CANVAS 1 and 2: analysis of clinical response at day 3 in two phase 3 trials of ceftaroline fosamil versus vancomycin plus aztreonam in treatment of acute bacterial skin and skin structure infections.

Scientific 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.

Integrated safety summary of FOCUS 1 and FOCUS 2 trials: Phase III randomized, double-blind studies evaluating ceftaroline fosamil for the treatment of patients with community-acquired pneumonia.

OBJECTIVES: Ceftaroline fosamil, the prodrug of the active metabolite ceftaroline, is a broad-spectrum, parenteral cephalosporin approved for treatment of moderate to severe bacterial infections, including community-acquired pneumonia (CAP). This report provides an integrated safety summary of the ceFtarOline Community-acquired pneUmonia trial versuS ceftriaxone (FOCUS) 1 and 2 trials (registration numbers: NCT00621504 and NCT00509106). METHODS: Patients hospitalized with CAP requiring intravenous therapy and having Pneumonia Outcomes Research Team (PORT) risk class scores of III or IV were randomized (1:1) to receive 600 mg of ceftaroline fosamil administered intravenously every 12 h or 1 g of ceftriaxone administered intravenously every 24 h for 5-7 days. All patients were followed for treatment-emergent adverse events (TEAEs) occurring from the start of the initial study drug infusion up to the test-of-cure visit; serious adverse events (SAEs) including deaths occurring up to the late follow-up visit or within 30 days after the last dose were additionally recorded. Scheduled laboratory testing was conducted up to the test-of-cure visit; unscheduled testing continued up to the late follow-up visit. RESULTS: A total of 1228 patients (613 in the ceftaroline fosamil group and 615 in the ceftriaxone group) received any amount of drug and were included in the safety analysis. The incidences of TEAEs (47.0% versus 45.7%), SAEs (11.3% versus 11.7%), discontinuations (4.4% versus 4.1%) and deaths (2.4% versus 2.0%) were similar between the ceftaroline fosamil and the ceftriaxone groups, respectively. Diarrhoea (4.2%), headache (3.4%) and insomnia (3.1%) were the most commonly reported TEAEs in patients treated with ceftaroline fosamil. The distribution of TEAEs based on severity was also similar between groups, and the majority of patients in both treatment groups (∼75%) had either no TEAEs or only mild TEAEs. CONCLUSIONS: 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.