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Publications

Journal Article Ahead of print

PubMed: 42524757 DOI: 10.1002/bcp.70712

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

Authors: John H McDermott, Sian Hilton, Cinzia Dello Russo, Nicola Booth, Simon Drysdale, Philip Howard, Stephen Hughes, Mallinath Chakraborty, Helen McDevitt, Charlotte Alston, Maya Desai, Mike Beadsworth, Adam Reynolds, Serim Min, Katherine Payne, Munir Pirmohamed, William G Newman

Affiliations

  • Division of Evolution, Infection and Genomics, School of Biological Sciences, University of Manchester, Manchester, UK.
  • Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
  • Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
  • Department of Translational Medicine and Surgery, Section of Pharmacology, Università Cattolica del Sacro Cuore - Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
  • Neonatal Intensive Care Unit, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
  • Oxford Vaccine Group, Children's Hospital, University of Oxford, Oxford, UK.
  • NHS England and NHS Improvement - North East and Yorkshire, NHS England North-East and Yorkshire, Leeds, UK.
  • Department of Pharmacy, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
  • Neonatal Medicine, University Hospital of Wales, Cardiff, UK.
  • Neonatal Unit, Royal Hospital for Children, Glasgow, UK.
  • Newcastle Highly Specialised Mitochondrial Diagnostic Service, North East and Yorkshire Genomic Laboratory Hub, Newcastle, UK.
  • Department of Cystic Fibrosis and Respiratory Medicine, Birmingham Women's and Children's Hospital, Birmingham, UK.
  • Liverpool School of Tropical Medicine, Liverpool, UK. Specialist and Academic Medicine, Royal Liverpool University Hospital, Liverpool, UK.
  • Royal Jubilee Maternity Hospital, Belfast Health and Social Care Trust, Belfast, UK.
  • Manchester Centre for Health Economics, Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, University of Manchester, Manchester, UK.
  • The Wolfson Centre for Personalised Medicine, Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.

Abstract

Aminoglycosides are broad-spectrum antibiotics used in the management of severe infections. Aminoglycosides are associated with nephrotoxicity and ototoxicity. Although dosing strategies such as once-daily administration and therapeutic drug monitoring have reduced the incidence of nephrotoxicity, ototoxicity remains unpredictable and may occur at therapeutic concentrations. A strong association between specific mitochondrial DNA variants in MT-RNR1 (m.1555A > G, m.1494C > T and m.1095 T > C) and aminoglycoside-induced hearing loss exists. These variants (frequency ~1 in 330 individuals across populations) predispose to irreversible, sensorineural hearing loss following aminoglycoside exposure, sometimes after a single dose. Avoidance of aminoglycosides is recommended at any detectable variant level. In England, laboratory-based MT-RNR1 testing is nationally commissioned, whereas point-of-care testing in time-critical settings like neonatal sepsis is delivered in some centres. Approximately 20% of aminoglycoside use is predictable providing opportunities for pre-emptive pharmacogenetic testing. Where MT-RNR1 testing results are unavailable and clinical urgency is high, aminoglycoside treatment should not be delayed. Early health economic evidence suggests that point-of-care testing in neonates may be cost-saving by preventing lifelong hearing loss. Regulatory and Health Technology Assessment bodies support targeted implementation of testing alongside further evidence generation. Overall, integration of MT-RNR1 pharmacogenetic testing offers a feasible and proportionate strategy to reduce harm while preserving access to life-saving antibiotic therapy. This guideline is grounded in the latest evidence in this field but cannot account for all individual factors relevant to patient care. Therefore, prescribers must conduct a thorough assessment of each patient's risk-benefit profile, ensuring that therapy is optimized to maximize benefits while minimizing potential harms.

MeSH

Research Design, Ototoxicity, Point-Of-Care Systems, Pharmaceutical Preparations, Hearing, Pharmacology, Aminoglycosides, Genotype, Therapeutics, Hearing Loss, Point-Of-Care Testing, Pharmacogenomic Testing