Tissue Penetration of Antifungal Agents - University of Aberdeen

22 Pages·2013·2.53 MB·English

Tissue Penetration of Antifungal Agents

Timothy Felton, Peter F. Troke and William W. Hope
Clin. Microbiol. Rev. 2014, 27(1):68. DOI:
10.1128/CMR.00046-13.

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Tissue Penetration of Antifungal Agents
TimothyFelton,a,bPeterF.Troke,cWilliamW.Hopeb
TheUniversityofManchester,AcademicHealthScienceCentre,UniversityHospitalofSouthManchesterNHSFoundationTrust,Manchester,UnitedKingdoma;
AntimicrobialPharmacodynamicsandTherapeutics,DepartmentofMolecularandClinicalPharmacology,UniversityofLiverpool,Liverpool,UnitedKingdomb;
TheOldCourt,Kingsgate,Kent,UnitedKingdomc
SUMMARY...................................................................................................................................................68
D
INTRODUCTION..............................................................................................................................................68
o
PENETRATIONOFANTIFUNGALAGENTSINTOTISSUES:CONCEPTS,IMPORTANCE,ANDCURRENTGAPSINKNOWLEDGE ...........................69 w
ImportanceofTissueConcentrationsforanUnderstandingofAntifungalPharmacodynamics..........................................................69 n
DeterminantsofDistributionofAntifungalAgentsintoTissues...........................................................................................69 lo
a
LimitationsofCurrentUnderstandingandApproaches...................................................................................................72
d
ANTIFUNGALDRUGCONCENTRATIONSINORGANS,TISSUES,ANDBODYFLUIDS.......................................................................72 e
BrainandCerebrospinalFluid..............................................................................................................................73 d

Eye.........................................................................................................................................................74 fr
o
Lung.......................................................................................................................................................75 m
PulmonaryLymphFluid...................................................................................................................................76
h
PleuralFluid................................................................................................................................................76 t
t
BronchialSecretions.......................................................................................................................................76 p
:
Saliva,Sputum,BuccalMucosa,andEsophagus...........................................................................................................76 //
c
Heart.......................................................................................................................................................76 m
Liver........................................................................................................................................................77 r
.
Kidney.....................................................................................................................................................77 a
s
Spleen.....................................................................................................................................................77 m
Pancreas...................................................................................................................................................78 .
o
Peritoneum................................................................................................................................................78 r
GenitalSystem.............................................................................................................................................78 g
/
Bone.......................................................................................................................................................78 o
Muscle.....................................................................................................................................................79 n

SkinandNails..............................................................................................................................................79 J
a
UNDERSTANDINGTISSUECONCENTRATIONSFOROPTIMALUSEOFEXISTINGAGENTSANDDEVELOPMENTOFNEWERANTIFUNGALAGENTS....80 n
CurrentStateoftheArt....................................................................................................................................80 u
a
BeyondStateoftheArt....................................................................................................................................80 r
y
ACKNOWLEDGMENTS.......................................................................................................................................80
6
REFERENCES.................................................................................................................................................80 ,

AUTHORBIOS................................................................................................................................................88 2
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SUMMARY However,awiderangeofotherfungi,oftenwithlimitedsuscep- U
Understanding the tissue penetration of systemically adminis- tibility to first-line antifungal agents, may also cause infection. n
iv
teredantifungalagentsiscriticalforaproperappreciationoftheir Mortality from IFI remains high (e.g., that from aspergillosis is e
antifungalefficacyinanimalsandhumans.Boththetimecourse (cid:2)50%[3,4],andthatfromcandidemiais10to49%[5,6,7]).An rs
ofanantifungaldruganditsabsoluteconcentrationswithintis- understandingofthepharmacologicalpropertiesofanyantifun- ity

sues may differ significantly from those observed in the blood- galagentiscrucialforoptimizingpatientoutcomesforallthese o
f

stream.Inaddition,tissueconcentrationsmustalsobeinterpreted infections(8).Thismaybeespeciallytrueforanincreasinglyrec- A
b
withinthecontextofthepathogenesisofthevariousinvasivefun- ognizedgroupofpatientswhohavenotpreviouslybeenconsid- e
r
galinfections,whichdiffersignificantly.Therearemajortechnical eredtobeathighriskofIFI,suchascriticallyillpatientsandthose d
e
obstaclestotheestimationofconcentrationsofantifungalagents with chronic obstructive pulmonary disease (COPD), who may e
n
invarioustissuesubcompartments,yettheseagents,eventhose demonstratemarkedpharmacokinetic(PK)variability(9,10).
withinthesameclass,mayexhibitmarkedlydifferenttissuedis- Penetrationintothesiteofinfectiontoachievemicrobe-elim-
tributions.Thisreviewexplorestheseissuesandprovidesasum- inatingconcentrationsisakeyrequirementforefficacyofallan-
mary of tissue concentrations of 11 currently licensed systemic timicrobialagents(11,12,13,14,15).Theimportanceoftissue
antifungalagents.Italsoexploresthetherapeuticimplicationsof concentrationsforthevariousclassesofantibacterialagentshas
theirdistributionatvarioussitesofinfection. been reviewed extensively, but relatively less attention has been
INTRODUCTION
Despiterecentadvancesinantifungalchemotherapy,invasive AddresscorrespondencetoWilliamW.Hope,[email protected].
fungalinfections(IFI)remainasignificantcauseofmorbid- Copyright©2014,AmericanSocietyforMicrobiology.AllRightsReserved.
ityandmortality(1).Candidaspecies,Aspergillusfumigatus,and doi:10.1128/CMR.00046-13
Cryptococcus neoformans are the most common pathogens (2).
68 cmr.asm.org ClinicalMicrobiologyReviews p.68–88 January2014 Volume27 Number1
TissuePenetrationofSystemicAntifungalAgents
paidtothecurrentlyavailableantifungalagents(12,16,17,18,
19).Thisreviewexaminesthetissuepenetrationof11commonly
used systemic antifungal agents (amphotericin B deoxycholate
[AmBd],amphotericinBlipidcomplex[ABLC],liposomalam-
photericinB[L-AMB],fluconazole,itraconazole,posaconazole,
voriconazole, 5-fluorocytosine [5FC], anidulafungin, caspofun-
gin,andmicafungin)intotheclinicallyrelevantcompartmentsfor
humaninfectionanddisease.Allhumandata,rangingfromcase
studiesthroughautopsiestosmallclinicalstudiesinvolunteersor
patients,wereincluded.Wealsoconsideredkeylaboratoryanimal
data,whererelevant,especiallyiftherespectiveinformationfor
humansisabsent.Becauseonlyfreedrugisconsideredtobebio- D
logically active (20, 21, 22), tissue and fluid concentrations are o
w
placedincontextwiththekeyphysicochemicalpropertiesofeach n
agent.Themajororgansystemscoveredincludethelungs,liver, lo
a
kidney,spleen,andheart.Attentionhasalsobeengiventodrug d
e
penetration into sanctuary sites (e.g., brain and eye), with the d

corresponding therapeutic implications. We have also reviewed fr
o
thedataforkeyinterstitialfluids,includingbronchialsecretions, m
epithelialliningfluid(ELF),pleuralfluid,pericardialfluid,syno- h
vial fluid, prostatic fluid, and cerebrospinal fluid (CSF), and tt
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placedthesedatainaclinicalcontext(23). :/
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PENETRATIONOFANTIFUNGALAGENTSINTOTISSUES: r.
a
CONCEPTS,IMPORTANCE,ANDCURRENTGAPSIN s
m
KNOWLEDGE .
o
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ImportanceofTissueConcentrationsforanUnderstanding g
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ofAntifungalPharmacodynamics o
n
Thepotentialrelevanceofthetissueconcentrationsofanyanti-infec- J
tiveagentmustbeconsideredincontextwiththepathogenesisofthe a
n
invading fungal organism (24). There must be colocalization of u
a
“drugandbug”withintissuebedsandtissuesubcompartments. r
y
Suchconsiderationsarerelevantattheleveloftheorganandtissue 6
,
subcompartments but may be elucidated further at the cellular 2
andevenmolecularlevels(25,26,27,28,29). 0
1
Most agents ultimately exert their effects on microorganisms 4

b
residingwithintissues.However,thedistributionofagentsfrom y
thebloodstreamtovarioustissuesubcompartmentsisoftenchar- FIG1Potentialdifferencesinplasmaandtissueconcentrations.Theremaybe U
discordanceinconcentrationsbetweenthesetwocompartments.“Hysteresis”
acterized by considerable variability, beyond that observed in referstodiscordanceintheshapesoftheconcentration-timeprofiles. niv
plasmaalone.Consequently,targetsiteconcentrationsoftendif- e
r
fermarkedlyfromthosemeasuredinplasma,especiallyinsanc- s
it
tuarysitessuchastheeyeorcentralnervoussystem(CNS).Fur- thisreviewaresummarizedinTable1.Thefourmajorclassesof y

o
thermore, there may be discordance in the shape of the antifungal agents, i.e., the echinocandins, polyenes, pyrimidine f

concentration-timeprofilesforplasmaandtissues.Thisphenom- analogues(5FC),andtriazoles,arereviewed.Thesecompounds A
b
enoniscalledhysteresis(Fig.1)andmayexplainpersistentanti- arealldistinctintermsoftheirchemicalstructure,molecularsize, e
r
fungalactivitywhenplasmaconcentrationsareloworundetect- lipophilicity,andmetabolism,andthesedifferenceshaveamajor d
e
able (e.g., as seen with L-AMB [30], caspofungin [31], and impactupontheirpharmacokineticandpharmacodynamic(PD) e
n
itraconazole[76]).Conversely,suboptimaltargetsiteconcentra- characteristics.Furthermore,theremaybesignificantdifferences
tionsmaywellexplainsomecasesoftherapeuticfailure(11,13). withinaclass.Forexample,thelipophilicities(expressedaslogD
Inaddition,asmostfungalinfectionsareextracellular,interstitial valuesinTable1)ofthefourtriazolesvaryfrom0.5to(cid:3)5.0,and
fluid may be the closest measurable compartment to the site of plasma protein binding ranges from 12% to (cid:3)99% (Table 1).
infection.However,theimportantcompartmentforprophylaxis Thesephysicochemicalpropertiesdeterminetherateandextent
maybedifferent,whichinturnisrelatedtodifferencesinpatho- oftissuepenetrationandbioavailabilitywithinatissue,organ,or
genesisandthestageofinfection(Fig.2A)(32,33). fluid (13, 34). Tissue and fluid concentrations for the three tri-
azoles(fluconazole,voriconazole,anditraconazole),asmultiples
DeterminantsofDistributionofAntifungalAgentsinto ofthoseinbloodorplasma,areshowninFig.3to5toillustrate
Tissues this.
Theprincipalchemicalandpharmacokineticpropertiesinfluenc- Inverygeneralterms,smallpolarcompoundswithlowplasma
ingthetissuedistributionofthe11systemicantifungalagentsin proteinbinding(e.g.,fluconazoleand5FC)havevolumesofdis-
January2014 Volume27 Number1 cmr.asm.org 69
Feltonetal.
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FIG2Differentstagesofinvasivepulmonaryaspergillosis(IPA)andthepotentialtherapeuticimportanceofdifferenttissuesubcompartments.(A)Inthevery s
earlieststagesofdisease,therelevantsubcompartmentsincludeepithelialliningfluid,alveolarepithelialcells,pulmonaryendothelialcells,andpulmonary ity
alveolarmacrophages(PAMs).(B)Intheearlystagesofestablisheddisease,ahalosignmaybeseenthatconsistsofanodule(n)surroundedbyahalo(h),which o
iscausedbyactiveinfectionandinflammationaroundthenodule.Inthiscase,therelevantsubcompartmentsarewithinthenoduleandcontiguouslung.(C)In f
A
latedisease,anaircrescentsignmaybepresent,whichrepresentsanorganizingsequestrum.(Apulmonarysequestrum[s]issurroundedbyanaircrescent[ac].)
b
Thetherapeuticchallengeinthiscaseistheachievementofantifungaldrugconcentrationswithinarelativelyavasculararea.(Reprintedfromreference262with e
permission;imaginganddetailskindlyprovidedbyReginaldGreene.) rd
e
e
n
tribution that approximate total body water (Table 1), achieve hibit tissue/plasma concentration ratios that exceed 1. Despite
betterpenetrationintoaqueoussites(e.g.,CSF,synovialfluid,and this,theymaynotnecessarilypenetratewellintosanctuarysites
anterior chamber of the eye), and generally have body fluid/ suchasthebrain,prostate,andeye.Thepolyenes(amphotericin
plasma concentration ratios that are (cid:4)1. A compound with an B)andtheechinocandinshavevariabletissuepenetrationbutmay
“intermediate”lipophilicity,volumeofdistribution,andplasma alsoexhibitprolongedresidencetimes.
proteinbinding(e.g.,voriconazole)isalsopredictedtodistribute Arangeofotherfactorsmayalsohaveasignificantimpactupon
intoaqueoussitesbuttoattainrelativelyhighertissueconcentra- tissuepenetration,including(i)pharmacologicfactors,e.g.,route
tions than those of fluconazole or 5FC. In contrast, more lipo- ofdrugadministration,suchasaerosolorparenteraltherapy(35),
philiccompounds(suchasitraconazoleandposaconazole)have orformulatingdrugswithinlipids,e.g.,amphotericinBcolloidal
muchlargervolumesofdistribution(Table1),tendtopenetrate dispersion (ABCD) and L-AMB (36), which may modify their
preferentiallyintotissueswithhighlipidcontent,andoftenex- distributionandaltertheirsafety(37,38)andpotency(39);and
70 cmr.asm.org ClinicalMicrobiologyReviews
TissuePenetrationofSystemicAntifungalAgents
TABLE1Principlephysicochemicalandpharmacokineticpropertiesofantifungaldrugsinhumansthathaveapotentialimpactonplasma
concentrationsandtissuepenetration
Molwta LogDat %Plasma AUC
0–24
Compound (particlesize[(cid:5)m]) pH7.4 proteinbinding t (h) (mg·h/liter) V b(liters/kg) References
1/2 ss
Triazoles
Fluconazolec,d 305 0.5 12 24–30 38 0.7 17,18,67
Itraconazolee,f 706 (cid:3)5 99.8 34 8.7–25 11 17,226,227
Posaconazolec 700 2.15 (cid:3)98 20–31 33–39 7–25 228,229
Voriconazolee 349 1.8 58 6 13 4.6 84,230
Polyenes
AmBd(conventionalamphotericinB)e 924((cid:6)0.04) (cid:7)2.8 95–99 10–24 1–30 0.5–5 17,144,231–233
ABLC(Abelcet)e 924(1.6–11) (cid:7)2.8 95–99 24 9.5–14(cid:8)7 1.12–8.8 17,144,231,232,234 D
o
L-AMB(Ambisome)e 924(0.08) (cid:7)2.8 95–99 6–23 131(cid:8)126 0.11–0.7 17,144,233 w
n
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Nucleoside a
5-Fluorocytosinec,d 120 (cid:7)2.34 5 3–5 576,1289g 0.6–2.23 91,179 d
e
d
Echinocandins f
r
Anidulafunginc 1,140 (cid:7)3.32 84–99 26 110.3 0.8 235,236 o
m
Caspofungine 1,093 (cid:7)3.88 97 9–11 57–96 0.15 235,236

Micafunginc 1,291 (cid:7)1.62 (cid:3)99 15–17 29.6(cid:8)4.6 0.24–0.39 182,235 ht
t
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aFromreference18. :
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bVolumeofdistributionatsteadystate. /c
cDose-proportionalpharmacokinetics. m
dExceptinpatientswithrenalimpairment. r.
eConcentration-dependentpharmacokinetics. as
fDatafromoralsolutionandi.v.formulationincyclodextrin. m
gValuesfororalandi.v.formulations,respectively. .o
r
g
/

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(ii) physiological factors, such as inflammation, which may in- modification of plasma protein composition and hence drug n

J
creasetissuepermeability,i.e.,bydisruptionofnormalphysiolog- binding(42,43,44);therecruitmentofdrug-containingphago- a
n
icalbarrierssuchastheblood-brainbarrier(29,40);theunderly- cytic cells, i.e., the “dump truck phenomenon,” which may in- u
ingdisease(41),whichmayresultinarangeofeffects,including creasedrugconcentrationsatthesiteofinfection(12,13,32,45, a
r
y
46);drugexportviapumps,e.g.,foritraconazoleandP-glycopro-
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FIG4Voriconazoletissueandfluidconcentrationsinhumansasmultiplesof
FIG3Fluconazoletissueandfluidconcentrationsinhumansasmultiplesof themaximalorsimultaneouslymeasuredconcentrationinplasma((cid:5)g/ml)
themaximalorsimultaneouslymeasuredconcentrationinplasma((cid:5)g/ml) aftersystemicadministration.Tissuemultiplesarefrom(cid:5)g/gtissuevalues.
aftersystemicadministration.Tissuemultiplesarefrom(cid:5)g/gtissuevalues. Fluidmultiplesarefrom(cid:5)g/mlconcentrations.*,autopsydata;inthesecases,
Fluidmultiplesarefrom(cid:5)g/mlconcentrations.Numbersinparenthesesindi- themultiplesarebasedonplasmaC valuesatthesamedoseinvolunteers
max
caterelevantreferences. (188).
January2014 Volume27 Number1 cmr.asm.org 71
Feltonetal.
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FIG6Crosssectionofthebrainofamousewithcryptococcalmeningoen- f
r
cephalitis.Theorganismwasstainedwithanantibodydirectedtowardthecryp- o
m
tococcalcapsule.Thediseaseismultifocal.Attemptstousewhole-brainhomoge-
FIG5Itraconazoletissueandfluidconcentrationsinhumansasmultiplesof natestoestimatedrugconcentrationsatthesiteofinfectionmaybemisleading. h
Ftahfltueeirdmsmayxsutimeltmiaplilceosaradsrmiemifnruoilstmtarna(cid:5)etiogou/nms.lylTcimossneucaeesnumtrreuadlttiicoponlness.ceanrterafrtioomni(cid:5)ngp/glatsimssaue((cid:5)vagl/umels). (ARmeperriicnate[dtafkreonmbryefJeurleienScech2w63arbtzy,pCehrmarilsessioRnivoefrtLhaebIonrfaetcotrioieuss].D)iseasesSocietyof ttp://c
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.
a
icallyusefulformatisalsoproblematic.Oneofthemostcommon s
tein (75); variable oral bioavailability, e.g., of itraconazole (47) presentationmethodsistousearatiotoplasmaconcentration, m
.
andposaconazole(228);andinterpatientvariabilityinclearance, whichmaybeflawedforanumberofreasons.Thisratioisdepen- or
e.g.,ofvoriconazole(48). dentonboththedenominatorandthenumerator,e.g.,thebone g/

tissue/plasmaconcentrationratioforABLCinrabbitsis42,while o
n
LimitationsofCurrentUnderstandingandApproaches thecorrespondingratioforL-AMBis0.66,suggestingthatABLC J
Consideringtissueconcentrationsinisolationisoflimitedvalue. penetratesbonemoreeffectivelythanL-AMB.However,theac- an
Adrugmaybepresentatasitebutataconcentrationbeneaththe tualamphotericinconcentrationsachievedwiththetwolipidfor- u
a
thresholdrequiredforactivity,locatedinthewrongsubcompart- mulationsinbonearesimilar(35.4(cid:5)g/gand39.5(cid:5)g/gforABLC ry
ment,ornotbiologicallyavailable.Ideally,therefore,tissuecon- and L-AMB, respectively) and, in both cases, superior to that 6
,
centrations should be analyzed with concomitant pharmacody- achievedwithAmBd(19).Comparisonofconcentrationstakenat 2
namic data. Examples of this problem include AmBd and asingletimepointisalsoliabletoinduceerrorsbecauseofhys- 01
itraconazole, which have low concentrations in the CSF yet are teresis (Fig. 1), with a delay occurring as drug moves from the 4

b
effectiveagentsfortreatmentofcryptococcalmeningitis(49,50). vasculartothetissuecompartment(55).Forthisreason,itmaybe y
Tissuehomogenatesarefrequentlyusedtoestimatetissuecon- moreusefultopresentthetissueareaundertheconcentration- U
centrations, but they are a relatively crude and potentially mis- timecurve(AUC)forcomparison.Therearefewstudiesthatdo niv
leading matrix when used for this purpose. Mouton and col- thisforhumans(56,57,58,59,60,61,62),andwithoneexception e
r
leagues (51) highlighted the potential pitfalls in using drug (59),alldealwithpulmonarydistribution. s
it
concentrations within whole-tissue homogenates for drawing Mostoftheantifungalagentsconsideredinthisreviewdoex- y

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conclusionsrelatedtotheactivityandefficacyofadrug,especially hibithysteresis.Thispersistenceoftissueconcentrationsmayex- f

forextracellularpathogens.Thismaybeaparticularissueforam- plain why, in specific situations, linking the tissue pharmacoki- A
b
photericin B (irrespective of formulation), where there is long- netic data with pharmacodynamic data produces a significantly e
r
standinguncertaintyrelatedtotheamountofbiologicallyavail- morerobustPK/PDmodelthanusingplasmaPKdataalone(31, d
e
abledrugintissues.Thepotentialreasonsthattissuehomogenates 63).ThetechniqueofcomodelingbothPKandPDdatamayalso e
n
mayprovideinaccurateinformationregardingthe“true”concen- produceamoreinsightfulreflectionoftheimpactoftissuecon-
tration at the site of infection include (i) discordance between centrationthanthesimplisticcomparisonofpeaktissueconcen-
intra- and extracellular drug concentrations versus where the trationwiththebreakpointMIC(64).
pathogenisactuallylocated,e.g.,forposaconazole(33);(ii)mul-
tifocalversusdiffusedisease,resultinginaltereddrugpenetration ANTIFUNGALDRUGCONCENTRATIONSINORGANS,
atthesiteofinfectioncomparedwiththenormalcontiguoustis- TISSUES,ANDBODYFLUIDS
sue, e.g., pulmonary aspergilloma (257) or cerebral cryptococ- ThepapersinthisreviewwerepublishedbetweenJanuary1965
coma(Fig.6);(iii)theconcentrationoftotalversusbiologically andDecember2012.Inevitably,theyuseddifferingdrugdosagesand
active drug, e.g., free amphotericin B versus drug that remains formulations,withdifferentroutesofsystemicadministrationanda
complexedtolipid(29,52,53,54);and(iv)incompleteextraction rangeofdrug extraction and assay methods (e.g., bioassay, gas-
ofdrugfromtissue,e.g.,foramphotericinB(29,52,53,54). liquid chromatography, high-pressure liquid chromatography,
Reportingtissueconcentrationsofanti-infectivedrugsinaclin- 14C-autoradiography,and18F-nuclearmagneticresonance[18F-
72 cmr.asm.org ClinicalMicrobiologyReviews
TissuePenetrationofSystemicAntifungalAgents
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FIG7Concentrationsintissuesandbodyfluidsforeachsystemicantifungalagentrelativetoitsconcentrationinplasma.X,humandata;O,animaldata.Colors sm
illustratedifferingratios;multiplecolorswithinacolumngivetherangeofpublisheddata.Red,frombelowlevelofdetectionto(cid:2)0.5timestheplasma .
concentration;yellow,from(cid:3)0.5timesto(cid:2)5timestheplasmaconcentration;green,(cid:3)5timestheplasmaconcentration;white,nodata.(cid:2),pleuralfluid,buccal o
r
mucosa,orpancreaticpseudocyst;opendiamond,basedonautopsydataandhumanpharmacokinetics;(cid:9),woundfluid;o2,onlydetectedininflamedeyes;o3, g
/
bronchialsecretions;x3,belowlevelofdetectioninbronchialsecretions;o4,pulmonarylymph;x5,bronchialbiopsyspecimen. o
n

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a
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NMR]).Thedatawerealsopotentiallyinfluencedbytheunderly- plasma,withsomeminorregionalvariation(71).However,infive a
ing disease of the host. Consequently, we only used data where surgicalpatients,fluconazolebraintissue/plasmaconcentrationra- ry

bothplasmaandtissueconcentrationswerereportedwithinthe tiosof0.7to2.4weremeasuredwhenthefluconazoleplasmacon- 6
,
samestudy(exceptforsomepostmortemstudiesinwhichtissue centrationswereat90%ofsteady-statevalues(72).Fluconazoleisa 2
0
concentrationsalonewerereported). recognizedtherapyforcryptococcalandCandidameningoenceph- 1
4
Mosthumandataarefromhealthyadultvolunteersand/ora alitis.
b
fewpatients,andtheirapplicabilitytoyoungchildrenorneonates Incontrast,itraconazoleconcentrationsinhumanCSFarevery y

requiresfurtherstudy(65).Informationismostcomprehensive low,withCSF/plasmaconcentrationratiosof(cid:6)0.002to0.12(Fig. U
n
fortheoldertriazoles(fluconazoleanditraconazole),whileboth 5and7)(73,74).Itraconazolepenetratesthebrainsofratsrapidly, iv
humanandanimaldatafortheneweragents(posaconazoleand e
andinadose-dependentmanner,upto8minafterdrugadmin- r
thethreeechinocandins)aremorelimited.HumandataforAmBd istration(25).However,tissueconcentrationsarelessthanthose sit
(discoveredinthe1950s)and5FC(discoveredinthe1970s)are intheplasma(ratioof0.2at60minpostdose)andsubsequently y o
alsosurprisinglysparse. f
declinemorerapidly(half-lifeof0.4h)thanthoseineitherthe A
Despite the caveats discussed in the introduction, the pub-
plasmaorlivertissue(half-lifeof5h)(25).Thiseffecthasbeen b
lisheddataareexpressedastissueorbodyfluid/plasmaorblood e
ascribedtoitsactiveeffluxfromthebrainviaP-glycoprotein(Fig. r
concentrationratios.TheyaresummarizedinFig.7asthreedif- d
6). Studies in mice by Imbert and colleagues (75) confirm the e
ferently colored ratio bands. The colors in the figure illustrate e
impact of P-glycoprotein on itraconazole efflux from the brain n
differingdrugconcentrationratiobandsbutdonotimplydiffer-
butalsoindicatethatintracerebralinfectionwithC.neoformans
encesinefficacywithinvarioustissuesorbetweendrugs.
increases itraconazole exposure in the brain 2.6-fold compared
BrainandCerebrospinalFluid withthatinuninfectedanimals.However,inanotherratstudy,
ThebrainandCSFaresanctuarysites,astheyaresurroundedby uninfectedanimalsgivenasingleintravenousdoseofitraconazole
lipidmembraneswithinward-andoutward-facingtransporters (10mg/kgofbodyweight)hada(mean)braintissueconcentra-
(66).Datafromhumanstudiessuggestthatfluconazoleconcen- tionthatwas1.7timestheconcentrationinplasmaat1hpost-
trations in CSF are dose dependent and vary between 50% and dose,increasingto21timesat24hpostdose,asthebrainconcen-
100%oftheconcentrationobservedintheplasma(67,68,69,70) tration increased further, while the plasma concentration
(Fig. 3 and 7). Fluconazole is also readily detectable in human decreased(76).NoitraconazoleisdetectableintheCSFofrabbits
brain parenchyma. Studies with 18F-fluconazole in volunteers treatedwithoralitraconazoleforcryptococcalmeningitis.Never-
showedbraintissueconcentrationsthatweresimilartothosein theless, itraconazole achieves an efficacy comparable to that of
January2014 Volume27 Number1 cmr.asm.org 73
Feltonetal.
fluconazoleinthismodel,eventhoughfluconazoleisreadilyde- from0.002to0.54,whileinthebraintissueofanotherpatient,the
tectableinrabbitCSF,withaCSF/plasmaconcentrationratioof tissue/plasmaconcentrationratiowasonly0.17(106,107,252).Mi-
0.6to0.8(77).Itraconazolealsoexhibitsefficacyinhumancryp- cafunginpenetrationintorabbitbrainsisdosedependent,andsignif-
tococcosis, suggesting that it does penetrate the meninges and icantlyhigherconcentrationsaremeasurableinthemeningesthanin
cerebralparenchymaandachievestheconcentrationsrequiredfor eitherthecerebrumorcerebellum(108).However,theconcentra-
antifungalactivity(50,78). tionsinthesevarioussubcompartmentsarealsosufficienttoachieve
Voriconazole has a lipophilicity that is intermediate between asignificantanti-Candidaeffect.Animalmodelssuggestequiva-
those of fluconazole and itraconazole (Table 1). Voriconazole lentefficaciesbetweentheechinocandinsandamphotericinBfor-
penetrateshumanbraintissue(79,80)andabscessmaterial(81), mulations. The clinical value of the echinocandins for various
achievingpeakconcentrationssimilartoorevenexceedingthose fungalCNSinfectionsremainstobeestablished(18).
seeninplasma(Fig.4and7)(243).However,humanCSFcon-
centrations of voriconazole tend to be lower, with CSF/plasma Eye D
concentrationratiosof0.22to1.0(81,82,83).Thisisconsistent Endogenousfungalendophthalmitis,mostcommonlycausedby o
w
withitsintermediateplasmaproteinbindinginhumansof58% CandidaorAspergillusspp.,arisesfromhematogenousdissemi- n
(84). Voriconazole is the agent of choice for CNS aspergillosis nation(109).Arangeofsyndromesareseen,includingchorioretini- lo
a
(243). Posaconazole, which resembles itraconazole structurally tis, vitritis, and pan-endophthalmitis. Successful therapy requires d
e
butislesslipophilic(Table1),alsopenetratestheCSFrelatively penetrationofdrugintotherelevantsubcompartment(s)oftheeye, d
poorly (85), with CSF/plasma concentration ratios of (cid:6)0.009 i.e.,thechoroid,retina,vitreoushumor,andaqueoushumor(16). fr
o
(86). Its diffusion into the CSF may be increased by meningeal Formanyantifungalagents,suboptimalpenetrationcanmeanthat m
inflammation.Thus,CSFconcentrationsintwopatientswithbac- medicaltherapyaloneisineffective,andsuccessfultreatmentmay h
terial meningitis and cerebral fungal infection were 44% and requirevitrectomyand/orintracameralinjection(Fig.7). tt
p
230%,respectively,ofthoseinplasma(87).Inmiceinfectedwith Early human and animal data for azoles, polyenes, and 5FC :/
/
c
Cryptococcus gattii or Fonsecaea monophora, a bioassay revealed havebeenwellsummarizedelsewhere(16).Fluconazole(110,111, m
that brain tissue concentrations of posaconazole were approxi- 112),voriconazole(113,114,252),and5FC(115,116)aredetect- r
.
mately53%ofthoseinserumatdailydosesof(cid:2)20mg/kgbut ableinboththeaqueousandvitreoushumorsofanimaland/or as
m
increasedto70%to80%atadailydoseof40mg/kg(88,89). humaneyes,withandwithoutendophthalmitis,atconcentrations
.
Postmortem studies of humans show that amphotericin B is approximately 40% to 100% of those observed in serum. Al- o
r
g
detectable,butonlyatlowconcentrations,inthebraintissueof thoughtheuseof5FCisnowuncommon,bothtriazolesareem- /

patientsreceivingAmBdandL-AMB(52,53,90).AmphotericinB ployedquiteextensivelyfortreatingfungalophthalmicinfections o
n
concentrations in the CSF are also low after administration of inhumans(109,117).Thevisualadverseeventsexperiencedby J
a
intravenousAmBd(91).SimilarCSFandbraindataforAmBd, some patients receiving systemic voriconazole are related to n
L-AMB,andABLC(i.e.,CSFandtissue/plasmaconcentrationra- plasmaexposure(258)butnotyettoretinalconcentrationsperse. u
a
tiosof(cid:6)0.3)havebeenrecordedforrabbits(92).Incontrasttothe Theseadverseevents,whichhavebeenascribedtoinhibitionof ry
casewithposaconazole,inflammationdoesnotseemtoincrease theBwaveof“ON”bipolarcellsintheretina(118),donotappear 6
,
theconcentrationofanyamphotericinformulationinthebrain, toresultinlong-termadverseeffectsortoxicity(119). 2
0
atleastinanimals(40,92).Toovercomethesepotentiallimita- Penetrationofitraconazoleintotheeyesofrabbitsafterasingle 1
tions,intraventricularinstillationofAmBdviaanOmmyareser- oraldoseisminimal(120).Nodrugisdetectable(usingbioassay) 4

voirhasbeenusedforseverecerebralinfections(93,94,95). intheaqueousorvitreousofuninflamedeyes,withonly0.3(cid:5)g/ml by

The concentrations of 5FC in human CSF are similar to its observed in the cornea, despite plasma concentrations of more U
n
correspondingserumconcentrations(91,96,250),andacombi- than10timesthisvalue.Withinflamedeyes,concentrationsinthe iv
nation of 5FC with AmBd or L-AMB is a recognized first-line aqueousandvitreousarestill4-and10-foldlower,respectively, e
r
inductiontherapyforcryptococcalmeningitis(97). than those in the plasma, while in the cornea they are low and s
it
The three echinocandins, i.e., caspofungin, micafungin, and unchangedrelativetothoseinuninflamedeyes.Despitethesere- y

o
anidulafungin, are large, amphipathic, cyclic peptides—proper- sults,itraconazoleisasefficaciousasketoconazoleandflucona- f

ties that do not ordinarily favor penetration into the brain and zoleagainstCandidaalbicansendophthalmitisinvivowhenther- A
b
CSF(98,99).Therearenohumandataforanidulafungin.How- apyisinitiatedwithin24hofinfection(120).Similarly,asingle e
r
ever, its concentration in rabbit brains after multiple dosing is patientwithC.albicansendophthalmitiswastreatedsuccessfully d
e
onlyabout10%ofthemaximumconcentrationofdruginserum with200mg/dayofitraconazole(capsules)andtwovitrectomies e
n
(C )(100,101).Deliveryof14C-anidulafungin(astotaldrug- (121).Thiswasdespiteconcentrationsintheaqueousandvitre-
max
derivedradioactivity)intothebrainsofratsisdelayedcompared oushumorsthatwereundetectableand0.02(cid:5)g/ml,respectively,
tothatintothebloodandothertissues,anditisnotdetectablein whileplasmaconcentrationswereapproximately0.5(cid:5)g/ml.Hey-
braintissueuntil24hafterasingledose(102).Incontrast,CSF kants and colleagues (122) have also reported that itraconazole
concentrationsaresimilartothoseinthebloodwithin30minof concentrationsinhumanaqueousareusuallyonly1to2ng/ml.
dosing (102). The administration of caspofungin to rodents re- Thereareminimaldataforposaconazole,butthesesuggestthat
sultsinbraintissueconcentrationsandexposuresthatareapprox- it does penetrate into the inflamed eye. In a single patient with
imately10%ofthoseinplasma(103,104).Inasinglepatientwith Fusarium solani keratitis and ophthalmitis, receiving 200 mg
CNS coccidioidomycosis, CSF concentrations of caspofungin orally (p.o.) four times daily plus topical instillation of the oral
wereundetectable,despiteconcentrationsinplasmaof2.7to5.5 solution, the aqueous and vitreous/plasma concentration ratios
(cid:5)g/ml (105). Similarly, the CSF/plasma concentration ratios of were0.6and0.21,respectively,andtherapywassuccessful(244).
threepatientsreceivingmicafunginwerelowandvariable,ranging Two patients, with rhinofacial and orbital zygomycoses, each
74 cmr.asm.org ClinicalMicrobiologyReviews
TissuePenetrationofSystemicAntifungalAgents
received0.6mg/kgintravenous(i.v.)AmBd(123).Penetrationof conazolewas7(139),whileHeykantsandcolleagues(73)reported
AmBdintoboththeaqueousandvitreousoftheinfectedeyewas concentrations0.9to2.4timeshigherthanthoseintheplasmasof
higherinthepatientwithrhinofacialdiseaseandextensiveretinal fourpatients.However,itraconazoleconcentrationsinbronchoal-
inflammation(fluid/serumconcentrationratioof0.4)thaninthe veolarlavage(BAL)fluidandairwaytissuewere10-foldlowerthan
secondpatient,whohadminimalretinalinflammation(ratioof thoseinplasmainapatientwithallergicbronchopulmonaryasper-
0.06).PenetrationofallformulationsofamphotericinBintothe gillosis(ABPA)(140).Itraconazolehasbeenusedextensivelytotreat
eyesofrabbitsisalsoenhancedbyinflammation(124,125,249). pulmonaryfungalinfections.
Indeed,amphotericinBisnotdetectedinnoninflamedeyes,even Postmortemstudiesshowlungtissuehomogenateconcentra-
aftermultipledosingofAmBd,ABLC,orL-AMB(16,124,125). tionsforvoriconazolethatarecomparablewiththeplasmacon-
Consequently,intracameralinjectionisthefavoreddeliveryroute centrations(80,141).Involunteersreceivingani.v.loadingdose
for these agents in patients with severe keratomycosis or endo- onday1andthen200mgofvoriconazolep.o.twiceaday(b.i.d.),
phthalmitis. For AmBd, this may lead to significant local toxicity, the ELF/plasma concentration ratio was 11 (142). However, in D
whichissomewhatamelioratedbylipidformulations(109). volunteersreceivingthesamei.v.loadingdoseonday1,butfol- o
w
Allthreeechinocandinsalsoshowlimitedpenetrationintothe lowedbythreedosesof4mg/kgi.v.every12h(q12h),theELF/ n
aqueousandvitreoushumorsoflaboratoryanimalsaftersystemic plasmaconcentrationratioatsteadystatevariedover12hfrom lo
a
administration, with either undetectable or low concentrations approximately 6 to 9, while for alveolar macrophages the ratio d
e
relativetothoseinplasma(100,108,109,126,127,128).However, variedfromapproximately3.8to6.5(58).Posaconazoleexhibits d

micafunginconcentrationsspecificallyintheretinaandchoroid ELFconcentrationsinhumanssimilartothoseseenintheplasma, fr
o
of the eyes of rabbits range from 0.75 to 15.97 (cid:5)g/ml and are buttheexposureinalveolarcellsisover30timesthatinplasmain m
comparablewiththeconcentrationsinplasma(129).Aswitham- both volunteers (57) and lung transplant patients (143). It has h
photericinB,inflammationappearstoimprovetheextentofechi- been suggested that high intracellular posaconazole concentra- tt
p
nocandin penetration (127). Potentially subtherapeutic vitreal tionsmayexplainitseffectivenessforprophylaxis(Fig.2A)(33). :/
/
c
penetration of caspofungin has been associated with treatment Meanlungtissueconcentrationsofposaconazoleinrabbitshave m
failureinCandidaalbicansendophthalmitis(130),andlowcon- beenreportedtorangefrom0.3(cid:5)g/mlto2.1(cid:5)g/mlafterdosingat r
.
a
centrationsofcaspofunginweremeasuredintheaqueousofone 2to6mg/kg(145). s
m
humanendophthalmitispatient(113).Similarly,lowmicafungin TheadministrationofallformulationsofamphotericinBre-
.
concentrationsintheaqueousandvitreousofaC.albicansendo- sultsinquantifiableconcentrationsintheELFinbothrabbitsand o
r
g
phthalmitispatient(0.001%ofthesimultaneousconcentrationin humans,buttheplasma/ELFconcentrationratiosappeartodiffer /

plasma)wereassociatedwithclinicalfailure(131),andthedrug betweenformulationsandspecies.Theprecisestateoftheampho- o
n
wasalsoineffectiveinapatientwithendophthalmitiscausedby tericin in these studies is not clear (i.e., free, protein bound, or J
a
Candidatropicalis,despitesevereinflammationandaMICof0.03 lipidassociated).Furthermore,thebiologicalrelevanceoftheto- n
(cid:5)g/ml(132). tal concentrations associated with each formulation is also un- u
a
clear. Human data for the various amphotericin formulations ry
Lung suggestthattheremaybesomedifferencescomparedwithrabbits 6
,
Pulmonaryinfectionbeginswithintheairspace(Fig.2A).There- (146,147).Thus,intravenousABLCproducesELFamphotericin 2
0
fore,fortheagentsusedforprophylaxisortreatmentofinfection Bconcentrationsthatareapproximately4timesthoseproduced 1
confinedtotheairspace,concentrationsinepithelialliningfluid afteradministrationofL-AMBinhumans(147).In18patients 4

b
(ELF)andwithinpulmonaryalveolarmacrophagesareofdirect undergoingthoracotomyandresectionforlungcancer,asingle y

importance.TheinhalationofaerosolizedamphotericinBformu- doseof1.5mg/kgi.v.ofL-AMBresultedinhysteresis,suchthat U
n
lationsisapotentialoptionforprophylaxis(133,134,135).Anti- tissue/plasmaconcentrationratioswere0.29and2.5at10and25 iv
fungaldrugconcentrationswithinELFafteraerosolinhalationor hpostdose,respectively(248).Inapostmortemstudy,lungtissue e
r
systemic administration were recently reviewed (12). However, homogenateconcentrationswerefoundtobe3timeshigherwith s
it
fortreatmentofestablishedinvasiveinfections,drugconcentra- asimilardoseofABLCthanwithL-AMB(90).Similarly,ABLC y

o
tionsinthelungparenchymamaybemorerelevant(Fig.2Band concentrations in mouse lung homogenates exceeded those for f

C).Drugconcentrationsmayalsobemeasurableinanumberof equivalentdosesofL-AMB(39).Pulmonaryinflammationmay A
b
otherrespiratoryfluids,includingbronchialsecretions,sputum, increase amphotericin concentrations following administration e
r
pleuralfluid,andpulmonarylymph(seebelowandFig.7). ofL-AMB(148).TheamphotericinBformulationsremainfirst- d
e
Humanstudiessuggestthat18F-fluconazoledistributesrapidly lineagentsforthetherapyofpulmonaryfungalinfections. e
n
intothelungtissueofvolunteers,producingconcentrationsap- Therearenopublisheddataforechinocandinconcentrations
proximatelydoublethoseinplasma(71).In20patientsreceiving withinhumanlungtissue.However,theconcentrationsofcaspo-
asingle200-mgdoseoffluconazole,thelungtissue/plasmacon- fungininalveolarmacrophageswere(cid:3)5timesthecorresponding
centrationratiorangewas1.1to1.6(136).Similarly,theflucona- concentrationsinplasmainasinglepatient(149).Bothanidula-
zole ELF/plasma concentration ratio in cats was 1.2 (137). Flu- funginandmicafunginalsoaccumulatedinthealveolarmacro-
conazolealsoreadilypenetratestheextracellularspaceoftherat phagesofvolunteers,attainingconcentrationsapproximately14
lung(fluid/plasmaconcentrationratioof1.38),andthisisunaf- and4timeshigherthanthoseinplasma,respectively(58,62).In
fected by inflammation (138). Itraconazole exhibits ELF expo- 18lungtransplantpatientsreceivingasingle150-mgi.v.micafun-
suresthatareone-thirdoftheplasmaAUCinhumanvolunteers, gindose,ELF/plasmaandalveolarcell/plasmaconcentrationra-
while the AUC in alveolar cells is more than double that of the tios varied with time postdose. Mean ratios ranged from 0.1 to
plasma(56).Inpostmortemsamplesfromfourhematologypa- 1.53 at 3 h and from 1.1 to 6.2 at 24 h postdose (62). The vast
tients, the mean lung tissue/plasma concentration ratio of itra- majority of anidulafungin and micafungin found in the ELF is
January2014 Volume27 Number1 cmr.asm.org 75
Feltonetal.
presentwithinmacrophagesratherthaninthefluiditself(58,61, (67,157,158)anditraconazole(73,159)havebothbeendetected
62).Caspofungin,micafungin,andanidulafunginexhibitlungtis- inthesalivaandsputumofpatients(Fig.7).Consistentwiththeir
sueexposuresinrodentsthatexceedthoseinplasmaby1.1-fold, physicochemicalproperties(Table1),theconcentrationratiosfor
2.8-fold,and10-fold,respectively(102,103,150). fluconazoleinsalivaandsputumcomparedwithserumare(cid:4)1,
whileforitraconazoletheyaregenerallymuchlower(73)andvery
PulmonaryLymphFluid variable (159). Itraconazole can also be detected in esophageal
Therearenohumandataforantifungaldrugconcentrationsin tissue,at3timestheconcentrationinplasma(160),andinbron-
pulmonarylymph,butHoeprichandcolleagues(151)examined chialexudates(73).However,clinicaldatasuggestthatflucona-
theconcentrationsof5FCandAmBdinsheepcannulatedviathe zole is superior to itraconazole for treating oropharyngeal and
afferentductoftherightcaudalmediastinallymphnode.Alldrugs esophagealcandidiasis(161,162).Voriconazoleispresentinthe
tested (also including ketoconazole, the triazole Bay n733, and salivaofvolunteers,andconcentrationsincreaseovertime,using
AmBdmethylester[AME])appearedpromptlyinthelymphafter astandarddose.Thus,salivaryexposureonday1isapproximately D
asingleintravenousdose,withtheirconcentrationssubsequently 25%ofthatinplasmaandincreasesto88%ofthatinplasmawith o
w
decayingexponentially.Ingeneral,theconcentrationsofallfive multipledosing(163).Fluconazoleandvoriconazoleshowcom- n
drugs in lymph slightly exceeded those in plasma measured parableefficaciesinimmunocompromisedpatientswithesopha- lo
a
shortly after the end of the 30-min infusion period (maximum gealcandidiasis(164).Whiletherearenopublisheddataforpo- d
e
ratioforlymphtoplasmaof1.0to1.9),exceptforAME,where saconazole concentrations in saliva, sputum, or mucosal and d

lymphatic concentrations were lower. Koizumi and colleagues esophagealtissues,thisdrugisaseffectiveasfluconazoleintreat- fr
o
(152) also examined AmBd concentrations in sheep lung and ingHIVpatientswithoropharyngealcandidiasis(165). m
lymphafterani.v.infusion.Theconcentrationsinthelymphwere BuccalmucosalconcentrationsofamphotericinBincreaseina h
similarto(orslightlyexceeded)thoseintheplasma,dependingon dose-dependentmannerinhumansafterL-AMBadministration tt
p
thedurationoftheinfusion.Giventherangeoflipophilicitiesand and attain concentrations approximately 7 to 43 times those in :/
/
c
plasmaproteinbindingoftheaboveantifungalagents,theseproper- plasma (166). A wide range of amphotericin B concentrations m
tiesdonotseemtohaveasignificantimpactonpenetrationintothe were also detectable in esophageal autopsy samples from seven r
.
a
lymphaticsystem,atleastfollowingintravenousadministration. patientsafterAmBdadministration(54). s
m
Theconcentrationsof5FCinhumansalivaareslightlylower
.
PleuralFluid thanthoseintheplasma,butthe5FCconcentrationsmeasuredin o
r
g
Dataonantifungaldrugpleuralfluidconcentrationsarelimited thebronchialsecretionsofdogsarecomparabletoserumconcen- /

(Fig.7).Voriconazolepenetratesintothepleuralfluid,producing trations(91). o
n
troughconcentrationsinhumansthataresimilartopairedplasma Therearenohumanorlaboratoryanimaldatagivingthecon- J
a
concentrations (153, 154). For AmBd, pleural fluid concentra- centrationsofcaspofunginormicafunginatthesesites.Anidula- n
tionsareapproximately50%ofthoseinplasma(91,247).How- funginispresentinboththesalivaandesophagusinrabbitswith u
a
ever,pleuralfluidamphotericinconcentrationsfollowingthead- oropharyngealandesophagealcandidiasis,butonlyatconcentra- ry
ministrationofL-AMBorABCDareapproximately5%to25%of tionsbetween1%and33%ofthoseinplasma(167).However,all 6
,
theirplasmaexposures(60,155).Penetrationoftheechinocan- threeechinocandinsshowefficacyattheendoftherapyequivalent 2
0
dinsintopleuralfluidappearstobelow.Thus,foranidulafungin tothatoffluconazoleafterintravenousadministrationtopatients 1
inonepatientwithCandidaempyemaandforthreemicafungin withAIDSandoropharyngealoresophagealcandidiasis(168,169, 4

b
patients,pleuralfluidconcentrationswerelessthan1%and10%, 170).Therearenodatatoindicatewhetheranyefficacydiffer- y

respectively,ofthosemeasuredintheplasma(107,251). encesbetweenfluconazoleandtheechinocandinsseenonlon- U
n
ger-termfollow-upofthesepatientsarerelatedtoresidualtis- iv
BronchialSecretions sueconcentrations. e
r
Watkinsandcolleagues(140)demonstrated,foronepatient,that s
itraconazoleaccumulatestoapproximatelytwicetheplasmacon- Heart ity

o
centrationinbronchialbiopsytissueandisalsodetectable(atonly Fluconazoleandvoriconazoleconcentrationsinhumanhearttis- f

ng/ml concentrations) in BAL fluid and bronchial washings. suearecomparabletothoseinplasma,basedon18F-NMRstudies A
b
However,noallowancewasmadeforthesignificantdilutionfac- inhealthyvolunteersandautopsydata,respectively(71,80).The e
r
torinvolvedwiththeirsamplingmethods.Theyconcludedthat pericardialfluid/plasmaconcentrationratiosoffluconazolein20 d
e
itraconazoleispresentin“relativelyhigh”concentrationsinpul- patientsrangedfrom0.9to1.0(136).Datafromasinglepatient e
n
monary fluids and tissues. In contrast, amphotericin B was de- withdisseminatedaspergillosisalsosuggestthatvoriconazoledif-
tected,butonlybrieflypostdoseandatlowconcentrations,inthe fusesintothepericardialfluid,ataconcentrationcomparableto
trachealsecretionsofhumans(91)andthetracheasofdogsfol- theplasmaconcentration(153).Autopsydataalsoindicatethat
lowingadministrationofAmBd(91),althoughpenetrationmay myocardial voriconazole concentrations are similar to those in
bedosedependent(156).For5FC,concentrationsindogbron- otherbodyorgans,includingthelungandkidney(80).Incon-
chialsecretionsareapproximately75%ofcorrespondingplasma trast, itraconazole exposure in the hearts of mice after a single
concentrations(156). 10-mg/kgi.v.doseisonly8%ofthatinplasma(171).However,in
rats, at 1 h postdose, the concentration is 6 times the level in
Saliva,Sputum,BuccalMucosa,andEsophagus plasma,andboththeabsoluteconcentrationandtheplasmaratio
Theattainmentofeffectiveantifungaldrugconcentrationswithin increasefurtherafter24h(76).Therearenopublishedhuman
the saliva, sputum, and bronchial fluid is critical for therapy of heart tissue concentration data for itraconazole. Nevertheless,
oropharyngeal,esophageal,andbronchialinfections.Fluconazole itraconazolecancausecongestiveheartfailure(172)vianegative
76 cmr.asm.org ClinicalMicrobiologyReviews