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

Abstract

Ceftaroline fosamil is a β-lactam antibiotic approved as a 600 mg twice daily dose (≤1h infusion, 'standard dosing') or a 600 mg thrice daily dose (2h 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. A population PK model was developed using data from 12healthy 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 12h [q12h]→ every 8h [q8h]); (2) infusion duration (1h→2h); and (3)individual and total daily dose (400→900 mg, i.e. TDD 1200→1800mg), as well as for varying susceptibility of S.aureus (MIC 0.032-8 mg/L). 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 ≤1mg/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 2h infusions declined, and increased TDD improved ƒT>MIC the most. The analysis calls to mind consideration of dose increases when prolonging the infusion duration in the case of low bacterial susceptibility.