title: Development of breakpoints of cephems for intraabdominal infections based on pharmacokinetics and pharmacodynamics in the peritoneal fluid of patients.
abstract: 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 > or =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.
authors.affiliation: Department of Clinical Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan. ikawak@hiroshima-u.ac.jp
authors.forename: Kazuro
authors.initials: K
authors.lastname: Ikawa
authors.forename: Norifumi
authors.initials: N
authors.lastname: Morikawa
authors.forename: Kayo
authors.initials: K
authors.lastname: Ikeda
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohge
authors.forename: Taijiro
authors.initials: T
authors.lastname: Sueda
mesh_terms: D000005:Abdomen / Q000601:surgery*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001202:Ascitic Fluid / Q000737:chemistry*; D000077723:Cefepime; D015310:Cefotiam / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D002511:Cephalosporins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D004755:Enterobacteriaceae / Q000187:drug effects; D004756:Enterobacteriaceae Infections / Q000382:microbiology / Q000517:prevention & control*; D006801:Humans; D007813:Laparotomy; D008826:Microbial Sensitivity Tests / Q000592:standards*; D009010:Monte Carlo Method; D011183:Postoperative Complications / Q000382:microbiology / Q000517:prevention & control; D013530:Surgical Wound Infection / Q000382:microbiology / Q000517:prevention & control*; D000097586:Cefozopran
chemical_list: D000900:Anti-Bacterial Agents; D000077723:Cefepime; D015310:Cefotiam; D002511:Cephalosporins; D000097586:Cefozopran; C045693:flomoxef