Aminoglycoside Induced Deafness

Aminoglycoside antibiotic-induced ototoxicity is a major cause of irreversible deafness in many parts of the world (134,135). In China, because of the widespread use of aminoglycosides, in some areas, up to 25% of the cases of deafness were found to be caused by aminoglycosides (136). The pathogenesis of aminoglycoside-induced ototoxicity is divided into two types. One is prolonged or high-level drug exposure, and the other is idiosyncratic reaction resulting from minimal or regular exposure. The latter individuals are observed to be clustered in certain families, suggesting that genetic factors play a role in the susceptibility to aminoglycoside-induced ototoxicity. Studies in the Chinese and Japanese families have shown that the inheritance is exclusively through the maternal line (137-139).

The mechanism of the antimicrobial action of aminoglycosides is to bind to the 30S subunit of the bacterial ribosome, which ultimately leads to the inhibition of protein synthesis. It interferes with the initiation complex of peptide formation, which induces misreading of the code on the mRNA template and causes a breakup of polysomes into nonfunctional monosomes. Recent evidence suggests that the A1555G mutation in the mitochondrial 12S rRNA gene leads to susceptibility to aminoglycoside ototoxcity (140). The mutation causes the human mitochondrial rRNA to be more structurally similar to the bacterial rRNA that is the target of aminoglycoside action (141). The A1555G mutation has indeed been shown to cause an increase in the binding of aminoglycoside to the mito-chondrial rRNA (142), and there is a decrease in mitochondrial protein synthesis in cells carrying the A1555G mutation (143). A T961C has now been discovered in an Italian family and in a Japanese patient (135,140).

The neuro-otological characteristics in patients with the A1555G mutation have been described (134). First, these patients exhibit a progressive loss of hearing. In most patients, the interval between the first complaint of hearing loss after aminoglycoside exposure and complete deafness was more than 10 years. Second, a better residual pure-tone threshold was found in these patients, suggesting that the organ of Corti was more or less preserved. Third, there was a lower threshold for electrical promontory stimulation in patients with the mutation than in those without. Fourth, the vestibular function was well preserved in these patients suggesting that increased susceptibility to aminogly-cosides seems to occur mainly in the cochlea. It has been thought that the progressive hearing loss associated with this mutation is partly due to progressive reduction of the endocochlear potential production from the stria vascularis, which is known to contain many mitochondria in the intermediate cells (134). Screening for these mutations may lead to a reduction in the number of victims of progressive deafness induced by aminoglycosides.

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