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.
The SmPC for framycetin ear drops provides a special warning and precaution in use that is summarised as follows:
- There have been observed cases of an increased risk of ototoxicity with aminoglycosides administered to patients with mitochondrial mutations, particularly the m.1555A>G mutation, including cases where the patient’s aminoglycoside serum levels were within the recommended range.
- Although no cases were identified with topical preparations of framycetin, based on a shared mechanism of action, the potential for a similar effect with topical framycetin cannot be ruled out.
Bioavailability of aminoglycosides by topical routes is lower than parenteral and it is unknown whether administration by any of these other routes would routinely cause ototoxicity in patients at increased risk of AIHL, but it cannot be ruled out.
Testing recommendations
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.
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 and in consultation with an infection specialist and audio vestibular physician.
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 labs 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.
Alternative routes of administration:
The highest systemic exposure and consequently the highest risk of AIHL is associated with parenteral and intraperitoneal administration of aminoglycosides, followed by inhaled and use of orthopaedic cement containing aminoglycosides. Avoidance may be considered in patients with increased risk MT-RNR1 variants. There are reports of hearing loss after intrathecal or intraventricular administration of aminoglycosides, but the role of MT-RNR1 in this type of AIHL is unknown. Bioavailability of aminoglycosides by enteral, topical, intrathecal or intraventricular routes, or by bladder irrigation, is lower, and it is unknown whether administration by any of these other routes would routinely cause ototoxicity in patients at increased risk of AIHL, but it cannot be ruled out.
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. The Clinical Pharmacogenetic Implementation Consortium (CPIC®) advise 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
Neon Healthcare Ltd (2025) Sofradex Ear/Eye Drops, solution SmPC. Available at: https://www.medicines.org.uk/emc/product/100047/smpc (Accessed online 21st November 2025).
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://cpicpgx.org/guidelines/cpic-guideline-for-aminoglycosides-and-mt-rnr1/ (Accessed online 16th April 2025).
