Impact of genetic variation on response to therapy
UK licensed ear drops containing framycetin are available for topical use.
There is an increased risk of ototoxicity including aminoglycoside-induced hearing loss (AIHL) in patients with variants in the mitochondrial MT-RNR1 gene. However, topical administration of aminoglycosides is unlikely to cause AIHL, even in individuals with MT-RNR1 variants due to low absolute bioavailability (typically <1%).
The SmPC for Sofradex® ear drops provides a special warning and precaution for use that there have been observed cases of an increased risk of ototoxicity with aminoglycosides administered to patients with mitochondrial mutations, including cases where the patient’s aminoglycoside serum levels were within the recommended range. While no cases were identified with topical framycetin, there is the potential for a similar effect with framycetin based on a shared mechanism of action.
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 is not required for topical or enteral use of aminoglycosides unless absorption is expected to be clinically significant.
- For all other routes of administration testing 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.
- 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.
Therapeutic recommendations
Carriers of MT-RNR1 variants that predispose to aminoglycoside-induced hearing loss:
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 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
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.
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.
Neon Healthcare Ltd (2025) Sofradex Ear/Eye Drops, solution SmPC. Available at: https://www.medicines.org.uk/emc/product/100047/smpc (Accessed online 21st 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 16th April 2025).
