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

Abstract

Recently, complicated intra-abdominal infections (cIAI) have been caused not only by Escherichiacoli, Klebsiellapneumoniae, Enterobacter cloacae, and Pseudomonasaeruginosa, but also by extended-spectrum β-lactamase-producing Enterobacterales members. Ceftolozane-tazobactam (CTLZ-TAZ) is considered to exhibit therapeutic effects against cIAI. Studies on the concentrations of antibiotics in abdominal tissues directly affected by cIAI are limited. Therefore, in this study, we investigated the pharmacokinetics of CTLZ-TAZ in abdominal tissue and simulated the administration regimen required to achieve the pharmacodynamic target for cIAI-causing bacteria. Patients scheduled for elective lower gastrointestinal surgery were intravenously administered preoperative CTLZ-TAZ (1g CTLZ and 0.5g TAZ). Plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue samples were collected during the surgery, and CTLZ as well as TAZ concentrations were measured. The noncompartmental and compartmental pharmacokinetic parameters were then estimated. Site-specific pharmacodynamic target attainment analysis using 1.5g of CTLZ-TAZ was performed. CTLZ-TAZ was administered to nine patients (once to five patients and twice to four patients). The mean peritoneal fluid-to-plasma ratio (one dose/two doses) for CTLZ was 0.74/1.15, which was slightly higher than the mean peritoneal fluid-to-plasma ratio for TAZ (0.95/1.13). The ratio for subcutaneous adipose was lower than those for peritoneal fluid and peritoneum tissues. We also discovered that the average ratio of CTLZ and TAZ concentrations in all tissues was maintained at or above 2:1. In our investigation of pharmacodynamic target attainment in each tissue, the desired bactericidal effect was attained with all CTLZ-TAZ (1.5g) administration regimens [q12h (3g/day), q8h (4.5g/day), and q6h (6g/day)]. To the best of our knowledge, this is the first study investigating the optimal pharmacodynamic level of CTLZ-TAZ in the abdominal tissue against cIAI-causing bacteria. This study also serves as a guideline for designing an optimal administration regimen based on pharmacodynamic target attainment for cIAI-causing bacteria. The institutional review board of Hiroshima University Hospital, CRB6180006. The Japan Registry of Clinical Trials, jRCTs061190025.