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 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.

Ceftolozane–Tazobactam Pharmacokinetics in the Abdominal Tissue of Patients Undergoing Lower Gastrointestinal Surgery: Dosing Considerations Based on Site-Specific Pharmacodynamic Target Attainment

“…Nevertheless, only a few studies investigated the tissue concentrations of antibiotics in tissues directly affected by cIAI (i.e., peritonitis), such as peritoneal fluid, peritoneum, and subcutaneous adipose tissue. Murao et al [18] performed a simulation of the optimal administration regimen of piperacillin-TAZ (PIPC-TAZ) used against cIAI by measuring the PIPC-TAZ concentrations in the peritoneal fluid and peritoneum samples collected during surgery of patients with IBD. However, to the best of our knowledge, this is the first study in which a simulation of noncompartmental pharmacokinetic parameters, compartmental pharmacokinetic parameters, and site-specific pharmacodynamic target attainment has been performed by measuring the tissue concentration of CTLZ-TAZ.…”

“…The exclusion criteria were (1) pregnant or breastfeeding, (2) a history of allergy to cephem or b-lactam antibiotics, (3) a history of cerebrospinal diseases, and (4) a creatinine clearance (Ccr) level below 50 mL/min according to the Cockcroft-Gault formula. This study used methods of sample collection or antibiotic assays similar to those of our previous studies [15][16][17][18]. However, our study differs significantly from the previous studies in that it newly analyzed concentrations in subcutaneous adipose tissue.…”

“…For each CTLZ-TAZ regimen (1 g CTLZ and 0.5 g TAZ, every 12, 8, 6, or 4 h; 1 h infusion), the duration for which the drug concentration was above the minimum inhibitory concentration (T [ MIC) for CTLZ in the peritoneal fluid, peritoneum, and subcutaneous adipose tissue was predicted. Using the same method as that described for previous simulations [15][16][17][18], the drug concentration was not adjusted for protein binding but instead treated as the free fraction. The protein-binding levels of CTLZ in these abdominal sites are currently unknown.…”

Distribution evaluation of tacrolimus in the ascitic fluid of liver transplant recipients with liver cirrhosis by a sensitive ultra‐performance liquid chromatography‐tandem mass spectrometry method

“…Systemic drug disposition could be influenced when the drug is highly distributed in ascitic fluid. For instance, intravenous penems could penetrate the ascitic fluid rapidly and extensively [18][19][20][21]. As a first-line immunotherapy drug, TAC is used as a long-term medication after liver transplantation surgery [22].…”

Tolerability, Safety, Pharmacokinetics and Drug Interaction of Cefotaxime Sodium–Tazobactam Sodium Injection (6:1) Following Single and Multiple Intravenous Doses in Chinese Healthy Subjects

“…Tazobactam (TAZ) is considered to have a stronger inhibitory effect on β-lactamases than first- and second-generation inhibitors ( Papp-Wallace and Bonomo, 2016 ). The partner β-lactams, which can still play an antimicrobial role against a significant portion of extended-spectrum β-lactamases (ESBLs) ( Gutiérrez-Gutiérrez et al., 2016 ), have been introduced into the clinical setting, such as piperacillin (PIP) and TAZ ( Li et al., 2013 ; Chen et al., 2016 ; Murao et al., 2017 ), as well as ceftolozane (CLZ) and TAZ ( Papp-Wallace and Bonomo, 2016 ; Kratzer et al., 2019 ). Cefotaxime sodium–tazobactam sodium (CTX–TAZ) (6:1) is a novel combination of β-lactam-β-lactamase inhibitor.…”