Aminoglycoside antibiotics

Aminoglycosides are a large class of antibiotics widely used around the world for the treatment of infection. They include gentamicin, amikacin, tobramycin, streptomycin and neomycin. Aminoglycosides are typically administered by intravenous or intramuscular injection for the treatment of gram-negative bacterial infections, or as synergistic treatment for gram-positive bacterial infections.

In the UK, NICE advises the use of intravenous benzylpenicillin in combination with gentamicin as the first-choice regimen for empirical treatment of early onset neonatal infection, and gentamicin is the most widely prescribed antibiotic on UK neonatal units.

• In high doses, or with protracted dosing regimens, aminoglycosides are known to cause nephrotoxicity and ototoxicity. The latter can manifest as either vestibulotoxicity (balance disturbance) or cochleotoxicity (hearing loss).
• Aminoglycoside-induced hearing loss (AIHL), whether moderate or profound in severity, can be rapid onset, bilateral and permanent.
• Variants in the MT-RNR1 gene can predispose affected individuals to ototoxicity after just a single dose of aminoglycoside.
• Aminoglycosides inhibit protein synthesis by binding to the aminoacyl site (A-site) of 16S ribosomal RNA (rRNA) in the bacterial 30S ribosomal subunit, a structure responsible for mRNA translation within the prokaryotic cell. If the 16S rRNA A-site is bound to an aminoglycoside, this severely interrupts normal protein synthesis and results in mistranslation by inducing codon misreading, causing error-prone protein synthesis.
• In eukaryotic cells, the 12S rRNA subunit is the mitochondrial homologue of the prokaryotic 16S rRNA and is responsible for the translation of messenger RNAs (mRNAs) into mitochondrial proteins. The 12S rRNA subunit is encoded by the MT-RNR1 gene.
• Variants in the MT-RNR1 gene can alter the conformation of the 12S rRNA subunit, increasing its structural similarity to the bacterial 16S rRNA. Therefore, in individuals with these variants, aminoglycosides can cause cellular damage, particularly in the inner hair cells of the cochlea.

• In the UK, there are currently no guidelines that explicitly mandate MT-RNR1 testing prior to aminoglycoside prescription.
• In 2021, the UK Medicines and Healthcare products Regulatory Agency advised that clinicians should consider genomic testing in patients receiving aminoglycoside antibiotics, particularly in those requiring recurrent or long-term treatment, but that urgent treatment should not be delayed (see the resources list below).
• Recent Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines have identified three MT-RNR1 variants that can cause AIHL, meaning that aminoglycosides should be avoided:
  • 1555A>G (by far the most common MT-RNR1 variant, and therefore the most clinically relevant, with a population prevalence of around 1 in 500 in the UK);
  • 1494C>T; and
  • 1095T>C.
• In 2021, the CPIC guidance advised that any individual with the m.1555A>G, m.1494C>T or m.1095T>C variants should avoid aminoglycoside antibiotics unless the high risk of permanent hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies.
• A recent NICE assessment provisionally recommended the use of a point-of-care test approach, which allows clinicians to identify babies in neonatal intensive care units who are at risk of AIHL due to an RNR1 variant prior to gentamicin administration.
• MT-RNR1 variants are subject to mitochondrial inheritance, so families should be counselled that any positive results are relevant to relatives along the maternal line.
• For more information about genomic testing for MT-RNR1 variants and how results can affect patient management, see Presentation: Patient requiring aminoglycoside antibiotics and Results: Patient with a known MT-RNR1 variant requiring aminoglycoside antibiotics.

For clinicians

• Medicines and Healthcare products Regulatory Agency: Drug safety update: Aminoglycosides (gentamicin, amikacin, tobramycin, and neomycin): Increased risk of deafness in patients with mitochondrial mutations
• National Library of Medicine: Gentamicin therapy and MT-RNR1 genotype
• NICE: Genedrive MT-RNR1 ID Kit for detecting a genetic variant to guide antibiotic use and prevent hearing loss in babies: early value assessment

References:

• McDermott JH, Mahaveer A, James RA and others. ‘Rapid point-of-care genotyping to avoid aminoglycoside-induced ototoxicity in neonatal intensive care’. Journal of the American Medical Association Pediatrics 2022: volume 176, issue 5, pages 486–492. DOI: 10.1001/jamapediatrics.2022.0187
• McDermott JH, Wolf J, Hoshitsuki K and others. ‘Clinical Pharmacogenetics Implementation Consortium guideline for the use of aminoglycosides based on MT-RNR1 genotype’. Clinical Pharmacology & Therapeutics 2021: volume 111, issue 2, pages 366–372. DOI: 10.1002/cpt.2309