Integrated Analysis of CANVAS 1 and 2: Phase 3, Multicenter, Randomized, Double‐Blind Studies to Evaluate the Safety and Efficacy of Ceftaroline versus Vancomycin plus Aztreonam in Complicated Skin and Skin‐Structure Infection

Corey, G. Ralph; Wilcox, Mark H.; Talbot, George H.; Friedland, H. David; Baculik, Tanya; Witherell, Gary W.; Critchley, Ian A.; Das, Anita; Thye, Dirk

doi:10.1086/655827

Cited by 216 publications

(152 citation statements)

References 39 publications

Supporting

Mentioning

144

Contrasting

Order By: Relevance

“…To date, no antibiotic has proven superior to vancomycin in contemporary regulatory studies for the treatment of cSSSI (29)(30)(31). Our observations support these past clinical trial findings in that even with a potentially low exposure level at the site of infection, vancomycin displays significant killing of MSSA and MRSA.…”

Section: It Is Well Established That Vancomycin Is An Antibiotic Withsupporting

confidence: 82%

In Vitro Pharmacodynamics of Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus: Considering the Variability in Observed Tissue Exposure

Hamada

Kuti

Nicolau

2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Vancomycin is considered a first-line antibiotic for complicated skin and skin structure infections (cSSSI) because of the risk of methicillin-resistant Staphylococcus aureus (MRSA). The vancomycin exposure of tissue can vary widely in patients with cSSSI, yet most models test only the average exposure. The in vitro pharmacodynamic model was used to simulate three tissue exposure levels attained by administering vancomycin at 1 g every 12 h (q12h), based on the median (50th), 25th, and 10th percentile tissue area under the concentration-time curve (AUC) values observed during an in vivo microdialysis study of diabetic patients. Four clinical isolates (two of MRSA [vancomycin MIC, 1 and 2 g/ml] and two of methicillin-susceptible S. aureus [MSSA] [MIC, 1 and 2 g/ml]) were evaluated. Experiments were performed over 72 h in duplicate. Time-kill curves were constructed, and the area under the bacterial killing and regrowth curve (AUBC) during the final 24-h dosing interval (48 to 72 h) (AUBC 48 -72 ) was calculated. Reductions in the 72-h number of CFU/ml and AUBC 48 -72 at the different exposure levels were compared. Target tissue vancomycin exposure levels for the 50th (AUC 0 -12 , 102.0 ؎ 9.1 g · h/ml), 25th (AUC 0 -12 , 44.3 ؎ 1.8 g · h/ml), and 10th (AUC 0 -12 , 25.3 ؎ 3.1 g · h/ml) percentiles were obtained in all studies. No differences in the 72-h number of CFU or AUBC were observed between exposure levels when all of the isolates were analyzed together. However, for the two MRSA isolates, the 10th percentile exposure level achieved a lower 72-h number of CFU/ml (؊1.4 ؎ 0.4 log 10 CFU/ml, P ‫؍‬ 0.007) and a greater AUBC 48 -72 (97.1 ؎ 20.0 log 10 CFU · h/ml, P ‫؍‬ 0.011) than the higher exposure levels. The majority of the tissue exposure levels achieved with a vancomycin dosing regimen of 1 g q12h resulted in substantial killing of MSSA and MRSA; however, the lowest exposure levels observed in a minority of the population may explain the poor vancomycin response. C omplicated skin and skin structure infections (cSSSI) are among the most common infections in hospitalized patients (1, 2). These infections are frequently caused by Gram-positive bacteria, including Staphylococcus aureus and Streptococcus pyogenes (2). Methicillin-resistant S. aureus (MRSA) can be present in as many as 60% of cases (3, 4) and has been linked with outcomes worse than those of methicillin-susceptible S. aureus (MSSA) infections (5, 6). As a result of this epidemiology and the long history of vancomycin use, it is considered a first-line antibiotic for the empirical treatment of cSSSI (2, 7).In addition to possessing in vitro microbiological activity against the causative pathogen, the treatment antibiotic must be able to penetrate to the site of infection with sufficient exposure to kill the organism. Comorbidities often present in patients with cSSSI, including diabetes mellitus and peripheral vascular disease, can result in altered and varied tissue perfusion to the site of infection, making it increasingly difficult to predict a...

show abstract

Section: It Is Well Established That Vancomycin Is An Antibiotic Withsupporting

confidence: 82%

In Vitro Pharmacodynamics of Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus: Considering the Variability in Observed Tissue Exposure

Hamada

Kuti

Nicolau

2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…10 Ceftaroline fosamil therapy resulted in similar clinical cure rates compared with vancomycinaztreonam in 2 phase 3 clinical trials in patients with cSSSIs. 94 Ceftaroline fosamil was also as effective against MRSA cSSSIs (clinical cure rate, 93.4%) as vancomycin-aztreonam (94.3%). In 2012, a retrospective study was published on the results of an analysis of clinical response at earlier time points in a population of 400 patients who had ABSSSIs consistent with the definition provided by the FDA guidance for ABSSSI trials.…”

Section: Treatment Failurementioning

confidence: 95%

“…In pivotal trials, ceftaroline fosamil was well tolerated and had a safety profile consistent with the cephalosporin class of antibiotics. 94 The most common treatment-emergent AEs were nausea (5.9%), headache (5.2%), diarrhea (4.9%), and pruritus (3.5%). 96 New IV drugs are in development for MRSA ABSSSIs.…”

Section: Treatment Failurementioning

confidence: 99%

Hospitalist Perspective on the Treatment of Skin and Soft Tissue Infections

Amin

Cerceo

Deitelzweig

et al. 2014

Mayo Clinic Proceedings

View full text Add to dashboard Cite

The prevalence of skin and soft tissue infections (SSTIs) has been increasing in the United States. These infections are associated with an increase in hospital admissions. Hospitalists play an increasingly important role in the management of these infections and need to use hospital resources efficiently and effectively. When available, observation units are useful for treating low-risk patients who do not require hospital admission. Imaging tools may help to exclude abscesses and necrotizing soft tissue infections; however, surgical exploration remains the principal means of diagnosing necrotizing soft tissue infections. The most common pathogens that cause SSTIs are streptococci and Staphylococcus aureus. Methicillin-resistant S aureus (MRSA) is a prevalent pathogen, and concerns are increasing regarding the unclear distinctions between community-acquired and hospital-acquired MRSA. Other less frequent pathogens that cause SSTIs include Enterococcus species, Escherichia coli, Klebsiella species, Enterobacter species, and Pseudomonas aeruginosa. Cephalexin and clindamycin are suitable options for infections caused by streptococcal species and methicillin-susceptible S aureus. The increasing resistance of S aureus and Streptococcus pyogenes to erythromycin limits its use in these infections, and better alternatives are available. Parenteral cefazolin, nafcillin, or oxacillin can be used in hospitalized patients with nonpurulent cellulitis caused by streptococci and methicillin-susceptible S aureus. When oral MRSA therapy is indicated, clindamycin, doxycycline, trimethoprim-sulfamethoxazole, or linezolid is appropriate. Vancomycin, linezolid, daptomycin, tigecycline, telavancin, and ceftaroline fosamil are intravenous options that should be used in MRSA infections that require patient hospitalization. In the treatment of patients with SSTIs, hospitalists are at the forefront of providing proper patient care that reduces hospital costs, duration of therapy, and therapeutic failures. This review updates guidelines on the management of SSTIs with a focus on infections caused by S aureus, particularly MRSA, and outlines the role of the hospitalist in the effective management of SSTIs.

show abstract

“…Even those currently under development are nothing more than new, improved versions of these old natural products, because the chemical modification of existing molecules remains the most costefficient way to develop novel drugs active against resistant strains. As examples, we can cite the cephalosporin ceftaroline (Corey et al, 2010), the tetracycline amadacycline (PTK0796), the streptogramin NXL-103 (Politano & Sawyer, 2010) and the macrolide CEM-101 (Woosley et al, 2010). However, the perspective that these agents, new but based on old molecular scaffolds, will in their turn face the development of bacterial resistance, prompted both the academic community and the biotech/pharmaceutical companies to look for alternative strategies.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial Peptides: New Frontiers in the Therapy of Infections

Zucca¹,

Scutera²,

Savoia³

2011

Drug Development - A Case Study Based Insight Into Modern Strategies

View full text Add to dashboard Cite

Integrated Analysis of CANVAS 1 and 2: Phase 3, Multicenter, Randomized, Double‐Blind Studies to Evaluate the Safety and Efficacy of Ceftaroline versus Vancomycin plus Aztreonam in Complicated Skin and Skin‐Structure Infection

Abstract: ClinicalTrials.gov identifiers: NCT00424190 for CANVAS 1 and NCT00423657 for CANVAS 2.

Cited by 216 publications

References 39 publications

In Vitro Pharmacodynamics of Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus: Considering the Variability in Observed Tissue Exposure

In Vitro Pharmacodynamics of Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus: Considering the Variability in Observed Tissue Exposure

Hospitalist Perspective on the Treatment of Skin and Soft Tissue Infections

Antimicrobial Peptides: New Frontiers in the Therapy of Infections

Contact Info

Product

Resources

About