A Population Pharmacokinetic Model-Guided Evaluation of Ceftolozane-Tazobactam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration

• Published in: Antimicrobial agents and chemotherapy Vol. 64; no. 1
• Main Authors: Sime, Fekade B, Lassig-Smith, Melissa, Starr, Therese, Stuart, Janine, Pandey, Saurabh, Parker, Suzanne L, Wallis, Steven C, Lipman, Jeffrey, Roberts, Jason A
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 20.12.2019
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - microbiology; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - therapeutic use; Cephalosporins - administration & dosage; Cephalosporins - pharmacokinetics; Cephalosporins - therapeutic use; Confidence Intervals; Continuous Renal Replacement Therapy; Critical Illness; Hemodiafiltration - methods; Humans; Microbial Sensitivity Tests; Pharmacology; Prospective Studies; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - pathogenicity; Tazobactam - administration & dosage; Tazobactam - pharmacokinetics; Tazobactam - therapeutic use; ceftolozane-tazobactam; pharmacokinetics; renal replacement therapy; CRRT; hemodiafiltration
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.01655-19

The aim of this work was to describe optimized dosing regimens of ceftolozane-tazobactam for critically ill patients receiving continuous venovenous hemodiafiltration (CVVHDF). We conducted a prospective observational pharmacokinetic study in adult critically ill patients with clinical indications for ceftolozane-tazobactam and CVVHDF. Unbound drug concentrations were measured from serial prefilter blood, postfilter blood, and ultrafiltrate samples by a chromatographic assay. Population pharmacokinetic modeling and dosing simulations were performed using Pmetrics. A four-compartment pharmacokinetic model adequately described the data from six patients. The mean (± standard deviation [SD]) extraction ratios for ceftolozane and tazobactam were 0.76 ± 0.08 and 0.73 ± 0.1, respectively. The mean ± SD sieving coefficients were 0.94 ± 0.24 and 1.08 ± 0.30, respectively. Model-estimated CVVHDF clearance rates were 2.7 ± 0.8 and 3.0 ± 0.6 liters/h, respectively. Residual non-CVVHDF clearance rates were 0.6 ± 0.5 and 3.3 ± 0.9 liters/h, respectively. In the initial 24 h, doses as low as 0.75 g every 8 h enabled cumulative fractional response of ≥85% for empirical coverage against , considering a 40% (percentage of time the free drug concentration was above the MIC) target. For 100% , doses of at least 1.5 g every 8 h were required. The median (interquartile range) steady-state trough ceftolozane concentrations for simulated regimens of 1.5 g and 3.0 g every 8 h were 28 (21 to 42) and 56 (42 to 84) mg/liter, respectively. The corresponding tazobactam concentrations were 6.1 (5.5 to 6.7) and 12.1 (11.0 to 13.4) mg/liter, respectively. We suggest a front-loaded regimen with a single 3.0-g loading dose followed by 0.75 g every 8 h for critically ill patients undergoing CVVHDF with study blood and dialysate flow rates.