Pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) considerations of ceftaroline and ceftobiprole for the treatment of Staphylococcus aureus infections: a systematic review.

BACKGROUND: Ceftaroline and ceftobiprole are fifth-generation cephalosporins with activity against methicillin-resistant Staphylococcus aureus. Like other β-lactam antimicrobials, their efficacy correlates with the percentage of the dosing interval during which unbound drug concentrations exceed the minimum inhibitory concentration (MIC) of the pathogen (% fT>MIC). However, achieving optimal exposures may be challenging in patients with altered pharmacokinetics or deep-seated infections. METHODS: A systematic review was performed using MEDLINE (Pubmed), Embase, Web of Science and Scopus libraries. Peer-reviewed studies reporting the pharmacokinetics of ceftaroline and ceftobiprole and/or their pharmacokinetics/pharmacodynamics in S. aureus infections were included. Screening, data extraction, and quality assessment were performed independently by two reviewers. RESULTS: Thirty-one studies for ceftaroline and 22 studies for ceftobiprole met the inclusion criteria. Literature appraisal revealed substantial pharmacokinetic variability in special populations, particularly critically ill patients, with increased volumes of distribution and variable clearance. In patients without severe infections, standard dosing generally achieved high probabilities of attaining pre-clinical pharmacokinetic/pharmacodynamic targets for bacteriostasis, 1-log₁₀ and 2-log₁₀ kill (20%, 26%, and 37% fT>MIC for ceftaroline, 8.8%, 13.5%, and 23% for ceftobiprole) up to the clinical breakpoints. By contrast, in patients with altered pharmacokinetics or deep-seated infections, intensified dosing and prolonged infusions were often required to achieve plasma and tissue pharmacokinetic/pharmacodynamic targets, particularly for stringent endpoints such as 100% fT>MIC. CONCLUSIONS: Ceftaroline and ceftobiprole pharmacokinetics are highly variable in hospitalized patients, potentially compromising attainment of stringent pharmacokinetic/pharmacodynamic targets for S. aureus infections. Intensified doses and prolonged infusions may therefore be necessary to ensure adequate drug exposure.