Determination of pharmacokinetic-pharmacodynamic cutoff values of oxytetracycline in calves and adult cattle using population pharmacokinetic modelling

Abstract

In Europe, there is currently no harmonized clinical breakpoint for interpretation of antimicrobial susceptibility testing of oxytetracycline in cattle. The objective of this meta-analysis of oxytetracycline pharmacokinetic (PK) data in cattle was to determine the PK/PD cutoff of oxytetracycline in order to propose clinical breakpoints for interpretating antimicrobial susceptibility testing. The PK/PD cutoff is the highest MIC for which the critical value of the pharmacodynamic index (fAUC/MIC) can be achieved in 90% of cattle with the recommended dosing regimen. It was determined by simulations of a population PK model built with intravenous and intramuscular data. The data set included 1,730 oxytetracycline plasma concentrations from 69 cattle. All animals received a dose of 20 mg/kg intramuscularaly and/or an intravenous dose of 20 mg/kg or 40 mg/kg. A 3-compartment model with two absorption phases was selected. The final model included age as covariate for clearances and volumes of distribution. The fAUC/MIC index was calculated for a range of dosing intervals. The pharmacodynamic index (PDI) target selected was established to 24 h i.e. the average free plasma concentration of oxytetracycline over the 24-hour dosing interval, under steady-state conditions, is equal to the selected MIC. The PK/PD cutoff was established at 2 mg/L for adult cattle and 1 mg/L for calves for long-acting products administered intramuscularly at a dose rate of 20 mg/kg and a duration of efficacy of 48 hours. The difference in PK/PD cutoff between calves and adult cattle was due to a higher clearance in calves. This implies that, at a dose rate of 20 mg/kg, oxytetracycline will be effective in adult cattle against pathogens with a one higher MIC dilution compared to calves. These PK/PD cutoffs can be used, with the epidemiological cutoff distribution of wildtype bacteria, to establish clinical breakpoints of oxytetracycline in cattle.