Kay W. Chang

It is important for physicians to be aware of the large number of systemic and topical agents that can cause functional impairment and cellular damage to the inner ear. Ototoxicity-induced hearing loss can result in significant disability to the affected individual, especially young children who are still in the process of speech and language development. Ototoxic effects on the vestibular system can result in significant balance disorder and impair even simple activities of daily life. Recognizing the early signs of ototoxicity may allow for discontinuation or reduction of the offending agent, thus minimizing permanent hearing and balance impairment. As our knowledge of the genetics of ototoxicity improves, it may be possible to identify patients who are at high risk of developing ototoxicity prior to exposure to the drug. Furthermore, a number of promising otoprotective agents are emerging that may also diminish or completely prevent ototoxicity.


Table 158.1 summarizes the major agents implicated in ototoxicity. The categories that are responsible for the majority of ototoxicity clinically observed in presentday medicine are the aminoglycosides and platinum-containing chemotherapy agents.


Aminoglycoside antibiotics have been an important part of our antibacterial drug armamentarium since the discovery of streptomycin in 1943 by Waksman, who was awarded the Nobel Prize for this discovery. While they possess potent activity against Pseudomonas aeruginosa and most other aerobic gram-negative bacilli, their toxicity has resulted in restrained use in developed countries with the introduction of broad-spectrum cephalosporins, carbapenems, and fluoroquinolones. However, since many aminoglycosides are significantly cheaper than alternative drugs, aminoglycoside use remains relatively high in emerging countries in East Asia and Latin America. Aminoglycosides are also frequently utilized in patients with cystic fibrosis. In the United States, eight aminoglycosides (gentamicin, tobramycin, amikacin, streptomycin, neomycin, kanamycin, paromomycin, and spectinomycin) are approved by the FDA (1). Aminoglycosides ending in “mycin” are fermentation products or semisynthetic derivatives from Streptomyces, while those ending in “micin” are products of Micromonospora (2). Nephrotoxicity occurs in 5% to 25% of patients receiving aminoglycosides (2,3,4,5,6,7), while ototoxicity results in hearing loss in 3% to 13% (8,9,10,11,12,13), and vestibular impairment in 1% to 11% (4,9,14,15,16,17).

It is somewhat uncommon to have both vestibular and cochlear symptoms in the same patient; however, either or both may occur with any of the aminoglycosides (17). Auditory symptoms of hearing loss and tinnitus are most prevalent with neomycin, followed in order of decreasing toxicity by gentamicin, tobramycin, amikacin, and netilmicin (2,9,16,18,19). Vestibular symptoms of dizziness, imbalance, nausea, and oscillopsia are seen most with gentamicin and tobramycin, less frequent with amikacin, and least frequent with netilmicin (14,16,17). Aminoglycosides have been found to be the most common cause of bilateral vestibular dysfunction (20).

Platinum Compounds

In 1965, Barnett Rosenberg discovered that electrolysis of platinum electrodes generated a soluble platinum complex that inhibited binary fission in Escherichia coli (21). Cisplatin was noted to be the most active platinum complex in experimental tumor systems, and since the mid-1970s has been one of most widely used chemotherapy agents. Platinum compounds are non-cell-cycle-specific agents that inhibit deoxyribonucleic acid (DNA)
replication, inducing apoptosis and/or necrosis in tumor cells. The mechanism of cisplatin ototoxicity is multifactorial with changes noted in the stria vascularis, spiral ganglion cells, and outer hair cells (OHCs) (22). In contrast, carboplatin appears to be preferentially toxic to the inner hair cells (IHCs) (23,24,25).













Cytotoxic agents

Platinum compounds




Others (nedaplatin, AMD-473, satraplatin)

Vinca alkaloids





Nitrogen mustard

Loop diuretics


Ethacrynic acid


Others (piretanide, azosemide, triflocin, indapamide)





Ketolides (Telithromycin)


(primarily in conjunction with aminoglycosides)

Iron-chelating agents


Anti-inflammatory agents




Heavy metals




Antiseptic/disinfectant agents





Cisplatin is associated with severe nausea and vomiting in almost all patients (26). 5-hydroxytryptamine receptor antagonists can dramatically reduce the severity of nausea and vomiting and allows cisplatin to be administered in an ambulatory care setting (27). Nephrotoxicity of cisplatin can be severe but can also be moderated with aggressive hydration with normal saline, together with infusion of hypertonic saline and mannitol-induced diuresis (28,29,30). Amifostine has also been shown to protect against cisplatin-induced nephrotoxicity (31) though it has not been able to protect against ototoxicity (32,33). Neurotoxicity of cisplatin includes peripheral sensory neuropathy, autonomic neuropathy (most commonly producing constipation), and ototoxicity (high-frequency hearing loss). Neuropathy can occur in 30% to 50% receiving high cumulative doses of cisplatin (34,35). Ototoxicity can occur at much lower doses, and has become the major dose-limiting toxicity of this drug, particularly in young children (36).

The reported incidence of cisplatin ototoxicity varies from 9% to 91%, due to differences in chemotherapy regimens, patient populations, the definition of ototoxicity, and variations and inconsistencies in the assessment and grading of the hearing loss (37,38,39,40,41,42,43,44,45,46,47,48). The clinical presentation of cisplatin ototoxicity includes tinnitus and a bilateral and usually symmetric high-frequency sensorineural hearing loss (SNHL) with a progression toward lower frequencies with cumulative doses. The hearing loss is permanent and usually irreversible, though occasionally recovery can be observed (49,50,51,52), as well as worsening of hearing loss following cessation of treatment (53,54,55,56). Predisposing risk factors include age extremes (particularly young children), previous or concurrent cranial irradiation, renal disease or insufficiency, IV bolus administration or high cumulative dosage of cisplatin, coadministration with aminoglycosides or loop diuretics, excessive noise exposure, poor volume status, previous history of hearing loss, and concomitant use of other ototoxic chemotherapy agents (cytarabine, bleomycin, nitrogen mustard, vincristine, and vinorelbine) (57,58,59,60,61,62,63,64,65).

The rate of ototoxicity when carboplatin is given alone with conventional dose regimens is generally reported in only 1% of patients. However, the incidence following high-dose or combination therapy with cisplatin rises to 33% to 82% (66,67,68,69,70). Nedaplatin is a second-generation platinum compound that may be less ototoxic than cisplatin, but more ototoxic than carboplatin (71,72,73). Oxaliplatin is a third-generation cisplatin analogue that is not associated with either nephrotoxicity or ototoxicity (74,75,76,77). However, peripheral sensory neuropathy aggravated by exposure to cold is a significant dose-limiting toxicity (78).

Vinca Alkaloids

Vinca alkaloids are antitumor drugs derived from an alkaloid obtained from the periwinkle plant Vinca rosea (vincristine, vinblastine) or a semisynthetic alkaloid (venorelbine)
(79). Sporadic reports suggest that vinca alkaloids are associated with risk for ototoxicity at higher doses; however, it is impossible to isolate vinca alkaloids as the responsible agent since they are typically used with other ototoxic chemotherapeutic agents (e.g., cisplatin) (57,61,80,81,82). A rare otolaryngologic complication of vincristine is vocal cord paralysis (83).

Loop Diuretics

Furosemide, bumetanide, and ethacrynic acid are the most commonly used loop diuretics, with ethacrynic acid reserved for those cases allergic or refractory to furosemide (84). Loop diuretics are used in the treatment of congestive heart failure, renal failure, cirrhosis, and hypertension. They are widely used in the neonatal intensive care unit in the treatment of bronchopulmonary dysplasia (85). Risk factors for ototoxicity include renal impairment, prematurity, and associated aminoglycoside use (86). The mechanism of ototoxicity appears to be a dose-related, reversible reduction in endocochlear potential (87,88).

The ototoxicity of ethacrynic acid initially was reported to be temporary (89,90,91,92); however, other reports documented permanent hearing loss in patients with impaired renal function (93,94,95,96,97,98,99). The incidence of ototoxicity from ethacrynic acid was estimated to be 7 patients per 1,000 treated (100). Rapid infusion (101,102) and large bolus dosings (103) of furosemide have been noted to cause a high incidence of hearing loss. While permanent hearing loss with furosemide after IV administration has been reported (104), most cases of furosemide ototoxicity have been reversible (105,106). Bumetanide is more potent but less ototoxic than furosemide (107,108,109); however, its higher cost appears to be a rate-limiting factor in its clinical use.


Erythromycin works by inhibiting protein synthesis in bacteria by reversibly binding 50S ribosomal subunits (110). Most reported ototoxicity has been reversible (111,112,113,114,115,116,117,118), though some irreversible cases have also been reported (119,120). Renal impairment (117,121,122,123,124), hepatic impairment (125), and transplant recipients (126,127) appear to have increased risk for ototoxicity. The second-generation macrolide azithromycin has been reported to cause reversible hearing loss in HIV patients (128,129,130) and elderly patients (131,132). There is a single case report of complete deafness (133) as well as a few of irreversible hearing loss (134,135). Clarithromycin likewise has been reported to sometimes result in ototoxicity (136,137,138). Telithromycin is a ketolide and represents a newer class of macrolide antibiotic with zero cases of ototoxicity reported among 2,045 patients in eight phase III trials (139).


Vancomycin has been primarily associated with ototoxicity when given in conjunction with an aminoglycoside (140,141). However, in a group of patients not receiving any other ototoxic agents, 1/31 (3.2%) receiving once-daily vancomycin dosing and 5/32 (15.6%) receiving twice-daily vancomycin dosing developed hearing loss (142). Age extremes may be another risk factor. Ototoxicity after an average of 27 days of vancomycin therapy was also found in 19% of patients older than 53 years old (143). A recent study also suggested an increased risk of vancomycin ototoxicity in neonates (144).

Salicylates, Nsaids, and Quinine

Acetylsalicylic acid (ASA), commonly known as aspirin, is one of the most widely used drugs. ASA ototoxicity has been reported to occur in 11 per 1,000 patients (100,145), and results in tinnitus and a reversible mild to moderate bilaterally symmetric hearing loss (146). Recovery usually occurs 24 to 72 hours after cessation of the drug (147). Onset of tinnitus has been often used as the earliest clinical sign of salicylate toxicity (148,149,150). Nonsteroidal anti-inflammatory drugs (NSAIDs) share similar therapeutic actions and ototoxicity side effects with salicylates (147,151,152,153).

Quinine is an antimalarial drug that has been decreasing in use due to less toxic semisynthetic derivatives; however, it is still occasionally used for nocturnal leg cramps (147). Large doses of quinine produce reversible hearing loss and tinnitus, similar to salicylates (86,147,154,155). Transient vestibular effects have also been noted with quinine (156).

Iron-Chelating Agents

Deferoxamine (DFO) is an iron-chelating agent used in the treatment of acute iron intoxication and chronic iron overload secondary to multiple transfusions (157). Ototoxicity from DFO was first recognized in thalassemia major patients in the 1980s (158,159,160,161

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May 24, 2016 | Posted by in OTOLARYNGOLOGY | Comments Off on Ototoxicity
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