Ceftobiprole 500mg powder for solution for infusion vials

BackgroundThe comparative efficacy of ceftaroline and ceftobiprole against standard of care for Staphylococcus aureus infections, including methicillin-resistant S. aureus remains uncertain. Thus, we conducted a systematic review and Bayesian meta-analysis to assess the efficacy and safety of ceftaroline and ceftobiprole monotherapy for non-urinary S. aureus infections.MethodsWe registered the protocol in PROSPERO. We searched PubMed, Embase, Scopus, and Web of Science. We included randomized controlled trials and comparative non-randomized studies reporting adjusted estimates, enrolling patients with non-urinary S. aureus infections. The primary analysis assessed clinical cure in randomized trials using a Bayesian random-effects model with a vague prior. For ceftaroline, we additionally conducted an exploratory analysis using an observationally informed prior derived from non-randomized studies with variance inflation. Risk of bias was assessed with RoB 2 and ROBINS-I and certainty of evidence with GRADE.ResultsSixteen studies met inclusion criteria [11 ceftaroline (1030 subjects); 5 ceftobiprole (1265 subjects)]. In the primary analysis, the pooled odds ratio for clinical cure was 1.38 (95% CrI 0.81-2.44) for ceftaroline and 0.99 (95% CrI 0.59-1.62) for ceftobiprole. The exploratory ceftaroline analysis using an observationally informed prior yielded an odds ratio of 1.45 (95% CrI 0.91-2.38). Adverse events and serious adverse events were similar between groups. Certainty of evidence was low for ceftaroline and moderate for ceftobiprole.ConclusionsCurrent evidence does not demonstrate superiority of ceftaroline or ceftobiprole over standard-of-care therapy for clinical cure in non-urinary S. aureus infections. Estimates remain imprecise and are largely driven by registrational trials and subgroup data. These findings support cautious, indication-specific interpretation rather than routine preference of these agents over established therapies.

Abstract licence: CC BY

BackgroundCeftaroline 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.MethodsA 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.ResultsThirty-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.ConclusionsCeftaroline 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.

Abstract licence: CC BY