Successful treatment of a recurrent Aspergillus niger otomycosis with local application of voriconazole

(1)

Case report/Cas clinique

Successful treatment of a recurrent Aspergillus niger otomycosis with local application of voriconazole

M. Chappe

^a

, S. Vrignaud

^a,

*, L. de Gentile

^b

, G. Legrand

^c

, F. Lagarce

^a,d

, Y. Le Govic

^b,e

aPharmacieCentrale,CHUd’Angers,49933Angers,France

bLaboratoiredeparasitologie-mycologie,CHUd’Angers,49933Angers,France

cCabinetd’otorhinolaryngologie,cliniquedel’Anjou,49000Angers,France

dInsermU1066,CNRS6021,micro-etnanome´decinesbiomime´tiques,universite´ Bretagne-Loire,49933Angers,France

eGrouped’e´tudedesinteractionsHoˆte–Pathoge`ne,EA3142,universite´ Bretagne-Loire,499333Angers,France

1. Introduction

Otomycosisisafungalinfectionoftheouterearcanal(OEC).It accountsfor approximately10%ofallacuteotitis externacases [1]. Anatomical characteristicsof theOEC indeed provide ideal conditions for such infections, which mainly involve species belongingtotheAspergillus(especiallyA.nigerandA.fumigatus)or Candidagenus[2].Riskfactorsforsuchinfectionsincludewarm, moistweather,andexcessiveaccumulationofcerumenintheOEC.

ThisisparticularlytruewhentheOECremainswetafterswimming orbathing.Althoughusuallybenign,managementofotomycosis maybechallenging becauseofits highrecurrence rate[1],the paucityoftherapeuticoptionsand theemergenceof antifungal resistance [3,4]. Besides patient’s discomfort, its possibility to evolvetowardsaninvasivefungalinfectionjustiﬁesappropriate care.Here,wereporttheﬁrstcaseofrecurrentA.nigerotomycosis that wassuccessfullytreated bytopical administration ofa 1%

voriconazolesolutionalongwithaliteraturereviewofantifungal therapyofA.nigerotomycosis.

2. Casereport

In March 2015, a 45-year-old woman practicing swimming consulted her familydoctor complaining of leftauricular pain, hearingloss,andtinnitus,alongwithchangesinhertoneofvoice.

Eardrum was undamaged. The patient was given oﬂoxacin eardrops, 1.5mg bid for 7 days, followedby a 5-day courseof cefpodoximeperos100mgbid.Despitecompliancetotreatment, thesymptomsdidnotimproveandblackresiduesappearedinthe OEC.Fifteendayslater,duringanotorhinolaryngologyconsulta- tion,anearcleaningsuctionwasperformedandalocaltreatment with nystatin (Auricularum¹, Grimberg) was prescribed for 15days;eardropswereinstilledtwicedaily.Therewasamarked improvementbutclinicalsignsreappearedquickly.Microbiolog- icalexaminationwasundertakenandmycologicalculturesfroma swab taken from the OEC grew Aspergillus niger, which was identiﬁed morphologically according to standard descriptions [5].Thesamelocaltreatmentwasprescribedforafurther15days, along withcustom-madeearplugstopreventwaterpenetration intotheearcanalduringaquaticactivities.

InJuly2015,duringaconsultationinmycology,andfollowing another15-daycourseoflocalnystatin,ayellowishmaterialwas sampledfromtheleftOEC,butculturesremainedsterile.Despite clinical recurrence and signiﬁcantdiscomfort, thepossibility of JournaldeMycologieMe´dicalexxx(2018)xxx–xxx

* Correspondingauthor.

E-mailaddress:[email protected](S.Vrignaud).

ARTICLE INFO

Historiquedel’article: Received19December2017 Receivedinrevisedform21March2018 Accepted22March2018

Keywords:

Aspergillusniger Otomycosis Otitisexterna Voriconazole Nystatin

ABSTRACT

Fungalotitis(otomycosis)isacommoninfectionencounteredbyotolaryngologists.Nevertheless,its managementcanbechallengingbecauseofitshighrecurrence rateandofthelimitedtherapeutic options.A45-year-oldwomansufferedfromrecurrentotomycosis.Theineffectivenessofsuccessive antibioticcuresandrepeatedtopicaltreatmentswithnystatinandthenwitheconazolecreamledto performmicrobiologicalanalyses.CultureofearswabgrewAspergillusniger.Theuseofa1%voriconazole sterilesolutionpreviouslyvalidatedfortreatmentofeyeinfectionswasconsideredafterensuringthe absenceofknownototoxiceffectsoftheantifungalandoftheexcipients.Thepatientwasadvisedto applylocallythisvoriconazolesolutiondailyfor14days(3drops,3–4timesaday).Fullrecoverywas obtainedattheendofthetreatment,andnorelevantsideeffectswerenoticed.Morethanoneyearafter completionoftherapy,therewasnorecurrence.Ourobservationshowsthatvoriconazole1%solutionis aninterestingoptionfortreatingotomycosiswhichfailedto respondto usualtherapeutic options.

Furtherprospectivestudiesarenowwarrantedtoconﬁrmtheseﬁndings.

C 2018ElsevierMassonSAS.Allrightsreserved.

GModel

MYCMED-790;No.ofPages3

Pleasecitethisarticleinpressas:ChappeM,etal.SuccessfultreatmentofarecurrentAspergillusnigerotomycosiswithlocalapplication ofvoriconazole.JournalDeMycologieMe´dicale(2018),https://doi.org/10.1016/j.mycmed.2018.03.009

Availableonlineat

ScienceDirect

www.sciencedirect.com

https://doi.org/10.1016/j.mycmed.2018.03.009

1156-5233/^C 2018ElsevierMassonSAS.Allrightsreserved.

(2)

usinganoralantifungalagent(eitheritraconazoleorvoriconazole) was rejected given the potential side effects associated with systemicdeliveryandthelackofconsensusonitsimplementation inthis indication.The patientno longer usedtheearplugs and stoppedgoingtotheswimmingpool.

Seven months later, i.e., about one year post-onset of symptoms, the patient came back to our hospital. A total of 4clinicalrecurrenceswerenoticed,andthesymptomsworsened withthe appearanceof eczema-like lesions at thelevel of the tragusandantitragus,dischargeﬂowingdowntheleftearlobe,and severeitching.Blackish debris wereremovedfromtheleftear, allowingtherecoveryofA.nigeragainbycultures(Fig.1Aand1B).

Inthiscontext,anantifungalsusceptibilitytestingwasperformed onthepatient’sisolateusingnystatinandvoriconazolebythedisk diffusionandE-testmethods,respectively(Fig.1C).Averyslight inhibition zone(11mm)wasnoticedaround thenystatin disk, indicating little activity against this strain, which probably contributedtodiseaserelapses.Bycontrast,voriconazoleexhibi- ted excellent in vitro activity, with a minimal inhibitory concentrationof0.064

m

g/mL,whichismarkedlylowerthanthe epidemiological cutoff value reported for voriconazole against A.niger[6].Meanwhile,a treatmentwitheconazolecream was startedbutsuchformulationwasdifﬁculttoapplyduetothedeep, peritympanicspreadof thefungus.Thehospital pharmacy was contactedtoinvestigatethe possibilityof using anazole-based aqueoussolutionaseardrops.Finally,a1%voriconazoleophthal- micsolutionwaschosen,usedoutsideofmarketingauthorisation, afterexcludingototoxicityrisksduetotheeyedropcomponents.

Eardropswerethusprescribed,tobeaddedfor10to15minutes, 3to4timesadayfor14days.

Completerecoverywasachievedattheendoftreatmentwith voriconazolewithoutanysideeffects.TheskinoftheOECbecame normalandthepatientwasadvisedtoavoidswimmingforsome timeandreuseofthesiliconeearplugstopreventfurtherfungal colonization.Atthetwo-monthfollow-upvisit,otoscopicexami- nationwasunremarkableandearswabculturesremainedsterile, indicatingmycologicalcure.Morethanoneyearaftercompleting treatment,thepatienthadnorecurrenceofotitis.

3. Discussion

InFrance,nystatinistheonlyantifungallicensedasapowderor assuspension(incombinationwithoxytetracycline,polymyxinB anddexamethasone)forlocaltreatmentofotomycosis[7].Since otherantifungalsarenotavailable ina formulationsuitablefor auricularuse,theprescriptionofnystatinisrecommendedasthe first-line treatment of otomycosis for up to 15 days. Like amphotericin B, nystatin exhibits a broad spectrum including theaspergilliandCandidayeasts,whicharemostlyresponsiblefor otomycosis.However,lackofefficacyhasbeenreportedinseveral cases of Aspergillus otomycoses [8,9]. Several other ototopical antifungalsareavailableinsomecountries,butthemosteffective druginthiscontextremainstobedefined.Clotrimazoleisthemost widelyusedtopicalimidazole[9].IntheUSA,itisconsideredasthe drugofchoicefortreatmentofuncomplicatedotomycosis[10].It displaysahighinvitroactivityagainstmostyeastsandmolds[11]

andsuccessratesrangingfrom50%to100%havebeenreported [12–14].However,allthesestudieswereconductedonalimited numberofpatients,andeffectivenesswasoftenbasedonsymptom resolutionratherthanmycologicalassessments.

Consequently,whether ornottreatment failureswithclotri- mazolecouldbeattributedtoaparticularpathogen,i.e.,A.niger,is unknown. Miconazoleand bifonazole, as well as ciclopiroxolamine, can also be used. Compared to clotrimazole, the two imidazole drugs exhibit similar activity, but varying from one fungal species to another. For instance, del Palacio et al. [15]

investigatedtheefﬁcacyoftopicalbifonazoleon40infectedears andtheyfoundaclinicalcurefor72.5%ofthemwhilemycological cureratereached57.5%.Ofnote,duringlong-termfollow-up(2–5 years),10earswerere-infected,8ofthemwithA.nigeratbaseline.

Theseresultsareinlinewithanotherstudyalsoperformedbydel Palacio et al. [16]. Among the 40 infected earstreated with a ciclopiroxolamine-basedpreparation,seven(17.5%)relapseswere noticed, of which four (10%) were due to A. niger [16]. The effectiveness of ciclopiroxolamine versus miconazole was also investigated[17].Ciclopiroxolamineshowedanarrowerspectrum, sinceitinhibitedonly57%oftheselectedstrainscomparedto90%

withmiconazole[17].Terbinafinealsoshowedapotentinvitro antifungal activity against several aspergilli, including A. niger [18,19].Unfortunately,ototoxiceffectsoftopicallyadministered terbinafine have been reported in an animal model [20], thus limitingitsusefulnessinthefield.Unliketerbinafine,tolnaphtate wasnotototoxicinanimalmodels[12],butitisineffectiveagainst A.niger[11].

Inourcase,relapsecouldbeattributedtoaninsufﬁcientactivity of nystatin against the causative agent, as attested by our experimentaldata.Multiplerecurrencesofotomycosiscouldalso beexplainedbytheuseoforalandtopicalantibiotics,whichmay havedestabilizedthelocalﬂoraandpermittedfungalproliferation, orbytheuseofearplugsduringaquaticactivities,apossiblesource ofre-infection[12].

To treat these recalcitrant forms, prescribers must seek an alternativeamongtheantifungalmedicationsclassicallyusedby Fig.1.Mycologicalinvestigationsperformedonearwaxmass.A.Macroscopic

aspect of culture on Sabouraud’s agar, consistent with Aspergillus niger. B.

ObservationofanA.nigercolonywithabinocularmagniﬁer,showinghyaline conidiophoresbearing dark-brownconidial heads. C. Susceptibility testing of A.nigeragainstnystatin(diskdiffusion)andvoriconazole(E-test).

M.Chappeetal./JournaldeMycologieMe´dicalexxx(2018)xxx–xxx 2

GModel

(3)

anotherrouteofadministrationthantheoticroute,andtherefore beyondmarketing authorization.Such a procedurerequires the patient’s consent as well as the veriﬁcation of the tympanic membraneintegrity.Inthepresentcase,nystatintreatmentwas switchedtoeconazolecream,butitseffectwaslimitedduetopoor penetrationof this formulation into theOEC. Econazole is also availableasasolutionbut itisappliedusinga pressurizedvial, whichisnotsuitablefordirectapplicationintotheOEC.

Anothertherapeuticoptioncompatiblewithauricularapplica- tionandeffectiveontheisolatedfunguswasthereforesearched.

According to the European Pharmacopoeia, auricular solution intendedforapplicationtoaninjured earshouldbesterileand freeof antimicrobialpreservatives and shouldnot inducetoxic effectsorlocalirritation[21].Giventheurgencyofthesituation andtheresultsofantifungalsusceptibilitytesting,itwasdecided to investigate the opportunity of using a sterile voriconazole solutionpreparedbytheAP–HP(Assistancepublique-Hoˆpitauxde Paris,Paris,France)intheformofeyedropsinmulti-dosevials (8mL),andcontainingvoriconazole10mg/mLandbeta-cyclodex- trinsulfobutylethersodiumsalt160mg/mLasstabilizingagent.

Althoughtheeffectivenessoforalvoriconazoleforthetreatmentof Aspergillusotitishasbeenreported[22],atwelve-weekduration therapywasrequired,withtheriskofsideeffects.Conversely,the topicaluseofvoriconazolesolutionfortreatmentofotomycosis hasneverbeenreportedtodate.Thepharmacists’approachwasto checktheabsenceofototoxicity.Abibliographicalsearchdidnot revealototoxiceffectsregardingthelocaladministrationoftheeye dropsolutioncomponents,voriconazoleandcyclodextrin,which wasconﬁrmedby makinginquiriestoPﬁzer laboratory(which markets voriconazole products) and contacting the Regional Pharmacovigilance Centre. Furthermore, the physicochemical properties of this formulation wereconsidered to be safe and compatible with ear instillation (pH: 7.00.1, osmolarity:

56210mosm/L)[23].Finally,thistreatmentwasprescribed,which allowedtocurethepatient.Toourknowledge,thisisthefirstreport onthesafetyandefficacyofa1%sterilevoriconazolesolutiontotreat arecurrent,nystatin-resistantotomycosis.Thelocalapplicationof thismolecule avoids systemic treatment for an extended period, potentiallyresponsibleforundesirableeffects.Thesedatashouldbe confirmedbyalarger-scalestudyenrollingpatientswithrecurrent otomycosisunresponsivetostandardtreatments.

Disclosureofinterest

Theauthorsdeclarethattheyhavenocompetinginterest.

Acknowledgments

Writteninformedconsentwasobtainedfromthepatientfor publicationofthiscasereportandaccompanyingimages.Acopyof the consent form is available for review by the Editor of this journal.

We would like to thank M. Pihet for his help with picture editing.

References

[1]HoT,VrabecJT,YooD,CokerNJ.Otomycosis:clinicalfeaturesandtreatment implications.OtolaryngolHeadNeckSurg2006;135:787–91.

[2]KaurR,MittalN,KakkarM,etal.Otomycosis:aclinicomycologicstudy.Ear NoseThroatJ2000;79:606–9.

[3]KayaAD,KirazN.InvitrosusceptibilitiesofAspergillusspp.causingotomycosis toamphotericinB,voriconazoleanditraconazole.Mycoses2007;50:447–50.

[4]Yenis¸ehirliG,BulutY,Gu¨venM,Gu¨ndayE.Invitroactivitiesofﬂuconazole, itraconazoleandvoriconazoleagainstotomycoticfungalpathogens.JLaryngol Otol2009;123:978–81.

[5]deHoogGS,GuarroJ,FiguerasMJ,Gene´ J.Atlasofclinicalfungi,2nded.,Reus, Spain:CentraalbureauvoorSchimmelcultures,Utrecht,TheNetherlandsand UniversitatRoviraIVirgili;2000.p.1124.

[6]Espinel-IngroffA,Cuenca-Estrella M,FothergillA,FullerJ, GhannoumM, JohnsonE,etal.Wild-typeMICdistributionsandepidemiologicalcutoffvalues for amphotericinBand Aspergillus spp.forthe CLSIbroth microdilution method(M38-A2document).AntimicrobAgentsChemother2011;55:5150–4.

[7]HauteAutorite´ desante´,CommissiondelaTransparence.Avisdu16de´cembre 2015.Availableat:https://www.has-sante.fr/portail/upload/docs/evamed/

CT-12750_AURICULARUM_PIC_RI_REEV_Avis2_CT12750&14297.pdf [acces- sed7July2017].

[8]PauloseKO,AlKhalifaS,ShenoyP,SharmaRK.Mycoticinfectionoftheear (otomycosis):aprospectivestudy.JLaryngolOtol1989;103:30–5.

[9]MungiaR,DanielSJ.Ototopicalantifungalsotomycosis:areview.IntJPediatr Otorhinolaryngol2008;72:453–9.

[10]SanderR.Otitisexterna:apracticalguidetotreatmentandprevention.Am FamPhysician2001;63:927–36[941–2].

[11]SternJC,ShahMK,LucenteFE.Invitroeffectivenessof13agentsinotomycosis andreviewoftheliterature.Laryngoscope1988;98:1173–7.

[12]VennewaldI,KlemmE.Otomycosis:diagnosisandtreatment.ClinDermatol 2010;28:202–11.

[13]JackmanA,WardR,AprilM,BentJ.Topicalantibioticinducedotomycosis.IntJ PediatrOtorhinolaryngol2005;69:857–60.

[14]MofattehMR,NaseripourYazdiZ,YouseﬁM,NamaeiMH.Comparisonofthe recoveryrateofotomycosisusingbetadineandclotrimazoletopicaltreat- ment. Braz J Otorhinolaryngol 2017, 10.1016/j.bjorl.2017.04.004. http://

dx.doi.org/10.1016/j.bjorl.2017.04.004[pii:S1808-8694(17)30056-3].

[15]delPalacio A,Lopez-SusoMJ,MooreMK,CuetaraMS,Garcia-La Calle C, Noriega AR. Long-term follow-upof otomycosis and its treatment with bifonazole.JMedVetMycol1993;31:435–47.

[16]delPalacioA,Cue´taraMS,Lo´pez-SusoMJ,AmorE,GarauM.Randomized prospectivecomparativestudy:short-termtreatmentwithciclopiroxolamine (cream and solution) versus boric acid inthe treatment of otomycosis.

Mycoses2002;45:317–28.

[17]BassiounyA,KamelT,MoawadMK,HindawyDS.Broadspectrumantifungal agentsinotomycosis.JLaryngolOtol1986;100:867–73.

[18]KaraarslanA,ArikanS,OzcanM,OzcanKM.Invitroactivityofterbinaﬁneand itraconazoleagainstAspergillusspeciesisolatedfromotomycosis.Mycoses 2004;47:284–7.

[19]SzigetiG, Kocsube´ S,Do´czi I,BereczkiL,Va´gvo¨lgyiC,VargaJ. Molecular identiﬁcationandantifungalsusceptibilitiesofblackAspergillusisolatesfrom otomycosiscasesinHungary.Mycopathologia2012;174:143–7.

[20]AydınE,Tas¸tanE,AydogˇanF,KaracaG,AsımS¸afakM.Ototoxiceffectoftopical oxiconazoleandterbinaﬁneinrats.JOtolaryngolHeadNeckSurg2012;41:

78–83.

[21]Council of Europe.Ear preparations monograph. Eur Pharmacopoeia 90 2017;I:855–7.

[22]HoHC,HsiaoSH,LeeCY,TsaiCC.TreatmentofrefractoryAspergillusotomy- cosiswithvoriconazole:caseseriesandreview.JLaryngolOtol2014;128:

547–51.

[23]DupuisA,TournierN,LeMoalG,VenisseN.Preparation andstabilityof voriconazole eye drop solution. Antimicrob Agents Chemother 2009;53:798–9.

M.Chappeetal./JournaldeMycologieMe´dicalexxx(2018)xxx–xxx 3

GModel