www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
ORIGINAL
ARTICLE
Comparison
of
the
recovery
rate
of
otomycosis
using
betadine
and
clotrimazole
topical
treatment
夽
Mohammad
Reza
Mofatteh
a,
Zahra
Naseripour
Yazdi
b,
Masoud
Yousefi
c,
Mohammad
Hasan
Namaei
c,∗aBirjandUniversityofMedicalScience,SchoolofMedicine,DepartmentofEars,NoseandThroat,Birjand,Iran bBirjandUniversityofMedicalSciences,SchoolofMedicine,Birjand,Iran
cBirjandUniversityofMedicalScience,InfectiousDiseasesResearchCenter,Birjand,Iran
Received21February2017;accepted12April2017 Availableonline6May2017
KEYWORDS Otomycosis; Topicalbetadine; Topicalclotrimazole; Recoveryrate Abstract
Introduction:Otomycosisisacommondiseasesthatcanbeassociatedwithmanycomplications includinginvolvementoftheinnerearandmortalityinrarecases.Managementofotomycosis canbechallenging,andrequiresaclosefollow-up.Treatmentoptionsforotomycosisinclude localdebridement,localandsystemicantifungalagentsandutilizationoftopicalantiseptics.
Objective:This study was designed tocompare therecovery rateofotomycosis using two therapeuticmethods;topicalbetadine(Povidone-iodine)andclotrimazole.
Methods:Inthissingle-blindclinicaltrial,204patientswithotomycosis wereselectedusing anon-probabilityconvenientsamplingmethodandwererandomlyassignedtotwotreatment groupsoftopicalbetadineandclotrimazole(102patientsineachgroup).Responsetotreatment wasassessedat4,10and20daysaftertreatment.Datawereanalyzedusingtheindependent
t-test,Chi-SquareandFisherexacttestinSPSSv.18software,atasignificancelevelofp<0.05.
Results:Theresultsshowedthatoutof204patientswithotomycosis,fungitypeisolated inclu-dedAspergillusin151cases(74%),andCandidaalbicansin53patients(26%).Onthefourth dayaftertreatment,13patients(13.1%)inthegrouptreatedwithbetadineand10patients (9.8%)inthegrouptreatedwith clotrimazoleshowedagoodclinicalresponsetotreatment (p=0.75).Agoodresponsetotreatmentwasreportedfor44(43.1%)and47patients(46.1%) onthetenthdayafterthetreatment(p=0.85);and70(68.6%)and68patients(67.6%)onthe
夽 Pleasecitethisarticleas:MofattehMR,YazdiZN,YousefiM,NamaeiMH.Comparisonoftherecoveryrateofotomycosisusingbetadine
andclotrimazoletopicaltreatment.BrazJOtorhinolaryngol.2018;84:404---9.
∗Correspondingauthor.
E-mail:mhnamaei@hotmail.com(M.H.Namaei).
PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial. https://doi.org/10.1016/j.bjorl.2017.04.004
1808-8694/©2017Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
twentiethdayaftertreatment(p=0.46)inthegroupstreatedwithbetadineandclotrimazole, respectively.Theresponsetotreatmentwasthusnotsignificantlydifferentinthetwogroups.
Conclusion: Inthepresentstudytheefficacyofbetadineandclotrimazolewasthesameforthe treatmentofotomycosis.Theresultofthisstudysupportstheuseofbetadineasaneffective antifungalinotomycosistreatment,helpingtoavoidtheemergenceofresistantorganisms. © 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
PALAVRASCHAVE
Otomicose; Betadinatópica; Clotrimazoltópico; Taxaderecuperac¸ão
Comparac¸ãodataxaderecuperac¸ãodeotomicosecomousodetratamentotópico combetadinaeclotrimazol
Resumo
Introduc¸ão: Aotomicoseéumadasdoenc¸ascomunsassociadasamuitascomplicac¸ões,como envolvimentodaorelhainternaemortalidadeemcasosraros.Otratamentodaotomicosepode serrealmentedesafiadorerequerumacompanhamentorigoroso.Asopc¸õesdetratamentopara otomicosepodemincluirdesbridamentolocal,agentesantifúngicoslocaisesistêmicoseusode antissépticostópicos,osmedicamentostópicosrecomendadosparaotratamentodaotomicose.
Objetivo: Compararataxaderecuperac¸ãodeotomicoseutilizandodoismétodosterapêuticos debetadinatópica(Povidona-iodo)eclotrimazol.
Método: Nesteensaioclínicosimplescego,204pacientescomotomicoseforamselecionados utilizando-se um métododeamostragemde nãoprobabilidade convenienteerandomizados para doisgrupos detratamento,combetadina tópicae comclotrimazol(102pacientesem cadagrupo).Arespostaaotratamentofoiavaliadaaos4,10e20diasapósotratamento.Os dadosforamanalisadosutilizandootestetindependente,qui-quadradoetesteexatodeFisher nosoftwareSPSSv.18,comníveldesignificânciadep<0,05.
Resultados: Osresultadosmostraramquedos204pacientescomotomicose,ostiposde fun-gos isoladosincluíram Aspergillusem 151casos (74%) e Candida albicans em 53 pacientes (26%).Noquartodiaapósotratamento,13pacientes(13,1%)nogrupotratadocombetadinae 10 pacientes(9,8%) nogrupo tratadocomclotrimazol apresentaram boarespostaao trata-mento(p=0,75).Umaboarespostaaotratamentofoirelatadapara44(43,1%)e47pacientes (46,1%)nodécimo diaapósotratamento(p=0,85);e70(68,6%)e68 pacientes(67,6%)no vigésimodia apósotratamento(p=0,46)nogrupotratadocombetadinaeclotrimazol, res-pectivamente.Assim,arespostaaotratamentonãofoisignificativamentediferentenosdois grupos.
Conclusão:Nopresenteestudo,aeficáciadabetadinaedoclotrimazolfoiamesmano trata-mentodaotomicose.Oresultadodesteestudoapoiaousodebetadinacomoumantifúngico eficaznotratamentodaotomicosequepodeajudaraevitarosurgimentodeorganismos resis-tentes.
© 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Publicado por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http:// creativecommons.org/licenses/by/4.0/).
Introduction
External ear infection is a common inflammation of the external ear canaland auricle that occurs due tovarious localinfectionsfactorsorasamanifestationofasystemic disease.About 10% ofpeople suffer frominfectionof the externalearcanalintheirlives,90%ofwhichisunilateral.1,2
Fungalinfectionofexternalearcanal(Otomycosis)isa com-mondiseaseaccountingfor9%3,4to27.2%5ofpatientswith
signsandsymptomsofexternalotitismediareferredtoEar, Nose and Throat (ENT) centers.The infection is also the causeofmorethan30%ofpatientswitheardischargeand is acommoncauseof resistancetotreatment ofexternal
otitis.6Otomycosisisusuallycausedbypredisposingfactors,
suchasentryofforeignbodiesintotheearcanal, trauma-ticinseminationofwoodparticles,plantmaterialsanddirt intotheearcanal,scratchingandmanipulationoftheear canalwithnon-sterile equipment,living in dusty areas or wetatmosphere,humidityoftheearcanalafterswimming and bathing, and fungal nail infection and dermatophitic lesionsaroundtheear.7,8
Otomycosisisassociatedwithmanycomplications inclu-ding involvement of the inner ear withmortality in rare cases.Formationofa fungusball orfungal massof myce-lia, epithelial cells, and wax in the ear canal: exposure of this mass to the tympanic membrane are causes of
hearingloss.Neck skinandearcartilagearealsoaffected inacute infections.In chronic cases,a falseveil ofyeast indifferentcolors(depending onthetypeof fungus)may occurintheearcanal.Themycosiscanhaveapoor progno-sisinimmunocompromised individuals, especiallyincases ofcellularimmunodeficiencyandneutropenia.Thedisease presents many challenges, both for patients and for ENT specialists,andmayrecurdespitelong-termtreatmentand follow-up.9---11
The main treatment of otomycosis is the removal of visible debris and fungal elements. Topical medications recommendedforthecontrolofthisconditioninclude ste-roids, antiseptics, acidic solutions, antifungal agents and driers.Antifungalmedicationsofotomycosisdonotalways curethediseaseandinadditiontreatmentshouldimprove thephysiologicalsignsofexternalearcanal.12,13Usingboric
acidinan alcohol solutionforthe treatmentof diseaseis associated with 23% recurrence rate. Furthermore, using antifungalsolutions,suchasclotrimazoleornystatin,may beeffective for the treatment of Candidainfections, but
Aspergillusinfectionsrespondpoorlytotreatment.14,15This
iswhileawiderangeoffungihavebeenreportedtocause otomycosis and the most common species is Aspergillus.
Therefore,an appropriatetreatmentregimenis necessary fortreatment.Ontheotherhand,widespreadand unneces-saryuseofantibacterialtreatmentformedialandexternal otitis may cause fungal overgrowth in this area, so the adverseeffectsofusingwide-spectrumantibiotics arethe secondaryovergrowthoffungusandincreasingprevalence ofotomycosis.16,17
Given the importanceof otomycosis treatment asone ofthe challenges facingENTspecialists, thisstudy aimed tocompare the recovery rateof otomycosis using topical betadineandclotrimazole.
Methods
Studygroup
Thissingle-blindclinicaltrialwasconductedon204patients witha definitive diagnosis of otomycosis. After receiving permission from the Ethics Committee of the University and recording in Iranian Registry of Clinical Trials by the registration number (IRCT2014123020484N1), the partici-pantswereselectedfromthosereferredtotheENTclinic of Imam Reza and Vali-Asr Hospitals of Birjand Univer-sity of Medical Sciences during the first six months of 2014. Patientswith clinical signs and symptoms including pain,itching, mass in the external auditory canal, stuffy feelingassociatedwithhearinglossanddischargewere con-sidered suspicious for otomycosis. The objectives of the study were explained to the participants and they were recruited into the study if they were willing to partici-pate and had none of the exclusion criteria, including: otitismediawithrestrictionofexternalearcanal,chronic mucusfromear,historyofearsurgery,historyoftreatment withantifungalagentsandcorticosteroids,andexternalear anomaly.
Afterrecordingthedemographiccharacteristicssuchas age, sex, and obtaining informed consent, a total of 204 patientswithotomycosiswereenrolledintothestudyand
recruitedintooneofthetwotreatmentgroups(102patients ineachgroup)byblockingrandomization. All204enrolled patientssignedinformedconsentforms.
Collectionofsamples
Sampleswere takenby aspecialspeculumfromthe mass intheearcanal.Furthermore,inthepresenceof pusand mucus,thesewerealsoseparatedinasterilecontainerand senttospecializedlaboratoriesofmycologyofBirjand Uni-versityofMedicalSciences(BUMS).
Mycologicalinvestigation
Inthelaboratory,thesampleswereevaluatedbya microbio-logyspecialistusingKOHmethod,andthepresenceoffungal elementswasconsideredasdefinitediagnosisofotomycosis. Aportionofthesamplewasspreadonacleanslideglass fordirectexaminationandanothersampleinoculatedinthe Sabouraud dextroseagar (Merck, Germany) supplemented withchloramphenicol(Fina Daru,Iran) medium forfungal growth.Theplateswereincubatedatroomtemperaturefor twoweeks.Fungiwereidentifiedbystandardprocedures.18
Furthermore,germtubesonhumanseraandproductionof vesiclesoncornmealagar(Merck,Germany)supplemented withtween80(Sigma-Aldrich,Germany)weredoneforthe identificationofyeast.
Recoveryrateofotomycosis
Inthestudy,onepatientgroupwastreatedwith povidone-iodine sothat at eachvisit, thepatient’searwaswashed by thephysicianusing10mLbetadine solution10%witha syringe.Theothergroupreceived8dropsofantifungal clo-trimazole,everyeighthours.Patientswereexaminedon4, 10and20daysaftertreatmentbyanENTspecialistwhodid notknow aboutthetypeof treatment.The patientswere categorized intothree groups based on clinical response: good response (dry external ear canal and the tympanic membrane and lack of secretion),partial response(slight dischargebutnotdry),andnoanswer(hypersecretioninthe external auditorycanal). Ifcomplete response,the treat-mentwasdiscontinued;otherwisetreatmentwascontinued. Finallynon-responderswereconsideredtreatment-resistant onthetwentiethdayandtreatmentregimenwascontinued withTolnaftateandVioletdegentian.
Statisticalanalysis
Inthepresentstudy,toanalyzethedescriptivedata,tables andchartsofdistributionfrequencyandfortheinferential part, theindependentt-test, Chi-squareand Fisher exact test wereusedinSPSSv.18software.Thesignificant level wasconsideredatp<0.05.
Results
In this study, a total of 204 patients with otomycosis wereinvestigatedintwotreatmentgroupsofbetadineand clotrimazole (102 patients in each group). Overall, 86
Table1 Comparisonofdemographiccharacteristicsanddistributionoffungiinpatientswithotomycosisbasedonthetreatment type.
Demographiccharacteristics Topicalbetadinegroup(%) Topicalclotrimazolegroup(%) p-Value
Age(years)a 38.61±15.45 40.37±16.15 0.43 Gender 0.40 Male 40(39.2) 46(45.1) Female 62(60.8) 56(54.9) Fungalagent 0.63 Aspergillusspp. 77(75.4) 74(72.5) Candidaalbicans 25(24.5) 28(27.5)
a Valuesintablearemean±SD.
Table2 Comparisonofresponsetotreatmentonthefourth,tenthandtwentiethdayaftertreatmentinpatientsbasedonthe treatmenttype.
Courseoftreatment Typeoftreatment Responsetotreatment p-Value
Noresponse(%) Partialresponse(%) Goodresponse(%)
4days Betadinea 31(31.3) 55(55.6) 13(13.1) 0.75 Clotrimazole 32(31.4) 60(58.8) 10(9.8) 10days Betadine 8(7.8) 50(49) 44(43.1) 0.85 Clotrimazole 9(8.8) 46(45.1) 47(46.1) 20days Betadine 13(12.7) 19(18.6) 70(68.6) 0.46 Clotrimazole 9(8.8) 25(24.5) 68(66.7)
a Threepatientsdidnotattendonthefourthdayafterthetreatment.
(42.15%) of the patients withotomycosis were males and 118 (57.85%) were females. The average age of patients in two groups treated with betadine and clotrimazole was 38.61±15.45 and 40.37±16.15 years old, respecti-vely. In this study, Aspergillus spp. was responsible for 75.4% and Candida albicans for 24.5% of otomycosis in the patient group treated with betadine. Prevalence of
Aspergillusspp.andC.albicanswasreportedfor72.5and 27.5percentagesofpatientswithotomycosistreatedwith clotrimazole.
Overall,thestudyshowednosignificantdifference accor-dingtoage(p=0.43),sex(p=0.4)andthecausativeagent of otomycosis(p=0.63)between twotreatment groupsof betadineandclotrimazole(Table1).
Inthestudy,recoveryrateofotomycosiswasevaluated intwotreatmentgroupsofbetadineandclotrimazole.The results demonstrated that on the fourth day after treat-ment,13patients(13.1%)inthegrouptreatedwithbetadine and10patients(9.8%)inthegrouptreatedwithclotrimazole hadagoodresponsetotreatment(p=0.75).Agoodresponse totreatment wasreportedfor 44(43.1%) and47patients (46.1%)onthetenthdayafterthetreatment(p=0.85);and 70(68.6%)and68patients(67.6%)onthetwentiethdayafter treatment(p=0.46)inthegrouptreatedwithbetadineand clotrimazole,respectively.Itisnoteworthythatinnoneof the patients treated with betadine any side effects were observed.
Inourstudy,therewasnostatisticallysignificant diffe-renceintermsofresponsetotreatmentinthefourth,tenth
andtwentiethdayaftertreatmentbetweentwotreatment groupsofbetadineandclotrimazole(p<0.05)(Table2).
Discussion
Otomycosisisoneofthecommondiseasesthatare associa-tedwithmany complicationsincludinginvolvementofthe innerearandmortalityinrarecases.Thediseasepresents manychallenges,bothforpatientsandforENTspecialists, andmayrecurdespitetheconcernforlong-termtreatment andfollow-up.9,11
Resultsofthisstudyshowedthatamong204patientswith otomycosis,Aspergillus spp. wasresponsible for 74% (151 cases)and C. albicansfor 26% (53patients) of the infec-tion.InthePradhanetal.study,AspergillusspeciesandC. albicanswerereportedasthemostcommonspeciesoffungi isolatedfrompatientswithotomycosisin2003.19 Thestudy
conductedby Satish and colleagues showedthat Aspergi-llusspecies(77%)wasthemost commonlyisolatedfungus intheimmunocompetentgroupwhileCandida(53.4%)was commonlyisolatedintheimmunocompromisedgroup.20 In
anotherstudy on95patientssuspectedofhavingthe fun-galinfection,72casesoffungalcultureswerepositiveand
Aspergilluswasidentifiedasthemostcommonfungusgrown inculture(41.1%)andC.albicanswasinthenextgrade,with aprevalence of8.2%.21The resultsofourstudywere
con-sistentwiththeresultsabove.Aspergillusspeciesareone ofthemostcommoncausesofopportunisticinvasivefungal infections,especiallyotomycosis.Thismaybeduetoitshigh
prevalenceindustandtheacidicnatureoftheearcanal, asAspergillusspeciesgrowinpH5to7.22
Aftercompletionofthetreatmentcourseinthepresent study,theresultsshowedthatonthefourthdayafter treat-ment,55.6% and 58.8% of patients treated withbetadine andclotrimazolehadpartialresponsetotreatment, respec-tively.Inaddition,onthetenthdayaftertreatment,49%of patientstreatedwithpovidone-iodinehadpartialresponse totreatment, and 46.1% of patientshad a goodresponse totreatment with clotrimazole. Finally, onthe twentieth dayaftertreatment, 68.6%of patientstreatedwith beta-dineand 66.7% of patients treated withclotrimazole had goodresponsetotreatment.Overall,inourstudytherewas nostatisticallysignificant difference interms ofresponse totreatment inthefourth, tenthandtwentiethdayafter treatmentbetweentwotreatment groupsofbetadineand clotrimazole.Regardingtheantifungaltreatmenteffecton otomycosis,severalstudieshavebeenconductedsofar.In asingle-blindrandomizedclinicalstudy,theeffectof beta-dine7.5%incomparisonwithclotrimazole1%andlignocaine wasevaluatedonpatientswithotomycosis.Afterthe treat-mentperiod,inthebetadinepatientsgroup,thesymptoms ofitching,dischargefromtheear,earfullness,tinnitusand deafnessweretreated in83.3%,97.1%, 83.3%,91.7%,and 91.7%ofcases,andearpainwastreatedin100%ofcases. While,inpatientstreatedwithclotrimazoleandlignocaine drops,thesymptomsofitching,eardischargeandfullness werecuredin93.3%,earpainin86.7%andtinnitusin100% ofcases.23Inanotherstudy,thetherapeuticeffectof
mico-nazole ointment and clotrimazole drop was compared in patients withotomycosis. All patients were examined for responsetotreatmentoneandtwoweeksaftertreatment. Theresultsofthefinalanalysisshowedthatandtherewas nodifferencein terms ofresponse totreatment between thetwotreatment groups.24 Sternandcolleagues
demons-tratedthatclotrimazole waseffectiveagainstmostyeasts andmoldsbuttolnaftatehadnoimpactonotomycosis.25In
anotherstudy,clotrimazoleandeconazolwerecitedasthe drugofchoiceinthetreatmentofotomycosis.26
Accordingtotheabove-mentionedissues,itcanbe decla-redthat the treatment of otomycosisis today oneof the challenges facing ENT specialists, as a great number of fungalinfections ofexternalearareresistanttothe avai-lableantifungaldrugs.Otomycosistreatmentrequiresearly detectionand timely treatment of patients regarding the possibilityofdrugresistanceinchronicinfections.Itshould benotedthatthe basisof thetreatment ofotomycosis is keepingtheeardryandtheearhygiene,andtheappropriate treatmentprotocol shouldbeconsidered accordingtothe differenttypesoffungicausingthediseaseandsensitivityto differentantifungaldrugs.16,27Inourstudy,clotrimazoleand
povidone-iodinewereusedastwodrugregimensfor treat-mentofotomycosis.Clotrimazoleisamedicinecontaining azolegroupsthatisusedtotreatinfections.Betadineisalso aremedyforinfectionsthatiseasilyaccessibleanditseffect hasbeenprovenonchronicsuppurativeotitismediaasthe precipitatingfactors of otomycosis. This drug is a stable, inexpensivesubstance,andbacterialandfungalresistance toit hasnot yet been reported. Therefore,betadine can bea good choice for otomycosis treatment in developing countries, due to its low cost, effectiveness and lack of ototoxicity.28,29
Conclusion
Accordingtotheresults,efficacyofbetadineand clotrima-zoleregimenswasidenticalintreatmentofotomycosis.Our findingsreinforcetheuseofbetadineforotomycosis treat-mentduetocost-effectivenessandappropriatetherapeutic effectonAspergillusspeciesandC.albicans,themost com-moncausesofotomycosis.Suchtreatmentcanhelptoavoid theemergenceofresistantorganisms.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgments
ThisresearchwassupportedbyBirjandUniversityofMedical Sciences,Birjand,Iran(Grantno.657).
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