Intravenously delivered aminoglycoside antibiotics, tobramycin and amikacin, are not ototoxic in mice

Abstract

Many drugs on the World Health Organization's list of critical medicines are ototoxic, destroying sensory hair cells within the ear. These drugs preserve life, but patients can experience side effects including permanent hearing loss and vestibular dysfunction. Aminoglycoside ototoxicity was first recognised 80 years ago. However, no preventative treatments have been developed. In order to develop such treatments, we must identify the factors driving hair cell death. In vivo, studies of cell death are typically conducted using mouse models. However, a robust model of aminoglycoside ototoxicity does not exist. Previous studies testing aminoglycoside delivery via intraperitoneal or subcutaneous injection have produced variable ototoxic effects in the mouse. As a result, surgical drug delivery to the rodent ear is often used to achieve ototoxicity. However, this technique does not accurately model clinical practice. In the clinic, aminoglycosides are administered to humans intravenously (i.v.). However, repeated i.v. delivery has not been reported in the mouse. This study evaluated whether repeated i.v. administration of amikacin or tobramycin would induce hearing loss. Daily i.v. injections over a two-week period were well tolerated and transient low frequency hearing loss was observed in the aminoglycoside treatment groups. However, the hearing changes observed did not mimic the high frequency patterns of hearing loss observed in humans. Our results indicate that the i.v. delivery of tobramycin or amikacin is not an effective technique for inducing ototoxicity in mice. This result is consistent with previously published reports indicating that the mouse cochlea is resistant to systemically delivered aminoglycoside ototoxicity.

Keywords: Aminoglycoside; Intravenous; Mouse; Nephrotoxic; Ototoxic; Resistant.