REVIEW ARTICLE

d

a,

McGill Auditory Sciences Laboratory, McGill University, Montreal, Qc., Canada H3H1P3

Contents

1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4532. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454

2.1. Symptoms and predisposing factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4542.2. Causal agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4542.3. Topical treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454

tions, sometimes involving the middle ear. The pre-

The extensive and sometimes unnecessary use of

International Journal of Pediatric Otorhinolaryngology (2008) 72, 453459

identified organisms. Antifungals from the Azole class seem to be the most effective,followed by Nystatin and Tolnaftate.# 2007 Elsevier Ireland Ltd. All rights reserved.H3H1P3. Tel.: +1 514 412 4304; fax: +1 514 412 4342.1. Background

Otomycosis, also known as fungal otitis externa, hasbeen used to describe a fungal infection of theexternal auditory canal and its associated complica-

valence of otomycosis has been reported to be aslow as 9% of cases of otitis externa [1], and as high as30.4% in patients presenting with symptoms of otitisor inflammatory conditions of the ear [2]. Preva-lence is also related to the geographical area, asotomycosis is most commonly present in tropical andsubtropical humid climates.

* Corresponding author at: McGill University, Department ofOtolaryngology, 2300 Rue Tupper B-240, Montreal, Qc., Canada3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458bMcGill University, Department of Otolaryngology, Montreal, Qc., Canada H3H1P3

Received 13 September 2007; received in revised form 12 December 2007; accepted 14 December 2007Available online 14 February 2008

KEYWORDSOtomycosis;Ototopical;Antifungals;Ototoxicity

Summary There has been an increase in the prevalence of otomycosis in recentyears. This has been linked to the extensive use of antibiotic eardrops. Treatment ofotomycosis is challenging, and requires a close follow-up. We present a review of theliterature on otomycosis, the topical antifungals most commonly used, and discusstheir ototoxic potential. Candida albicans and Aspergillus are the most commonlyaOtotopical antifungals an

Raymundo Munguia a, Sam J. DanielE-mail address: sam.daniel@mcgill.ca (S.J. Daniel).

0165-5876/$ see front matter # 2007 Elsevier Ireland Ltd. All rigdoi:10.1016/j.ijporl.2007.12.005otomycosis: A review

b,*

www.elsevier.com/locate/ijporlantibiotic eardrops for the treatment of otitis media

hts reserved.

and otitis externa has been linked to the important

related articles published between January 1951and March 2007. The resulting set of 576 articles

tion, diabetes, increased use of ototopical antibio-

454 R. Munguia, S.J. Danielwas then restricted to those using topical antifun-gals. Electronic search with topical antimycotic ORotomycosis OR antifungal drops OR antifungal ear-drops identified 96 studies, of which 18 wereconsidered appropriate for review. Selected articleshad to specify the number of patients presentingwith otomycosis, the topical medication used, andthe efficacy of the treatment. Reviewing individualcited references identified additional studies.

We present in this article a summary of the datain the literature with regards to the topical treat-ment of otomycosis, the treatment efficacy, and therisk of ototoxicity.

2.1. Symptoms and predisposing factors

The most prominent symptoms present at the timeof diagnosis were: otalgia, otorrhea, hearing loss,aural fullness, pruritus, and tinnitus [1,2,4]. Veryoften, fungal external ear infections manifest onlyin the presence of predisposing factors. Some iden-tified culprits include humid climate, presence ofcerumen acting as a support for fungal growth,configuration of the ear canal, weak immune func-increase in the prevalence of otomycosis. Secondaryovergrowth of fungi is a well-known and recognizedcomplication of the use of broad-spectrum antibio-tics like quinolones [3].

To date, there are four main classes of drugs forthe treatment of fungal infections: polyenes, tria-zoles, nucleoside analogues, and echinocandins.The polyenes family includes amphotericin B andnystatin. The triazoles family, better known asazoles includes: fluconazole, clotrimazole andmico-nazole. The mechanism of action of the polyenesand azole families involves an essential chemicalcomponent called ergosterol found in the fungal cellmembrane. The drug binds to ergosterol and createsa polar pore in the fungal membranes. This causesions (predominantly K+ and H+) and other moleculesto leak out of the cell, leading to its death. Thenucleoside analogues such as flucytosine work byinterfering with nucleotide synthesis; a key step incell energy production, metabolism, and signaling.Finally, the echinocandins are a novel class of anti-fungal agents. Their mechanism of action involvesinterference with cell wall biosynthesis. Their use inotomycosis has not been reported.

2. Methods

We performed a MEDLINE search for otomycosis-tics, and prolonged use of broad-spectrumantibiotics such as fluoroquinolones. Other factorsthat predispose patients to otomycosis include:pregnancy, use of systemic steroids, presence ofopen mastoid cavities, hearing aids with occlusivemolds, trauma, and bacterial infections. Severalrecent articles have also established the potentialrisk of autoinoculation of the ear canal by patientssuffering of dermatomycoses [1,5].

2.2. Causal agents

Many species of fungi have been identified as thecause of otomycosis in the literature reviewed.These are listed in Table 1 along with the antifungalagent utilized for each study. Aspergillus niger andCandida albicans are the most common causativeagents of otomycosis. Aspergillus is considered thepredominant causal organism in tropical and sub-tropical regions [6]. Aspergillus niger is the mostcommonly described agent in the literature [7,8].

Many authors believe that it is important toidentify the causal agent of otomycosis in order touse the appropriate treatment. It is also recom-mended that the antimycotic treatment chosenshould be based on the susceptibility of the identi-fied species [9,10]. However, others believe that themost important therapeutic strategy is to select aspecific treatment for otomycosis based on theefficacy and characteristics of the drug regardlessof the causal agent [11,12].

2.3. Topical treatments

To date there is no FDA approved antifungal oticpreparation for the treatment of otomycosis. Manyagents with various antimycotic properties havebeen used, and clinicians have struggled to identifythe most effective agent to treat this condition.Antifungal agents typically reach some popularityfor a short period of time, until non-desirable sideeffects are identified or until a new medicationappears on the market. However, the use of fewtopical antifungals has persisted throughout time,including Nystatin and the azoles family. In additionto topical therapy, the reviewed literature empha-sized the importance of aural hygiene in the treat-ment of otomycosis, as intuitively ototopicalmedications work best following cleaning of secre-tions and debris [1,13].

Table 2 summarizes the studies using topicalantifungal agents, the dosage utilized, and theefficacy of treatment.

Azoles are synthetic agents that reduce the con-centration of ergosterol, an essential sterol in the

Ototopical antifungals and otomycosis 455

Table 1 Otomycosis: description of the most common causal agents and treatment

le

ole

leCausal agent Treatment

Aspergillus (species not specified) Clotrimazo

Ketoconaz

Itraconazonormal cytoplasmic membrane. They are a class offive-membered nitrogen heterocyclic ring com-pounds containing at least one other noncarbonatom, nitrogen, sulfur or oxygen [14]. Clotrimazoleis the most widely used topical azole [15,16]. Itappears to be one of the most effective agents

Clotrimazole

Aspergillus flavus Itraconazole,

Aspergillus fumigatus MiconazoleAmphotericinAcetic acidClotrimazole

Tolnaftate

Aspergillus niger BorneolTolnaftateCiclopiroxolamItraconazoleMercurochrom

Boric acidClotrimazole5-FluorocytosItraconazole,FluconazoleAmphotericinThimerosal

Aspergillus terreus Lanoconazole

Candida albicans Ketoconazole

ThimerosalAmphotericin

Clotrimazole

ItraconazoleFluconazoleTolnaftateAcetic acid

Candida parapsilosis Clotrimazole,Fluconazole

Scedosporium apiospermum Clotrimazole

Scopulariopsis brevicaulis NystatinAuthor

Ologe and Nwabuisi [17]Bassiouny et al. [10]Nong et al. [19]Ho et al. [1]Nong et al. [19]for the management of otomycosis, with a reportedrate of effectiveness that varies from 95% to 100% inmost studies [6,10] with the exception of one studyreporting a lower efficacy rate of 50% [3]. Clotri-mazole has an antibacterial effect, and this is anadded advantage when treating mixed bacterial

Schrader (2003)

terbinafide Karaarslan et al. [24]

Dyckhoff et al. [21]B Kintzel et al. [26]

Jackman et al. [3]Jackman et al. [3]Martin et al. [13]Martin et al. [13]

Chang and Li [7]Damato [30]

ine, boric acid del Palacio et al. [37]Hoshino and Matsumoto [8]

e Mgbor and Gugnani [4]Mishra et al. [32]Ozcan et al. [5]Pradhan et al. [15]

ine Than et al. [38]terbinafide Karaarslan et al. [24]

Kurnatowski and Filipiak [2]B Ette et al. [27]

Tisner et al. [31]

Egami et al. [14]

Cohen and Thompson [20]Ho et al. [1]Tisner et al. [31]

B Ette et al. [27]ODay (2004)Jhadav (2003)Schrader (2003)Bassiouny et al. [10]Ologe and Nwabuisi [17]Jackman et al. [3]Martin et al. [13]Nong et al. [19]Kurnatowski and Filipiak [2]Martin et al. [13]Jackman et al. [3]

tolnaftate Martin et al. [13]Kurnatowski et al. [2]

Bhally et al. [16]

Besbes et al. [25]

456R.Mungu

ia,S.J.

Dan

iel

Table 2 Otomycosis: topical treatment efficacy represented in percentage

Author Study design Antifungal Posology Number ofpatients

Efficacy(%)

Jadhav et al. [6] Prospective Clotrimazole 1% solution 4 drops tid 1 month 79 100Piantoni et al. [23] Prospective Bifonazole 1% solution, once a day 415 days 23 100Nong et al. [19] Randomized prospective Miconazole Once a day 2 weeks 110 97.6

Ketoconazole Once a day 2 weeks 97.5Clotrimazole Once a day 2 weeks 90Thymol alcohol Three times per day for 2 weeks 80

Ologe and Nwabuisi [17] Prospective Clotrimazole 1% cream once a day 2 weeks 141 96Kley [18] Prospective Clotrimazole 0.25 mg/ml once a day 812 days 39 94.8Tisner et al. [31] Prospective Thimerosal Not reported 152 93.4Than et al. [38] Prospective 5-Fluorocytosine 10% ointment 710 days 189 90Ho et al. [1] Retrospective Cresylate otic Three times per day 13 weeks 51 86

Ketoconazole otic 13 cc one application 1 week 48 95Aluminium acetate otic 0.5% solution 13 weeks 18 86

Kurnatowski et al. [2] Prospective Fluconazole 0.2% solution/three times per day 21 days 96 89.4Mgbor and Gugnani [4] Randomized prospective Locacorten-vioform 1% solution every other day 710 days 23 66.6

Mercurochrome 1% solution every other day 710 days 23 95.8Clotrimazole 1% solution every other day 710 days 24 75

del Palacio et al. [37] Randomized prospective Cyclopirox olamine 11% cream 1 week 20 80Cyclopirox olamine 1% solution 1 week 20 95Boric acid 1 week 40 72.5

Ozcan et al. [5] Prospective Boric acid 4% solution in alcohol 87 77Cohen and Thompson [20] Prospective Ketoconazole Not reported 9 100

Jackman et al. [3] Retrospective Acetic acid otic Not reported 15 40Clotrimazole 8 50Nystatin 2 50Aluminium acetate otic 1 0

Bhally et al. [16] Case report Clotrimazole 0.25 mg/ml 1 100Mishra et al. [32] Case report Mercurochrome 1% solution 1 100Dyckhoff et al. [21] Review Miconazole 0.25% solution

Bassiouny et al. [10] In vitro Clotrimazole otic 014 mg/ml 100Econazole 1% solution 100Miconazole 0.14 mg/ml 90Cyclopirox olamine otic Not reported 57

Egami et al. [14] In vitro Lanoconazole 0.1 mg/ml 100

fungal infections. It is considered free of ototoxiceffects [17,18]. There are no reports of clinicalevidence of clotrimazole ototoxicity. Clotrimazoleis available as a powder, a lotion, and a solution.

Ketoconazole and fluconazole are azole antifun-gal agents that have a broad spectrum of activity.This family of chemical components is effective intreating the most common etiological agents of

otomycosis. Ketoconazole has shown an efficacyof 95100% in vitro against Aspergillus speciesand Candida albicans; it is available as a 2% cream.[1,19,20]. Topical fluconazole has been reportedeffective in 90% of cases in several series. Flucona-zole suspension is available with either 350 mg or1400 mg of fluconazole. After reconstitution with24 ml of distilled water or purifiedwater (USP), each

Ototopical antifungals and otomycosis 457

Table 3 Otomycosis treatment and risk of ototoxicity

Antifungal Tested for ototoxicity Author

5-fluorocytosine Not tested Than et al. [38]

Acetic acid otic Ototoxic Jackman et al. [3]Jinn et al. [36]

Aluminium acetate otic Non ototoxic Ho et al. [1]Jackman et al. [3]

Amphotericin B Not tested Nong et al. [19]

Bifonazole Not tested Piantoni et al. [23]

Boric Acid Ototoxic del Palacio et al. [37]Ozcan et al. [5]

Clotrimazole Non ototoxic Bhally et al. [16]Jackman et al. [3]Tom [29]Mgbor and Gugnani [4]Ologe and Nwabuisi [17]Bassiouny et al. [10]Jadhav et al. [6]

Cresylate otic Ototoxic Ho et al. [1]

Cyclopirox olamine 1% otic Not tested Bassiouny et al. [10]del Palacio et al. [37]

Cyclopirox olamine 11% otic Not tested del Palacio et al. [37]Econazole Not tested Bassiouny et al. [10]

Fluconazole Non ototoxic Kurnatowski et al. [2]Nong et al. [19]

Itraconazole Not tested Nong et al. [19]

Ketoconazole Non ototoxic Cohen and Thompson [20]Nong et al. [19]Ho et al. [1]

Lanoconazole Not tested Egami et al. [14]

Locacorten-vioform Ototoxic Mgbor and Gugnani [4]

Mercurochrome 1% Non ototoxic (FDA banned) Mgbor and Gugnani [4]Mishra et al. [32]

Miconazole Non ototoxic Bassiouny et al. [10]Dyckhoff et al. [21]

liteNystatin Not tested

Gentian Violet Ototoxic

Thimerosal Not tested

The bolded text refers to drugs that have been classified in thehave been classified as ototoxic (non-safe).Jackman et al. [3]

Tom [29]Spandow [35]

Tisner et al. [31]

rature as non-ototoxic (safe). The italic text refers to drug that

ml of reconstituted suspension contains 10 mg or include cyclopirox olamine, boric acid, and 5-fluor-

fungal RNA and protein synthesis [37,5,38]. Table 3lists the ototoxicity potential for some of the anti-

of otomycosis with Aspergillus niger and Candida

The authors wish to thank Ms Francoise Brosseau-Lapre for her assistance, and for editing the manu-

458 R. Munguia, S.J. Daniel40 mg of fluconazole [2,13]. Miconazole cream 2%has also demonstrated an efficacy rate of 90%[10,21]. Bifonazole is an antifungal agent that wascommonly used in the 1980s. The antifungal potencyof bifonazole 1% solution has been reported to besimilar to that of clotrimazole and miconazole;however, it varies from species to species. Bifona-zole and derivatives inhibited the growth of mostfungi with an efficacy of up to 100% [22,23].

Nystatin is a polyene macrolide antibiotic thatinhibits sterol synthesis in the cytoplasmic mem-brane [24]. Many molds and yeasts are sensitive tonystatin, including Candida species. A major advan-tage of nystatin is the fact that it is not absorbedacross intact skin. Nystatin is not available as an oticpreparation; however it can be prepared as a solu-tion or a suspension for the treatment of otomyco-sis. Nystatin can be administered as a cream, anointment, or a powder. Reported efficacy rates varyfrom 50% to 80% [3,25].

Amphotericin B is a member of the polyenesfamily. It has been replaced by safer agents in mostcases but is still used, despite its side effects, forlife-threatening fungal infections. Nong in 1999reported that Aspergillus and Candida albicansweresensitive to the use amphotericin B as demonstratedin antifungal susceptibility tests [19,26,27].

Tolnaftate acts by distorting hyphae and inhibit-ing the mycelial growth of susceptible fungi thatcause skin infections, including tinea pedis (ath-letes foot), tinea cruris (jock itch), and ringwormit.It has been recommended in refractory cases ofotomycosis, and was shown to be non-ototoxic[28,29]. Tolnaftate is available as a 1% solution thatcan be easily instilled into the ear [30].

In recent years, there have been attempts to useMercurochrome, a well-known topical antiseptic, totreat otomycosis. Along with merthiolate (thimer-osal), mercurochrome is no longer approved by theFDA due to the fact that it contains mercury. Tisnerin 1995 reported an efficacy of 93.4% with the use ofthimerosal (merthiolate) for the treatment of oto-mycosis [31]. Mercurochrome has been used speci-fically for cases reported in humid environmentswith a reported efficacy rate between 95.8% and100% [32,4].

Gentian Violet is typically prepared as a weak(e.g. 1%) solution in water. It has been used since the1940s to treat otomycosis as it is an aniline dye withantiseptic, anti-inflammatory, antibacterial, andantifungal activity. It is still in use in some countries,and is FDA approved. Studies report an efficacy rateof up to 80%. [20,3335].

Other available topical medications for the treat-ment of otomycosis reported in the literaturescript.

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3. Conclusions

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Ototopical antifungals and otomycosis: A reviewBackgroundMethodsSymptoms and predisposing factorsCausal agentsTopical treatments

ConclusionsAcknowledgementsReferences