Pharmacokinetics, pharmacodynamics and dosing regimen of long-acting oxytetracycline in nile tilapia (Oreochromis niloticus)

Abstract

Antimicrobial resistance has become a serious global problem and is steadily increasing worldwide. In aquaculture, there are limited antimicrobial options for treatment. Thus, there are growing needs for more specific dosing regimens of existing antimicrobial drugs that are not only to obtain therapeutic efficacy but also to minimize the resistance of pathogens. The purposes of this study were to determine pharmacokinetics (PK) of long-acting oxytetracycline (OTC) after intraperitoneal (IP) administration in Nile tilapia. One hundred and twenty healthy male tilapia (450±37.47 g) were divided into two experimental groups (60 fish/group). Each group received OTC-LA single IP injection at dosage of 50 mg/kg or 100 mg/kg bodyweight. Blood samples were collected at various times post-dosing and plasma OTC were analyzed using high performance liquid chromatography (HPLC). For pharmacodynamics (PD) study, 56 S. agalactiae isolates from diseased tilapia were determined for minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) by agar dilution method. The results showed that the Cmax and Tmax of OTC were 110.70 ± 5.61 µg/ml at 2 h for the dosage of 50 mg/kg, and 287.85 ± 8.03 µg/ml at 4 h for the dosage of 100 mg/kg. OTC level in plasma was slowly depleted and remained at 3.99 ± 0.48 µg/ml and 23.00 ± 2.51 µg/ml at 168 h (7 day) after administration OTC-LA at the dosages of 50 and 100 mg/kg, respectively. From 56 S. agalactiae samples, MIC range was 0.5 to 2 µg/ml, with MIC50 and MIC90 at 0.5 µg/ml and 1 µg/ml, respectively. MPC range was 4 to 512 µg/ml, with MPC50 and MPC90 at 32 µg/ml and 128 µg/ml, respectively. For the ratio of MPC and MIC and mutant selection window (MSW) results, MPC50/MIC50 ratio was 64 (MSW: 0.5 - 32 µg/ml) and MPC90/MIC90 ratio was 128 (MSW: 1 -128 µg/ml). From the integrated PK/PD parameters, both OTC-LA at the dosages of 50 mg/kg and 100 mg/kg dosages achieved the target values and provided plasma OTC level above MIC for at least 7 days. While PK/PD parameters based on MPC, only OTC-LA at 100 mg/kg dosage can prevent the resistant-mutant subpopulation. Therefore, OTC-LA treatment at 100 mg/kg bodyweight IP administration would be suggested as the optimal dosing regimen to attain therapeutic efficacy and prevent the emergence of resistant-mutant subpopulation and possible to be used as a single administration for the infection caused by S. agalactiae.