ABSTRACT
Spread of antimicrobial resistance and shortage of novel antibiotics have led to an urgent need for new antibacterials. Although aminoglycoside antibiotics (AGs) are very potent anti-infectives, their use is largely restricted due to serious side-effects, mainly nephrotoxicity and ototoxicity. We evaluated the ototoxicity of various AGs selected from a larger set of AGs on the basis of their strong antibacterial activities against multidrug-resistant clinical isolates of the ESKAPE panel: gentamicin, gentamicin C1a, apramycin, paromomycin and neomycin. Following local round window application, dose-dependent effects of AGs on outer hair cell survival and compound action potentials showed gentamicin C1a and apramycin as the least toxic. Strikingly, although no changes were observed in compound action potential thresholds and outer hair cell survival following treatment with low concentrations of neomycin, gentamicin and paromomycin, the number of inner hair cell synaptic ribbons and the compound action potential amplitudes were reduced. This indication of hidden hearing loss was not observed with gentamicin C1a or apramycin at such concentrations. These findings identify the inner hair cells as the most vulnerable element to AG treatment, indicating that gentamicin C1a and apramycin are promising bases for the development of clinically useful antibiotics.
Subject(s)
Anti-Bacterial Agents/adverse effects , Gentamicins/pharmacology , Hearing Loss/genetics , Nebramycin/analogs & derivatives , Ototoxicity/metabolism , Aminoglycosides/adverse effects , Aminoglycosides/pharmacology , Animals , Anti-Infective Agents/adverse effects , Anti-Infective Agents/pharmacology , Cell Line , Drug Resistance, Bacterial/drug effects , Drug Resistance, Bacterial/genetics , Gentamicins/adverse effects , Gentamicins/therapeutic use , Guinea Pigs , Hair Cells, Auditory, Inner/drug effects , Hair Cells, Auditory, Inner/pathology , Hearing Loss/chemically induced , Hearing Loss/pathology , Humans , Nebramycin/adverse effects , Nebramycin/pharmacology , Neomycin/adverse effects , Neomycin/pharmacology , Ototoxicity/pathology , Protein Synthesis Inhibitors/adverse effects , Protein Synthesis Inhibitors/pharmacology , Round Window, Ear/drug effects , Round Window, Ear/pathologyABSTRACT
An increasing range of antibacterial compounds is being used for nonclinical purposes, especially in the fields of animal husbandry and fish farming. As in human medicine, exposure to antibiotics has lead to the emergence of antibiotic-resistant bacteria in animal populations. The potential impact of antibiotic use in animals on human health and the management of clinical infections in humans is discussed in light of growing evidence to suggest that "new" resistance genes and multiresistant pathogens with increased pathogenicity are emerging in food animals as a direct consequence of antibiotic exposure.
