Abstract
Pharmacokinetic-pharmacodynamic (PK/PD) integration and modelling were used to predict dosage schedules for florfenicol for two pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Pharmacokinetic data were pooled for two bioequivalent products, pioneer and generic formulations, administered intramuscularly to pigs at a dose rate of 15 mg/kg. Antibacterial potency was determined in vitro as minimum inhibitory concentration (MIC) and Mutant Prevention Concentration in broth and pig serum, for six isolates of each organism. For both organisms and for both serum and broth MICs, average concentration:MIC ratios over 48 h were similar and exceeded 2.5:1 and times greater than MIC exceeded 35 h. From in vitro time-kill curves, PK/PD modelling established serum breakpoint values for the index AUC24h/MIC for three levels of inhibition of growth, bacteriostasis and 3 and 4log10 reductions in bacterial count; means were 25.7, 40.2 and 47.0 h, respectively, for P. multocida and 24.6, 43.8 and 58.6 h for A. pleuropneumoniae. Using these PK and PD data, together with literature MIC distributions, doses for each pathogen were predicted for: (1) bacteriostatic and bactericidal levels of kill; (2) for 50 and 90% target attainment rates (TAR); and (3) for single dosing and daily dosing at steady state. Monte Carlo simulations for 90% TAR predicted single doses to achieve bacteriostatic and bactericidal actions over 48 h of 14.4 and 22.2 mg/kg (P. multocida) and 44.7 and 86.6 mg/kg (A. pleuropneumoniae). For daily doses at steady state, and 90% TAR bacteriostatic and bactericidal actions, dosages of 6.2 and 9.6 mg/kg (P. multocida) and 18.2 and 35.2 mg/kg (A. pleuropneumoniae) were required. PK/PD integration and modelling approaches to dose determination indicate the possibility of tailoring dose to a range of end-points.
Highlights
In recent years there have been major advances in designing dosage schedules of antimicrobial drugs, through integration and modelling of pharmacodynamic (PD) and pharmacokinetic (PK) data
Increasingly used is mutant prevention concentration (MPC), the concentration preventing the growth of the least susceptible cells in high-density bacterial populations [9]
minimum inhibitory concentration (MIC) and MPCs were determined for six isolates each of P. multocida and A. pleuropneumoniae, in broth and pig serum
Summary
In recent years there have been major advances in designing dosage schedules of antimicrobial drugs, through integration and modelling of pharmacodynamic (PD) and pharmacokinetic (PK) data. These approaches have improved strategies for predicting drug dosages that optimise efficacy and minimise opportunities for emergence of resistance [1,2,3,4,5,6,7]. As well as generating PK/PD breakpoints, these PK and PD data may be used, with wild type MIC distributions, to estimate optimal doses to provide pre-determined levels of kill, whilst minimising emergence of resistance. As discussed by Giraudel et al [12], Lees et al [13] and Toutain and Lees [14], dose determination through linking PK and PD data is generally preferred to dose titration studies, in which the body may be regarded as a black box; the doses are administered and responses measured but nothing is known of the plasma concentration-effect relationship and estimated dosages may be effective but are unlikely to be optimal
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