International Journal of Pediatric Otorhinolaryngology (2008) 72, 453459

www.elsevier.com/locate/ijporl

REVIEW ARTICLE

Ototopical antifungals and otomycosis: A review

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

McGill Auditory Sciences Laboratory, McGill University, Montreal, Qc., Canada H3H1P3 McGill University, Department of Otolaryngology, Montreal, Qc., Canada H3H1P3

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

KEYWORDS
Otomycosis; Ototopical; Antifungals; Ototoxicity

Summary There has been an increase in the prevalence of otomycosis in recent years. This has been linked to the extensive use of antibiotic eardrops. Treatment of otomycosis is challenging, and requires a close follow-up. We present a review of the literature on otomycosis, the topical antifungals most commonly used, and discuss their ototoxic potential. Candida albicans and Aspergillus are the most commonly identied 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. 2. Background . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . 2.1. Symptoms and predisposing factors 2.2. Causal agents . . . . . . . . . . . . . . 2.3. Topical treatments . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . Acknowledgements. . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453 454 454 454 454 458 458 458

3.

1. Background
Otomycosis, also known as fungal otitis externa, has been used to describe a fungal infection of the external auditory canal and its associated complica* Corresponding author at: McGill University, Department of Otolaryngology, 2300 Rue Tupper B-240, Montreal, Qc., Canada H3H1P3. Tel.: +1 514 412 4304; fax: +1 514 412 4342. E-mail address: sam.daniel@mcgill.ca (S.J. Daniel).

tions, sometimes involving the middle ear. The prevalence of otomycosis has been reported to be as low as 9% of cases of otitis externa [1], and as high as 30.4% in patients presenting with symptoms of otitis or inammatory conditions of the ear [2]. Prevalence is also related to the geographical area, as otomycosis is most commonly present in tropical and subtropical humid climates. The extensive and sometimes unnecessary use of antibiotic eardrops for the treatment of otitis media

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

454 and otitis externa has been linked to the important increase in the prevalence of otomycosis. Secondary overgrowth of fungi is a well-known and recognized complication of the use of broad-spectrum antibiotics like quinolones [3]. To date, there are four main classes of drugs for the treatment of fungal infections: polyenes, triazoles, nucleoside analogues, and echinocandins. The polyenes family includes amphotericin B and nystatin. The triazoles family, better known as azoles includes: uconazole, clotrimazole and miconazole. The mechanism of action of the polyenes and azole families involves an essential chemical component called ergosterol found in the fungal cell membrane. The drug binds to ergosterol and creates a polar pore in the fungal membranes. This causes ions (predominantly K+ and H+) and other molecules to leak out of the cell, leading to its death. The nucleoside analogues such as ucytosine work by interfering with nucleotide synthesis; a key step in cell energy production, metabolism, and signaling. Finally, the echinocandins are a novel class of antifungal agents. Their mechanism of action involves interference with cell wall biosynthesis. Their use in otomycosis has not been reported.

R. Munguia, S.J. Daniel tion, diabetes, increased use of ototopical antibiotics, and prolonged use of broad-spectrum antibiotics such as uoroquinolones. Other factors that predispose patients to otomycosis include: pregnancy, use of systemic steroids, presence of open mastoid cavities, hearing aids with occlusive molds, trauma, and bacterial infections. Several recent articles have also established the potential risk of autoinoculation of the ear canal by patients suffering of dermatomycoses [1,5].

2.2. Causal agents

Many species of fungi have been identied as the cause of otomycosis in the literature reviewed. These are listed in Table 1 along with the antifungal agent utilized for each study. Aspergillus niger and Candida albicans are the most common causative agents of otomycosis. Aspergillus is considered the predominant causal organism in tropical and subtropical regions [6]. Aspergillus niger is the most commonly described agent in the literature [7,8]. Many authors believe that it is important to identify the causal agent of otomycosis in order to use the appropriate treatment. It is also recommended that the antimycotic treatment chosen should be based on the susceptibility of the identied species [9,10]. However, others believe that the most important therapeutic strategy is to select a specic treatment for otomycosis based on the efcacy and characteristics of the drug regardless of the causal agent [11,12].

2. Methods
We performed a MEDLINE search for otomycosisrelated articles published between January 1951 and March 2007. The resulting set of 576 articles was then restricted to those using topical antifungals. Electronic search with topical antimycotic OR otomycosis OR antifungal drops OR antifungal eardrops identied 96 studies, of which 18 were considered appropriate for review. Selected articles had to specify the number of patients presenting with otomycosis, the topical medication used, and the efcacy of the treatment. Reviewing individual cited references identied additional studies. We present in this article a summary of the data in the literature with regards to the topical treatment of otomycosis, the treatment efcacy, and the risk of ototoxicity.

2.3. Topical treatments

To date there is no FDA approved antifungal otic preparation for the treatment of otomycosis. Many agents with various antimycotic properties have been used, and clinicians have struggled to identify the most effective agent to treat this condition. Antifungal agents typically reach some popularity for a short period of time, until non-desirable side effects are identied or until a new medication appears on the market. However, the use of few topical antifungals has persisted throughout time, including Nystatin and the azoles family. In addition to topical therapy, the reviewed literature emphasized the importance of aural hygiene in the treatment of otomycosis, as intuitively ototopical medications work best following cleaning of secretions and debris [1,13]. Table 2 summarizes the studies using topical antifungal agents, the dosage utilized, and the efcacy of treatment. Azoles are synthetic agents that reduce the concentration of ergosterol, an essential sterol in the

2.1. Symptoms and predisposing factors

The most prominent symptoms present at the time of diagnosis were: otalgia, otorrhea, hearing loss, aural fullness, pruritus, and tinnitus [1,2,4]. Very often, fungal external ear infections manifest only in the presence of predisposing factors. Some identied culprits include humid climate, presence of cerumen acting as a support for fungal growth, conguration of the ear canal, weak immune func-

Ototopical antifungals and otomycosis

Table 1 Otomycosis: description of the most common causal agents and treatment Causal agent Aspergillus (species not specied) Treatment Clotrimazole Ketoconazole Itraconazole Clotrimazole Aspergillus avus Aspergillus fumigatus Itraconazole, terbinade Miconazole Amphotericin B Acetic acid Clotrimazole Tolnaftate Aspergillus niger Borneol Tolnaftate Ciclopiroxolamine, boric acid Itraconazole Mercurochrome Boric acid Clotrimazole 5-Fluorocytosine Itraconazole, terbinade Fluconazole Amphotericin B Thimerosal Aspergillus terreus Candida albicans Lanoconazole Ketoconazole Thimerosal Amphotericin B Clotrimazole Author Ologe and Nwabuisi [17] Bassiouny et al. [10] Nong et al. [19] Ho et al. [1] Nong et al. [19] Schrader (2003) Karaarslan et al. [24] Dyckhoff et al. [21] Kintzel et al. [26] Jackman et al. [3] Jackman et al. [3] Martin et al. [13] Martin et al. [13]

455

Chang and Li [7] Damato [30] del Palacio et al. [37] Hoshino and Matsumoto [8] Mgbor and Gugnani [4] Mishra et al. [32] Ozcan et al. [5] Pradhan et al. [15] Than et al. [38] Karaarslan et al. [24] Kurnatowski and Filipiak [2] Ette et al. [27] Tisner et al. [31] Egami et al. [14] Cohen and Thompson [20] Ho et al. [1] Tisner et al. [31] 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] Martin et al. [13] Kurnatowski et al. [2] Bhally et al. [16] Besbes et al. [25]

Itraconazole Fluconazole Tolnaftate Acetic acid Candida parapsilosis Scedosporium apiospermum Scopulariopsis brevicaulis Clotrimazole, tolnaftate Fluconazole Clotrimazole Nystatin

normal cytoplasmic membrane. They are a class of ve-membered nitrogen heterocyclic ring compounds containing at least one other noncarbon atom, nitrogen, sulfur or oxygen [14]. Clotrimazole is the most widely used topical azole [15,16]. It appears to be one of the most effective agents

for the management of otomycosis, with a reported rate of effectiveness that varies from 95% to 100% in most studies [6,10] with the exception of one study reporting a lower efcacy rate of 50% [3]. Clotrimazole has an antibacterial effect, and this is an added advantage when treating mixed bacterial

456

Table 2 Otomycosis: topical treatment efcacy represented in percentage Author Jadhav et al. [6] Piantoni et al. [23] Nong et al. [19] Study design Prospective Prospective Randomized prospective Antifungal Clotrimazole Bifonazole Miconazole Ketoconazole Clotrimazole Thymol alcohol Clotrimazole Clotrimazole Thimerosal 5-Fluorocytosine Cresylate otic Ketoconazole otic Aluminium acetate otic Fluconazole Locacorten-vioform Mercurochrome Clotrimazole Cyclopirox olamine Cyclopirox olamine Boric acid Boric acid Ketoconazole Acetic acid otic Clotrimazole Nystatin Aluminium acetate otic Clotrimazole Mercurochrome Miconazole Clotrimazole otic Econazole Miconazole Cyclopirox olamine otic Lanoconazole Posology 1% solution 4 drops tid 1 month 1% solution, once a day 415 days Once a day 2 weeks Once a day 2 weeks Once a day 2 weeks Three times per day for 2 weeks 1% cream once a day 2 weeks 0.25 mg/ml once a day 812 days Not reported 10% ointment 710 days Three times per day 13 weeks 13 cc one application 1 week 0.5% solution 13 weeks 0.2% solution/three times per day 21 days 1% solution every other day 710 days 1% solution every other day 710 days 1% solution every other day 710 days 11% cream 1 week 1% solution 1 week 1 week 4% solution in alcohol Not reported Not reported Number of patients 79 23 110 Efcacy (%) 100 100 97.6 97.5 90 80 96 94.8 93.4 90 86 95 86 89.4 66.6 95.8 75 80 95 72.5 77 100 40 50 50 0 100 100 100 100 90 57 100

Ologe and Nwabuisi [17] Kley [18] Tisner et al. [31] Than et al. [38] Ho et al. [1]

Prospective Prospective Prospective Prospective Retrospective

141 39 152 189 51 48 18 96 23 23 24 20 20 40 87 9 15 8 2 1 1 1

Kurnatowski et al. [2] Mgbor and Gugnani [4]

Prospective Randomized prospective

del Palacio et al. [37]

Randomized prospective

Ozcan et al. [5] Cohen and Thompson [20] Jackman et al. [3]

Prospective Prospective Retrospective

Bhally et al. [16] Mishra et al. [32] Dyckhoff et al. [21] Bassiouny et al. [10]

Case report Case report Review In vitro

0.25 mg/ml 1% solution 0.25% solution 014 mg/ml 1% solution 0.14 mg/ml Not reported 0.1 mg/ml

R. Munguia, S.J. Daniel

Egami et al. [14]

In vitro

Ototopical antifungals and otomycosis fungal infections. It is considered free of ototoxic effects [17,18]. There are no reports of clinical evidence of clotrimazole ototoxicity. Clotrimazole is available as a powder, a lotion, and a solution. Ketoconazole and uconazole are azole antifungal agents that have a broad spectrum of activity. This family of chemical components is effective in treating the most common etiological agents of
Table 3 Otomycosis treatment and risk of ototoxicity Antifungal 5-uorocytosine Acetic acid otic Aluminium acetate otic Amphotericin B Bifonazole Boric Acid Clotrimazole Tested for ototoxicity Not tested Ototoxic Non ototoxic Not tested Not tested Ototoxic Non ototoxic 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]

457 otomycosis. Ketoconazole has shown an efcacy of 95100% in vitro against Aspergillus species and Candida albicans; it is available as a 2% cream. [1,19,20]. Topical uconazole has been reported effective in 90% of cases in several series. Fluconazole suspension is available with either 350 mg or 1400 mg of uconazole. After reconstitution with 24 ml of distilled water or puried water (USP), each

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] 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]

Cresylate otic Cyclopirox olamine 1% otic Cyclopirox olamine 11% otic Econazole Fluconazole Itraconazole Ketoconazole

Ototoxic Not tested Not tested Not tested Non ototoxic Not tested Non ototoxic

Lanoconazole Locacorten-vioform Mercurochrome 1% Miconazole Nystatin Gentian Violet Thimerosal

Not tested Ototoxic Non ototoxic (FDA banned) Non ototoxic Not tested Ototoxic Not tested

The bolded text refers to drugs that have been classied in the literature as non-ototoxic (safe). The italic text refers to drug that have been classied as ototoxic (non-safe).

458 ml of reconstituted suspension contains 10 mg or 40 mg of uconazole [2,13]. Miconazole cream 2% has also demonstrated an efcacy rate of 90% [10,21]. Bifonazole is an antifungal agent that was commonly used in the 1980s. The antifungal potency of bifonazole 1% solution has been reported to be similar to that of clotrimazole and miconazole; however, it varies from species to species. Bifonazole and derivatives inhibited the growth of most fungi with an efcacy of up to 100% [22,23]. Nystatin is a polyene macrolide antibiotic that inhibits sterol synthesis in the cytoplasmic membrane [24]. Many molds and yeasts are sensitive to nystatin, including Candida species. A major advantage of nystatin is the fact that it is not absorbed across intact skin. Nystatin is not available as an otic preparation; however it can be prepared as a solution or a suspension for the treatment of otomycosis. Nystatin can be administered as a cream, an ointment, or a powder. Reported efcacy rates vary from 50% to 80% [3,25]. Amphotericin B is a member of the polyenes family. It has been replaced by safer agents in most cases but is still used, despite its side effects, for life-threatening fungal infections. Nong in 1999 reported that Aspergillus and Candida albicans were sensitive to the use amphotericin B as demonstrated in antifungal susceptibility tests [19,26,27]. Tolnaftate acts by distorting hyphae and inhibiting the mycelial growth of susceptible fungi that cause skin infections, including tinea pedis (athletes foot), tinea cruris (jock itch), and ringwormit. It has been recommended in refractory cases of otomycosis, and was shown to be non-ototoxic [28,29]. Tolnaftate is available as a 1% solution that can be easily instilled into the ear [30]. In recent years, there have been attempts to use Mercurochrome, a well-known topical antiseptic, to treat otomycosis. Along with merthiolate (thimerosal), mercurochrome is no longer approved by the FDA due to the fact that it contains mercury. Tisner in 1995 reported an efcacy of 93.4% with the use of thimerosal (merthiolate) for the treatment of otomycosis [31]. Mercurochrome has been used specically for cases reported in humid environments with a reported efcacy rate between 95.8% and 100% [32,4]. Gentian Violet is typically prepared as a weak (e.g. 1%) solution in water. It has been used since the 1940s to treat otomycosis as it is an aniline dye with antiseptic, anti-inammatory, antibacterial, and antifungal activity. It is still in use in some countries, and is FDA approved. Studies report an efcacy rate of up to 80%. [20,3335]. Other available topical medications for the treatment of otomycosis reported in the literature

R. Munguia, S.J. Daniel include cyclopirox olamine, boric acid, and 5-uorocytocine [36]. Cyclopirox acts by chelating polyvalent cations (Fe3+ or Al3+) resulting in inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell. Boric acid is a mild acid often used as an antiseptic, and insecticide. Boric acid can be used to treat yeast and fungal infections such as vaginal yeast infections caused by Candida albicans. It is also used to prevent athletes foot. 5-Fluorocytocine (also known as ucytosine) acts penetrating fungal cells and is converted to uorouracil, which competes with uracil interfering with fungal RNA and protein synthesis [37,5,38]. Table 3 lists the ototoxicity potential for some of the antifungals.

3. Conclusions
Many species of fungi have been identied as a cause of otomycosis with Aspergillus niger and Candida albicans being the most common culprits. Overall antifungals from the azoles class such as clotrimazole, uconazole, ketoconazole and miconazole are more effective, followed by nystatin and tolnaftate. Our review of the literature did not reveal any case reports of antifungals ototopical medication causing ototoxicity when used to treat otomycosis with an intact tympanic membrane. Less data exists regarding the safety of the use of ototopical medications in the presence of a tympanic membrane perforation.

Acknowledgements
The authors wish to thank Ms Franc oise BrosseauLapre for her assistance, and for editing the manu script.

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