ppi-0903 and Skin-Diseases--Bacterial

Tedizolid, the active moiety of tedizolid phosphate, is approved in the United States, the European Union, Canada and a number of other countries for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). This network meta-analysis (NMA) evaluates the comparative effectiveness of tedizolid and other antibacterials indicated for the treatment of ABSSSI caused by MRSA.. Systematic review of 10 databases was undertaken to inform an NMA to estimate the relative effectiveness of tedizolid and established monotherapy comparators (ceftaroline, daptomycin, linezolid, teicoplanin, tigecycline, vancomycin) for treating MRSA-associated ABSSSI. Randomized controlled trials enrolling adults with ABSSSI or complicated skin and skin structure infections caused by suspected/documented MRSA were eligible for inclusion. Networks were developed based on similarity of study design, patient characteristics, outcome measures and available data. Outcomes of interest included clinical response at end of therapy (EOT), post-therapy evaluation (PTE) or test-of-cure assessment and treatment discontinuations resulting from adverse events (AEs). Bayesian NMA was conducted for each outcome using fixed-effects and random effects models.. Literature searches identified 3,618 records; 15 trials met the inclusion criteria and were considered suitable for NMA comparison. In fixed-effects models, tedizolid had higher odds of clinical response at EOT (odds ratio [OR], 1.7; credible interval, 1.0, 3.0) and PTE than vancomycin (OR, 1.6; credible interval, 1.1, 2.5). No differences in odds of clinical response at EOT or PTE were observed between tedizolid and other comparators. There was no evidence of a difference among treatments for discontinuation due to AEs. Results from random effects and fixed-effects models were generally consistent.. Tedizolid was superior to vancomycin for clinical response at EOT and PTE. There was no evidence of a difference between tedizolid and other comparators and no evidence of a difference between tedizolid and all comparators when evaluating discontinuation due to AEs. These findings suggest that tedizolid provides an alternative option for the management of serious skin infections caused by suspected or documented MRSA. This study is subject to the limitations inherent in all NMAs, and the results should be interpreted accordingly.

Topics: Anti-Bacterial Agents; Bayes Theorem; Ceftaroline; Cephalosporins; Daptomycin; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Organophosphates; Oxazoles; Oxazolidinones; Skin Diseases, Bacterial; Staphylococcal Infections; Tetrazoles; Vancomycin

A systematic literature review and meta-analysis were conducted to estimate the antibacterial treatment effect for linezolid and ceftaroline to inform on the design of acute bacterial skin and skin structure infection (ABSSSI) noninferiority trials. The primary endpoints included an early clinical treatment response (ECTR) defined as cessation of lesion spread at 48 to 72 h postrandomization and the test-of-cure (TOC) response defined as total resolution of the infection at 7 to 14 days posttreatment. The systematic review identified no placebo-controlled trials in ABSSSI, 4 placebo-controlled trials in uncomplicated skin and soft tissue infection as a proxy for placebo in ABSSSI, 12 linezolid trials in ABSSSI, 3 ceftaroline trials in ABSSSI, and 2 trials for nonantibacterial treatment. The ECTR rates at 48 to 72 h and corresponding 95% confidence intervals (CI) were 78.7% (95% CI, 61.1 to 96.3%) for linezolid, 74.0% (95% CI, 69.7 to 78.3%) for ceftaroline, and 59.0% (95% CI, 52.8 to 65.3%) for nonantibacterial treatment. The early clinical treatment effect could not be estimated, given no available placebo or proxy for placebo data for this endpoint. Clinical, methodological, and statistical heterogeneity influenced the selection of trials for the meta-analysis of the TOC treatment effect estimation. The pooled estimates of the TOC treatment response were 31.0% (95% CI, 6.2 to 55.9%) for the proxy for placebo, 88.1% (95% CI, 81.0 to 95.1%) for linezolid, and 86.1% (95% CI, 83.7 to 88.6%) for ceftaroline. The TOC clinical treatment effect estimation was 25.1% for linezolid and 27.8% for ceftaroline. The antibacterial treatment effect estimation at TOC will inform on the design and analysis of future noninferiority ABSSSI clinical trials.

Topics: Adolescent; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Humans; Linezolid; Randomized Controlled Trials as Topic; Skin; Skin Diseases, Bacterial

Skin infections have traditionally been classified by the US FDA as uncomplicated and complicated. In August 2010, the FDA released a new guidance document for the development of drugs to treat acute bacterial skin and skin structure infections (ABSSSI) and this was updated in 2013. Several new issues were addressed and henceforth skin infections in clinical trials were termed ABSSSI. In the USA, the annual prevalence of methicillin-resistant Staphylococcus aureus-related skin infections have continuously increased from 32.7% in 1998 to 53.8% in 2007. Ceftaroline fosamil is the only cephalosporin approved in the USA for monotherapy treatment of ABSSSI including infections caused by methicillin-resistant S. aureus. The efficacy of ceftaroline fosamil was shown in the CANVAS clinical trials. The CANVAS Day-3 analyses met an earlier, primary efficacy time point requested by the FDA. Ceftaroline has minimal drug-drug interactions, is well tolerated and possesses the safety profile associated with the cephalosporin class.

Topics: Acute Disease; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Drug Approval; Drug Design; Drug Interactions; Humans; Methicillin-Resistant Staphylococcus aureus; Skin Diseases, Bacterial; Staphylococcal Infections; United States; United States Food and Drug Administration

Bacterial resistance is increasing on a global basis, making treatment options more limited. The development of new agents to meet this threat is a matter of urgency. Ceftaroline fosamil , a member of an advanced cephalosporin class of antimicrobials, is currently approved by the US Food and Drug Administration for use in for acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia. Ceftaroline displays activity against Gram-positive and Gram-negative bacteria, including both methicillin-susceptible and resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae (including penicillin- and ceftriaxone-resistant strains), respiratory pathogens (such as Moraxella catarrhalis and Haemophilus influenzae, including beta-lactamase-producing strains) and limited coverage against Enterobacteriaceae.. Chemistry, mechanism of action, spectrum of activity, resistance, pharmacokinetics/pharmacodynamics, indications for use, safety and special populations are covered in this review.. Ceftaroline's unique activity against MRSA and penicillin- and ceftriaxone-resistant S. pneumoniae strains is due to its high affinity for penicillin binding protein (PBP)-2a and PBP-2x, respectively. In randomized, double-blinded, clinical trials, ceftaroline fosamil was found to be non-inferior to ceftriaxone for the treatment CABP and to vancomycin plus aztreonam for ABSSSI. Substantial differences between the cephalosporins exist. Ceftaroline has unique characteristics that may make it useful in specific clinical circumstances, especially against multi-drug-resistant Gram-positive organisms.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Drug Resistance, Bacterial; Humans; Pneumonia, Bacterial; Skin Diseases, Bacterial

Ceftaroline fosamil is a cephalosporin antibacterial approved by the US Food and Drug Administration (FDA) for use in the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). After intravenous administration, ceftaroline fosamil is rapidly converted to its bioactive metabolite, ceftaroline. Ceftaroline has broad-spectrum in vitro activity against Gram-positive and Gram-negative bacteria, including contemporary resistant Gram-positive phenotypes, such as methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae. Because of its unique spectrum of activity, the Clinical and Laboratory Standards Institute (CLSI) designated ceftaroline as a member of a new subclass of β-lactam antimicrobials, cephalosporins with anti-MRSA activity. The activity of ceftaroline against S. aureus extends to heteroresistant vancomycin-intermediate, vancomycin-intermediate, vancomycin-resistant and daptomycin-nonsusceptible isolates. Ceftaroline has low minimum inhibitory concentrations (MICs) for all tested species of streptococci, and has potent activity against S. pneumoniae isolates with varying degrees of penicillin resistance. The activity of ceftaroline is limited against Enterococcus faecalis and Enterococcus faecium and against anaerobes such as Bacteroides fragilis. The in vitro activity of ceftaroline includes many Gram-negative pathogens, but does not extend to bacteria that produce extended-spectrum β-lactamases, class B metallo-β-lactamases or AmpC cephalosporinases, or to most nonfermentative Gram-negative bacilli. Ceftaroline fosamil has been studied for the treatment of complicated skin and skin structure infections (cSSSI) and community-acquired pneumonia (CAP) in phase III randomized, double-blind, international, multicentre noninferiority clinical trials. Two identical trials (CANVAS 1 and CANVAS 2) compared the efficacy of ceftaroline fosamil with that of vancomycin plus aztreonam in 1378 adults with cSSSI. Results demonstrated that ceftaroline was noninferior to vancomycin plus aztreonam, with 91.6% in the ceftaroline fosamil group (pooled analysis) achieving clinical response compared with 92.7% in the vancomycin plus aztreonam group (difference -1.1%, 95% CI -4.2, 2.0). An additional analysis evaluated clinical cure in a subgroup of patients who met the FDA guidance definition of ABSSSI at treatment day 3. Clinical response, defined as cessation o

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Double-Blind Method; Humans; Pneumonia, Bacterial; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial

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

To review the pharmacology, microbiology, chemistry, in vitro activity, pharmacokinetics, clinical efficacy, safety, dosage, and administration of ceftaroline fosamil (Teflaro, Forest Laboratories, Inc.), a novel parenteral broad-spectrum cephalosporin approved by the Food and Drug Administration (FDA) on October 29, 2010, for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).. A search of MEDLINE (1966-July 2011) using the search terms ceftaroline fosamil, ceftaroline, TAK-599, PPI-0903, PPI-0903M, and T-91825 was performed. Supplementary sources included program abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society of Microbiology, European Congress on Clinical Microbiology and Infectious Diseases, and the Infectious Diseases Society of America from 2005 to 2010, as well as information available from the manufacturer's Web site.. All English-language articles identified from the data sources were evaluated. In vitro, preclinical, and Phase 1, 2, and 3 clinical trials were included.. Clinical trials have been conducted evaluating use of ceftaroline for treatment of ABSSSI and CABP. Safety data from Phase 1, 2, and 3 clinical trials suggest that it is well tolerated and has a safety and tolerability profile common to the cephalosporin class. Ceftaroline has excellent in vitro activity against gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), which makes it an attractive monotherapy for the treatment of ABSSSI. However, it lacks activity against problem gram-negative bacteria (eg, Pseudomonas spp.), which will likely limit its use for serious health care-associated infections. While its role in treating CABP is supported by excellent in vitro activity against Streptococcus pneumoniae and clinical efficacy data, currently available comparators may offer some advantages over ceftaroline. Finally, data are lacking to assess its role in the treatment of serious infections due to MRSA (eg, pneumonia, bacteremia).. These considerations should be part of the formulary review process; however, when considering the significant role MRSA plays in ABSSSI in both the community and hospital settings, we believe that ceftaroline will provide clinicians with a welcome option in addition to currently available anti-MRSA therapies for the treatment of ABSSSI.

Topics: Animals; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Drug Evaluation, Preclinical; Humans; Methicillin-Resistant Staphylococcus aureus; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial; Staphylococcal Infections

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

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Humans; Pneumonia, Bacterial; Skin Diseases, Bacterial

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

Infections caused by resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) are now posing a major health risk for patients in hospital and community settings. There is a need to evaluate new antibiotics that would offer reliable clinical efficacy combined with a favorable safety profile for the treatment of such infections. Ceftaroline is a new member of the cephalosporin class of antibiotics with expanded activity against Gram-positive pathogens such as MRSA, vancomycin-intermediate S. aureus, vancomycin-resistant S. aureus and multidrug-resistant Streptococcus pneumoniae, while retaining good activity against common Gram-negative organisms. Phase II and III studies have shown ceftaroline to be an effective and well-tolerated treatment for complicated skin and skin-structure infections compared with standard therapy. Trials are ongoing in the treatment of community-acquired pneumonia.

Topics: Adult; Animals; Ceftaroline; Cephalosporins; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Mice; Skin Diseases, Bacterial; Treatment Outcome

Ceftaroline has in vitro activity against bacterial isolates, including methicillin-resistant Staphylococcus aureus. This is the first study to investigate ceftaroline fosamil in pediatric patients with acute bacterial skin and skin structure infections (ABSSSIs).. A multicenter, observer-blinded study (NCT01400867) in pediatric patients (2 months-17 years of age) with ABSSSIs. Patients were randomized 2:1 to receive intravenous (IV) ceftaroline fosamil or IV comparator (vancomycin or cefazolin, plus optional aztreonam) with optional switch to oral antibacterials from Day 4. Safety and clinical outcomes were assessed.. Of 163 enrolled patients, 159 received treatment. Treatment groups were comparable for baseline characteristics. Rates of study drug-related treatment-emergent adverse events were similar for ceftaroline fosamil [22% (23/106)] and comparator [23% (12/53)]. One serious adverse event, considered to be related to IV study drug, occurred in the ceftaroline fosamil group (hypersensitivity). In both the treatment groups, 85% (ceftaroline fosamil, 91/107 and comparator, 44/52) of the modified intent-to-treat population achieved early clinical response (≥20% reduction in infection area from baseline). Clinical cure rates at test-of-cure were high [ceftaroline fosamil, 94% (101/107) and comparator, 87% (45/52)]. For patients evaluated 8 to 15 days after the last dose of any antibiotic (IV or oral), from whom methicillin-resistant Staphylococcus aureus was initially isolated, a favorable microbiologic response (reflecting the efficacy of oral/IV therapy and capturing a relapse or reinfection) was achieved with ceftaroline fosamil [89% (16/18)] and comparator [57% (4/7)].. Ceftaroline fosamil, with optional oral switch, was as well-tolerated and effective in pediatric patients with ABSSSIs as comparator therapy.

Topics: Acute Disease; Adolescent; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Child; Child, Preschool; Female; Humans; Infant; Male; Microbial Sensitivity Tests; Skin Diseases, Bacterial; Staphylococcus aureus; Streptococcus pyogenes; 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

Ceftaroline, the active form of ceftaroline fosamil, is a broad-spectrum cephalosporin antibiotic. A population pharmacokinetic (PPK) model for ceftaroline was developed in NONMEM® using data from 185 healthy subjects and 92 patients with acute bacterial skin and skin structure infection (ABSSSI). Data from 128 patients with community-acquired bacterial pneumonia (CABP) were used for external model validation. Healthy subjects received 50-2,000 mg ceftaroline fosamil via intravenous (IV) infusion over 1 hour or intramuscular (IM) injection q12h or q24h. ABSSSI and CABP patients received 600 mg of ceftaroline fosamil IV over 1 hour q12h. A three-compartment model with zero-order IV or parallel first-order IM input and first-order elimination described ceftaroline fosamil PK. A two-compartment model with first-order conversion of prodrug to ceftaroline and parallel linear and saturable elimination described ceftaroline PK. Creatinine clearance was the primary determinant of ceftaroline exposure. Good agreement between the observed data and both population (r(2)  = 0.93) and individual post-hoc (r(2)  = 0.98) predictions suggests the PPK model can adequately approximate ceftaroline PK using covariate information. Such a PPK model can evaluate dose adjustments for patients with renal impairment and generate ceftaroline exposures for use in pharmacokinetic-pharmacodynamic assessments of efficacy in patients with ABSSSI or CABP.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Double-Blind Method; Female; Humans; Infusions, Intravenous; Injections, Intramuscular; Male; Middle Aged; Models, Biological; Pneumonia, Bacterial; Skin Diseases, Bacterial; Young Adult

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.

Topics: Acute Disease; Aged; Aged, 80 and over; Anti-Bacterial Agents; Aztreonam; Biomarkers; Ceftaroline; Cephalosporins; Drug Administration Schedule; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Injections, Intravenous; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Retrospective Studies; Skin Diseases, Bacterial; Treatment Outcome; Vancomycin

Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of complicated skin and skin-structure infection (cSSSI). Increasing antimicrobial resistance in cSSSI has led to a need for new safe and effective therapies. Ceftaroline was evaluated as treatment for cSSSI in 2 identical phase 3 clinical trials, the pooled analysis of which is presented here. The primary objective of each trial was to determine the noninferiority of the clinical cure rate achieved with ceftaroline monotherapy, compared with that achieved with vancomycin plus aztreonam combination therapy, in the clinically evaluable (CE) and modified intent-to-treat (MITT) patient populations.. Adult patients with cSSSI requiring intravenous therapy received ceftaroline (600 mg every 12 h) or vancomycin plus aztreonam (1 g each every 12 h) for 5-14 days.. Of 1378 patients enrolled in both trials, 693 received ceftaroline and 685 received vancomycin plus aztreonam. Baseline characteristics of the treatment groups were comparable. Clinical cure rates were similar for ceftaroline and vancomycin plus aztreonam in the CE (91.6% vs 92.7%) and MITT (85.9% vs 85.5%) populations, respectively, as well as in patients infected with MRSA (93.4% vs 94.3%). The rates of adverse events, discontinuations because of an adverse event, serious adverse events, and death also were similar between treatment groups.. Ceftaroline achieved high clinical cure rates, was efficacious against cSSSI caused by MRSA and other common cSSSI pathogens, and was well tolerated, with a safety profile consistent with the cephalosporin class. Ceftaroline has the potential to provide a monotherapy alternative for the treatment of cSSSI.. ClinicalTrials.gov identifiers: NCT00424190 for CANVAS 1 and NCT00423657 for CANVAS 2.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Aztreonam; Ceftaroline; Cephalosporins; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Skin Diseases, Bacterial; 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

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

The objective of this study was to determine if real-world ceftaroline treatment in adults hospitalized for acute bacterial skin and skin structure infections (ABSSSI) is associated with decreased infection-related length of stay (LOS

Topics: Acute Disease; Adult; Aged; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Female; Humans; Male; Middle Aged; Retrospective Studies; Skin; Skin Diseases, Bacterial; Treatment Outcome; Vancomycin

This post-hoc analysis compared the pharmacokinetics and clinical outcomes of ceftaroline fosamil 600 mg every 12 (q12h) versus every 8 hours (q8h) in patients with acute bacterial skin and skin-structure infection (ABSSSI) and signs of sepsis. Clinical outcomes at test-of-cure in patients with ABSSSI and systemic inflammatory signs/systemic inflammatory response syndrome (SIRS) as well as ceftaroline minimum inhibitory concentrations (MICs) against baseline pathogens were compared between the COVERS trial (ceftaroline fosamil 600 mg q8h, 2-h infusion) and the CANVAS 1 and 2 trials (ceftaroline fosamil 600 mg q12h, 1-h infusion). Ceftaroline exposure among patients in COVERS with or without markers of sepsis was compared using population pharmacokinetic modelling. In COVERS, 62% (312/506) and 41% (208/506) of ceftaroline fosamil-treated patients had ≥1 systemic inflammatory sign or SIRS, respectively, compared with 55% (378/693) and 22% (155/693), respectively, in the CANVAS trials. Clinical cure rates for the modified intent-to-treat population in COVERS and CANVAS were similar for ceftaroline fosamil-treated patients with ≥1 sign of sepsis [82% (255/312) and 85% (335/394)] and for those with SIRS [84% (168/199) and 85% (131/155)]. Ceftaroline MIC distributions were similar across trials. Sepsis did not affect predicted individual steady-state ceftaroline exposure. Clinical cure rates in patients with ≥1 systemic inflammatory sign or SIRS were comparable for both ceftaroline fosamil dosage regimens. Pathogen susceptibilities to ceftaroline were similar across trials. Ceftaroline exposure was not affected by disease severity. Ceftaroline fosamil 600 mg q12h is a robust dosage regimen for most ABSSSI patients with sepsis [ClinicalTrials.gov ID: NCT01499277, NCT00424190, NCT00423657].

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteria; Ceftaroline; Cephalosporins; Clinical Trials, Phase III as Topic; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Randomized Controlled Trials as Topic; Retrospective Studies; Skin Diseases, Bacterial; Systemic Inflammatory Response Syndrome; Treatment Outcome

Ceftaroline fosamil has recently received US Food and Drug Administration approval for treatment of acute bacterial skin/skin structure infections (SSSIs), including those caused by methicillin-resistant Staphylococcus aureus and community-acquired bacterial pneumonia for pediatric patients ≥2 months old. We evaluated the potency and spectrum of ceftaroline and comparators when tested against community-acquired respiratory tract infection (CARTI) and SSSI pathogens from pediatric patients. A total of 3141 consecutive, unique pediatric patient isolates of clinical significance (1460 CARTI and 1681 SSSI isolates) were collected from 29 US medical centers and tested for susceptibility to ceftaroline and comparators by broth microdilution methods. The organism collection included Streptococcus pneumoniae (n = 754), Haemophilus influenzae (487), S. aureus (1399), β-hemolytic streptococci (214), Enterobacteriaceae (112), Pseudomonas aeruginosa (58), Klebsiella spp. (39), Escherichia coli (26) and miscellaneous other bacteria (52). Susceptibility results were analyzed according to patient age as follows: ≤1, 2-5, 6-12 and 13-17 years old. Overall, 99%-100% of Gram-positive isolates and H. influenzae were susceptible to ceftaroline according to Clinical and Laboratory Standards Institute clinical breakpoint criteria. Ceftaroline exhibited potent in vitro activity against bacterial pathogens from CARTI and SSSI recently (2012-2014) collected from pediatric patients in US medical centers. Ceftaroline was particularly active against methicillin-resistant S. aureus from SSSI ([minimum inhibitory concentration for 50% and 90% of isolates (MIC50/90,)] and ceftriaxone-nonsusceptible isolates of S. pneumoniae from CARTI (MIC50/90, 0.25/0.5 μg/mL; 98.3% susceptible).

Topics: Adolescent; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Child; Child, Preschool; Community-Acquired Infections; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Haemophilus influenzae; Hospitals; Humans; Infant; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Respiratory Tract Infections; Retrospective Studies; Skin Diseases, Bacterial; Staphylococcal Infections; Streptococcus pneumoniae; United States

Ceftaroline, the active form of the prodrug ceftaroline fosamil, is approved for use in adults with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infections (ABSSSI) in the United States and for similar indications in Europe. Pharmacokinetic (PK) data from 5 pediatric (birth to <18 years) studies of ceftaroline fosamil were combined with PK data from adults to update a population PK model for ceftaroline and ceftaroline fosamil. This model, based on a data set including 305 children, was used to conduct simulations to estimate ceftaroline exposures and percentage of time that free drug concentrations were above the minimum inhibitory concentration (%fT>MIC) for pediatric dose regimens. With dose regimens of 8 mg/kg every 8 hours (q8h) in children aged 2 months to <2 years and 12 mg/kg (up to a maximum of 400 mg) q8h in children aged 2 years to <18 years or 600 mg q12h in children aged 12 to <18 years, >90% of children were predicted to achieve a target of 36% fT>MIC at an MIC of 2 mg/L, and >97% were predicted to achieve 44% fT>MIC at an MIC of 1 mg/L. Thus, high PK/pharmacodynamic target attainment would be maintained in children for targets associated with 1-log kill of Staphylococcus aureus and Streptococcus pneumoniae. The predicted ceftaroline exposures for these dose regimens were similar to those in adults given 600 mg q12h ceftaroline fosamil. This work contributed to the approval of dose regimens for children aged 2 months to <18 years by the FDA and EMA, which are presented.

Topics: Acute Disease; Adolescent; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Child; Child, Preschool; Clinical Trials as Topic; Community-Acquired Infections; Computer Simulation; Female; Humans; Infant; Male; Microbial Sensitivity Tests; Models, Biological; Pneumonia, Bacterial; Skin Diseases, Bacterial; Staphylococcus aureus; Streptococcus pneumoniae

The Clinical Assessment Program and Teflaro(®) Utilization Registry (CAPTURE) is a multicenter registry study of acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP) patients treated with ceftaroline fosamil in the US. Data for this analysis were collected between August 2011 and February 2013 at US study centres by randomly ordered chart review. Clinical success rates among ABSSSI patients were >81% when ceftaroline fosamil was used as first- or second-line therapy, including monotherapy and concurrent therapy. Among CABP patients, clinical success rates were >77% among first-line and second-line patients and patients who received first-line concurrent therapy or second line monotherapy or concurrent therapy. For CABP patients treated with ceftaroline fosamil as first-line monotherapy, the clinical success rate was 70%. Ceftaroline fosamil is an effective treatment option for patients with ABSSSI or CABP with similar clinical success rates when used as first-line or second-line treatment.

Topics: Adult; Aged; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Female; Humans; Male; Middle Aged; Pneumonia, Bacterial; Registries; Retrospective Studies; Skin Diseases, Bacterial

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

Ceftaroline fosamil is a novel cephalosporin approved by the United States Food and Drug Administration (US FDA) for treatment of acute bacterial skin and skin structure infection, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). We evaluated the activity of ceftaroline and comparator agents tested against S. aureus isolated from surgical skin and skin structure infections (SSSI).. Clinically substantial isolates (one/patient episode) from SSSI were consecutively collected from 64 medical centers in the United States over a 6-y period (2008-2013) and tested for susceptibility by broth microdilution methods against ceftaroline and several comparator agents.. Among 794 strains tested, 50.5% were MRSA. Ceftaroline was active against all methicillin-susceptible Staphylococcus aureus (MSSA; minimal inhibitory concentration [MIC]90, 0.25 mcg/mL) and nearly all MRSA (MIC90, 1 mcg/mL). Against MSSA, ceftaroline was 16-fold more potent than ceftriaxone (MIC90, 4 mcg/mL) and the highest ceftaroline MIC was 0.5 mcg/mL. Among MRSA, 97.5% and 100.0% of strains were inhibited at ≤1 and ≤2 mcg/mL of ceftaroline. Furthermore, 27.4% and 67.5% of MRSA were resistant to clindamycin and levofloxacin, respectively. Daptomycin (MIC50/90, 0.25/0.5 mcg/mL), linezolid (MIC50/90, 1/2 mcg/mL), tigecycline (MIC50/90, 0.06/0.12 mcg/mL) and vancomycin (MIC50/90, 1/2 mcg/mL) were also highly active against S. aureus strains.. Ceftaroline exhibited potent in vitro activity against S. aureus causing SSSI in a large number of US hospitals, including MRSA. On the basis of this in vitro data, ceftaroline fosamil may represent a valuable option for treatment of surgical SSSI, and should be further evaluated as an agent for surgical prophylaxis that would cover MRSA.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Skin Diseases, Bacterial; Staphylococcal Infections; Staphylococcus aureus

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

The Clinical Assessment Program and Teflaro(®) Utilization Registry (CAPTURE) is a multicenter retrospective study, conducted in the USA, describing the contemporary use of ceftaroline fosamil. Ceftaroline is primarily excreted by the kidneys and the dose should be reduced in patients with moderate to severe renal insufficiency. This article describes the clinical effectiveness of ceftaroline fosamil in the treatment of acute bacterial skin and skin structure infection (ABSSSI) or community-acquired bacterial pneumonia (CABP) patients with renal insufficiency. There were 985 ABSSSI patients and 344 CABP patients, of which 22 and 31%, respectively, had renal insufficiency. Ceftaroline fosamil was mostly administered to patients as second-line therapy. Overall clinical success was 78-91% among ABSSSI or CABP patients with renal insufficiency and, overall, >50% of patients were discharged to home. Ceftaroline fosamil is an effective treatment option for ABSSSI or CABP patients with renal insufficiency.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Female; Humans; Male; Middle Aged; Pneumonia; Renal Insufficiency; Retrospective Studies; Skin Diseases, Bacterial; Young Adult

In this study, the probability of pharmacokinetic/pharmacodynamic target attainment (PTA) of ceftaroline against clinical isolates causing community-acquired bacterial pneumonia (CABP) and complicated skin and skin-structure infection (cSSSI) in Europe was evaluated. Three dosing regimens were assessed: 600 mg every 12 h (q12 h) as a 1-h infusion (standard dose) or 600 mg every 8 h (q8 h) as a 2-h infusion in virtual patients with normal renal function; and 400 mg q12 h as a 1-h infusion in patients with moderate renal impairment. Pharmacokinetic and microbiological data were obtained from the literature. The PTA and the cumulative fraction of response (CFR) were calculated by Monte Carlo simulation. In patients with normal renal function, the ceftaroline standard dose (600 mg q12 h as a 1-h infusion) can be sufficient to treat CABP due to ceftazidime-susceptible (CAZ-S) Escherichia coli, CAZ-S Klebsiella pneumoniae, meticillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis (CFR>90%). However, against meticillin-resistant S. aureus (MRSA), the CFR was 72%. In cSSSI, the CFR was also <80% for MRSA. Administration of ceftaroline 600 mg q8 h as a 2-h infusion or 400 mg q12 h as a 1-h infusion in patients with moderate renal insufficiency provided a high probability of treatment success (CFR ca. 100%) for most micro-organisms causing CABP and cSSSI, including MRSA and penicillin-non-susceptible S. pneumoniae. These results suggest that in patients with normal renal function, ceftaroline 600 mg q8 h as a 2-h infusion may be a better option than the standard dose, especially if the MRSA rate is high.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Europe; Humans; Infusions, Intravenous; Kidney; Kidney Function Tests; Monte Carlo Method; Pneumonia, Bacterial; Skin Diseases, Bacterial; Treatment Outcome

A total of 4533 isolates from community-acquired respiratory tract infections (CARTIs) and 8446 from skin and skin structure infections (SSSIs) were consecutively collected in 149 US medical centers in 2013. Strains were susceptibility tested by broth microdilution method against ceftaroline and numerous comparators. Ceftaroline (MIC(50/90), ≤0.015/0.12 μg/mL) was more potent than ceftriaxone (MIC(50/90), ≤0.06/1 μg/mL) against Streptococcus pneumoniae and highly active against ceftriaxone-nonsusceptible strains (n=201; MIC(90), 0.25 μg/mL). Ceftaroline was also very active against Haemophilus influenzae (MIC(50/90), 0.008/0.015 μg/mL), methicillin-susceptible (MIC(50/90), 0.25/0.25 μg/mL) and methicillin-resistant Staphylococcus aureus (MIC(50/90), 1/1 μg/mL), and β-hemolytic streptococci (highest MIC, 0.03 μg/mL). Ceftaroline exhibited good activity against non-extended-spectrum β-lactamase (ESBL) phenotype isolates of Klebsiella spp. and Escherichia coli (96.7% susceptible and MIC(90) of 0.25 μg/mL for both) but limited activity against ESBL phenotype isolates. In summary, ceftaroline exhibited potent in vitro activity against a large collection of bacterial isolates causing CARTI and SSSI in US medical centers.

Topics: Academic Medical Centers; Anti-Bacterial Agents; Bacteria; Ceftaroline; Cephalosporins; Microbial Sensitivity Tests; Respiratory Tract Infections; Skin Diseases, Bacterial; United States

Bacterial skin and skin-structure infections (SSSIs) are frequent settings for antibiotic use. We surveyed their UK aetiology and pathogen susceptibility, including susceptibility to ceftaroline.. Consecutive SSSI isolates were collected at 35 UK hospitals, to a maximum of 60/site, together with 15 'supplementary' MRSA/site. Isolates were re-identified and BSAC susceptibility testing was performed, with parallel CLSI agar testing for ceftaroline.. Isolates (n = 1908) were collected from 1756 hospitalized patients, predominantly with surgical and traumatic infections, abscesses and infected ulcers and largely from general medicine and general surgery patients. They included 1271 Staphylococcus aureus (201 MRSA), 162 β-haemolytic streptococci, 269 Enterobacteriaceae, 138 Pseudomonas aeruginosa and 37 enterococci. Most (944/1756) patients had monomicrobial MSSA infections. Rates of resistance to quinolones, gentamicin and cephalosporins were <20% in Enterobacteriaceae and <10% in P. aeruginosa. MRSA rates varied greatly among hospitals and were 2.5-fold higher in general medicine than in general surgery patients. At breakpoint, ceftaroline inhibited: (i) all MSSA and 97.6% of MRSA, with MICs of 2 mg/L for the few resistant MRSA; (ii) all β-haemolytic streptococci; and (iii) 83% of Enterobacteriaceae. High-level ceftaroline resistance in Enterobacteriaceae involved ESBLs or AmpC enzymes. Ceftaroline MICs by CLSI methodology generally equalled those by BSAC or were 2-fold higher, but this differential was 4-16-fold for P. aeruginosa.. Irrespective of patient group, SSSIs were dominated by S. aureus. Most pathogens were susceptible, but 15.8% of S. aureus were MRSA, with locally higher prevalence.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteria; Ceftaroline; Cephalosporins; Cross Infection; Drug Resistance, Bacterial; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Skin Diseases, Bacterial; United Kingdom; Young Adult

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

Ceftaroline-avibactam and comparator agents were tested against clinical isolates collected at 174 medical centers from patients with acute bacterial skin and skin structure infection (ABSSSI) in the United States (USA) during 2010-2012. Isolates were processed at the medical centers and forwarded to a central laboratory for confirmatory identification and susceptibility testing using reference methods. Ceftaroline-avibactam was highly active against methicillin-susceptible (MIC50/90, 0.25/0.25 μg/mL) and methicillin-resistant Staphylococcus aureus (MRSA; MIC50/90, 0.5/1 μg/mL). Vancomycin, tigecycline, daptomycin, and linezolid were also active (>99.9% susceptible) against MRSA (51.4% of S. aureus), but activity against MRSA was decreased for erythromycin, levofloxacin, and clindamycin (10.8, 40.3, and 81.9% susceptible, respectively). β-Hemolytic streptococci were highly susceptible to β-lactam antimicrobials, including ceftaroline-avibactam (MIC50/90, ≤0.03/≤0.03 μg/mL). Ceftaroline-avibactam was very active against Escherichia coli and Klebsiella pneumoniae (MIC50/90, 0.03/0.06 and 0.06/0.25 μg/mL, respectively) including extended-spectrum β-lactamase (ESBL) screen-positive phenotypes (MIC50/90, 0.06/0.12 and 0.12/1 μg/mL, respectively). Susceptibility of ESBL screen-positive E. coli and K. pneumoniae was 100.0/97.9% for tigecycline and 99.2/56.1% for meropenem, respectively. Susceptibility to other agents for ESBL screen-positive E. coli and K. pneumoniae was decreased. Ceftaroline-avibactam exhibited a broad-spectrum of in vitro activity against isolates from patients in the USA with ABSSSI including MRSA, β-hemolytic streptococci, E. coli, and K. pneumoniae as well as ESBL screen-positive phenotype isolates and merits further study in clinical indications where these resistant organisms may be a concern.

Topics: Academic Medical Centers; Anti-Bacterial Agents; Azabicyclo Compounds; Bacteria; Ceftaroline; Cephalosporins; Humans; Microbial Sensitivity Tests; Skin Diseases, Bacterial; United States

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.

Topics: Aged; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Female; Humans; Male; Middle Aged; Pneumonia, Bacterial; Retrospective Studies; Skin Diseases, Bacterial

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

The Clinical Assessment Program and Teflaro Utilization Registry (CAPTURE) is a multicenter study, assessing the contemporary use of ceftaroline fosamil in patients with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infection. This article discusses the data collected from 528 evaluable patients with CABP, from 39 sites in the United States, between August 2011 and April 2013. The majority of patients (51%) were elderly (aged ≥ 65 years), most of whom were treated in general hospital wards (70%). Approximately one quarter of elderly patients had ≥ 2 comorbidities (26%), the most common of which was structural lung disease (51%). The majority of elderly patients received ceftaroline fosamil as second-line therapy (85%), concurrently with other antibiotics (61%). Similar patterns of ceftaroline fosamil usage were noted in younger patients (aged < 65 years). Fifteen patients died (3%), 10 of whom were elderly. The overall clinical success of ceftaroline fosamil was 81% for elderly patients with CABP and 82% for younger patients. These data suggest that ceftaroline fosamil is a potentially effective treatment option for CABP in the elderly.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Drug Therapy, Combination; Drug Utilization; Female; Humans; Male; Middle Aged; Pneumonia, Bacterial; Retrospective Studies; Skin Diseases, Bacterial

Ceftaroline fosamil is a broad-spectrum antibiotic approved by the US Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia. The Clinical Assessment Program and Teflaro Utilization Registry (CAPTURE) is a multicenter registry study of patients treated with ceftaroline fosamil in the United States for ABSSSI or community-acquired bacterial pneumonia.. To describe the clinical effectiveness of ceftaroline fosamil in the treatment of ABSSSI in obese patients [body mass index (BMI) ≥ 30] compared with patients with a normal BMI (18.5 to ≤ 24.9).. Data were collected at US study centers by randomly ordered chart review.. Data from 261 patients with a normal BMI and 690 patients with an obese BMI were collected. The percentage of males was higher in the normal BMI than in the obese category (58.2% and 49.0%, respectively). The mean and median ages at baseline were similar. Most patients (91%) were treated on a general hospital ward, and the mean and median lengths of stay were similar between the 2 groups (approximately 11 days and 7 days, respectively). A total of 73.2% of normal BMI patients and 77.5% of obese patients were discharged to home. Rates of diabetes mellitus were 26.4% in the normal BMI group and 55.1% in the obese group. Methicillin-resistant Staphylococcus aureus was isolated from 26.1% of normal BMI patients and 20.5% of obese patients (16.4% morbidly obese subset). Mean treatment duration for all patients was 5.9 days. Of patients with a normal BMI, 57.5% received ceftaroline fosamil as monotherapy as did 63.3% of obese patients. Clinical success was high in both the normal BMI (85.1%) and the obese (89.0%) groups.. Ceftaroline fosamil is an effective treatment option for obese patients with ABSSSI with a similar clinical success rate, mean and median length of stay, and discharge destination to home when compared with normal BMI patients.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Female; Humans; Length of Stay; Male; Middle Aged; Obesity; Patient Discharge; Retrospective Studies; Sex Factors; Skin Diseases, Bacterial; Socioeconomic Factors; United States; Young Adult

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

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 budgetary impact of adding ceftaroline fosamil to a hospital formulary for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) was evaluated.. A three-year hospital budget impact model was constructed with three initial treatment options for ABSSSIs: ceftaroline fosamil, vancomycin plus aztreonam, and other vancomycin-containing regimens. The target population was hospitalized adult patients with an ABSSSI. Clinical cure rates with initial treatment were assumed to be similar to those from ceftaroline fosamil clinical trials. Patients who did not respond to initial treatment were assumed to be treated successfully with second-line antimicrobial therapy. Length of stay and cost per hospital day (by success or failure with initial treatment) were estimated based on a large database from more than 100 U.S. hospitals. Other model inputs included the annual number of ABSSSI admissions, projected annual case growth rate, proportion of ABSSSI target population receiving vancomycin-containing regimen, expected proportion of ABSSSI target population to be treated with ceftaroline fosamil, drug acquisition cost, cost of antibiotic administration, and cost of vancomycin monitoring. Sensitivity analysis using 95% confidence limits of clinical cure rates was also performed.. The estimated total cost of care for treating a patient with an ABSSSI was $395 lower with ceftaroline fosamil ($15,087 versus $15,482) compared with vancomycin plus aztreonam and $72 lower ($15,087 versus $15,159) compared with other vancomycin-containing regimens.. Model estimates indicated that adding ceftaroline fosamil to the hospital formulary would not have a negative effect on a hospital's budget for ABSSSI treatment.

Topics: Acute Disease; Adult; Anti-Bacterial Agents; Aztreonam; Ceftaroline; Cephalosporins; Costs and Cost Analysis; Drug Therapy, Combination; Economics, Hospital; Formularies, Hospital as Topic; Humans; Length of Stay; Models, Economic; Skin Diseases, Bacterial; Vancomycin

The Clinical Assessment Program and TEFLARO Utilization Registry (CAPTURE) is a multicentre retrospective cohort study in the USA describing treatment of acute bacterial skin and skin structure infection (ABSSSI) with ceftaroline fosamil (CPT-F). Charts for review were chosen by random selection. Among 647 evaluable patients, 52% were obese, 46% had diabetes mellitus (DM), and 19% had peripheral vascular disease (PVD). Methicillin-resistant Staphylococcus aureus (MRSA) was recovered in 28% and methicillin-susceptible S. aureus (MSSA), 11%. Antibiotics were administered prior to CPT-F treatment in 80%, and concurrently in 39%. Clinical success overall was 85%; in patients with DM, 83%; with PVD, 76%; and in obese patients, 88%. Clinical success was ≥ 79% across all infection types; 81% for MRSA and 83% for MSSA; and 86% for ceftaroline monotherapy and 84% for concurrent therapy. These high clinical success rates support CPT-F as an effective treatment option for ABSSSI, including infections due to MRSA and patients with significant co-morbidities.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ceftaroline; Cephalosporins; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Retrospective Studies; Skin; Skin Diseases, Bacterial; Skin Diseases, Infectious; Staphylococcal Infections; Young Adult

Topics: Aztreonam; Biomarkers; Ceftaroline; Cephalosporins; Female; Humans; Male; Skin Diseases, Bacterial; Vancomycin

The activities of ceftaroline, the active metabolite of the pro-drug ceftaroline fosamil, a novel anti-meticillin-resistant staphylococcal cephalosporin, and nine comparators were determined against surveillance isolates collected in 2008-2009. Over 3000 isolates associated with complicated skin and skin-structure infections (cSSSIs) were collected from 106 centres in 19 countries. MICs were determined using CLSI broth microdilution methodology. Clonal relatedness of meticillin-resistant Staphylococcus aureus (MRSA) with raised ceftaroline MICs (2 mg/L) was assessed by MLST, PFGE and mec typing. The presence of Panton-Valentine leukocidin in these isolates was also determined. Ceftaroline was active against 500 MRSA and 479 meticillin-susceptible S. aureus, with MIC(50/90) values of 0.5/2 mg/L and 0.25/0.25 mg/L, respectively. For coagulase-negative staphylococci (CoNS), the ceftaroline MIC(50/90) values for meticillin-resistant strains (n=159) were the same as those seen for MRSA. Meticillin-susceptible CoNS (n=113) had the same MIC(90) as that seen with S. aureus, but the MIC(50) was lower at 0.06 mg/L. Ceftaroline was also active against β-haemolytic streptococci (n=526; MIC(50/90)=0.004/0.015 mg/L), other streptococci (n=75; 0.015/0.06 mg/L), common Enterobacteriaceae (n=897; 0.25/≥128 mg/L) and Enterococcus faecalis (n=329; 1/16 mg/L). Those MRSA with ceftaroline MICs of 2mg/L were found to be from four clonal groups associated with the country of origin. These data confirm the broad-spectrum in vitro activity of ceftaroline against cSSSI pathogens. Ceftaroline is unique among clinically available cephalosporins, having good in vitro activity against MRSA and meticillin-resistant CoNS and moderate activity against Gram-negative bacteria.

Topics: Anti-Bacterial Agents; Bacteria; Ceftaroline; Cephalosporins; DNA, Bacterial; Electrophoresis, Gel, Pulsed-Field; Europe; Genotype; Humans; Microbial Sensitivity Tests; Middle East; Multilocus Sequence Typing; Skin Diseases, Bacterial

Several studies have shown that the rates of resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus (VISA), hetero-VISA, and penicillin-resistant Streptococcus pneumoniae have witnessed a substantial global increase. Ceftaroline fosamil is the prodrug form of ceftaroline, a new cephalosporin active against resistant Gram-positive pathogens and common Gram-negative organisms that do not produce extended-spectrum-β-lactamases and do not express AmpC. Ceftaroline fosamil was found to be effective and well-tolerated for the treatment of complicated skin and skin-structure infections and community-acquired bacterial pneumonia compared with standard therapy. The drug has recently been granted US FDA approval for both indications.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Mice; Microbial Sensitivity Tests; Pneumonia, Bacterial; Rabbits; Skin Diseases, Bacterial

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Humans; Infusions, Intravenous; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Skin Diseases, Bacterial; Staphylococcal Infections

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Humans; Methicillin Resistance; Pneumonia, Bacterial; Skin Diseases, Bacterial; Staphylococcal Infections

A dramatic increase in infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has been observed, in part as a result of the epidemic of community-associated MRSA skin and skin-structure infections (SSSIs). Simultaneously, decreasing sensitivities of S. aureus to vancomycin have been reported and invasive infections caused by these strains have been associated with worse clinical outcomes. Clearly, new agents active against MRSA are needed. Ceftaroline is a new cephalosporin active against MRSA and many Gram-negative bacteria, though it is not active against Pseudomonas spp. and extended spectrum beta-lactamase producers (ESBL).. In this review we focus on the properties of ceftaroline such as in vitro activity, the pharmacokinetic and pharmacodynamic characteristics, and its efficacy and safety observed in the clinical trials of patients with SSSI. Finally, we provide an overview of the possible future role of ceftaroline and other compounds in development for the treatment of SSSIs. The literature search was based on PubMed articles plus review of the abstracts presented in the most important international conferences in the field.. The reader will gain clear concepts to understand the value that ceftaroline might have in the treatment of SSSIs, including those caused by MRSA.. Ceftaroline has shown bactericidal activity against common pathogens associated with SSSIs including MRSA, noninferiority in clinical trials of patients with complicated SSSI (cSSSI), and a favorable safety profile.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Methicillin-Resistant Staphylococcus aureus; Skin Diseases, Bacterial; Staphylococcal Infections

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