Gentamicin (brand names Garamycin, Cidomycin, and Septopal) is an aminoglycoside antibiotic that is used to treat sepsis. Gentamicin is administered by injection to treat serious infections caused by gram-negative bacteria (for example, Pseudomonas aeruginosa, Proteus species, Escherichia coli, Klebsiella-Enterobacter-Serratia species, and Citrobacter species). Additionally, gentamicin is used as an adjuvant treatment for infections caused by gram-positive bacteria (such as Staphylococcus species) (1). Gentamicin may also be used topically to treat ophthalmic and dermatological infections.
In most individuals, prolonged exposure to high gentamicin levels will cause ototoxicity (damage to the inner ear). However, among individuals who have specific variants in the mitochondrial gene MT-RNR1, a single dose of gentamicin can result in hearing loss (cochleotoxicity). This toxicity occurs in genetically susceptible individuals, despite serum drug concentrations within the normal therapeutic range (2). This hearing loss can be triggered not only by gentamicin, but by other aminoglycoside antibiotics and is referred to as aminoglycoside-induced hearing loss (AIHL).
Substantial literature has reported that a high proportion of individuals with the MT-RNR1 m.1555A>G variant (NC_012920.1:m.1555A>G) develop hearing loss after receiving aminoglycoside therapy. The onset of hearing loss among these individuals varies, but once it occurs, it is usually moderate to profound, bilateral, and irreversible (3). Additional MT-RNR1 genotypes associated with increased risk of AIHL include m.1095T>C and m.1494C>T (4).
The FDA-approved drug label for gentamicin does not include a statement regarding MT-RNR1 (5); however, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has published guidelines for administration of aminoglycosides, including gentamicin, with respect to variants in the MT-RNR1 gene (4). These guidelines (Table 1) recommend avoiding the use of aminoglycoside antibiotics, such as gentamicin unless there are no satisfactory alternatives, by individuals who have a MT-RNR1 genotype that puts them at high risk for AIHL. The CPIC guideline further advises that individuals with normal-risk alleles or uncertain-risk alleles at the MT-RNR1 locus should all use aminoglycosides at standard doses for the shortest feasible course, with regular evaluation for hearing loss. This extends the 2014 American College of Medical Genetics and Genomics guideline with the following recommendation: “Single-gene testing may be warranted in cases in which the medical or family history, or presentation of the hearing loss, suggests a specific etiology. For example, testing for mitochondrial DNA variants associated with aminoglycoside ototoxicity may be considered for individuals with a history of use of aminoglycoside antibiotics” (6, 7).