Circadian variation of gentamicin toxicity in rats.

OBJECTIVES/HYPOTHESIS: Two undesired effects of the aminoglycoside antibiotic gentamicin are ototoxicity and nephrotoxicity. This study investigated if these adverse effects vary according to the circadian time of its administration.

STUDY

DESIGN

This study entails laboratory animal research.

METHODS

Four groups of Sprague-Dawley rats were synchronized to a 12:12 light/dark schedule. Each group receiving the antibiotic (100 mg/kg gentamicin sulfate) at a different circadian time. Auditory brainstem response was obtained at pretreatment and at 2, 4, and 6 weeks.

RESULTS

At all measured frequencies, hearing losses were significantly (P < .001) greater when gentamicin was administered during the diurnal rest span than the nighttime activity span. At 4 weeks, the average total hearing loss, quantified by elevation of threshold values over the tested auditory frequencies, was 31.3 and 25.6 dB for the 2 hours after lights on (HALO) and 8 HALO groups, respectively. The loss progressed at 6 weeks to 42.5 (2 HALO) and 37.5 (8 HALO) dB. At 6 weeks, the 14 and 20 HALO groups had losses of 17.5 and 26.3 dB, respectively. Trough serum gentamicin concentration significantly (P < .01) increased during treatment, being the highest at 4 weeks. Urine urea nitrogen 24-hour levels of the 2 and 8 HALO groups differed significantly (P < .01) from the 14 and 20 HALO groups.

CONCLUSIONS

Ototoxicity was greater when gentamicin was administered during their diurnal rest than during nocturnal activity. A dosing paradigm may be used to deliver a lower therapeutic antimicrobial concentration during the nighttime rest period when the studied adverse effects are of highest risk.