Ototoxic Medications

Timothy C. Hain, MD

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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).

Chemotherapy ototoxicity references

ANTIBIOTICS WITH GOOD EVIDENCE FOR OTOTOXICITY

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 Yes 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
Metronidizole toxic (rarely) unknown  
Capreomycin   yes  

 

Antibiotics for which there is some suspicion of ototoxicity

Antibiotic with suspected ototoxicity Comment
Floxins Anecdotal evidence of dizziness

 

Comment: Occasionally a persistent ataxia is reported following use of a floxin (e.g. ciprofloxacin, etc). All cases so far are anecdotal and there is no strong evidence for ototoxicity. Toxicity, if it exists, might involve some other structure (such as the cerebellum). Because toxicity is so sporadic it may require both exposure as well as a genetic predisposition for toxicity.

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:

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. Most persons with gentamicin toxicity have hearing appropriate for their age. Certain persons with mitochondrial deletions in the 12S subunit are much more susceptible to Gentamicin than the general population. Commercial tests are presently available to detect this deletion (the A1555 deletion). The prevalence of this mutation is not clear, but 1% of the population is estimated based on available data. It is likely that there are many other genetic mutations that confer susceptibility, so far undocumented by present day medicine.

Metronidizole (Flagyl) has been reported on several occasions to be ototoxic (Blake and Butt 1984; Hibberd, Nicoll et al. 1984; Hibberd, Nicoll et al. 1984; Lawford and Sorrell 1994; Iqbal, Murthy et al. 1999; Riggs et al, 1990). Metronidizole toxicity fortunately appears to be rare and documented only by sporadic case reports..

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.

Streptomycin, the first clinically used aminoglycoside is now used primarily in treating tuberculosis because many gram-negative bacteria are resistant and because of substantial ototoxicity. Streptomycin is now rarely used in the United States.

Tobramycin is only rarely associated with ototoxicity, perhaps because it is less commonly used than gentamicin, but there is clear evidence that it can produce a vestibular syndrome similar to gentamicin. Most cases of Tobramycin toxicity have occurred in persons with renal impairment. It is suspected that tobramycin is ototoxic to hearing in neonates (de Hoog et al, 2002).

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 susceptibility 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 negligible 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. No cases have been reported of tobramycin drops resulting in ototoxicity. The vestibulotoxicity of most ear drops has so far not been studied, although case reports suggest that gentamicin containing drops are toxic.

There are several known interactions between families of ototoxic medications. Loop diuretics (see following) potentiate aminoglycoside toxicity. Vancomycin is synergistic with gentamicin in that it is more likely to cause toxicity, 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)

References:

 

OTOTOXIC DIURETICS

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 syndrome 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).

References:

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 ANALGESICS

Aspirin 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. Arthrotec (diclofenac and misoprostel) has been associated with tinnitus and hearing reduction (Bombardier, Peloso et al. 1995).

Hydrocodone in combination with acetaminophen has also been associated with hearing loss (Friedman, House et al. 2000; Oh, Ishiyama et al. 2000).

Fiorinal contains aspirin, which is well known to be an ototoxin capable of causing a sensorineural hearing loss and tinnitus (Brien 1993).

Over the counter headache powders also commonly contain aspirin or related compounds (salicylates) and therefore have a potential for causing hearing toxicity.

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 severe arthritis. Occasionally persons with Menieres syndrome will develop a hearing disturbance from a small amount of a NSAID.

Acetaminophen is not generally thought to be ototoxic although in combination with hydrocodone as noted above there have been cases of hearing lost.

References:

MISCELLANEOUS OTOTOXIC DRUGS

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      

 

Other Toxins (not medications):

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 ototoxins

Little 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).

 

 


General references: