Dose optimization of cefotaxime as pre-emptive treatment in critically ill adult patients: A population pharmacokinetic study

Eveline E. Roelofsen*, Alan Abdulla, Anouk E. Muller, Henrik Endeman, Diederik Gommers, Annemieke Dijkstra, Nicole G. M. Hunfeld, Brenda C. M. de Winter, Birgit C. P. Koch

*Corresponding author for this work

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Abstract

Aims: To describe the pharmacokinetics (PK) of cefotaxime as pre-emptive treatment in critically ill adult patients, including covariates and to determine the probability of target attainment (PTA) of different dosage regimens for Enterobacterales and Staphylococcus aureus.

Methods: Five samples were drawn during 1 dosage interval in critically ill patients treated with cefotaxime 1 g q6h or q4h. PK parameters were estimated using NON-MEM (v7.4.2). The percentage of patients reaching 100% fT>MICECOFF was used to compare different dosage regimens for Enterobacterales and S. aureus.

Results: This study included 92 patients (437 samples). The best structural model was a 2-compartment model with a combined error, interindividual variability on clearance, central volume and intercompartmental clearance. Correlations between interindividual variability were included. Clearance increased with higher estimated glomerular filtration rate (eGFR; creatinine clearance) and albumin concentration. For Enterobacterales, 1 g q8h reached 95% PTA and continuous infusion (CI) of 4 g 24 h(-1) 100% PTA at the highest eGFR and albumin concentration. For S. aureus the predefined target of 95% PTA was not reached with higher eGFR and/or albumin concentrations. CI of 6 g 24 h(-1) for S. aureus resulted in a minimum of 99% PTA.

Conclusion: Cefotaxime PK in critically ill patients was best described by a 2-compartment model with eGFR and albumin concentration as covariates influencing clearance. For Enterobacterales 1 g q8h or CI of 4 g 24 h(-1) was adequate for all combinations of eGFR and albumin concentration. For S. aureus CI of 6 g 24 h(-1) would be preferred if eGFR and albumin concentration exceed 80 mL min(-1) and 40 g L-1 respectively.

Original languageEnglish
Number of pages9
JournalBritish Journal of Clinical Pharmacology
DOIs
Publication statusE-pub ahead of print - 27 Sep 2022

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