Gentamicin

Impact of genetic variation on response to therapy

There is an increased risk of ototoxicity including aminoglycoside-induced hearing loss (AIHL) in patients with variants in the mitochondrial MT-RNR1 gene, even if aminoglycoside serum levels are within the recommended range during treatment. There have been reports of single doses of aminoglycosides causing profound hearing loss in individuals with MT-RNR1 variants associated with AIHL. Alternative treatment options should be considered in such patients.

Testing recommendations

The UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx) recommend that:

• Pharmacogenetic testing of variants in MT-RNR1 should be undertaken in all individuals, of all age groups where this is possible in a clinically achievable time frame prior to use for all aminoglycosides and for all routes of administration, except topical or enteral (unless absorption is expected to be clinically significant).
• Aminoglycoside treatment should not be delayed in acute clinical settings for the treatment of sepsis or suspected sepsis, in the absence of a pharmacogenetic test result, as the benefit exceeds the risk.

The MHRA advises that genetic testing should be considered especially in patients requiring recurrent or long-term treatment with aminoglycosides, but that testing should not delay urgently needed treatment.

The SmPC for gentamicin states that genetic testing prior to administration, or alternative treatments, should be considered in patients with a maternal history of either relevant mutations or aminoglycoside induced hearing loss.

Therapeutic recommendations

Carriers of MT-RNR1 variants that predispose to aminoglycoside-induced hearing loss

• Avoid aminoglycosides unless the increased risk of hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.
• If no effective alternative is thought to be available use for the shortest time possible with frequent assessment for hearing loss during and after therapy, therapeutic drug monitoring, and in consultation with an infectious disease expert and audio-vestibular physician.
• It is recommended to avoid aminoglycosides via any routes of administration, except topical or enteral (unless absorption is expected to be clinically significant).

Examples of MT-RNR1 variants associated with an increased risk of aminoglycoside induced hearing loss

• m.1555A>G
• m.1095T>C
• m.1494C>T

Further information

Individuals with no detectable MT-RNR1 variant or carrying variants considered to be normal risk

Variants in the MT-RNR1 gene are only one possible cause of increased risk of hearing loss with aminoglycosides, and targeted testing methods frequently used by genetics laboratories may not identify all possible variants associated with an increased risk. Individuals with no detectable MT-RNR1 variant or carrying variants considered to be normal risk, should therefore still be considered at risk of AIHL. 

Individuals with a maternal history of MT-RNR1 variants

MT-RNR1 variants are subject to mitochondrial inheritance, so positive results are relevant to relatives along the maternal line. This means that MT-RNR1 variants are passed down from mother to child. If an individual is found to carry an MT-RNR1 variant, their siblings, mother and relatives on their mother’s side of the family may be at risk and should follow the same recommendations as carriers of MT-RNR1 variants unless genetic testing has confirmed that they are not carriers themselves.

The SmPC for gentamicin states that genetic testing prior to administration, or alternative treatments, should be considered in patients with a maternal history of either relevant mutations or aminoglycoside induced hearing loss.

Alternative routes of administration

Aminoglycosides are highly bioavailable by intramuscular, intravenous, intraperitoneal, and inhaled administration and so avoidance of aminoglycosides in carriers of increased risk MT-RNR1 variants is recommended.  Ototoxicity has been reported following use of orthopaedic cement containing aminoglycosides, and avoidance of use may be considered in patients with increased risk MT-RNR1 variants.

Enteral and topical administration of aminoglycosides is unlikely to cause AIHL, even in individuals with MT-RNR1 variants due to low absolute bioavailability (typically <1%). Absorption of aminoglycosides from the gastrointestinal tract may occur in the presence of severe epithelial damage, such as in patients with severe inflammation, so pharmacogenetic testing and avoidance of use in patients with increased risk MT-RNR1 variants would be appropriate if available in this setting.

Carriers of MT-RNR1 variants who have previously received aminoglycosides

If an individual known to carry a MT-RNR1 variant associated with AIHL has previously received aminoglycosides and not developed hearing loss, this does not abolish the risk from subsequent doses. Therefore, aminoglycosides should be avoided, if possible, in this situation.

Vaccines

Aminoglycoside antibiotics are commonly used during the manufacture of vaccines. Many of these agents are removed during the purification process, but some can remain as trace excipients. It is recommended that the extremely low theoretical risk of AIHL from vaccines is greatly outweighed by the benefits of vaccination, and presence of MT-RNR1 variants associated with an increased risk of AIHL should not impact routine vaccination schedules.

References

McDermott JH, Hilton S, DelloRusso C, et al. MT-RNR1 genotype testing for preventing aminoglycoside-mediated ototoxicity: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx). Br J Clin Pharmacol. 2026;1‐10 https://doi.org/10.1002/bcp.70712.

ADVANZ Pharma (2025) Cidomycin 80mg/2ml Solution for Injection SmPC. Available at: https://www.medicines.org.uk/emc/product/14742/smpc (Accessed online 20th October 2026).

Medicines and Healthcare products Regulatory Agency (2021). Aminoglycosides (gentamicin, amikacin, tobramycin, and neomycin): increased risk of deafness in patients with mitochondrial mutations. Drug Safety Update. Available at: https://www.gov.uk/drug-safety-update/aminoglycosides-gentamicin-amikacin-tobramycin-and-neomycin-increased-risk-of-deafness-in-patients-with-mitochondrial-mutations (Accessed online 19th March 2025).

Clinical Pharmacogenetics Implementation Consortium (CPIC®) (2021). CPIC® Guideline for Aminoglycosides and MT-RNR1. Available at: https://www.clinpgx.org/guideline/PA166251466 (Accessed online 19th March 2025).