A dog with elephant-like skin

Key Facts

Ototoxicity can result from oral or parenteral drug therapy or from the application of topical agents to the external ear canal If the tympanic membrane has been perforated.
Although the ototoxic action of Intratympanic application of aminoglycoside antibiotics Is well documented, gentamicin and neomycin are still the most common antimicrobial agents used to treat otitis externa.
If antiseptic solutions are Infused Into the middle ear through a perforated tympanic membrane, such Irreversible effects as partial or total loss of vestibular and cochlear function can result.
In patients that are at risk, agents that are known to be ototoxic should be avoided or used cautiously.

An OTOTOXIC AGENT is a substance that can induce hearing loss or disturbances of equilibrium by injuring structures within the inner ear. The loss can be obvious to the pet owner or apparent only during audiometric testing. Ototoxic injury to the vestibular apparatus can produce mild to severe ataxia, head tilt, circling, and nystagmus.¹ Tinnitus and dizziness are relatively common signs in humans^2,3 but are usually not detected in animals. Cochlear and vestibular damage can occur together or separately; such damage can be unilateral or bilateral.

Clinical signs can be acute or can progress insidiously. Signs can be transient or permanent, can progress after the therapeutic agent is withdrawn, and can be dose related or idiosyncratic.² There apparently is no significant species-specific reaction to ototoxic drugs or agents.

Ototoxicity can follow therapy with oral and parenteral drugs or the application of topical agents to the external ear canal (if the tympanic membrane has been perforated).³ The effects of certain chemicals and drugs on hearing and balance have been documented in experimental animal studies.^3-11 In veterinary practice, the primary route of ototoxicity apparently is the application of topical preparations for treating otitis externa.

Fifty percent of dogs with chronic otitis externa have concurrent rupture of the tympanic membrane and infection of the tympanic cavity.¹² Topical agents freely pass into the middle ear if rupture of the tympanum occurs secondary to infection, if the membrane is accidentally perforated, or if myringotomy is performed.

From the middle ear, topical agents can enter the inner ear through the cochlear (round) or vestibular (oval) window.^1,2 Oral and parenteral drugs enter the inner ear by hematogenous routes.^2,13 A review of the basic anatomy and physiology of the inner ear is presented here to facilitate understanding of the adverse effects of ototoxic agents.

The inner ear is medial to and adjacent to the middle ear. The inner ear communicates with the middle ear by the oval window (covered by the footplate of the stapes) and the round window (covered by a thin membrane) (Figure I). The inner ear is located within the petrous temporal bone and consists of the cochlea and the vestibular apparatus. The entire structure is a series of interconnecting bony cavities (the osseous labyrinth) (Figure 2). Within these cavities are several communicating membranous sacs and ducts (the membranous labyrinth).¹⁴

The perilymph fills the spaces between the osseous and membranous labyrinths and has a composition similar to that of extracellular fluid.¹³ The perilymph is apparently formed by an influx of cerebrospinal fluid and by ultra-filtration from vessels in the tissue that covers the inner walls of the osseous labyrinth. The potassium-rich endolymph within the membranous labyrinth is similar to intracellular fluid in ionic composition.¹³ The endolymph is believed to originate from the vascular secretory bed (stria vascularis) of the cochlea and from the secretory epithelium of the vestibular apparatus.¹³

THE ANATOMY OF the membranous labyrinth is complex. Simply stated, within the cochlea is the spiral organ of Corti, the receptor for hearing. Within the vestibular apparatus are the semicircular canals and the vestibule. The vestibule is composed of two saclike structures: the saccule and the utricle.¹⁴

All sensory organs in the membranous labyrinth depend on the hair cells for function.¹³ The hair cells are mechanoreceptor cells with nonmotile cilia that protrude from the surface. The basal portions of these cells synapse with the dendritic terminals of afferent nerve fibers.

Although the hair cells function similarly in the cochlea and the vestibular apparatus, the biologic signals that are generated differ. This difference is caused by the distinct mechanical properties and central nervous system pathways of the specific anatomic areas.

In air, sound is a series of compression waves and rarefactions that strike the tympanic membrane and make it vibrate. The vibratory motion is transmitted through the ossicles to the oval window; here movement of the footplate of the stapes sets the fluid of the inner ear in motion. This traveling wave causes the basilar membrane on which the organ of Corti rests to undulate. Different frequencies of the stimulating sound cause maximum displacement of the membrane at different points. Movement of the basilar membrane bends the cilia of the hair cells in the organ of Corti; this action causes the cells to depolarize. This depolarization generates impulses that travel along the axons of the cochlear nerve.¹⁵

In the vestibular apparatus, the three semicircular canals detect angular acceleration of the head of the animal. The saccule and utricle are sensitive to linear motion. At specific sites within these structures, hair cells are oriented in various directions and the cilia protrude into the endolymph. Because of its inertia, the endolymph tends to remain stationary, When the head moves, the relative fluid flow in the labyrinth in a direction opposite to the movement results in mechanical stimulation and depolarization of the hair cells. The generated impulses travel along the axons of the vestibular portion of the eighth cranial nerve.¹⁵

The primary sites of drug action within the inner ear apparently are the sensory receptors (i.e. , the hair cells) and stria vascularis of the cochlea or the analogous structures of the vestibular apparatus.¹³ Several factors govern the distribution of drugs in the fluid compartments of the inner ear and the accessibility of drugs to sensory receptors. The perilymphatic fluid compartment of the cochlea is continuous with the vestibular system. Agents that gain access to the perilymphatic fluid can thus be distributed to the cochlear and vestibular sensory receptors and to the associated nerve endings.¹³

By contrast, the circulation of endolymph in the membranous labyrinth is not continuous between the cochlea and the vestibular apparatus. It is thus unlikely that drugs entering the endolymph of the cochlea or the vestibular apparatus are distributed by the fluid to the other system.¹³

The stria vascularis of the cochlea apparently is another source of entry for systemic administration of drugs into the inner ear.¹³ Diffusion or active transport of drugs into this vascular secretory bed might explain the selective cochlear toxicity evident with some drugs.¹³

Although drugs can gain access to the receptors by passive or active transport from the capillary beds of the vascular system, a blood-cochlea barrier is present. The barrier is apparently similar to the blood-brain barrier and is important in determining which systemic drugs gain access to the cochlea.¹³ It is not known whether a similar barrier exists in the vestibular portion of the inner ear.

Some ototoxic substances are categorized in the listing on page 334. The most commonly used substances are discussed here.

Most of the antibiotics that have ototoxic properties are aminoglycosides. Unlike other common antibiotics, aminoglycosides concentrate in the perilymph and endolymph; the hair cells are thus exposed to high concentrations of these drugs. Although all aminoglycosides can damage auditory and vestibular receptors, streptomycin and gentamicin have the greatest effect on the vestibular apparatus while neomycin, kanamycin, tobramycin, and amikacin sulfate cause more damage to the auditory system.^3,15

STREPTOMYCIN AND GENTAMICIN cause swelling of sensory hairs and deformation of cell surfaces.² These drugs evidently damage the plasma membrane and membrane components of mitochondria, thereby increasing cell permeability much like the effect of these drugs on bacterial cells.² Kanamycin and neomycin apparently first affect the hair cells of the basal coil of the cochlea; the agents primarily cause high-frequency sensorineural hearing loss with later damage progressing toward the apex.


Aminoglycoside Antibiotics
Streptomycin^2,3	Amikacin sulfate^2,3
Gentamicin^2-4	Netilmicin sulfate³
Kanamyciw,³	Sisomicin³
Tobramycin^2,3	Framycetin³
Neomycin^2,3
Nonaminoglycoside Antibiotics
Polymixin B^2,3	Erythromycin³
Colistin (polymixin E)^2,3	Chloramphenicol^1,2,5
Minocycline^2,3	Vancomycin^2,3
Antiseptics
Ethanol^1,2,8	Benzalkonium chloride^1,3,11
Iodine and iodophors^1,3,9	Benzethonium chloride^1,3,11
Chlorhexidine^1,3,10	Centrimide^1,10
Diuretics
Ethacrynic acid^2,3	Furosemide^2,3,6
Bumetanide^3,6
Antineoplastic Agents
Nitrogen mustard^2,3	Cisplatin^3,7
Miscellaneous Agents and Chemicals
Quinine²	Ceruminolytic agents¹⁶
Salicylates²	Arsenic^2,3
Propylene glycol³	Lead^2,3
Detergents¹⁶	Mercury^2,3

The hair cells that are most abundantly supplied with large, richly granulated nerve endings evidently are the most vulnerable. Degeneration of nerve endings and nerve fibers begins soon after loss of the corresponding hair cells; such degeneration does not occur without loss of sensory cells.² The primary effect on the hair cells apparently is on cell membrane permeability similar to that seen with anoxic damage. The nuclei and ribosomes (the protein-synthesizing organelles) are most affected. The nerve endings, which do not synthesize protein, are not damaged. Again, the toxic effects on sensory cells can be the same as the effects on bacterial cells.²

The ototoxic action of intratympanic application of aminoglycoside antibiotics is well documented.³ Nevertheless, gentamicin and neomycin are still the most commonly used antimicrobial agents. for treating otitis externa in dogs and cats. In cats, topical application of 3% gentamicin solution to the tympanic bulla is demonstrated to be toxic to the sensory receptors of the cochlea and the vestibular apparatus.^3.4 In guinea pigs, long-term application of 0.3% gentamicin solution kills hair cells in the cochlea and the vestibular apparatus.³ The effects of topical and systemic aminoglycoside antibiotics are generally similar. The severity of injury is dose related.

Nonaminoglycoside antibiotics that are ototoxic if topically applied include polymixin B ^2,3 and chloramphenicol.^2,3,5 The polypeptide antibiotics (polymixin B and polymixin E) are potentially ototoxic if systemically administered, but there is no evidence that systemically administered chloramphenicol injures the neuroreceptors of the inner ear.³

Antiseptic solutions that are infused into the middle ear through a perforated tympanic membrane can produce such irreversible effects as partial or total loss of vestibular and cochlear function.^1,10,11 Antiseptics determined to be ototoxic in experimental studies or clinical cases include ethanol,^1,2,8 iodine, iodophors,^1-3,9 chlorhexidine,^1,3,10 and three quaternary ammonium compounds (benzalkonium chloride,^1,3,7 benzethonium chloride, ^1,3,7 and cetrimide^1,10).

Chlorhexidine and quaternary ammonium compounds are cytotoxic to bacteria and thus destroy the cytoplasmic membrane and alter membrane function.¹⁰ These actions might explain the immediate cochlear and vestibular dysfunction evident after instillation of the products into the middle ear.¹⁰ In addition to degeneration of cochlear and vestibular hair cells, fibrosis and ossification can develop in the labyrinthine structures.¹

Diuretics that are potentially ototoxic include ethacrynic acid,^2,3 bumetanide,^3,6 and furosemide^.2,3,6 These drugs are referred to as the loop diuretics because the primary action is inhibition of chloride reabsorption in the thick, ascending limb of Henle's loop. The agents selectively affect the auditory system. Morphologic changes occur in the stria vascularis of the cochlea; but there is no histologic change in the organ of Corti, spiral ganglion, efferent nerves, or afferent nerves.³ The mechanism of ototoxicity is not fully understood but is presumed to be related to acute electroIyte alterations in the cochlear endolymph; the same mechanism produces diuresis in the kidneys.²

FUROSEMIDE IS THE LOOP diuretic most commonly used in veterinary medicine. The drug is the least ototoxic of the group, and the effects are dose related. Experimental animal studies indicate that the ototoxic effect is reversible and of relatively short duration. Hearing loss induced by furosemide in humans is not always reversible.³

Cis-diamminedichloroplatinum (cisplatin) is a forerunner in modem chemotherapy and is the only currently used antineoplastic agent that is ototoxic.³ Cisplatin causes hair cell damage in the cochlea; the damage is morphologically similar to the injury caused by the aminoglycosides. High-frequency hearing loss occurs first; low-frequency hearing is affected later in the course of intoxication.^3,7

The dose at which cochlear damage is induced varies, and the effects apparently are idiosyncratic.^3,7 Loss of hearing might be temporary, but the injury is generally irreversible. Cisplatin therapy has not produced toxicity of the vestibular system in animals, but such toxicity has been documented in humans.³

Vehicles used in otic preparations can be ototoxic. Propylene glycol, a commonly used medium, causes granulation and ossification of the auditory bulla as well as morphologic changes in the organ of Corti.³ Although dimethyl sulfoxide is apparently not ototoxic, caution is advisable in using the product as a vehicle for toxic substances. ototoxicity was reported in a human patient with skin surfaces that were topically treated with an ointment consisting of 1% neomycin and 11% dimethyl sulfoxide.¹³

Ceruminolytic agents and detergents are reportedly contraindicated if the tympanic membrane is perforated.¹⁶ Although definitive information is unavailable, clinical observations implicate these products as possible causes of injury to structures in the middle or inner ear.

The product labels of some cleaning agents provide a warning to avoid use in the ear if the tympanum might be perforated. Some labels do not have warnings. Queries concerning product safety have been addressed to the manufacturers of products without warnings. Manufacturers who have responded state that no safety or ototoxicity studies have been performed using their products in dogs or cats with perforated tympanic membranes.

Although the prevalence of injury caused by ototoxic drugs is uncertain, risk is involved for animals treated with the agents. The risk can be reduced by selective use of ototoxic agents and by strict adherence to appropriate dose and duration of treatment,

Systemic therapy with ototoxic drugs, especially the aminoglycoside antibiotics, is inherently risky, Several factors increase the risk of aminoglycoside-induced ototoxicity (see the listing on this page),³ If these antibiotics are administered, renal function should be used as a monitor of ototoxicity. Determination of serum drug levels might be helpful; however, peak and trough levels have not been demonstrated to correlate closely with ototoxicity.¹⁷ In the perilymph, aminoglycoside antibiotics reach peak levels two to five hours after parenteral administration. The half-life of aminoglycosides is 5 to 12 hours in the perilymph and 90 minutes in the serum.¹⁸

A ruptured tympanic membrane is a dilemma in the treatment of otitis extema. Topical agents that are known to be ototoxic should be avoided. If abundant cerumen or exudate precludes examination of the tympanic membrane, the clinician cannot ascertain the status of the tympanum. In such instances, water or saline solution is used to irrigate the auditory canal.

CLEANSING THE EAR by irrigation with rubber bulb syringes, plastic syringes, or water-jet appliances can result in rupture of the tympanic membrane. In tests conducted on fresh canine cadavers and live dogs, insufflation of the ear canal with a pressure of 300 mm Hg failed to rupture normal tympanic membranes. In ears with even slight inflammation, however, insufflation of 80 mm Hg caused rupture.¹⁸

Detergents and ceruminolytic agents can be necessary for adequate cleaning and visualization of the tympanic membrane. If ototoxic agents are applied in an auditory canal with a perforated membrane, immediate irrigation of the tympanic cavity with water or saline can remove the offending agents and reduce injury. Further risk of injury can be avoided by using nontoxic agents. Diagnostic evaluation (e.g., cytologic examination, microbiologic culture and sensitivity testing, and intradermal allergy testing) facilitates the selection of appropriate treatment.

Dr. Mansfield, who is a Diplomate of the American Board of Veterinary Practitioners, is affiliated with the Department of Small Animal Surgery and Medicine, College of Veterinary Medicine, Auburn University, Auburn, Alabama