Ceftaroline-Fosamil efficacy against methicillin-resistant Staphylococcus aureus in a rabbit prosthetic joint infection model

Abstract

Ceftaroline (CPT), the active metabolite of the prodrug ceftaroline-fosamil (CPT-F), demonstrates in vitro bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and is effective in rabbit models of difficult-to-treat MRSA endocarditis and acute osteomyelitis. However, its in vivo efficacy in a prosthetic joint infection (PJI) model is unknown. Using a MRSA-infected knee PJI model in rabbits, the efficacies of CPT-F or vancomycin (VAN) alone and combined with rifampin (RIF) were compared. After each partial knee replacement with a silicone implant that fit into the tibial intramedullary canal was performed, 5 × 10(7) MRSA CFU (MICs of 0.38, 0.006, and 1 mg/liter for CPT, RIF, and VAN, respectively) was injected into the knee. Infected animals were randomly assigned to receive no treatment (controls) or CPT-F (60 mg/kg of body weight intramuscularly [i.m.]), VAN (60 mg/kg i.m.), CPT-F plus RIF (10 mg/kg i.m.), or VAN plus RIF starting 7 days postinoculation and lasting for 7 days. Surviving bacteria in crushed tibias were counted 3 days after ending treatment. Although the in vivo mean log10 CFU/g of CPT-treated (3.0 ± 0.9, n = 12) and VAN-treated (3.5 ± 1.1, n = 12) crushed bones was significantly lower than those of controls (5.6 ± 1.1, n = 14) (P < 0.001), neither treatment fully sterilized the bones (3/12 were sterile with each treatment). The mean log10 CFU/g values for the antibiotics in combination with RIF were 1.9 ± 0.5 (12/14 were sterile) for CPT-F and 1.9 ± 0.5 (12/14 were sterile) for VAN. In this MRSA PJI model, the efficacies of CPT-F and VAN did not differ; thus, CPT appears to be a promising antimicrobial agent for the treatment of MRSA PJIs.

FIG 1

In vitro time-kill curves for methicillin-resistant Staphylococcus aureus strain ST20121238, using different antibiotics and combinations thereof at concentrations equivalent to 4× MIC. CPT, ceftaroline; VAN, vancomycin; RIF, rifampin.

FIG 2

Antibiotic effect against a rabbit methicillin-resistant Staphylococcus aureus strain ST20121238 prosthetic knee infection model. Rabbits were injected for 14 days with ceftaroline (CPT) (60 mg/kg i.m. b.i.d.) or vancomycin (VAN) (60 mg/kg i.m. b.i.d.) alone or combined with rifampin (RIF) (10 mg/kg i.m. b.i.d.). Bone was considered sterile when the culture showed no growth after incubation for 48 h at 37°C and the number of recorded CFU was the lowest detectable bacterial count (1.64 to 1.84 CFU/g of bone, depending on the weight of the sample).