Ototoxic Medications
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CHEMOTHERAPY AGENTS
| Drug | Vestibulotoxicity | Hearing Toxicity | Toxic Level |
| Actinomycin | |||
| Bleomycin | |||
| Cisplatin | Minor | 69% | total dose > 200 mg/sq meter. |
| carboplatin | 1-10% | ||
| nitrogen mustard | yes | yes | |
| Vincristine | yes | yes | |
| DCM | yes | yes |
Comment: While reportedly ototoxic, these medications are rarely encountered as a source of vestibular dysfunction. Cisplatin is the most widely used anticancer drug currently and unfortunately, it is cochleotoxic. The toxicity of cisplatin is synergistic with gentamicin, and high doses of cisplatin have been reported to cause total deafness. In animals, cisplatin ototoxicity is related to lipid peroxidation and the use of antioxidant agents are protective (Rybak et al, 2000).
| Drug | Vestibulotoxicity | Hearing Toxicity | Toxic Level |
| Erythromycin | yes | High IV doses only | |
| Gentamicin | 8.6% | minor | Usually 2 weeks |
| Streptomycin | very toxic | minor | |
| dihydrostreptomicin | minor toxic | very toxic | |
| Tobramycin | minor in 6% | Less toxic than Gentamicin | |
| Netilmicin | 2.4% | ||
| Amikacin | not toxic | 13.9% | |
| Neomycin | minor | very toxic | In topical ear drops |
| Kanamycin | minor | very toxic | |
| Etiomycin | moderate | ||
| Vancomycin | nontoxic | none to moderate | synergistic with gentamicin |
| Capreomycin | yes |
Antibiotics for which there is some suspicion of ototoxicity
| Antibiotic | Comment |
| Flagyl (metronidazole) | May be synergistic with Gentamicin (Riggs et al, 1999) |
| Floxins | Anecdotal evidence of dizziness |
Antibiotics generally considered safe
| Antibiotics Generally Considered Safe |
| Aztreonam |
| Penicillins |
| Cephalosporins |
| Macrolides (e.g. Azithromycin and Erythromycin), except in very high doses. |
Comments about antibiotics:
Streptomycin, the first clinically used aminoglycoside is now used only in treating tuberculosis because many gram-negative bacteria are resistant and because of substantial ototoxicity. Streptomycin is no longer used in the United States.
Neomycin, isolated in 1949, is now used mainly topically because of renal toxicity and ototoxicity (to hearing). Hearing ototoxicity from oral absorption of Neomycin has been reported (Rappaport et al, 1986) and there may also be toxicity from ear drops in patients with perforated ear drums. This issue is still unsettled (as of 12/1/98).
Kanamycin, developed in 1957, has been replaced by newer aminoglycosides such as gentamicin, tobramycin, netilmicin, and amikacin. It is not thought to be as ototoxic as neomycin.
Gentamicin is presently the biggest problem antibiotic with respect to ototoxicity as most of the other ototoxic antibiotics have been replaced. Netilmicin has equivalent ototoxicity to Gentamicin (Tange et al, 1995). Gentamicin was released for clinical use in the earlier 1960's. (Matz, 1993); Hearing toxicity generally involves the high frequencies first. Vestibulotoxicity is the major problem rather than hearing toxicity. Certain persons with mitochondrial deletions in the 12S subunit are much more susceptable to Gentamicin than the general population. The prevalence of this mutation is not clear, but 1% of the population is a reasonable estimate based on available data.Vancomycin, by itself, appears to have only minor ototoxicity, but it potentiates the ototoxicity of gentamicin as well as (probably) other aminoglycosides such as Tobramycin. Occasional persons do appear to have substantial vestibular toxicity from Vancomycin. The reason why occasional persons are more sensitive is not clear but might resemble the situation with Gentamicin where there is a susceptability mutation.
Ear drops may contain antibiotics, some of which can be ototoxic when administered to persons with perforated ear drums. Cortisporin otic solution appears to be the most ototoxic to the cochlea of guinea pigs, with much less toxicity for gentamicin drops. Ofloxacin ear drops have negligable toxicity (Barlow et al, 1995). Neomycin containing ear drops have been reported to contribute to hearing loss (Podoshin et al, 1989) in a relatively small way, but a definitive assessment of risk has not yet been made. The vestibulotoxicity of ear drops has so far not been studied, although case reports suggest that gentamicin containing drops are toxic.
There are several known interactions. Loop diuretics (see following) potentiate aminoglycoside toxicity. Vancomycin is synergistic with gentamicin, as is noise. Vancomycin, by itself in appropriate doses, is not ototoxic (Gendeh et al, 1998).
Delayed ototoxicity, meaning essentially toxicity which continues for several months after the drug has been stopped, has been well documented because the aminoglycosides are retained within the inner ear much longer than in the blood. Gentamicin has been reported to persist for more than 6 months in animals. Neomycin, streptomycin and kanamycin are also known to be eliminated from the inner ear slowly (Thomas et al, 1992)
| DRUG | Vestibulotoxicity | Hearing Toxicity | Comment |
| Lasix (furosemide) | No | Yes | Rarely significant |
| Bumex (bumetanide) | No | Yes | Less than Lasix |
| Edecrin (ethacrynic acid) | No | Yes | Same as lasix |
Diuretics generally considered Safe: Chlorthiazide
Diuretics are rarely a source of vestibulotoxicity. They are possibly a source of hearing disturbance. They may be synergistic with other aminoglycoside ototoxins such as gentamicin, neomycin, streptomycin and kanamycin. It seems prudent to attempt to avoid exposure to these agents if hearing is impaired.
Rybak LP. Furosemide ototoxicity: clinical and experimental aspects. Laryngoscope 1985 Sep;95(9 Pt 2 Suppl 38):1-14.
QUININE DERIVATIVES| DRUG | Vestibulotoxicity | Hearing Toxicity | Comment |
| Quinidex | No | Yes | Tinnitus |
| Atabrine | No | Yes | |
| Plaquenil | No | Yes | |
| Quinine Sulfate | No | Yes | |
| mefloquine (Lariam) | Probable | Yes | Tinnitus and dizziness |
| Chloroquine | No | Yes |
Comment: While quinine ingestion can cause a sydrome including tinnitus, sensorineural hearing loss and vertigo, quinine derivative drugs are rarely by themselves a source of hearing disturbance. Some quinine derivatives taken for malaria prevention cause significant and long-lasting tinnitus. Recent studies suggest that quinine impairs outer hair cell motility (Jarboe and Hallworth, ARO abstracts, 1999, #237).
We thank Lariam Action USA (email LariamInfo@yahoo.com; web site http://lariaminfo.homestead.com),for supplying some of the references above related to lariam.
ASPIRIN, NSAIDS and other ANALGESICSAspirin and Nsaids (non-steroidal anti-inflammatory agents) -- commonly used, and apparently only toxic to hearing . These include Advil, Nuprin, Motrin (Ibuprofen), Aleve, Naprosyn, Anaprox (Naproxen), Feldene, Dolobid, Indocin, Lodine, Relafin, Toradol, Volteran, Salicylates: Aspirin, disalcid, Bufferin, Ecotrin, Trilisate, Ascriptin, Empirin, Excedrin, Fiorinal.
Rarely hearing loss is reported from other types of analgesics, for example hydrocodone/acetaminophen combination (Friedman et al, 2000; Oh et al, 2000)
Permanent hearing disturbances are possible but rare. They are most commonly seen in individuals who take aspirin in large doses for long periods, such as for treatment of arthritis. Occasionally persons with Menieres syndrome will develop a hearing disturbance from a small amount of a NSAID.
| DRUG | Vestibulotoxicity | Hearing Toxicity | Comment |
| PTU | No | Yes | |
| Desferroxamine | No | Yes | May protect against gentamicin toxicity |
| hexadimethrine (Polybrene) | |||
| Calcium Channel blockers | Probably | No evidence of this to date | |
| Sulfonamides | |||
| Phenylbutazine |
Mercury and lead are heavy metals which are ototoxic. Practically speaking, these agents are infrequent causes of hearing disturbance.
Toluene affects the ear (outer hair cells) causing hearing loss, as well as the brain.
Noise: e.g. Rock concerts, power equipment, gunfire.
Noise exposure is the most common source of hearing loss. Industrial exposure characteristically causes a "noise notch", with the hearing loss at mid-high frequencies bilaterally. Guns and other unilateral sources of noise cause more circumscribed lesions.
Noise is often also a co-factor in medication type ototoxicity. Those who have hearing loss from an ototoxic antibiotic, for example, may be at much greater risk from noise. There is some evidence that heavy salt eaters are more susceptable to damage from noise.
Protection from ototoxinsLittle is known about protection. Noise avoidance is likely important, but even here the story is complicated. Moderate amounts of noise may protect from extreme amounts of noise. Anti-oxidants protect partially from noise or toxins in several animal models. In theory, protection from oxidative stress might be obtained by prevention of reactive oxygen species, neutralization of toxic products, and blockage of the apoptosis pathway . . Toxic waste products can be neutralized with glutathione and derivatives (Rybak et al, 2000). Apoptosis can be blocked using capsase inhibitors. At this writing, 2/1999, all of these approaches are investigational and are not being used clinically. Most also require delivery systems that go directly into the inner ear, and are therefore impractical for clinical use (Van de Water and others, ARO abstracts, 1999, #21).