Experimental Studies

Many reports have identified ototoxic substances in animals, including dogs and cats. Some of the ingredients found in topical preparations that are safely used on the skin in the external ear canal can cause damage to the respiratory tissues that line the middle ear cavity and to the nervous structures in the inner ear. Some drugs are ototoxic when used systemically but do not seem to have the same ototoxic potential when used topically. One example of this phenomenon is tobramycin. Numerous reports of ototoxicity have been published in regard to the injectable form; however, there are no published reports of ototoxicity from topical otic use of tobramycin.³

Many experimental trials demonstrating ototoxic potential are done in normal laboratory animals. They involve placing medication or ear cleaners directly into one of the tympanic bullae for several days. Usually saline is infused into the opposite bulla as a negative control. But for a positive contol, gentamicin infusion into the tympanic cavity of laboratory animals may be substituted. In ototoxicity studies, brain-auditory-evoked-response (BAER) testing is done to determine hearing loss prior to euthanizing the experimental animals. Cochlear damage occurs initially in the cells detecting high-frequency sounds, so these animals first lose the ability to detect high-pitched sounds. Neurologic examinations are used to assess the function of the vestibular system. Screening for ototoxicy using the BAER test during safety tests of any otic drug or chemical should be done before its release for use in animals.

Histopathologic analyses of the tympanic bulla and the inner ear from these experimental animals are used to verify evidence of damage to the epithelium of the bulla or to the neurologic structures in the inner ear.

Care is prudent in interpreting the studies done in laboratory animals and extrapolating the results to dogs and cats with diseased middle ears. Studies from normal experimental animals provide clues for potential ototoxicity concerns in dogs and cats; the results bear further investigation. For example, there have been many reported cases of acute deafness in dogs associated with the use of otic products containing gentamicin. One product containing gentamicin, clotrimazole, and betamethasone even warns on the drug label that the product “has been associated with deafness or partial hearing loss in a small number of sensitive dogs.” However in a controlled experiment in 10 normal dogs, when low-dose aqueous gentamicin solution (3 mg/ml) was placed directly into one tympanic bulla twice daily for 21 days, neither cochlear nor vestibular function was affected.⁴

In another study that used juvenile guinea pigs to compare the ototoxicity of polymyxin and gentamicin directly instilled into the bullae, it was determined that the polymyxin group showed a 66% loss of cochlear hair cells compared with a 6.5% loss with gentamicin.⁵ In human medicine, most people with gentamicin ototoxicity have vestibulotoxicity rather than deafness. It has been estimated that up to 1% of the human population has a genetic predisposition to gentamicin ototoxicity.⁶

Ticarcillin (Ticar, SmithKline, Beecham) and ticarcillin with clavulanate potassium (Timentin, SmithKline, Beecham) have been successfully used topically and parenterally for the treatment of refractory Pseudomonas otitis externa and media.⁷ However, chinchilla studies using these compounds have demonstrated significant pathologic effects when they were injected as single applications into normal middle ears.⁸

Can a medication toxic to one species of animal also be ototoxic to another? Can a substance toxic to the cochlea in one species show toxicity to the vestibular apparatus in another species? It is possible that there are genetic differences among animals that confer susceptibility to certain drugs and chemicals, but most of these are undocumented.

Vehicles

Some of the studies done in animals reveal that other factors besides the active ingredient of the drug itself cause neurologic damage. For example, the alcohol bases of disinfectants, not the disinfectant itself, may cause the damage. Aqueous povidone iodine seems to be safe in the middle ear, but tincture of iodine contains alcohol, so it is not safe to use. Alcohol-containing products should be avoided if the status of the eardrum cannot be determined. Could it be that some of the carrier vehicles in ointment bases cause increased contact of the antibiotic with these sensitive epithelial and nervous tissues? Many topical otic products contain propylene glycol, which may cause some inflammation in the external ear canal. However, in the middle ear, it causes increased inflammation of the mucoperiosteum, leading to excessive granulation tissue and bony changes within the bulla.⁹

Dilutional Factors

Some topical products that are ototoxic if used as supplied may not be ototoxic at lower concentrations. Acetic acid at 5% seems to cause more problems than acetic acid at 2%. However, simply diluting a product may not render it safe.

In a series of studies done in cats, chlorhexidine gluconate was shown to cause degeneration of the hair cells in the labyrinthine vestibule of the vestibular apparatus. At a 2% concentration, chlorhexidine caused profound degeneration of these cells, but at a concentration of 0.05% there was less degeneration of these cells.¹⁰ However, even in the dilute chlorhexidine group there were still clinical vestibular signs. Subsequent studies in cats showed loss of hair cells in the organ of Corti over a very wide range at both concentrations. This indicates a cause for hearing loss after the use of chlorhexidine gluconate.¹¹ Chlorhexidine gluconate also caused the loss of the mucociliary clearance function in the mucosa of the tympanic bulla as it produced subsequent cell destruction.¹²

The use of systemic drugs such as salicylates and furosemide causes increased concentrations of gentamicin in the endolymph in the cochlea within the inner ear, resulting in clinical ototoxicity.¹³ Salicylates may actually increase the membrane conductance of the outer cochlear hair cells, increasing the amplification of sound. In human medicine, this results in tinnitus, a high-pitched ringing in the ears.¹⁴ Other systemic drugs such as erythromycin, streptomycin, and cisplatin are also known ototoxins.