Efficacy of Ceftaroline Fosamil in a Staphylococcal Murine Pneumonia Model

Abstract

Ceftaroline fosamil is a cephalosporin with activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The objective of this study was to characterize the dose-response relationship of ceftaroline fosamil against S. aureus in an immunocompromised murine pneumonia model, as well as to evaluate the efficacy of the humanized regimen of 600 mg intravenously (i.v.) every 12 h. Seventeen S. aureus (2 methicillin-susceptible Staphylococcus aureus [MSSA], 15 MRSA) isolates with ceftaroline MICs of 0.5 to 4 g/ml were utilized. The pharmacokinetics of ceftaroline in serum and epithelial lining fluid (ELF) were evaluated to determine bronchopulmonary exposure profiles in infected and uninfected animals, using single and human-simulated doses. Serum fT>MIC (the percentage of time that free drug concentrations remain above the MIC) of 17% to 43% was required to produce a 1-log 10 kill in the dose-ranging studies. These targets were readily achieved with the humanized exposure profile, where decreases of 0.64 to 1.95 log 10 CFU were observed against 13 MRSA and both MSSA isolates tested. When taken as a composite, the fT>MICs required for stasis and a 1-log 10 kill were 16% and 41%, respectively. ELF concentrations were similar to serum concentrations across the dosing interval in infected and uninfected animals. The serum fT>MIC targets required in this lung infection model were similar to those observed with ceftaroline against S. aureus in a murine thigh infection model. Exposures simulating the human dose of 600 mg i.v. every 12 h achieved pharmacodynamic targets against MRSA and MSSA considered susceptible by current U.S. FDA breakpoints.T he prevalence of methicillin-resistant Staphylococcus aureus (MRSA) continues to rise and poses a significant health care burden (10,14). MRSA is one of the many potential pathogens that contribute to community-and hospital-acquired pneumonias (CAP and HAP, respectively). A survey among 59 U.S. hospitals between January 2002 and January 2004 identified MRSA as the pathogen responsible for 8.9% of CAP and 22.9% of HAP cases (10). Frequently, pneumonias caused by MRSA, especially strains that produce the Panton-Valentine leukocidin (PVL) toxin, can result in severe cases of necrotizing pneumonia, which is difficult to treat (14).Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, has a broad spectrum of in vitro activity against common Gram-negative and Gram-positive pathogens, including Streptococcus pneumoniae and MRSA (5, 15). Ceftaroline displays high affinity for penicillin binding protein PBP2a, which plays an important role in methicillin resistance in MRSA strains (12, 15). Ceftaroline fosamil is currently approved in the United States for the treatment of acute bacterial skin and skin structure infections and non-MRSA community-acquired bacterial pneumonia at a dose of 600 mg intravenously (i.v) every 12 h (5).The objective of this study was to evaluate the dose-response relationship of ceftaroline in the neutropeni...

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

“…Indeed, the mean CPT AUC 0 -24 in the rabbits was 76.2 mg · h/liter versus 65 mg · h/liter in healthy adults (12), and the mean peak plasma concentrations in the rabbits and in healthy adults were 38 mg/liter and 31 mg/liter, respectively. With this equivalent dose the plasma CPT concentration in this study exceeded the test strain MIC for Ͼ50% of the 12-h between-dose periods; this concentration provided a suitable PD parameter to obtain a bactericidal effect in vitro and in vivo (14).…”

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

“…Ceftaroline epithelial lining fluid concentrations in a murine model were similar to serum concentrations, and exposures simulating human doses of 600 mg twice daily achieved recommended pharmacodynamic targets [113]. Isolates with an MIC > 1 mg/L may require a dose increase, but there are no data to support this.…”

“…There have, however, been in vitro comparisons of ceftaroline versus linezolid, vancomycin and daptomycin showing equivalent efficacy where the ceftaroline MIC is 2 mg/L [111], and a study showing a potential role in isolates with reduced susceptibility to linezolid, daptomycin or vancomycin [112]. Data demonstrating adequate lung penetration [113] and also a case involving the clinical use of ceftaroline have been described [114].…”

Efficacy of Ceftaroline against Methicillin-Susceptible Staphylococcus aureus Exhibiting the Cefazolin High-Inoculum Effect in a Rat Model of Endocarditis

“…Antibiotic doses administered to the rats were based on our own PK/PD data for CPT. The CPT dose was selected to achieve an fT ϾMIC that has been shown to have efficacy against S. aureus in murine thigh and lung infection and rabbit endocarditis models (24,58,59). Doses of NAF and CFZ were selected based on previously published studies demonstrating in vivo efficacy in experimental endocarditis (21,44,45).…”