Pharmacokinetics of piperacillin-tazobactam in plasma, peritoneal fluid and peritoneum of surgery patients, and dosing considerations based on site-specific pharmacodynamic target attainment

Abstract Piperacillin-tazobactam(PIP-TAZ) is commonly used to treat intraabdominal infections; however, its penetration into abdominal sites is unclear. A pharmacokinetic analysis of plasma, peritoneal fluid, and peritoneumdrug concentrations was conducted to simulate dosing regimens needed to attain the pharmacodynamictarget in abdominal sites. PIP-TAZ (4 g-0.5 g) was intravenously administered to 10 patients before abdominal surgeryfor inflammatory bowel disease. Blood, peritoneal fluid, and peritoneumsamples were obtained at the end of infusion (0.5 h) and up to 4 h thereafter. PIP and TAZ concentrations were measured, both noncompartmental and compartmental pharmacokinetic parameters were estimated, and a simulation was conducted to evaluate site-specific pharmacodynamictarget attainment. The mean peritonealfluid:plasma ratios in the area under the drug concentration-time curve (AUC) were 0.75 for PIP and 0.79 for TAZ, and the mean peritonealfluid:plasma ratios in the AUC were 0.49 for PIP and 0.53 for TAZ. The mean PIP:TAZ ratio was 8.1 at both peritonealsites. The regimens that achieved a bactericidal effect with PIP (time above minimum inhibitory concentration [MIC] >50%) at both peritonealsites were PIP-TAZ 4.5 g twice daily for an MIC of 8 mg/L, as well as 4.5 g three times daily, and 3.375 g four times daily for an MIC of 16 mg/L. These findings clarify the peritonealpharmacokinetics of PIP-TAZ, and help consider the dosing regimens for intraabdominal infectionsbased on site-specific pharmacodynamictarget attainment.