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Ototoxic Medications

Timothy C. Hain, MD Page last modified: November 8, 2014

 

The purpose of this page is to list drugs well known to be toxic to the ear. It is not all-inclusive and it should not be relied upon for medical care.

CHEMOTHERAPY AGENTS

Drug Vestibulotoxicity Hearing Toxicity Toxic Level
Carboplatin   1-10%  
Cisplatin Minor 69% total dose > 200 mg/sq meter.
nitrogen mustard yes yes  
Vincristine yes yes  

Comment: While reportedly ototoxic, chemotherapeutic medications are rarely encountered as a source of vestibular dysfunction. Cisplatin is the most widely used anticancer drug currently and unfortunately, it is cochleotoxic, and may injure supporting cells (Ramirez-Camacho et al, 2004). The toxicity begins in the outer hair cells (Reavis et al, 2011) and for this reason DPOAE's have been suggested to be a reasonable method of detecting toxicity. 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 such as vitamin E are protective (Rybak et al, 2000; Kalkanis et al, 2004).

There are many chemotherapy agents which have no credible evidence for ototoxicity, and also many in whom there are single case reports of dubious significance. In general, drugs that are "broad" in their effects on the body would be expected to also have some ototoxicity. Drugs that are very narrow, perhaps aimed at cell markers, would not be reasonably expected to be ototoxic. Some chemotherapy drugs are used in treatment of inner ear disease -- i.e. cytoxin, methotrexate, and Enbrel. These would obviously not be expected to be ototoxic.

Chemotherapy ototoxicity references

ANTIBIOTICS WITH GOOD EVIDENCE FOR OTOTOXICITY

Drug Vestibulotoxicity Hearing Toxicity Toxic Level
Amikacin not toxic 13.9%  
Azithromycin not known occasional Very high dose required
Capreomycin   yes  
Chloramphenicol   yes sporadic reports only
Clarithromycin   occasional  
Dibekacin yes yes  
Dihydrostreptomycin minor toxic very toxic  
Erythromycin   yes High IV doses only
Gentamicin 8.6% minor Usually 2 weeks
Metronidizole toxic (rarely) unknown  
Neomycin minor very toxic In topical ear drops
Netilmicin Yes 2.4%  
Polymyxin B     In ear drops
Streptomycin very toxic minor  
Tobramycin Yes minor in 6% Less toxic than Gentamicin
Vancomycin nontoxic or rarely toxic none to moderate synergistic with gentamicin

 

Comments about antibiotics with well recognized ototoxicity.

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 1-2% 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.

Neomycin, another aminoglycoside, was isolated in 1949. It is now used mainly topically because of renal toxicity and ototoxicity (to hearing). Neomycin is poorly absorbed from the normal gastrointestinal tract -- about 97% is excreted in the feces. Neomycin is quickly and almost totally absorbed from body surfaces (except the urinary bladder) after local irrigation and when applied topically in association with surgical procedures. With repeated dosing, progressive accumulation occurs in the inner ear. Release occurs slowly over several weeks after dosing has been stopped. 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). Neomycin toxicity is often delayed in onset and may not be noted until long after neomycin has been discontinued (Information primarily from the manufacturers literature, Teva Pharmaceuticals, 11/1999).

Kanamycin, also an aminoglycoside, was developed in 1957, and has been replaced by newer aminoglycosides such as gentamicin, tobramycin, netilmicin, and amikacin. It is not thought to be as ototoxic as neomycin.

Minocycline in large doses is associated with dizziness, sometimes attributed to vestibular side effects.

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 (about 1/150 according to Neu et al, 1986), but there is clear evidence that it can produce a vestibular syndrome similar to gentamicin (Barrsma, 1979; Lehmann, 1976). Most cases of Tobramycin toxicity have occurred in persons with renal impairment. There has been little ototoxicity seen in persons with repeated dosing (Pedersen et al, 1987; Thomesen et al, 1979), which suggests that it may be handled differently by the ear. It is suspected that tobramycin is ototoxic to hearing in neonates but there is little evidence to prove this(de Hoog et al, 2002; 2003). In animals, tobramycin is much less ototoxic than gentamicin (Bamonte et al, 1986; Kitasato, 1990; McCormick et al, 1985; Petorossi et al, 1986).

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.

 

References concerning specific antibiotics:

Related to tobramycin

 

 

Antibiotics for which there is some suspicion of ototoxicity

Antibiotic with suspected ototoxicity Comment
Floxins Anecdotal evidence of dizziness

 

Comment: Although there is some evidence for dizziness, it is unlikely that the floxins are ototoxic.

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.

Also, some of the floxins can have an affect on blood glucose. Gatifloxicin (Tequin) can cause severe persistent hypoglycemia in elderly diabetics taking hypoglycemic drugs, and may cause hyperglycemia in patients with no history of diabetes (Medical letter, 2003). While these effects are not ototoxic, they might account for some dizziness side effects, which should respond to withdrawal of medication.

 

Antibiotics generally considered safe

 

Antibiotics Generally Considered Safe
Aztreonam
Penicillins
Cephalosporins
Macrolides (e.g. Azithromycin and Erythromycin), except in very high doses.

 

Macrolides and other antibiotics that are only slightly ototoxic:

Azithromycin, is a macrolide -- and not in the same family as Gentamicin. Nevertheless, there are occasional reports of ototoxicity, when there have been prolonged and high levels. The high levels generally require intravenous dosing.

Clindamycin has not been reported to cause ototoxicity, by itself, and is probably safe.

Chloramphenicol has been sporadically reported to be ototoxic systemically.

Erythromycin, although not an aminoglycoside like gentamicin, is ototoxic in high intravenous doses. (McGhan et al. 2003) . Pathologically McGhan and Merchant reported strial edema in all of the cochlear turns (in a single case report). This might account for the relatively flat threshold loss with good speech discrimination that is the hallmark of erythromycin ototoxicity. It might also account for some reversibly to the hearing loss.

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.

References r.e. Metronidizole:

References re macrolides:

Other useful information about ototoxins

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 when given over long periods of time.

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 especially 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 regarding ototoxicity of antibiotics:

 

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
Piretamide      

 

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
Hydroxychloroquine Unlikely Rare Hearing loss
Chloroquine (Malaquin) No reports Yes Tinnitus

 

Comment: While quinine ingestion can cause a syndrome including tinnitus, sensorineural hearing loss and vertigo (Obasikene et al, 2012), quinine derivative drugs are rarely by themselves a source of hearing disturbance. Some quinine derivatives, such as mefloquine (Larium) taken for malaria prevention rarely cause significant and long-lasting tinnitus. There is also some suspicion of vestibulotoxicity and CNS toxicity (Dow et al, 2006). Recent studies suggest that quinine impairs outer hair cell motility (Jarboe and Hallworth, ARO abstracts, 1999, #237).

References:

We thank Lariam Action USA ( web site http://www.lariaminfo.org/),for supplying some of the references above related to Lariam.

ASPIRIN, NSAIDS and other ANALGESICS

Aspirin and Nsaids (non-steroidal anti-inflammatory agents) -- are commonly used, and apparently are 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).

Kyle and associates performed a systemic review of the effect of aspirin, and summarized 37 studies containing 185,155 participants. Aspirin intake grater than 1.95 g/day (i.e. about 6 "regular" aspirin tablets), was associated with worsened hearing. They reported that no data was available to "confirm that long-term doses of 81 mg or 325 mg daily have no hearing consequences". In other words, it is possible that daily "low dose" aspirin may also cause hearing deterioration, presumably to a lesser extent. (Kyle et al, 2014).

Hydrocodone in combination with acetaminophen (e.g Vicodin) has also been associated with hearing loss (Friedman, House et al. 2000; Oh, Ishiyama et al. 2000). A similar case of deafness associated with methodone has also been reported (Vorasubin et al, 2013). Complete deafness, treated with a cochlear implant, can occur in persons addicted to these medications. This clinical picture is sometimes misdiagnosed as autoimmune inner ear disease.

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.

Medications for ulcerative colitis, such as Asacol contain salycylates. While they are designed to be mainly confined to the large bowel and rectum, nevertheless, if 20% is absorbed of a 400 mg tablet, and 1.2 to 1.6 grams is given/day, it is easy to see that this is the equivalent of roughly 300mg of salycilate -- which is enough to affect the inner ear.

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.

Naproxen has been associated with deafness (Kewitz 1986; McKinnon and Lassen 1998). I have also encountered patients reporting tinnitus and hearing reductions after taking Naproxen.

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

Organic solvents:

Styrene, toluene, and trichloroethylene have been reported to be ototoxic. These substances are highly lipid soluble and can also be neurotoxic. Their toxicity may be due to effects on central structures rather than the ear itself.

References:

Other drugs

Although nearly all antidepressants impair balance, the mechanism of this effect is uncertain, and probably not due to ototoxicity.

A single case has been reported of deafness following ingestion of sildenafil. This involved a 44 year old man who took 50 mg every day for 15 days (Mukherjee and Shivakumar, 2006).

 

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      
Tacrolimus   Yes Weak evidence (see Rifal, 2006)

 

Calcium channel blockers are often used to treat vestibular disorders, and by this reasoning, might be vestibular suppressants. In the authors practice, rarely calcium channel blockers appear to be associated with bilateral vestibular paresis, but nothing has written about this in the literature.

Tricyclic antidepressants impair balance (Li et al, 1996). This is probably due to their anticholinergic side effects. According to the same author, SSRI type antidepressants do not affect balance.

 

References:

 

Other Toxins (not medications):

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). Vitamin E may protect against cisplatin ototoxicity(Kalkanis, Whitworth et al. 2004). Apoptosis can be blocked using capsase inhibitors. Intratympanic dexamethasone has been reported to protect from cis-platin ototoxicity in rodents and humans (Murphy and Daniel, 2011; Marshak et al, 2014).

At this writing, 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). 

Grading of ototoxicity. 

Recently effort has been put towards developing methods of grading ototoxicity that are clinically relevant, and in particular, related to hearing aid needs (Chang, 2011).  Far more thought is needed about this.

References:

 


General references:

Copyright November 8, 2014 , Timothy C. Hain, M.D. All rights reserved. Last saved on November 8, 2014