Pharmacokinetics of ertapenem in critically ill patients receiving continuous venovenous hemodialysis or hemodiafiltration

Abstract

This study characterizes the pharmacokinetics of ertapenem, a carbapenem antibiotic, in critically ill adult subjects receiving continuous renal replacement therapy (CRRT). Eight critically ill patients with suspected/known Gram-negative infections receiving continuous venovenous hemodialysis (CVVHD) or continuous venovenous hemodiafiltration (CVVHDF) and ertapenem were enrolled. One gram of ertapenem was infused over 30 min. Predialyzer blood samples were drawn with the first dose of ertapenem from the hemodialysis tubing at time zero, 30 min, and 1, 2, 4, 8, 12, 18, and 24 h after the start of the ertapenem infusion. Effluent was collected at the same time points. Ertapenem total serum, unbound serum, and effluent concentrations from all eight subjects were used simultaneously to perform a population compartmental pharmacokinetic modeling procedure using NONMEM. Monte Carlo simulations were performed to evaluate the ability of several ertapenem dosing regimens (500 mg once daily, 750 mg once daily, 500 mg twice daily, and 1,000 mg once daily) to obtain effective unbound serum concentrations above 0.5, 1, and 2 μg/ml. For our simulated patients, all regimens produced unbound ertapenem concentrations above 2 μg/ml for 40% of the dosing interval for at least 96% of simulated patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00877370.).

Figures

FIG 1

Average total and unbound ertapenem concentrations over a 24-h dosing interval. Closed circles represent total ertapenem serum concentrations, and open circles represent unbound concentrations. Lines connecting the data points are for clarity. Vertical bars represent the SD of the mean ertapenem concentration at the respective time point.

FIG 2

Observed and modeled ertapenem concentration-time profile for the eight subjects. The closed circles (total), open circles (unbound), and diamonds (effluent) depict the observed ertapenem concentrations. The solid lines depict the model-derived concentrations.

FIG 3

Relationship between free ertapenem serum concentrations and protein binding.

FIG 4

Simulated mean ± SD concentration-time profiles (means of 1,000 simulations) for four ertapenem regimens: 500 mg q12h (A), 500 mg q24h (B), 750 mg q24h (C), and 1,000 mg q24h (D). The closed circles represent total ertapenem serum concentrations, and open circles represent unbound concentrations. Lines connecting the data points are for clarity. The dashed line at 2 μg/liter depicts the sensitivity breakpoint for methicillin-sensitive Staphylococcus aureus.