Efficacy of Ceftobiprole and Daptomycin at Bone Concentrations Against Methicillin-Resistant Staphylococcus aureus Biofilm: Results of a Dynamic In Vitro PK/PD Model

Background: The presence of biofilms and low antimicrobial concentrations in bone tissue make prosthetic joint infections (PJI) difficult to treat. Ceftobiprole (CTO) has a potential role in MRSA PJI. This study evaluated the efficacy of ceftobiprole and daptomycin (DAP) alone and in combination against MRSA biofilms at expected bone tissue concentrations. We assessed whether CTO-DAP outperformed DAP combined with a non-anti-MRSA beta-lactam (cefazolin [CZO]). Methods: A dynamic in vitro PK/PD biofilm model (CDC biofilm reactor) was used to simulate concentrations expected in cortical bone at a standard dosing of DAP (10 mg/kg/24 h), CTO (500 mg/8 h), and CZO (2 g/8 h), and assess performance against a 48-h MRSA biofilm from two clinical isolates that cause PJI (MRSA-1811 and MRSA-1733). Time-kill curves using the log change method (Delta log10 CFU/cm2) assessed antimicrobial efficacy over 56 h. Resistance emergence was monitored. Results: Although both monotherapies were active, neither reached bactericidal levels nor was one superior to the other (Delta log10 CFU/cm2 CTO vs. DAP: -1.44 +/- 0.25 vs. -1.50 +/- 0.01 [p = 0.686] and -1.55 +/- 0.74 vs. -0.56 +/- 0.36 [p = 0.108] for MRSA-1811 and MRSA-1733, respectively). Only in the MRSA-1811 isolate did the CTO-DAP combination improve the activity of each monotherapy, without achieving a synergistic effect (Delta log10 CFU/cm2: CTO-DAP -2.087 +/- 0.048 vs. CTO -1.436 +/- 0.249 [p = 0.013] and vs. DAP -1.503 +/- 0.011 [p = 0.006]). No combination therapy (CTO-DAP vs. DAP-CZO) outperformed the other in either strain. No resistant bacterial subpopulations appeared with any antibiotic regimen. Conclusions: At clinically relevant concentrations, ceftobiprole and daptomycin showed similar activity against MRSA biofilms. The CTO-DAP combination showed comparable efficacy to DAP-CZO.