Original Paper
Audiology
Neurotology Audiol Neurotol
DOI: 10.1159/000501540
Eradicating Otomycosis with Terbinafine
Solution: Basic and Clinical Investigation
Ting-Hua Yang Yi-Ho Young
Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan
Keywords
Otomycosis · Terbinafine · Ototoxicity · Vestibular evoked
myogenic potential
Abstract
Background: Otomycosis still remains intractable in clinical
practice, likely because topical antifungal agents lack effi-
cacy or are potentially toxic to the inner ear end organs. Ob-
jectives: The aim of this study was to investigate whether
terbinafine solution is a potential candidate for treating in-
tractable otomycosis in humans. In addition, the toxic effect
on the inner ear was also assessed by animal models treated
with terbinafine. Methods: Guinea pigs were instilled with
0.1 mL terbinafine (10 and 25 mg/mL) in the left round win-
dow membrane. At 2 weeks after treatment, all animals un-
derwent an inner ear test battery and were then sacrificed
for morphological study. Clinically, 20 patients with otomy-
cosis were treated with terbinafine solution at a dosage of
0.4 mg. Results: All terbinafine-treated animals showed in-
tact inner ear function when total dosage of terbinafine was
< 2.5 mg, which was further confirmed by morphological
study. Subsidence of otomycosis was achieved in all 20 pa-
tients 1 week after treatment with terbinafine (0.4 mg) with-
© 2019 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/aud
Received: May 1, 2019
Accepted after revision: June 17, 2019
Published online: August 27, 2019
out untoward effect. No evidence of recurrence was noted 1
year after treatment. Conclusion: The paucity of inner ear
toxicity of terbinafine even at a dosage of 2.5 mg was identi-
fied in guinea pig models morphologically and physiologi-
cally. Topical application of terbinafine solution at a dosage
of 0.4 mg may be a potential treatment for otomycosis in
humans. © 2019 S. Karger AG, Basel
Introduction
Athlete’s foot is caused by fungal infection. Terbin-
afine has proven effective in eradicating this intractable
dermatitis [Revankar et al., 2008]. Similarly, fungal infec-
tion may also occur in the ear (termed otomycosis), as a
subacute or chronic infection of the external ear canal
sometimes involving the middle ear, manifested as exfo-
liation, pruritus, otalgia, and otorrhea. The common
causative organisms of otomycosis include Aspergillus
and Candida species, and Aspergillus is the predominant
species in tropical and subtropical areas [Chander et al.,
1996; Jadhav et al., 2003].
137.111.162.20 - 8/28/2019 8:24:28 PM
Yi-Ho Young
Department of Otolaryngology, National Taiwan University Hospital
1, Chang-Te St.
MacQuarie University
Taipei 10048 (Taiwan)
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E-Mail youngyh @ ntu.edu.tw
 Conventional management of otomycosis in humans
requires meticulous cleansing of cerumen and debris in
the external ear canal, followed by topical administration
of an antifungal agent. Many agents with various antifun-
gal properties have been adopted, and clotrimazole is the
most widely used topical azole in clinics, with an efficacy
rate varying between 50 and 100% [Perez et al., 2013;
Munguia and Daniel, 2008]. Nevertheless, otomycosis
still remains intractable in clinical practice, likely because
topical antifungal agents lack efficacy or are potentially
toxic to the inner ear end organs.
Terbinafine, a synthetic allylamine antifungal agent,
changes cell membrane permeability and causes fungal
cell lysis by inhibiting ergosterol synthesis via inhibition
of squalene epoxidase [Petranyi et al., 1984; Leyden,
1998]. Terbinafine, which is effective in vitro against
some species of Aspergillus, Candida, and other filamen-
tous fungi [Schmit et al., 1988; Torres-Rodríguez et al.,
1998; Jessup et al., 2000], is widely utilized for treating
dermatophyte infection. Thus, terbinafine solution may
be a potential candidate for treating otomycosis, although
its toxicity to the inner ear end organs remains unclear.
Currently, all the inner ear end organs can be compre-
hensively evaluated via an inner ear test battery in guinea
pig models and humans [Yang et al., 2010b; Young, 2013],
which comprises audiometry or auditory brainstem re-
sponse (ABR) for assessing cochlear function, caloric test
for the function of semicircular canals, and ocular ves-
tibular evoked myogenic potential (oVEMP) and cervical
VEMP (cVEMP) tests for evaluating the function of utri-
cle and saccule, respectively. This inner ear test battery
may help assess the toxic effect of various agents. The aim
of this study was to investigate whether terbinafine solu-
tion is a potential candidate for treating intractable oto-
mycosis in humans, and its toxicity was also investigated
in animal models treated with terbinafine.
Materials and Methods
Guinea Pig Models
Hartley-strained guinea pigs weighing 200–220 g were used.
Terbinafine was dissolved in ethanol as a stock solution, then di-
luted in distilled water to a solution of terbinafine with the concen-
tration of 10, 25, 50, and 100 mg/mL. Since the latter two concen-
trations (50 and 100 mg/mL) induce severe dermatitis in the exter-
nal ear canal in most animals, finally terbinafine at a dosage of 10
mg/mL (n = 10) and 25 mg/mL (n = 10) was selected for the ex-
periment. The rationale to use 10 mg/mL as a minimum dosage is
based on the same concentration of the commercially available ter-
binafine solution (Lamisil® solution; Novartis, Nyon, Switzer-
land).
2 Audiol Neurotol
DOI: 10.1159/000501540
Under general anesthesia with intraperitoneal pentobarbital
sodium (35 mg/kg), both tympanic bullae were opened under an
operating microscope. The saline (0.1 mL) and terbinafine solu-
tion (0.1 mL, 10 or 25 mg/mL) were instilled into the right and left
round window membranes, respectively.
At 2 weeks after treatment, each animal underwent an inner ear
test battery comprising ABR, and cVEMP, oVEMP, and caloric
tests. Then, the animals were sacrificed for morphological study.
Auditory Brainstem Response
Under general anesthesia, click stimuli (0.1 ms) were delivered
through a plastic tube inserted into the ear canal. The repetition
rate was 20/s, and 400 sweeps were averaged. The stimulus inten-
sity was from 100 dB SPL initially, followed by 5 dB step decrement
until the absence of the waveforms, and the threshold of ABR was
determined [Day et al., 2007].
Caloric Test
The vigilant guinea pig was restrained. A pair of clip electrodes
was attached to the bilateral canthi, and a reference electrode was
on the vertex. Ice water (4 ° C, 5 mL) was used to irrigate the ear
canal in 5 s with an electronystagmographic (ENG) recorder (NY-
13; Rion, Tokyo, Japan). Once the caloric response was absent, the
animal underwent caloric test again after an intermission of 5 min
[Young et al., 2002]. To analyze the caloric nystagmus curve, cali-
bration of eye movement in ENG recordings was set at 6°/10 mm.
The maximum slow phase velocity of each derived caloric nystag-
mus was calculated by dividing the amplitude of the slow phase by
the duration, and recorded as °/s [Young et al., 2002].
oVEMP Test
The guinea pig was fixed in the prone position. One active elec-
trode was inserted vertically to the inferior extraocular muscle.
Another reference electrode was approximately 15 mm below the
active one, while the ground electrode was on the parietal area. The
operator held the vibrator (Type 4810, minishaker; Bruel & Kjaer
P/L, Denmark) by hand and delivered a repeatable tap on the mid-
line frontal bone of a guinea pig. During recording (Smart EP 3.90;
Intelligent Hearing Systems, Miami, FL, USA), electromyographic
signals were amplified. Stimulation rate was 5/s; analysis time for
each response was 24 ms, and 30 responses were averaged for each
run. The initial negative-positive biphasic waveform comprised
peaks nI and pI. Consecutive runs were performed to confirm the
reproducibility of peaks nI and pI, and oVEMPs were deemed to
be present [Yang et al., 2010a].
cVEMP Test
A pair of needles-electrodes was placed on both neck extensors,
while a reference electrode was on the occipital area at the midline.
Click stimuli (0.1 ms, 120 dB SPL) were generated via a short tube
inserted into the ear canal. Monaural acoustic stimulation with
unilateral recording was performed. The stimulation rate was 5/s,
and the analysis time for each response was 24 ms, and 100 re-
sponses were averaged. The positive/negative polarities of biphasic
waveforms were termed waves I and II [Yang and Young, 2005].
Morphological Study
Having finished the inner ear test battery, guinea pigs were sac-
rificed for morphological study. The membranous labyrinth as a
whole mount preparation was dissected immediately from the
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MacQuarie University
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 Control Terbinafine-treated

50 dB SPL
50 dB SPL

40 40

30 30

20 20

0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12
ms ms
a

10°/s

250 µV nI
nI

139 dB FL 139 dB FL
pl pl
nI nI

c 134 dB FL pl
134 dB FL pl

I
I
20 µV

120 dB SPL
120 dB SPL II II

I I

110 dB SPL II 110 dB SPL

II

0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
d ms ms

Fig. 1. Guinea pigs at 2 weeks after treatment with saline (control) and terbinafine (25 mg/mL) in the right and
left ears, respectively. Both ears reveal an ABR threshold at 40 dB SPL (arrows) (a) and normal responses in the
caloric (b), oVEMP (c), and cVEMP (d) tests. b Upper trace, time base; middle trace, eye movement; lower trace,
eye velocity.
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Eradicating Otomycosis Audiol Neurotol 3

DOI: 10.1159/000501540
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 Table 1. Effect of terbinafine on the inner ear function of guinea pigs at 2 weeks after treatment

Groups Saline Terbinafine p value

10 mg/mL 25 mg/mL

Ears, n 20 10 10
ABR
Threshold, dB SPL 46±4 45±5 43±6 NS
Caloric test
Duration, s 55±25 58±22 49±17 NS
Slow phase velocity, °/s 5.0±1.6 5.2±1.1 4.9±2.0 NS
oVEMP
nI latency, ms 3.2±0.4 3.0±0.3 3.0±0.2 NS
pI latency, ms 4.8±0.3 4.6±0.4 4.4±0.4 NS
nI-pI amplitude, µV 67±48 68±37 60±12 NS
cVEMP
Positive I latency, ms 6.4±0.8 6.1±0.4 6.6±0.2 NS
Negative II latency, ms 7.4±0.5 7.6±0.6 7.9±0.3 NS
I-II amplitude, µV 5.8±2.0 6.4±1.7 6.3±1.0 NS

Data are expressed as mean ± SD. NS, nonsignificant difference (p > 0.05) among the three groups, one-way
analysis of variance (ANOVA) test; ABR, auditory brainstem response; SPL, sound pressure level; oVEMP and
cVEMP, ocular and cervical vestibular-evoked myogenic potential.

temporal bones. The cochlear and vestibular explants were fixated
and stained with a conjugated rhodamine-phalloidin probe (1:100,
Texas Red X-phalloidin, Molecular Probes) in phosphate-buffered
saline (PBS) for 1 h. When the fluorescent dye rhodamine conju-
gates with phalloidin, it emits red fluorescence and labels F-actin.
The tissues were then washed 3 times with PBS and mounted on
glass slides with Fluoromount (Molecular Probes, USA). Finally,
slides were examined via confocal microscopy (Zeiss LSM 510
Meta, Germany) [Yang et al., 2010b].
Clinical Patients
From January 2016 to December 2016, a total of 20 patients
with intractable otomycosis were admitted to our clinic of the uni-
versity hospital. Six were men and 14 were women, with their ages
ranging from 20 to 78 (mean, 52 ± 17) years. Right, left, and both
ears were affected in 10, 7, and 3 patients, respectively. The otomy-
cosis was characterized by malodorous discharge, inflammation,
debris containing fungal spores, and hyphae in the external ear
canal, and further confirmed by microbiological culture. The term
“intractable” meant that conventional antifungal otic drugs for >2
weeks failed to improve the fungal infection. Those with eardrum
perforation or previous ear surgery were excluded.
All patients were in the supine position. The external ear canals
were examined under an operating microscope. The discharge and
debris inside the ear canal were meticulously cleansed. Then, 0.4
mg (10 mg/mL) of terbinafine film-forming solution (Lamisil® so-
lution; Novartis, Nyon, Switzerland) without adding other agents
was applied on the surface of the eardrum and external ear canal.
All patients were regularly followed at our clinic monthly during
the first 3 months and 1 year after treatment.
For comparison, another 10 patients (3 males and 7 females;
mean age 52 ± 17 years) with otomycosis admitted in 2015 were
also included for comparison. All patients received 3 drops of con-
ventional otic drugs containing nystatin, twice daily for 2 weeks.
There was no significant difference in terms of age and sex ratio
between the terbinafine and conventional otic drug groups (p >
0.05, Fisher’s exact or unpaired t test).
Statistical Methods
The age and sex ratio between the two groups were compared by
Fisher’s exact or unpaired t test. The mean ABR threshold, duration,
and slow phase velocity of the caloric nystagmus, and the charac­
teristic parameters (latency and amplitude) of the cVEMPs and
oVEMPs between the control and treated ears were compared by the
one-way analysis of variance test with the Bonferroni-adjusted t test.
Results
Terbinafine-Treated Guinea Pigs
Six hours after operation, all 20 terbinafine-treated an-
imals awoke from anesthesia. Neither spontaneous nor
positional nystagmus was observed. All animals moved
freely in the cage with mean body weight gain of 46 ±
11 g at 2 weeks after treatment. None of the terbinafine-
treated animals showed dermatitis.
At 2 weeks after treatment, all terbinafine-treated ears
revealed normal ABR waveforms (Fig.  1a), with mean
ABR thresholds of 45 ± 5 and 43 ± 6 dB SPL for the groups
of 10 mg/mL (n = 10) and 25 mg/mL (n = 10), respec-
tively, which did not significantly differ when compared
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4 Audiol Neurotol Yang/Young

DOI: 10.1159/000501540
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a b
Fig. 2. Normal inner ear end organs in a
guinea pig at 2 weeks after treatment with
terbinafine (25 mg/mL). a Cochlear hair
cells. b Crista ampullaris. c Utricular mac-
c d
ula. d Saccular macula. Bar, 10 µm.
with 46 ± 4 dB SPL in the saline group (n = 20, p > 0.05;
Table 1). Morphologically, the cochlear explants exhib-
ited intact hair cells regardless of saline- or terbinafine-
treated guinea pigs (Fig. 2a).
As regards the vestibular function, all 20 guinea pigs
underwent a vestibular test battery comprising caloric,
oVEMP, and cVEMP tests (Fig. 1b–d). The duration and
slow-phase velocity of the caloric nystagmus in animals
treated with terbinafine were 58 ± 22 s and 5.2 ± 1.1 °/s
for the 10 mg/mL group, and 49 ± 17 s and 4.9 ± 2.0 °/s
for the 25 mg/mL group, respectively; the difference be-
tween saline and terbinafine groups was nonsignificant
regardless of the concentration of terbinafine (p > 0.05;
Table 1).
Both the saline- and terbinafine-treated groups showed
100% prevalence of clear oVEMPs and cVEMPs (Fig. 1c,
d). Likewise, the characteristic parameter (latencies and
amplitude) of oVEMP and cVEMP did not significantly
differ between the terbinafine-treated groups (10 or 25
mg/mL) and saline group (p > 0.05; Table 1).
Eradicating Otomycosis
Color version available online
Morphologically, the vestibular explants taken from 5
guinea pigs treated with terbinafine (25 mg/mL) demon-
strated normal crista ampullaris, utricle, and saccule
(Fig. 2b–d), and further confirmed that terbinafine solu-
tion at a dosage of <2.5 mg does not damage the inner ear
end organs of guinea pig models morphologically and
physiologically.
Clinical Patients
In 2015, 10 patients with otomycosis were treated with
conventional otic drugs (containing nystatin) for at least
2 weeks. However, none were effective, as evidenced by
persistent discomfort with exfoliation and mass of debris
in the external ear canal. Thus, terbinafine was adopted
to combat the intractable otomycosis in 2016.
Clinical manifestation in 20 patients with otomycosis
comprised hearing loss, blocked ear, and pruritus in 17
patients (85%), followed by tinnitus, otalgia, and mal-
odorous discharge (65%). All debris mixed with black,
brown, or whitish fungal mass in the eardrum and exter-
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Audiol Neurotol 5
DOI: 10.1159/000501540
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a c
b d
Fig. 3. Case No. 1, otomycosis by Aspergillus niger, before (a) and 1 week after (b) terbinafine treatment. Case
No. 16, otomycosis by Aspergillus terreus, before (c) and 1 week after (d) terbinafine treatment. Case No. 13, oto-
mycosis by Candida parapsilosis, before (e) and 1 week after (f) terbinafine treatment.
nal ear canal was meticulously cleansed under micros-
copy (Fig. 3a, c, e), and the debris was sent for microbio-
logical culture. Thereafter, terbinafine film-forming solu-
tion (Lamisil® solution) at a dosage of 0.4 mg (10 mg/mL)
was applied on the surface of the eardrum and external
ear canal.
At 1 week after treatment, relief of clinical symptoms
and subsidence of fungal debris were observed in all pa-
tients (Fig. 3b, d, f). Microbiological study revealed 100%
culture rate of Aspergillus species including Aspergillus
nigra with/without Candida parapsilosis, Aspergillus ter-
reus, and Aspergillus flavus (Table 2). Suppuration due to
superimposed bacterial infection was also noted in 4 pa-
tients (20%) including staphylococci in 3 and Propioni-
bacterium in 1 (Table 2).
Monthly follow-up by otoscopy revealed intact ear-
drum and ear canal without recurrence of otomycosis
during the first 3 months, indicating that single applica-
tion (one time, one dose) is sufficient to eradicate otomy-
6 Audiol Neurotol
DOI: 10.1159/000501540
Color version available online
e
f
cosis. One year after treatment, both the eardrum and ex-
ternal ear canal were intact in all 20 patients as demon-
strated by otoscopy. No evidence of otomycosis recurrence
was identified.
Discussion
Basic Investigation
The ranges of minimum inhibitory and fungicidal
concentrations of terbinafine for the Aspergillus species
are 0.02–1.60 and 0.05–3.20 μg/mL, respectively [Schmitt
et al., 1988]. Initially, terbinafine solution is prepared to
the concentration of 10, 25, 50, and 100 mg/mL instilled
into the round window membrane of guinea pigs, which
is far (>7,000×) more than needed to produce strong in-
hibitory and fungicidal activities against Aspergillus and
Candida species. However, most guinea pigs exhibited se-
vere inflammation of the ear canals when the concentra-
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Table 2. Clinical information on 20 patients with otomycosis

Case No. Sex Age, years Side Pathogens Terbinafine dose, Outcome
mg

1 F 47 R Aspergillus niger 0.4 cured

2 F 49 L Aspergillus niger 0.4 cured
3 F 54 R Aspergillus niger 0.4 cured
4 F 32 L Aspergillus niger 0.4 cured
5 F 23 R Aspergillus niger 0.4 cured
6 M 70 B Aspergillus niger 0.4 cured
7 M 43 R Aspergillus niger 0.4 cured
8 F 75 L Aspergillus niger 0.4 cured
9 M 75 R Aspergillus niger 0.4 cured
10 F 64 R Aspergillus niger 0.4 cured
11 F 78 L Aspergillus niger 0.4 cured
12 F 69 R Aspergillus niger 0.4 cured
13 F 63 B Aspergillus niger + Candida parapsilosis 0.4 cured
14 F 52 R Aspergillus niger + Candida parapsilosis 0.4 cured
15 M 33 L Aspergillus terreus 0.4 cured
16 F 48 R Aspergillus terreus + staphylococci 0.4 cured
17 M 48 R Aspergillus terreus + staphylococci 0.4 cured
18 M 20 L Aspergillus terreus + staphylococci 0.4 cured
19 F 50 B Aspergillus flavus 0.4 cured
20 F 46 L Aspergillus flavus + Propionibacterium acnes 0.4 cured

tion of administered terbinafine was ≥50 mg/mL. Thus, Clinical Investigation

ototoxicity by terbinafine should be investigated. Fortu-
nately, an emerging inner ear test battery comprising
ABR, and caloric, oVEMP, and cVEMP tests has been uti-
lized for assessing the inner ear toxicity in guinea pig
models, which may help resolve this problem [Young,
2018].
The mean ABR thresholds between the saline- and ter-
binafine-treated ears did not differ significantly (Table 1),
indicating well-preserved auditory function following
terbinafine administration, which was in agreement with
the literature stating that terbinafine does not cause per-
manent hearing loss [Sagit et al., 2013]. Likewise, no sig-
nificant difference was identified in the characteristic pa-
rameters of the caloric, oVEMP, and cVEMP test results
between the saline- and terbinafine-treated groups (Table
1), implying that the vestibular function was also intact
after terbinafine treatment.
Morphologically, the cochlear and vestibular explants
harvested from terbinafine-treated guinea pigs did not
show substantial change in the cochlea, semicircular ca-
nals, utricle, or saccule via confocal microscopy (Fig. 2).
Compared to terbinafine (10 mg/mL) used in humans,
even at high concentration (25 mg/mL), terbinafine does
not exhibit toxicity in the inner ear of guinea pig models
physiologically and morphologically.
Otomycosis, commonly encountered at ear clinics in
tropical regions, accounts for 30% of ear inflammation
cases [Karaarslan et al., 2004], particularly for patients
with diabetes, compromised immune system, patients us-
ing systemic steroids and hearing aids with occlusive
mold, or those with an open mastoid cavity after surgery.
Additionally, prolonged use of antibiotic eardrops may
facilitate ear fungal infection.
The most common pathogen for otomycosis in tropi-
cal and subtropical regions is Aspergillus species, as evi-
denced by 100% culture rate in this study (Table 2). Dur-
ing the last century, eradicating otomycosis has been
challenging likely because a treatment agent with high
potency and low toxicity is lacking. Terbinafine is effec-
tive in vitro against Aspergillus species, and is more potent
in vitro against some Aspergillus species than itraconazole
or amphotericin B [Moore et al., 2001]. A potent antifun-
gal agent for athlete’s foot, namely terbinafine, has there-
fore been considered as an alternative for combating ear
fungal infection [Kurnatowski and Filipiak, 2001].
All 20 patients with intractable otomycosis were treat-
ed with terbinafine, and a 100% efficacy rate was achieved
without untoward effect. No evidence of recurrence was
noted 1 year after treatment. Nevertheless, before terbin-
afine could be widely utilized in clinical patients, its toxic-
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Eradicating Otomycosis Audiol Neurotol 7

DOI: 10.1159/000501540
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ity on the inner ear must be evaluated [Sagit et al., 2013;
Aydin et al., 2012].
In this study, a single application (one time, one dose)
of terbinafine solution with a dosage of 0.4 mg on the ear-
drum and external ear canal was sufficient to eradicate the
fungal infection (Fig.  3), because the newly developed
film-forming solution slowly releases the terbinafine in
the external ear canal within 1 week. Meanwhile, a total
dosage of 0.4 mg (0.04 mL) is sufficient to cover the ear
drum (approximately 50 mm2) and affected external ear
canal (approximately 350 mm2).
In other words, terbinafine solution may replace the
conventional antifungal otic drugs (containing nystatin)
for eradicating the intractable otomycosis in patients with
intact eardrum, but not perforated one, because ototoxic-
ity may be of delayed onset.
tion of terbinafine solution at a dosage of 0.4 mg may be
a potential treatment for otomycosis in humans.
Statement of Ethics
This study was approved by the institutional review board of
the University Hospital, and each patient signed the informed con-
sent form to participate. The animal experiment was conducted in
accordance with the guideline for the care and use of laboratory
animals of the Animal Research Committee at National Taiwan
University College of Medicine.
Disclosure Statement
The authors declare that they have no conflict of interest.

Conclusion Funding Sources

The absence of inner ear toxicity of terbinafine at a This study was supported by the National Science Council, Tai-
dosage of <2.5 mg was identified in guinea pig models wan (grant No. Most 105-2314-B-002-163-MY3), and National
Taiwan University Hospital (NTUH 106-S3591), Taipei, Taiwan.
morphologically and physiologically. Topical applica-

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8 Audiol Neurotol Yang/Young

DOI: 10.1159/000501540
MacQuarie University
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