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Ototopical antifungals and otomycosis: A

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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
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.

Contents
1.
2.

3.

Background . . . . . . . . . . . . . . . . . . .
Methods . . . . . . . . . . . . . . . . . . . . .
2.1. Symptoms and predisposing factors
2.2. Causal agents . . . . . . . . . . . . . .
2.3. Topical treatments . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . .
Acknowledgements. . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . .

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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).

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453
454
454
454
454
458
458
458

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 inflammatory 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: fluconazole, 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 flucytosine 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.

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 identified 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 efficacy of the treatment. Reviewing individual
cited references identified 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 efficacy, and the
risk of ototoxicity.

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 identified culprits include humid climate, presence of
cerumen acting as a support for fungal growth,
configuration of the ear canal, weak immune func-

R. Munguia, S.J. Daniel

tion, diabetes, increased use of ototopical antibiotics, and prolonged use of broad-spectrum
antibiotics such as fluoroquinolones. 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 identified 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 identified species [9,10]. However, others believe that the
most important therapeutic strategy is to select a
specific treatment for otomycosis based on the
efficacy and characteristics of the drug regardless
of the causal agent [11,12].

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 identified 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
efficacy of treatment.
Azoles are synthetic agents that reduce the concentration 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

Itraconazole
Clotrimazole

Ologe and Nwabuisi [17]

Bassiouny et al. [10]
Nong et al. [19]
Ho et al. [1]
Nong et al. [19]
Schrader (2003)

Aspergillus flavus

Itraconazole, terbinafide

Karaarslan et al. [24]

Aspergillus fumigatus

Miconazole
Amphotericin B
Acetic acid
Clotrimazole

Dyckhoff et al. [21]

Kintzel et al. [26]
Jackman et al. [3]
Jackman et al. [3]
Martin et al. [13]
Martin et al. [13]

Ketoconazole

Tolnaftate
Aspergillus niger

Borneol
Tolnaftate
Ciclopiroxolamine, boric acid
Itraconazole
Mercurochrome
Boric acid
Clotrimazole
5-Fluorocytosine
Itraconazole, terbinafide
Fluconazole
Amphotericin B
Thimerosal

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]

Aspergillus terreus

Lanoconazole

Egami et al. [14]

Candida albicans

Ketoconazole

Itraconazole
Fluconazole
Tolnaftate
Acetic acid

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]

Candida parapsilosis

Clotrimazole, tolnaftate
Fluconazole

Martin et al. [13]

Kurnatowski et al. [2]

Scedosporium apiospermum

Clotrimazole

Bhally et al. [16]

Scopulariopsis brevicaulis

Nystatin

Besbes et al. [25]

Thimerosal
Amphotericin B
Clotrimazole

normal cytoplasmic membrane. They are a class of

five-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 efficacy 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 efficacy represented in percentage

Author

Study design

Antifungal

Posology

Number of
patients

Jadhav et al. [6]

Piantoni et al. [23]

Prospective
Prospective

Clotrimazole
Bifonazole

1% solution 4 drops tid  1 month

1% solution, once a day  415 days

Nong et al. [19]

Randomized prospective

Miconazole
Ketoconazole
Clotrimazole
Thymol alcohol

Once a day  2 weeks

Once a day  2 weeks
Once a day  2 weeks
Three times per day for 2 weeks

110

97.6
97.5
90
80

Ologe and Nwabuisi [17]

Kley [18]
Tisner et al. [31]
Than et al. [38]

Prospective
Prospective
Prospective
Prospective

Clotrimazole
Clotrimazole
Thimerosal
5-Fluorocytosine

1% cream once a day  2 weeks

0.25 mg/ml once a day  812 days
Not reported
10% ointment  710 days

141
39
152
189

96
94.8
93.4
90

Ho et al. [1]

Retrospective

Cresylate otic
Ketoconazole otic
Aluminium acetate otic

Three times per day  13 weeks

13 cc one application  1 week
0.5% solution  13 weeks

51
48
18

86
95
86

Kurnatowski et al. [2]

Mgbor and Gugnani [4]

Prospective
Randomized prospective

Fluconazole
Locacorten-vioform
Mercurochrome
Clotrimazole

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

96
23
23
24

89.4
66.6
95.8
75

del Palacio et al. [37]

Randomized prospective

Ozcan et al. [5]

Cohen and Thompson [20]

Prospective
Prospective

Cyclopirox olamine
Cyclopirox olamine
Boric acid
Boric acid
Ketoconazole

11% cream  1 week

1% solution  1 week
1 week
4% solution in alcohol
Not reported

20
20
40
87
9

80
95
72.5
77
100

Jackman et al. [3]

Retrospective

Acetic acid otic

Clotrimazole
Nystatin
Aluminium acetate otic

Not reported

15
8
2
1

40
50
50
0

Bhally et al. [16]

Mishra et al. [32]
Dyckhoff et al. [21]

Case report
Case report
Review

Clotrimazole
Mercurochrome
Miconazole

0.25 mg/ml
1% solution
0.25% solution

1
1

100
100

Bassiouny et al. [10]

In vitro

Clotrimazole otic
Econazole
Miconazole
Cyclopirox olamine otic

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

100
100
90
57

Egami et al. [14]

In vitro

Lanoconazole

0.1 mg/ml

100

79
23

Efficacy
(%)
100
100

R. Munguia, S.J. Daniel

Ototopical antifungals and otomycosis

457

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 fluconazole 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

otomycosis. Ketoconazole has shown an efficacy

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

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

Econazole

Not tested
Not tested

del Palacio et al. [37]

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]

Nystatin

Not tested

Jackman et al. [3]

Gentian Violet

Ototoxic

Tom [29]
Spandow [35]

Thimerosal

Not tested

Tisner et al. [31]

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

458
ml of reconstituted suspension contains 10 mg or
40 mg of fluconazole [2,13]. Miconazole cream 2%
has also demonstrated an efficacy 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 efficacy 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 efficacy 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 efficacy of 93.4% with the use of
thimerosal (merthiolate) for the treatment of otomycosis [31]. Mercurochrome has been used specifically for cases reported in humid environments
with a reported efficacy 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-inflammatory, antibacterial, and
antifungal activity. It is still in use in some countries,
and is FDA approved. Studies report an efficacy 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-fluorocytocine [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 flucytosine) acts
penetrating fungal cells and is converted to fluorouracil, 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 identified 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, fluconazole, 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 Francoise BrosseauLapre
for her assistance, and for editing the manuscript.

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