Evidence suggests an increased risk of aminoglycoside-associated ototoxicity in patients with mitochondrial mutations, including cases in which the patient’s aminoglycoside serum levels were within the recommended range (1,2)
- mitochondrial mutations are rare and penetrance is uncertain
- genetic testing should not delay urgently needed aminoglycoside treatment but may be considered, especially before the start of recurrent or long-term treatment (1)
Advice for healthcare professionals (1):
- aminoglycoside use can result in rare cases of ototoxicity; some evidence suggests an association between mitochondrial mutations (particularly the m.1555A>G mutation) with an increased risk of this ototoxicity
- some cases reported ototoxicity in patients with mitochondrial mutations who had aminoglycoside serum levels within the recommended ranges
- these mitochondrial mutations are rare, and the penetrance of the observed increased ototoxic effect is unknown
- consider the need for genetic testing especially in patients, particularly in those requiring recurrent or long-term treatment with aminoglycosides, but do not delay urgent treatment in order to test
- when making prescribing decisions in patients with susceptible mutations, consider the need for aminoglycoside treatment versus alternative options available
- to minimise the risks of adverse events, including ototoxicity, continuous monitoring (before, during and after treatment) of renal function (serum creatinine, creatinine clearance) and auditory function, as well as hepatic and laboratory parameters, is recommended for all patients
- patients with known mitochondrial mutations or a family history of ototoxicity are advised to inform their doctor or pharmacist before they take an aminoglycoside
- report suspected adverse reactions experienced to the Yellow Card scheme
Risk of ototoxicity with aminoglycosides
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.
Mitochondrial mutations and aminoglycoside ototoxicity
- several published epidemiological studies have shown an increased risk of deafness in patients with the m.1555A>G mutation who were given aminoglycosides (1)
- 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.
- 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 (2)
- mutation is associated with sensorineural deafness and occurs in families with maternally transmitted deafness
- m.1555A>G means that there is a single nucleotide substitution in the mitochondrial DNA at base pair 1555, with a change from adenine to guanine (4)
- corresponds to a change in the MT-RNR1 gene.
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.
Rapid genetic point-of-care testing may be used to avoid aminoglycoside-induced ototoxicity in neonates, and clinicians are able to integrate genetic data into their routine practice in the acute setting (3)
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