Ceftaroline-Fosamil Efficacy against Methicillin-Resistant Staphylococcus aureus in a Rabbit Prosthetic Joint Infection Model

Abstract

c 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 MRSAinfected 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 log 10 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 log 10 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. O rthopedic joint replacement is an increasingly common surgical procedure worldwide, reflecting the aging of the population (1). While prosthetic joint infection (PJI) is uncommon, it can be a serious complication which entails major morbidity and high costs (1). Perioperative contamination is responsible for most PJIs, which are mainly caused by Staphylococcus aureus or Staphylococcus epidermidis (2). These microorganisms are often resistant to many commonly used antibiotics. At present, vancomycin (VAN) or daptomycin (DAP) combined with rifampin (RIF) is recommended as the first-line therapy of device-related osteoarticular infections due to methicillin-resistant S. aureus (MRSA) (3). However, the efficacy of VAN might not be optimal when the MIC of the responsible strain is Ͼ1 g/ml (3, 4). Strains with reduced susceptibilities to DAP were described in experimental PJI models and in patients without treatment and in those after VAN or DAP administration (4,5). Thus, alternative therapies are still needed.Ceftaroline (CPT) is a broad-spectrum cephalosporin with a high in vitro affinity for penicillin-binding protein 2a and bactericidal activity against MRSA. CPT is the active metabolite of the prodrug ceftaroline-fosamil (CPT-F). This compound was recently approved in the United States for the treatment of complicated skin...

Oral-Only Linezolid-Rifampin Is Highly Effective Compared with Other Antibiotics for Periprosthetic Joint Infection

“…Ceftaroline is a novel 5th-generation cephalosporin with activity against MRSA. The efficacy of the ceftaroline-rifampin combination was similar to that of the other rifampin combinations, a finding consistent with the efficacy of ceftaroline-rifampin treatment in a rabbit model of PJI 33 . The toxicity profile of ceftaroline is similar to that of other cephalosporins, which are generally well tolerated, and does not require serum-level testing as required for vancomycin 34 .…”

Surgical Debridement Is Superior to Sole Antibiotic Therapy in a Novel Murine Posttraumatic Osteomyelitis Model

“…aureus strain for bacterial inoculation was used in almost all of them, since this is the most common pathogen in the setting of osteomyelitis [ 3 ]. In most animal models, implant associated infections were examined or fracture models that needed to be stabilized by foreign bodies [ 20 – 22 , 30 , 32 – 34 , 43 – 49 ]. Furthermore, rats and rabbits were used in most studies, as they are big enough to create stable long bone infections without tremendous efforts, but on the other hand are small enough to be housed and handled easily [ 22 , 43 – 45 , 48 – 51 ].…”

Recent Advances in the Evaluation of Antimicrobial Materials for Resolution of Orthopedic Implant-Associated Infections In Vivo

“…Orthopedic implant-associated infection in vivo models that incorporate antimicrobial biomaterials have been developed to treat established infections following an initial debridement in a variety of species including mice, ,,,,− rats, ,,,,,,− rabbits, ,,,,,,,,− and dogs, for example (Table ). Models that evaluate treatment of implant infections generally involve an initial implantation of a tibial or femoral implant and bacterial inoculation.…”