Efficacy of ceftaroline fosamil for bacteremia associated with community-acquired bacterial pneumonia.

OBJECTIVES: Few publications of prospective studies have described patient outcomes in community-acquired bacterial pneumonia (CABP)-associated bacteremia. Our objective, in performing this subgroup analysis, was to assess outcomes in subjects with CABP-associated bacteremia in 2 randomized, double-blind clinical studies comparing treatment with ceftaroline fosamil versus ceftriaxone. METHODS: Our analysis summarizes baseline subject demographics, distribution of baseline pathogens isolated from blood cultures, clinical response rates at Day 4, and clinical cure rates at end of therapy and test of cure (8 to 15 days after end of therapy) in subjects with bacteremic CABP in the ceFtarOline Community-acquired pneUmonia trial vS ceftriaxone in hospitalized patients (FOCUS) studies. RESULTS: In the FOCUS studies, 23 of 614 patients in the ceftaroline fosamil-treated group and 22 of 614 patients in the ceftriaxone-treated group had CABP-associated bacteremia. Baseline demographics were similar between groups. Streptococcus pneumoniae was the most common baseline bloodstream isolate. For subjects with CABP-associated bacteremia, clinical response/cure rates were similar at Day 4 (60.9% vs 59.1%), end of therapy (69.6% vs 72.7%), and test of cure (69.6% vs 68.2%) for ceftaroline fosamil and ceftriaxone, respectively. CONCLUSIONS: In subjects with CABP-associated bacteremia, ceftaroline fosamil demonstrated similar clinical outcomes at Day 4, end of therapy, and test of cure compared with ceftriaxone.

FOCUS 2: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia.

OBJECTIVES: Ceftaroline (active form of the prodrug ceftaroline fosamil) is a novel cephalosporin with activity against pathogens commonly associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and Gram-negative pathogens. This randomized, double-blind, Phase III study evaluated the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ -10%] of clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. METHODS: Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 2 registration number NCT00509106 (http://clinicaltrials.gov/ct2/show/NCT00509106). RESULTS: The study enrolled 627 patients, 315 of whom received ceftaroline fosamil and 307 of whom received ceftriaxone. Patients in both treatment groups had comparable baseline characteristics. Clinical cure rates were as follows: CE population, 82.1% (193/235) for ceftaroline fosamil and 77.2% (166/215) for ceftriaxone [difference (95% CI), 4.9% (-2.5, 12.5)]; and MITTE population, 81.3% (235/289) for ceftaroline fosamil and 75.5% (206/273) for ceftriaxone [difference (95% CI), 5.9% (-1.0, 12.7)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE (mMITTE) population were 83.3% (35/42) and 70.0% (28/40) for ceftaroline fosamil and ceftriaxone, respectively. Ceftaroline fosamil and ceftriaxone were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations due to an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, hypokalaemia, insomnia and phlebitis, and the most common AEs for ceftriaxone-treated patients were diarrhoea, insomnia, phlebitis and hypertension. CONCLUSIONS: Ceftaroline fosamil achieved high clinical cure and microbiological response rates in patients hospitalized with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile that is similar to that of ceftriaxone and other cephalosporins. Ceftaroline fosamil is a promising agent for the treatment of CAP.

Review of ceftaroline fosamil microbiology: integrated FOCUS studies.

Ceftaroline fosamil, the prodrug form of ceftaroline, is a novel broad-spectrum parenteral cephalosporin that exhibits antibacterial activity against typical respiratory pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and common Gram-negative pathogens. In particular, ceftaroline has activity against resistant Gram-positive cocci, including penicillin- and multidrug-resistant S. pneumoniae, as well as methicillin-resistant S. aureus. The activity of ceftaroline against these phenotypes is attributed to its ability to bind to modified penicillin-binding proteins with high affinity when compared with other ß-lactams. The activity of ceftaroline is not compromised by the ability of H. influenzae to produce ß-lactamase. Ceftaroline fosamil was compared with ceftriaxone for safety and efficacy in two randomized, double-blinded, controlled Phase III clinical trials for the treatment of community-acquired pneumonia (CAP). Microbiological assessments at baseline included respiratory specimen cultures, blood cultures, urinary antigen testing and atypical pathogen serology testing. By-subject and by-pathogen microbiological outcomes were assessed in the microbiologically evaluable population at the test-of-cure visit. The favourable microbiological response rates by subject for ceftaroline were 87.0% compared with 81.0% for ceftriaxone. The by-pathogen microbiological response rates of ceftaroline and ceftriaxone were 87.3% and 72.9% for S. pneumoniae, 83.3% and 85.0% for H. influenzae and 76.0% and 70.4% for S. aureus, respectively. Key baseline pathogens such as S. pneumoniae, H. influenzae and methicillin-susceptible S. aureus were susceptible to ceftaroline, with MIC(90)s of 0.03, 0.03 and 0.25 mg/L, respectively, supporting its utility as a promising new agent for treatment of CAP.

FOCUS 1: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia.

OBJECTIVES: Ceftaroline, the active form of the prodrug ceftaroline fosamil, is a novel cephalosporin with bactericidal activity against important pathogens associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and common Gram-negative pathogens. FOCUS 1 is a randomized, double-blinded, Phase III study that was conducted to evaluate the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ -10%] in clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. METHODS: Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Patients also received two 500 mg doses of oral clarithromycin every 12 h administered on day 1. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 1 registration number NCT00621504 (http://clinicaltrials.gov/ct2/show/NCT00621504). RESULTS: Of 613 enrolled patients, 298 received ceftaroline fosamil and 308 received ceftriaxone. Baseline characteristics between treatment groups were comparable. Clinical cure rates were as follows: CE population, 86.6% (194/224) for ceftaroline fosamil and 78.2% (183/234) for ceftriaxone [difference (95% CI), 8.4% (1.4, 15.4)]; and MITTE population, 83.8% (244/291) for ceftaroline fosamil and 77.7% (233/300) for ceftriaxone [difference (95% CI), 6.2% (-0.2, 12.6)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE population were 88.9% (24/27) and 66.7% (20/30) for ceftaroline fosamil and ceftriaxone, respectively. Both agents were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations because of an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, insomnia and nausea, and the most common AEs for ceftriaxone-treated patients were hypokalaemia, hypertension, nausea and diarrhoea. CONCLUSIONS: Ceftaroline fosamil demonstrated high clinical cure and microbiological response rates in hospitalized patients with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile similar to that of ceftriaxone and consistent with the cephalosporin class. In this study, ceftaroline fosamil was an effective and well-tolerated treatment option for CAP.

Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity.

Ceftaroline fosamil is a novel cephalosporin with broad-spectrum activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae, and common Gram-negative organisms. The activity of ceftaroline against MRSA is attributed to its ability to bind to penicillin-binding protein (PBP) 2a with high affinity and inhibit the biochemical activity of PBP 2a more efficiently than other presently available ß-lactams. The activity of ceftaroline against MRSA and the ß-haemolytic streptococci makes it an attractive monotherapy agent for the treatment of complicated skin and skin structure infections (cSSSIs). Recent profiling and surveillance studies have shown that ceftaroline is active against contemporary skin pathogens collected from US and European medical centres in 2008. The mean free drug %T  >  MIC (percentage of time the drug concentration remains above the MIC) needed for stasis ranged from 26% for S. aureus to 39% for S. pneumoniae in the murine thigh infection model. Pharmacokinetic and pharmacodynamic target attainment predictions for 600 mg of ceftaroline fosamil every 12 h showed that the mean %T  >  MICs for which plasma free-drug concentrations exceeded an MIC of 1 and 2 mg/L were 71% and 51% of the dosing interval, respectively. For a 40% T  >  MIC target, the predicted attainments for infections due to pathogens for which ceftaroline MICs were 1 or 2 mg/L were 100% and 90%, respectively. Clinical and microbiological successes of ceftaroline fosamil in treating cSSSIs were demonstrated in two Phase III clinical studies, in which 96.8% of all baseline cSSSI isolates from the microbiologically evaluable population were inhibited by ceftaroline at ≤ 2 mg/L. Ceftaroline fosamil is a promising broad-spectrum agent for the treatment of cSSSIs.