Pharmacokinetic/pharmacodynamic integration and modelling of oxytetracycline for the porcine pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida

Pharmacokinetic-pharmacodynamic (PK/PD) integration and modelling were used to predict dosage schedules of oxytetracycline for two pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in broth and porcine serum. PK/PD integration established ratios of average concentration over 48h (Cav0-48h)/MIC of 5.87 and 0.27g/mL (P.multocida) and 0.70 and 0.85g/mL (A.pleuropneumoniae) for broth and serum MICs, respectively. PK/PD modelling of invitro time-kill curves established broth and serum breakpoint values for area under curve (AUC(0-24h))/MIC for three levels of inhibition of growth, bacteriostasis and 3 and 4 log(10) reductions in bacterial count. Doses were then predicted for each pathogen, based on Monte Carlo simulations, for: (i) bacteriostatic and bactericidal levels of kill; (ii) 50% and 90% target attainment rates (TAR); and (iii) single dosing and daily dosing at steady-state. For 90% TAR, predicted daily doses at steady-state for bactericidal actions were 1123mg/kg (P.multocida) and 43mg/kg (A.pleuropneumoniae) based on serum MICs. Lower TARs were predicted from broth MIC data; corresponding dose estimates were 95mg/kg (P. multocida) and 34mg/kg (A.pleuropneumoniae).