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

Corey, G. Ralph; Wilcox, Mark H.; Talbot, George H.; Thye, Dirk; Friedland, David; Baculik, Tanya; Mehra, Purvi; Alpert, Marc; Baird, Ian M.; Klein, Stanley R.; Litow, J.; Marsh, Peter; Penn, R.; Augustinsk, J.; Young, David M.; Bunce, C.; Green, D.; Eyzaguirre, R.; Ambasch, Germán; Curcio, Daniel; Lopardo, Gustavo; Minguez, Angel Ramon; Oliva, María Eugenia; Teglia, Osvaldo; Campos, M.; Gaete, P.; Acuna, G.; Jansen, Lisa; Jauregui, A.; Pérez, Cristian; Seas, Carlos; Gutierrez, Johnny; Mayorga, M.; Bubnova, N. A.; Goryunov, S. V.; Krylov, K. M.; Macheret, E. A.; Novozhilov, A. A.; Жидков, К. П.; Kozlov, Roman; Florescu, Ioan Petre; Orăsan, Remus Ioan; Trifu, V.; Ockenfels, H.-M.; Hermes, B.; Brockmeyer, N.; Dippel, E.; Kujath, P.; Kowalzick, L.; Ulrich, J.; Krasnodebski, I.; Jaworski, R.; Zaniewski, M.; Wallner, G.; Kapinska-Mrowiecka, M.; Dziki, A.; Motyka, M.; Borschivsky, V. M.; Gerych, Igor; Lukashov, S. M.; Pyptyuk, O. V.

doi:10.1093/jac/dkq254

Cited by 139 publications

(203 citation statements)

References 20 publications

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“…Vancomycin should also be considered equally effective for the treatment of patients with gram-positive SSTIs; linezolid can be considered an exception, but physicians should be aware that data Talbot et al, 41 2007 Corey et al, 39 2010 Wilcox et al, 40 2007 Wilcox et al, 25 2009 Wunderink et al, 26 2008 Jaksic et al, 32 2006 Kohno et al, 30 2007 Itani et al, 29 2010 Table 31 2007 Kaplan et al, 35 2003 Weigelt et al, 34 2005 Wunderink et al, 36 2003 Rubinstein et al, 38 2001 Stevens et al, 37 Overall, comparators were associated with higher treatment success in the analyses of patients with S aureus and MRSA infections. Again, only linezolid was more effective than vancomycin for S aureus infections; we also noticed a trend toward higher effectiveness of telavancin (Pϭ.09).…”

Section: Discussionmentioning

confidence: 99%

“…a These numbers correspond to 2 different randomized controlled trials that were published as one in Clinical Infectious Diseases. 50 45 2005 Corey et al, 39 2010 D'Antonio et al, 55 2004 Florescu et al, 44 2008 Gilbert et al, 72 1991 Jaksic et al, 32 2006 Kureishi et al, 69 1991 Lin et al, 27 2008 Noel et al, 43 2008 Noel et al, 42 2008 Rolston et al, 66 1994 Rolston et al, 58 1999 Rubinstein et al, 38 2001 Rubinstein et al, 50 2011 (0015) …”

Section: Discussionmentioning

confidence: 99%

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Meta-analysis of Randomized Controlled Trials of Vancomycin for the Treatment of Patients With Gram-Positive Infections: Focus on the Study Design

Vardakas

Mavros

Roussos

et al. 2012

Mayo Clinic Proceedings

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Objective: To study the effectiveness and safety of vancomycin compared with that of other antibiotics for the treatment of gram-positive infections. Methods: Major electronic databases were searched. Data from published randomized controlled trials (January 1, 1950, to September 15, 2011 were pooled using a meta-analytic method. Results: Fifty-three trials comparing vancomycin with linezolid, daptomycin, quinupristin-dalfopristin, tigecycline, ceftaroline, ceftobiprole, telavancin, teicoplanin, iclaprim, and dalbavancin were included in the meta-analysis. Individual antibiotics were as effective as vancomycin, except for linezolid, which was more effective than vancomycin for the treatment of skin and soft tissue infections (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.07-2.43). Comparators were as effective as vancomycin in the intent-to-treat population (OR, 1.08; 95% CI, 0.98-1.18) but were more effective in the clinically evaluable population (OR, 1.14; 95% CI, 1.02-1.27) when all infections were pooled. When available data from all trials were pooled, no differences were noted when patients with febrile neutropenia (OR, 1.07; 95% CI, 0.82-1.39), pneumonia (OR, 1.10; 95% CI, 0.87-1.37), bacteremia (OR, 1.05; 95% CI, 0.76-1.45), and skin and soft tissue infections (OR, 1.11; 95% CI, 0.89-1.39) were studied. Comparators were more effective in open-label (OR, 1.28; 95% CI, 1.08-1.50) but not in double-blind trials (OR, 1.04; 95% CI, 0.90-1.20). Total adverse events attributed to studied antibiotics (OR, 1.07; 95% CI, 0.90-1.28) and patients withdrawn from trials (OR, 0.86; 95% CI, 0.68-1.09) were similar in the compared groups. Mortality was not different between vancomycin and comparator antibiotics when all trials were included in the analysis (OR, 1.09; 95% CI, 0.96-1.23). Comparators were associated with higher mortality in open-label (OR, 1.27; 95% CI, 1.05-1.54) but not double-blind trials (OR, 0.96; 95% CI, 0.80-1.14). Conclusion: On the basis mainly of data from open-label trials, vancomycin is a treatment choice that is as effective as other available antibiotics for patients with gram-positive infections. Study design seems to make a major contribution to the outcome.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Meta-analysis of Randomized Controlled Trials of Vancomycin for the Treatment of Patients With Gram-Positive Infections: Focus on the Study Design

Vardakas

Mavros

Roussos

et al. 2012

Mayo Clinic Proceedings

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“…Ceftaroline has also performed well against Gram-positive and Gram-negative pathogens in multiple clinical studies (9)(10)(11)(12). For the treatment of CABP, including infections with multidrug-resistant S. pneumoniae, pooled success frequency was 84.3% (11,12).…”

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confidence: 99%

Large Retrospective Evaluation of the Effectiveness and Safety of Ceftaroline Fosamil Therapy

Casapao

Davis

Barr

et al. 2014

Antimicrob Agents Chemother

103

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Ceftaroline has been approved for acute bacterial skin infections and community-acquired bacterial pneumonia. Limited clinical experience exists for use outside these indications. The objective of this study was to describe the outcomes of patients treated with ceftaroline for various infections. Retrospective analyses of patients receiving ceftaroline >72 h from 2011 to 2013 were included. Clinical and microbiological outcomes were analyzed. Clinical success was defined as resolution of all signs and symptoms of infection with no further need for escalation while on ceftaroline treatment during hospitalization. A total of 527 patients received ceftaroline, and 67% were treated for off-label indications. Twenty-eight percent (148/527) of patients had bacteremia. Most patients (80%) were initiated on ceftaroline after receipt of another antimicrobial, with 48% citing disease progression as a reason for switching. The median duration of ceftaroline treatment was 6 days, with an interquartile range of 4 to 9 days. A total of 327 (62%) patients were culture positive, and the most prevalent pathogen was Staphylococcus aureus, with a frequency of 83% (271/327). Of these patients, 88.9% (241/271) were infected with methicillin-resistant S. aureus (MRSA). Clinically, 88% (426/484) achieved clinical success and hospital mortality was seen in 8% (40/527). While on ceftaroline, adverse events were experienced in 8% (41/527) of the patients and 9% (28/307) were readmitted within 30 days after discharge for the same infection. Patients treated with ceftaroline for both FDA-approved and off-label infections had favorable outcomes. Further research is necessary to further describe the role of ceftaroline in a variety of infections and its impact on patient outcomes.

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“…Such data are in reasonable agreement with the proposed fT MIC target of Ն25 to 30% based on our data. Ceftaroline fosamil has been shown to be noninferior to vancomycin plus aztreonam in two phase III randomized, double-blind studies (NCT00424190 and NCT00423657) in patients with complicated skin and skin structure infections (21,22). The MIC 90 s for ceftaroline in these studies were 1 g/ml and 0.5 g/ml (for all strains with MICs of Յ0.5 g/ml), respectively; hence, as yet, strains with MICs of 2 g/ml are rare in clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of Ceftaroline against Staphylococcus aureus Studied in an In Vitro Pharmacokinetic Model of Infection

MacGowan

Noel

Tomaselli

et al. 2013

Antimicrob Agents Chemother

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An in vitro single-compartment dilutional pharmacokinetic model was used to study the pharmacodynamics of ceftaroline against Staphylococcus aureus (both methicillin-susceptible S. aureus [MSSA] and methicillin-resistant S. aureus [MRSA]). Mean serum free concentrations of ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) dosed in humans at 600 mg every 12 h (q12h) were simulated, and activities against 12 S. aureus strains (3 MSSA strains and 9 MRSA strains, 3 of which had a vancomycin-intermediate phenotype) were determined. Ceftaroline produced 2.5-to 4.0-log 10 -unit reductions in viable counts by 24 h with all strains and a 0.5-to 4.0-log-unit drop in counts at 96 h. The antibacterial effect could not be related to the strain MIC across the ceftaroline MIC range from 0.12 to 2.0 g/ml. In dose-ranging studies, the cumulative percentage of a 24-h period that the free drug concentration exceeded the MIC under steady-state pharmacokinetic conditions (fT MIC ) of 24.5% ؎ 8.9% was associated with a 24-h bacteriostatic effect, one of 27.8% ؎ 9.5% was associated with a ؊1-log-unit drop, and one of 32.1% ؎ 8.1% was associated with a ؊2-log-unit drop. The MSSA and MRSA strains had similar fT MIC values. fT MIC values increased with increasing duration of exposure up to 96 h. Changes in ceftaroline population analysis profiles were related to fT MIC . fT MIC s of <50% were associated with growth on 4؋ MIC recovery plates at 96 h of drug exposure. These data support the use of ceftaroline fosamil at doses of 600 mg q12h to treat S. aureus strains with MICs of <2 g/ml. An fT MIC of 25 to 30% would make a suitable pharmacodynamic index target, but fT MIC values of >50% are needed to suppress the emergence of resistance and require clinical evaluation. C eftaroline fosamil (CPT) has been approved by the U.S. FDA for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia: market authorization in the European Union (EU) for complicated skin and soft tissue infections and community-acquired pneumonia is pending.Ceftaroline fosamil (previously PP1-0903, T-91825, and TAK-599) is the prodrug of ceftaroline and is the first ␤-lactam with activity against methicillin-resistant Staphylococcus aureus (MRSA) marketed for clinical use in the United States. International surveillance studies conducted on MRSA strains in North America and the EU indicate that in the United States, the ceftaroline MIC 50 and MIC 90 are 1 and 1 g/ml, respectively, with 5.2% of strains having MICs of Ͼ1 g/ml. In contrast, in Europe the MIC 50 and MIC 90 are 1 and 2 g/ml, respectively, with 17.3% of strains having MICs of Ͼ1 g/ml. The FDA clinical breakpoint for susceptibility among S. aureus isolates is Յ1 g/ml (1, 2). The proposed European (EUCAST) clinical breakpoint has not yet been published, but a breakpoint similar to that used in the United States will present significant problems in laboratory testing of ceftaroline, as it will cut through the MRSA MIC distribution.Ceftar...

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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

Cited by 139 publications

References 20 publications

Meta-analysis of Randomized Controlled Trials of Vancomycin for the Treatment of Patients With Gram-Positive Infections: Focus on the Study Design

Meta-analysis of Randomized Controlled Trials of Vancomycin for the Treatment of Patients With Gram-Positive Infections: Focus on the Study Design

Large Retrospective Evaluation of the Effectiveness and Safety of Ceftaroline Fosamil Therapy

Pharmacodynamics of Ceftaroline against Staphylococcus aureus Studied in an In Vitro Pharmacokinetic Model of Infection

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