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

OBJECTIVES

Ceftaroline and ceftobiprole are fifth-generation cephalosporins with activity against methicillin-resistant Staphylococcus aureus. The aims of this review are to summarize pharmacokinetics and pharmacokinetics/pharmacodynamics evidences on these drugs in healthy volunteers and across different patient populations, their targets associated with clinical efficacy, and the probability of target attainment for different dosing strategies.

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.