GENTSANDApr2009p16481651Vol53No40doi101128AAC0114807Copyr - PDF document

1 GENTSAND,Apr.2009,p.1648–1651Vol.53,No.4
GENTSAND,Apr.2009,p.1648–1651Vol.53,No.40doi:10.1128/AAC.01148-07Copyright©2009,AmericanSocietyforMicrobiology.AllRightsReserved.VoriconazoleUseforEndemicFungalInfectionsAlisonFreifeld,*LaurieProia,DavidAndes,LarryM.Baddour,JanisBlair,BradSpellberg,SandraArnold,ArnoldLentnek,andL.JosephWheatUniversityofNebraskaMedicalCenter,Omaha,Nebraska EndemicfungalinfectionsintheUnitedStatesduetotoplasmacapsulatumBlastomycesdermatitidis,andioidesimmitisaregenerallytreatedwithamphotericinBfor-mulations,itraconazole,oruconazole(6,9,27).Eachofthesestandardantifungalshaslimitationsthatprecludeitsusebysomepatients.RenalandinfusionaltoxicitiesassociatedwithamphotericinBformulationsandgastrointestinalabsorptionandintolerancedifcultieswithoralitraconazolearethemostnotable.Voriconazoleisawell-tolerated,orallybioavailablenewertriazoleantifungalwithabroadrangeofactivityagainst *Correspondingauthor.Mailingaddress:985400NebraskaMedicalCenter,Omaha,NE68198.Phone:(402)559-8650.Fax:(402)559-5581.E-mail:afreifeld@unmc.edu.Publishedaheadofprinton12January2009. TABLE1.Characteristics,treatments,andoutcomesofthepatientsdescribedinthisreport Diseaseandcaseno.(reference)Age(yr),sex,underlyingClassicationbasedondiagnosticcriteriaPriorantifungaltreatment(no.ofdays)ReasonforVoritreatmentResponsetoVoriwithinrst2moReasonVoristopped(totalno.ofdaysgiven)Survival(totalno.ofdaysfromdiagnosis)1(8)18,F,kidneyTxDisseminatedprovenItra,Flu(44)Failure(increasingantigenuria)ImprovedCompletedtherapy(315)Alive(478)2(8)54,F,liverTxDisseminatedprobable(positiveforbloodandurineantigen,pulmonarylesions)AmB,Itra(25)Intolerance(gastrointestinalwithItra)StableCompletedtherapy(293)Alive(322)3(8)52,F,kidneyTxDisseminatedprovenAmB(1)Intolerance(chillswithAmB)StableCost(22)Alive(360)415,F,kidneyTxDisseminatedprobable(positiveforbloodandurineantigen,pulmonarylesions)Itra(459)Intolerance(noncompliance)ImprovedCompletedtherapy(559)Alive(1,104)559,M,SLE,RAonDisseminatedprovenFlu,L-AmB,Itra(28)Cliniciandecision(lowserumItralevel)Stable(butpersistentantigenuriadespiteclinicalstability)Persistentantigenuria,switchedtoItrasolution(151)Alive(561)641,M,kidneyTxDisseminatedprovenItra(30)Intolerance(gastrointestinalwithItra)StableCost(243)Alive(535)722,F,nonePulmonaryprovenItra,L-AmB(91)Failure(persistentsignsandsymptomsonItra),toxicity(nephrotoxicitywithStableCompletedtherapy(31)Alive(150)871,M,renalfailureDisseminatedCNSprovenPrimary(combinedwithAmBfor6wk)ImprovedCompletedtherapy(640)Alive(697)937,F,MSPulmonaryprovenItra(123)Toxicity(alopeciaandfatiguewithItra)StableCompletedtherapy(91)Alive(578)1061,M,heartTxPulmonaryprovenABLC,AmB(4)Toxicity(nephrotoxicitywithAmB)StableCompletedtherapy(234)Alive(243)1142,M,kidneyTxDisseminatedprovenABLC(1)Toxicity(nephrotoxicitywithABLC)StableCliniciandecisiontoswitchbacktoItra(45)Alive(413)1254,M,liverTxPulmonaryprovenL-AmB,Flu,Caspo,ABLC,Itra(104)Cliniciandecision:lowserumItralevel)ImprovedCompletedtherapy,relapsed90daysafterstoppingVori(234)Deathunrelatedtomycosis(486)1359,M,noneDisseminatedprovenABLC,Itra(138)Intolerance(gastrointestinalwithItra)StableContinuedVorichronicsuppressivetherapy(238)Alive(376)1468,M,kidneyTxPulmonaryprovenPrimaryImprovedCompletedtherapy(147),relapsed36daysafterstoppingVori(147)Deathrelatedtomycosis(buddingyeastcompatibleblastomycosisinlungatautopsy)(183)15(12)44,M,noneDisseminatedCNSprovenAmB(12)Toxicity(ototoxicitywithAmB)StableCompletedtherapy(179)Alive(317)1639,F,noneDisseminatedprovenL-AmB(29)Toxicity(nephrotoxicitywithL-AmB)StableCompletedtherapy(366)Alive(426)1731,M,malignantthymomaonDisseminatedmeningitisprovenL-AmB(40)Toxicity(nephrotoxicitywithL-AmB)ImprovedDeath(84)Deathunrelatedtomycosis(124)1846,M,allergicaspergillosisonDisseminatedmeningitisprobable(positiveCSFItra,Flu(532)Failure(worseningCNSsymptomsonhigh-doseFlu)ImprovedToxicity(elevatedLFTs)(53)Deathrelatedt

2 omycosis(293)1935,F,anorexianervosaDisse
omycosis(293)1935,F,anorexianervosaDisseminatedprobable(positiveserumserology)Flu(Unk)Intolerance(gastrointestinal,rash)StableContinuedVori,chronicsuppressivetherapy(553)Alive(602)2066,F,bonemarrowTxPulmonaryprovenL-AmB(48)Toxicity(nephrotoxicitywithL-AmB)StableContinuedVori,chronicsuppressivetherapy(649)Alive(712)2167,M,noneDisseminatedmeningitisprobable(positiveCSFFlu(395)Failure(progressiveCNSsymptomsonhigh-doseFlu)ImprovedCompletedtherapy(355)Alive(753)2232,M,diabetesDisseminatedmeningitisprovenFlu(14)Toxicity(elevatedLFTswithFlu)Failure(alsoreceivedDeath(22)Deathrelatedtomycosis(33)2344,M,noneDisseminatedprovenFlu,AmB,ABLC(40)CliniciandecisionStableContinuedVori(1,120),chronicsuppressivetherapyAlive(1,711)24(19)30,M,noneDisseminatedmeningitisprobable(positiveCSFandserumserology)Flu,AmB,ABLC,Flu,intrathecalAmB(588)Toxicity(tinnitus,diplopia,headache,nauseawithintrathecalAmB)ImprovedContinuedVori,chronicsuppressivetherapy(1,797)Alive(2,163)Abbreviations:M,male;F,female;Caspo,caspofungin;Vori,voriconazole;Tx,transplant;Itra,itraconazole;L-AmB,liposomalamphotericinB;ABLC,amphotericinBlipidcomplex;MS,multiplesclerosis;AmB,amphotericinB-desoxycholate;SLE,systemiclupuserythematosus;Flu,uconazole;RA,rheumatoidarthritis..53,2009VORICONAZOLEUSEFORENDEMICFUNGALINFECTIONS1649 lessactivethan,itraconazoleorposaconazoleagainst(10,15,26),buttheinvivocorrelationofthisobser-vationisunknown.Voriconazolehasnotbeenstudiedinani-malmodelsofhistoplasmosis.Theinvitroinhibitoryeffectsofthedrugonanditshighbioavailabilitysuggestitsutilityfortreatingclinicalhistoplasmosis.AsshowninTable1,alloftheninepatientswithhistoplasmosistreatedwithvoriconazoleeitherprimarily(no.8,plusamphotericinB)orduetofailureorintoleranceofotherantifungals(no.1to7and9)eitherimprovedorremainedclinicallystablefollowinginitiationofvoriconazole.Onepatientwhoimprovedclinicallyonvoriconazolewaslaterswitchedbacktoitraconazolewhenantigenuriafailedtodecline.Anumberofothershavereportedsuccessfultreatmentofhistoplasmosis(1,11,23–25)withvoriconazole,althoughfailurehasalsobeenreported,withsubsequentresponsetoposaconazole(21).Cross-resistancebetweenuconazoleandvoriconazolehasbeendescribedinisolatesfrompatientsinfectedwithhumanimmunodeciencyvirus(26).Voriconazoleisalsoactiveinvitroagainstexhibitingasusceptibilitypatternsimilartothatofitraconazole(16).Ithasnotbeenstudiedinananimalmodelofblastomy-cosis.Amongtheeightpatientswithblastomycosisinthisse-ries,alleitherimprovedorremainedstableafterstartingvori-conazole,althoughtworelapsedafterstoppinglongcoursesofthedrug.Onerenaltransplantpatient(no.14)whoreceivedvoriconazoleasinitialtherapyforpulmonaryblastomycosisimprovedclinicallyandcompleteda4-monthcourseoftherapybutrelapsed36daysafterstoppingtherapyanddiedshortlythereafter,withpulmonaryblastomycosisidentiedatautopsy.Anotherimmunosuppressedpatient(no.12,withalivertransplant)respondedtovoriconazolerapidlyaftermultipleantifungalsfailedtocontrolhisrecurrentpulmonaryblas-tomycosis.Afterachieving10monthsofstablediseaseonvoriconazole,hediedasaconsequenceofsepsisandmultior-ganfailurewithevidenceofrecurrentblastomycosisinthelungs.Thiscaseillustratesthecriticalimportanceofhostim-munologiccompetenceincontaininganderadicatingendemicfungalinfections.Anantifungalagentcannotalonecuredeepinvasivemycoseswithoutsomelevelofhostimmunedefense.TwootherpatientswithCNSblastomycosis(no.15withnounderlyingdisease,no.17withcancer)wereswitchedtovori-conazoleafterdevelopingintolerancetoamphotericinprod-ucts(after12and40days,respectively),andbothrespondedfavorably.Othershavereportedsuccessfulvoriconazoletreat-mentofpatientswithCNSblastomycosisfailingotherazoles(4,5,12,16).Goodpenetrationofthebrainandcerebrospinaluidbyvoriconazolehasbeendocumentedinanimalsandimmunocompromisedpatients(14).Itshouldbeemphasized,however,thatInfectiousDiseasesSocietyofAmericaguide-linesst

3 ronglyadvocateamphotericinBoritslipidfor
ronglyadvocateamphotericinBoritslipidformulationsastheinitialtreatmentforCNSblastomycosis,aswellasforCNShistoplasmosis;azolesshouldbereservedforsalvagetherapy,asinthecasesreportedherein(6,27).Voriconazoleisactiveinvitroagainstexhibitingsusceptibilitypatternscomparabletothoseof(13).Furthermore,invitrosusceptibilitytovoriconazolewassomewhatbetterthantoitraconazole.Voriconazolehasnotbeenstudiedinanani-malmodelofcoccidioidomycosis,butithasbeenusedsuc-cessfullyinafewpatients(2,18,19).Inthisreport,sixofthesevenpatientswithcoccidioidomycosiswhoweretreatedwithvoriconazole,afterotherantifungaltoxic-ity/intoleranceorforphysicianpreference,respondedtothedrugfavorably.Threeofthefourpatientswithunresponsivetoavarietyofotherantifungalsimprovedafterswitchingtovoriconazole.Onepatient(no.18)withmeningitisinitiallyimprovedonvoriconazolebutdiedofrecurrentdiseasewhenswitchedbacktolong-termuconazole(whichhadprevi-ouslyfailedtocontainhisinfection).Thereareafewothercasereportsofsuccessfultreatmentofcoccidioidomycosiswithvoriconazole(2,7,18),includingmeningitis(7).Combiningalloftheresultsfromthislimitedcaseseries,thereisevidencethatpatientswithendemicfungalinfectionswhore-ceivedvoriconazolefortoxicity,intolerance,orfailureofotherantifungalsarelikelytoremainstableorbeimprovedclinicallyafterstartingthedrug.Only1ofthe24patientsreportedherediedoftheendemicfungalinfectionwhilereceivingvoriconazole,althoughtworelapsesofblastomycosis(onefatal)occurredwithin1to3monthsafterstoppinglongcoursesofthedrug.Itisnotablethatthedurationofvoriconazoletherapyvariedsigni-cantlyaccordingtotheunderlyingdisease,thelocationoftheinfection,andthedegreeofimmunocompromise.Thesemanage-mentvariationshighlightthegapsinknowledgeabouttreatingendemicfungalinfections.Severalcaveatsshouldbeconsideredinapplyingthendingsofthisreporttothemanagementofpatientswithendemicmycoses.First,assessmentofeffectivenessandtolerabilityisdifcultinaretrospectivereview,andtheac-curacyofretrospectiveobservationsisnotveriable.Thelackoftolerabilitydatainthisreportis,inpart,duetothisconstraint.Second,thefollow-upperiodwasshort,lessthan1yearinmanyofthepatients.Third,thenumberofpatientsreceivingvoricon-azoleforinitialtreatmentor“salvage”treatmentafterfailureofanotheragentwassmall.Fourth,adherenceanddrugexposurewerenotevaluated.Fifth,effectivenesscannotbeadequatelyas-sessedinpatientswhoreceivedvoriconazolebecauseofintoler-anceortoxicityofotheragents.Recognizingthelimitations,ourndingsstillsuggestthatvoriconazolecanbeusefulinsomepatientswithendemicmycoses,particularlythosewhohavedem-onstratedintolerancetootherantifungalagents.However,pro-spectivestudiesareneededtofullyassesstheutilityofvoricon-azoleinthissetting.Wereceivedresearchsupportorserveonthespeaker’sbureauorasconsultantsforpharmaceuticalcompaniesthatmarketantifungalagentsdescribedinthisreportasfollows:PzerInc.,A.F.;Schering-PloughCorporation,A.F.,L.J.W.,andL.P.;Enzon,Inc.,A.F.WeacknowledgethetremendouseffortsofPennyHardiman,with-outwhomthisresearchcouldnothavebeenaccomplished.Al-Agha,O.M.,M.Mooty,andA.Salarieh.2006.A43-year-oldwomanwithacquiredimmunodeciencysyndromeandfeverofundeterminedorigin.Arch.Pathol.Lab.Med.Antony,S.J.,P.Jurczyk,andL.Brumble.2006.Successfuluseofcombina-tionantifungaltherapyinthetreatmentofcoccidioidesmeningitis.J.Natl.Med.Assoc.Ascioglu,S.,J.H.Rex,B.dePauw,J.E.Bennett,J.Bille,F.Crokaert,D.W.Denning,J.P.Donnelly,J.E.Edwards,Z.Erjavec,D.Fiere,O.Lortholary,J.Maertens,J.F.Meis,T.F.Patterson,J.Ritter,D.Selleslag,P.M.Shah,D.A.Stevens,T.J.WalshonbehalfoftheInvasiveFungalInfectionsCooperativeGroupoftheEuropeanOrganizationforResearchandTreat-mentofCancerandMycosesStudyGroupoftheNationalInstituteofAllergyandInfectiousDiseases.2002.Deningopportunisticinvasivefungal1650FREIFELDETAL. infectionsinimmunocompromisedpatientswithcancerandhematopoieticstemcelltransplants:aninternationalcon

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