Peritoneal penetration of doripenem after intravenous administration in abdominal-surgery patients

Objectives: This study aimed to examine the peritoneal penetration of intravenous doripenem, a novel carbapenem used for the treatment of intra-abdominal infections. Patients and methods: Doripenem (500 mg) was administered to 10 patients before abdominal surgery. Venous blood and peritoneal exudate samples were obtained at the end of infusion (0.5 h) and every hour for 6 h afterwards. The drug concentrations in serum and exudate were measured using HPLC, estimated by non-compartmental pharmacokinetic analysis and fitted to a three-compartment pharmacokinetic model in order to assess the exposure time that the drug concentration remained above MIC. Results: The AUC(0-infinity) was 59.3 +/- 7.2 mg.h/L (mean +/- SD) in serum and 49.3 +/- 6.5 mg.h/L in exudate, and the exudate/serum ratio was 0.84 +/- 0.13. The observed maximum concentration was 46.9 +/- 7.4 mg/L at 0.5 h in serum and 24.5 +/- 6.5 mg/L at 0.7 +/- 0.4 h in exudate, and the exudate/serum ratio was 0.53 +/- 0.17. The compartmental analysis showed that the average concentrations remained higher in exudate than in serum after 0.81 h post-dose, and the average drug-exposure times in serum (91% fraction unbound) and exudate were: 73.6% and 78.2% at an MIC of 1 mg/L; 37.0% and 41.5% at 4 mg/L; and 12.7% and 13.1% at 16 mg/L. Conclusions: Following intravenous administration, doripenem penetrated well into peritoneal exudate of abdominal-surgery patients, and the drug-exposure times in exudate were greater than or equal to those estimated from serum data.