Beruflich Dokumente
Kultur Dokumente
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
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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
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IfpatientscannottolerateazolesthenAbelcet/AmBisome3mg/kgMonFrionDCUmaybe
considered
.