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Ceftaroline Fosamil Injection (Teflaro)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
A broad-spectrum, parenteral, cephalosporin with activity against both gram-positive and gram-negative bacteria has been approved by the FDA. Ceftaroline fosamil is the prodrug of ceftaroline and is marketed by Forest Pharmaceuticals as Teflaro.
Ceftaroline is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSI) and community-acquired bacterial pneumonia (CABP) due to susceptible microorganisms.1 For ABSSI, these organisms include Staphylococcus aureus (including methicillin-susceptible and resistant isolates), Streptococcus pyogenes, Streptococcus agalactiace, Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca. For CABP, Streptococcus pneumoniae (including cases with concurrent bacteremia), S. aureus (including methicillin-susceptible isolates only), Haemophilus influenzae, K. pneumoniae, K. oxytoca, and E.coli.
The recommended dose for ABSSI is 600 mg every 12 hours, given by intravenous infusion over 1 hour, for 5–14 days. For CABP, the dose is 600 mg every 12 hours for 5–7 days.1 The dose needs to be reduced with reduced creatinine clearance.
Ceftaroline is available as 400 mg and 600 mg single-use vials.
Ceftaroline is the first cephalosporin to show antibacterial activity against methicillin-resistant S. aureus (MRSA). There is minimal potential for drug-drug interactions involving the CYP450 isoenzyme system.
Ceftaroline is susceptible to beta-lactamases produced by gram-negative bacteria.1
Ceftaroline is a fifth-generation cephalosporin with antibacterial activity against gram-negative and gram-positive bacteria including MRSA. Its efficacy was shown in 4 Phase 3 studies, two in CABP (FOCUS I and II), and two in ABSSI (CANVAS I and CANVAS II).1-5 For CABP, adult patients (n = 1231) with radiographically confirmed CAP requiring hospitalization and treatment with IV antimicrobial therapy were randomized to ceftaroline (600 mg every 12 hours) or ceftriaxone (1 g every 24 hours) for 5-7 days.1,2 The primary objective was to determine noninferiority in clinical cure rates of ceftaroline and ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITT) populations at the test-of-cure (TOC) visit (8-15 days after end of therapy). The CE population represents the subset that adhered to protocol and the MITT represents the population that received any amount of the drug. In both cases, ceftaroline met noninferiority margins well above the predetermined -10%. Overall the clinical cure rates were 84.3% for ceftaroline and 77.7% for ceftriaxone in the CE population and 82.6% and 76.6%, respectively, for the MITT population. Ceftaroline was noninferior to ceftriaxone (although the cure rates were numerally higher). For ABSSI, patients with complicated skin and skin structure infections (n = 1378) were randomized to ceftaroline (600 mg every 12 hours) or vancomycin and aztreonam (1 g each every 12 hours) for 5–14 days.1,4,5 The primary objective was similar to that for CABP. Overall cure rate for the CE population was 91.6% for ceftaroline and 92.7% for vancomycin/aztreonam. For the MITT, rates were 85.9% and 85.5%, respectively.3 Ceftaroline was demonstrated to be noninferior to vancomycin/aztreonam. Cure rates were similar for MRSA and MSSA.3 The FDA also analyzed these studies based on clinical response on day 3 for ABSSI (cessation of lesion spread and absence of fever) and day 4 for CABP (stable vital signs and improved symtoms). Response rates were similar between ceftaroline and comparator in these studies.1 Ceftaroline is well tolerated with low frequencies of adverse events (e.g., diarrhea, nausea, constipation, rash, increased transaminases, phlebitis) 5% or less.1
Ceftaroline is the newest antimicrobial for the treatment of CABP and ASSBI. Ceftriaxone is a mainstay for CABP and ceftaroline was noninferior to ceftriaxone and was numerically better. For ASSBI, ceftaroline was noninferior to vancomycin/aztreonam. Ceftaoline looks promising, but its role in the treatment of these infections remains to be determined.
1. Teflaro Prescribing Information. Forest Laboratories, Inc. October 2010.
2. File TM, et al. Integrated analysis of FOCUS 1 and FOCUS 2: Randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia. Clin Infect Dis 2010;51:1395-1405.
3. Corey GR, et al. Integrated analysis of CANVAS 1 and 2: Phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis 2010;51:641-650.
4. Corey GR, et al. CANVAS 1: the first Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. J Antimicrob Chemother 2010;65 Suppl 4:iv41-51.
5. Wilcox MH, et al. CANVAS 2: The second Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. J Antimicrob Chemother 2010;65 Suppl 4:iv53-65.