International Journal of Pediatric Otorhinolaryngology (2008) 72, 453—459

www.elsevier.com/locate/ijporl

REVIEW ARTICLE

Ototopical antifungals and otomycosis: A review

Raymundo Munguia a, Sam J. Daniel a,b,*

aMcGill Auditory Sciences Laboratory, McGill University, Montreal, Qc., Canada H3H1P3bMcGill 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 commonlyidentified organisms. Antifungals from the Azole class seem to be the most effective,followed by Nystatin and Tolnaftate.# 2007 Elsevier Ireland Ltd. All rights reserved.

Contents

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

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

3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458

1. Background

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

* Corresponding author at: McGill University, Department ofOtolaryngology, 2300 Rue Tupper B-240, Montreal, Qc., CanadaH3H1P3. Tel.: +1 514 412 4304; fax: +1 514 412 4342.

E-mail address: sam.daniel@mcgill.ca (S.J. Daniel).

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

tions, sometimes involving the middle ear. The pre-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.

The extensive and sometimes unnecessary use ofantibiotic eardrops for the treatment of otitis media

hts reserved.

454 R. Munguia, S.J. Daniel

and otitis externa has been linked to the importantincrease 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-related articles published between January 1951and March 2007. The resulting set of 576 articleswas 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-

tion, diabetes, increased use of ototopical antibio-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

Causal agent Treatment Author

Aspergillus (species not specified) Clotrimazole Ologe and Nwabuisi [17]Bassiouny et al. [10]

Ketoconazole Nong et al. [19]Ho et al. [1]

Itraconazole Nong et al. [19]Clotrimazole Schrader (2003)

Aspergillus flavus Itraconazole, terbinafide Karaarslan et al. [24]

Aspergillus fumigatus Miconazole Dyckhoff et al. [21]Amphotericin B Kintzel et al. [26]Acetic acid Jackman et al. [3]Clotrimazole Jackman et al. [3]

Martin et al. [13]Tolnaftate Martin et al. [13]

Aspergillus niger Borneol Chang and Li [7]Tolnaftate Damato [30]Ciclopiroxolamine, boric acid del Palacio et al. [37]Itraconazole Hoshino and Matsumoto [8]Mercurochrome Mgbor and Gugnani [4]

Mishra et al. [32]Boric acid Ozcan et al. [5]Clotrimazole Pradhan et al. [15]5-Fluorocytosine Than et al. [38]Itraconazole, terbinafide Karaarslan et al. [24]Fluconazole Kurnatowski and Filipiak [2]Amphotericin B Ette et al. [27]Thimerosal Tisner et al. [31]

Aspergillus terreus Lanoconazole Egami et al. [14]

Candida albicans Ketoconazole Cohen and Thompson [20]Ho et al. [1]

Thimerosal Tisner et al. [31]Amphotericin B Ette et al. [27]

O’Day (2004)Clotrimazole Jhadav (2003)

Schrader (2003)Bassiouny et al. [10]Ologe and Nwabuisi [17]Jackman et al. [3]Martin et al. [13]

Itraconazole Nong et al. [19]Fluconazole Kurnatowski and Filipiak [2]Tolnaftate Martin et al. [13]Acetic acid Jackman et al. [3]

Candida parapsilosis Clotrimazole, tolnaftate Martin et al. [13]Fluconazole Kurnatowski et al. [2]

Scedosporium apiospermum Clotrimazole Bhally et al. [16]

Scopulariopsis brevicaulis Nystatin Besbes et al. [25]

normal 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

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—

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 � 4—15 days 23 100

Nong et al. [19] Randomized prospective Miconazole Once a day � 2 weeks 110 97.6Ketoconazole 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 � 8—12 days 39 94.8Tisner et al. [31] Prospective Thimerosal Not reported 152 93.4Than et al. [38] Prospective 5-Fluorocytosine 10% ointment � 7—10 days 189 90

Ho et al. [1] Retrospective Cresylate otic Three times per day � 1—3 weeks 51 86Ketoconazole otic 1—3 cc one application � 1 week 48 95Aluminium acetate otic 0.5% solution � 1—3 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 � 7—10 days 23 66.6

Mercurochrome 1% solution every other day � 7—10 days 23 95.8Clotrimazole 1% solution every other day � 7—10 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 01—4 mg/ml — 100Econazole 1% solution — 100Miconazole 0.1—4 mg/ml — 90Cyclopirox olamine otic Not reported — 57

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

Ototopical antifungals and otomycosis 457

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

Table 3 Otomycosis treatment and risk of ototoxicity

Antifungal Tested for oto

5-fluorocytosine Not tested

Acetic acid otic Ototoxic

Aluminium acetate otic Non ototoxic

Amphotericin B Not tested

Bifonazole Not tested

Boric Acid Ototoxic

Clotrimazole Non ototoxic

Cresylate otic Ototoxic

Cyclopirox olamine 1% otic Not tested

Cyclopirox olamine 11% otic Not testedEconazole Not tested

Fluconazole Non ototoxic

Itraconazole Not tested

Ketoconazole Non ototoxic

Lanoconazole Not tested

Locacorten-vioform Ototoxic

Mercurochrome 1% Non ototoxic (

Miconazole Non ototoxic

Nystatin Not tested

Gentian Violet Ototoxic

Thimerosal Not tested

The bolded text refers to drugs that have been classified in the litehave been classified as ototoxic (non-safe).

otomycosis. Ketoconazole has shown an efficacyof 95—100% 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

toxicity Author

Than et al. [38]

Jackman et al. [3]Jinn et al. [36]

Ho et al. [1]Jackman et al. [3]

Nong et al. [19]

Piantoni et al. [23]

del Palacio et al. [37]Ozcan et al. [5]

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]

Ho et al. [1]

Bassiouny et al. [10]del Palacio et al. [37]

del Palacio et al. [37]Bassiouny et al. [10]

Kurnatowski et al. [2]Nong et al. [19]

Nong et al. [19]

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

Egami et al. [14]

Mgbor and Gugnani [4]

FDA banned) Mgbor and Gugnani [4]Mishra et al. [32]

Bassiouny et al. [10]Dyckhoff et al. [21]

Jackman et al. [3]

Tom [29]Spandow [35]

Tisner et al. [31]

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

458 R. Munguia, S.J. Daniel

ml of reconstituted suspension contains 10 mg or40 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-lete’s 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%. [20,33—35].

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

include cyclopirox olamine, boric acid, and 5-fluor-ocytocine [36]. Cyclopirox acts by chelating poly-valent cations (Fe3+ or Al3+) resulting in inhibition ofthe metal-dependent enzymes that are responsiblefor the degradation of peroxides within the fungalcell. Boric acid is a mild acid often used as anantiseptic, and insecticide. Boric acid can be usedto treat yeast and fungal infections such as vaginalyeast infections caused by Candida albicans. It isalso used to prevent athlete’s foot.

5-Fluorocytocine (also known as flucytosine) actspenetrating fungal cells and is converted to fluor-ouracil, which competes with uracil interfering withfungal RNA and protein synthesis [37,5,38]. Table 3lists the ototoxicity potential for some of the anti-fungals.

3. Conclusions

Many species of fungi have been identified as a causeof otomycosis with Aspergillus niger and Candidaalbicans being the most common culprits.

Overall antifungals from the azoles class such asclotrimazole, fluconazole, ketoconazole and mico-nazole are more effective, followed by nystatin andtolnaftate.

Our review of the literature did not reveal anycase reports of antifungals ototopical medicationcausing ototoxicity when used to treat otomycosiswith an intact tympanic membrane. Less data existsregarding the safety of the use of ototopical med-ications in the presence of a tympanic membraneperforation.

Acknowledgements

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

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