ppi-0903 and Soft-Tissue-Infections

Ceftaroline and ceftobiprole are advanced generation cephalosporins with activity against methicillin-resistant Staphylococcus aureus (MRSA). This review summarizes their clinical efficacy for complicated skin and soft tissue infections (cSSTIs).. Both these agents retain excellent in vitro activity against both MRSA and Gram-negative isolates from patients with CSSTIs. Both these agents are registered for the management of cSSTIs based on the results of large scale phase III noninferiority trials. Ceftaroline and ceftobiprole are noninferior to the combination of vancomycin and aztreonam as this was assessed by their clinical cure rate at the test-of-cure visits. Furthermore, ceftobiprole is noninferior to comparators for the achievement of early clinical success at 72 h. Ceftaroline achieves 81% clinical cure against diabetic foot infections.. Ceftaroline and ceftobiprole can be used as monotherapy for the treatment of cSSTIs.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Soft Tissue Infections; Staphylococcal Infections

This exploratory pooled analysis assessed the efficacy and safety of ceftaroline fosamil and comparators across six phase III clinical trials in adults with community-acquired pneumonia (CAP) or complicated skin and soft-tissue infection (cSSTI) and secondary bacteraemia.. In each trial, FOCUS 1 and 2 (CAP), Asia CAP trial, CANVAS 1 and 2 (cSSTI) and COVERS (cSSTI), patients were randomised to ceftaroline fosamil [600 mg q12h by 1-h i.v. infusion, except in COVERS (600 mg q8h by 2-h i.v. infusion), adjusted for renal function] or comparator. Efficacy assessments included clinical and microbiological responses at test-of-cure visit [microbiological modified intent-to-treat (mMITT) population]. Safety outcomes were assessed.. The pooled mMITT population comprised 1976 patients, of whom 138 had baseline bacteraemia (ceftaroline fosamil, n = 72; comparator, n = 66). Predominant baseline blood pathogens were Staphylococcus aureus (n = 29), Streptococcus pneumoniae (n = 19) and other streptococci (n = 12). Clinical cure rates in bacteraemic patients were 55/72 (76.4%) and 51/66 (77.3%) for ceftaroline fosamil and comparators, respectively, and in non-bacteraemic patients were 822/966 (85.1%) and 717/872 (82.2%). Favourable microbiological response rates in bacteraemic patients were 56/72 (77.8%) for ceftaroline fosamil and 54/66 (81.8%) for comparators, and in non-bacteraemic patients were 825/966 (85.4%) and 719/872 (82.5%). Adverse events in bacteraemic patients were consistent with the known ceftaroline fosamil safety profile or the underlying indications.. These pooled clinical and microbiological efficacy data demonstrate generally favourable outcomes for ceftaroline fosamil in patients with CAP or cSSTI and secondary bacteraemia. [Trial Registration: NCT00621504, NCT00509106; NCT01371838; NCT00424190, NCT00423657; NCT01499277].

Topics: Adult; Bacteremia; Ceftaroline; Cephalosporins; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Humans; Pneumonia; Soft Tissue Infections; Treatment Outcome

Community-acquired pneumonia (CAP)/community-acquired bacterial pneumonia (CABP) and complicated skin and soft tissue infection (cSSTI)/acute bacterial skin and skin structure infection (ABSSSI) represent major causes of morbidity and mortality in children. β-Lactams are the cornerstone of antibiotic treatment for many serious bacterial infections in children; however, most of these agents have no activity against methicillin-resistant Staphylococcus aureus (MRSA). Ceftaroline fosamil, a β-lactam with broad-spectrum in vitro activity against Gram-positive pathogens (including MRSA and multidrug-resistant Streptococcus pneumoniae) and common Gram-negative organisms, is approved in the European Union and the United States for children with CAP/CABP or cSSTI/ABSSSI. Ceftaroline fosamil has completed a pediatric investigation plan including safety, efficacy, and pharmacokinetic evaluations in patients with ages ranging from birth to 17 years. It has demonstrated similar clinical and microbiological efficacy to best available existing treatments in phase III-IV trials in patients aged ≥ 2 months to < 18 years with CABP or ABSSSI, with a safety profile consistent with the cephalosporin class. It is also approved in the European Union for neonates with CAP or cSSTI, and in the US for neonates with ABSSSI. Ceftaroline fosamil dosing for children (including renal function adjustments) is supported by pharmacokinetic/pharmacodynamic modeling and simulations in appropriate age groups, and includes the option of 5- to 60-min intravenous infusions for standard doses, and a high dose for cSSTI patients with MRSA isolates, with a ceftaroline minimum inhibitory concentration of 2-4 mg/L. Considered together, these data suggest ceftaroline fosamil may be beneficial in the management of CAP/CABP and cSSTI/ABSSSI in children.

Topics: Ceftaroline; Cephalosporins; Child; Humans; Infant, Newborn; Methicillin-Resistant Staphylococcus aureus; Pneumonia; Soft Tissue Infections

Skin and soft tissue infections (SSTIs) are a common cause of hospital admission among elderly patients, and traditionally have been divided into complicated and uncomplicated SSTIs. In 2010, the FDA provided a new classification of these infections, and a new category of disease, named acute bacterial skin and skin structure infections (ABSSSIs), has been proposed as an independent clinical entity. ABSSSIs include three entities: cellulitis and erysipelas, wound infections, and major cutaneous abscesses This paper revises the epidemiology of SSTIs and ABSSSIs with regard to etiologies, diagnostic techniques, and clinical presentation in the hospital settings. Particular attention is owed to frail patients with multiple comorbidities and underlying significant disease states, hospitalized on internal medicine wards or residing in nursing homes, who appear to be at increased risk of infection due to multi-drug resistant pathogens and treatment failures. Management of ABSSSIs and SSTIs, including evaluation of the hemodynamic state, surgical intervention and treatment with appropriate antibiotic therapy are extensively discussed.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Carbapenems; Ceftaroline; Cephalosporins; Daptomycin; Female; Fluoroquinolones; Glycopeptides; Hospitalization; Humans; Iatrogenic Disease; Internal Medicine; Linezolid; Lipoglycopeptides; Male; Minocycline; Oxazolidinones; Skin Diseases, Infectious; Soft Tissue Infections; Teicoplanin; Tigecycline; Vancomycin

Antimicrobial drug-resistance continues to force adaptation in our clinical practice. We explore new evidence regarding adjunctive antibiotic therapy for skin and soft tissue abscesses as well as duration of therapy for intra-abdominal abscesses. As new evidence refines optimal practice, it is essential to support clinicians in adopting practice patterns concordant with evidence-based guidelines. We review a simple approach that can 'nudge' clinicians towards concordant practices. Finally, the use of novel antimicrobials will play an increasingly important role in contemporary therapy. We review five new antimicrobials recently FDA-approved for use in drug-resistant infections: dalbavancin, oritavancin, ceftaroline, ceftolozane-tazobactam, and ceftazidime-avibactam.

Topics: Abdominal Abscess; Anti-Bacterial Agents; Bacterial Infections; Ceftaroline; Cephalosporins; Drug Administration Schedule; Drug Approval; Drug Combinations; Drug Resistance, Microbial; Glycopeptides; Humans; Lipoglycopeptides; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Soft Tissue Infections; Teicoplanin; United States; United States Food and Drug Administration

Intravenous ceftaroline fosamil (Zinforo™), a prodrug that is rapidly converted to its active metabolite ceftaroline, is approved for use in adults and children (from 2 months of age) with complicated skin and soft tissue infections (cSSTIs) or community-acquired pneumonia (CAP). In several multinational trials, ceftaroline fosamil was an effective and generally well tolerated treatment in adult and paediatric patients with cSSTIs or CAP. In the phase 3 CANVAS trials, ceftaroline fosamil treatment was noninferior to vancomycin plus aztreonam in adults with cSSTIs. Based on a meta-analysis of three similarly designed, phase 3 trials (FOCUS 1, FOCUS 2 and an Asian trial), ceftaroline fosamil treatment was superior to ceftriaxone in adults with CAP of Pneumonia Outcomes Research Teams (PORT) risk class III or IV. Ceftaroline fosamil was also associated with high clinical cure rates in hospitalized children (aged 2 months to 17 years) with cSSTIs or CAP. With its broad spectrum of in vitro activity against clinically relevant Gram-positive [including methicillin-resistant Staphylococcus aureus (MRSA) and drug-resistant Streptococcus pneumoniae isolates] and Gram-negative pathogens implicated in cSSTIs and CAP, ceftaroline fosamil is an important treatment option for cSSTI and CAP in adults and children from the age of 2 months.

Topics: Animals; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Humans; Pneumonia; Soft Tissue Infections; Staphylococcal Skin Infections

Ceftaroline fosamil was approved in 2010 by the United States Food and Drug Administration (USA-FDA) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). After approval, several studies and case reports have described the postmarketing clinical experience with ceftaroline in ABSSSIs and CABP and in patients with invasive methicillin-resistant Staphylococcus aureus (MRSA) infections, many of whom had failed prior antibiotics. Successful clinical outcomes observed among the majority of these patients were supported by preapproval and postapproval in vitro surveillance of ceftaroline activity using breakpoint criteria that have been harmonized between the USA-FDA and CLSI. MIC90 values/percentage of strains susceptible to ceftaroline has remained stable over the period 2009-2012. Taken together, these postapproval studies support the use of ceftaroline for ABSSSI as well as CABP. Importantly, these data also suggest that ceftaroline can be effective in patients with serious invasive MRSA infections who have failed other therapies.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Drug Approval; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Product Surveillance, Postmarketing; Soft Tissue Infections; Staphylococcal Infections; Treatment Outcome; United States

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil (Zinforo, Teflaro), is an advanced-generation, parenteral cephalosporin with broad-spectrum antibacterial activity in vitro against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug resistant Streptococcus pneumoniae and Gram-negative bacteria, including Haemophilus influenzae and Moraxella catarrhalis, but not Pseudomonas aeruginosa. Ceftaroline has demonstrated a low potential for the selection of resistance in vitro for drug-resistant Gram-positive organisms, including MRSA, as well as for Gram-negative respiratory pathogens. In pivotal phase III studies, intravenous ceftaroline fosamil demonstrated noninferiority to intravenous vancomycin plus aztreonam in patients hospitalized with complicated skin and soft tissue infections (cSSTIs) and intravenous ceftriaxone in patients hospitalized with community-acquired pneumonia (CAP) [Pneumonia Outcomes Research Team (PORT) risk class III or IV]; however, patients with CAP admitted to the intensive care unit were not evaluated. Ceftaroline fosamil was generally well tolerated in these trials, with an adverse event profile similar to that of other cephalosporins. Diarrhoea was the most commonly reported adverse event; however, the risk of Clostridium difficile-associated diarrhoea with ceftaroline fosamil appeared to be low. Potential limitations of the drug include the lack of an oral formulation and the requirement for twice-daily administration. Nonetheless, ceftaroline fosamil represents an attractive option (either alone or in combination with other agents) for the initial empirical treatment of patients hospitalized with cSSTIs (including those with suspected MRSA infection) or CAP (PORT risk class III or IV) who require intravenous antimicrobial therapy. As with all antibacterial agents, ceftaroline fosamil should be used in accordance with good antimicrobial stewardship.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Humans; Pneumonia; Skin Diseases, Infectious; Soft Tissue Infections

Ceftaroline is a novel broad-spectrum cephalosporin antibiotic currently under US Food and Drug Administration (FDA) review for a new drug application (NDA), filed by Cerexa, Inc. (a wholly owned subsidiary of Forest Laboratories), for the treatment of complicated skin and skin-structure infections (cSSSIs) and community-associated pneumonia (CAP). The antibiotic acts by binding to penicillin-binding proteins in bacteria, consistent with other β-lactams. The antimicrobial spectrum of ceftaroline ranges from aerobic and anaerobic Gram-positive bacteria, including drug-resistant isolates of staphylococci, i.e. heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA), to anaerobic Gram-negative pathogens such as Moraxella catarrhalis and Haemophilus influenzae (including β-lactamase-positive strains), as well as bacteria with multiple resistance phenotypes. Ceftaroline fosamil is the prodrug that is rapidly dephosphorylated by in vivo plasma phosphatases to the active drug ceftaroline, which follows a two-compartmental pharmacokinetic model and is eliminated primarily by renal excretion, with a plasma half-life of ca. 2.5 h. Ceftaroline is well tolerated, which is consistent with its good safety profile similar to other cephalosporins in clinical trials. Thus, it would be a promising drug to fight multidrug-resistant superbugs such as S. aureus and Streptococcus pneumoniae for the treatment of cSSSIs and CAP.

Topics: Anti-Bacterial Agents; Bacteria; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Drug Approval; Humans; Pneumonia, Bacterial; Prodrugs; Skin Diseases, Bacterial; Soft Tissue Infections; United States

Ceftaroline fosamil, the prodrug of the active metabolite, ceftaroline, is a new, broad-spectrum cephalosporin recently approved in the USA for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). Ceftaroline has potent in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae, as well as common Gram-negative organisms. The high affinity of ceftaroline for penicillin-binding proteins is responsible for the potent activity observed against clinically relevant pathogens. With respect to the treatment of CABP, the activity of ceftaroline against pathogens such as S. pneumoniae, S. aureus, Haemophilus influenzae and Moraxella catarrhalis demonstrates coverage across a broad range of pathogens typically encountered in clinical practice. Ceftaroline is also very active against common pathogens seen in ABSSSIs such as S. aureus (methicillin-susceptible S. aureus and methicillin-resistant S. aureus) and Streptococcus pyogenes. Ceftaroline exhibits a dose-proportional pharmacokinetic profile, similar to other renally excreted cephalosporins, and has a well-tolerated safety profile consistent with the cephalosporin class. Ceftaroline fosamil is compatible via Y-site administration with many other commonly administered parenteral drugs.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Pneumonia, Bacterial; Prodrugs; Skin Diseases, Bacterial; Soft Tissue Infections; United States

There is a choice of anti-MRSA antibiotic available with proven efficacy in the treatment of complicated skin and skin structure infection (cSSSI). Additional anti-MRSA antibiotics are in development, which have the potential to influence how such infections are managed. The emergence of resistance to current anti-MRSA agents, toxicity, and general lack of oral agents with proven efficacy for deep seated infection justify the development of new agents. However, there is a relative dearth of information specific to patients with orthopaedic-related infection. Combination therapy is often used in these patients, although there is a paucity of controlled trial data to support particular antibiotic combinations. As the choice of anti-MRSA agents increases, so does the need to identify which are best for the large variety of infections included in the group of cSSSIs. This is particular true for infections occurring in orthopaedic patients where poorly vascularised tissue, trauma or implanted prosthetic material, pose specific challenges.

Topics: Aminoglycosides; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Glycopeptides; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections; Teicoplanin

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

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials, Phase III as Topic; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Skin Diseases, Bacterial; Soft Tissue Infections; Treatment Outcome

Increasing the ceftaroline fosamil dose beyond 600 mg every 12 h may provide additional benefit for patients with complicated skin and soft tissue infections (cSSTIs) with severe inflammation and/or reduced pathogen susceptibility. A Phase III multicentre, randomized trial evaluated the safety and efficacy of ceftaroline fosamil 600 mg every 8 h in this setting.. Adult patients with cSSTI and systemic inflammation or comorbidities were randomized 2:1 to intravenous ceftaroline fosamil (600 mg every 8 h) or vancomycin (15 mg/kg every 12 h) plus aztreonam (1 g every 8 h) for 5-14 days. Clinical cure was assessed at the test of cure (TOC) visit (8-15 days after the final dose) in the modified ITT (MITT) and clinically evaluable (CE) populations. Non-inferiority was defined as a lower limit of the 95% CI around the treatment difference greater than -10%. An MRSA-focused expansion period was initiated after completion of the main study. Clinicaltrials.gov registration numbers NCT01499277 and NCT02202135.. Clinical cure rates at TOC demonstrated non-inferiority of ceftaroline fosamil 600 mg every 8 h versus vancomycin plus aztreonam in the MITT and CE populations: 396/506 (78.3%) versus 202/255 (79.2%) patients (difference -1.0%, 95% CI -6.9, 5.4) and 342/395 (86.6%) versus 180/211 (85.3%) patients (difference 1.3%, 95% CI -4.3, 7.5), respectively. In the expansion period, 3/4 (75%) patients treated with ceftaroline fosamil were cured at TOC. The frequency of adverse events was similar between groups.. Ceftaroline fosamil 600 mg every 8 h was effective for cSSTI patients with evidence of systemic inflammation and/or comorbidities. No new safety signals were identified.

Topics: Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Aztreonam; Ceftaroline; Cephalosporins; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Prospective Studies; Skin Diseases, Bacterial; Soft Tissue Infections; Systemic Inflammatory Response Syndrome; Treatment Outcome; Vancomycin; Young Adult

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a common cause of complicated skin and skin structure infections (cSSSIs). Increasing antibiotic resistance and significant morbidity in cSSSIs have led to a need for new effective and safe therapies. Ceftaroline fosamil, a novel parenteral cephalosporin with excellent in vitro activity against Gram-positive pathogens, including MRSA, and many Gram-negative pathogens, was evaluated as therapy for cSSSIs in a large multicentre study. The primary study objective was to determine non-inferiority [lower limit of 95% confidence interval (CI), -10%] in the clinical cure rate achieved with ceftaroline fosamil monotherapy compared with that achieved with vancomycin plus aztreonam in the clinically evaluable (CE) and modified intent-to-treat (MITT) patient populations.. Adult patients with cSSSIs requiring intravenous therapy received 600 mg of ceftaroline fosamil every 12 h or 1 g of vancomycin plus 1 g of aztreonam every 12 h for 5-14 days (randomized 1 : 1). Clinical and microbiological response, adverse events (AEs) and laboratory tests were assessed. Registration number NCT00424190 (http://clinicaltrials.gov/ct2/show/NCT00424190).. Of 702 enrolled patients, 353 received ceftaroline fosamil and 349 received vancomycin plus aztreonam. Baseline characteristics of treatment groups were comparable. Clinical cure rates were similar for ceftaroline fosamil and vancomycin plus aztreonam in the CE (91.1%, 288/316 versus 93.3%, 280/300; 95% CI, -6.6, 2.1) and MITT (86.6%, 304/351 versus 85.6%, 297/347; 95% CI, -4.2, 6.2) populations, respectively. The clinical cure rate for MRSA cSSSIs was 95.1% (78/82) for ceftaroline fosamil and 95.2% (59/62) for vancomycin plus aztreonam. The microbiological success rate was also similar for ceftaroline fosamil and vancomycin overall, and for MRSA. The rates of AEs, serious AEs, deaths and discontinuations because of an AE were similar for ceftaroline fosamil and vancomycin plus aztreonam. The most common AEs for ceftaroline fosamil and vancomycin plus aztreonam were diarrhoea (3.4% versus 3.2%), nausea (5.7% versus 4.6%), headache (5.1% versus 3.7%) and pruritus (3.1% versus 8.4%), respectively.. Ceftaroline fosamil achieved high clinical cure and microbiological success rates, was efficacious for cSSSIs caused by MRSA and other common cSSSI pathogens and was generally well tolerated. Ceftaroline fosamil has the potential to provide a monotherapy alternative for treatment of cSSSIs.

Topics: Adult; Aged; Anti-Bacterial Agents; Aztreonam; Ceftaroline; Cephalosporins; Double-Blind Method; Drug Therapy, Combination; Humans; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections; Treatment Outcome; Vancomycin; Young Adult

New therapies for complicated skin and skin structure infections (cSSSIs) are needed because of significant morbidity and increasing antimicrobial resistance. Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of cSSSIs. Ceftaroline fosamil, a novel parenteral cephalosporin with excellent in vitro activity against Gram-positive pathogens, including MRSA, and many Gram-negative pathogens, was evaluated as therapy for cSSSIs in a multinational Phase III study. The primary study objective was to determine non-inferiority [lower limit of 95% confidence interval (CI), -10%] in the clinical cure rate of ceftaroline fosamil monotherapy to that achieved with vancomycin plus aztreonam combination therapy in the clinically evaluable (CE) and modified intent-to-treat (MITT) analysis populations.. Adult patients with cSSSIs requiring intravenous therapy received 600 mg of ceftaroline fosamil every 12 h or 1 g of vancomycin plus 1 g of aztreonam every 12 h for 5-14 days (randomized 1 : 1). Clinical and microbiological response, adverse events (AEs) and laboratory tests were assessed. Registration number NCT00423657 (http://clinicaltrials.gov/ct2/show/NCT00423657).. The study enrolled 694 patients, 348 of whom received ceftaroline fosamil and 346 of whom received vancomycin plus aztreonam. The treatment groups had comparable baseline characteristics. Clinical cure rates for the ceftaroline fosamil and vancomycin plus aztreonam groups were similar in the CE (92.2%, 271/294 versus 92.1%, 269/292; 95% CI, -4.4, 4.5) and MITT (85.1%, 291/342 versus 85.5%, 289/338; 95% CI, -5.8, 5.0) populations, respectively. MRSA cSSSIs were cured in 91.4% (64/70) of patients in the ceftaroline fosamil group and 93.3% (56/60) of patients in the vancomycin plus aztreonam group. The microbiological success rate in the microbiologically evaluable population was 92.9% and 95.0% for ceftaroline fosamil and vancomycin plus aztreonam, respectively. Ceftaroline fosamil and vancomycin plus aztreonam had similar rates of AEs, serious AEs and discontinuations because of an AE. The most common AEs for ceftaroline fosamil and vancomycin plus aztreonam included diarrhoea (6.5% versus 4.4%), nausea (6.2% versus 5.6%), headache (5.3% versus 5.3%) and pruritus (3.8% versus 8.3%), respectively.. Ceftaroline fosamil demonstrated high clinical cure and microbiological success rates, was efficacious against cSSSIs caused by MRSA and other common cSSSI pathogens and was generally well tolerated. Monotherapy with ceftaroline fosamil has the potential to provide an alternative treatment for cSSSIs.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Aztreonam; Ceftaroline; Cephalosporins; Double-Blind Method; Drug Therapy, Combination; Humans; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections; Treatment Outcome; Vancomycin; Young Adult

Treatment of complicated skin and skin structure infections (cSSSIs) requires therapy that is effective against a range of Gram-positive and Gram-negative bacteria, including resistant pathogens such as methicillin-resistant Staphylococcus aureus. Equally important is the need to provide therapy that is safe and well tolerated. Ceftaroline fosamil is a new-generation, parenteral cephalosporin that was developed for the treatment of moderate to severe bacterial infections, including cSSSIs. This report provides an integrated safety summary of the CeftAroliNe Versus VAncomycin in Skin and Skin Structure Infections (CANVAS) 1 and 2 studies (registration numbers NCT00424190 and NCT00423657).. Adult patients with cSSSIs requiring intravenous therapy received 600 mg of ceftaroline fosamil every 12 h or 1 g of vancomycin plus 1 g of aztreonam every 12 h for 5-14 days (randomized 1 : 1). All patients were followed for treatment-emergent adverse events (TEAEs) occurring from the start of the initial study drug infusion up to the test-of-cure visit, ∼1 week following the last dose of study medication; serious adverse events (SAEs) that occurred within 30 days after the last dose were recorded.. A total of 1378 patients received any amount of study drug and were included in the safety analysis. The percentage of patients with an SAE was similar between the ceftaroline fosamil and the vancomycin plus aztreonam groups (4.3% versus 4.1%). The majority of patients (>75%) had either no or mild TEAEs and the distribution of TEAEs based on severity was comparable between the groups. The most commonly reported TEAEs in patients treated with ceftaroline fosamil included nausea (5.9%), headache (5.2%), diarrhoea (4.9%) and pruritus (3.5%).. Ceftaroline fosamil was well tolerated and did not result in any unexpected safety concerns. The data from the CANVAS trials suggest that ceftaroline fosamil has the expected safety and tolerability profile common to the cephalosporin class.

Topics: Adult; Anti-Bacterial Agents; Aztreonam; Ceftaroline; Cephalosporins; Double-Blind Method; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Methicillin-Resistant Staphylococcus aureus; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections; Treatment Outcome; Vancomycin

Ceftaroline, with a unique activity against methicillin-resistant Staphylococcus aureus (MRSA), was not launched in Taiwan before 2019. The in vitro susceptibility data of ceftaroline against important Taiwanese pathogens are lacking.. The in vitro susceptibility of ceftaroline against important pathogens collected from 2012 through 2018 were extracted from the Antimicrobial Testing Leadership and Surveillance program. Broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) to ceftaroline against all isolates.. From the pharmacodynamic perspectives, the ceftaroline dosage of 600 mg as a 2-h intravenous infusion every 8 h is effective against all S. aureus and other Gram-positive isolates regardless of acquisition sites in Taiwan. Before ceftaroline is prescribed in treatment of the patient with Gram-negative infection, a cautious evaluation about patient's healthcare-associated factor is warranted.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Haemophilus; Humans; Klebsiella pneumoniae; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Respiratory Tract Infections; Soft Tissue Infections; Staphylococcus aureus; Taiwan

Data on ceftaroline (CPT) susceptibility amongst clinical isolates of meticillin-resistant Staphylococcus aureus (MRSA, n=1284) and phenotypic non-extended-spectrum β-lactamase-producing (non-ESBL-P) Klebsiella pneumoniae (n=466), obtained from the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme from 2012 to 2018, and selected MRSA isolates from patients with bloodstream infections (BSIs) (n=95) from the Surveillance of Multicentre Antimicrobial Resistance in Taiwan (SMART) programme from 2018 to 2019 were analysed. The minimum inhibitory concentrations (MICs) of ATLAS isolates were determined using the broth microdilution method, whereas the MICs of SMART BSI-MRSA isolates were determined using the Etest and MicroScan system. The pharmacokinetic profiles and pharmacodynamic parameters of CPT were applied to explore the optimal dosage against infections caused by Taiwanese MRSA and K. pneumoniae isolates. Approximately 7.1% of ATLAS MRSA isolates were susceptible-dose dependent (S-DD) to CPT, and 19.7% of the non-ESBL-P K. pneumoniae isolates were not susceptible to CPT. Amongst the ATLAS MRSA isolates, the S-DD rates to CPT amongst isolates causing lower respiratory tract infections were 11.9% and 8.5% for isolates from intensive care units (ICUs) and general wards (GWs), and those causing skin and soft tissue infections (SSTIs) were 20% and 5.3% for isolates from ICUs and GWs, respectively (P=0.015). Of the SSTI MRSA isolates from GWs, 22.7% displayed vancomycin MICs >1 mg/L. Amongst 95 SMART BSI MRSA isolates, 28 (46.7%) isolates exhibited lower CPT MICs by the Etest compared with 60 isolates with CPT MICs of 1-2 mg/L by the MicroScan system. CPT 600 mg as a 2-h intravenous infusion every 8 h is suggested for treatment of infections caused by MRSA and phenotypic non-ESBL-P K. pneumoniae in Taiwan.

Topics: Anti-Bacterial Agents; beta-Lactamases; Ceftaroline; Cephalosporins; Drug Resistance, Bacterial; Humans; Klebsiella pneumoniae; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Respiratory Tract Infections; Skin Diseases, Bacterial; Soft Tissue Infections; Taiwan

To describe the pharmacokinetic/pharmacodynamic (PK/PD) modelling and microbiological data that were used to support the recent European approval of ceftaroline fosamil 600 mg q8h by 2 h intravenous (iv) infusion for patients with complicated skin and soft tissue infections (cSSTIs) caused by Staphylococcus aureus with ceftaroline MICs of 2 or 4 mg/L, and the associated EUCAST MIC breakpoint update for q8h dosing (intermediate = 2 mg/L and resistant >2 mg/L).. A population PK model for ceftaroline and ceftaroline fosamil was developed using PK data from 21 clinical studies. The final model was used to simulate PTA in patients with cSSTI receiving ceftaroline fosamil 600 mg q12h by 1 h iv infusion or 600 mg q8h by 2 h iv infusion. PTA was calculated by MIC for S. aureus PK/PD targets derived from preclinical studies (27% fT>MIC for stasis, 31% fT>MIC for 1 log10 kill and 35% fT>MIC for 2 log10 kill) and compared with S. aureus ceftaroline MIC distributions from a 2013 global surveillance study.. The final population PK model based on 951 subjects adequately described ceftaroline and ceftaroline fosamil PK. High PTA (>90%) was predicted for the ceftaroline fosamil 600 mg q12h dosage regimen against S. aureus isolates with ceftaroline MICs ≤2 mg/L. Greater than 90% PTA was predicted for the ceftaroline fosamil 600 mg q8h dosage regimen against S. aureus with ceftaroline MICs ≤4 mg/L.. The approved ceftaroline fosamil dosage regimens for adults and adolescents with cSSTI achieve high PTA against S. aureus at the associated EUCAST breakpoints.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Child; Clinical Trials as Topic; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Soft Tissue Infections; Staphylococcal Infections; Staphylococcal Skin Infections; Staphylococcus aureus; Young Adult

In 2018, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) introduced an intermediate breakpoint for ceftaroline against Staphylococcus aureus. The objective of this study was to compare data on resistance to ceftaroline among methicillin-resistant S. aureus (MRSA) isolates using versions 7.1 (March 2017) and 8.0 (January 2018) of the EUCAST breakpoints.. Participating centers were located in Africa, Asia, Europe, Oceania and South America. Isolates were collected from patients with complicated skin and soft-tissue infections and were cultured from integumentary sources. Methicillin resistance among S. aureus was confirmed locally using the oxacillin method. The CLSI broth microdilution method was used to measure ceftaroline MICs at the central laboratory. Versions 7.1 and 8.0 of the EUCAST breakpoints were used to interpret MIC data.. Between 2015 and 2016, 9559 isolates of S. aureus were collected, of which 5566 (58.2%) isolates were MRSA. Overall, the lowest rate of MRSA was in Asia (56.5%; 705/1247) and the highest rate was in Oceania (62.7%; 299/477). Using version 7.1 of the EUCAST breakpoints, 4.5% (250/5566) of all MRSA isolates were resistant to ceftaroline and when version 8.0 of the breakpoints was applied, 4.2% (235/5566) of MRSA were in the intermediate category and 0.3% (15/5566) of all isolates were considered resistant.. By applying version 8.0 of the EUCAST breakpoints, the majority of MRSA isolates that were resistant are now in the intermediate category for ceftaroline. Ceftaroline resistance among MRSA now appears rare.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Female; Global Health; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Soft Tissue Infections; Staphylococcal Skin Infections; Young Adult

The objective of this study was to analyse antimicrobial susceptibility testing data generated by the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) global surveillance programme for pathogens causing skin and soft tissue infections (SSTIs) in European countries in 2012.. Confirmation of pathogen identity by MALDI-TOF and antimicrobial susceptibility testing following the CLSI broth microdilution method were performed by a central laboratory.. Using CLSI breakpoint criteria, ceftaroline was active against MSSA (n = 1116; MIC90, 0.25 mg/L; 99.8% susceptible), MRSA (n = 1467; MIC90, 1 mg/L; 92.2% susceptible) and Streptococcus pyogenes (n = 312; MIC90, 0.008 mg/L; 100% susceptible). By CLSI interpretative criteria, two S. aureus isolates (2/2583, 0.08%) were ceftaroline resistant (MIC, ≥4 mg/L) and 114 isolates (114/2583, 4.4%) were ceftaroline intermediate (2 mg/L). By EUCAST interpretative criteria (MIC, >1 mg/L), 4.5% (116/2583) of S. aureus isolates were ceftaroline resistant. Most ceftaroline-non-susceptible isolates (81.0%, 94/116) were from Russia, Turkey, Italy and Hungary. Ceftaroline susceptibility was equal to or exceeded 99% for S. aureus isolates submitted by 7 of 17 countries. Against Escherichia coli (n = 349), Klebsiella pneumoniae (n = 215), Klebsiella oxytoca (n = 74) and Proteus mirabilis (n = 121), ceftaroline activity was dependent upon ESBL production. For ESBL-negative E. coli, K. pneumoniae, K. oxytoca and P. mirabilis, 87.5% (MIC90, 1 mg/L), 92.3% (MIC90, 0.5 mg/L), 93.2% (MIC90, 0.5 mg/L) and 85.1% (MIC90, 2 mg/L) of isolates were susceptible to ceftaroline, respectively.. Ceftaroline demonstrated potent in vitro activity against a contemporary collection of bacterial pathogens from patients with SSTIs in European countries, Russia and Turkey. Surveillance programmes such as AWARE are essential to global efforts to improve antimicrobial stewardship.

Topics: Anti-Bacterial Agents; Bacteria; Ceftaroline; Cephalosporins; Drug Resistance, Bacterial; Epidemiological Monitoring; Europe; Humans; Microbial Sensitivity Tests; Prevalence; Skin Diseases, Bacterial; Soft Tissue Infections; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Compare clinical and cost outcomes associated with ceftaroline fosamil with other commonly used antibiotics in complicated skin and soft tissue infections.. Retrospective analysis of hospital records from 2010 to 2013 in Premier's Perspective comparative database for adults with complicated skin and soft tissue infection treated with intravenous ceftaroline fosamil, vancomycin, daptomycin, linezolid or tigecycline. Length of stay, inpatient costs and mortality were compared between propensity score-matched treatment groups.. Compared with the other commonly used antibiotics, matched patients in the ceftaroline fosamil treatment group had an equivalent (1%) or lower (compared with linezolid, 2%) in-hospital mortality rate, and significantly lower (p < 0.001) average unadjusted and regression-adjusted length of stay and inpatient costs (savings of $3398.80 compared with daptomycin).

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Humans; Retrospective Studies; Soft Tissue Infections; Standard of Care; Treatment Outcome

The objective of this report was to document antimicrobial susceptibility testing surveillance data for ceftaroline and comparative agents from the AWARE (Assessing Worldwide Antimicrobial Resistance Evaluation) global surveillance program for bacterial pathogens causing skin and soft tissue and respiratory tract infections in African and Middle Eastern countries from 2012 through 2014. Pathogen identities were confirmed by MALDI-TOF and antimicrobial susceptibility testing performed by CLSI broth microdilution methodology in a central laboratory. All methicillin-susceptible Staphylococcus aureus (MSSA) (n= 923; MIC90, 0.25 μg/mL) and 91.8% of methicillin-resistant S. aureus (MRSA) (n= 1161; MIC90, 1 μg/mL) tested were susceptible to ceftaroline. The maximum ceftaroline MIC observed for isolates of MRSA was 2 μg/mL. All Streptococcus pyogenes (n= 174; MIC90, 0.008 μg/mL), Streptococcus agalactiae (n= 44; MIC90, 0.015 μg/mL), Streptococcus pneumoniae (n= 351; MIC90, 0.25 μg/mL), and Haemophilus influenzae (n= 84; MIC90, ≤0.015 μg/mL) were susceptible to ceftaroline. Rates of susceptibility to ceftaroline among ESBL-negative Escherichia coli (n= 338), Klebsiella pneumoniae (n= 241), and Klebsiella oxytoca (n= 97) were 89.1% (MIC90, 1 μg/mL), 94.2% (MIC90, 0.5 μg/mL), and 99.0% (MIC90, 0.5 μg/mL), respectively.

Topics: Africa; Anti-Bacterial Agents; Bacteria; Ceftaroline; Cephalosporins; Epidemiological Monitoring; Humans; Microbial Sensitivity Tests; Middle East; Respiratory Tract Infections; Skin Diseases, Bacterial; Soft Tissue Infections; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

In this study, the efficacy of ceftaroline versus vancomycin against biofilm-producing methicillin-resistant Staphylococcus epidermidis (MRSE) in a murine model of foreign-body and systemic infection was compared. Two bacteraemic biofilm-producing MRSE strains were used (SE284 and SE385). The minimum inhibitory concentrations (MICs) for strains SE284 and SE385, were, respectively, 0.25 mg/L and 0.5 mg/L for ceftaroline and 4 mg/L and 2 mg/L for vancomycin. The in vitro bactericidal activities of ceftaroline and vancomycin were evaluated using time-kill curves. A foreign-body and systemic infection model in neutropenic female C57BL/6 mice was used to ascertain in vivo efficacy. Animals were randomly allocated into three groups (n = 15) without treatment (controls) or treated with ceftaroline 50 mg/kg every 8 h or vancomycin 110 mg/kg every 6 h. In vitro, ceftaroline showed concentration-dependent bactericidal activity, whilst vancomycin presented time-dependent activity. In the experimental in vivo model, ceftaroline and vancomycin decreased the liver and catheter bacterial concentrations (P <0.05) and increased survival (P <0.05) for both strains. In conclusion, ceftaroline is as effective as vancomycin in the treatment of experimental foreign-body and systemic infection caused by biofilm-producing MRSE.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Biofilms; Ceftaroline; Cephalosporins; Disease Models, Animal; Female; Foreign Bodies; Methicillin Resistance; Mice, Inbred C57BL; Microbial Sensitivity Tests; Random Allocation; Sepsis; Soft Tissue Infections; Staphylococcal Infections; Staphylococcus epidermidis; Treatment Outcome; Vancomycin

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a new cephalosporin with bactericidal activity against resistant Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant strains of Streptococcus pneumoniae, and commonly isolated Gram-negative organisms, including ceftriaxone-susceptible Enterobacteriaceae. We evaluated the in vitro activity of ceftaroline and selected comparator agents against bacterial isolates collected from patients with acute bacterial skin and skin structure infections (ABSSSIs) in the USA. A total of 6222 isolates were collected from 67 medical centers distributed across all nine USA census regions between 2009 and 2011 and tested for susceptibility by reference broth microdilution methods. Ceftaroline was very active against S. aureus (MIC50/90, 0.5/1 μg/mL; 99.6% susceptible), including MRSA (MIC50/90, 0.5/1 μg/mL; 99.1% susceptible). Against β-hemolytic streptococci, the activity of ceftaroline (MIC50/90, ≤0.015/0.03 μg/mL; 100.0% susceptible) was comparable to that of both penicillin (MIC50/90, ≤0.06/≤0.06 μg/mL; 100.0% susceptible) and ceftriaxone (MIC50/90, ≤0.25/≤0.25 μg/mL; 100.0% susceptible). Ceftaroline was also highly active against viridans group streptococci (MIC50/90, 0.03/0.06 μg/mL). Similar to ceftriaxone and ceftazidime, ceftaroline was active against wild-type strains of Escherichia coli (MIC50/90, 0.12/0.25 μg/mL; 94.0% susceptible) and Klebsiella pneumoniae (MIC50/90, 0.12/0.25 μg/mL; 96.8% susceptible); however, the ceftaroline activity was compromised among strains with an extended-spectrum β-lactamase-phenotype (MIC50/90, >32/>32 μg/mL for both E. coli and K. pneumoniae). In summary, ceftaroline showed potent activity against a large contemporary collection (6222) of bacterial isolates associated with ABSSSI in the USA.

Topics: Academic Medical Centers; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Microbial Sensitivity Tests; Skin Diseases, Bacterial; Soft Tissue Infections; United States

Skin and soft tissue infections (SSTI) are relatively common. Although most of these infections are mild, a few are severe, requiring hospital admission for intravenous antimicrobial therapy and, fairly frequently, surgery. These infections can be produced by any microorganism, but the most frequent is Staphylococcus aureus. Traditionally, the bacteria causing community-acquired SSTI have been sensitive to antimicrobial agents but this situation has changed with the dissemination of community-acquired microbial resistance, as has occurred in many countries with the increase in methicillin-resistant S. aureus (MRSA). These changes complicate empirical therapy and increase the risk of monotherapy being insufficient to cover all the diagnostic possibilities of SSTI. Within this epidemiological framework, ceftaroline, because of its activity against MRSA, can be used as empirical monotherapy for SSTI.

Topics: Ceftaroline; Cephalosporins; Humans; Skin Diseases, Bacterial; Soft Tissue Infections

Ceftaroline, the active form of ceftaroline fosamil, is a cephalosporin with broad-spectrum bactericidal activity against resistant Gram-positive organisms, including methicillin-resistant Staphylococcus aureus, ceftriaxone-resistant Streptococcus pneumoniae and many Enterobacteriaceae species. Ceftaroline fosamil is approved in the United States for treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia in adults.. A total of 5291 consecutive unique pediatric patient strains of clinical significance were collected from 157 US medical centers. The isolates were identified locally and forwarded to a central monitoring laboratory for reference antimicrobial susceptibility testing. S. pneumoniae isolates from the 2011 to 2012 respiratory season were serotyped. Susceptibility results were analyzed according to patient age as follows: ≤ 1 years old (yo; 1857 strains); 2-5 (1342); 6-12 (1281) and 13-17 (811).. Methicillin-resistant Staphylococcus aureus rates were slightly lower in isolates from patients 13-17 yo (39.9%) compared with other age groups (48.2-51.5%), and ceftaroline was consistently active against S. aureus isolates from all 4 age groups [minimal inhibitory concentration (MIC50/90): 0.25-05/1 μg/mL; 99.8-100.0% susceptible]. Overall, 99.8% of methicillin-resistant Staphylococcus aureus were ceftaroline susceptible (MIC50/90: 0.5/1 μg/mL). All S. pneumoniae strains (1178) were ceftaroline susceptible (MIC50/90: ≤ 0.015/0.12 μg/mL), whereas ceftriaxone susceptibility varied from only 84.8 (≤ 1 yo) to 89.7% (13-17 yo). 19A was the most frequent serotype identified among S. pneumoniae and these isolates exhibited low susceptibility to ceftriaxone (42.4%) and most other antimicrobials tested. The highest ceftaroline MIC among Haemophilus influenzae (587 strains) was 0.12 μg/mL (100.0% susceptible), and β-lactamase production rates varied from 24.2 (13-17 yo) to 30.1% (6-12 yo); 27.9% overall. Ceftaroline was also active against β-hemolytic streptococci (556 strains, highest MIC, 0.06 μg/mL). Extended-spectrum β-lactamase (ESBL)-phenotype rates among Escherichia coli/Klebsiella spp. were 6.0/5.1, 11.0/11.5, 5.1/8.3 and 11.4/14.7% for the ≤ 1, 2-5, 6-12 and 13-17 yo age groups, respectively. Ceftaroline exhibited good activity against non-ESBL phenotype strains of E. coli and Klebsiella spp. (MIC90: 0.25 μg/mL for both organisms), but had limited activity against ESBL-producing strains.. Ceftaroline demonstrated potent in vitro activity when tested against S. aureus, S. pneumoniae, H. influenzae, β-hemolytic streptococci and non-ESBL-phenotype E. coli and Klebsiella spp. strains isolated from pediatric patients, independent of patient age.

Topics: Adolescent; Anti-Bacterial Agents; Bacteria; Ceftaroline; Cephalosporins; Child; Child, Preschool; Drug Resistance, Bacterial; Humans; Infant; Infant, Newborn; Microbial Sensitivity Tests; Serotyping; Skin Diseases, Bacterial; Soft Tissue Infections

Topics: Aztreonam; Ceftaroline; Cephalosporins; Drug Therapy, Combination; Humans; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial; Soft Tissue Infections; Vancomycin

Topics: Algorithms; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Opportunistic Infections; Postoperative Care; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections

Topics: Aged; Arthroplasty, Replacement, Hip; Ceftaroline; Cephalosporins; Dose-Response Relationship, Drug; Drug Therapy, Combination; Femoral Neck Fractures; Humans; Infusions, Intravenous; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Opportunistic Infections; Reoperation; Soft Tissue Infections; Staphylococcal Infections; Surgical Wound Infection

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a novel cephalosporin exhibiting bactericidal activity in vitro against Gram-positive organisms, including meticillin-susceptible Staphylococcus aureus (MSSA), meticillin-resistant S. aureus (MRSA), β-haemolytic streptococci, viridans group streptococci (VGS) and Streptococcus pneumoniae, as well as against many common Gram-negative organisms. The objective of this study was to determine the spectrum and potency of ceftaroline against recent (2010) leading pathogens causing complicated skin and soft-tissue infections (cSSTIs) isolated in Europe. A total of 2438 isolates from the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) programme were identified as cSSTI pathogens. Isolates were collected from patients in 52 medical centres in 19 European countries. Reference susceptibility testing for ceftaroline and commonly used antimicrobials was performed by broth microdilution methodologies. Ceftaroline was very active overall against S. aureus (MIC(50/90)=0.25/1 mg/L) and inhibited 100.0% of isolates at a MIC of ≤2 mg/L. Activity against MRSA was documented (MIC(50/90)=1/2 mg/L) but was lower than that observed against MSSA (MIC(50/90)=0.25/0.25 mg/L). Ceftaroline was also very active against 460 β-haemolytic streptococci and 93 VGS (MIC(90)=0.015 mg/L and 0.06 mg/L, respectively). Ceftaroline was active against Escherichia coli (MIC(50)=0.12 mg/L) and Klebsiella pneumoniae (MIC(50)=0.06 mg/L) not expressing extended-spectrum β-lactamases, with activity similar to ceftriaxone and ceftazidime. In summary, this study documents the potent in vitro activity of ceftaroline when tested against recent pathogens isolated from patients with cSSTI in Europe.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Escherichia coli; Europe; Gram-Positive Cocci; Humans; Klebsiella; Microbial Sensitivity Tests; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Skin Infections

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with in vitro bactericidal activity against resistant Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant strains of Streptococcus pneumoniae, and common Gram-negative organisms, including wild-type Enterobacteriaceae. We evaluated the in vitro activity of ceftaroline and selected comparator agents against bacterial isolates collected from patients with skin and soft tissue infections (SSTI) and community-acquired respiratory tract infections (CARTI) in the Asia-Pacific region and South Africa. A total of 2351 isolates, 1100 from SSTI and 1251 from CARTI, were collected from 25 medical centers distributed across 8 countries as part of the 2010 AWARE ceftaroline surveillance program and tested for susceptibility by reference broth microdilution methods. Ceftaroline was very active against S. aureus (MIC50/90, 0.25/1 μg/mL; 93.4% susceptible), including MRSA (MIC50/90, 1/2 μg/mL; 80.6% susceptible). Against β-hemolytic streptococci, ceftaroline demonstrated greater activity (MIC90, 0.015 μg/mL) than penicillin (MIC90, 0.06 μg/mL). Ceftaroline was also highly active against viridans group streptococci (MIC90, 0.12 μg/mL). Similarly to ceftriaxone, ceftaroline activity against Escherichia coli (MIC50/90, >32/>32 μg/mL) and Klebsiella spp. (MIC50/90, 0.12/>32 μg/mL) was compromised by the high prevalence of isolates with an ESBL phenotype in the region, particularly in China. Ceftaroline was the most potent β-lactam tested against S. pneumoniae (MIC50/90 of 0.015/0.25 μg/mL; 99.8% susceptible by Clinical and Laboratory Standards Institute [CLSI] criteria), and it was also highly potent against Haemophilus influenzae (MIC50/90, ≤ 0.008/0.03 μg/mL; 100% susceptible by CLSI criteria). Ceftaroline was also active against H. parainfluenzae (MIC50/90, ≤ 0.008/0.015 μg/mL) and Moraxella catarrhalis (MIC50/90, 0.06/0.12 μg/mL). In summary, ceftaroline showed potent in vitro activity against a large collection of bacterial isolates (2351) associated with SSTI and CARTI from the Asia-Pacific region and South Africa.

Topics: Anti-Bacterial Agents; Asia; Ceftaroline; Cephalosporins; Community-Acquired Infections; Haemophilus influenzae; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Moraxella catarrhalis; Respiratory Tract Infections; Skin Diseases, Bacterial; Soft Tissue Infections; South Africa; Staphylococcus aureus; Streptococcus pneumoniae

The US FDA recently approved ceftaroline tosamil (ceftaroline) for the treatment of acute bacterial skin and soft structure infections (ABSSSIs) and community-acquired pneumonia. In 2010, the FDA specified a new primary end point for ABSSSI of 3 days instead of the traditional test of cure. Friedland et al. used the new FDA end point in evaluating the CANVAS 1 and 2 trials. In the exploratory modified, intention-to-treat analysis, ceftaroline showed a superior clinical response at day 3 (74 vs 66.2%; difference 7.7%; 95% CI: 1.3-14%). The superior response of ceftaroline has biologic plausibility based on the in vitro activity of the antibiotic, suggesting that a true early clinical benefit may exist. However, owing to the potential for selection bias and lack of logistic regression analysis, caution should be used when extrapolating these results to clinical practice. Future trials utilizing this new end point in prospective ABSSSI trials will show over time the true value of such an end point.

Topics: Anti-Bacterial Agents; Aztreonam; Ceftaroline; Cephalosporins; Community-Acquired Infections; Endpoint Determination; Humans; Pneumonia; Randomized Controlled Trials as Topic; Retrospective Studies; Soft Tissue Infections; Time Factors; Treatment Outcome; Vancomycin

To assess the spectrum and potency of ceftaroline, a novel anti-methicillin-resistant staphylococcal cephalosporin, against a 2008 surveillance collection of clinical isolates from patients in the USA and Europe.. A collection of 14 169 isolates of various bacterial species from complicated skin and skin structure infections (cSSSIs) was tested for susceptibility to ceftaroline and 19 comparator agents in a central reference laboratory using CLSI broth microdilution methods. Organisms were received from 55 medical centres; 27 in the USA and 28 in Europe (12 countries, including Israel). The clonality of isolates of Staphylococcus aureus with elevated ceftaroline MICs (4 mg/L) was determined by PFGE and single and multilocus sequence typing, and the mechanism of ceftaroline non-susceptibility was assessed by molecular methods (PCR amplification and sequencing).. Ceftaroline, the active component of the parenteral prodrug ceftaroline fosamil, was active against 2988 methicillin-resistant S. aureus (MRSA) isolates, with an MI₉₀ of 1 mg/L. The MIC₉₀ for methicillin-susceptible strains was 0.25-0.5 mg/L. Ceftaroline was additionally active against coagulase-negative staphylococci (MIC₉₀, 0.5-1 mg/L), Enterococcus faecalis (MIC₅₀, 2 mg/L), β-haemolytic and viridans group streptococci (MIC₉₀, 0.015-0.25 mg/L) and three commonly isolated Enterobacteriaceae (Escherichia coli, Klebsiella spp. and Proteus mirabilis; MIC₉₀ values of 0.25 to > 16 mg/L). All but four isolates of MRSA (0.13%) had ceftaroline MIC values of ≤ 2 mg/L. The isolates for which ceftaroline MICs were 4 mg/L were clonal (single Greek hospital) and had detectable mecA mutations (N146K, N204K, E150K and H351N).. The ceftaroline yearly (2008) surveillance for the USA and Europe documented low MIC₅₀/₉₀ values for MRSA isolates at 1/1 and 1/2 mg/L, respectively. Ceftaroline demonstrated promising potency and coverage against Gram-positive and -negative pathogens known to cause cSSSIs, including MRSA and β-haemolytic streptococci.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials, Phase III as Topic; Europe; Gram-Negative Bacteria; Gram-Positive Cocci; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Population Surveillance; Skin Diseases, Bacterial; Soft Tissue Infections; Treatment Outcome; United States

Complicated skin and skin structure infections (cSSSIs) continue to pose a significant clinical challenge. The most frequent cause of these infections is Staphylococcus aureus, although other organisms, including Streptococcus pyogenes and, in certain circumstances, Enterobacteriaceae, are also involved. The relentless increase in methicillin resistance among S. aureus isolated in hospitals throughout the world has made it important to provide coverage for these organisms when treating cSSSIs in hospitals. More recently, however, there has been a striking increase in methicillin resistance among staphylococci isolated from infections acquired in the community, particularly in the USA. As a result, previous recommendations for empirical therapy of these important infections are now outdated. The papers in this Supplement detail the properties of a new broad-spectrum cephalosporin that has activity against MRSA and is, thus, an outstanding candidate for empirical therapy of cSSSIs. The papers included provide data on the in vitro activity, pharmacokinetics and pharmacodynamics as well as the clinical efficacy of ceftaroline fosamil, which is a welcome addition to our therapeutic armamentarium against cSSSIs.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials, Phase III as Topic; Drug Resistance, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Skin Infections

Ceftaroline fosamil is a new β-lactam antibiotic with an altered 3' side chain that allows it to interact with penicillin-binding protein (PBP) 2a, resulting in lower MIC values for methicillin-resistant Staphylococcus aureus (MRSA). Large MRSA collections repeatedly demonstrate MIC₉₀ values of 1 mg/L. The pharmacokinetics for ceftaroline fosamil are straightforward and reminiscent of many other cephalosporin antibiotics, with a terminal half-life of ∼2.6 h. Pharmacodynamic evaluation demonstrates that relatively short free drug T  >  MIC results in stasis or 1 log₁₀ cfu/g bacterial kill (mean values for four S. aureus isolates of 26% and 33% of the dosing interval, respectively). Monte Carlo simulation demonstrated high expected target attainment rates (> 97%) and clinical trial data showed clinically evaluable and microbiologically evaluable cure rates (96.7%) that are highly concordant with the pharmacodynamic analyses. Clinical trial data for ceftaroline fosamil are in excellent concordance with the pharmacodynamic analysis. Ceftaroline fosamil at a dose of 600 mg administered intravenously every 12 h is highly likely to be successful in clinical practice for treatment of complicated skin and skin structure infections.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Half-Life; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Penicillin-Binding Proteins; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections