Pharmacokinetics and pharmacokinetic/pharmacodynamic-based dosing regimens of long-acting oxytetracycline in Nile tilapia (Oreochromis niloticus) broodstock to minimize selection of drug resistance

This study aimed to determine the pharmacokinetics of long-acting oxytetracycline (OTC-LA) after intraperitoneal (IP) administration in Nile tilapia broodstock. Pharmacokinetic/pharmacodynamic (PK/PD) relationships were evaluated to determine the optimal dosing regimens of OTC-LA against Streptococcus agalactiae. A total of 120 healthy male tilapia (450 +/- 37.47 g) were arbitrarily divided into two groups (60 fish/group) that individually received OTC-LA single IP injection at dosages of 50 or 100 mg/kg body weight. Blood samples were collected at various times posttreatment, and plasma oxytetracycline (OTC) was analyzed using highperformance liquid chromatography. For pharmacodynamic study, 56 S. agalactiae isolates were subjected to agar dilution to determine the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC). Results showed that the Cmax and Tmax of OTC-LA were both 110.70 +/- 5.61 mu g/mL at 2 h for the dosage of 50 mg/kg and 287.85 +/- 8.03 mu g/mL at 4 h for the dosage of 100 mg/kg. Plasma OTC levels remained at 3.99 +/- 0.48 and 23.00 +/- 2.51 mu g/mL at 168 h (7 day) after OTC-LA administration at 50 and 100 mg/kg, respectively. The MIC50 and MIC90 of S. agalactiae were 0.5 and 1 mu g/mL, respectively, and its MPC50 and MPC90 were 32 and 128 mu g/mL, respectively. The mutant selection window of MIC50 and MPC50 was 0.5-32 mu g/mL, and that of MIC90 and MPC90 was 1-128 mu g/mL. OTC-LA at 50 and 100 mg/kg provided plasma OTC levels above MIC for at least 7 days. However, only OTC-LA at 100 mg/kg can provide plasma OTC to prevent the growth of resistant mutant subpopulation. Our study suggested that a single IP administration of OTC-LA at 100 mg/kg body weight is the optimal dosing regimen to attain therapeutic efficacy against S. agalactiae infection in tilapia and prevent the emergence of resistant mutant subpopulation.