William McKinney1, Al Yonovitz2, Michael H Smolensky3. 1. School of Public Health , University of Texas Health Science Center, Houston, Texas, U.S.A. 2. Department of Communicative Sciences and Disorders , University of Montana, Missoula, Montana, U.S.A. 3. Department of Biomedical Engineering , University of Texas at Austin, Austin, Texas, U.S.A.
Abstract
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.
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 ureanitrogen 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.
Authors: Caspar J Hodiamont; Annemieke K van den Broek; Suzanne L de Vroom; Jan M Prins; Ron A A Mathôt; Reinier M van Hest Journal: Clin Pharmacokinet Date: 2022-06-27 Impact factor: 5.577