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

• Published in: British journal of clinical pharmacology 2023-02, Vol.89 (2), p.705-713
• Main Authors: Roelofsen, Eveline E., Abdulla, Alan, Muller, Anouk E., Endeman, Henrik, Gommers, Diederik, Dijkstra, Annemieke, Hunfeld, Nicole G. M., Winter, Brenda C. M., Koch, Birgit C. P.
• Format: Article
• Language: English
• Subjects: Adult; Albumins; Anti-Bacterial Agents; Cefotaxime; cephalosporins; Critical Illness - therapy; critically ill; dosage regimens; Humans; Microbial Sensitivity Tests; Monte Carlo Method; Original; pharmacokinetic modelling; pharmacokinetics; pharmacometrics; Staphylococcus aureus; β‐lactam antibiotics
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.15487

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 NONMEM (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.