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

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 Pseudomonas aeruginosa, considering a 40% fT (>MIC) (percentage of time the free drug concentration was above the MIC) target. For 100% fT (>MIC), 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.