Intended for healthcare professionals

Practice Adverse Drug Reaction

Vestibulotoxicity with gentamicin

BMJ 2022; 378 doi: https://doi.org/10.1136/bmj-2022-070873 (Published 07 September 2022) Cite this as: BMJ 2022;378:e070873
  1. Karina Ferreira, specialist audiologist1,
  2. Suzanne Forbes, consultant nephrologist2,
  3. Diego Kaski, consultant neurologist3
  1. 1Department of Audiology, Ear Nose & Throat Eastman Dental Hospitals, London, UK
  2. 2Royal London Hospital, Barts Health NHS Trust, London, UK
  3. 3Department of Clinical and Movement Neurosciences, University College London, London, UK
  1. Correspondence to: D Kaski d.kaski{at}ucl.ac.uk

What you need to know

  • Ask for a history of gentamicin administration in patients who experience vestibular symptoms such as imbalance while walking or wobbly vision

  • Gentamicin related vestibulotoxicity is often permanent, but prompt diagnosis and early physical rehabilitation can improve gait and balance

  • Avoid gentamicin, if possible, for surgical prophylaxis and in patients with risk factors such as pre-existing kidney disease, overweight, or using other drugs that can potentiate its effects (such as vancomycin)

A patient reports feeling unsteady while walking. This has come up suddenly. He had a renal stent inserted for calculi removal two days previously, for which he received intravenous gentamicin as prophylaxis. He also reports wobbly vision on head movement, which resolves with his head held still. Neurological examination reveals severe gait imbalance, with the patient requiring support for walking even short distances. He is diagnosed with gentamicin related vestibulotoxicity and started on vestibular rehabilitation.

Aminoglycoside antibiotics are implicated in functional impairment and/or cellular damage to the vestibular system as an adverse reaction (box 1).4 Gentamicin is the most frequently used aminoglycoside antibiotic in adults.56 As with other aminoglycosides such as streptomycin and tobramycin, gentamicin related vestibulotoxicity is typically bilateral due to systemic administration. The damage can be permanent. Early diagnosis can help initiate measures to improve balance. This article focuses on gentamicin related vestibulotoxicity in adults. Symptoms and the indications for gentamicin use, dosing, and monitoring can differ in children.

Box 1

Safety warnings for gentamicin and aminoglycosides

  • The British National Formulary (BNF) advises caution regarding “vestibular disorder,” and avoidance of “prolonged" use1

  • The Electronic Medicines Compendium summary of product characteristics lists a special warning on ototoxicty (loss of balance and hearing loss) with use of aminoglycosides, including gentamicin2

  • The US Food and Drug Administration advises that ototoxicity, both vestibular and auditory, can occur in patients treated with gentamicin, primarily those with pre-existing renal damage and in patients with normal renal function treated with higher doses and/or for longer periods than recommended3

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What is gentamicin?

Gentamicin is used to treat several local and systemic infections and for surgical prophylaxis.17It is active against Gram negative aerobic bacteria (such as Pseudomonas, Acinetobacter, Klebsiella, and Enterobacter species) and certain Gram positive bacteria (including mycobacteria). The National Institute for Health and Care Excellence (NICE) guidelines recommend gentamicin as treatment for bacterial septicaemia, meningitis, urinary tract infections, some gastrointestinal tract infections (such as biliary sepsis), and soft tissue infection (such as necrotising fasciitis).7 It has minimal gastrointestinal absorption and is usually administered by parenteral routes, with systemic, topical, intraperitoneal, and ophthalmic formulations. It is used for the treatment of discharging ears by ear, nose, and throat specialists, even in the presence of tympanic performation, but evidence that this can lead to vestibulotoxicity is lacking.

How do patients with this adverse reaction present?

In our clinical experience, most patients present with gait disturbance and imbalance. This is possibly because systemic administration of gentamicin tends to affect bilateral vestibular function. Patients with acute bilateral vestibular loss will be unable to stand unaided. In more chronic states, inability to stand unaided may only be present if asked to stand on a foam surface.8 Other symptoms can include dizziness, vertigo, and oscillopsia91011 which arise from asymmetrical vestibular nerve firing.

Initial signs can go unnoticed. Gentamicin is primarily toxic to the vestibular rather than auditory system.1011 The majority (90%) of patients will not have accompanying hearing loss or tinnitus.12 Many patients will have been inpatients and bedbound when the drug was administered. They may only notice a balance problem when they become ambulant, at which point it is typically (incorrectly) attributed to critical illness and deconditioning.10

There are no robust data on time of onset of vestibulotoxicity symptoms relative to administration of gentamicin. In a retrospective case series (103 patients) time to diagnosis ranged from four days to 15 years.11 Gentamicin is renally excreted within hours but accumulates over months in the inner ear,13 accounting for the drug’s toxic effects much later.

How common are these reactions?

Clinically evident ototoxicity (hearing and/or vestibular loss) is estimated to affect 11% of people taking daily treatment with gentamicin, and between 0.2% and 6.2% of patients who have received a single dose.1415 The prevalence of vestibulotoxicity specifically is less well documented, and may be higher in at risk groups (for example, people with pre-existing kidney failure or obesity).15

Prevalence of vestibulotoxicity is usually estimated from clinical data in patients experiencing imbalance that is not attributable to another disorder (such as stroke, meningitis, head trauma) and who have been treated with gentamicin (hours or sometimes weeks earlier11). In a retrospective case series of 53 patients with bilateral vestibular failure, 17% (n=9) were attributed to gentamicin toxicity.16 At a specialist centre in the US, gentamicin toxicity was noted as the cause in 28% of 213 patients with bilateral weakness, the second commonest after “idiopathic.”17

What is the evidence?

Vestibulotoxicity is considered to be dose dependent1819 and commonly occurs when levels are high or renal clearance is poor. There is a lack of high quality data correlating symptoms with gentamicin levels in blood.1120

The mechanism by which gentamicin affects the vestibular (and cochlear) structures is not completely understood. Studies implicate gentamicin in interference with mitochondrial ribosomes, inhibiting protein synthesis and impairing cell respiration.21 This may lead to destruction of vestibular (and cochlear) hair cells through superoxide overproduction and cell apoptosis. Vestibular and cochlear hair cells are particularly prone to damage given their high density of mitochondria.22 Gentamicin generates free radicals within the inner ear, causing damage to sensory cells and neurons. Mutations in the mitochondrial 12S ribosomal RNA gene reportedly predispose carriers to cochlear (and presumably also vestibular) toxicity.2324

What factors increase the risk?

Vestibulotoxic effects are more common with multiple daily regimens versus single daily dosing.13 Concomitant use of other vestibulotoxic drugs can increase the risk. For example, vancomycin, commonly used in conjunction in sepsis, potentiates the toxic effects of gentamicin.25 Renal disease leads to reduced gentamicin excretion and hence raised drug levels, increasing the risk of toxicity.17 People who are overweight or obese can be more susceptible since dosing by weight can lead to higher doses and overestimate the volume of distribution.26 Genetic factors27 can increase risk of vestibulotoxicity in some people, but this is not proven.28

How is it managed?

Consider vestibulotixicty in patients prescribed gentamicin who present with gait imbalance or wobbly vision on head movement. Certain clinical tests can help confirm bilateral vestibular dysfunction (figs 1 and 2).2930 Performing and interpreting these requires training, and misinterpretation is common.31

Fig 1
Fig 1

Clinical test of dynamic visual acuity. The patient is first asked to read the lowest line she/he can on a visual acuity chart (baseline visual acuity). The patient’s head is then rotated left and right from behind by the examiner standing, at approximately 2 Hz. The patient is asked to read the lowest line on the chart. A drop in visual acuity of ≥2 lines indicates a possible unilateral vestibulopathy, whereas a drop of ≥4 lines is suggestive of bilateral vestibulopathy.

Fig 2
Fig 2

The head impulse test is a simple bedside test of the horizontal vestibulo-ocular reflex. Ask the patient to look at the examiner’s nose. Hold the patient’s head and turn it first to one side and then to the other. When the test is normal (left panel), the gaze remains on the examiner’s nose. In an abnormal head impulse test (middle and right panels), when the head is turned to the right, the eyes move with the head rather than staying fixed on the nose, followed by a corrective saccade back to the target. Such “catch-up” saccades occur when the head is turned in the direction of the damaged vestibular nerve side. In bilateral vestibular failure, the head impulse test will be abnormal to both sides.

Discontinue gentamicin if you suspect vestibulotoxicity and the patient is still taking it.20 We recommend referral within two weeks to a vestibular, balance, ENT, or neurology specialist for confirmatory vestibular testing (such as caloric, video head impulse test, or rotatory chair test).1732

Gentamicin related vestibular loss is permanent in most patients.1020 Vestibular hair cells cannot regenerate in humans once damaged,33 but early intervention with vestibular rehabilitation can improve long term functional outcomes.34 Treatment aims to enhance central nervous system compensatory mechanisms rather than reverse the damage. Patients can be taught34 compensatory strategies using vision and proprioception to improve motion and reduce postural anxiety.3536

More recently, a vestibular implant prototype—like cochlear implants for hearing loss—has shown promise in restoring a degree of vestibular function (the dynamic visual acuity) illustrating potential for clinical use.37

How can the risk of harm be minimised?

Use gentamicin sparingly, particularly in surgical prophylaxis, and for the shortest duration possible. Inform patients of vestibular dysfunction as a possible adverse event before administration. Ask them to promptly report if they experience related symptoms. We recommend baseline screening with dynamic visual acuity (fig 1) or head impulse test (fig 2) before gentamicin administration and 24 hours after each dose in all patients. Closer monitoring may be needed in patients at increased risk.

For adults, the BNF recommends measuring serum gentamicin concentrations after three or four doses of a multiple daily dose regimen and after a dose change. Blood samples are taken at 1 hour after intramuscular or intravenous administration (peak concentration) and just before the next dose (trough concentration).1 If the pre-dose (trough) concentration is high, the interval between doses is increased. If the post-dose (peak) concentration is high, the dose must be decreased.1

Loading and maintenance doses of gentamicin are usually calculated based on the patient’s weight and renal function using a nomogram.38 These are available as online applications (for example, Aminoglycoside Calculator - ClinCalc.com). In people who are overweight or obese, serum concentrations of gentamicin are closely monitored, and dose is reduced if required.2 Local guidelines typically exist for once daily dose regimens.

Tips for patients

  • When gentamicin is prescribed, ensure that possible risks to inner ear function have been discussed with you

  • Report any new issues with your balance or vision, particularly those that occur when you are moving (such as when walking rather than when you are sitting still) if you have recently received gentamicin

  • Ask your doctor whether antibiotics other than gentamicin may be given, particularly if you are >65 years old or have other medical problems that might increase the risk of damage to vestibular function

How patients were involved in the creation of this article

We discussed this article with a patient who had recently experienced acute unsteadiness after prophylactic gentamicin administration. He emphasised the importance of discussing potential side effects of gentamicin before its administration in non-life threatening situations and the need to raise awareness among doctors that gentamicin vestibular toxicity causes a severe impairment of balance function.

Education into practice

  • How many of your patients taking gentamicin had baseline vestibular function tests before its administration?

  • How would you explain possible risks of vestibular (balance) dysfunction to a patient before administering gentamicin?

Acknowledgments

Advisers to this series are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and City Hospital Birmingham, and Patricia McGettigan, reader in clinical pharmacology and medical education, Queen Mary University of London.

Footnotes

  • This is one of a series of occasional articles to help doctors prevent, diagnose, and respond to adverse drug reactions that may be serious if not recognised.

  • Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

  • Provenance and peer review: Not commissioned, externally peer reviewed.

References

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