Abstract
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.
Highlights
The aim of this work was to describe optimized dosing regimens of ceftolozane-tazobactam for critically ill patients receiving continuous venovenous hemodiafiltration (CVVHDF)
The aim of this work was, to describe optimized dosing regimens of ceftolozane-tazobactam in critically ill patients receiving CVVHDF based on a population pharmacokinetic (PK) model developed from simultaneous analysis of unbound concentrations in prefilter patient plasma, postfilter plasma, and renal replacement therapy (RRT) effluent during CVVHDF
We observed sieving coefficients that are consistent with previous findings for continuous hemofiltration and dialysis [14]
Summary
The aim of this work was to describe optimized dosing regimens of ceftolozane-tazobactam for critically ill patients receiving continuous venovenous hemodiafiltration (CVVHDF). With the exception of a few case reports [11,12,13], there are limited data to address the issue of whether underdosing was the reason for the increased treatment failure during CRRT or if higher doses achieve appropriate exposure without risking unnecessary accumulation of the drug. The aim of this work was, to describe optimized dosing regimens of ceftolozane-tazobactam in critically ill patients receiving CVVHDF based on a population pharmacokinetic (PK) model developed from simultaneous analysis of unbound concentrations in prefilter patient plasma, postfilter plasma, and RRT effluent during CVVHDF
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