What are the risks of ototoxicity associated with aminoglycosides (antibiotics) and how can they be mitigated?

Aminoglycosides and Ototoxicity: Risks and Mitigation Strategies

Aminoglycosides can cause permanent and irreversible ototoxicity affecting both vestibular and auditory function, primarily through damage to hair cells and neurons in the inner ear, with risk factors including advanced age, prolonged therapy, high doses, renal impairment, and genetic predisposition. 1, 2

Mechanisms and Manifestations of Ototoxicity

• Aminoglycosides accumulate in inner ear cells where they bind to ribosomes, causing permanent damage to sensory cells and neurons 3
• Ototoxicity manifests as both vestibular and auditory dysfunction:
  • Auditory effects: high-frequency hearing loss, tinnitus, roaring in the ears, and potential progression to total or partial irreversible bilateral deafness 1
  • Vestibular effects: dizziness, vertigo, ataxia, and nystagmus 4
• Different aminoglycosides have different toxicity profiles:
  • Streptomycin and gentamicin are primarily vestibulotoxic 4
  • Amikacin, neomycin, dihydrostreptomycin, and kanamycin are primarily cochleotoxic 4
• Ototoxicity occurs through several mechanisms:
  • Generation of free radicals within the inner ear 4, 5
  • Overexpression of NMDA receptors 5
  • Mitochondrial damage, particularly in genetically susceptible individuals 5

Risk Factors for Aminoglycoside Ototoxicity

• Pre-existing renal impairment 1, 2
• Advanced age 1, 2
• Dehydration 1, 2
• High dosage and/or prolonged therapy beyond recommended durations 1, 2
• High peak or trough serum concentrations 1, 2
• Genetic predisposition, particularly mutations in mitochondrial 12S rRNA (A1555G and C1494T) 4, 5
• Concurrent use of other ototoxic medications, including:
  • Other aminoglycosides
  • Cisplatin
  • Vancomycin
  • Loop diuretics (ethacrynic acid, furosemide)
  • Polymyxins (polymyxin B, colistin) 1, 2

Mitigation Strategies

Dosing Optimization

• Consider once-daily or extended-interval dosing regimens:
  • Once-daily aminoglycoside dosing may be less toxic and equally efficacious as multiple daily dosing 3
  • High-peak, low-trough dosing strategies may reduce toxicity while maintaining efficacy 3
• Adjust dosing based on renal function and therapeutic drug monitoring 3
• Consider streptomycin when vestibular toxicity is a particular concern, as it has been associated with less hearing loss compared to other aminoglycosides 3

Monitoring Recommendations

• Perform baseline assessment before starting therapy:
  • Renal function (BUN, serum creatinine, creatinine clearance) 1, 2
  • Audiometric testing in patients old enough to be tested, particularly high-risk patients 3
• During therapy:
  • Monitor serum aminoglycoside concentrations when feasible 1, 2
    • Avoid prolonged peak levels above 12 mcg/mL for gentamicin 1
    • Avoid prolonged peak concentrations above 35 mcg/mL for amikacin 2
    • Avoid trough levels above 2 mcg/mL for gentamicin 1
  • Monitor renal function regularly 3
  • Perform serial audiograms when feasible 3
  • Monitor urine for decreased specific gravity, increased protein excretion, and presence of cells or casts 1, 2
• Instruct patients to immediately report symptoms of ototoxicity (dizziness, vertigo, tinnitus, hearing changes) 3

Administration Considerations

• Administer the first dose in a supervised setting with personnel trained in resuscitation 3
• Use slow infusion rather than rapid administration to reduce risk of acute vestibular toxicity 3
• Consider tobramycin over gentamicin when possible, as some studies suggest it may be less nephrotoxic 3

Avoidance Strategies

• Avoid concurrent use of other ototoxic medications when possible 1, 2
• Particularly avoid concurrent use of potent diuretics (ethacrynic acid, furosemide) 1, 2
• Ensure proper hydration status 1, 2
• Consider alternative antibiotics in high-risk patients, especially those with known mitochondrial DNA mutations associated with aminoglycoside sensitivity 5
• Limit treatment duration to the shortest effective period 1, 2

Special Considerations

• Discontinue aminoglycosides or adjust dosage at first sign of ototoxicity or nephrotoxicity 1, 2
• In case of overdosage or toxic reactions, hemodialysis may aid in removal of aminoglycosides from the blood 1
• Exercise extreme caution in pregnant women as aminoglycosides can cause fetal harm 1
• Consider genetic testing for susceptibility mutations in high-risk populations or those with family history of aminoglycoside-induced hearing loss 5

By implementing these monitoring and mitigation strategies, clinicians can minimize the risk of permanent ototoxicity while still leveraging the therapeutic benefits of aminoglycoside antibiotics when clinically necessary.