Aminoglycosides (gentamicin, amikacin, tobramycin, and neomycin): increased risk of deafness in patients with mitochondrial mutations – GOV.UK

Advice for healthcare professionals:

Aminoglycosides are broad-spectrum bactericidal antibiotics. The group includes gentamicin, amikacin, tobramycin, and neomycin.

There is a narrow therapeutic window for aminoglycosides and their use can result in toxicity, including nephrotoxicity and ototoxicity, which can result in permanent hearing loss. This effect is related to the dose and duration of treatment and is exacerbated by renal or hepatic impairment or both and is more likely in elderly people and newborn babies.

To minimise the risk of ototoxicity with systemic aminoglycosides, regular serum concentration monitoring is recommended to maintain aminoglycoside levels below the toxic threshold for the cochleo-vestibular system. The product information for each medicine provides dosing considerations and recommendations for toxicity thresholds.

Assessment of auditory, vestibular, and renal function is particularly necessary in patients with additional risk factors.

In 2020, we conducted a safety review following concerns received about the impact of mitochondrial mutations on the risk of ototoxicity with aminoglycosides. We identified several published epidemiological studies showing an increased risk of deafness in patients with the m.1555A>G mutation who were given aminoglycosides. There have also been reported cases of deafness in m.1555A>G patients with aminoglycoside use within the recommended serum levels. Some cases were associated with a maternal history of deafness or mitochondrial mutations or both.

Although no cases were identified with neomycin or topical preparations of gentamicin, amikacin, or tobramycin, based on a shared mechanism of action there is the potential for a similar effect with neomycin and other aminoglycosides that are administered at the site of toxicity (the ear).

The m.1555A>G mutation is the most common mitochondrial DNA (mtDNA) mutation, with an estimated prevalence of 0.2% in the general population. The mutation is associated with sensorineural deafness and occurs in families with maternally transmitted deafness.

Clinicians should follow local guidelines on mitochondrial mutation screening in patients with a maternal history of deafness or mitochondrial mutations or both and who require aminoglycoside therapy. Genetic screening may be especially appropriate in patients requiring recurrent or long-term aminoglycoside therapy where the risk of ototoxicity is increased.

Our review focused on four key epidemiological studies that reported an association between having mitochondrial mutations and an increased risk of deafness with aminoglycoside use. In addition, 10 case reports were identified from the medical literature indicating this toxicity. This evidence is further supported by a plausible biological mechanism where mutated mitochondrial ribosome more closely resembles the bacterial ribosome and may provide a binding site for aminoglycosides; this effect has been shown in biochemical tests.

While many of the epidemiological studies had weak statistical power due to the rarity of the mitochondrial mutations, the evidence is considered sufficient to update the product information for aminoglycoside products with systemic absorption or that are administered at the site of toxicity (the ear).

The product information will be updated to include warnings of a potentially increased risk of ototoxicity in patients with known mitochondrial mutations. The patient information leaflet will ask patients to talk to their doctor or pharmacist before taking this medicine if they know (or think they have) a mitochondrial disease.

These mitochondrial mutations are rare, and the penetrance of the observed increased ototoxic effect is unknown. For patients known to have susceptible mutations, it is important to consider the need for aminoglycoside treatment and the alternative treatment options available when making prescribing decisions.

Any suspected adverse drug reactions to aminoglycosides should be reported to us on a Yellow Card.

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset, treatment dates, and product brand name.

Report suspected side effects to medicines, vaccines or medical device and diagnostic adverse incidents used in coronavirus (COVID-19) using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.

Article citation: Drug Safety Update volume 14, issue 6: January 2021: 6.

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Aminoglycosides (gentamicin, amikacin, tobramycin, and neomycin): increased risk of deafness in patients with mitochondrial mutations - GOV.UK