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)

Three variants in the mitochondrially encoded ribosomal RNA gene MT-RNR1 (m.1555A>G, m.1494C>T, m.1095T>C) predispose to irreversible sensorineural hearing loss after aminoglycoside exposure, sometimes after a single dose.

Aminoglycosides remain essential in severe infections but carry an unpredictable risk of ototoxicity that may occur at therapeutic concentrations, even though once-daily dosing and therapeutic drug monitoring have reduced nephrotoxicity. Three mitochondrial DNA variants in MT-RNR1 (m.1555A>G, m.1494C>T and m.1095T>C), found in about 1 in 330 individuals across populations, predispose to irreversible sensorineural hearing loss that can follow a single dose. This UK CERSI-PGx guideline recommends avoiding aminoglycosides at any detectable variant level and notes that around 20 % of aminoglycoside use is predictable and therefore amenable to pre-emptive genotyping. In England laboratory-based testing is nationally commissioned and point-of-care testing is delivered in some centres for time-critical settings such as neonatal sepsis, where early health economic evidence suggests testing may be cost-saving by preventing lifelong hearing loss. The guideline states that where results are unavailable and clinical urgency is high, aminoglycoside treatment should not be delayed.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is one of the rare situations where pharmacogenetics yields a binary instruction rather than a dose adjustment: variant detected, change antibiotic. The difficulty is entirely logistical — the useful window in neonatology is too short for a conventional laboratory pathway, which makes point-of-care testing the only realistic option — and the guideline wisely states outright that antibiotic therapy must not be delayed while waiting for a genotype. That said, the 80 % of unpredictable prescriptions will always escape a strategy built on anticipating exposure.

Analysis by Dr Thibaut Benquey