New developments in aminoglycoside therapy and ototoxicity

Abstract

After almost seven decades in clinical use, aminoglycoside antibiotics still remain indispensible drugs for acute infections and specific indications such as tuberculosis or the containment of pseudomonas bacteria in patients with cystic fibrosis. The review will describe the pathology and pathophysiology of aminoglycoside-induced auditory and vestibular toxicity in humans and experimental animals and explore contemporary views of the mechanisms of cell death. It will also outline the current state of protective therapy and recent advances in the development of aminoglycoside derivatives with low toxicity profiles for antimicrobial treatment and for stop-codon suppression in the attenuation of genetic disorders.

Fig. 1

Organ of Corti explant from a post-natal day 3 mouse. The preparation was stained for F-actin with rhodamine phalloidin (red fluorescence), outlining a bright outer rim of hair cells. Scale bar = 2 mm.

Fig. 2

Gentamicin-induced hair cell loss. Organotypic cultures of the organ of Corti of the mouse were stained with myosin VIIa (red fluorescence) outlining hair cells. Scale bar = 20 µm. a: The basal part of an explant, control without drug treatment. b to d: Progressive loss of OHC from base to the apex following a 24-h incubation with 0.2 mM gentamicin. b, basal part of explant, severe loss of OHC; c, middle section of the same explant with deranged and partly lost hair cells; d, hair cells in the apical portion remain intact.

Fig. 3

Biochemical reactions preceding gentamicin-induced hair cell loss in mouse organotypic cultures of the organ of Corti. All examples are from comparable basal regions of explants. Scale bar = 20 µm. a and b. Control explant (a) and explant after gentamicin treatment (b) stained for myosin VIIa to outline hair cells (red) and for nitrotyrosine, a marker for ROS action (green). Blue fluorescence is a marker for nuclei. Nitrotyrosine appears in outer hair cells after exposure to the drug. c and d: Control explant (c) and explant after gentamicin treatment (d) stained for myosin VIIa to outline hair cells (red) and for histone acetylation (H3 AcK9, green). Blue fluorescence is a marker for nuclei. Acetylated histone H3 is found in outer and inner hair cells and (more strongly) in supporting cells. After drug treatment, histone acetylation has almost completely disappeared from the cells.