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2017619 AntifungalAgentsMedicalMicrobiologyNCBIBookshelf

NCBIBookshelf.AserviceoftheNationalLibraryofMedicine,NationalInstitutesofHealth.

BaronS,editor.MedicalMicrobiology.4thedition.Galveston(TX):UniversityofTexasMedicalBranchat
Galveston1996.

Chapter76 AntifungalAgents
DennisM.DixonandThomasJ.Walsh.

GeneralConcepts

Definition
Anantifungalagentisadrugthatselectivelyeliminatesfungalpathogensfromahostwithminimal
toxicitytothehost.

PolyeneAntifungalDrugs
Amphotericin,nystatin,andpimaricininteractwithsterolsinthecellmembrane(ergosterolin
fungi,cholesterolinhumans)toformchannelsthroughwhichsmallmoleculesleakfromthe
insideofthefungalcelltotheoutside.

AzoleAntifungalDrugs
Fluconazole,itraconazole,andketoconazoleinhibitcytochromeP450dependentenzymes
(particularlyC14demethylase)involvedinthebiosynthesisofergosterol,whichisrequiredfor
fungalcellmembranestructureandfunction.

AllylamineandMorpholineAntifungalDrugs
Allylamines(naftifine,terbinafine)inhibitergosterolbiosynthesisatthelevelofsqualene
epoxidase.Themorpholinedrug,amorolfine,inhibitsthesamepathwayatalaterstep.

AntimetaboliteAntifungalDrugs
5FluorocytosineactsasaninhibitorofbothDNAandRNAsynthesisviatheintracytoplasmic
conversionof5fluorocytosineto5fluorouracil.

Introduction
Thedevelopmentofantifungalagentshaslaggedbehindthatofantibacterialagents.Thisisa
predictableconsequenceofthecellularstructureoftheorganismsinvolved.Bacteriaare
prokaryoticandhenceoffernumerousstructuralandmetabolictargetsthatdifferfromthoseofthe
humanhost.Fungi,incontrast,areeukaryotes,andconsequentlymostagentstoxictofungiare
alsotoxictothehost.Furthermore,becausefungigenerallygrowslowlyandofteninmulticellular
forms,theyaremoredifficulttoquantifythanbacteria.Thisdifficultycomplicatesexperiments
designedtoevaluatetheinvitroorinvivopropertiesofapotentialantifungalagent.

Despitetheselimitations,numerousadvanceshavebeenmadeindevelopingnewantifungalagents
andinunderstandingtheexistingones.Thischaptersummarizesthemorecommonantifungal
agents.Threegroupsofdrugsareemphasized:thepolyenes,theazoles,andone
antimetabolite.Table761summarizesthemostimportantantifungalagentsandtheirmostcommon
uses.

Table761

TheMajorAntifungalAgentsandTheirCommonUsers.

PolyeneAntifungalDrugs

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Thepolyenecompoundsaresonamedbecauseofthealternatingconjugateddoublebondsthat
constituteapartoftheirmacrolideringstructure(Fig.761).Thepolyeneantibioticsareall
productsofStreptomycesspecies.Thesedrugsinteractwithsterolsincellmembranes(ergosterolin
fungalcellscholesterolinhumancells)toformchannelsthroughthemembrane,causingthecells
tobecomeleaky(Fig.762).Thepolyeneantifungalagentsincludenystatin,amphotericinB,and
pimaricin.

Figure761

Structuresofsomecommonantifungalagents.

Figure762

Generalizedfungalcelldepictingthesitesofactionofthe
commonantifungalagents.

AmphotericinBisthemainstayantifungalagentfortreatmentoflifethreateningmycosesandfor
mostothermycoses,withthepossibleexceptionofthedermatophytoses.DiscoveredbyGoldin
1956,itcantrulybesaidtorepresentagoldstandard.Itsbroadspectrumofactivityincludesmost
ofthemedicallyimportantmouldsandyeasts,includingdimorphicpathogenssuchasCoccidioides
immitis,Histoplasmacapsulatum,Blastomycesdermatitidis,andParacoccidioidesbrasiliensis.It
isthedrugofchoiceintreatingmostopportunisticmycosescausedbyfungisuchasCandida
species,Cryptococcusneoformans,Aspergillusspecies,andtheZygomycetes.Resistancetothis
agentisrare,butisnoteworthyforPseudallescheriaboydii,Fusariumspp.,Trichosporonspp.,
certainisolatesofCandidalusitaniaeandCandidaguilliermondii.

Thedrugmustbeadministeredintravenouslyandisassociatedwithnumeroussideeffects,ranging
fromphlebitisattheinfusionsiteandchillstorenaltoxicity,whichmaybesevere.Amajor
advanceintheuseofthisagenthasresultedfromanunderstandingofthemechanismofitsrenal
toxicity,whichispresumedtoinvolvetubuloglomerularfeedback.Thesuppressionofglomerular
filtrationcanbereducedbyadministeringsodiumchloride.

Nystatinwasthefirstsuccessfulantifungalantibiotictobedeveloped,anditisstillingeneraluse.
Itisrepresentativeofthepolyeneantifungalagentsdevelopedlater.Thepromiseofitsbroad
spectrumantifungalactivityisoffsetbyhosttoxicity.Therefore,itislimitedtotopicaluse,whereit
hasactivityagainstyeastssuchastheCandidaspecies.

Pimaricin(natamycin),anotherpolyene,isusedtopicallytotreatsuperficialmycoticinfectionsof
theeye.Itisactiveagainstbothyeastsandmoulds.

AzoleAntifungalDrugs
Theazoleantifungalagentshavefivememberedorganicringsthatcontaineithertwoorthree
nitrogenmolecules(theimidazolesandthetriazolesrespectively).Theclinicallyusefulimidazoles
areclotrimazole,miconazole,andketoconazole.Twoimportanttriazolesareitraconazoleand
fluconazole.Ingeneral,theazoleantifungalagentsarethoughttoinhibitcytochromeP450
dependentenzymesinvolvedinthebiosynthesisofcellmembranesterols.

Ketoconazolesetthestagefortheorallyadministeredantifungalazoles.Itcanbeadministeredboth
orallyandtopicallyandhasarangeofactivityincludinginfectionsduetoHcapsulatumandB
dermatitidis,forwhichitisoftenusedinnonimmunocompromisedpatients.Itisalsoactiveagainst
mucosalcandidiasisandavarietyofcutaneousmycoses,includingdermatophyteinfections,
pityriasisversicolor,andcutaneouscandidiasis.Itisnotindicatedfortreatmentofaspergillosisorof
systemicinfectionscausedbyyeasts.

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Thetriazoles(fluconazole,itraconazole)havebecomethestandardfortheazoles,andhave
replacedamphotericinBformanagingcertainformsofthesystemicmycoses.Fluconazoleisnow
routinelyusedtotreatcandidemiainnonneutropenichosts,andisgainingacceptanceforusein
cryptococcosisandselectedformsofcoccidioidomycosis.Itraconazolehasproventobeeffective
forhistoplasmosis,blastomycosis,sporotrichosis,coccidioidomycosis,consolidationtreatmentfor
cryptococcosis,andcertainformsofaspergillosis.Fluconazolecanbeadministeredeitherorally,or
intravenously.Thelicensedformulationforitraconazoleisoral,butanintravenousformulationis
understudy,andcouldbeasignificantadditiondirectedatbioavailabilityproblemsrelatingto
absorptionoftheoralformulation.

SideeffectsarenotascommonwiththeazolesaswithamphotericinB,butlifethreateningliver
toxicitycanarisewithlongtermuse.Livertoxicitynotedwithketoconazolehasbeenless
problematicwiththetriazoles.Othersideeffectsincludenauseaandvomiting.Druginteractions
areapotentialproblembetweenazolesandotherdrugclassesandincludecyclosporin,certain
antihistamines,anticoagulants,andantiseizure,oralhypoglycemicandothermedicationsthatare
metabolizedviasimilarpathwaysintheliver.

5Fluorocytosine
Incontrasttothesituationwithantibacterialagents,fewantimetabolitesareavailableforuse
againstfungi.Thebestexampleis5fluorocytosine,afluorinatedanalogofcytosine.Itinhibits
bothDNAandRNAsynthesisviaintracytoplasmicconversionto5fluorouracil.Thelatteris
convertedtotwoactivenucleotides:5fluorouridinetriphosphate,whichinhibitsRNAprocessing,
and5fluorodeoxyuridinemonophosphate,whichinhibitsthymidylatesynthetaseandhencethe
formationofthedeoxythymidinetriphosphateneededforDNAsynthesis.Aswithother
antimetabolites,theemergenceofdrugresistanceisaproblem.Therefore,5fluorocytosineis
seldomusedalone.IncombinationwithamphotericinBitremainsthetreatmentofchoicefor
cryptococcalmeningitisandiseffectiveagainstanumberofothermycoses,includingsomecaused
bythedematiaceousfungiandperhapsevenbyCalbicans.

OtherAntifungalAgents
GriseofulvinisanantifungalantibioticproducedbyPenicilliumgriseofulvum.Itisactiveinvitro
againstmostdermatophytesandhasbeenthedrugofchoiceforchronicinfectionscausedbythese
fungi(e.g.,nailinfectionswithTrichophytonrubrum)sinceitisorallyadministeredand
presumablyincorporatedintoactivelygrowingtissue.Itisstillusedinsuchinstancesbutisbeing
challengedbysomeofthenewerazoleantifungalagents.Thedruginhibitsmitosisinfungi.

Potassiumiodidegivenorallyasasaturatedsuspensionisuniquelyusedtotreatcutaneousand
lymphocutaneoussporotrichosis.Thiscompound,interestingly,isnotactiveagainstSporothrix
schenckiiinvitro.Itappearstoactbyenhancingthetransepidermaleliminationprocessinthe
infectedhost.

Twootherclassesofantifungalagentsrepresentnewadditionstotopicaltreatmentofthe
dermatomycosesinEurope.Thetwoallylamines(naftifineandterbinafine)inhibitergosterol
synthesisatthelevelofsqualeneepoxidaseonemorpholenederivative(amorolfine)inhibitsata
subsequentstepintheergosterolpathway.

SelectionofAntifungalAgents
Invitrosusceptibilitytestingwiththefungiisnotyetstandardized,andtheresultsofinvitrotests
donotalwayscomparetotheresultsobtainedinvivo.Therefore,preliminaryselectionofan
antifungalagentforclinicaluseismadeprimarilyonthebasisofthespecificfungalpathogen
involved.Thespectrumofactivityforthelicensedantifungalagentsiswelldefinedthroughthe
resultsofpreclinicalandclinicaltestingwiththemostcommonfungalpathogens.Thisapproachis
usefulinavoidingselectionofantifungalsforspeciesoffungithatareknowntohaveprimary
resistancetotheagent,butlessusefulinselectingantifungalsforspeciesthatareknowntodevelop
secondary(druginduced)resistancetoaparticularagent.

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Antifungaldrugresistancehasbecomeanincreasingproblemwiththedevelopmentofalarger
compendiumofantifungalagents.Drugresistancetothepolyeneantifungalsisalmostalways
primaryresistanceratherthansecondaryresistance.Thatis,thesusceptibilityprofilesforthe
speciesarecharacteristicandinherent,andrarelychangeinresponsetoexposuretotheagent.For
example,amphotericinBresistantspeciessuchasPseudallescheriaboydiiandCandidalusitaniae
arewellknown,anddonotappeartohaveoriginatedfromexposuretotheantifungal.Despite
decadesofwidespreadclinicaluseofamphotericinBinCandidaalbicansinfections,the
developmentofsecondaryresistancehasbeenexceedinglyrare.Incontrast,bothprimaryand
secondaryresistanceto5fluorocytosineareknowntooccurforstrainsofCandidaspecies,serving
asthebasisforrestrictinguseofthisagenttocombinationtherapywithotherantifungaldrugs.

Thequestionoffungalresistancetotheazoledrugsisconsiderablymorecomplexandiscurrently
underevaluation.Examplesofbothprimaryandsecondaryresistanceareknownforthemedically
importantyeastsandselectedazoleantifungals.Candidakruseiasaspeciesistypicallyresistantto
fluconazole.Candidaalbicansstrainsaretypicallysusceptibletofluconazoleandcertainother
azoleantifungals,butthereareincreasingreportsofresistance,especiallyinHIVinfectedhosts
havingundergonerepeatedcoursesofazoleantifungaltherapy.Thequestionofdrugresistanceis
complicatedbythelimitationsintheavailablesusceptibilitytestingmethodologyandtheabilityto
distinguishbetweenmicrobiologicalandclinicaldrugresistance.Thelattertypicallyoccurswhen
aninhibitoryantifungalagentreachesthelimitsofitsactivityinahostwithadecreasinglyefficient
immunesystem.

Withtheadventofthepolyenes,azoles,andfluorocytosine,previouslyfatalinfectionscannowbe
treated.However,asmodernmedicinecontinuestoextendlifethroughaggressivetherapyofother
lifethreateningdiseasessuchascancer,thereisanincreasingpopulationatriskforopportunistic
fungalinfections.Suchpatientsrepresentaspecialchallengebecausetheyoftenareleftwithlittle
hostimmunefunction.Therefore,chemotherapeuticagentsshouldbefungicidalandnotjust
fungistatic.Thesearchcontinuesforfungicidalagentsthatarenontoxictothehost.Researchis
alsodirectedtowardimmunomodulatingagentsthatcanreversethedefectsofnativehost
immunity.

References

1.CasadevallA,ScharffMD.Returntothepast:Thecaseforantibodybasedtherapiesin
infectiousdiseases.ClinInfectDis.199521:15061.[PubMed:7578724]
2.ComoJA,DismukesWE.Oralazoledrugsassystemicantifungaltherapy.NewEnglJ
Med.1994330:263272.[PubMed:8272088]
3.DixonDM.Invivomodels:evaluatingantifungalagents.MethodsFindExpClin
Pharmacol.19879:729.[PubMed:3448452]
4.EspinelIngroffA,ShadomyS.Invitroandinvivoevaluationofantifungalagents.EurJ
ClinMicrobiol.19898:352.[PubMed:2497014]
5.FrancisP,WalshTJ.Evolvingroleofflucytosineinimmunocompromisedpatients:New
insightsintosafety,pharmacokinetics,andantifungaltherapy.ClinInfectDis.
199215:10031018.[PubMed:1457631]
6.FromtlingRA(ed):RecentTrendsintheDiscovery,DevelopmentandEvaluationof
AntifungalAgents.Prous,Barcelona,1987.
7.GalgianiJN.Antifungalsusceptibilitytests.AntimicrobAgentsChemother.198731:1867.
[PMCfreearticle:PMC175816][PubMed:3326524]
8.GraybillJR.Newantifungalagents.EurJ.ClinMicrobiol.19898:402.[PubMed:2546775]
9.HeidemannJF,GerkensJF,SpickardWA.AmphotericinBnephrotoxicityinhumans
decreasedbysaltrepletion.AmJ.Med.198375:476.[PubMed:6614033]
10.IwataK:Drugresistanceinhumanpathogenicfungi.EurJEpidemiol8:407421,1992
RinaldiMG,DixonDM(eds):Theevolvingetiologiesofinvasivemycoses.InfectDisClin
Practice1994:3(suppl):S47S112.
11.VandenBosscheH.Molecularmechanismsofdrugresistanceinfungi.Trendsin
Microbiology.19942:393400.[PubMed:7850208]

https://www.ncbi.nlm.nih.gov/books/NBK8263/ 4/5
2017619 AntifungalAgentsMedicalMicrobiologyNCBIBookshelf

12.WalshTJ.Recentadvancesinthetreatmentoffungalinfections.MethFindExpClin
Pharmacol.19879:769.[PubMed:2834615]

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