Ceftaroline fosamil, the prodrug of the active metabolite, ceftaroline, is a new, broad-spectrum cephalosporin recently approved in the USA for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). Ceftaroline has potent in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae, as well as common Gram-negative organisms. The high affinity of ceftaroline for penicillin-binding proteins is responsible for the potent activity observed against clinically relevant pathogens. With respect to the treatment of CABP, the activity of ceftaroline against pathogens such as S. pneumoniae, S. aureus, Haemophilus influenzae and Moraxella catarrhalis demonstrates coverage across a broad range of pathogens typically encountered in clinical practice. Ceftaroline is also very active against common pathogens seen in ABSSSIs such as S. aureus (methicillin-susceptible S. aureus and methicillin-resistant S. aureus) and Streptococcus pyogenes. Ceftaroline exhibits a dose-proportional pharmacokinetic profile, similar to other renally excreted cephalosporins, and has a well-tolerated safety profile consistent with the cephalosporin class. Ceftaroline fosamil is compatible via Y-site administration with many other commonly administered parenteral drugs.

The data from the FOCUS 1 and FOCUS 2 trials presented in this integrated safety summary demonstrate that ceftaroline fosamil is well tolerated, with a tolerability profile similar to ceftriaxone and the cephalosporin class overall, with no unexpected safety concerns being identified.

bScientific and regulatory interest in assessing clinical endpoints after 48 to 72 h of treatment for acute bacterial skin and skin structure infections (ABSSSI) has increased. Historical, pre-antibiotic-era data suggest that a treatment effect relative to untreated controls can be discerned in this time interval. Ceftaroline fosamil, a broad-spectrum bactericidal cephalosporin with activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), and Gram-negative organisms was efficacious in two phase 3 trials of complicated skin infections (CANVAS 1 and 2) using clinical cure rates at the test-of-cure visit. To assess an early clinical response in the CANVAS trials, a retrospective analysis using a day 3 clinical endpoint was conducted. Adults with ABSSSI received intravenous ceftaroline fosamil at 600 mg every 12 h (q12h) or vancomycin at 1 g plus aztreonam at 1 g (V/A) q12h for 5 to 14 days. Clinical response at day 3, defined as cessation of infection spread and absence of fever, was analyzed in patients with a lesion size of >75 cm 2 and either deep and/or extensive cellulitis, major abscess, or an infected wound. Day 3 integrated CANVAS clinical response rates were 74.0% (296/400) for ceftaroline and 66.2% (263/397) for V/A (difference, 7.8%; 95% confidence interval [CI], 1.3% to 14.0%). In the individual studies, absolute treatment differences of 9.4% (CANVAS 1) and 5.9% (CANVAS 2) favoring ceftaroline were observed. For ABSSSI due to MRSA, response rates were 81.7% and 77.4% in the ceftaroline and V/A groups, respectively. In this retrospective analysis, ceftaroline fosamil monotherapy had a numerically higher clinical response than V/A at day 3 in the treatment of ABSSSI.

Background: Ceftaroline (active metabolite of ceftaroline fosamil) was efficacious in 2 phase 3 community-acquired pneumonia (CAP) trials (FOCUS 1 and 2) using clinical cure rates at the test-of-cure visit. Recent US Food and Drug Administration guidelines for design of noninferiority CAP trials recommend evaluation of clinical response at 72 to 96 hours after initiating therapy (day 4) rather than traditional test of cure. The day 4 end point may be more clinically relevant with respect to hospital discharge and oral stepdown therapy.Methods: A retrospective integrated analysis of the FOCUS trials was conducted in 309 adult patients with moderate to severe CAP and at least 1 proven typical bacterial pathogen at baseline. Patients received intravenous ceftaroline fosamil (600 mg) every 12 hours or ceftriaxone (1 g) every 24 hours for 5 to 7 days. Clinical response at day 4 included normalization of signs (fever, white blood cell count, blood pressure, respiratory rate) and improvement in respiratory symptoms (cough, dyspnea, sputum production, chest pain).Results: Day 4 clinical response rates were 69.5% (107/154) for ceftaroline and 59.4% (92/155) for ceftriaxone (difference 10.1%; 95% confidence interval, j0.6% to 20.6%). In individual studies, absolute treatment differences of 14.1% (FOCUS 1) and 6.8% (FOCUS 2) fa-voring ceftaroline were observed. Clinical response rates at day 4 associated with the most common pathogens, Streptococcus pneumoniae (ceftaroline, 54/74 [73.0%]; ceftriaxone, 42/75 [56.0%]) and Staphylococcus aureus (ceftaroline, 14/24 [58.3%]; ceftriaxone, 17/31 [54.8%]), were numerically higher for ceftaroline.Conclusions: Ceftaroline appears to provide clinical benefit over ceftriaxone at day 4 for treatment of community-acquired bacterial pneumonia.

Of the 73 drugs evaluated, 64 were compatible and 7 were incompatible with ceftaroline fosamil 2.22 mg/mL in 3 standard infusion solutions. Nine drugs in 23 admixtures were observed to exhibit signs of incompatibility with ceftaroline fosamil within four hours of mixing; those drugs should not be simultaneously administered via a Y-site with ceftaroline preparations.