Dose Optimization of Cefpirome Based on Population Pharmacokinetics and Target Attainment during Extracorporeal Membrane Oxygenation

Abstract

To obtain the optimal dosage regimen in patients receiving extracorporeal membrane oxygenation (ECMO), we developed a population pharmacokinetics model for cefpirome and performed pharmacodynamic analyses. This prospective study included 15 patients treated with cefpirome during ECMO. Blood samples were collected during ECMO (ECMO-ON) and after ECMO (ECMO-OFF) at predose and 0.5 to 1, 2 to 3, 4 to 6, 8 to 10, and 12 h after cefpirome administration. The population pharmacokinetic model was developed using nonlinear mixed effects modeling and stepwise covariate modeling. Monte Carlo simulation was used to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) according to the MIC distribution. Cefpirome pharmacokinetics were best described by a two-compartment model. Covariate analysis indicated that serum creatinine concentration (SCr) was negatively correlated with clearance, and the presence of ECMO increased clearance and the central volume of distribution. The simulations showed that patients with low SCr during ECMO-ON had lower PTA than patients with high SCr during ECMO-OFF; so, a higher dosage of cefpirome was required. Cefpirome of 2 g every 8 h for intravenous bolus injection or 2 g every 12 h for extended infusion over 4 h was recommended with normal kidney function receiving ECMO. We established a population pharmacokinetic model for cefpirome in patients with ECMO, and appropriate cefpirome dosage regimens were recommended. The impact of ECMO could be due to the change in patient status on consideration of the small population and uncertainty in covariate relationships. Dose optimization of cefpirome may improve treatment success and survival in patients receiving ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.).

Keywords: ECMO; beta-lactams; cephalosporin; pharmacodynamics; population pharmacokinetics.

Copyright © 2020 American Society for Microbiology.

Figures

FIG 1

The prediction-corrected visual predictive check plot showed that the 5th to 95th percentiles of the predicted data overlapped most of the observed data. Open circles, observed cefpirome concentrations; solid line, median; lower and upper dashed lines, 5th and 95th percentiles of the observed data, respectively; shaded areas, 95% confidence intervals for simulated predicted median, 5th, and 95th percentile constructed from 5,000 simulated data sets of individuals from the original data set.

FIG 2

Probability of target attainment for 5,000 simulated subjects administered cefpirome. Simulated probability of target attainment (PTA) according to cefpirome dosing, serum creatinine concentration (SCr), and the presence of ECMO. i.v.-bolus, intravenous bolus injection; EI over 4h, extended infusion over 4 h; ECMO-ON, patients during ECMO; ECMO-OFF, patients after ECMO termination. The target for the analysis was for free plasma concentrations to be above the MIC for at least 65% of the dosing interval.

FIG 3

Cumulative fraction of response after administration of the recommended dosage of cefpirome based on serum creatinine concentration range in patients during extracorporeal membrane oxygenation. Simulated cumulative fraction of response (CFR) according to the recommended dose for intravenous bolus injection (top) or extended infusion over 4 h (bottom) based on Pseudomonas aeruginosa.