Otolaryngol Clin N Am

40 (2007) 669–683

Ototoxicity of Ototopical
DropsdAn Update
David S. Haynes, MDa,*, John Rutka, MD, FRCSCb,
Michael Hawke, MD, FRCSCb, Peter S. Roland, MDc
a
The Otology Group of Vanderbilt, Department of Otolaryngology-Head and Neck Surgery,
Vanderbilt University Medical Center, Medical Center East S. Tower 7209,
1215 21st Avenue South, Nashville, TN 37232-5555, USA
b
Department of Otolaryngology, University of Toronto, 190 Elizabeth Street, Room 3S438,
Fraser Elliot Building, Toronto, Ontario M5G 2N2, Canada
c
Department of OtolaryngologydHead and Neck Surgery, The University of Texas
Southwestern Medical Center, Dallas, TX, USA

Topical antibiotic solutions are frequently indicated in patients who have

external or middle ear infections. It is well known that any substance that
can enter the middle ear can access the inner ear via the permeability of
the round window membrane (RWM) (and theoretically the annular liga-
ment of the stapes/microfractures of the otic capsule), where it may cause
adverse effects to the cochlear and vestibular apparatus [1]. The actual po-
tential for ototoxicity of these ototopical preparations has been a subject
of considerable debate. The introduction of non-ototoxic fluoroquinolone
ear drops in 1997–1998, recent literature regarding the possible issues
of unrecognized ototoxicity from ototopical preparations, and increasing
litigation from alleged inappropriate use of ototopical drops has garnered
significant attention among practitioners on the subject of ototoxicity
from ototopical preparations. This ongoing debate led the American Acad-
emy of Otolaryngology–Head and Neck Surgery (AAO-HNS) to convene
expert panels to review this issue and address the issue of ototoxicity of
ototopical preparations and make an evidence-based recommendation
regarding their use [2].
A recent survey in the United Kingdom noted that 98% of otolaryngol-
ogists would use drops in the presence of a tympanic membrane (TM) per-
foration, whereas only 43% of general practitioners would do the same for

* Corresponding author.
E-mail address: david.haynes@vanderbilt.edu (D.S. Haynes).

0030-6665/07/$ - see front matter Ó 2007 Published by Elsevier Inc.

doi:10.1016/j.otc.2007.03.010 oto.theclinics.com
670 HAYNES et al

fear of ototoxicity [3]. This article addresses the basic science, clinical re-
search, and clinical issues concerning the ototoxicity of ototopical prepara-
tions. Current AAO-HNS guidelines and position statements are reviewed.
The authors’ experience in giving expert testimony and consultation in med-
icolegal cases concerning ototoxicity of these drops is also summarized.

Causes of tympanic membrane perforation

The anatomic integrity of the TM may be disrupted by a surgical
(therapeutic or diagnostic) procedure, trauma (blunt head trauma or blast
injury), acute otitis media (AOM) or chronic infection (so-called ‘‘chronic
suppurative otitis media’’ [CSOM]).

Tympanic membrane perforations associated with infection

Although relatively uncommon, AOM, if severe, may result in perfora-
tion of the TM with resulting acute otorrhea [4]. After perforation of the
TM, the patient in some instances may develop a chronically draining ear
(CSOM) with a persistent perforation of the TM [5]. Although the exact def-
inition is debatable, chronic perforation associated with chronic mucosal
disease (with or without cholesteatoma) with otorrhea of 3 months’ duration
seems to be an acceptable definition of CSOM [6,7].
AOM frequently evolves into otitis media with effusion, however [5]. A
persistent effusion often leads to myringotomy and insertion of pressure
equalizing tubes (PETs) or tympanostomy tubes (TTs), which are placed
in more than 1 million patients annually in the United States. Acute or
chronic otorrhea from PETs may result from persistent middle ear or mas-
toid disease [5,8]. The reported frequency of post-tympanostomy tube otor-
rhea (PTTO) varies from 21% to 68%, depending on the study [9,10]. The
2000 Consensus Panel Report estimated the incidence of PTTO to be
approximately 20% [5]; however, a recent meta-analysis suggested that
the incidence could be much higher [11].

Microbiology
In patients with a perforated TM after AOM or patients who have an
AOM complicating PETs, the most frequently cultured bacteria are Strepto-
coccus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis
[12–14]. A recent study on PTTO recovered S pneumoniae in 17%, H influenzae
in 18%, Staphylococcus aureus in 13%, and Pseudomonas aeruginosa in 12%
and demonstrated that the causative organism is frequently not sensitive to
oral antibiotics [15].
In patients who have CSOM, the most frequently cultured organisms are
S aureus, P aeruginosa, and other aerobic and anaerobic organisms [16–18].
 OTOTOXICITY OF OTOTOPICAL DROPS 671

The microbiology of PTTO is often a combination of the organisms found

in AOM and CSOM and varies with age and the number of infections. For
example, H influenzae, S pneumoniae, and Staphylococcus epidermidis were
cultured in children younger than 3 years (42%, 18%, and 16%, respec-
tively), whereas S aureus, P aeruginosa, and S epidermidis were cultured in
children older than age 3 years (39%, 24%, and 16%, respectively) [19,20].

Management of otorrhea
Topical antibiotics are recommended as first-line agents in uncomplicated
cases [2,5]. Because ototopical antibiotics provide a high concentration of
antibiotic directly into the middle ear, they should reduce the likelihood
of the development of bacterial resistance. Ciprofloxacin hydrochloride
and ciprofloxacin dexamethasone otic suspension and ofloxacin otic solu-
tion 0.3% contain concentrations 3000 mg/mL of ciprofloxacin and ofloxa-
cin, respectively. Even if the causative organisms have previously developed
partial resistance, the high concentration of antibiotic in the middle ear
achieved with these topical drops undoubtedly exceeds the minimum inhib-
itory concentration of organisms encountered in the middle ear space. The
risk for various systemic adverse effects, such as nausea, vomiting, diarrhea,
and allergic reactions, also remains negligible with topical therapy.

Mechanisms of potential ototoxicity

Several years ago, a survey of otolaryngologists in the United States
found that few were concerned about ototoxicity from topical medications
in patients with TM perforations [21]. Whether ototopical solutions actually
can pass through TM perforations or PETs and whether certain ototopical
(especially aminoglycoside containing) antibiotics might cause a sensorineu-
ral hearing loss has been questioned by some clinicians [22].
The passage of otic solutions through PETs into the middle ear has been
demonstrated using an artificial model of the ear [23]. In this model, mas-
sage of the tragus created pressures that exceeded those needed for passage
of otic solutions through even small TTs [23]. In patients with active CSOM,
instillation of a solution of gentamicin into the external auditory canal was
associated with detectable plasma levels of gentamicin, which indicated sys-
temic absorption [24]. Several reports in the literature described symptoms
of ototoxicity after administration of ototopical agents in patients with
TM perforations or TTs in place, which also indicated passage of the drops
into the middle ear space [22–27]. Kaplan and colleagues [28] used commer-
cially available gentamicin betamethasone otic drops as a solution for
vestibular ablation in patients with Meniere’s disease. The drops were
administered to patients with PETs in place and were consistently able to
achieve a significant degree of vestibular ablation. This study clearly showed
672 HAYNES et al

that commercially prepared otic drops not only can enter the middle ear
space via a PET but also can cause significant ototoxicity.
The most likely route for medication to pass from the middle ear to the
inner ear is through the RWM into the perilymph of the scala tympani [25].
The RWM is a three-layered structure that contains micropinocytotic vesi-
cles in all three layers [29,30], which allows passage of many substances,
such as electrolytes, peroxidase, and albumin [31]. The passage of substances
into the inner ear is not just a passive phenomenon but involves three differ-
ent mechanisms: diffusion, interepithelial transport, and intraepithelial
transport. The permeability of the RWM was also found to increase approx-
imately 48 hours after middle ear infection was experimentally induced
[32,33]. Conversely, in patients with CSOM, the RWM may become thick-
ened secondary to an immune response and the deposition of connective tis-
sue (including mucosal web formation), which renders the membrane less
permeable during this chronic inflammatory state [31]. One reason that
any reduction in permeability of the RWM should protect the inner ear
from the products of inflammation and conceivably, the potentially ototoxic
components of ototopical preparations.

Ototoxicity of topical preparations

Ototoxicity (and nephrotoxicity) associated with systemic use of amino-
glycosides was noted soon after the introduction of streptomycin by Waks-
man [34] in 1949. Newer agents (neomycin, 1949; gentamicin, 1963) were
developed with the intent to introduce an effective and less toxic substitute
[35,36]. These agents have demonstrated varying degrees of vestibular and
cochlear toxicity, however. For example, in virtually all patients with pro-
longed high plasma levels of an aminoglycoside, vestibulocochlear damage
occurs [37]. Even when the plasma levels of an aminoglycoside are within
what has been considered to be a safe therapeutic range (ie, normal plasma
peak and trough levels), some patients may develop ototoxicity (the amino-
glycoside can continue to concentrate within the inner ear independent of its
renal excretion/hepatic metabolism). In approximately 17% of patients who
develop ototoxicity, a specific mutation (1555 A / G) of the mitochondrial
12S ribosomal RNA gene has been identified [37,38]. Whether there is a ge-
netic susceptibility to ototoxicity from topically administered aminoglyco-
sides is not known. Because of the risks associated with the use of
systemic aminoglycosides, some clinicians have abandoned their use, partic-
ularly because equally effective systemic and topical alternatives without risk
for ototoxicity are currently available [25,27,39].
In 1957, the potential for topical ototoxicity in humans was demonstrated
by Schuknecht [40]. In his treatment paradigm, streptomycin was adminis-
tered transtympanically for patients with incapacitating Meniere’s disease.
Schuknecht achieved good results for the relief of vertigo, but this treatment
usually resulted in a severe deafness in the treated ear.
 OTOTOXICITY OF OTOTOPICAL DROPS 673

The possibility that ototopical aminoglycoside preparations have the po-

tential for ototoxicity has been investigated in several animal models. Sev-
eral studies have documented the ototoxicity of various aminoglycosides
when administered topically: gentamicin in bullfrogs [41], guinea pigs [42],
and cats [43]; streptomycin in guinea pigs [44] and pigeons [45]; streptomycin
and gentamicin in gerbils [46]; and neomycin in guinea pigs [47–49]. The
deleterious effect of polymyxin B/neomycin/hydrocortisone on hair cells
of chinchillas [50] and guinea pigs [51] also was documented. Some species
differences were noted. In primates (ie, baboons), polymyxin B and neomy-
cin caused hair cell loss and strial injury, although the hair cell loss was less
severe than that seen in chinchillas [52].
Although the demonstrated ototoxicity of aminoglycosides in various
laboratory animal models suggests that these drugs also are ototoxic in hu-
mans, interspecies differences in the anatomy and physiology of the RWM
confound the predictability of the response. In humans, the structure of the
RWM is similar to that of baboons (but thicker) and is much thicker than
that of chinchillas [53]. The anatomic location of the round window niche in
humans is such that it is not as exposed as in chinchillas and guinea pigs
[31,54]. Overall, the extrapolation of results from animal studies to humans
from topical ototoxicity should be done with caution [55].
Further evidence for the clinical ototoxicity of gentamicin is demon-
strated by its intratympanic treatment of patients with Meniere’s disease
[28,56–58]. In most cases the topical gentamicin solution used in intratym-
panic therapy for Meniere’s disease is prepared in the pharmacy using gen-
tamicin solutions intended for intravenous administration. This preparation
results in a high concentration of gentamicin being administered intratym-
panically (between 24 and 40 mg/mL, depending on whether the solution
is buffered). One unique study, however, demonstrated that a commercially
available ototopical gentamicin preparation (Garasone [gentamicin 3 mg/
mL/1% betamethasone]) could ablate vestibular function if used in a pro-
longed fashion [24]. Most patients had objective evidence of a vestibulo-
ototoxic effect as judged by absent or diminished caloric responses on the
treated side [28]. Unfortunately, 10 of 23 patients in this study had a wor-
sening of their hearing, which indicated that this topical preparation contai-
ning gentamicin also could be cochleotoxic [28].
The ability of gentamicin to pass through the RWM into the inner ear was
demonstrated in another unique study of patients who had Meniere’s disease
or vestibular schwannomas who were scheduled for either labyrinthectomy or
translabyrinthine surgery [59]. Gentamicin was injected into the middle ear ei-
ther transtympanically before surgery (two patients) or intraoperatively
through the facial recess. During surgery, samples of labyrinthine fluid, cere-
brospinal fluid, and blood were obtained and analyzed for gentamicin [59].
The authors showed that gentamicin was concentrated in the labyrinthine
fluid after transtympanic injection [59]. This study confirmed that as in ani-
mals, the RWM allows small molecules (ie, %1000 molecular weight) to
674 HAYNES et al

pass into the inner ear [59]. Each of the aminoglycosidesdneomycin, strepto-
mycin, gentamicin, kanamycin, and tobramycindhas a molecular weight
!1000 molecular weight so that each may readily pass from the middle ear
into the inner ear through the RWM [30,59].
Despite the widespread use of aminoglycoside drops worldwide, relatively
few cases of ototoxicity seem to have been documented in the literature [60].
Cases that have been reported are primarily case reports or reports from rel-
atively small series of patients [22,61–69]. Roland’s [70] review of the current
world literature in 1994 estimated the incidence of ototoxicity (as measured by
reports of hearing loss) from ototopical aminoglycoside drops to be approx-
imately 1 in 10,000 or lower. The largest series of documented cases of ototox-
icity with aminoglycoside drops were reported by Rutka and colleagues [1,28]
in Toronto. They noted that ototoxicity may be underreported if hearing loss
alone is used as a determination for documenting ototoxicity and that there
was a greater incidence of vestibular symptoms in their series than hearing
loss, especially from topical gentamicin preparations.
That Rutka and colleagues accumulated this series in Canada is not
coincidental. The primary ototopical agent in Canada at the time was Ga-
rasone (gentamicin/betamethasone), whereas the aminoglycoside-containing
ototopical agent with the largest market share in the United States was Cor-
tisporin Otic (or the generic equivalent neomycin/polymyxin B/hydrocorti-
sone). Overall, gentamicin has been found to be more vestibulotoxic than
cochleotoxic, which may explain the greater incidence of acute vestibular
loss and chronic disequilibrium from the Canadian studies. These adverse
reports have led Health and Welfare Canada, the governmental department
that oversees public health issues, to issue warnings as early as 1997 regard-
ing the use of these drops in open or infected middle ears with a TM defect
[71]. Informed consent warning patients of possible ototoxic side effects of
aminoglycoside ear drops has been suggested [72] and was recommended
by the 2004 AAO-HNS consensus panel in their evidence-based medicine
and best practice review [2].

Ototoxicity of other topical preparations

Nonaminoglycoside antibiotics
Chloramphenicol, one of the first antibiotics to be used as an ototopical
agent, has shown evidence of ototoxicity in animals [73,74]. Vasocidin ophthal-
mic solution has been used as an alternative to aminoglycoside-containing oto-
topical agents. Animal studies (chinchillas) have shown that this preparation has
no toxic effect on inner ear function but is irritating to middle ear mucosa [75].
Antifungal agents
Fungal external otitis remains a commonly encountered and difficult-to-
treat disorder. Currently, no topical otic agent exists that has been approved
 OTOTOXICITY OF OTOTOPICAL DROPS 675

by the US Food and Drug Administration for the treatment of otomycosis.

Otolaryngologists, by necessity, have used multiple off-label topical antifun-
gal agents in the treatment of otomycosis, with variable efficacy and safety.
Merthiolate (thimerosal) has been reported to be effective for otomycosis
[76] but has been banned for use as a topical antiseptic because it contains
mercury [77].
In animal studies (guinea pigs), miconazole, clotrimazole, tolnaftate, and
nystatin have demonstrated no evidence of ototoxicity when used as topical
antimycotic agents [47]. Gentian violet, used for years as a topical antifungal
agent, has shown significant evidence of ototoxicity in animal studies
[47,78]. Cresylate and VoSol (hydrocortisone and acetic acid, nonaqueous
2%), commonly used as ototopical agents in the treatment of otomycosis,
also have demonstrated evidence of ototoxicity in animal studies [79–81].

Antiseptics
In addition to Cresylate, VoSol, and gentian violet, other ototopical an-
tiseptics have been implicated as having potential for ototoxicity. Ethanol
has been studied in guinea pigs and povidone iodine has been studied in
chinchillas, and both demonstrate evidence of ototoxicity [82]. Clinical evi-
dence with betadine in ear surgery and with otorrhea management would
suggest that it is safe, however.
Chlorhexidine, an antiseptic used for skin preparation for surgery, has
been shown to cause ototoxicity if introduced to the middle ear [83]. Acetic
acid and preparations that contain acetic acid, have been found to be toxic
to isolated chinchilla cochlear outer hair cells [81]. Similarly, in chinchillas
an otic solution that contained acetic acid was ototoxic, as demonstrated
by changes in compound action potentials after the medications was in-
stilled into the inner ear through the RWM [80].

Corticosteroids
Corticosteroids (hydrocortisone, dexamethasone) have been used in com-
bination ear drops for years because of their anti-inflammatory effects.
These agents, considered to be safe and effective, have been found to have
a protective effect on the cochlea and are used transtympanically to reverse
hearing loss and possibly control symptoms of Meniere’s disease [84].
Spandow and colleagues [85], however, showed in rats that topical applica-
tion of hydrocortisone may lead to hearing impairment.

Agents that provide a protective effect on the cochlea

Although multiple agents have demonstrated cochlear and vestibular tox-
icity in animals and humans, many studies have focused on which drugs may
have a protective effect on the inner ear. Agents that have shown a positive
676 HAYNES et al

protective effect (primarily against parentally administered drugs) include

iron chelators [86,87], glutathione [88], corticosteroids [89], salicylates [90],
alpha lipoic acid [48], glial cell line–derived neurotrophic factor [91,92],
leupeptin [93], and N-methyl-D-aspartate receptor antagonists [94].

Efficacy and ototoxicity of fluoroquinolone-containing otic drops

Clinical studies that involve adults who have CSOM [95–98] and children
who have PTTO [20,99,100] show no evidence of ototoxicity. Basic science
and research studies have shown no evidence of ototoxicity with
ciprofloxacin or ofloxacin [51,100–105]. Clinical studies support the efficacy
of fluoroquinolones in the treatment of otorrhea associated with TTs
[20,99,100,106–110] and in the treatment of CSOM [18,95–98,103,105,111–
115]. The reader is referred to the cited references for further elaboration on
these studies.

A chronology of evolving guidelines from the American Academy

of Otolaryngology–Head and Neck Surgery concerning ototopical
preparations
Historically the AAO-HNS adopted a position statement on ototopical
antibiotics in 1994, which was reaffirmed in 1998, that recognized the appro-
priateness of treating ear disease with topical antibiotics, including amino-
glycoside antibiotics.
In 2000, a consensus panel convened to address the issue of ototopical
drops and their potential for causing ototoxicity. A summary of these
recommendations is as follows [5]:
1. Topical antibiotics remain the first-line treatment of choice for uncom-
plicated otorrhea.
2. Non-ototoxic drops should be considered as first-line treatment of un-
complicated CSOM and PTTO.
3. The safety and efficacy of the non-ototoxic drops (ciprofloxacin, oflox-
acin) have been established, but other issues, such as cost and availabil-
ity, should be considered in selecting therapy.
4. Negligible risk exists when using ototoxic preparations when the TM is
intact.
5. Culture-directed therapy is indicated when systemic antibiotics are
required.
In 2004, a consensus panel convened by the American Academy of Oto-
laryngology-Head and Neck Surgery (AAO-HNS) published the following
guidelines in a March 2004 supplement to the Academy journal [2]:
1. When possible, topical antibiotic preparations free of potential ototox-
icity should be preferred over ototopical agents that have the potential
for ototoxic injury if the middle ear and mastoid are open.
 OTOTOXICITY OF OTOTOPICAL DROPS 677

2. If used, potentially ototoxic antibiotic preparations should be used only

in infected ears. Use should be discontinued shortly after the infection
has resolved.
3. If potentially ototoxic antibiotics are prescribed for use in the open mid-
dle ear or mastoid, the patient should be warned of the risk of
ototoxicity.
4. If potentially ototoxic antibiotics are prescribed, the patient should be
specifically instructed to call the physician or return to his or her office
if the patient develops the following:
a. Dizziness or vertigo
b. Hearing loss
c. Tinnitus
5. If the TM is known to be intact and the middle ear and mastoid are
closed, then the use of potentially ototoxic preparations presents no
risk of ototoxic injury.

Medicolegal issues
Recent attention has been given to medical cases in the United States and
Canada involving litigation in which patients were claiming injury or
negligence stemming from inappropriate use of ototopical preparations.
Researching these medicolegal cases and their outcomes is difficult [60].
The exact number of these cases is unknown, but the same authors have
given expert consultation and opinion in numerous cases in the United
States and Canada. Some of the issues and recurrent themes from our
combined experiences are outlined as follows:
 The symptoms of vertigo, not hearing loss, may predominate in these
cases. A subjective complaint of vertigo, with or without objective find-
ings (without objective evidence of hearing loss), may be the only
complaint.
 Most cases occurred in patients treated after 1997–1998, the year in
which fluoroquinolone drops were introduced. The AAO-HNS position
statement on this issue was not published until June 2000, with a second,
stronger, more definitive statement published in March 2004. These
dates are significant because the March 2004 consensus statement is
much stronger in recommending non-ototoxic alternatives. (See the
AAO-HNS position statements in the previous section.)
 The fact that a safer and equally effective alternative ototopical agent
(fluoroquinolone drops) without risk for ototoxicity was available and
not used is emphasized.
 Treatment with drops for prolonged periods of time (O7 days) or mul-
tiple refills of potentially ototoxic drops, especially when the otorrhea
has ceased, without an intervening patient examination are significant.
 Ophthalmologic drops that contain potentially ototoxic antibiotics are
particularly addressed because they are used off-label and are not
678 HAYNES et al

approved by the US Food and Drug Administration for use in the ear.
Although frequently used and considered to be a superior alternative to
many otologic drops, these drops have no written or approved indica-
tion for use in the ear, and this fact is often emphasized.
 Costs, availability, and insurance formularies are often not considered
significant issues.
 Failure to provide the appropriate informed consent on the potential for
the aminoglycoside containing drops to result in ototoxicity is empha-
sized, despite the fact that the need to give informed consent has been
addressed only recently.

Summary
That ototopical drops can enter a PET or perforation and have adverse
effects on the inner ear is no longer a topic of debate. The clinical incidence
of ototoxicity, especially in the presence of inflammation, remains low but
not insignificant, however. Recent literature suggests that this incidence,
especially that of vestibular ototoxicity, may be underrecogonized and
underreported. Ototopical agents are a highly effective and powerful tool
for clinicians and should be used as a first-line agent for otorrhea. Non-
ototoxic preparations should be used when the clinical situation allows.

Acknowledgments
The authors wish to acknowledge the valuable contributions and exper-
tise of Robert K. Shapter, MD, Lucille Woodroof, and Project House in
the preparation of the manuscript.

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