Pharmacokinetics of erythromycin in rainbow trout and sea bream

INTRODUCTION Erythromycin (ERY) is a macrolide mainly active against gram + bacteria. ERY is widely used in aquaculture against bacterial kidney disease (Renibacterium salmoninarum), and it shows efficacy also against Lactococcus garvieae and Streptococcus iniae. In literature, studies on pharmacokinetics of ERY in fish are limited to salmon and yellow tail species. The aim of this study was to evaluate the pharmacokinetics of ERY in rainbow trout (Oncorhynchus mykiss) and sea bream (Sparus aurata), species most frequently farmed in Italy. MATERIALS AND METHODS Eighty trout and 80 sea bream were treated with medicated feed, at the rate of 1% of the biomass, containing ERY to obtain a nominal dose of 75 mg kg)1 b.w. Blood samples from 10 fish each sample time were taken at 1, 2, 4, 6, 8, 10, 12, 24 h after treatment. The quantitative analysis of ERY was performed by Agilent 6540 UHD accurate mass Q-TOF LC/MS. Pharmacokinetic parameters obtained from concentration/time curves were calculated using a mono-compartmental (only for trout) and a non-compartmental model (WinNonLin 6.1). RESULTS In trout, concentrations of ERY increased from 8.30 ± 5 lg ml)1 (mean ± standard deviation) at the first time-point (1 h post treatment), to 20.24 ± 13.32 lg ml)1 at 6 h, then decreased to 5.97 ± 3.89 lg ml)1 at 24 h. In sea bream, higher blood concentrations (10.04 ± 11.81 lg ml)1) were observed at 1 h, followed by a decrease down to 0.42 ± 0.21 lg ml)1 at 24 h. CONCLUSIONS In sea bream, ERY is quickly absorbed and quickly eliminated. This rapid pattern is probably due to the warm farming water temperature and to the activity of erythromycin N-demethylase,a liver microsomal enzyme present in this species (Akdogan, 2010). Nielsen et al. (2011) have observed that T > MIC and AUC/MIC are both PK/PD predictors of ERY efficacy and reported that against Streptococcus pyogenes ERY has a bactericidal effect at a ratio AUC/MIC equal to 34 and a T > MIC equal to 41%. Due to a lack in literature of a MIC value for ERY in sea bream pathogens, we cannot correlate obtained concentration with efficacy. In trout, ERY mean serum concentrations ranged from 47.74 to 161.96 times the MIC value (0.125 mg ml)1) reported by Vendrell (2008) for Lactococcus garvie for the complete observation period, and the ratio AUC/MIC was equal to 2150.56. Those data allow us to hypothesize that a dosage of 75 mg kg)1 b.w. per day is effective in the treatment of this infection in trout. REFERENCES 1. Akdogan, H.A. & Sen A. (2010). Characterization of drug metabolizing enzymes and assessment of aging in the gilthead seabream (Sparus aurata) liver. Veterinarni Medicina, 55: 463–471. 2. Vendrell D., Serarols, L., Balca´zar, J.L., de Blas, I., Ruiz- Zarzuela I. & Mu´ zquiz J.L. (2008) Minimum inhibitory concentrations of erythromycin in Lactococcus garvieae strains isolated from cultured rainbow trout (Oncorhynchus mykiss) in Spain. Bull. Eur. Ass. Fish Pathol. 28: 125–128. 3. Nielsen E.I., Cars, O. & Friberg, L.E., (2011) Pharmacokinetic/ Pharmacodynamic (PK/PD) indices of antibiotics predicted by a semimechanistic PKPD Model: a step toward model-based dose optimization. Antimicrob. Agents Chemother. 55, 4619–4630.