| With the rapid development of intensive aquaculture in recent years, A. hydrophila disease prevalence become more and more serious. A. hydrophila is considered one of the major pathogens threatening the freshwater fish cultivation industry,causing fish farming damage and higher mortality. Amphenicols has been extensivly applied in aquaculture for the prevention and treatment of bacterial infections, due to the rapid absorption 、 extend distribution and broad spectrum antibacterial. However, the serious abuse of drugs resulted in the fast-speed emergence of bacterial drug tolerance and a significantly decrease in the drug efficacy. In theoretically and practically, integrated pharmacodynamics(PD) and pharmacokinetics(PK) parameters, which had guide significance for establishing rational dosage regimens to prevent drug resistant bacteria. In this study, we applied PK/PD parameters, based on mutant prevent concentration(MPC)and mutant selection window(MSW), to draw reasonable medication regimens of thiamphenicol and florfenicol in crucian carp(Carassius auratus gibelio) and grass carp(Ctenopharyngodon idella) to control the haemorrhagic septicemia caused by pathogenic Aeromonas hydrophila and prevent drug resistant bacteria. 1 Medication regimen of thiamphenicol in crucian carp(Carassius auratus gibelio) against a pathogenic Aeromonas hydrophila strain(AH10)The in vitro pharmacodynamic results showed that the minimal inhibitory concentration(MIC) of thiamphenicol on AH10 was 1.0 μg/m L, and the minimum bactericidal concentration(MBC) was 2.0 μg/m L; the post-antibiotic effect(PAE) of thiamphenicol evaluated by 2, 4, and 8 times MIC was 1.30±0.13 h, 1.83±0.14 h, and 2.1±0.12 h, respectively; the MPC was 8.0 μg/m L(8MIC); the MSW of thiamphenicol on AH10 was 1.0-8.0 μg/m L. The pharmacokinetic parameters of thiamphenicol in serum of crucian carp after oral gavage of 20, 30, 40 mg/kg showed that the half-life of elimination(T1/2β) was 11.636 h, 27.813 h, and 35.88 h, respectively; the half-life of distribution(T1/2α) was 0.89 h, 0.408 h, and 1.762 h, respectively; the peak level(Cmax) was 14.917μg/m L, 17.685μg/m L, and 24.218μg/m L, respectively; time to Cmax(Tmax) was 1.0h, 0.5h, and 0.5h, respectively; the area under the curve(AUC24) was 89.539μg/m L·h, 174.56μg/m L·h, and 251.68μg/m L·h, respectively. The results indicated that thiamphenicol was absorbed fast, eliminated slowly and distributed extensively in crucian carp.Integrated PK/PD parameters showed that: AUC24/MIC and Cmax/MIC of thiamphenicol in serum were 89.539 and 14.92 at the dosage of 20 mg/kg, respectively; 174.560 and 17.69 at the dosage of 30 mg/kg, respectively; 251.682 and 24.22 at the dosage of 40 mg/kg, respectively; The time of thiamphenicol concentration in serum above MPC was 3h at the dosage of 20 mg/kg, 8h at the dosage of 30 mg/kg, and 22 h at the dosage of 40 mg/kg. Considering the drug remained in the plasma with a concentration above MPC for(24-PAE)h and AUC24/MIC≥100 or Cmax/MIC>8, thiamphenicol is determined to be applicable for the prevention and treatment of bacterial diseases of crucian carp. The recommendation of the dosing regimen to prevent the selection of drug-resistance is 40 mg/kg, at the intervals of 24 h for a day, and the proposed withdrawal peroid should not be less than 15 d at the water temperature of(22±1)℃. 2 Medication regimen of florfenicol in crucian carp(Carassius auratus gibelio) and grass carp(Ctenopharyngodon idella) against a pathogenic Aeromonas hydrophila strain(CAAh01)The in vitro pharmacodynamic results showed that the MIC of florfenicol on CAAh01 was 0.5μg/m L, and the MBC was 1.0 μg /m L; the PAE of florfenicol evaluated by 2, 4, and 8 times MIC was 1.44±0.12 h, 1.76±0.11 h, and 2.32±0.13 h, respectively; the MPC was 6.0μg/m L(12MIC); the MSW of florfenicol on CAAh01 was 0.5-6.0 μg/m L. The pharmacokinetic parameters of florfenicol in serum of crucian carp after oral gavage of 10, 20, 30 mg/kg showed that T1/2β was 92.108 h, 32.66 h, and 46.86 h, respectively; T1/2α was 2.175 h, 0.829 h, and 0.624 h, respectively; Tmax was 4.0h, 2.0h, and 2.0h, respectively; Cmax was 7.79μg/m L, 10.66μg/m L, and 15.62μg/m L, respectively; AUC24 was 88.53μg/m L·h, 132.95μg/m L·h, and 213.25μg/m L·h, respectively; The results indicated that florfenicol was absorbed fast and eliminated slowly in crucian carp serum. Integrated PK/PD parameters showed that:: AUC24/MIC and Cmax/MIC of florfenicol in serum were 177.06 and 15.59 at the dosage of 10 mg/kg, respectively; 265.90 and 21.32 at the dosage of 20 mg/kg, respectively; 426.50 and 31.24 at the dosage of 30 mg/kg, respectively. The time of florfenicol concentration in serum of crucian carp above MPC was 5h at the dosage of 10 mg/kg, 8h at the dosage of 20 mg/kg, and 24 h at the dosage of 30 mg/kg.The pharmacokinetic parameters of florfenicol in serum of grass carp showed that the T1/2β was 20.11 h, 11.655 h, and 8.28h; T1/2α was 2.63 h, 2.26 h, and 3.13h; Tmax was 6.0h, 4.0h, and 1.0h; Cmax was 2.37μg/m L, 5.04μg/m L, and 9.99μg/m L; AUC24 was 19.30μg/m L·h, 37.54μg/m L·h, and 60.97μg/m L·h. The results showed that florfenicol was absorded and eliminated fast in grass carp serum. Integrated PK/PD parameters: AUC24/MIC and Cmax/MIC of florfenicol in serum were 38.60 and 4.75 at the dosage of 10 mg/kg, respectively; 75.08 and 10.08 at the dosage of 20 mg/kg, respectively; 121.94 and 19.99 at the dosage of 30 mg/kg, respectively. The time of florfenicol concentration in serum of grass carp above MPC was 0h, 0h, and 3h, respectively.Considering the drug remained in the plasma with a concentration above MPC and PK/PD parameters, Florfenicol is determined to be applicable for the prevention and treatment of bacterial diseases of crucian carp. The recommendations of the dosing regimen to prevent the selection of drug-resistance is 30 mg/kg, at the intervals of 24 h for 1 day, the proposed withdrawal period should not be less than 20 d. However, it can not be used continuously to control and treat bacterial diseases in grass garp. |
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