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

• Published in: International journal of antimicrobial agents Vol. 50; no. 3; pp. 393 - 398
• Main Authors: Murao, Naoki, Ohge, Hiroki, Ikawa, Kazuro, Watadani, Yusuke, Uegami, Shinnosuke, Shigemoto, Norifumi, Shimada, Norimitsu, Yano, Raita, Kajihara, Toshiki, Uemura, Kenichiro, Murakami, Yoshiaki, Morikawa, Norifumi, Sueda, Taijiro
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2017
• Subjects: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents - pharmacokinetics; Ascitic Fluid - chemistry; beta-Lactamase Inhibitors - pharmacokinetics; Female; Humans; Inflammatory bowel disease; Inflammatory Bowel Diseases - surgery; Male; Microbial Sensitivity Tests; Middle Aged; Penicillanic Acid - analogs & derivatives; Penicillanic Acid - pharmacokinetics; Peritoneum - chemistry; Peritonitis; Pharmacodynamics; Pharmacokinetics; Piperacillin; Piperacillin - pharmacokinetics; Plasma - chemistry; Preoperative Care; Prospective Studies; Tazobactam; Young Adult; Inflammatory bowel disease; CLSI; Cmax; Pharmacodynamics; Tazobactam; EUCAST; Piperacillin; PIP-TAZ; MIC; Pharmacokinetics; Peritonitis; AUC
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2017.03.025

•The actual penetration of piperacillin-tazobactam (PIP-TAZ) into abdominal tissues is unclear.•After the administration of PIP-TAZ, peritoneal fluid and peritoneum were obtained, and drug concentrations were measured.•Pharmacokinetic parameters were estimated, and simulation was conducted to evaluate pharmacodynamic target attainment.•PIP-TAZ penetrated well into peritoneal fluid and peritoneum. 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 peritoneum drug concentrations was conducted to simulate dosing regimens needed to attain the pharmacodynamic target in abdominal sites. PIP-TAZ (4 g-0.5 g) was intravenously administered to 10 patients before abdominal surgery for inflammatory bowel disease. Blood, peritoneal fluid, and peritoneum samples 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 pharmacodynamic target attainment. The mean peritoneal fluid: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 peritoneal fluid: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 peritoneal sites. The regimens that achieved a bactericidal effect with PIP (time above minimum inhibitory concentration [MIC] >50%) at both peritoneal sites 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 peritoneal pharmacokinetics of PIP-TAZ, and help consider the dosing regimens for intraabdominal infections based on site-specific pharmacodynamic target attainment.