CEFTAROLINE FOSAMIL (ZINFORO )

Transcription

1 Page 1 London New Drugs Group APC/DTC Briefing Document CEFTAROLINE FOSAMIL (ZINFORO ) Contents Summary 1 Background 3 Ceftaroline 4 Clinical efficacy 6 FOCUS 1 and 2 6 CANVAS 1 and 2 9 Health economics 14 References 14 Appendices 16 Produced for the London New Drugs Group by: Alexandra Denby, Regional MI Manager Medicines Information Service Northwick Park Hospital Middlesex HA1 3UJ Tel: nwlh-tr.medinfo@nhs.net Further copies of this document are available from URL: The drug and the review Ceftaroline fosamil ( ceftaroline, Zinforo ) is a new broad-spectrum intravenous cephalosporin antibiotic. Ceftaroline binds to penicillin-binding protein enzymes on the bacterial cell wall, leading to cell death and has shown activity against MRSA. Ceftaroline was approved in the EU for the treatment of community acquired pneumonia (CAP) and complicated skin and soft tissue infections (cssti) in adults over 18 years of age in August This review evaluates the four main phase III studies submitted for the marketing approval. Background CAP occurs in 5-11 per 1000 adults in the UK, resulting in approximately 83,000 hospital admissions each year. The British Thoracic Society guidelines recommend that empirical therapy for patients with severe CAP should be started with intravenous antibiotics such as broad spectrum betalactamase stable penicillin or 2 nd /3 rd generation cephalosporin for patients with penicillin allergy plus clarithromycin. Complicated SSSIs range from minor superficial infections to necrotising infections and there are many causes, such as diabetes, impetigo, bites and surgical wounds. The incidence of infections due to MRSA, which is resistant to many penicillin, cephalosporin and carbapenem antibiotics, has risen over the last few decades. Literature We searched Medline and Embase (see p15 for search terms). Four phase 3 studies were identified: FOCUS 1 and 2, for CAP and CANVAS 1 and 2 for csssi. Both FOCUS studies and both CANVAS studies had identical design and data were pooled for integrated analyses. Efficacy studies FOCUS 1 and 2, and CANVAS 1 and 2 were randomised, double-blind, non-inferiority trials. FOCUS 1 and 2 In the FOCUS studies, ceftaroline 600mg IV every 12 hours was compared with ceftriaxone 1g IV every 24 hours for treating adults with CAP of PORT risk class III or IV. Treatment was given for 5-7 days. Patients enrolled in FOCUS 1 also received 2 doses of oral clarithromycin to comply with North American treatment guidelines and enable enrolment from this geographical area. The primary endpoint was to determine non-inferiority for clinical cure rates in the CE and the MITTE populations. MITT efficacy (MITTE; all randomised who received any study drug and with only PORT III or IV, ceftaroline n= 580 and ceftriaxone n=573); Clinically evaluable (CE; MITTE meeting all evaluability criteria, n=459 and 449). The primary endpoint of non-inferiority was met. Clinical cure rates were 6.7% (95% CI; 1.6 to 11.8) and 6.0% (95% CI; 1.4 to 10.7) higher in the ceftaroline groups vs. ceftriaxone in the CE and MITTE populations respectively (84.3% vs. 77.7% and 82.6% vs. 76.6%). Clinical cure rates for the most common pathogens isolated at baseline were numerically higher with ceftaroline than with ceftriaxone, e.g. S. pneumoniae: 85.5% vs. 68.6%, multidrug-resistant S. pneumoniae: 100% vs. 22.2%, S. aureus 72% vs. 60%, H. influenzae 85% vs. 83.3%. Patients with confirmed/suspected CAP caused by MRSA at baseline were excluded from the study. PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

2 Page 2 CANVAS 1 and 2 In the CANVAS studies, ceftaroline 600mg IV plus placebo was compared with vancomycin 1g IV plus aztreonam 1g IV twice a day to treat complicated skin and skin-structure infections in adults. Treatment was given for 5-14 days. Aztreonam (or placebo) could be discontinued if no gram-negative pathogen was isolated. The primary outcome was to determine non-inferiority of the per-patient clinical cure rate in the CE and MITT populations: MITT (all randomised who received any study drug, ceftaroline n=693, vanc/az n=685), clinically evaluable (CE, MITT who met all evaluability criteria, n=610 and n=592). The efficacy of ceftaroline was similar to that of vancomycin/aztreonam in the CE and MITT populations: 91.6% vs. 92.7% (95% CI; -4.2 to 2.0) and 85.9% vs. 85.5% (95% CI; -3.4 to 4.0) respectively. Non-inferiority was shown. Clinical cure rates for MRSA isolated at baseline were similar between the two groups. Higher cure rates with vancomycin/aztreonam than ceftaroline were seen against gram negative bacteria (24/24, 100% vs. 29/34, 85.3% (95% CI; to -1.2) respectively) though patient numbers were small. In patients with bacteraemia the cure rates were (21/21, 100% vs. 22/26, 84.6% (95% CI; to 1.5)) for vancomycin/ aztreonam and ceftaroline respectively. This data does not reach statistical significance. In a retrospective integrated analysis, clinical response rates based on a Day 3 endpoint were numerically higher in the ceftaroline group than with vancomycin/aztreonam (296/400, 74.0% vs. 263/397, 66.2% respectively (95% CI 1.3% to 14.0%) Safety The overall incidence of adverse events, discontinuations due to AEs and serious AEs was similar between treatment groups in each study. The main AEs reported in the trials were diarrhoea, nausea and rash. No differences in the incidences of liver, renal or haematological adverse events were seen. Patients with renal failure should receive a lower dose (400mg bd for CrCl >30 to 50mL/min and 300mg BD for CrCl 15 to <30mL/min). Critical evaluation FOCUS: The differences in cure rates for S. pneumoniae infections, including multi-drug resistant S. pneumoniae, may be due to differences in the affinities of the two cephalosporins for this bacterium: ceftaroline has a higher affinity for penicillin-binding protein 2X (seen in S. pneumoniae), 2a and 2b, than ceftriaxone. The clinical cure rates in FOCUS 1 vs. 2 were minimally higher, but were unlikely to be due to two clarithromycin doses. Patient populations who are often encountered in clinical practice such as immunocompromised patients, those who had prior treatment for CAP within 96 hours, patients on ITU or those at high risk for MRSA pneumonia were excluded. CANVAS In practice, patients with csssi may receive antibiotics for bacteria outside of the spectrum of ceftaroline. Clinical cure rates did not differ when sensitivity analysis was carried out on the outcome data after patients with abscesses were excluded: small abscesses do not usually require IV antibiotics but those present in the CANVAS studies were larger, surrounded by cellulitis or with systemic symptoms. Vancomycin and aztreonam were chosen as the comparator treatment based on the spectrum of activity and global acceptability to regulators and investigators, but may not be the first choice of treatment in clinical practice. Patients who were immunocompromised or those with severe infections were excluded from CANVAS. Potential benefits over existing technologies Ceftaroline is another cephalosporin, but has the advantage of activity against methicillin-resistant S. aureus (as shown in patients with csssi but not CAP). Ceftaroline also shows additional activity against strep pneumoniae, including multi-drug resistant strep pneumonia (compared with ceftriaxone) Side effects are similar to those seen with other cephalosporin antibiotics. Potential disadvantages over existing technologies Ceftaroline has only been studied in and the licence is for the treatment of adults; other cephalosporins are available which are licensed for use in all ages, such as ceftriaxone and cefotaxime. Paediatric studies are ongoing.

3 Page 3 Health Economics The cost of ceftaroline has yet to be confirmed. The budget impact of ceftaroline depends on a number of factors: Proportion of patients admitted with csssi or CAP, and the percentage of these requiring IV antibiotics. Local treatment guidelines for csssi and CAP, which may vary between Trusts. Local price negotiations for antibiotics. Taking these factors into consideration, the use of ceftaroline may be more or less than current practice. Astra Zeneca has a comprehensive budget impact model than can be tailored to individual Trusts patient populations and antibiotic guidelines, for budget holders. Issues for consideration Ceftaroline is a fifth generation cephalosporin with activity against MRSA and multidrug resistant S. pneumoniae. It is given by a 1 hour intravenous infusion every 12 hours. Initially it will only be licensed for treating adults with CAP or csssi. The studies excluded patient groups that will be seen in clinical practice, such as the immunocompromised or those on ITU. The CAP trials excluded patients with risk factors for MRSA pneumonia due to the comparative arm of ceftriaxone, which does not have activity against MRSA. However this means there is a lack of clinical data for ceftaroline against MRSA pneumonia which may be one of the desired indications in clinical practice. Ceftaroline is likely to be reserved for specialist use, which would be in line with current microbial stewardship for appropriate use of a cephalosporin antibiotic. This document reflects the views of the London New Drugs Group and may not reflect those of the reviewers. Background Ceftaroline fosamil ( ceftaroline ) is a new broadspectrum intravenous antibiotic. 1 Ceftaroline was approved in the EU for the treatment of community acquired pneumonia (CAP) and complicated skin and soft tissue infections (csssi) in adults over 18 years of age in August Community-acquired pneumonia (CAP) occurs in 5-11 per 1000 adults in the UK, resulting in approximately 83,000 hospital admissions each year. 3;4 It is the fifth leading cause of death in the UK, with a mortality rate of 1%, ranging from % for those hospitalised, and 22-54% for those requiring intensive care. 3;4 The main organisms causing CAP include Streptococcus pneumoniae (most commonly in the winter months), Mycoplasma pneumoniae (epidemics spanning 3 winters tend to occur every 4 years in the UK), Haemophilus influenzae, Staphylococcus aureus (more common in winter months), Legionella spp (most common June October, with 46% related to travel abroad) and Chlamydophila pneumoniae (epidemics occur in closed communities). 3 Antibiotic therapy reduces the risk of complications and mortality but a concern is resistance among S. pneumoniae. The British Thoracic Society recommendations for the empirical therapy for CAP are in table 1. 3 There are no rigid recommendations on how long parenteral therapy should be given before switching to oral therapy, but patients should have shown clear evidence of improvement and no fever for 24 hours. A total of 7 days therapy is usually adequate for mild to moderate severity CAP, while high severity CAP should be treated for 7-10 days, or longer depending on the patient s clinical condition. Skin and skin structure (soft tissue) infections range from minor superficial infections to lifethreatening necrotizing infections. 5 There are a number of pathogens associated with skin and soft tissue infections and this varies according to the patients underlying pathology and the nature of the infection. For example, diabetes related skin and soft tissue infections are polymicrobial involving S. aureus, group B streptococci, anaerobes, Gram-negative bacilli. Impetigo,

4 Page 4 Table 1: BTS guidelines for the treatment of community acquired pneumonia 3 Severity (treatment site) Mild (community) Low severity: most patients can be adequately treated with oral therapy (hospital) Moderate severity: most patients can be adequately treated with oral therapy (hospital) High severity: parenteral antibiotics should be used (hospital) 1 st choice, oral Amoxicillin Amoxicillin Amoxicillin plus macrolide * plus levofloxacin if Legionella spp suspected 2 nd choice, oral 1 st choice parenteral 2 nd choice parenteral Doxycycline OR Clarithromycin Doxycycline OR Clarithromycin Doxycycline OR Levofloxacin OR Moxifloxacin Not recommended Amoxicillin or benzyl penicillin OR clarithromycin Amoxicillin or benzyl penicillin plus clarithromycin Broad-spectrum beta lactamase-stable antibiotic (coamoxiclav) plus macrolide (clarithromycin)* Levofloxacin OR Cefuroxime / cefotaxime / ceftriaxone, plus clarithromycin. Cefuroxime / cefotaxime / ceftriaxone, plus clarithromycin* erysipelas or cellulitis (S. aureus, group A strep), necrotizing infections (group A strep, S. aureus, Clostridia), animal and human bites (e.g. S. aureus, Pasteurella multocida), surgical wounds (S. aureus, group A strep ± Enterobacteriaceae) and intravascular catheter-associated infections (S. aureus, coagulase-negative staphylococci). 5;6 Over the past couple of decades more infections have been caused by methicillinresistant Staphylococcus aureus (MRSA). 5 Methicillin resistance has increased from 4% in 1993, peaking at 36-39% between 2001 to 2006, and falling to 19.3% in About 25-30% of the population carry S. aureus on their skin and in their nose, and about 1-3% of the population have MRSA. 7 MRSA are resistant to penicillins, cephalosporins and carbapenem antibiotics. 7 In the UK, intravenous vancomycin is widely used to treat MRSA infections. 8 Ceftaroline Ceftaroline fosamil is a beta-lactam antibiotic with a structure derived from the fourthgeneration cephalosporin cefprozan. 1 Ceftaroline fosamil (prodrug) is converted into the active ceftaroline in plasma by phosphatase enzymes and concentrations of the prodrug are measurable in plasma primarily during intravenous infusion. 9 Ceftaroline binds to penicillin-binding protein (PBP) enzymes on the bacterial cytoplasmic membrane which are essential for cell wall biosynthesis. 10 Beta-lactams inhibit the transpeptidation reaction required for cell wall biosynthesis, leading to cell death, but MRSA evades this because of a modified PBP (known as PBP2a or PBP2), encoded by the meca gene. PBP2a functions as a surrogate transpeptidase enzyme, allowing the bacteria to maintain cell wall biosynthesis at beta-lactam concentrations that would inhibit beta-lactam sensitive PBPs. 10 Ceftaroline has high affinity for PBPs 1, 2 and 3 of methicillin-susceptible S. aureus and exhibits antibacterial activity against MRSA. 10 The bacteria that ceftaroline is active against are listed in table 2. 9 Pharmacokinetic and pharmacodynamics studies predict that a 600mg ceftaroline dose every 12 hours would provide a high enough percentage of time that the drug concentration is above the minimum inhibitory concentration (%T>MIC) for key skin pathogens with a ceftaroline MIC of 2mg/mL. 10

5 Page 5 Table 2: Ceftaroline spectrum of activity 9 Complicated skin and soft tissue infections Gram-positive micro-organisms Staphylococcus aureus (including methicillinresistant strains) Streptococcus pyogenes Streptococcus agalactiae Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus) Streptococcus dysgalactiae Gram-negative micro-organisms Escherichia coli Klebsiella pneumoniae Klebsiella oxytoca Morganella morganii Community-acquired pneumonia No cases of CAP due to MRSA were enrolled into the studies. The available clinical data cannot substantiate efficacy against penicillin non-susceptible strains of S. pneumoniae. Gram-positive micro-organisms Streptococcus pneumoniae Staphylococcus aureus (methicillin-susceptible strains only Gram-negative micro-organisms Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Antibacterial activity against other relevant pathogens. Clinical efficacy has not been established against the following pathogens although in vitro studies suggest that they would be susceptible to ceftaroline in the absence of acquired mechanisms of resistance: Anaerobic micro-organisms Gram-positive micro-organisms: Peptostreptococcus spp. Gram-negative micro-organisms: Fusobacterium spp. In vitro data indicate that the following species are not susceptible to ceftaroline: Chlamydophila spp., Legionella spp., Mycoplasma spp., Proteus spp., Pseudomonas aeruginosa Dosing For the treatment of cssti and CAP, the recommended dose is 600 mg administered every 12 hours by intravenous infusion over 60 minutes in patients aged 18 years or older. The recommended treatment duration for cssti is 5 to 14 days and the recommended duration of treatment for CAP is 5 to 7 days. 9 Dose adjustment is needed in patients with moderate renal impairment (CrCl >30 to 50mL/ min). 9 There are insufficient data to make specific dosage adjustment recommendations for patients with severe renal impairment (CrCl 30mL/min) and end stage renal disease, including patients undergoing haemodialysis. The pharmacokinetics of ceftaroline in patients with hepatic impairment has not been established. 9 As ceftaroline does not appear to undergo significant hepatic metabolism, the systemic clearance of ceftaroline is not expected to be significantly affected by hepatic impairment. Therefore, no dosage adjustment is recommended for patients with hepatic impairment. Ceftaroline should only be used in pregnant women if the benefit outweighs the risk due to the lack of adequate and well-controlled studies in human pregnancy. It is not known if ceftaroline is excreted into human breast milk. 9 Ceftaroline is not licensed for use in children and its safety and efficacy in this age group has not been established. 9 Drug interactions No drug-drug interaction studies have been carried out. 9 There is minimum potential for drug interactions between ceftaroline and CYP450 substrates, inhibitors or inducers or drugs that undergo active renal secretion (renal uptake transporters OCT2, OAT1 and OAT3). Adverse events The most commonly reported adverse events in clinical trials were diarrhoea, nausea and rash and were generally mild to moderate in severity. 9

6 Page 6 Clinical efficacy Four phase 3, randomised, controlled, doubleblind non-inferiority trials have been carried out. FOCUS 1 and 2 evaluated the safety and efficacy of ceftaroline in treating communityacquired pneumonia. 11;12 CANVAS 1 and 2 evaluated the safety and efficacy of ceftaroline in treating MRSA complicated skin and skintissue infections (cssti). 13;14 Integrated analyses of the FOCUS and CANVAS studies have been reported; each pair of studies had identical designs and protocols to allow for pooling of results for a larger database of pathogens and safety information. 15;16 FOCUS 1 and 2 The FOCUS (ceftaroline Community-acquired pneumonia trial vs. ceftriaxone in hospitalised patients) trials were designed to evaluate the safety and efficacy of intravenous (IV) ceftaroline vs. IV ceftriaxone in treating hospitalised adults (but not in ITU), with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV. 16 There were a number of exclusion criteria, including CAP suitable for outpatient treatment with oral therapy, presence of risk factors for MRSA infection, previous therapy with an antibiotic for CAP within 96 hours of randomisation, severe renal impairment (CrCl 30mL/min) or significant hepatic disease such as viral hepatitis or AST/ ALT >10xULN. Patients were stratified by PORT risk class (see Appendix 1) and randomised to treatment with either ceftaroline 600mg IV every 12 hours or ceftriaxone 1g IV every 24 hours, for 5-7 days. A switch to oral therapy or outpatient parenteral therapy was not allowed. Patient enrolled in FOCUS 1 also received 2 doses of oral clarithromycin 500mg as adjunctive therapy to enable enrolment from North America. This was limited to a 24 hour course to minimise potential confounding of study drug treatment effects. [Adjunctive macrolide therapy is recommended by the Infectious Diseases Society of America, but few patients were enrolled from this area, probably reflecting the lack of a full macrolide course. 11 ] Patients with CrCl 31-50mL/min had their ceftaroline dose reduced to 400mg every 12 hours. A total of 610 patients were required in each FOCUS study to achieve >90% power (i.e. there was a 10% likelihood of missing a true difference between the two groups being studied). Noninferiority for each study was concluded if the lower limit of the 95% confidence interval (CI) was -10% (the non-inferiority margin). The patient groups were well balanced at baseline. The majority were white (92%), mean age was 61 years, 62% had PORT III risk class and 80% were enrolled in Europe. A quarter of patients had structural lung disease (COPD, bronchiectasis or interstitial fibrosis). The primary objective was to determine noninferiority in clinical cure rates of ceftaroline vs. ceftriaxone in the clinically evaluable (CE) and modified intention-to-treat efficacy (MITTE) populations at the test-of-cure (TOC) visit. See figures 1 and 2 for definitions and disposition of patients. Secondary objectives included determination of clinical cure in the microbiologically evaluable (ME) and microbiological MITTE (mmitte) populations at TOC, clinical cure at the end-of-therapy (EOT) visit, microbiological outcome at TOC and overall success at TOC. 16 See appendix 2 for definitions. The overall duration of therapy was 6.6±0.9 days (CE) and 6.5±1.1 days (MITTE) [range 5-8 for >95% of patients]. Overall, 88% of the mmitte patients had CAP caused by typical pathogens; the most common of which were S. pneumoniae (41.7%) and S. aureus (16.5%). In the integrated analysis, clinical cure rates were 6.7% and 6.0% higher for ceftaroline than ceftriaxone in the CE and MITTE populations respectively (table 3). Clinical cure rates in the ME and mmitte populations were 85.1% and 83.6% with ceftaroline, vs. 75.5% and 75% with

7 Page 7 Figure 1: Disposition of patients in FOCUS 1 and 2 16 Intention to treat (ITT) All randomised, n=1240 Ceftaroline = 621 (100%), Ceftriaxone = 619 (100%) No drug received Modified Intention to treat (MITT) ITT who received any study drug, n=1228 (99%) Ceftaroline = 614 (98.9%), Ceftriaxone = 614 (99.2%) No baseline typical CAP pathogen. Did not meet minimal CAP criteria. MITT Efficacy (MITTE) mitt with only PORT III and IV, n=1153 (93%) Ceftaroline = 580 (93.4%), Ceftriaxone = 573 (92.6%) Failed evaluability criteria. Did not meet minimal CAP Microbiological MITT Efficacy (mmitte) Only PORT III or IV and 1 bacterial pathogen, n=333 (26.9%) Ceftaroline = 165 (26.6%), Ceftriaxone = 168 (27.1%) Clinically Evaluable (CE) MITTE who met all evaluability criteria, n=908 Ceftaroline = 459 (79.1%), Ceftriaxone = 449 (78.4%) Microbiologically evaluable (ME) 1 baseline pathogen, met all evaluability criteria, n=301 (26.1%) Ceftaroline = 154 (26.6%), Ceftriaxone = 147 (25.7%) Figure 2: Definitions used in FOCUS 1 and 2 16 and CANVAS 1 and 2 15 Clinical cure: FOCUS: All signs and symptoms of pneumonia resolved, or improvement such that no further antibiotics were required. Patient afebrile for 24 consecutive hours with a return of CAP signs and symptoms to baseline levels. CANVAS: all signs and symptoms or baseline infection or improvement such that no further antibiotics were necessary. Microbiological eradication (CANVAS only): absence of baseline pathogen. Relapse: Clinical cure at the TOC visit but return of symptoms requiring addition antimicrobial therapy at last follow-up. Recurrence: Isolation of baseline pathogen at last follow-up. Reinfection: Isolation of new pathogen at last follow-up.

8 Page 8 ceftriaxone, differences of 9.7% and 8.7% respectively. Non-inferiority was achieved for all four evaluated populations in the integrated analysis. In each FOCUS study, ceftaroline achieved non-inferiority to ceftriaxone in the co -primary populations, as well as in the integrated analysis. In FOCUS 1, the difference in the success rates in the CE, the ME and mmitte populations were in statistically significant in favour of ceftaroline (no p values quoted). Clinical cure rates for infections caused by a typical pathogen alone were 84.7% with ceftaroline and 75.8% with ceftriaxone (treatment difference 9.0, 95% CI -0.6 to 18.7). Cure rates were similar in patients who received prior antibiotic therapy (82.2% vs. 81.4%). In treatment-naïve patients, higher cure rates were seen with ceftaroline than with ceftriaxone (85.8% vs. 74.9%, treatment difference 11.2, 95% CI 4.5 to 18). Relapse rates in the CE and MITTE populations at the last follow up were slightly but not significantly higher with ceftaroline than with ceftriaxone but none of the ME or mmitte population had a recurrence or reinfection (see table 3). Clinical cure rates for the most common baseline pathogens in the mmitte and ME population (integrated analysis) are shown in table 4. [See Appendix 2 for individual FOCUS 1 and 2 results] The majority of cure rates were higher with ceftaroline than with ceftriaxone in each FOCUS study, but all were higher with ceftaroline in the integrated analysis. In the microbiologically evaluable population, clinical cure rates for S. pneumoniae, MDRSP and S. aureus were higher with ceftaroline than with ceftriaxone. In summary: Ceftaroline was non-inferior to ceftriaxone in treating CAP, with some differences statistically significant (p values not stated). Cure rates for the most common pathogens isolated at baseline were higher with ceftaroline, but note that some of the pathogens, such as multi-drug resistant S. pneumoniae, occurred in small numbers of patients. The difference in clinical cure rates may be due to differences in the affinities of the Table 3: Results from the integrated FOCUS studies 16 Ceftaroline (n=621) Ceftriaxone (n=619) Difference, %, (95% CI) CE 387/459 (84.3%) 349/449 (77.7%) 6.7 (1.6 to 11.8)* MITTE 479/580 (82.6%) 439/573 (76.6%) 6.0 (1.4 to 10.7)* ME 131/154 (85.1%) 111/147 (75.5%) 9.7 (0.7 to 18.8)* mmitte 138/165 (83.6%) 126/168 (75%) 8.7 (-0.0 to 17.4) Relapse rates at last follow up CE 7/360 (1.9%) 4/321 (1.2%) 0.7 (-1.4 to 2.9) MITTE 8/479 (1.7%) 5/439 (1.1%) 0.5 (-1.2 to 2.3) co-primary endpoints * statistically significant in favour of ceftaroline Modified ITT (mitt) Randomised patients who received any amount of study drug. MITT Efficacy (MITTE) MITT patients with CAP of PORT III or IV (PORT score , see Appendix 1). Modified MITTE (mmitte) MITT patients who met minimum criteria for CAP of PORT III or IV and had 1 bacterial pathogen isolated. Clinically evaluable (CE) MITTE patients who met all evaluability criteria. Microbiologically evaluable (ME) Clinically evaluable patients who had a pathogen isolated at baseline

9 Page 9 Table 4: Clinical cure rates by the most common baseline pathogen at test-of-cure visit: integrated FOCUS studies 16 Microbiological modified intention-to-treat efficacy population (mmitte) Gram positive Ceftaroline Ceftriaxone S. pneumoniae 59/69 (85.5%) 48/70 (68.6%) MDRSP 4/4 (100%) 2/9 (22.2%) S. aureus 18/25 (72%) 18/30 (60%) MRSA* n/a 1/2 (50%) Gram negative H. influenzae 17/20 (85%) 20/24 (83.3%) H. parainfluenzae 16/17 (94.1%) 15/18 (83.3%) K. pneumoniae 14/15 (93.3%) 10/13 (76.9%) E. coli 10/12 (83.3%) 9/13 (69.2%) Microbiologically evaluable population (ME) Gram positive Ceftaroline Ceftriaxone S. pneumoniae 54/63 (85.7%) 41/59 (69.5%) MDRSP 4/4 (100%) 1/4 (25%) S. aureus 18/25 (72%) 15/27 (55.6%) MDRSP: Multidrug resistant S. pneumoniae, strains resistant to 2 antimicrobial classes of drugs, including penicillin, macrolides, tetracyclines, fluoroquinolones, chloramphenicol, co-trimoxazole and cephalosporins. * Patients with confirmed or suspected CAP caused by MRSA were excluded from the study. two cephalosporins in their affinity for S. pneumoniae penicillin-binding proteins (PBPs). Ceftaroline has been shown to have a higher affinity for PBP 2x (primary determinant of beta -lactam resistance in S. pneumoniae), 2a and 2b than ceftriaxone, reflected in a clinical cure rate 17% higher in patients infected with this at baseline and treated with ceftaroline. The clinical cure rates from FOCUS 1 are minimally higher than from FOCUS 2 but this is unlikely to be due to the 1 day of clarithromycin therapy. Patient populations who would be encountered in clinical practice were excluded from this study, such as immunocompromised, prior treatment for CAP within 96 hours, patients on ITU or those at high risk for MRSA pneumonia. CANVAS 1 and 2 The CANVAS (CeftAroliNe Versus vancomycin in Skin and skin-structure infections, csssi) studies compared ceftaroline monotherapy with vancomycin plus aztreonam (V/A) combination therapy for the treatment of adults with csssi severe enough to require 5 days of intravenous antibiotics. 15 At least three clinical signs of infection had to be present and the infection had to either involve deep soft tissue or require significant surgical intervention, or be cellulitis or an abscess of a lower extremity in patients with diabetes mellitus or peripheral vascular disease. Exclusion criteria included pathogens suspected or known to be resistant to vancomycin or aztreonam, prior antibiotic treatment (>24 hours) within 96 hours of randomisation, creatinine clearance 30mL/min, Pseudomonas aeruginosa or anaerobic infections, bites or necrotising fasciitis. Patients were randomised to receive ceftaroline 600mg plus normal saline placebo, or 1g vancomycin plus 1g aztreonam, twice a day for 5-14 days. There was no mention of continuing therapy with oral antibiotics for conditions such as S. aureus bacteraemias. Patients with a creatinine clearance >30 and 50mL/min received ceftaroline 400mg bd. Vancomycin doses were adjusted according to local protocols. Test-of-cure and late follow-up visits occurred 8-

10 Page 10 Figure 3: Disposition of patients in CANVAS 1 and 2 15 Intention to treat (ITT) All randomised, n=1396 Ceftaroline = 701, Vanc/Az = 695 Modified Intention to treat (MITT) ITT who received any study drug, n=1378 (98.7%) Ceftaroline = 693 (98.8%), Vanc/Az = 685 (98.5%) Clinically Evaluable (CE) MITT with clinical response and no confounding factors, n=1202 (86.1%) Ceftaroline = 610 (87%), Vanc/Az = 592 (86.4%) Microbiological MITT (mmitt), n = 1062 (76%) MITT meeting clinical criteria for csssi + 1 bacterial pathogen Ceftaroline = 540 (77%), Vanc/Az = 522 (75.1%) Primary efficacy population Safety population Microbiologically evaluable (ME) CE with 1 baseline pathogen, met all evaluability criteria, n=914 (65.4%) Ceftaroline = 468 (66.8%), Vanc/Az = 446 (64.1%) 15 days and days after the last dose of study drug. Aztreonam (or placebo) could be discontinued if a gram-negative pathogen was neither identified nor suspected. See figures 2 and 3 for definitions and disposition of patients. The primary outcome measure was the perpatient clinical cure rate at the test-of-cure visit in the CE and MITT populations. Secondary endpoints included per-patient microbiological response and per-pathogen clinical and microbiological response at the TOC visit, and relapse and reinfection rates at the last followup visit. A sample size of 690 patients for each study would give 90% power. Non-inferiority was concluded if the lower limit of the 95% CI was above -10% (the non-inferiority margin). The groups were well balanced at baseline, twothirds were male, 74% were white, 17.5% had diabetes mellitus and 13.5% had peripheral vascular disease. Infection areas were, on average, 10 x 15cm in size but ranged from x cm, and the majority were lower limb infections. Infection types occurred in similar numbers of patients, with cellulitis, major abscess and infected wounds accounting for the majority (see Appendix 3). The most common pathogen isolated was S. aureus, with MRSA accounting for 42% of these infections in the ceftaroline group and 36% in the vancomycin group (see Appendix 2). In the integrated analysis in the CE and MITT populations, the efficacy of ceftaroline was similar to that of vancomycin/aztreonam (V/A) (CE: 91.6% vs. 92.7%, and MITT: 85.9% vs. 85.5%). Non-inferiority was shown (lower limit of the 95% CIs were above -10%, the predefined

11 Page 11 requirement) (see table 5). Small, uncomplicated abscess can be treated with incision and drainage alone, with antimicrobial therapy only required for large abscesses surrounded by cellulitis or accompanied by systemic symptoms, such as those present in the CANVAS studies. Significant efficacy was maintained in both groups when abscesses were excluded from the analyses. In the microbiologically evaluable (ME) population, efficacy of the two treatments against gram positive, mixed gram positive and negative and polymicrobial infections were similar. V/A gave significantly higher cure rates against gram negative bacteria, though note that patient numbers were small and the 95% CI was wide. Cure rates were also similar between the Table 5: Clinical cure rates, CANVAS studies: integrated analysis, at the test-of-cure visit 15 Ceftaroline (n=610) Vancomycin / aztreonam (n=592) Difference* (95% CI) Clinically evaluable 559/610 (91.6%) 549/592 (92.7%) -1.1 (-4.2 to 2.0) Clinically evaluable (major abscesses excluded) 91.9% 92.1% Not stated Modified ITT 595/693 (85.9%) 586/685 (85.5%) 0.3 (-3.4 to 4.0) Microbiologically evaluable 434/468 (92.7%) 421/446 (94.4%) -1.7 (-4.9 to 1.6) Gram positive (+ve) 348/371 (93.8%) 330/350 (94.3%) -0.5 (4.1 to 3.1) Gram negative (-ve) 29/34 (85.3%) 24/24 (100%) (-31.6 to -1.2) Mixed gram +ve and -ve 57/63 (90.5%) 67/72 (93.1%) -2.6 (-13.4 to 7.2) Polymicrobial infection 125/136 (91.9%) 134/139 (96.4%) -4.2 (-10.5 to 1.5) Type of infection Underlying comorbidity Cellulitis 213/229 (93%) 222/243 (91.4%) 1.7 (-3.4 to 6.7) Major abscess 184/202 (91.1%) 177/188 (94.1%) -3.0 (-8.5 to 2.3) Infected wound 73/84 (86.9%) 65/73 (89%) -2.2 (-12.8 to 8.7) Infected ulcer 48/53 (90.6%) 47/50 (94%) -3.5 (-15.7 to 8.3) Infected burn 25/25 (100%) 18/18 (100%) 0.0 (-13.6 to 17.9) Infected bite 9/9 (100%) 9/9 (100%) 0.0 Other 4/5 (80%) 9/9 (100%) Diabetes mellitus 96/110 (87.3%) 100/110 (90.9%) -3.5 (-12.2 to 5.0) Peripheral vascular disease 80/90 (88.9%) 75/84 (89.3%) -0.2 (-10.0 to 9.7) Bacteraemia 22/26 (84.6%) 21/21 (100%) (-33.8 to 1.5) S. aureus 16/18 (88.9%) 9/9 (100%) (-33.2 to 5.7) MRSA 6/7 (85.7%) 2/2 (100%) (-53.5 to 58.4) * ceftaroline monotherapy minus vancomycin/aztreonam combination therapy Microbiological MITT (mmitt) Clinically evaluable (CE) Microbiologically evaluable (ME) MITT patients with clinical disease criteria for csssi and 1 bacterial pathogen isolated from blood or csssi. MITT patients who met clinical disease criteria for csssi, received a pre-specified minimum amount of study drug and had outcome information. Clinically evaluable patients who had 1 pathogen isolated at baseline, did not include patients with Pseudomonas aeruginosa or anaerobes.

12 Page 12 Table 6: Clinical cure rates for selected baseline isolates at test-of-cure vist 15 Isolates identified in ME population Ceftaroline Vancomycin / aztreonam Isolates identified in mmitt population Ceftaroline Vancomycin / aztreonam Staphylococcus aureus 352/378 (93.1%) 336/356 (94.4%) 377/425 (88.7%) 356/409 (87%) MRSA (methicillin resistant) 142/152 (93.4%) 115/122 (94.3%) 155/179 (86.6%) 124/151 (82.1%) MSSA (methicillin sensitive) 212/228 (93%) 225/238 (94.5%) 221/245 (90.2%) 233/258 (90.3%) Streptococcus pyogenes 56/56 (100%) 56/58 (96.6%) 56/63 (88.9%) 57/62 (91.9%) Streptococcus agalactiae 21/22 (95.5%) 18/18 (100%) 25/27 (92.6%) 19/21 (90.5%) Enterococcus faecalis 20/25 (80%) 22/24 (91.7%) 20/28 (71.4%) 23/28 (82.1%) Escherichia coli 20/21 (95.2%) 19/21 (90.5%) 21/23 (91.3%) 19/21 (90.5%) Pseudomonas aeruginosa n/a n/a 20/25 (80%) 22/25 (88%) Proteus mirabilis 10/15 (66.7%) 20/21 (95.2%) 11/16 (68.8%) 20/23 (87%) Klebsiella pneumoniae 17/18 (94.4%) 13/14 (92.9%) 17/18 (94.4%) 14/19 (73.7%) two groups with respect to infection types and patient subgroups, with the exception of bacteraemia (bacteria in the blood stream), although patient numbers with this were small. Analysis of clinical response at day 3: A retrospective analysis of the individual and combined CANVAS trials was performed using a clinical response endpoint at day 3 (~48 hours) in a subgroup of patients who met FDA guidance definition of acute bacterial skin and skin structure infections (ABSSSI), previously called uncomplicated and complicated SSSI. 17 Clinical response was defined as cessation of infection spread plus absence of fever (temperature 37.6 C). Non-responders were those who did not meet both criteria or who had incomplete or missing information on day 3. A total of 797 patients (ceftaroline 400, V/A 397) met the FDA criteria for ABSSSI and were included in the exploratory-mitt population. Comorbid conditions included diabetes mellitus in 15.5% and 19.1% of the ceftaroline and V/A groups respectively, and peripheral vascular disease in 9.0% and 9.8% respectively. Staph aureus was the most common pathogen, with MRSA accounting for 42.3% (ceftaroline) and 35.4% (V/A) of isolates. Clinical response at day 3 was 74% (296/400) in the ceftaroline group and 66.2% (263/397) for the V/A group (difference 7.8%, 05% CI 1.3 to 14.0). In the individual trials, treatment differences of 9.4% (95% CI 0.4 to 18.2, CANVAS 1) and 5.9% (95% CI -3.1 to 14.9, CAN- VAS 2), in favour of ceftaroline were observed. Day 3 endpoints can be used in clinical practice; early indication of treatment failure can guide reselection of antimicrobial therapy within 72 hours, avoiding prolonged use of inappropriate antibiotics. In summary: Ceftaroline was shown to be noninferior to vancomycin plus aztreonam for treating csssi infections caused by a range of pathogens, most which were S. aureus. The cure rates were over 93% in the microbiologically evaluable population. This population consisted of patients who who met the clinical disease criteria for csssi, had 1 baseline pathogen isolated, received a prespecified minimum amount of study drug and had an outcome assessed. The ME population was about 2/3 of those randomised. The exclusion of cure rates from patients with major abscess did not affect the results. Microbiological responses to gram

13 Page 13 negative bacteria and for bacteraemia were higher in the vancomycin group than in the ceftaroline group, but both had small number of cases and the observations are of unknown significance. Gram negative pathogens are not common causes of csssis but coverage may be required, especially if treatment is empirical. 14 Clinical response rates at day 3 (analysed retrospectively) were higher with ceftaroline treatment than with vancomycin plus aztreonam. There were a number of study limitations, such as the results do not address all patient types seen in practice. 13;14 There were a small number of non-caucasian patients and those >75 years old, and patients <18 years of age were excluded. Patients who were immunocompromised due to e.g. corticosteroid therapy, HIV, chemotherapy, were not enrolled, nor were those with severe infections such as necrotising fasciitis or myositis. In practice, patients may also receive antibiotics for bacteria outside the spectrum of ceftaroline, such as P. aeruginosa and extended spectrum beta-lactamase (ESBL)-producing gram-negative bacilli. Vancomycin and aztreonam were chosen as the comparator treatment based on the spectrum of activity and global acceptability to regulators and investigators, but may not be the first choice of treatment in clinical practice. 13;14 Limitations to the Day 3 retrospective analysis are that this evaluation was of an endpoint that was not prespecified in the original CANVAS trials, data collection was not optimised for this outcome measure and there was no prespecified hypothesis with corresponding power calculations for this endpoint. Adverse events In the FOCUS and CANVAS studies, the incidences of adverse events were similar between the ceftaroline and comparator treatment groups (see Appendix 4). 15;16 The most common AEs were diarrhoea, headache, nausea, rash and insomnia. drug: 2 in the ceftaroline group (fatigue and sudden death) and 3 in the ceftriaxone group (2 cases of hepatic failure, raised hepatic enzymes). A total of 27 patients died during the study, with two deaths (one in each study group) considered to be related to the study drug. One 73 year old treated with ceftaroline, who had cardiac disease and a history of smoking, and one 60 year old treated with ceftriaxone, with a history of smoking, alcohol abuse and hypertension, who died of multi-organ failure. No differences in the incidences of liver (0.33% vs. 0.81%), renal (0.33% both groups) or haematological (0.33% vs. 0%) events were seen between the ceftaroline and ceftriaxone groups respectively. Serious adverse events occurring in the ceftaroline group were worsening of pneumonia, COPD, pleural effusion, pulmonary embolism, lung abscess, lung neoplasm, malignant, pyothorax, respiratory failure, sudden death, empyema. In the CANVAS studies, 15 the most common reason for discontinuation was possible allergic reaction (ceftaroline 1.9%, vancomycin 2.9%). C. difficile infection occurred in 2 patients treated with ceftaroline and 1 treated with vancomycin / aztreonam. Pruritus was more common in the vancomycin group. Neutropenia, thrombocytopenia and liver failure did not occur during the studies. Three patients treated with ceftaroline died, from respiratory failure, neck cancer and cardiopulmonary insufficiency; none of the deaths was considered to be related to the study drug or the infection. Serious adverse events seen in the ceftaroline group included congestive cardiac failure, cardiomyopathy, stroke, 13 myocardial infarction, multi-organ failure, anaphylactic shock, central line infection, hyperglycaemia, convulsion, acute pre-renal failure, renal failure, acute pulmonary oedema and pulmonary embolism. 14 In the FOCUS studies, 16 5 severe treatmentemergent AEs lead to discontinuation of study

14 Page 14 Health economics / budget impact model The cost of ceftaroline has yet to be confirmed. The budget impact of ceftaroline depends on a number of factors: Proportion of patients admitted with csssi or CAP, and the percentage of these requiring IV antibiotics. Local treatment guidelines for csssi and CAP, which may vary between Trusts. Local price negotiations for antibiotics. Taking these factors into consideration, the use of ceftaroline may be more or less than current practice. Astra Zeneca has a comprehensive budget impact model than can be tailored to individual Trusts patient populations and antibiotic guidelines, for budget holders. Should you require this information please contact Neil Marsh (Medical Science Liaison Executive): neil.marsh@astrazeneca.com Reference List (1) Lim L, Sutton E, Brown J. Ceftaroline: a new broad-spectrum cephalosporin. Am J Health Syst Pharm 2011; 68: (2) AstraZeneca Plc (AZN) granted marketing authorisation in Europe for Zinforo. 28/08/12 ClinicaSpace News (3) British Thoracic Society. BTS Guidelines for the management of community acquired pneumonia in adults: update Thorax 2009; 64(Supplement III):iii1-iii61. (4) Pneumonia. [PatientPlus article, last updated 24/5/10]. (5) Moellering Jr RC. The problem of complicated skin and skin structure infections: the need for new agents. J Antimicrob Chemother 2010; 65(Suppl 4):iv3-iv8. (6) Eron LJ, Lipsky BA, Low DE et al. Manageing skin and soft tissue infections: expert panel recommendations on key decision points. J Antimicrob Chemother 2003; 52(Suppl S1):i3 -i17. (7) Meticillin-resistant Staphylcoccus aureus (MRSA). [PatientPlus article]. (8) Gould FK, Brindle R, Chadwick PR et al. Guidelines (2008) for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the United Kingdom. J Antimicrob Chemother 2009; 63(5): jac.oxfordjournals.org/ content/63/5/849.abstract (9) Summary of Product Characteristics. Zinforo 600mg powder for concentrate for solution for infusion. Date of first authorisation 23 rd August AstraZeneca (10) Biek D, Critchley IA, Riccobene TA et al. Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-grampositive activity. J Antimicrob Chemother 2010; 65(Suppl 4):iv9-iv16. (11) File TM, Low DE, Eckburg PB et al. FOCUS 1: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother 2011; 66(S3):iii19- iii32. (12) Low DE, File TM, Eckburg PB et al. FOCUS 2: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother 2011; 66(S3):iii33- iii44. (13) Corey GR, Wilcox MH, Talbot GH 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

15 Page 15 infections. J Antimicrob Chemother 2010; 65(S4):iv (14) Wilcox MH, Corey GR, Talbot GH 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(S4):iv (15) Corey GR, Wilcox M, Talbot GH et al. Integrated analysis of CANVAS 1 and 2: Phase 3, multicenter, randomized, doubleblind, studies to evaluate the safety and efficacy ceftaroline versus vancomycin plus aztreonam in complicated skin and skinstructure infection. Clin Infect Dis 2010; 51 (6): (16) File TM, Low DE, Eckburg PB et al. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, double-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 (12): EMBASE; *CEFTAROLINE/; 67 results. 2. EMBASE; 1 [Limit to: Human and English Language]; 18 results. 3. MEDLINE; ceftaroline.af; 106 results. 4. MEDLINE; 3 [Limit to: Humans and English Language]; 73 results. 6. MEDLINE; PNEUMONIA/; results. 7. MEDLINE; COMMUNITY-ACQUIRED INFECTIONS/; 8509 results. 8. MEDLINE; 6 AND 7; 1970 results. 10. MEDLINE; *COMMUNITY-ACQUIRED INFECTIONS/ AND *PNEUMONIA/; 851 results. 11. MEDLINE; 10 [Limit to: Publication Year 2010-Current and Humans and English Language]; 87 results. 12. MEDLINE; *SKIN DISEASES, BACTERIAL/; 1811 results. 13. MEDLINE; 12 [Limit to: Humans and (Age Groups All Adult 19 plus years) and English Language]; 781 results. 14. MEDLINE; 13 [Limit to: Publication Year 2008-Current and Humans and (Age Groups All Adult 19 plus years) and English Language and (Age Groups All Adult 19 plus years)]; 204 results. 15. MEDLINE; 14 [Limit to: Review Articles and Publication Year 2008-Current and Humans and (Age Groups All Adult 19 plus years) and English Language and (Age Groups All Adult 19 plus years)]; 18 results. 16. MEDLINE; *SKIN DISEASES, BACTERIAL/dt [Drug Therapy]: 355 results 17 MEDLINE; 16 [Limit to: Publication Year 2006-Current and Humans and English Language]: 128 results (17) Friedland HD, O'Neal T, Biek D et al. CANVAS 1 and 2: Analysis of clinical response at day 3 in two phase 3 trials of ceftaroline fosamil vs. vancomycin plus aztreonam in the treatment of acute bacterial skin and skin structure infections. Antimicrob Agents Chemother 2012; doi /aac aac.asm.org/content/early/2012/02/01/ AAC abstract Produced by the London New Drugs Group. Correspondence to Alexandra Denby, Regional MI Manager, London Medicines Information Centre, Northwick Park Hospital, Watford Road, Harrow, Middlesex. HA1 3UJ. alexandra.denby@nhs.net. This document reflects the views of the LNDG and may not reflect those of the reviewers. The LNDG would like to thank Lisa Boateng, Antimicrobial pharmacist, Royal London Hospital for comments on this review. Astra Zeneca has commented on this review.

16 Page 16 Appendix 1: PSI/PORT Score: Pneumonia Severity Index for Adult CAP If unsure, leave it blank. Age.. years old 1 point per year Female? Yes -10 Nursing home resident? Yes +10 Neoplastic disease history? Yes +30 Liver disease? Yes +20 CHF? Yes +10 Cerebrovascular disease? Yes +10 Renal disease? Yes +10 Altered mental status? Yes +20 Respiratory rate > 29? Yes +20 Systolic blood pressure < 90? Yes +20 Temperature < 35C (95F) or > 39.9C (103.8F)? Yes +15 Pulse > 124? Yes +10 ph < 7.35? Yes +30 BUN > 29? Yes +20 Sodium < 130? Yes +20 Glucose > 249 (US) or > 13.8 (SI)? Yes +10 Hematocrit < 30%? Yes +10 Partial pressure of Oxygen < 60? Yes +10 Pleural effusion on x-ray? Yes +10 Score points 50 = Risk Class I 52 = Risk Class II 71 = Risk Class III 91 = Risk Class IV % mortality. Outpatient treatment reasonable, barring other factors affecting care % mortality. Outpatient treatment reasonable, barring other factors affecting care % mortality. Outpatient or inpatient treatment, depending on clinical judgment. >2.8% mortality. Hospitalisation recommended based on risk. From:

17 Page 17 Appendix 2: Results from the FOCUS studies 16 Study Treatment CE MITTE ME mmitte FOCUS 1 FOCUS 2 Integrated analysis Relapse rates at last follow up Ceftaroline (n=304) 194/224 (86.6%) 244/291 (83.8%) 62/69 (89.9%) 66/75 (88%) Ceftriaxone (n=309) 183/234 (78.2%) 233/300 (77.7%) 54/71 (76.1%) 60/80 (75%) Difference, %, (95% CI) 8.4 (1.4 to 15.4)* 6.2 (-0.2 to 12.6) 13.8 (1.3 to 26.4)* 13.0 (0.7 to 25.2)* Ceftaroline (n=317) 193/235 (82.1%) 235/289 (81.3%) 69/85 (81.2%) 72/90 (80%) Ceftriaxone (n=310) 166/215 (77.2%) 206/273 (75.5%) 57/76 (75%) 66/88 (75%) Difference, %, (95% CI) 4.9 (-2.5 to 12.5) 5.9 (-1.0 to 12.7) 6.2 (-6.7 to 19.2) 5.0 (-7.4 to 17.4) Ceftaroline (n=621) 387/459 (84.3%) 479/580 (82.6%) 131/154 (85.1%) 138/165 (83.6%) Ceftriaxone (n=619) 349/449 (77.7%) 439/573 (76.6%) 111/147 (75.5%) 126/168 (75%) Difference, %, (95% CI) 6.7 (1.6 to 11.8)* 6.0 (1.4 to 10.7)* 9.7 (0.7 to 18.8)* 8.7 (-0.0 to 17.4) Ceftaroline 7/360 (1.9%) 8/479 (1.7%) 0 0 Ceftriaxone 4/321 (1.2%) 5/439 (1.1%) 0 0 Difference, %, (95% CI) 0.7 (-1.4 to 2.9) 0.5 (-1.2 to 2.3) - - co-primary endpoints * statistically significant in favour of ceftaroline Modified ITT (mitt) Randomised patients who received any amount of study drug. MITT Efficacy (MITTE) MITT patients with CAP of PORT III or IV (PORT score , see Appendix 1). Modified MITTE (mmitte) MITT patients who met minimum criteria for CAP of PORT III or IV and had 1 bacterial pathogen isolated. Clinically evaluable (CE) MITTE patients who met all evaluability or minimum CAP criteria. Microbiologically evaluable (ME) Clinically evaluable patients who had a pathogen isolated at baseline Clinical cure rates by the most common baseline pathogen at test-of-cure visit 16 Microbiological modified intention-to-treat efficacy population (mmitte) Focus 1 Focus 2 Integrated FOCUS Ceftaroline Ceftriaxone Ceftaroline Ceftriaxone Ceftaroline Ceftriaxone Gram positive S. pneumoniae 24/27 (88.9%) 20/30 (66.7%) (83.3%) 28/40 (70%) 59/69 (85.5%) 48/70 (68.6%) MDRSP 2/2 (100%) 0/1 (0%) 2/2 (100%) 2/8 (56.3%) 4/4 (100%) 2/9 (22.2%) S. aureus 8/10 (80%) 9/14 (64.3%) 10/15 (66.7%) 9/16 (56.3%) 18/25 (72%) 18/30 (60%) MRSA* n/a 0/1 (0%) n/a 1/1 (100%) n/a 1/2 (50%) Gram negative H. influenzae 4/5 (80%) 7/10 (70%) 13/15 (86.7%) 13/14 (92.9%) 17/20 (85%) 20/24 (83.3%) H.parainfluenzae 7/8 (87.5%) 9/10 (90%) 9/9 (100%) 6/8 (75%) 16/17 (94.1%) 15/18 (83.3%) K. pneumoniae 7/8 (87.5%) 3/5 (60%) 7/7 (100%) 7/8 (87.5%) 14/15 (93.3%) 10/13 (76.9%) E. coli 8/8 (100%) 5/7 (71.4%) 2/4 (50%) 4/6 (66.7%) 10/12 (83.3%) 9/13 (69.2%) Microbiologically evaluable population (ME) Integrated FOCUS Gram positive Ceftaroline Ceftriaxone S. pneumoniae 54/63 (85.7%) 41/59 (69.5%) MDRSP 4/4 (100%) 1/4 (25%) S. aureus 18/25 (72%) 15/27 (55.6%) MDRSP: Multidrug resistant S. pneumoniae, strains resistant to 2 antimicrobial classes of drugs, including penicillin, macrolides, tetracyclines, fluoroquinolones, chloramphenicol, co-trimoxazole and cephalosporins. * Patients with confirmed or suspected CAP caused by MRSA were excluded from the study.