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Introduction This retrospective analysis compares the probability of target attainment (PTA) for ceftriaxone, levofloxacin and ceftaroline fosamil against Staphylococcus aureus , Streptococcus pneumoniae and Haemophilus influenzae in a representative patient population with moderate-to-severe community-acquired pneumonia (CAP). Methods Published pharmacokinetic (PK) models for levofloxacin and ceftriaxone, and an existing model for ceftaroline, were used with standard dosage regimens for simulating individual PK data with covariates representative of patients with CAP (5000 patients/drug regimen). PTA for clinically relevant pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated from steady state PK profiles for a range of minimum inhibitory concentrations (MICs). Cumulative fractions of response (CFRs) were also calculated using MIC distributions from 2012 to 2017 global surveillance data. Results Ceftaroline fosamil (600 mg q12 h) achieved > 90% PTA at all exposure targets for each pathogen at European Committee on Antimicrobial Susceptibility Testing (EUCAST)/Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints, and CFRs were > 99%. Ceftriaxone, but not levofloxacin, achieved 100% PTA and > 90% CFR against S. pneumoniae . Both levofloxacin and ceftriaxone achieved high PTA and CFR against H. influenzae . Levofloxacin achieved PTAs < 90% at EUCAST/CLSI breakpoints and ceftriaxone achieved PTAs < 90% at MICs up to 2 mg/L against S. aureus ; both agents produced generally low CFRs against S. aureus (except levofloxacin against methicillin-sensitive S. aureus ), reflecting the lack of activity of these agents against methicillin-resistant S. aureus . Conclusion Ceftaroline fosamil demonstrated higher overall PTA rates than levofloxacin and ceftriaxone, in particular against S. aureus. These results provide insight regarding the potential comparative efficacy of the described antibiotics for moderate-to-severe CAP. Funding Pfizer.