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Clinical Pharmacokinetics

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Open Access 26-11-2023 | Original Research Article

Impact of Key Components of Intensified Ceftaroline Dosing on Pharmacokinetic/Pharmacodynamic Target Attainment

Authors: Iris K. Minichmayr, Sebastian G. Wicha, Peter Matzneller, Charlotte Kloft, Markus Zeitlinger

Published in: Clinical Pharmacokinetics | Issue 1/2024

Abstract

Background and Objective

Ceftaroline fosamil is a β-lactam antibiotic approved as a 600 mg twice daily dose (≤1 h infusion, ‘standard dosing’) or a 600 mg thrice daily dose (2 h infusion) to treat complicated skin and soft tissue infections caused by Staphylococcus aureus (minimum inhibitory concentration [MIC] 2–4 mg/L). We sought to systematically evaluate the relative impact of the three key components of the intensified dosing regimen (i.e. shortened dosing interval, prolonged infusion duration and increased total daily dose [TDD]) on the pharmacokinetic/pharmacodynamic (PK/PD) target attainment given different grades of bacterial susceptibility.

Methods

A population PK model was developed using data from 12 healthy volunteers (EudraCT-2012-005134-11) receiving standard or intensified dosing. PK/PD target attainment (ƒT_>MIC = 35% and 100%) after 24 h was compared following systematically varied combinations of the (1) dosing interval (every 12 h [q12h]→ every 8 h [q8h]); (2) infusion duration (1 h→2 h); and (3) individual and total daily dose (400→900 mg, i.e. TDD 1200→1800 mg), as well as for varying susceptibility of S. aureus (MIC 0.032–8 mg/L).

Results

A two-compartment model with linear elimination adequately described ceftaroline concentrations (n = 274). The relevance of the dosing components dosing interval/infusion duration/TDD for ƒT_>MIC systematically changed with pathogen susceptibility. For susceptible pathogens with MIC ≤1 mg/L, shortened dosing intervals appeared as the main driver of the improved target attainment associated with the intensified dosing regimen, followed by increased TDD and infusion duration. For less susceptible pathogens, the advantage of q8h dosing and 2 h infusions declined, and increased TDD improved ƒT_>MIC the most.

Conclusion

The analysis calls to mind consideration of dose increases when prolonging the infusion duration in the case of low bacterial susceptibility.

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Title: Impact of Key Components of Intensified Ceftaroline Dosing on Pharmacokinetic/Pharmacodynamic Target Attainment
Authors: Iris K. Minichmayr
Sebastian G. Wicha
Peter Matzneller
Charlotte Kloft
Markus Zeitlinger
Publication date: 26-11-2023
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 1/2024
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-023-01325-4

At a glance: The STEP trials

Springer Medicine

Impact of Key Components of Intensified Ceftaroline Dosing on Pharmacokinetic/Pharmacodynamic Target Attainment

Abstract

Background and Objective

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background and Objective

Methods

Results

Conclusion

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