A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment.

BACKGROUND: ADS-5102, a delayed-release, extended-release (DR/ER) amantadine, improved walking speed in MS in a Phase 2 trial. OBJECTIVE: The aim of this study was to present primary results of a Phase 3, double-blind, ADS-5102 trial (INROADS) for walking speed. METHODS: Adult participants with MS and walking impairment, not currently using amantadine or dalfampridine, underwent 4-week placebo run-in before randomization 1:1:1 to placebo, 137 or 274 mg/day ADS-5102 for 12 weeks. Primary outcome was the proportion of responders (20% increase in Timed 25-Foot Walk (T25FW) speed) for 274 mg ADS-5102 versus placebo at end of double-blind (Study Week 16). Additional measures included Timed Up and Go (TUG), 2-Minute Walk Test (2MWT), and 12-item Multiple Sclerosis Walking Scale (MSWS-12). RESULTS: In total, 558 participants were randomized and received double-blind treatment. Significantly more participants responded with 274 mg ADS-5102 (21.1%) versus placebo (11.3%). Mean T25FW speed also significantly improved (0.19 ft/s) versus placebo (0.07 ft/s). Other measures were not significant using prespecified hierarchical testing procedure. Adverse events led to discontinuation for 3.8% (placebo), 6.4% (137 mg ADS-5102), and 20.5% (274 mg ADS-5102). CONCLUSION: INROADS met its primary endpoint, showing a significantly greater proportion of participants with meaningful improvement in walking speed for 274 mg ADS-5102 versus placebo. Numeric dose response was seen for some secondary efficacy outcomes and adverse events.

Safety and efficacy of ADS-5102 (amantadine) extended release capsules to improve walking in multiple sclerosis: A randomized, placebo-controlled, phase 2 trial.

BACKGROUND: Walking impairment causes disability and reduced quality of life in patients with multiple sclerosis (MS). OBJECTIVE: Characterize the safety and efficacy of ADS-5102 (amantadine) extended release capsules, 274 mg administered once daily at bedtime in patients with MS with walking impairment. METHODS: This randomized, double-blind, placebo-controlled, 4-week study was conducted at 14 trial sites in the United States. Study objectives included safety and tolerability of ADS-5102, and efficacy assessments (Timed 25-Foot Walk (T25FW), Timed Up and Go (TUG), 2-Minute Walk Test, and Multiple Sclerosis Walking Scale-12). Fatigue, depression, and cognition also were assessed. RESULTS: A total of 60 patients were randomized (30 to ADS-5102 and 30 to placebo); 59 of whom were treated. The most frequent adverse events (AEs) were dry mouth, constipation, and insomnia. Five ADS-5102 patients and no placebo patients discontinued treatment due to AEs. One patient in the ADS-5102 group experienced a serious AE-suspected serotonin syndrome. A 16.6% placebo-adjusted improvement was seen in the T25FW test ( p < 0.05). A 10% placebo-adjusted improvement in TUG was also observed. No changes in fatigue, depression, or cognition were observed. CONCLUSION: ADS-5102 was generally well tolerated. These data demonstrate an effect of ADS-5102 on walking speed. Further studies are warranted to confirm these observations.

Patient-Reported Outcome Assessments as Endpoints in Studies in Infectious Diseases.

The goal of administering medical interventions is to help patients live longer or live better. In keeping with this goal, there has been increasing interest in taking the "voice" of the patient into account during the development process, specifically in the evaluation of treatment benefits of medical interventions, and use of patient-centered outcome data to justify reimbursement. Patient-reported outcomes (PROs) are outcome assessments (OAs) used to define endpoints that can provide direct evidence of treatment benefit on how patients feel or function. When PROs are appropriately developed, they can increase the efficiency and clinical relevance of clinical trials. Several PROs have been developed for OA in specific infectious diseases indications, and more are under development. PROs also hold promise for use in evaluating adherence, adverse effects, satisfaction with care, and routine clinical practice.

Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program.

BACKGROUND: When combined with ceftazidime, the novel non-ß-lactam ß-lactamase inhibitor avibactam provides a carbapenem alternative against multidrug-resistant infections. Efficacy and safety of ceftazidime-avibactam plus metronidazole were compared with meropenem in 1066 men and women with complicated intra-abdominal infections from 2 identical, randomized, double-blind phase 3 studies (NCT01499290 and NCT01500239). METHODS: The primary end point was clinical cure at test-of-cure visit 28-35 days after randomization, assessed by noninferiority of ceftazidime-avibactam plus metronidazole to meropenem in the microbiologically modified intention-to-treat (mMITT) population (in accordance with US Food and Drug Administration guidance), and the modified intention-to-treat and clinically evaluable populations (European Medicines Agency guidance). Noninferiority was considered met if the lower limit of the 95% confidence interval for between-group difference was greater than the prespecified noninferiority margin of -12.5%. RESULTS: Ceftazidime-avibactam plus metronidazole was noninferior to meropenem across all primary analysis populations. Clinical cure rates with ceftazidime-avibactam plus metronidazole and meropenem, respectively, were as follows: mMITT population, 81.6% and 85.1% (between-group difference, -3.5%; 95% confidence interval -8.64 to 1.58); modified intention-to-treat, 82.5% and 84.9% (-2.4%; -6.90 to 2.10); and clinically evaluable, 91.7% and 92.5% (-0.8%; -4.61 to 2.89). The clinical cure rate with ceftazidime-avibactam plus metronidazole for ceftazidime-resistant infections was comparable to that with meropenem (mMITT population, 83.0% and 85.9%, respectively) and similar to the regimen's own efficacy against ceftazidime-susceptible infections (82.0%). Adverse events were similar between groups. CONCLUSIONS: Ceftazidime-avibactam plus metronidazole was noninferior to meropenem in the treatment of complicated intra-abdominal infections. Efficacy was similar against infections caused by ceftazidime-susceptible and ceftazidime-resistant pathogens. The safety profile of ceftazidime-avibactam plus metronidazole was consistent with that previously observed with ceftazidime alone. CLINICAL TRIALS REGISTRATION: NCT01499290 and NCT01500239.

Ceftaroline fosamil versus ceftriaxone for the treatment of community-acquired pneumonia: individual patient data meta-analysis of randomized controlled trials.

BACKGROUND: We conducted a meta-analysis of clinical trials of adults hospitalized with pneumonia outcomes research team (PORT) risk class 3-4 community-acquired pneumonia (CAP) receiving ceftaroline fosamil versus ceftriaxone. METHODS: Three Phase III trials (clinicaltrials.gov registration numbers NCT00621504, NCT00509106 and NCT01371838) including 1916 hospitalized patients with CAP randomized 1:1 to empirical ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (1-2 g every 24 h) for 5-7 days were included in the meta-analysis. Primary outcome was clinical response at the test-of-cure visit (8-15 days after end of treatment) in the PORT risk class 3-4 modified ITT (MITT) and clinically evaluable (CE) populations. Data were tested for heterogeneity (χ(2) test) and, if not significant, results were pooled and OR and 95% CI constructed. A logistic regression analysis assessed factors impacting cure rate and treatment interactions. RESULTS: Clinical cure rates in each trial consistently favoured ceftaroline fosamil versus ceftriaxone, with no evidence of heterogeneity. In the meta-analysis, ceftaroline fosamil was superior to ceftriaxone in the MITT (OR: 1.66; 95% CI 1.34, 2.06; P < 0.001) and CE (OR: 1.65; 95% CI 1.26, 2.16; P < 0.001) populations. Results were consistent across various patient- and disease-related factors including patients' age and PORT score. Prior antimicrobial use within 96 h of starting study treatment was associated with diminished differences in cure rates between treatments. CONCLUSIONS: Ceftaroline fosamil was superior to ceftriaxone for empirical treatment of adults hospitalized with CAP. Receipt of prior antimicrobial therapy appeared to diminish the observed treatment effect.

Evaluation of the effect of a supratherapeutic dose of intravenous ceftaroline fosamil on the corrected QT interval.

A randomized, double-blind, placebo-controlled, 3-period crossover study was conducted in 54 healthy adults to assess the effect of ceftaroline fosamil on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using an individual correction formula (QTcIb), was determined predose and at 1, 1.25, 1.5, 2, 4, 8, 12, and 24.5 h after intravenous dosing with a supratherapeutic dose (1,500 mg) of ceftaroline fosamil, 400 mg moxifloxacin (positive control), and placebo. The pharmacokinetic profile of ceftaroline was also evaluated. At each time point following ceftaroline fosamil administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from predose baseline in QTcIb (ΔΔQTcIb) was below 10 ms (maximum, 3.4 ms at 1.5 h after dosing), indicating an absence of clinically meaningful QTc increase. The lower limit of the 90% CI of ΔΔQTcIb for moxifloxacin versus placebo was greater than 5 ms at 5 time points (maximum, 12.8 ms at 1 h after dosing), demonstrating assay sensitivity. There was no apparent correlation between ceftaroline plasma concentrations and ΔΔQTcIb. The supratherapeutic dose of ceftaroline fosamil (1,500 mg) resulted in substantially greater systemic exposure to ceftaroline than previously observed with standard therapeutic doses. Ceftaroline fosamil was well tolerated after a single 1,500-mg intravenous dose, and no clinically meaningful abnormalities in laboratory values or vital signs were observed.

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.

Clinically important change on the Unified Dyskinesia Rating Scale among patients with Parkinson's disease experiencing dyskinesia.

Background: The Unified Dyskinesia Rating Scale (UDysRS) evaluates dyskinesia in patients with Parkinson's disease (PD). A minimal clinically important change (MCIC)-the smallest change in a treatment outcome that a patient considers important-remains undefined for the UDysRS. Objective: To utilize pivotal amantadine delayed-release/extended-release (DR/ER) trial data to derive MCICs for the UDysRS total score in patients with PD experiencing dyskinesia. Methods: Pivotal trials included PD patients with ≥1 h daily ON time with troublesome dyskinesia and baseline scores ≥2 on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part IV, item 4.2. Patients randomized to amantadine DR/ER or placebo completed two consecutive 24-h diaries before each clinic visit and were evaluated during ON time with dyskinesia using the UDysRS, MDS-UPDRS, and Clinician Global Impression of Change (CGI-C). The UDysRS changes from baseline to week 12 were anchored to corresponding changes in MDS-UPDRS item 4.2 scores. A minimal clinically important improvement in the CGI-C and diary-reported ON time with troublesome dyskinesia (≥0.5 h) were supportive anchors. Receiver operating characteristic curves determined the UDysRS change values optimizing sensitivity and specificity to at least minimal improvement on each anchor. Results: The analyses included 196 patients. Week 12 UDysRS total score reduction of ≥8 points corresponded to at least minimal MDS-UPDRS item 4.2 improvement. UDysRS reduction of ≥9 points corresponded to decreased ON time with troublesome dyskinesia of ≥0.5 h per patient diaries, and UDysRS reduction of ≥10 points corresponded to at least minimal improvement on the CGI-C. Conclusion: Anchored to the MDS-UPDRS Part IV, item 4.2, an 8-point reduction in the UDysRS total score can be considered an MCIC for PD patients with dyskinesia.

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.

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.

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.

BACKGROUND: Ceftaroline, the active form of ceftaroline fosamil, is a broad-spectrum cephalosporin with bactericidal activity against pathogens causing community-acquired pneumonia (CAP), including Streptococcus pneumoniae. Ceftaroline was evaluated for the treatment of CAP in 2 randomized, double-blind, multicenter trials: Ceftaroline Community Acquired Pneumonia Trial versus Ceftriaxone in Hospitalized Patients (FOCUS) 1 and FOCUS 2. METHODS: Patients hospitalized (but not admitted to an intensive care unit) with Pneumonia Outcomes Research Team risk class III or IV CAP requiring intravenous therapy were randomized to ceftaroline 600 mg every 12 h or ceftriaxone 1 g every 24 h for 5-7 days. Patients in FOCUS 1 received 2 doses of oral clarithromycin 500 mg every 12 h on day 1. RESULTS: In the individual trials, clinical cure rates in the clinically evaluable (CE) population for ceftaroline versus ceftriaxone were as follows: FOCUS 1, 86.6% vs 78.2% (difference, 8.4%; 95% confidence interval [CI], 1.4%-15.4%); FOCUS 2, 82.1% vs 77.2% (difference, 4.9%; 95% CI, -2.5% to 12.5%). In the integrated analysis, 614 patients received ceftaroline and 614 received ceftriaxone. Of the CE patients treated with ceftaroline, 84.3% achieved clinical cure, compared with 77.7% of ceftriaxone-treated patients (difference, 6.7%; 95% CI, 1.6%-11.8%). Clinical cure rates in the modified intent-to-treat efficacy population were 82.6% versus 76.6% for ceftaroline and ceftriaxone (difference, 6.0%; 95% CI, 1.4%-10.7%). Ceftaroline and ceftriaxone were well tolerated; rates of adverse events, serious adverse events, deaths, and premature discontinuations caused by an adverse event were similar in both treatment arms. CONCLUSIONS: Ceftaroline was noninferior to ceftriaxone in the individual trials. In this integrated analysis, clinical cure rates for the ceftaroline group were numerically higher than those for the ceftriaxone group. Ceftaroline was well tolerated, with a safety profile similar to that of ceftriaxone.

Macrolide therapy for community-acquired pneumonia due to atypical pathogens: outcome assessment at an early time point.

BACKGROUND: Therapy directed against atypical pathogens in patients with community-acquired pneumonia (CAP) is often recommended. This post-hoc analysis evaluated the effect of addition of a macrolide to ceftaroline fosamil or ceftriaxone treatment in atypical CAP. METHODS: Two phase 3, double-blind, comparative safety and efficacy studies of ceftaroline fosamil vs. ceftriaxone, FOCUS 1 and FOCUS 2, enrolled adults with CAP. Only FOCUS 1 included 24-h adjunctive clarithromycin therapy for all patients on day 1. Day 4 and test-of-cure (TOC) outcomes were compared for adjunctive vs. no adjunctive therapy. RESULTS: Of 1240 enrolled patients, 130 patients with CAP due to atypical pathogens alone were included (FOCUS 1, n = 64; FOCUS 2, n = 66). Among patients infected with Mycoplasma pneumoniae and/or Chlamydophila pneumoniae alone, a higher clinical response rate was observed with clarithromycin plus ceftaroline fosamil or ceftriaxone compared with treatment without additional clarithromycin at day 4 [38/49 (77.6%; FOCUS 1) vs. 24/43 (55.8%; FOCUS 2)], but not at the TOC assessment [42/49 (85.7%; FOCUS 1) vs. 41/43 (95.3%; FOCUS 2)]. In patients infected with Legionella pneumophila alone, a higher clinical response rate with adjunctive clarithromycin therapy was observed at the TOC assessment alone [12/12 (100%; FOCUS 1) vs. 14/19 (73.7%; FOCUS 2)]. The unadjusted odds ratio of a favourable clinical response at day 4 with adjunctive clarithromycin vs. no adjunctive clarithromycin was 2.4 (95% confidence interval 1.1-5.1; P = 0.0299) for all pathogens combined. CONCLUSIONS: These results suggest that empirical antibiotic therapy against atypical pathogens may improve early clinical response rate. This hypothesis is best evaluated in a prospective trial.

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.

Assessment of ceftaroline fosamil in the treatment of community-acquired bacterial pneumonia due to Streptococcus pneumoniae: insights from two randomized trials.

Ceftaroline fosamil resulted in higher cure rates than ceftriaxone in patients with community-acquired bacterial pneumonia in 2 randomized trials (FOCUS 1 and FOCUS 2). The present analysis examines the subgroup of patients with Streptococcus pneumoniae infection to determine whether the apparent difference in cure rates persists after adjusting for potential covariates. We retrospectively pooled subjects with S. pneumoniae isolated at baseline in the original studies and employed logistic regression to evaluate the independent relationship between clinical cure and treatment with ceftaroline. Covariates evaluated included demographics, severity of illness, bacteremia, and pathogen characteristics. The final cohort included 139 subjects (69 ceftaroline, 70 ceftriaxone). Unadjusted cure rates were 85.5% and 68.6% (P = 0.009) in the ceftaroline and ceftriaxone groups, respectively. After logistic regression, ceftaroline remained associated with higher cure rates. Our findings indicate that ceftaroline may result in improved outcomes of S. pneumoniae pneumonia. Formal clinical trials are warranted to confirm this hypothesis.

Panton-Valentine leukocidin is not the primary determinant of outcome for Staphylococcus aureus skin infections: evaluation from the CANVAS studies.

The impact of Panton-Valentine leukocidin (PVL) on the severity of complicated skin and skin structure infections (cSSSI) caused by Staphylococcus aureus is controversial. We evaluated potential associations between clinical outcome and PVL presence in both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) isolates from patients enrolled in two large, multinational phase three clinical trials assessing ceftaroline fosamil for the treatment of cSSSI (the CANVAS 1 and 2 programs). Isolates from all microbiologically evaluable patients with monomicrobial MRSA or MSSA infections (n = 473) were genotyped by PCR for pvl and underwent pulsed-field gel electrophoresis (PFGE). Genes encoding pvl were present in 266/473 (56.2%) isolates. Infections caused by pvl-positive S. aureus were associated with younger patient age, North American acquisition, and presence of major abscesses (P<0.001 for each). Cure rates of patients infected with pvl-positive and pvl-negative S. aureus were similar overall (93.6% versus 92.8%; P = 0.72), and within MRSA-infected (94.5% vs. 93.1%; P = 0.67) and MSSA-infected patients (92.2% vs. 92.7%; P = 1.00). This finding persisted after adjustment for multiple patient characteristics. Outcomes were also similar when USA300 PVL+ and non-USA300 PVL+ infections were compared. The results of this contemporary, international study suggest that pvl presence was not the primary determinant of outcome in patients with cSSSI due to either MRSA or MSSA.