Comparison of antimicrobial pharmacokinetic/pharmacodynamic breakpoints with EUCAST and CLSI clinical breakpoints for Gram-positive bacteria

Abstract

This study compared the susceptibility breakpoints based on pharmacokinetic/pharmacodynamic (PK/PD) models and Monte Carlo simulation with those defined by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for antibiotics used for the treatment of infections caused by Gram-positive bacteria. A secondary objective was to evaluate the probability of achieving the PK/PD target associated with the success of antimicrobial therapy. A 10000-subject Monte Carlo simulation was executed to evaluate 13 antimicrobials (47 intravenous dosing regimens). Susceptibility data were extracted from the British Society for Antimicrobial Chemotherapy database for bacteraemia isolates. The probability of target attainment and the cumulative fraction of response (CFR) were calculated. No antibiotic was predicted to be effective (CFR≥90%) against all microorganisms. The PK/PD susceptibility breakpoints were also estimated and were compared with CLSI and EUCAST breakpoints. The percentages of strains affected by breakpoint discrepancies were calculated. In the case of β-lactams, breakpoint discrepancies affected <15% of strains. However, higher differences were detected for low doses of vancomycin, daptomycin and linezolid, with PK/PD breakpoints being lower than those defined by the CLSI and EUCAST. If this occurs, an isolate will be considered susceptible based on CLSI and EUCAST breakpoints although the PK/PD analysis predicts failure, which may explain treatment failures reported in the literature. This study reinforces the idea of considering not only the antimicrobial activity but also the dosing regimen to increase the probability of clinical success of an antimicrobial treatment.