Use of Monte Carlo simulation to determine pharmacodynamic cutoffs of amoxicillin to establish a breakpoint for antimicrobial susceptibility testing in pigs

Objective: To determine pharmacodynamic cutoffs with pharmacokinetic-pharmacodynamic principles and Monte Carlo simulation (MCS) for use of amoxicillin in pigs to set interpretive criteria for antimicrobial susceptibility testing. Sample: 191 plasma disposition curves of amoxicillin obtained from 21 IV, 104 IM, and 66 PO administrations corresponding to 2,098 plasma concentrations. Procedures: A population model of amoxicillin disposition in pigs was developed for PO and IM administration. The MCS method was then used to determine, for various dosage regimens, the proportion of pigs achieving plasma amoxicillin concentrations greater than a selection of possible minimal inhibitory concentrations (MICs) ranging from 0.0625 to 4 mg/L for at least 40% of a 24-hour period. Results: A target attainment rate (TAR) of 90% was never achieved with the breakpoint recommended by the Clinical and Laboratory Standards Institute (0.5 mg/L) when the usual recommended dosage (20 mg/kg/d) was used. Only by dividing the orally administered daily dose into 12-hour administration intervals was a TAR > 90% achieved when the total dose was at least 40 mg/kg for a pathogen having an MIC <= 0.0625 mg/L. For the IM route, the TAR of 90% could only be achieved for MICs of 0.0625 and 0.125 mg/L with the use of 15 and 30 mg/kg doses, respectively. Conclusions and Clinical Relevance: Population kinetics and MCS are required to determine robust species-specific interpretive criteria (susceptible, intermediate, and resistant classifications) for antimicrobial susceptibility testing breakpoints (taking into account interanimal variability)