Ototoxicity from aminoglycosides

Loop diuretics (especially as i.v. boluses) potentiate ototoxicity of aminoglycosides and nephrotoxicity of some cephalosporins. NSAIDs tend to cause sodium retention which counteracts the effect of diuretics the mechanism may involve inhibition of renal prostaglandin formation. Diuretic treatment of a patient taking lithium can precipitate toxicity from this drug (the increased sodium loss is accompanied by reduced lithium excretion). Reference is made above to drug treatments which, when combined with diuretics, may lead to hyper-kalaemia, hypokalaemia, hyponatraemia, or glucose intolerance. 

Kimnra N, Nishizaki K, Orita Y, Masnda Y. 4-methyl-catechol, a potent inducer of nerve growth factor synthesis, protects spiral ganglion neurons from aminoglycoside ototoxicity—preliminary report. Acta Otolaryngol Suppl 1999 540 12-15. 

Deafness occurred after 5 days treatment with dantrolene 25 mg/day in a patient who was also taking long-term baclofen and diazepam (8). This may have been coincidental, but the authors suggested that dantrolene may have caused the effect by interfering with the release of calcium from the sarcoplasmic reticulum. It is therefore interesting that one hypothesis that explains the ototoxicity of aminoglycoside antibiotics involves disturbance of calcium ion binding and phosphorylation processes (SED-11, 549). 

Jiang H, Sha SH, Schacht J (2005) NF-kappaB pathway protects cochlear hair cells from aminoglycoside-induced ototoxicity. J Neurosci Res 79(5) 644-651... 

Ototoxicity results from aminoglycoside-induced damage to the hair cells of the Organ of Corti. Nephrotoxicity occurs in the proximal tubular cells which endocytose aminoglycosides and are subsequently killed. Acute nephrotoxicity is reversible. 

M. Yagi, E. Magal, Z. Sheng, K. A. Ang, and Y. Raphael, Hair cell protection from aminoglycoside ototoxicity by adenovirus-mediated overexpression of glial cell line-derived neurotrophic factor. Hum. Gene Ther., 10 (1999) 813-823. 

The principal arninoglycoside toxicides are neuromuscular paralysis, ototoxicity, and nephrotoxicity. Neuromuscular paralysis is a relatively rare complication resulting from high aminoglycoside concentrations at the neuromuscular junctions following, for example, rapid bolus intravenous injection or peritoneal instillation, rather than the normal intravenous infusion. The mechanism apparentiy involves an inhibition of both the presynaptic release of acetylcholine and the acetylcholine postsynaptic receptors (51). 

The question then arises whether the formation of ROS can indeed be causally related to cell death or whether it simply constitutes an epiphenomenon. The strongest evidence for a causal relationship comes from studies that demonstrate the ability of iron chelators and antioxidants to protect against aminoglycoside-induced ototoxicity. Effective protectants include chelators such as deferoxamine and dihydroxybenzoic acid and a variety of other antioxidant molecules includ-... 

All the aminoglycosides produce cochlear and vestibular damage (ototoxicity) which is a dose and duration of treatment related side effect. Another serious side effect is nephrotoxicity. Aminoglycosides also reduce the acetylcholine release from the motor nerve endings and cause neuromuscular blockade. 

Bums. Infection may be reduced by application of silver sulphadiazine cream. Substantial absorption can occur from any raw surface and use of aminoglycoside, e.g. neomycin, preparations can cause ototoxicity. 

In a quantitative assessment of vestibular hair cells and Scarpa s ganglion cells in 17 temporal bones from 10 individuals with aminoglycoside ototoxicity, streptomycin caused a significant loss of both type I and type II hair cells in all five vestibular sense organs (19). The vestibular ototoxic effects of kanamycin appeared to be similar to those of streptomycin, whereas neomycin did not cause loss of vestibular hair cells. There was no significant loss of Scarpa s ganglion cells. 

Differences between sera from patients with resistance or susceptibility to aminoglycoside ototoxicity have been described in vitro (53). Sera from sensitive but not from resistant individuals metabolized aminoglycosides to cytotoxins, whereas no sera were cytotoxic when tested without the addition of aminoglycosides. This effect persisted for up to 1 year after aminoglycoside treatment. 

Etacrynic acid potentiates aminoglycoside ototoxicity by facilitating the entry of the antibiotics from the systemic circulation into the endolymph (33). Animal evidence suggests that this effect may be potentiated by glutathione depletion (34). Conversely, neomycin can enhance the penetration of etacrynic acid into the inner ear (35). 

Furosemide increases the ototoxic risks of aminoglycoside antibiotics (30,31) by reducing their clearance by about 35% (32) permanent deafness has resulted from the use of this combination. 

Histological examination of the temporal bones from two individuals with ototoxicity due to tobramycin showed reductions in the numbers of both ganglion cells and hair cells (21). Spiral ganglion cell loss was not necessarily subadjacent to areas of hair cell loss in cases of aminoglycoside ototoxicity. Instead, there may be a reduction in the number of ganglion cells in segments of the cochlea with normal-appearing hair cells. 

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