Efficacy of the new cephalosporin ceftaroline in the treatment of experimental methicillin-resistant Staphylococcus aureus acute osteomyelitis

Jacqueline, Cédric; Amador, Gilles; Caillon, Jocelyne; Mabecque, Virginie Le; Batard, Éric; Miègeville, Anne-Françoise; Biek, Donald; Ge, Yigong; Potel, G.; Hamel, Antoine

doi:10.1093/jac/dkq193

Cited by 61 publications

(34 citation statements)

References 19 publications

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“…It has potent activity against community-associated MRSA isolates and showed bactericidal activity against VISA, VRSA, hVISA and daptomycin-non-susceptible S. aureus isolates [78]. Animal studies support ceftaroline as a promising therapeutic option for the treatment of severe MRSA infections, including osteomyelitis and endocarditis [79,80]. Ceftaroline has been evaluated for cSSSI in two identical phase III clinical trials.…”

Section: Developmental Agentsmentioning

confidence: 99%

Management of serious meticillin-resistant Staphylococcus aureus infections: what are the limits?

Gould

Cauda

Esposito

et al. 2011

International Journal of Antimicrobial Agents

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Severe (life-threatening) meticillin-resistant Staphylococcus aureus (MRSA) infection continues to be treated with vancomycin despite accumulating evidence of poor outcome, increasing resistance and unachievable pharmacokinetic/pharmacodynamic (PK/PD) targets. The minimum inhibitory concentration (MIC) susceptibility breakpoint for vancomycin was recently reduced to 2 mg/L. Whilst the great majority of clinical isolates are thus still classified as susceptible, the available clinical evidence argues for a method-dependent breakpoint of 0.5 mg/L (broth dilution) or 1.0 mg/L (Etest), which would classify many strains as resistant, or at best intermediate. However, automated susceptibility testing systems are not currently capable of performing accurately at this low level, and such low breakpoints are unsatisfactory because the poor reproducibility of tests (plus or minus one doubling dilution) results in a critical non-reproducibility around the modal MIC of 1 mg/L described in most published data. Therefore, vancomycin should be used with caution in severe (life-threatening) staphylococcal disease and the MIC should always be reported by method. Daptomycin is generally preferred for bacteraemia/endocarditis and linezolid for pneumonia. Better outcome data for vancomycin, based on achievable PK/PD targets and using robust MIC tests, are urgently required.

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Section: Developmental Agentsmentioning

confidence: 99%

Management of serious meticillin-resistant Staphylococcus aureus infections: what are the limits?

Gould

Cauda

Esposito

et al. 2011

International Journal of Antimicrobial Agents

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“…This compound was recently approved in the United States for the treatment of complicated skin and skin structure infections caused by Gram-positive bacteria. It was effective against rabbit models of difficult-to-treat MRSA endocarditis and acute osteomyelitis (6,7), but the in vivo efficacy of CPT against a MRSA PJI model (4,8,9) has not been tested. This study was undertaken to compare the efficacies of CPT-F or VAN alone or combined with RIF against MRSA in a knee PJI model in rabbits that closely simulates human infection.…”

mentioning

confidence: 99%

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

Gatin

Saleh‐Mghir

Tasse

et al. 2014

Antimicrob Agents Chemother

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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...

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“…Also, in a rabbit MRSA osteomyelitis model (vancomycin MIC, 0.78 g/ml) (42), ceftobiprole was able to sterilize 100% of the animals compared to 73% of vancomycin-or linezolid-treated animals. Notably, ceftaroline, another cephalosporin with anti-MRSA bactericidal activity, performed better than vancomycin against MRSA rabbit endocarditis and acute osteomyelitis (18,19). The previously reported good in vivo activity of ceftobiprole monotherapy, noted early in experimental endocarditis (13), remains only partially understood; its bactericidal effect against MRSA might play a role.…”

Section: Discussionmentioning

confidence: 99%

Ceftobiprole Efficacy In Vitro against Panton-Valentine Leukocidin Production and In Vivo against Community-Associated Methicillin-Resistant Staphylococcus aureus Osteomyelitis in Rabbits

Saleh‐Mghir

Dumitrescu

Dinh

et al. 2012

Antimicrob Agents Chemother

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Efficacy of the new cephalosporin ceftaroline in the treatment of experimental methicillin-resistant Staphylococcus aureus acute osteomyelitis

Abstract: The present study supports ceftaroline as a promising therapeutic option for the treatment of severe MRSA infections, including osteomyelitis.

Cited by 61 publications

References 19 publications

Management of serious meticillin-resistant Staphylococcus aureus infections: what are the limits?

Management of serious meticillin-resistant Staphylococcus aureus infections: what are the limits?

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

Ceftobiprole Efficacy In Vitro against Panton-Valentine Leukocidin Production and In Vivo against Community-Associated Methicillin-Resistant Staphylococcus aureus Osteomyelitis in Rabbits

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