Population pharmacokinetic/pharmacodynamic study suggests continuous infusion of ceftaroline daily dose in ventilated critical care patients with early-onset pneumonia and augmented renal clearance

Alexia Chauzy, Nicolas Gregoire, Martine Ferrandière, Sigismond Lasocki, Karim Ashenoune, Philippe Seguin, Matthieu Boisson, William Couet, Sandrine Marchand, Olivier Mimoz, Claire Dahyot-Fizelier, Alexia Chauzy, Nicolas Gregoire, Martine Ferrandière, Sigismond Lasocki, Karim Ashenoune, Philippe Seguin, Matthieu Boisson, William Couet, Sandrine Marchand, Olivier Mimoz, Claire Dahyot-Fizelier

Abstract

Objectives: Ceftaroline could be suitable to treat early-onset ventilator-associated pneumonia (VAP) because of its antibacterial spectrum. However, augmented renal clearance (ARC) is frequent in ICU patients and may affect ceftaroline pharmacokinetics and efficacy. The objective of the study was to explore the impact of ARC on ceftaroline pharmacokinetics and evaluate whether the currently recommended dosing regimen (600 mg every 12 h) is appropriate to treat VAP in ICU patients.

Methods: A population pharmacokinetic model was developed using pharmacokinetic data from 18 patients with measured creatinine clearance (CLCR) ranging between 83 and 309 mL/min. Monte Carlo simulations were conducted to determine the PTA and the cumulative fraction of response (CFR) against Streptococcus pneumoniae and MRSA for five dosing regimens. Study registered at ClinicalTrials.gov (NCT03025841).

Results: Ceftaroline clearance increased non-linearly with CLCR, with lower concentrations and lower probability of reaching pharmacokinetic/pharmacodynamic targets when CLCR increases. For the currently recommended dosing regimen, the probability of having unbound ceftaroline concentrations above the MIC over the entire dose range is greater than 90% for MICs below 0.125 mg/L. Considering the distribution of MICs, this regimen would not be effective against MRSA infections (CFR between 21% and 67% depending on CLCR), but would be effective against S. pneumoniae infections (CFR >86%).

Conclusions: The recommended dosing regimen of ceftaroline seems sufficient for covering S. pneumoniae in ICU patients with ARC, but not for MRSA. Among the dosing regimens tested it appears that a constant infusion (50 mg/h) after a loading dose of 600 mg could be more appropriate for MRSA infections.

© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.

Figures

Figure 1.
Figure 1.
Mean (+SD) plasma concentration of ceftaroline and ceftaroline M-1 following the first administration of 600 mg of ceftaroline fosamil as a 1 h infusion (PK1, left panel) and at least the fifth administration (between fifth and ninth) (PK2, right panel).
Figure 2.
Figure 2.
Plot of the predicted clearance of ceftaroline (CLceftaroline) versus CLCR measured in the patients enrolled in this study. Circles represent the individual predictions for the different CLCRs calculated on the 2 days of PK sampling and lines represent the typical predictions calculated according to the power function used to describe the significant effect of CLCR on the clearance of ceftaroline: CLceftaroline = CLceftaroline, pop × (CLCR/180)CLCR, cov1
Figure 3.
Figure 3.
Impact of dose fractionation on PTA (fT>MIC = 100%) in simulated patients with CLCR = 80, 130, 210 or 300 mL/min receiving the same daily dose of ceftaroline (1200 mg/24 h), overlaid with ceftaroline MIC distributions for WT MRSA.
Figure 4.
Figure 4.
Simulated unbound steady-state concentrations of ceftaroline after a constant infusion of 1200 mg over 24 h for various CLCR values. Circles represent individual simulated concentrations (n = 1000 for each CLCR value), the red solid line represents the median of the simulated data and the red area represents the 90% prediction interval. The grey dashed line corresponds to the 90th percentile of the WT distribution (MIC90) for S. aureus. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

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