Ototoxicity caused by once- and twice-daily administration of amikacin in rabbits

Abstract

Objective

The cochleotoxic effects of aminoglycosides, such as amikacin, are well-established. The aim of the present study was to investigate the possible differences in cochleotoxic effects between once-daily administration (ODA) and twice-daily administration (TDA) of amikacin simulating pediatric dosing.

Methods

Twenty-one rabbits were used. Seven animals received intramuscularly amikacin once daily (ODA-group) and seven received the drug twice daily (TDA-group), for a total time period of 2 weeks. All the animals were subjected to Distortion Product Otoacoustic Emissions (DPOAEs) every 3 days since beginning of the experiment. The rest 7 animals did not receive any medication and served as controls (Control group). Two measurements (7 and 14 days) were obtained following the cease of drug administration.

Results

Reduced cochlear activity (as depicted in the respective reduced DPOAE-amplitudes) compared to the pre-treatment state was found in both ODA- and TDA-groups. Cochlear activity was reduced at a wider range of frequencies (from 593 to 4031 Hz in TDA-group and from 593 to 1093 Hz in ODA-group) and to a higher degree in group B than in group A. Cochlear activity was reduced earlier in ODA-group than in TDA-group. No differences to the pre-treatment state were observed in the control group.

Conclusions

The above findings suggest that less frequent administration in higher dose of amikacin is associated with minimal cochleotoxicity.

Introduction

Aminoglycosides are bactericidal aminoglycosidic aminocyclitols. They were discovered in the 1940s and are the treatment of choice for tuberculosis and advanced bacterial infections. They were the first class of drugs to call the attention to the problem of ototoxicity when streptomycin and dihydrostreptomycin were used to treat tuberculosis [1].

Dosing regimens for aminoglycosides, can be classified as conventional or pulse. The majority of clinicians is familiar with conventional dosing in which the antibiotic is administered in equal doses every 8–12 h. Pulse-dosing involves administering the drug in a single dose per dosing interval. Many authors prefer the term “pulse-dosing” to the term “once-daily” aminoglycoside because the interval may exceed 24 h [2]. This type of regimen aims at achieving optimum concentration-dependent bactericidal activity to maximize efficacy, avoid first-exposure adaptive bacterial resistance and use better post-antibiotic effect [3], [4], [5], [6], [7]. In the last two decades, animal experiments and clinical studies supported the efficacy of once-daily, high doses of aminoglycosides for severe gram-negative infections [8], [9].

The aim of the present study was to investigate the possible differences in cochleotoxic effects between once-daily administration (ODA) and twice-daily administration (TDA) of amikacin with the use of DPOAE.