Apredoselevelshouldbetakenwithin1
hourpriortothetimethatthedoseisdue.Thisshouldbesenttomicrobiologyinaredplaintop
(clotted)bloodbottle.
Additionallevelsshouldthenbesentduringoraltherapy.Alevelafter34daysoforaltreatment
canbesentfollowedbyatleastoneotherlevelfurtherintothecourseoftreatment.Levels
shouldalsobesentifdrugsarecommencedthatarelikelytoaffectvoriconazolemetabolismand
alsoifthereisachangeinpatientfactorsthatmayaffectthelevelsuchasanalterationinhepatic
function.
LevelsarereferredtoBristolandresultscangenerallybeexpectedwithin48hoursoftakingthe
level.WeekendsandBankHolidaysmayresultinlongerturnaroundtimes.
Predoselevelsshouldbe>1.0to5.5mg/L.
DuringtheIVphaseoftreatment,subtherapeuticlevelsorthosetowardsthebottomendofthis
rangeindicatealikelyneedforamaintenancedoseof300mgbdorally.Levelsatthehigherend
ofthisrangeduringIVtherapyindicateanoraltreatmentdoseof200mgbdshouldmaintain
acceptablelevels.
Voriconazoleismainlymetabolisedbytheliverandmaycauseatransientriseinliverenzymesso
LFTsshouldbemonitoreddaily
IVVoriconazoledoseshouldbereducedinpatientswithrenalimpairmentduetoaccumulationof
thecarrierproteinandshouldbeavoidedinpatientsinwhomtheCrClis<50ml/min
Voriconazolehasanumberofdruginteractions.Itshouldbeavoidedinpatientsreceiving
VincristineaspartoftheirchemotherapyregimenandforpatientsonCyclosporinethedose
shouldbehalvedandmonitoredcarefullyduringVoriconazoletreatment
Posaconazole
OralposaconazolemaybeconsideredforpatientswithsuspectedMucorinfections(sinus
fungalinfection)
Theusualtreatmentdoseis400mgbd(10ml)withfoodor200mgqdsiffoodnot
toleratedorriskfactorsforpoorabsorption
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Itisrecommendedthatposaconazoleisadministeredwithahighfatmealornutritional
supplement.Administrationwithfood,particularlyhighfatfoodincreasesthe
bioavailability
Levelsshouldbesenttomicrobiologyformonitoring
Mayoccasionallybeasprophylaxisatdoseof300mgbdor200mgtds
ItismainlymetabolisedbytheliverandLFTsshouldbemonitored
LikevoriconazoleithassimilardruginteractionsegwithcyclosporineA
Caspofungin
Thisisanalternativeechinocandinantifungalagentwithadifferentmodeofaction.Itisactive
againstmostCandidalspeciesandsometypesofAspergillus
ItmaybeusedinsteadofAmbisome/IVVoriconazoleforpatientswithseveredocumented
fungalinfectionwhohaverenalimpairmentwithAmbisomeorrarelyinconjunctionwith
AmBisome(egforthetreatmentofcerebralAspergillus,andseverepulmonaryAspergillus)
ItshouldbenotedthatCaspofunginhasnoactivityagainstMucorspeciesandthatifthisis
suspectedclinically(nasopharyngealinvolvement)thenAmBisomeisthedrugofchoice
ItshouldbeprescribedonlywithConsultantauthorisation
If>80kgthenloadingdoseis70mgfollowedby70mgdaily
If<80kgthenloadingdoseis70mgfollowedby50mgdaily
Theinfusionshouldbegivenover1hour
LFTsneedtobemonitoreddaily
MajordrugInteractionswithciclosporin(increasedcaspofunginlevelsincreasedliver
toxicity)
Rifampicin,carbamazepine,phenytoin,efavirenz,nevirapineanddexamethasonereduce
caspofunginlevelsconsiderincreasingthedose

4. MaintenanceTreatmentforProvenorStronglySuspectedFungalInfections
VoriconazoleorPosaconazole
PatientswhohaverespondedwelltoIVantifungaltherapyandwhosecountshaveregenerated
butwhohaveradiologicalevidenceofresidualfungalinfectionshouldbestartedonmaintenance
outpatienttherapyusingvoriconazole200mgbdorposaconazole200mgqds
Aninitialloadingdoseof400mgbdofvoriconazoleisrequiredfollowedby200mgbd
Thisshouldbecontinuedfor2weeks(NBinteractswithCSAsoreduceCSAdoseto50%)
Alternativelyposaconazolemaybeusedinthesecircumstances
Clinical guideline - Review date Aug 2014
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IfpatientscannottolerateazolesthenAbelcet/AmBisome3mg/kgMonFrionDCUmaybe
considered
.