Development of breakpoints of cephems for intraabdominal infections based on pharmacokinetics and pharmacodynamics in the peritoneal fluid of patients

We developed breakpoints for cephem antibacterial agents for intraabdominal infections based on pharmacokinetics (PK) and pharmacodynamics (PD) at the target site. Cefepime (CFPM), cefotiam (CTM), cefozopran (CZOP), and flomoxef (FMOX) were each administered to 8-10 patients before abdominal surgery, and venous blood and peritoneal fluid (PF) samples were obtained. The drug concentrations in plasma and PF were determined and analyzed using population pharmacokinetic modeling. Using the pharmacokinetic model parameters, a Monte Carlo simulation was conducted to estimate the probabilities of attaining the bacteriostatic and bactericidal targets (40% and 70% of the time above the minimum inhibitory concentration (T > MIC), respectively) in PF. The bacteriostatic and bactericidal breakpoints were determined as the highest MIC values at which the bacteriostatic and bactericidal probabilities in PF were ≥80%, which values varied with drug and dosing regimen. Site-specific PK-PD-based breakpoints for CFPM, CTM, CZOP, and FMOX are proposed, and should help us to select appropriate cephems and design their dosing regimens for intraabdominal infections.