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Author: James Kalkanis, MD , Staff Physician, Department of Surgery, Southern Illinois University School of Medicine Coauthor(s): Frank Glatz, MD , Staff Physician, Department of Otolaryngology-Head and Neck Surgery, Southern Illinois University School of Medicine; Kathleen CM Campbell, PhD , Director of Audiology, Professor, Department of Surgery, Division of Otolaryngology, Southern Illinois University School of Medicine; Leonard P Rybak, MD, PhD , Professor, Department of Surgery, Southern Illinois University School of Medicine Editor(s): Robert A Battista, MD, FACS , Clinical Instructor in Otolaryngology, Department of Otolaryngology, Northwestern University Medical School; Francisco Talavera, PharmD, PhD , Senior Pharmacy Editor, eMedicine; Gerard J Gianoli, MD , Clinical Associate Professor, Department of Otolaryngology-Head and Neck Surgery, Tulane University School of Medicine; Christopher L Slack, MD , Consulting Staff, Otolaryngology-Facial Plastic Surgery, Lawnwood Regional Medical Center; and Arlen D Meyers, MD, MBA , Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado Hospital
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Ototoxicity refers to medication-caused auditory and/or vestibular system dysfunction resulting in hearing loss or dysequilibrium. The propensity of specific classes of drugs to cause ototoxicity has been well established. The list includes certain antibiotics, certain antineoplastic agents, salicylates, and loop diuretics. Ototoxicity typically is associated with bilateral high-frequency sensorineural hearing loss and tinnitus. Hearing loss can be temporary, but it is usually irreversible with most agents. Generally, antibiotic-induced ototoxicity is bilaterally symmetrical, but it also can be asymmetrical. The usual time of onset is often unpredictable, and marked hearing loss can occur even after a single dose. Additionally, hearing loss may not manifest until several weeks or months after completion of antibiotic or antineoplastic therapy.
Many agents (eg, certain antibiotics, antineoplastics) produce hair cell damage, which begins at the basal turn of the cochlea and proceeds toward the apex. This initially produces high-frequency sloping hearing loss, which can progress into lower (or speech) frequencies. No therapy is currently available to reverse hair cell damage. Vestibular injury is also a notable adverse effect of aminoglycoside antibiotics and may appear early on with positional nystagmus. If severe, vestibular toxicity can lead to dysequilibrium and oscillopsia. Oscillopsia, which is caused by bilateral damage to the vestibular system, is inability of the ocular system to maintain a stable horizon, resulting in what has been described as a "jumbling of the panorama." Basic awareness of ototoxic medications and use of appropriate monitoring during treatment are important to preserve hearing. Throughout therapy, perform baseline hearing evaluations followed by periodic testing. Management emphasis is on prevention because most hearing loss is irreversible. Additionally, typical patients, without monitoring, are unaware of hearing loss until deficits reach mild-to-moderate levels (>30 dB hearing level [HL]) in the speech frequencies. For severe hearing loss, amplification may be the only treatment option.
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Since their introduction in 1944, multiple aminoglycoside preparations have become available, including streptomycin, dihydrostreptomycin, kanamycin, gentamicin, neomycin, tobramycin, netilmicin, and amikacin. These medications function by binding irreversibly to the 30S ribosome subunit of gram-negative aerobic bacilli. Ototoxicity in this class of antibiotics has been well described; however, aminoglycosides are still used frequently because of their effectiveness. Advantages to using aminoglycoside antibiotics include low incidence of Clostridium difficile diarrhea relative to other antibiotics and low risk of allergic reactions.
Alternative antibiotics (eg, third-generation cephalosporins, fluoroquinolones) are used more widely today because of less toxic adverse effects; however, aminoglycoside use has been increasing because tuberculosis and resistant organisms are becoming more prevalent.
Epidemiology In certain countries, antibiotics are prescribed freely or are available without prescription. In these areas, aminoglycosides cause as many as 66% of cases of deaf mutism. Depending on agent and dosing, 33% of patients may have audiometric changes with aminoglycoside treatment. Vestibular toxicity is also well documented; it occurs in as many as 4% of patients. Incidence of patients experiencing toxicity from aminoglycosides may be decreasing with improvements in monitoring and heightened awareness.
Pathophysiology Aminoglycosides have variable cochleotoxicity and vestibulotoxicity. Streptomycin and gentamicin are primarily vestibulotoxic, whereas amikacin, neomycin, dihydrostreptomycin, and kanamycin are primarily cochleotoxic. Less is known about netilmicin ototoxicity because netilmicin is used less commonly, but its ototoxic potential appears low. Aminoglycoside toxicity primarily targets renal and cochleovestibular systems; however, no clear correlation exists between degree of nephrotoxicity and ototoxicity. Ototoxic hearing loss usually begins in high frequencies and is secondary to irreversible destruction of outer hair cells in the organ of Corti, predominantly at the basal turn of the cochlea. In addition, aminoglycosides have been detected in the cochlea months after final dose administration.
Aminoglycoside retention may account for delayed onset of hearing loss and prolonged susceptibility to noise-induced hearing loss, which is often observed for several months following therapy discontinuation.
Several toxicity mechanisms have been described, including (1) impaired deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein synthesis; (2) impaired synthesis and degradation of prostaglandins, gangliosides, mucopolysaccharides, and lipids; and (3) disruption in metabolism and ion transport. Many of the previous observations can be explained by an interaction with phosphoinositide. This membrane lipid serves as a source of arachidonic acid and acts as an intracellular messenger involved in many of the above processes. A second potential target includes the enzyme ornithine decarboxylase, which is involved in cellular recovery following noxious stimuli.
Perhaps the most promising mechanism for chronic aminoglycoside toxicity involves iron chelation leading to production of a free-radical complex. Aminoglycoside ototoxicity is likely multifactorial, and further investigation is underway. Some studies are investigating iron chelators and antioxidants as possible agents to prevent hearing loss during therapy, while other studies are exploring forms of gene therapy as future treatment options. Currently, no treatment is available apart from amplification and cochlear implantation; therefore, prevention is paramount.
Risk factors Several risk factors have been identified for development and potentiation of aminoglycoside ototoxicity, including (1) therapy duration longer than 2 weeks, (2) elevated serum peak and trough levels, (3) age extremes, (4) family history of ototoxicity, (5) coadministration of other ototoxic agents, particularly loop diuretics, (6) renal failure, and (7) the specific aminoglycoside employed.
Signs and symptoms Aminoglycoside-induced ototoxicity can include high-frequency hearing loss, tinnitus, dysequilibrium, oscillopsia, and occasionally a vague sense of aural fullness.
Prevention Prevention of aminoglycoside ototoxicity involves careful monitoring of serum drug levels and renal function as well as hearing evaluations before, during, and after therapy. Measure baseline audiometric function before therapy; however, this is not always possible in acute situations. Daily administration decreases incidence of ototoxicity and should be considered whenever possible. Conscientiously identify high-risk patients and select alternative antibiotics for them. Lastly, because aminoglycosides remain in the cochlea long after therapy has ended, instruct patients to avoid noisy environments for 6 months after therapy completion because they remain more susceptible to noise-induced cochlear damage.
Specific aminoglycosides
Streptomycin: Streptomycin was the first clinically applied aminoglycoside and was used successfully against gram-negative bacteria in the past. Streptomycin preferentially affects the vestibular system rather than the auditory system. Because of its toxicity, and because of widespread resistance, this agent is used infrequently today. However, streptomycin use has risen for treatment of tuberculosis.
Neomycin: This agent is one of the most cochleotoxic aminoglycosides when administered orally and in high doses; therefore, systemic use generally is not recommended. Neomycin is among the slowest aminoglycosides to clear from the perilymph; consequently, delayed toxicity (1-2 wk) may ensue after discontinuation of therapy. Neomycin mainly is used as an effective otic and ototopical agent. Although neomycin is generally considered safe when used topically in the ear canal or on small skin lesions, exercise caution when treating patients with tympanostomy tubes or tympanic membrane perforations.
Kanamycin: Although less toxic than neomycin, kanamycin is quite ototoxic. Kanamycin has a propensity to cause profound cochlear hair cell damage, marked high-frequency hearing loss, and complete deafness. The damaging effect is primarily to the cochlea, while the vestibular system is usually spared injury. Kanamycin has limited clinical use today. As with neomycin, parenteral administration generally is not recommended.
Amikacin: Amikacin is a derivative of kanamycin and has very little vestibular toxicity. Its adverse effects primarily involve the auditory system; however, it is considered less ototoxic than gentamicin. In the treatment of severe infections, amikacin is mainly indicated on the basis of results of susceptibility tests and patient response.
Tobramycin: Ototoxicity of tobramycin is similar to that of amikacin; high-frequency hearing loss results. As with kanamycin, vestibular toxicity is less common. Tobramycin is frequently used in otic and topical preparations. Topical use, although not without controversy, generally is considered safe.
Gentamicin: As with streptomycin, gentamicin has a predilection for the vestibular system. Therapeutic peak serum levels of 10-12 mcg/mL are generally considered safe but still may be toxic in some patients. Carefully adjust dosing in patients with renal disease.
Netilmicin: In comparative studies, netilmicin appears to be the safest aminoglycoside; it has the lowest incidence of overall ototoxicity. Unlike other agents, netilmicin has only a 2% incidence of ototoxicity in neonates.
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Vancomycin Vancomycin is a glycopeptide antibiotic that was introduced in the 1950s, but it was replaced by other antibiotics around 1958 because of early reports of ototoxicity. Several other reports of hearing loss are associated with its use, but many involved patients receiving concomitant aminoglycoside therapy. The data are unclear but suggest that ototoxicity is reversible in at least some individuals. No studies demonstrate conclusive evidence of ototoxicity with vancomycin administration alone and in therapeutic doses. No recommendations have been made regarding its use; however, the authors suggest caution with coadministration of vancomycin and other ototoxic agents.
Erythromycin A macrolide antibiotic, this agent was introduced in 1952 and has seen widespread use in clinical medicine. Generally, erythromycin is considered a safe medication. The first reports of ototoxicity were not noted until 1973. Since then, only sporadic cases of ototoxicity have been reported, and they generally have been reversible. These patients tended to have other risk factors, including renal failure, hepatic failure, doses of more than 4 g/d, and intravenous administration. Clinically significant hearing loss also has been reported in recipients of renal allografts who were treated with intravenous erythromycin. Speech frequencies may be affected rather than higher frequencies, and effects seem reversible.
Azithromycin Another macrolide antibiotic, azithromycin was introduced in late 1991. It has seen widespread clinical use and has few adverse effects aside from minor gastrointestinal irritation. However, recently, some reports have appeared regarding possible ototoxic effects. Reports currently are sporadic, and further investigation is needed.
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Loop diuretics exert therapeutic effects at the loop of Henle. This class of medications includes several different chemical groups, including sulfonamides, phenoxyacetic acid derivatives, and heterocyclic compounds. These drugs are used to treat congestive heart failure, renal failure, cirrhosis, and hypertension. The most effective and frequently used diuretics (eg, ethacrynic acid, furosemide, bumetanide) can cause ototoxicity. Several less-commonly used loop diuretics also have been experimentally shown to cause ototoxicity; this group includes torsemide, azosemide, ozolinone, indacrinone, and piretanide.
Epidemiology Occurrence of loop diuretic ototoxicity depends on several factors, including dose, infusion rate, history of renal failure, and coadministration of other ototoxic agents.
Signs and symptoms Depending on the particular loop diuretic, patients usually relate a history of hearing loss soon after taking the agent. Patients also may complain of tinnitus and dysequilibrium; however, these symptoms are less common and seldom occur without hearing loss.
Pathophysiology Animal studies of commonly used loop diuretics suggest a similar effect on the cochlea. Animal models suggest that the stria vascularis is affected. Changes observed in the stria vascularis include cellular atrophy and intercellular edema. Evidence also suggests that endolymphatic potential is decreased; however, this is usually dose dependent and reversible.
Ototoxicity caused by ethacrynic acid seems to develop more gradually and take longer to resolve than that caused by furosemide or bumetanide. Overall, ototoxicity attributed to this group of medications usually is self-limited and reversible in adult patients, although irreversible hearing loss has been reported in neonates.
Prevention Prevention of ototoxicity caused by loop diuretics consists of using the lowest doses possible to achieve desired effects and avoiding rapid infusion rates. Additionally, the risk factors associated with administration of these drugs must be diligently assessed, including coadministration of other ototoxic medications and history of renal failure.
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Antineoplastic agents most commonly associated with ototoxicity are the platinum-based compounds cisplatin and, to a lesser degree, carboplatin. These agents are widely used in gynecologic, lung, central nervous system, head and neck, and testicular cancers. Antineoplastics are cell-cycle nonspecific alkylating agents that insert into the DNA helix, disrupting replication. Cisplatin is distributed widely, but the highest concentrations are found in the kidneys, liver, and prostate. Cisplatin irreversibly binds to plasma proteins and can be detected up to 6 months after completion of therapy. Carboplatin is not protein bound and is more readily cleared by the kidneys. Dose and efficacy of cisplatin and carboplatin are limited largely by adverse effects. Most notably, these agents produce nephrotoxicity and ototoxicity with increasing dose.
Epidemiology Incidence and severity of ototoxicity depend on dose, infusion rate, number of cycles, renal status, and coadministration of other ototoxic agents. Incidence and severity is also higher in the pediatric population and in patients receiving radiation therapy to the head and neck.
Pathophysiology The mechanism of platinum ototoxicity appears multifactorial, but it is partially mediated by free-radical production. Platinum compounds damage the stria vascularis in the scala media and cause outer hair cell death beginning at the basal turn of the cochlea.
Signs and symptoms Patients with platinum-induced ototoxicity may complain of tinnitus and subjective hearing loss. Hearing loss associated with cisplatin toxicity is usually bilateral, sensorineural, irreversible, and progressive. High-frequency hearing typically is affected first, but loss may not appear until several days or months after the last dose. Conversely, severe hearing loss may occur after a single dose.
Risk factors The following risk factors have been identified for development and potentiation of platinum-induced ototoxicity: (1) high dose and increasing number of cycles, (2) concurrent or past cranial irradiation, (3) age extremes, (4) dehydration, (5) coadministration of other ototoxic agents, and (6) renal failure.
Prevention Obtain baseline audiograms and periodic follow-up audiograms during therapy for all patients receiving these agents. Perform these studies immediately before subsequent drug cycles so the maximal effect of the previous cycle can be determined. Lastly, patients should continue to undergo audiometric testing because of significant drug retention long after completion of therapy. Also advise patients to avoid noise exposure for up to 6 months.
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Acetylsalicylic acid, commonly known as aspirin, is used widely for its anti-inflammatory, antipyretic, and analgesic properties. Aspirin is an inhibitor of platelet aggregation and is used to treat patients with a history of transient ischemic attacks, stroke, unstable angina, or myocardial infarction. Acetylsalicylic acid is absorbed rapidly after oral administration and is hydrolyzed in the liver to its active form, salicylic acid. Therapeutic levels range from 25-50 mcg/mL for analgesic and antipyretic effects to 150-300 mcg/mL for treatment of acute rheumatic fever. However, tinnitus can occur at serum levels as low as 200 mcg/mL.
Epidemiology Incidence of ototoxicity is as high as 1% and is most commonly observed in elderly patients, even at low doses.
Risk factors Risk factors associated with salicylate ototoxicity include high dose, elderly age, and dehydration.
Pathophysiology Salicylic acid quickly enters the cochlea, and perilymph levels parallel serum levels. Increasing levels produce tinnitus and, generally, a reversible flat sensorineural hearing loss. The mechanism is multifactorial but appears to cause metabolic rather than morphologic changes within the cochlea.
Signs and symptoms Tinnitus is the most common adverse effect of salicylate toxicity. Other adverse effects include hearing loss, nausea, vomiting, headache, confusion, tachycardia, and tachypnea.
Treatment Salicylate toxicity is treated by electrolyte monitoring and fluid administration, with the addition of alkaline diuresis, if necessary. Oxygen administration and mechanical ventilation also may be needed in severe cases.
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Derived from cinchona tree bark, quinine historically was used to treat malaria and for its antipyretic qualities. Use today is limited by availability of less toxic alternatives. Quinine is occasionally used to treat nocturnal leg cramps and as an adjunct to antimalarial therapy. Quinine primarily undergoes hepatic metabolism.
Signs and symptoms Quinine toxicity can produce tinnitus, hearing loss, vertigo, headache, nausea, and vision loss. Hearing loss is usually sensorineural and reversible. A characteristic sensorineural notch often is present at 4000 Hz. Irreversible hearing loss rarely has been reported with quinine use.
Treatment Treatment for quinine ototoxicity mainly consists of discontinuation of therapy; amplification can be used in rare cases of irreversible hearing loss.
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Begin monitoring for signs of ototoxicity before administration of potentially damaging agents. Whenever possible (eg, with patients receiving chemotherapy), perform a baseline audiometric evaluation. Follow baseline evaluation with routine testing during and after therapy. Frequently, ototoxicity can be detected before tinnitus onset and subjective hearing loss. Pure-tone air-conduction thresholds most commonly are obtained as a baseline for monitoring and are conducted in the conventional testing range of 250-8000 Hz. This simple test yields a great deal of information, and even small changes can be easily detected. However, many ototoxic agents initially produce hearing loss in the high-frequency range, above the 8000-Hz upper limit of the standard audiogram. Routine use of high-frequency audiometry therefore is essential.
This method determines pure-tone air-conduction thresholds from 10,000-20,000 Hz and makes early detection of hearing loss possible. Early detection allows modification of treatment protocol before speech frequencies are affected. However, one limitation of high-frequency audiometry is encountered in patients with preexisting high-frequency hearing loss (eg, elderly patients with presbycusis). Early detection methods are less effective in this patient population. Pure-tone bone-conduction testing is another important component of the standard audiogram. This method accurately determines true sensorineural function by bypassing the conductive system of the middle ear.
Serous otitis also is commonly observed following radiation to the head and neck as an adjunct to cancer therapy. Auditory system damage caused by ototoxicity may impair ability to discriminate spoken words in addition to affecting pure-tone hearing. Word recognition testing accurately evaluates the ability of a listener to recognize individual words and thus is another important component of standard audiometry. Scores are based on the percent of phonetically balanced words a patient correctly repeats to the audiologist. A score of more than 90% is normal. Standard pure-tone audiometry monitoring cannot always be implemented because it requires an alert and cooperative patient. Infants and critically ill patients, for example, cannot be reliably tested with standard audiometry.
For these patients, other techniques are available to perform reliable audiometric testing, including otoacoustic emission (OAE) and auditory brainstem response (ABR) testing. OAEs are signals produced by the cochlea, which are detected by a microphone placed in the ear canal. These emissions can occur both spontaneously and in response to sound conducted into the ear. Recordings of these emissions are made, and cochlear function can be determined across a wide range of frequencies. OAEs quickly can be obtained in infants and in comatose patients at the bedside. Testing usually takes less than 5 minutes per ear. However, patients with a history of hearing loss may have abnormal or absent OAEs. Therefore, as with other forms of audiometry, thorough baseline testing is important.
ABR testing is used widely in testing the conventional frequency range, although it is still under investigation for use in high frequencies. This makes ABR of limited clinical use in monitoring ototoxicity. Immittance audiometry also is of limited use; the test is used to exclude middle ear problems that can mimic ototoxic change, but it cannot actually monitor ototoxicity.
Management The primary concern is to maintain patient communication capabilities during what is generally a serious illness. Consult an audiologist early for baseline assessment. Additionally, counsel patients regarding importance of prompt reporting of symptoms such as tinnitus, hearing loss, oscillopsia, and dysequilibrium. Reassure patients that all measures will be taken to prevent any changes in hearing. Perform monitoring before, during, and after therapy, with test results immediately reported to the physician.
In some instances, treatment protocols cannot be altered, and hearing loss occurs. In these cases, fit patients with hearing aids to facilitate communication; however, keep gain and maximum power output as low as possible because these patients are more susceptible to noise-induced hearing loss.
Increased susceptibility to hearing loss can continue for several months after completion of aminoglycoside and platinum-compound therapy. Because of this, instruct patients to avoid excessive noise exposure for 6 months. Additionally, advise patients not to increase hearing aid maximum output during this critical time.
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NOTE:
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