ppi-0903 and Pneumonia--Bacterial

Community-acquired pneumonia (CAP) is one of the leading causes of admission to emergency departments. Ceftaroline is a fifth-generation cephalosporin with a potent In vitro activity against Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus, the three most important pathogens causing CAP. Three randomized and double-blind clinical trials compared the efficacy of ceftaroline versus ceftriaxone in patients with CAP and the results of each trial and a meta-analysis, concluded the superiority of ceftaroline in terms of clinical success. In particular, the major difference was observed among patients with CAP caused by S. aureus. Accordingly, ceftaroline has been included as a first-line option in the recent clinical guidelines for the management of CAP.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Humans; Pneumonia, Bacterial; Randomized Controlled Trials as Topic; Staphylococcus aureus

Pneumonia is a relevant clinical and public health issue worldwide frequently associated with infections caused by Multi-Drug Resistant (MDR) pathogens. Ceftaroline fosamil is a promising new antibiotics with broad-spectrum bacterial activity. The aim of this systematic review and meta-analysis is to assess the efficacy and the effectiveness of ceftaroline fosamil in community-acquired (CAP), hospital-acquired (HAP), healthcare-associated (HCAP) and ventilator-associated (VAP) pneumonia.. A systematic review and meta-analysis was carried out retrieving both experimental and observational studies.. A total of 2364 records was found and 14 manuscripts were finally considered eligible. The pooled efficacy/effectiveness was 81.2% (I. Ceftaroline fosamil showed a high efficacy/effectiveness in patients with any type of pneumonia with a good safety profile.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Cross Infection; Humans; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Retrospective Studies; Treatment Outcome

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

Topics: Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Humans; Pneumonia, Bacterial; Randomized Controlled Trials as Topic

The data on the effectiveness of new cephalosporin, ceftaroline, for the treatment of patients with extramural pneumonia in need of hospitalization. They show that the use of ceftaroline for 5-7 days for the treatment of hospitalized patients with extramural pneumococcal pneumonia exceeding standard therapy with ceftriaxone in terms of efficacy. Therapeutic effect of ceftaroline did not depend on S. pneumoniae serotype and persisted in severe cases complicated by bacteriemia. Another advantage of ceftaroline over ceftriaxone is it ensured an adequate response on day 4 of therapy. Evidently, properly designed prospective studies are needed to better understand the role of ceftaroline in the treatment of hospitalized patients with extramural pneumonia, estimate cost and effect ratio, and elucidate the frequency and character of adverse reactions related to the long stay of the patient in a clinic.

Topics: Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporins; Hospitalization; Humans; Pneumonia, Bacterial; Severity of Illness Index

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

In October 2010, the new cephalosporin, ceftaroline fosamil, was approved by the US Food and Drug Administration for therapy of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSIs). The active metabolite, ceftaroline, demonstrates in vitro activity against typical bacterial pathogens most often associated with CABP or ABSSSIs, including resistant Gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus. The efficacy and safety of ceftaroline fosamil was assessed in 2 large phase 3 programs of randomized, double-blind, clinical trials for CABP and ABSSSIs. For both indications, therapy with ceftaroline fosamil was observed to be noninferior to the comparator agents (ceftriaxone for CABP and vancomycin plus aztreonam for ABSSSIs) at both a standard test of cure assessment time (8-15 days after discontinuation of study drug) and an early assessment time point (day 3 or 4 of study). In the integrated analysis of the trials for CABP (FOCUS 1 and 2), clinical cure rates for the ceftaroline group were numerically higher than those for the ceftriaxone group (for the clinically evaluable population 84.3% vs 77.7%; difference: 6.6%; 95% confidence interval, 1.6%-11.8%). Among patients with CABP caused by S. pneumoniae, clinical cure rates were markedly higher in the ceftaroline treatment group than in the ceftriaxone treatment group (59 of 69 [85.5%] vs 48 of 70 [68.6%], respectively). For the ABSSSI studies (CANVAS 1 and 2), microbiologically evaluable (ME) success rates were similar between the treatment groups. Notably, the clinical cure rates in ME patients with methicillin-resistant S. aureus ABSSSIs were 142 of 152 (93.4%) and 115 of 122 (94.3%), for ceftaroline and vancomycin plus aztreonam, respectively, and did not differ from those achieved in infections due to methicillin-susceptible S. aureus (93.0%-94.5%). Ceftaroline fosamil was well tolerated, with a safety profile similar to the comparator agents used in these phase 3 trials.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Humans; Pneumonia, Bacterial; Staphylococcal Skin Infections

The growing prevalence of resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus continues to pose a dilemma to clinicians. With strains developing reduced susceptibility to vancomycin, effective and well-tolerated antibiotics to combat these resistant pathogens are needed. Ceftaroline is a new parenteral cephalosporin that has been available in the USA for almost 2 years. Similar to other cephalosporins, it is well tolerated with mostly mild adverse events; however, compared with existing parenteral cephalosporins, ceftaroline has the unique attribute of being bactericidal against resistant Gram-positive aerobes including both hospital- and community-acquired methicillin-resistant S. aureus, S. aureus strains with reduced susceptibility or complete resistance to vancomycin, and resistant Streptococcus pneumoniae including multidrug-resistant strains. Current indications in the USA and Europe include treatment of adults with complicated skin, skin-structure infections and community-acquired pneumonia. This paper will review the properties of ceftaroline, its spectrum of activity, clinical use, safety profile and future role.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Gram-Positive Bacteria; Humans; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Pneumonia, Bacterial; Rabbits; Staphylococcal Infections

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

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

Ceftaroline (PPI 0903, formerly TAK-599), the active metabolite of a N-phosphono prodrug, ceftaroline fosamil, has been approved by the US Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This antimicrobial agent binds to penicillin binding proteins (PBP) inhibiting cell wall synthesis and has a high affinity for PBP2a, which is associated with methicillin resistance. Ceftaroline is consistently active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus, including methicillin-resistant, vancomycin-intermediate, linezolid-resistant, and daptomycin-nonsusceptible strains. It possesses variable activity against Enterobacteriaceae and good activity against oral anaerobes. The drug is usually administrated intravenously at 600 mg every 12 h. Ceftaroline has low protein binding and is excreted by the kidneys and thus requires dose adjustments in individuals with renal failure. Clinical trials have demonstrated noninferiority when compared with vancomycin in the treatment of acute bacterial skin and skin structure infections and noninferiority when compared with ceftriaxone in the treatment of community-acquired bacterial pneumonia. Ceftaroline demonstrated a safety profile similar to that of comparator drugs in clinical trials.

Topics: Adult; Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Pneumonia, Bacterial; Rabbits; Staphylococcal Infections; Streptococcus pneumoniae

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

The factors associated with identifying an appropriate dose and schedule of an antimicrobial agent for treatment of hospitalized, seriously ill patients with pneumonia are straightforward. Information is required about the potency of the agent for typical pathogens likely to be encountered with pneumonia. It is helpful to understand the utility of the agent against pathogens that express resistance to older antimicrobial agents. The agent must be able to gain access to the site of infection at the dose and schedule chosen and at concentrations high enough to attain microbiologically effective targets [e.g. 1 or 2 log(10) (cfu/g) bacterial cell kill, accounting for between-patient variability]. Finally, therapeutic concentrations should be attained quickly at the primary site of infection to optimize clinical outcomes. When considering all of these factors, it is expected that ceftaroline fosamil will be a valuable addition to the therapeutic armamentarium for management of community-acquired pneumonia.

Topics: Anti-Bacterial Agents; Bacteria; Ceftaroline; Cephalosporins; Community-Acquired Infections; Hospitalization; Humans; Pneumonia, Bacterial

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

Current antibiotics available for the treatment of healthcare-associated pneumonia (HCAP) may result in clinical failure due to resistance development, side effect intolerance, or poor pharmacokinetic-pharmacodynamic profiles. New agents active against common HCAP pathogens are needed. The mechanism of action, spectrum of activity, pharmacokinetics, adverse effects, and clinical efficacy of seven new agents in clinical development or recently approved with either methicillin-resistant Staphylococcus aureus (MRSA) or pseudomonal activity are reviewed. They include doripenem, a new antipseudomonal carbapenem; ceftobiprole and ceftaroline, two anti-MRSA cephalosporins; iclaprim, a selective dihydrofolate reductase antagonist; and three glycopeptides, dalbavancin, telavancin, and oritavancin.

Topics: Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Ceftaroline; Cephalosporins; Cross Infection; Doripenem; Glycopeptides; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Pseudomonas Infections; Pyrimidines; Staphylococcal Infections; Teicoplanin

The broad-spectrum cephalosporin ceftaroline, a metabolite of the prodrug ceftaroline fosamil, has shown in vitro activity against clinical isolates from pediatric patients.. This multicenter, randomized, observer-blinded, active-controlled study (NCT01669980) assessed the safety and effectiveness of ceftaroline fosamil compared with ceftriaxone plus vancomycin in patients between 2 months and 17 years of age with complicated community-acquired bacterial pneumonia. Patients were randomized 3:1 (stratified by age cohort) to receive either ceftaroline fosamil or ceftriaxone plus vancomycin (comparator) as intravenous therapy for ≥3 days. Patients who met specific study criteria on or after Study Day 4 were permitted to switch to an oral study drug. Safety assessments were treatment-emergent adverse events, and the effectiveness of treatment was assessed by clinical and microbiologic outcomes.. The median duration of intravenous treatment was 9.0 (range, 3.0-19.0) days in the ceftaroline fosamil group (N=30) and 7.5 (5.0-13.0) days in the comparator group (N=10). At least one treatment-emergent adverse event was experienced by 12/30 patients (40%) in the ceftaroline fosamil group and 8/10 (80%) in the comparator group; most treatment-emergent adverse events in both groups were mild to moderate in intensity. Clinical response rates in the modified intent-to-treat population were 52% (15/29 patients) in the ceftaroline fosamil group and 67% in the comparator group (6/9); clinical stability at Study Day 4 was 21% (6/29) and 22% (2/9), respectively.. Ceftaroline fosamil was well tolerated and showed similar clinical response rates to ceftriaxone plus vancomycin in pediatric patients with complicated community-acquired bacterial pneumonia.

Topics: Adolescent; Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporins; Child; Child, Preschool; Community-Acquired Infections; Female; Humans; Infant; Infusions, Intravenous; Male; Pneumonia, Bacterial; Treatment Outcome; Vancomycin

Community-acquired bacterial pneumonia (CABP) remains a major infection among children, despite the use of pneumococcal vaccination. Ceftaroline fosamil is a broad-spectrum cephalosporin antibiotic with activity against many bacteria, including Streptococcus pneumoniae (both penicillin-nonsusceptible and multidrug-resistant strains) and Staphylococcus aureus (including methicillin-resistant S. aureus). This article describes the safety, tolerability, and effectiveness of ceftaroline fosamil in the treatment of pediatric patients hospitalized with CABP, from a randomized, active-controlled, observer-blinded clinical study (registration number NCT01530763).. Pediatric patients were stratified into 4 age cohorts and randomized (3:1) to receive either intravenous ceftaroline fosamil or ceftriaxone, with optional oral switch for a total treatment duration of 5-14 days. Enrollment was planned for 160 patients. Data collected included demographics, infection characteristics and pathogens. Treatment-emergent adverse events, clinical outcomes, and microbiologic responses were assessed.. Ceftaroline fosamil was well tolerated. Similar percentages of patients in the ceftaroline fosamil (55/121; 45%) and ceftriaxone (18/39; 46%) groups reported treatment-emergent adverse events. Coombs seroconversion was observed in 17% of patients in the ceftaroline fosamil group; however, no evidence of hemolytic anemia or hemolysis was found. No deaths were reported during the study. Ceftaroline fosamil had similar effectiveness to ceftriaxone, with high clinical cure rates at test-of-cure in the modified intent-to-treat population (94/107; 88% and 32/36; 89%, respectively). Three documented S. aureus infections were successfully treated in the ceftaroline group, including one caused by methicillin-resistant S. aureus.. The results of this study suggest that ceftaroline fosamil may be an important treatment option for pediatric patients hospitalized with CABP.

Topics: Adolescent; Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporins; Child; Child, Preschool; Community-Acquired Infections; Female; Hospitalization; Humans; Infant; Infusions, Intravenous; Male; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Prospective Studies; Staphylococcus aureus; Treatment Outcome

The primary driver of health care costs for patients with community-acquired pneumonia (CAP) is the hospital length of stay (LOS). Unfortunately, hospital LOS comparisons are difficult to make from phase III CAP trials because of their structured designs and prespecified treatment durations. However, an opportunity still exists to draw inferences about potential LOS differences between treatments through the use of surrogates for hospital discharge. The intent of this study was to quantify the time to a clinical response, a proxy for the time to discharge readiness, among hospitalized CAP patients who received either ceftaroline or ceftriaxone in two phase III CAP FOCUS clinical trials. On the basis of the Infectious Diseases Society of America and American Thoracic Society CAP management guidelines and recent FDA guidance documents for community-acquired bacterial pneumonia, a post hoc adjudication algorithm was constructed a priori to compare the time to a clinical response, a proxy for the time to discharge readiness, between patients who received ceftaroline or ceftriaxone. Overall, 1,116 patients (ceftaroline, n=562; ceftriaxone, n=554) from the pooled FOCUS trials met the selection criteria for this analysis. Kaplan-Meier analyses showed that ceftaroline was associated with a shorter time, measured in days, to meeting the clinical response criteria (P=0.03). Of the patients on ceftaroline, 61.0, 76.1, and 83.6% achieved a clinical response by days 3, 4, and 5, compared to 54.3, 69.8, and 79.3% of the ceftriaxone-treated patients. In the Cox regression, ceftaroline was associated with a shorter time to a clinical response (HR, 1.16, P=0.02). The methodology employed here provides a framework to draw comparative effectiveness inferences from phase III CAP efficacy trials. (The FOCUS trials whose data were analyzed in this study have been registered at ClinicalTrials.gov under registration no. NCT00621504 and NCT00509106.).

Topics: Adult; Aged; Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Female; Humans; Male; Middle Aged; Pneumonia, Bacterial; Treatment Outcome

Few publications of prospective studies have described patient outcomes in community-acquired bacterial pneumonia (CABP)-associated bacteremia. Our objective, in performing this subgroup analysis, was to assess outcomes in subjects with CABP-associated bacteremia in 2 randomized, double-blind clinical studies comparing treatment with ceftaroline fosamil versus ceftriaxone.. Our analysis summarizes baseline subject demographics, distribution of baseline pathogens isolated from blood cultures, clinical response rates at Day 4, and clinical cure rates at end of therapy and test of cure (8 to 15 days after end of therapy) in subjects with bacteremic CABP in the ceFtarOline Community-acquired pneUmonia trial vS ceftriaxone in hospitalized patients (FOCUS) studies.. In the FOCUS studies, 23 of 614 patients in the ceftaroline fosamil-treated group and 22 of 614 patients in the ceftriaxone-treated group had CABP-associated bacteremia. Baseline demographics were similar between groups. Streptococcus pneumoniae was the most common baseline bloodstream isolate. For subjects with CABP-associated bacteremia, clinical response/cure rates were similar at Day 4 (60.9% vs 59.1%), end of therapy (69.6% vs 72.7%), and test of cure (69.6% vs 68.2%) for ceftaroline fosamil and ceftriaxone, respectively.. In subjects with CABP-associated bacteremia, ceftaroline fosamil demonstrated similar clinical outcomes at Day 4, end of therapy, and test of cure compared with ceftriaxone.

Topics: Aged; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Double-Blind Method; Female; Humans; Male; Middle Aged; Pneumonia, Bacterial; Treatment Outcome

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

Ceftaroline (active form of the prodrug ceftaroline fosamil) is a novel cephalosporin with activity against pathogens commonly associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and Gram-negative pathogens. This randomized, double-blind, Phase III study evaluated the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ -10%] of clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations.. Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 2 registration number NCT00509106 (http://clinicaltrials.gov/ct2/show/NCT00509106).. The study enrolled 627 patients, 315 of whom received ceftaroline fosamil and 307 of whom received ceftriaxone. Patients in both treatment groups had comparable baseline characteristics. Clinical cure rates were as follows: CE population, 82.1% (193/235) for ceftaroline fosamil and 77.2% (166/215) for ceftriaxone [difference (95% CI), 4.9% (-2.5, 12.5)]; and MITTE population, 81.3% (235/289) for ceftaroline fosamil and 75.5% (206/273) for ceftriaxone [difference (95% CI), 5.9% (-1.0, 12.7)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE (mMITTE) population were 83.3% (35/42) and 70.0% (28/40) for ceftaroline fosamil and ceftriaxone, respectively. Ceftaroline fosamil and ceftriaxone were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations due to an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, hypokalaemia, insomnia and phlebitis, and the most common AEs for ceftriaxone-treated patients were diarrhoea, insomnia, phlebitis and hypertension.. Ceftaroline fosamil achieved high clinical cure and microbiological response rates in patients hospitalized with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile that is similar to that of ceftriaxone and other cephalosporins. Ceftaroline fosamil is a promising agent for the treatment of CAP.

Topics: Aged; Aged, 80 and over; Bacteria; Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Double-Blind Method; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Pneumonia, Bacterial; Treatment Outcome

Ceftaroline, the active form of the prodrug ceftaroline fosamil, is a novel cephalosporin with bactericidal activity against important pathogens associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and common Gram-negative pathogens. FOCUS 1 is a randomized, double-blinded, Phase III study that was conducted to evaluate the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ -10%] in clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations.. Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Patients also received two 500 mg doses of oral clarithromycin every 12 h administered on day 1. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 1 registration number NCT00621504 (http://clinicaltrials.gov/ct2/show/NCT00621504).. Of 613 enrolled patients, 298 received ceftaroline fosamil and 308 received ceftriaxone. Baseline characteristics between treatment groups were comparable. Clinical cure rates were as follows: CE population, 86.6% (194/224) for ceftaroline fosamil and 78.2% (183/234) for ceftriaxone [difference (95% CI), 8.4% (1.4, 15.4)]; and MITTE population, 83.8% (244/291) for ceftaroline fosamil and 77.7% (233/300) for ceftriaxone [difference (95% CI), 6.2% (-0.2, 12.6)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE population were 88.9% (24/27) and 66.7% (20/30) for ceftaroline fosamil and ceftriaxone, respectively. Both agents were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations because of an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, insomnia and nausea, and the most common AEs for ceftriaxone-treated patients were hypokalaemia, hypertension, nausea and diarrhoea.. Ceftaroline fosamil demonstrated high clinical cure and microbiological response rates in hospitalized patients with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile similar to that of ceftriaxone and consistent with the cephalosporin class. In this study, ceftaroline fosamil was an effective and well-tolerated treatment option for CAP.

Topics: Aged; Aged, 80 and over; Bacteria; Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Double-Blind Method; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Pneumonia, Bacterial; Treatment Outcome

Ceftaroline fosamil, the prodrug of the active metabolite ceftaroline, is a broad-spectrum, parenteral cephalosporin approved for treatment of moderate to severe bacterial infections, including community-acquired pneumonia (CAP). This report provides an integrated safety summary of the ceFtarOline Community-acquired pneUmonia trial versuS ceftriaxone (FOCUS) 1 and 2 trials (registration numbers: NCT00621504 and NCT00509106).. Patients hospitalized with CAP requiring intravenous therapy and having Pneumonia Outcomes Research Team (PORT) risk class scores of III or IV were randomized (1:1) to receive 600 mg of ceftaroline fosamil administered intravenously every 12 h or 1 g of ceftriaxone administered intravenously every 24 h for 5-7 days. 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; serious adverse events (SAEs) including deaths occurring up to the late follow-up visit or within 30 days after the last dose were additionally recorded. Scheduled laboratory testing was conducted up to the test-of-cure visit; unscheduled testing continued up to the late follow-up visit.. A total of 1228 patients (613 in the ceftaroline fosamil group and 615 in the ceftriaxone group) received any amount of drug and were included in the safety analysis. The incidences of TEAEs (47.0% versus 45.7%), SAEs (11.3% versus 11.7%), discontinuations (4.4% versus 4.1%) and deaths (2.4% versus 2.0%) were similar between the ceftaroline fosamil and the ceftriaxone groups, respectively. Diarrhoea (4.2%), headache (3.4%) and insomnia (3.1%) were the most commonly reported TEAEs in patients treated with ceftaroline fosamil. The distribution of TEAEs based on severity was also similar between groups, and the majority of patients in both treatment groups (∼75%) had either no TEAEs or only mild TEAEs.. The data from the FOCUS 1 and FOCUS 2 trials presented in this integrated safety summary demonstrate that ceftaroline fosamil is well tolerated, with a tolerability profile similar to ceftriaxone and the cephalosporin class overall, with no unexpected safety concerns being identified.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Double-Blind Method; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Pneumonia, Bacterial

Cephalosporins have been widely used over the last few decades (often as first-line antibiotic therapy) for numerous infections, owing primarily to their broad spectrum of microbiologic activity and favorable safety profile. Current Infectious Diseases Society of America guidelines identify a third-generation cephalosporin in combination with a macrolide antibiotic as an option for treatment of hospitalized adult patients with community-acquired pneumonia (CAP) outside the intensive care unit setting. Although ceftriaxone is a frequently used agent for CAP, increasing incidence of multidrug-resistant Streptococcus pneumoniae and concerns regarding poor outcomes associated with ineffective therapy have prompted the search for a well-tolerated treatment alternative that is effective against bacteria that can cause CAP. Ceftaroline fosamil, the prodrug of ceftaroline, is a new extended-spectrum cephalosporin that exhibits time-dependant bactericidal activity against numerous Gram-negative and Gram-positive organisms, including methicillin-resistant Staphylococcus aureus and penicillin-resistant S. pneumoniae. Notable exceptions include Pseudomonas spp. and Gram-negative organisms that produce extended-spectrum β-lactamases or carbapenemases. Two large Phase III clinical trials (FOCUS 1 and 2) reported that ceftaroline fosamil was well tolerated, with a clinical cure rate of CAP that was noninferior to that with ceftriaxone in nonintensive care unit adult inpatients with moderately severe (Pneumonia Outcomes Research Team score of III or IV) community-acquired pneumonia.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteria; Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Double-Blind Method; Europe; Female; Humans; Infusions, Intravenous; Male; Microbial Sensitivity Tests; Middle Aged; Pneumonia, Bacterial; Treatment Outcome; United States

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

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Double-Blind Method; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Pneumonia, Bacterial; Treatment Outcome

Topics: Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Pneumonia, Bacterial; Pseudomonas; Staphylococcal Infections; Staphylococcus aureus

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

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporins; Chlamydial Pneumonia; Chlamydophila pneumoniae; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Legionella pneumophila; Macrolides; Male; Middle Aged; Mycoplasma pneumoniae; Pneumonia, Bacterial; Pneumonia, Mycoplasma; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome

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

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

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

The Clinical Assessment Program and Teflaro(®) Utilization Registry (CAPTURE) is a multicenter cohort study designed to collect information on the contemporary use of ceftaroline fosamil in the US. Data collected from 398 evaluable patients with community-acquired bacterial pneumonia (CABP) (mean age 64 years) during the first 18 months of the study are presented. Most patients had co-morbidities (76%; primarily structural lung disease), and ≧2 signs and symptoms of CABP (76%). Overall clinical success was 79% which varied little with ceftaroline fosamil usage (monotherapy vs concurrent therapy; first-line vs second-line therapy). Most patients were discharged home (60%) or to another healthcare facility (35%). These data suggest that ceftaroline, in contemporary clinical use, is an effective antibiotic for the treatment of patients with CABP, including those with significant co-morbidities or who required a change of their prior antibiotic therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Cohort Studies; Community-Acquired Infections; Escherichia coli; Female; Humans; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Pneumonia, Bacterial; Staphylococcus aureus; Streptococcus pneumoniae; Young Adult

Community-acquired pneumonia (CAP) is a common infection in developed countries and causes a large number of hospital admissions and deaths. In recent years, the incidence of this disease has increased, caused by progressive population aging. Following the introduction of the conjugate vaccine against Streptococcus pneumoniae, there have been significant epidemiological changes that require close monitoring because of the possible emergence of new patterns of resistance. This article aims to review the role of ceftaroline fosamil, a new parenteral cephalosporin with antibacterial activity against Gram-negative and Gram-positive pathogens, in the treatment of pneumonia. Several in vitro and in vivo studies have shown the efficacy of ceftaroline fosamil against penicillin-resistant S. pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). Additionally, ceftaroline has shown similar efficacy and safety to ceftriaxone in the treatment of community-acquired pneumonia with severe prognosis (prognostic severity index III and IV) in two phase III clinical trials. Although a non-inferiority design was used for these clinical trials, some data suggest a superior efficacy of ceftaroline, with earlier clinical response and higher cure rate in infections caused by S. pneumoniae, making this drug particularly interesting for critically-ill patients admitted to the intensive care unit. Ceftaroline may also be considered for empirical and directed treatment of MRSA pneumonia.

Topics: Animals; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Cross Infection; Humans; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Pneumonia, Pneumococcal; Pneumonia, Staphylococcal; Streptococcus pneumoniae

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

Topics: Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Cross Infection; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Randomized Controlled Trials as Topic; Staphylococcal Infections

The US Food and Drug Administration approved ceftaroline in 2010 for the treatment of community-acquired pneumonia and skin and soft-tissue infections. The most common adverse reactions are diarrhoea, nausea and rash. To present the first case of neutropenia directly related to ceftaroline.. A 90-year-old female was given ceftaroline for treatment of a pneumonia complicated by methicillin-resistant Staphylococcus aureus bacteraemia and possible vertebral osteomyelitis. After 25 days of ceftaroline, she developed neutropenia. Ceftaroline was discontinued and her white blood cell count returned to normal within one week.. Although neutropenia is a potential cephalosporin class effect, we present the first case of neutropenia directly related to ceftaroline. Agranulocytosis and neutropenia are rare, yet potentially life-threatening adverse effects of cephalosporins. Healthcare providers should be aware of the potential for ceftaroline to cause neutropenia, particularly in patients treated for greater than two weeks.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Female; Humans; Neutropenia; Pneumonia, Bacterial

In 2007, 1.2 million people in the United States were hospitalized with pneumonia, and more than 52 000 died from the disease. Community-acquired bacterial pneumonia (CABP) can be caused by a variety of organisms as a result of patient factors such as comorbidities, epidemiologic conditions, or the setting in which the infection was contracted. Treatment of CABP differs depending on the types of bacteria that are suspected. In the last several years, due to the concern regarding multidrug-resistant organisms (MDROs), 2 new antibiotics have been developed and approved for use in CABP. Ceftaroline fosamil (Teflaro) was approved by the US Food and Drug Administration (FDA) in October 2010 and tigecycline (Tygacil) in March 2009. In clinical trials, both agents have been shown to be efficacious and are generally well tolerated. Although these agents have received approval as therapy for CABP, it is the responsibility of physicians and pharmacists to prudently use these antimicrobials where they are truly needed. Until these agents show superiority over conventional therapy for selected patient populations, given the wide variety of pharmacotherapy that can prove efficacious for pneumonia, the new agents should be reserved for patients who have known risk factors for MDROs. Further studies are warranted for these agents in the setting of CABP.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Drug Approval; Humans; Minocycline; Pneumonia, Bacterial; Randomized Controlled Trials as Topic; Tigecycline; United States

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

To document the spectrum of activity of ceftaroline, the active form of the prodrug, ceftaroline fosamil, a new cephalosporin with anti-methicillin-resistant staphylococcal activity, against a surveillance collection of clinical isolates obtained from the USA and Europe during 2008-09.. A selected group of species associated with community-acquired pneumonia (CAP; 6496 of 17 326 monitored strains) were tested for susceptibility in a central laboratory using CLSI broth microdilution methods. Organisms were sampled from 55 medical centres, 27 in the USA and 28 (12 countries) in Europe. Ceftaroline and comparator agents were tested and interpretations of MIC endpoints made by applying current CLSI (2010) and EUCAST (2010) breakpoint criteria.. Against 1340 Streptococcus pneumoniae, ceftaroline inhibited all isolates at ≤0.5 mg/L (MIC(50/90), ≤0.008/0.12 mg/L) and was 8-fold more active than ceftriaxone (MIC(90), 1 mg/L; only 79.2% coverage at EUCAST breakpoint). Haemophilus influenzae (n = 584; MIC(50/90), ≤0.008/0.015 mg/L), Moraxella catarrhalis (n = 377; MIC(50/90), 0.03-0.06/0.12 mg/L) and Staphylococcus aureus (n = 590; MIC(50/90), 0.5/1 mg/L) were very susceptible to ceftaroline, regardless of β-lactamase production or multidrug resistance (MDR) patterns. The potency of ceftaroline against three species of Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae) was similar to that of ceftriaxone, ceftazidime and piperacillin/tazobactam. Only modest differences in rates of ceftaroline susceptibility (breakpoint ≤2 mg/L) were noted with extended-spectrum β-lactamase-negative Enterobacteriaceae strains between the USA and Europe (97.9% versus 97.0% for E. coli). Ceftaroline, like ceftriaxone, was not active against ceftazidime-resistant E. coli (10.2%-26.2% susceptible at ≤2 mg/L) or K. pneumoniae (5.3%-11.2%).. The ceftaroline surveillance for 2008-09 (USA and Europe) documented low MIC(50/90) values for S. aureus isolates at 0.5/1 and 0.25/1 mg/L, respectively. More importantly, ceftaroline MIC(90) results for S. pneumoniae (0.12 mg/L), H. influenzae (0.015 mg/L) and M. catarrhalis (0.12 mg/L) were very low, all MICs being ≤0.5 mg/L. Ceftaroline exhibited promising high potency and wide coverage against Gram-positive and -negative pathogens known to cause CAP, especially isolates of MDR pneumococci and methicillin-resistant S. aureus.

Topics: Anti-Bacterial Agents; Bacteria; Ceftaroline; Cephalosporins; Community-Acquired Infections; Europe; Humans; Microbial Sensitivity Tests; Pneumonia, Bacterial; United States

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Humans; Pneumonia, Bacterial; Randomized Controlled Trials as Topic; Treatment Outcome

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

The activity of ceftaroline, a novel cephalosporin, was evaluated against 1337 isolates from patients with bacteraemic community-acquired pneumonia (CAP) requiring hospitalisation (including 119 Haemophilus influenzae, 9 Moraxella catarrhalis, 164 Staphylococcus aureus, 1007 Streptococcus pneumoniae and 38 Streptococcus pyogenes). Minimum inhibitory concentrations (MICs) were determined by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines, and susceptibility category assessments were made using CLSI or US Food and Drug Administration (FDA) breakpoints. Ceftaroline MICs were < or = 0.008-0.06 mg/L against H. influenzae, 0.25-2mg/L against methicillin-resistant S. aureus (MRSA), 0.06-1mg/L against methicillin-susceptible S. aureus, 0.015-0.5mg/L against M. catarrhalis and < or = 0.008-0.5mg/L against S. pneumoniae, and all S. pyogenes isolates had ceftaroline MICs < or = 0.008mg/L. Ceftaroline was more active than ceftriaxone or cefepime both against MRSA and penicillin-resistant pneumococci. More than 90% of MRSA isolates were resistant to clarithromycin and levofloxacin but were susceptible to linezolid or tigecycline. A high rate of clarithromycin resistance was also observed in the pneumococci. Ceftaroline was very active in vitro against all CAP isolates, including MRSA and penicillin-non-susceptible pneumococci, in contrast to the other beta-lactams tested. These data confirm ceftaroline as a new cephalosporin with enhanced anti-Gram-positive activity and suggest that ceftaroline has the potential to be a useful new agent in the treatment of CAP-associated bacteraemic infections.

Topics: Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Community-Acquired Infections; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Microbial Sensitivity Tests; Pneumonia, Bacterial

TAK-599 is a water-soluble prodrug of a cephalosporin compound, T-91825. In vitro and in vivo antibacterial activities of T-91825 and TAK-599, respectively, were examined. T-91825 was active against both gram-positive and gram-negative bacteria, unlike vancomycin and linezolid, which are inactive against gram-negative bacteria. The 90% minimum inhibitory concentration of T-91825 against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) was 2 micro g/ml. This activity was comparable to those of vancomycin, linezolid, teicoplanin, and arbekacin. T-91825 was similarly active against vancomycin-intermediate S. aureus. In a time-kill study, T-91825 showed more rapid and distinct decrease of viable cells of two MRSA strains than did vancomycin and linezolid in vitro. The effect of TAK-599 against systemic infection caused by clinical isolates of MRSA in mice was comparable or superior to that of vancomycin, linezolid, teicoplanin, and arbekacin. In addition, TAK-599 at a dose of 20 mg/kg significantly decreased bacterial counts in lungs of mice in an experimental pneumonia model caused by MRSA in which vancomycin and linezolid were totally ineffective at the same dose. These results suggest the usefulness of TAK-599 in the treatment of MRSA infections in humans.

Topics: Animals; Butyrates; Ceftaroline; Cephalosporins; Disease Models, Animal; Enterococcus; Male; Methicillin Resistance; Mice; Mice, Inbred CBA; Mice, Inbred ICR; Microbial Sensitivity Tests; Oxazoles; Pneumonia, Bacterial; Staphylococcal Infections; Staphylococcus