Ototoxicity From Ear Drops

Timothy C. Hain, MD

Last updated: 10/2012

Overview

While ototoxicity from intravenous aminoglycoside administration is well documented, there is considerable controversy regarding the existence and significance of ototoxicity from topical preparations. The literature reviewed here suggests that ear drops containing aminoglycosides (such as gentamicin or neomycin), can occasionally cause hearing loss if administered over a long period of time to a person with a perforated ear drum. There is also evidence for toxicity for select non-aminoglycoside preparations. Human studies are presently lacking, but it also seems very likely from animal studies and situations where similar solutions are used to ablate vestibular function that aminoglycoside ear drops used in this situation can cause vestibular damage even more frequently. As nontoxic ear drops are currently available [for example, Olfaction (ofloxacin) or ciprofloxin containing products], it would seem prudent in the future to use these agents instead of potentially toxic drugs, when there is a perforation.

Otic Preparations in Common Use

The following is a list of otic preparations that are in common use. The percentage use information is from Lundy and Graham, (1993)

  • Corticosporin otic solution (COS) — contains polymyxin B (10,000 U), neomycin (3.5 mg), hydrocortisone (10 mg) /ml. (94.5% usage)
  • Gentamicin 0.3% (GOS, garasone) — contains gentamicin 3 mg/ml. (81.6% usage)
  • Coly-Mycin otic solution– colistin sulfate 3mg/ml, hydrocortisone 10 mg/ml, neomycin (3.3 mg, 59.1% usage)
  • VoSol and Domeboro (Acetic acid, 2%, 62.4% usage, VoSol contains propylene glycol), xx% usage
  • Chloramphenicol otic solution (Chloromycetin, 0.5%, 38.4% usage)

Recent Studies

A literature review published by the British Association of Otolaryngologists (Phillips, 2007) emphasized the lack of well-designed clinical trials concerning ototoxicity from ear drops; animal studies and case reports make up the majority of available data. A consensus survey completed by otolaryngologists in the UK recommended use of aminoglycoside ear drops only in cases with documented infection, and for a maximum of two weeks. Papas (2006) recommended the use of quinolone ear drops as the first line of treatment, due to a safer profile.

In a retrospective review of 500 children treated with Cortosporine following ventilation tube placement, Berenholz (2006) found no cases of hearing loss associated with treatment. Macfadyen (2006) reported the finding of hearing loss in patients treated with chloramphenicol drops. Thomas (2005) reported the case of a patient who developed total hearing loss after using a cream containing triamcinolone, neomycin, gramicidin and nystatin (Tri-Adcortyl cream).

Park (2004) found steroids to prevent hair cell death in the laboratory. To our knowledge, this has not been tested in human trials.

Brummett et al. (1976) examined the effects of neomycin and polymyxin B in the guinea pig and found that AC cochlear potential was decreased and hair cell damage was noted following morphological examination. The study pointed out that there is less evidence for ototoxicity in humans than in animals, and suggested that this might be related to a less exposed round window in humans, a thinner membrane, and other factors such as the presence of infection or effusion.

Brummett theorized that detection of hearing loss due to otoxicity could often be attributed to the disease rather than treatment, and that traditional audiometry cannot detect the high frequency effects of drugs typically applied to the middle ear space. Therefore, the study concluded that the incidence of ototoxicity is greater than reported. Lemke and others (2009) examined the ototoxic effects of ciprofloxacin hydrochloride, 0.3%, plus dexamethsasone, 0.1% in the guinea pig middle ear. The study concluded that the combination of medications produced no elevation of auditory brainstem thresholds, while the ototoxic effects of neomycin sulfate were confirmed (positive control).

Morizono (1990) ompared 10 minutes of exposure of the middle ear of COS, VoSol, and Coly-Mycin, in Guinea pigs. In this situation, one would expect Coly-Mycin, which contains neomycin, to be the most toxic. Evoked responses were used as the measurement, at 24 hours. Coly-Mycin was found to be two times as toxic as COS, and VoSol, four times. This result would seem to suggest that the colistin component of Coly-Mycin is ototoxic, and also that propylene glycol in VoSol is ototoxic; however, little conclusion can be drawn about long term effects.

Welling and others (1995) examined the cochlear ototoxicity of a single application of COS in humans. Fifty children who received bilateral tympanostomy tubes received 0.5mL of COS to a single, randomly assigned ear. The study showed no statistical difference for pre and post-operative hearing thresholds.Mahadevan et al. (2008) reported surveys from otolaryngologists in New Zealand. Together, 75 physicians reported a total of 24 cases of toxicity from ototopical solutions (16 cases from Sofradex, 3 from Kenacomb otic, 2 frrom Locorten vioform, 2 from Maxitrol, and 1 from Gentamicin drops). The authors noted that there has been a trend away from prescribing ototoxic medications in high risk patients, while others continue to prescribe ototoxins because they are more cost-effective. There was universal support for the aid for the prescription of non-ototoxic medications.Barlow and others (1995) compared injections of 0.2 ml of COS, GOS and Ofloxacin in guinea pigs into the middle ear, and measured hair cell damage at 7 days. The mean cochlear hair cell damage was 66% for COS, 6.5% for GOS, and 1.1% for Ofloxacin. This study documents toxicity for a drug that penetrates the middle ear in animals. It does not address the question of whether there is a difference between human and animal toxicity, or relative vestibulotoxicity.

Linder and others (1995) reviewed 134 patient charts where ear drops were administered for potential ototoxicity. Two cases were found with bilateral profound hearing loss “directly attributable to topical ear drops.” Ten other suspected cases were insufficiently documented. Comment: this study suggests an incidence somewhere between 2 and 10%.

Wong and Rutka (1997) reported five patients with tympanic membrane perforations who they believed sustained ototoxicity from GOS. Case 1 developed vertigo after three weeks of treatment. Case 2 also developed unilateral vestibular loss and worsening of hearing. Cases 3, 4 and 5 developed bilateral vestibular loss after bilateral instillation over weeks to months. Comment: These cases are quite relevant and suggest that unilateral or bilateral vestibular loss can be associated with use of gentamicin-based ear drops.

A recent study by Berenholz et al. (2012) demonstrated no reduction in otoacoustic emission responses (a measure of inner ear hair cell function) when 52 pediatric ears were treated with cortosporin suspension. The authors concluded that there is little risk in using neomycin/polymyxin B/hydrocortisone drops, following ventilation tube insertion when done “responsibly” (Berenholz et al 2012).

Pickett, Shinn, and Smith (1997) considered evidence for and against ototoxicity from ear drops in a comprehensive review. They noted abundant animal evidence for ototoxicity of aminoglycosides solvents, such as propylene glycol (found in VoSol). They concluded that from animal data, it is clear that most ear drops that are used for treatment or prophylaxis of infection have ototoxic potential and point out the puzzling relative lack of common ototoxicity in humans. They suggest that either ototoxicity is not recognized as hearing loss, is attributed to underlying disease, or because of anatomic differences between animals and humans in the thickness of the round window membrane, there is less susceptibility to topical ototoxicity in humans. They pointed out that there was a lack of well-controlled studies on the use of ear drops in humans.

Bath and others (1999) documented 16 patients with vestibulotoxicity, possibly related to gentamicin/steroid-containing topical drops. An additional case was presented reporting intentional ablation of vestibular function using commercially available ear drops, in a patient with unilateral Meniere’s disease. Two drops, twice a day, were instilled through a ventilation tube over three weeks.
For a recent review of possible ototoxic otic preparations the interested reader is directed to Haynes (2007).

References

  • Barlow DW, Duckert LG, Kreig CS, Gates GA. 1995. Ototoxicity of topical otomicrobial agents. Acta oto-laryngologica 115: 231-5
  • Bath AP, Walsh RM, Bance ML, Rutka JA. 1999. Ototoxicity of topical gentamicin preparations. The Laryngoscope 109: 1088-93
  • Berenholz LP, Burkey JM, Farmer TL, Lippy WH. 2006. Topical otic antibiotics: clinical cochlear ototoxicity and cost consideration. Otolaryngology–head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery 135: 291-4
  • Berenholz LP, Rossi DL, Lippy WH, Burkey JM. 2012. Is there an ototoxicity risk from Cortisporin and comparable otic suspensions?
    Distortion-product otoacoustic emission findings. Ear, nose, & throat journal 91: 106-35
  • Brummett RE, Harris RF, Lindgren JA. 1976. Detection of ototoxicity from drugs applied topically to the middle ear space. The Laryngoscope 86: 1177-87
  • Haynes DS, Rutka J, Hawke M, Roland PS. 2007. Ototoxicity of ototopical drops–an update. Otolaryngologic clinics of North America 40: 669-83, xi
  • Lemke LE, McGee DH, Prieskorn DM, Wall GM, Dolan DF, et al. 2009. Safety of ciprofloxacin and dexamethasone in the guinea pig middle ear. Archives of otolaryngology–head & neck surgery 135: 575-80
  • Linder TE, Zwicky S, Brandle P. 1995. Ototoxicity of ear drops: a clinical perspective. The American journal of otology 16: 653-7
  • Lundy LB, Graham MD. 1993. Ototoxicity and ototopical medications: a survey of otolaryngologists. The American journal of otology 14: 141-6
  • Macfadyen CA, Acuin JM, Gamble C. 2006. Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations. Cochrane Database Syst Rev: CD005608
  • Mahadevan M, Wabnitz DA, McIntosh DL, Brown CR. 2008. Survey on the use of ototopical medications by New Zealand otolaryngologist/head and neck surgeons. The New Zealand medical journal 121: U2898
  • Morizono T, Ikeda K. 1990. Effect of Escherichia coli endotoxin on cochlear potentials following its application to the chinchilla middle ear. Eur Arch Otorhinolaryngol 247: 40-2
  • Pappas S, Nikolopoulos TP, Korres S, Papacharalampous G, Tzangarulakis A, Ferekidis E. 2006. Topical antibiotic ear drops: are they safe? International journal of clinical practice 60: 1115-9
  • Park SK, Choi D, Russell P, John EO, Jung TT. 2004. Protective effect of corticosteroid against the cytotoxicity of aminoglycoside otic drops on isolated cochlear outer hair cells. The Laryngoscope 114: 768-71
  • Pickett BP, Shinn JB, Smith MF. 1997. Ear drop ototoxicity: reality or myth? The American journal of otology 18: 782-9; discussion 89-91
  • Thomas SP, Buckland JR, Rhys-Williams SR. 2005. Potential ototoxicity from triamcinolone, neomycin, gramicidin and nystatin (Tri-Adcortyl) cream. The Journal of laryngology and otology 119: 48-50
  • Welling DB, Forrest LA, Goll F, 3rd. 1995. Safety of ototopical antibiotics. The Laryngoscope 105: 472-4
  • Wong DL, Rutka JA. 1997. Do aminoglycoside otic preparations cause ototoxicity in the presence of tympanic membrane perforations Otolaryngology–head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery 116: 404-10