Aminoglycoside-Induced Cochleotoxicity: A Review

Abstract

Aminoglycoside antibiotics are used as prophylaxis, or urgent treatment, for many life-threatening bacterial infections, including tuberculosis, sepsis, respiratory infections in cystic fibrosis, complex urinary tract infections and endocarditis. Although aminoglycosides are clinically-essential antibiotics, the mechanisms underlying their selective toxicity to the kidney and inner ear continue to be unraveled despite more than 70 years of investigation. The following mechanisms each contribute to aminoglycoside-induced toxicity after systemic administration: (1) drug trafficking across endothelial and epithelial barrier layers; (2) sensory cell uptake of these drugs; and (3) disruption of intracellular physiological pathways. Specific factors can increase the risk of drug-induced toxicity, including sustained exposure to higher levels of ambient sound, and selected therapeutic agents such as loop diuretics and glycopeptides. Serious bacterial infections (requiring life-saving aminoglycoside treatment) induce systemic inflammatory responses that also potentiate the degree of ototoxicity and permanent hearing loss. We discuss prospective clinical strategies to protect auditory and vestibular function from aminoglycoside ototoxicity, including reduced cochlear or sensory cell uptake of aminoglycosides, and otoprotection by ameliorating intracellular cytotoxicity.

Keywords: aminoglycosides; cochleotoxicity; gentamicin; inflammation; nephrotoxicity; ototoxicity; systemic administration.

Figure 1

Chemical structures of selected aminoglycoside antibiotics. For gentamicin C₁: R₁ = R₂ = CH₃; gentamicin C₂: R₁ = CH₃, R₂ = H; and gentamicin C_1A: R₁ = R₂ = H. For kanamycin A: R₁ = NH₂, R₂ = OH; kanamycin B: R₁ = R₂ = NH₂; and kanamycin C: R₁ = OH, R₂ = NH₂.

Figure 2

(A) Cross-section of the cochlear duct, illustrating the perilymph-filled scala vestibuli and scala tympani, separated from the scala media by tight junctions between adjacent cells (black line) of Reissner’s membrane and reticular lamina of the organ of Corti resting on the basilar membrane. Within the organ of Corti are four longitudinal rows of sensory hair cells (in sky blue), under the tectorial membrane. The hair cells are innervated by afferent and efferent fibers (blue lines). Within the lateral wall of the cochlea is the highly-vascularized stria vascularis (upper right); enclosing several capillary beds (red circles) lined by tight-junction-coupled endothelial cells (black lines enclosing red circles) that form the cochlear BLB. (B) A nephron (kidney tubule) showing the glomerulus encapsulating a single capillary bed that gathers the ultrafiltrate from blood. The proximal tubule has a brush border of microvilli that recovers the majority of essential nutrients and ions, and the distal tubule recaptures the remaining nutrients, and excretes specific ions. Sites of major ion movements are shown. Both schematic diagrams are not to relative scale.