| Objective:Salmonella is an important pathogen of zoonotic diseases,which poses a great threat to the safety of the livestock breeding industry and public health.The new fourth-generation cephalosporin(cefloquine)is characterized by its excellent antibacterial activity and is ideally suited for the clinical treatment of salmonellosis.However,scientific methods of administration of cefloquine have not been established.In this paper,PK/PD synchronization model of cefquinome against swine Salmonella was studied.The relevant pharmacokinetic and pharmacodynamic parameters were obtained.Based on these parameters,the proper dosing interval was determined and a reasonable dosing schedule was established to make rational use in veterinary clinic.Quinonequine provides a scientific basis for reducing the incidence of drug resistance.Methods:The minimal inhibitory concentration of cefquinoxine against Salmonella was determined by micro-broth dilution method.According to the standard method of CLSI,the minimum bactericidal concentration was determined by the test tube method;according to the theory of "drug resistance selection window",the concentration of MPCpr against mutation was measured and determined then MSW was calculated.Salmonella infection disease model was established by artificial challenge of Salmonella and the comparative pharmacokinetics of cefquinoxine in healthy pigs and Salmonella infection model pigs was studied.The UPLC method was used to determine the drug concentration in the serum.Winnonlin Pharmacokinetic Pharmacodynamic Software was used to analyze the time-drug concentration data.RESULTS:In the in vitro antibacterial activity of cefquinome against Salmonella,the minimum inhibitory concentration(MIC)of cefquinome to Salmonella was 0.05 ?g/mL;the minimum bactericidal concentration was 0.2 ?g/mL;according to the theory of "resistance selection window",The MPCpr was measured to be 0.8 ?g/mL,the final MPC was 0.48?g/mL,and the MSW was 0.05 ?g/mL to 0.48 ?g/mL.Single intramuscular injection of 2mg/kg.bw of cefquinome to healthy pigs and pharmacokinetic parameters were obtained as follows:t1/2?(0.71±0.05h),t1/2?(1.98±0.19h),Tmax(0.71±0.11h),Cmax(1.63±0.45?g/mL),AUC(5.09±2.38 ?g.h/mL),Vd(0.71±0.08 L/kg),CL(0.36±0.08 L/h/kg).Single intramuscular injection of 2mg/kg.bw of cefquinome to Salmonella infection model pigs and pharmacokinetic parameters were showed as follows:t1/2?(0.81±0.16h),t1/2?(1.62 ± 0.43 h),Tmax(0.78±0.10h),Cmax(1.31±0.25?g/mL),AUC(6.21±2.11?g·h/mL),Vd(0.62±0.22L/kg),CL(0.47±0.19L/h/kg),SPSS software was used to analyze the difference,there was no significant difference in pharmacokinetic parameters between these two groups(P?0.05).Intramuscular injection of cefquinonze fit into the first-order absorption two-compartment model.cefquinome has a rapid absorption rate in pigs,a short half-life of the drug,a short peak time,a small apparent volume of distribution,and a high bioavailability.Combining the pharmacokinetic data of cefquinome in pigs and semi-in vivo MIC value,PK/PD parameters in porcine intramuscular injection of 2 mg/kg.b.w and 2 mg/kg.b.w after Salmonella infection were obtained.The AUC/MIC parameters were 101.8h and 124.2h.Based on the measured MIC value of 0.05 ?g/mL,the calculated dose of Salmonella infection was 0.96 mg/kg to 1.94 mg/kg.The results showed that the recommended dosage of 2mg/kg can be effective and kill pathogens while there will no drug resistance.Conclusion:There were no significant difference between pharmacokinetic parameters of cefquinome in healthy pigs and Salmonella infected models pigs;the PK-PD synchronization model of cefquinome can be effectively applied to the calculate of clinical using dosage that meets the "theory of resistance mutation window". |
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