ppi-0903 and Pneumonia

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

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

Severe community-acquired pneumonia (SCAP) is associated with high mortality. Factor such as early adequate antibiotic therapy, delay in intensive care unit (ICU) care and pneumonia caused by resistant pathogens are associated with worse outcomes in SCAP patients. Ceftaroline is a fifth-generation cephalosporin with bactericidal activity against Gram-positive pathogens (including methicillin-resistant Staphylococcus aureus [MRSA] and multidrug-resistant Streptococcus pneumoniae) and common Gram-negative organisms. The efficacy and safety for the treatment of pneumonia was evaluated in three randomized control trials were ceftaroline demonstrated superiority against ceftriaxone for the treatment of pneumonia in hospitalized patients with Pneumonia Severity Index (PSI) III - IV.

Topics: Ceftaroline; Cephalosporins; Community-Acquired Infections; Humans; Methicillin-Resistant Staphylococcus aureus; Pneumonia

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

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

Background Ceftaroline is a parentally administered cephalosporin that has an in vitro expanded spectrum of activity compared with other cephalosporins yet data is conflicting regarding its place in therapy. Aim of the Review To compare the efficacy and safety of ceftaroline against standard antibiotic regimens for community-acquired pneumonia (CAP) and complicated skin and skin structure infections (cSSSIs). Method The databases of MEDLINE, EBSCO, and Embase were searched up to June 2016. Manual review of references was completed and experts in the field were contacted for unpublished data. Randomized controlled trials of ceftaroline in CAP or cSSSI populations were included. Outcomes included clinical cure, mortality, adverse events, serious adverse events, and discontinuation due to adverse events. Meta-analysis was used to pool results for these outcomes. We performed subgroup analyses for gram positive infections in CAP and infections caused by methicillin-resistant Staphylococcus aureus in cSSSIs. Risk of bias was assessed for all studies. Results Six trials (three for each indication) were included, each of which had an unclear or high risk of bias in at least one domain. For CAP, ceftaroline was significantly more efficacious in achieving clinical cure than ceftriaxone [risk ratio (RR) 1.11, 95% confidence interval (CI) 1.04-1.19; I

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Drug Resistance, Multiple, Bacterial; Humans; Pneumonia; Randomized Controlled Trials as Topic; Staphylococcal Skin Infections

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

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

Only a parenteral formulation of ceftaroline is commercially available, and the prodrug, ceftaroline fosamil, is hydrolyzed quickly and completely upon intravenous administration. Ceftaroline is relatively minimally bound to plasma proteins (15-28 %), with a volume of distribution of 30-40 L. Ceftaroline undergoes minimal metabolism and does not appear to be a cytochrome P450 substrate. Its renal clearance (e.g. 4-7 L/h after multiple dosing) approximates glomerular filtration rate, with a terminal half-life of ~2.6 h in healthy subjects. The pharmacokinetics of ceftaroline have been described thoroughly in clinical investigations primarily conducted by the manufacturer. Despite its indications for treating skin and skin structure infections (SSSI) or community-acquired pneumonia (CAP), some studies that contributed data to the final drug labelling were conducted only in healthy volunteers. A significant amount of data have been contributed by the drug maker, and the overall quality of the pharmacodynamics and clinical data, based on our critical analysis provided in this review, is strong. Ceftaroline can be considered as a therapeutic alternative for complicated SSSI and CAP (Pneumonia Outcome Research Team Class III-IV). The current dosing regimen of ceftaroline 600 mg intravenously every 12 h appears sufficient to establish pharmacokinetic-pharmacodynamic relationships and achieve optimal clinical efficacy. More clinical studies are needed to define the place of ceftaroline in therapy for SSSI, CAP, and other indications such as osteomyelitis, endocarditis, and other types of pneumonia. Moreover, continued development in population modelling incorporating more patient-specific data would allow further analysis to identify intrinsic and extrinsic factors that influence the pharmacokinetics of ceftaroline in humans.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Drug Administration Schedule; Humans; Pneumonia; Precision Medicine; Skin Diseases, Infectious

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

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

Ceftriaxone with or without a macrolide antibiotic is a recommended treatment for patients with community-acquired pneumonia requiring hospital admission and intravenous antibiotic treatment. We aimed to assess the efficacy and safety of ceftaroline fosamil compared with ceftriaxone in the treatment of Asian patients admitted to hospital with community-acquired pneumonia.. In this international, randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial, adult Asian patients with Pneumonia Outcomes Research Team (PORT) risk class III-IV acute community-acquired pneumonia were randomly assigned (1:1) to receive intravenous ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (2 g every 24 h) for 5-7 days. Patients were randomly assigned via centralised telephone and web-based system; patients and treating clinicians were masked to treatment allocation. Investigators who did study assessments remained masked to treatment allocation until completion of the study. The primary endpoint was clinical cure at the test-of-cure visit (8-15 days after last dose of study drug) in the clinically evaluable population. Non-inferiority of ceftaroline fosamil was defined as a lower limit of the two-sided 95% CI for the difference in the proportion of patients clinically cured of -10% or higher; if non-inferiority was achieved, superiority was to be concluded if the lower limit of the 95% CI was greater than 0%. This trial is registered with ClinicalTrials.gov, number NCT01371838.. Between Dec 13, 2011, and April 26, 2013, 847 patients were enrolled at 64 centres in China, India, South Korea, Taiwan, and Vietnam, of whom 771 were randomly assigned and 764 received study treatment. In the clinically evaluable population (n=498) 217 (84%) of 258 patients in the ceftaroline fosamil group and 178 (74%) of 240 patients in the ceftriaxone group were clinically cured at the test-of-cure visit (difference 9·9%, 95% CI 2·8-17·1). The superiority of ceftaroline fosamil was consistent across all preplanned patient subgroup analyses (split by age 65 years, age 75 years, sex, PORT risk class, and previous antibiotic use) apart from patients younger than 65 years. The frequency of adverse events was similar between treatment groups and the safety results for ceftaroline fosamil were consistent with the cephalosporin class and previous clinical trial data.. Ceftaroline fosamil 600 mg given every 12 h was superior to ceftriaxone 2 g given every 24 h for the treatment of Asian patients with PORT III-IV community-acquired pneumonia. These data suggest that ceftaroline fosamil should be regarded as an alternative to ceftriaxone in empirical treatment regimens for this patient population.. AstraZeneca.

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

Pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy using phase III trial data from patients treated with a ceftaroline fosamil dosing regimen of 600 mg intravenously (i.v.) every 12 h (q12h) for 5 to 7 days for community-acquired bacterial pneumonia (CABP) were conducted. High clinical and microbiological success rates (84.7 and 86.3%, respectively) and percentages of time during the dosing interval that free-drug steady-state concentrations remained above the MIC (f%T>MIC) (98.4% had f%T>MIC values of ≥63.3) were observed among 124 microbiologically evaluable patients. As a result, significant PK-PD relationships could not be identified. These data provide support for the use of a ceftaroline fosamil dosing regimen of 600 mg i.v. q12h to treat patients with CABP.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Female; Humans; Male; Middle Aged; Pneumonia; Young Adult

Ceftaroline is an important therapeutic option for community-acquired pneumonia (CAP). Antimicrobial susceptibility to ceftaroline and other antimicrobial agents against Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae isolates collected worldwide from identified respiratory tract sources is reported by age groups (0-18, 19-65, and >65 years).. Antimicrobial susceptibility of isolates, collected as part of the ATLAS program (2017-2019), was performed per EUCAST/CLSI guidelines.. S. aureus (N = 7103; methicillin-susceptible S. aureus [MSSA] = 4203; methicillin-resistant S. aureus [MRSA] = 2791), S. pneumoniae (N = 4823; EUCAST/CLSI, penicillin-intermediate S. pneumoniae [PISP] = 1408/870; penicillin-resistant S. pneumoniae [PRSP] = 455/993), and H. influenzae (N = 3850; β-lactamase [βL]-negative = 3097; βL-positive = 753) isolates were collected from respiratory tract specimens. Susceptibility to ceftaroline was 89.08%-97.83% for S. aureus, 99.95%-100% for MSSA, and 78.07%-92.74% for MRSA isolates across age groups; S. aureus as well as MRSA isolates derived from the 0-18 years age group demonstrated the highest susceptibility rates to ceftaroline. Susceptibility to ceftaroline was 98.25%-99.77% for S. pneumoniae, 99.74%-100% for PISP, and 86.23%-99.04% for PRSP isolates across age groups. Across all age groups, susceptibility to ceftaroline was 89.53%-99.70% for H. influenzae, 93.02%-100% for βL-negative, and 77.78%-98.35% for βL-positive isolates.. Irrespective of age, susceptibility to ceftaroline was high among the majority of S. aureus, S. pneumoniae, and H. influenzae isolates collected in this study.

Topics: Aged; Anti-Bacterial Agents; Anti-Infective Agents; Ascomycota; Ceftaroline; Community-Acquired Infections; Haemophilus influenzae; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Penicillins; Pneumonia; Staphylococcus aureus; Streptococcus pneumoniae

Ceftaroline could be suitable to treat early-onset ventilator-associated pneumonia (VAP) because of its antibacterial spectrum. However, augmented renal clearance (ARC) is frequent in ICU patients and may affect ceftaroline pharmacokinetics and efficacy. The objective of the study was to explore the impact of ARC on ceftaroline pharmacokinetics and evaluate whether the currently recommended dosing regimen (600 mg every 12 h) is appropriate to treat VAP in ICU patients.. A population pharmacokinetic model was developed using pharmacokinetic data from 18 patients with measured creatinine clearance (CLCR) ranging between 83 and 309 mL/min. Monte Carlo simulations were conducted to determine the PTA and the cumulative fraction of response (CFR) against Streptococcus pneumoniae and MRSA for five dosing regimens. Study registered at ClinicalTrials.gov (NCT03025841).. Ceftaroline clearance increased non-linearly with CLCR, with lower concentrations and lower probability of reaching pharmacokinetic/pharmacodynamic targets when CLCR increases. For the currently recommended dosing regimen, the probability of having unbound ceftaroline concentrations above the MIC over the entire dose range is greater than 90% for MICs below 0.125 mg/L. Considering the distribution of MICs, this regimen would not be effective against MRSA infections (CFR between 21% and 67% depending on CLCR), but would be effective against S. pneumoniae infections (CFR >86%).. The recommended dosing regimen of ceftaroline seems sufficient for covering S. pneumoniae in ICU patients with ARC, but not for MRSA. Among the dosing regimens tested it appears that a constant infusion (50 mg/h) after a loading dose of 600 mg could be more appropriate for MRSA infections.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Critical Care; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Monte Carlo Method; Pneumonia; Renal Insufficiency; Streptococcus pneumoniae

Topics: Aged; Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Humans; Pneumonia

Ceftaroline is one of latest additions to the armamentarium for treating community-acquired pneumonia (CAP). This study aimed to describe the outcome of severe CAP (SCAP) in a cohort of hospitalised patients treated with ceftaroline.. A retrospective, observational study of patients with SCAP treated with ceftaroline in two hospitals in Spain and Italy. The primary objective was to explore 30-day mortality after diagnosis of SCAP.. During the study period the following were observed: there were 89 cases of SCAP treated with ceftaroline and 53 cases used in combination with other antibiotics (60%). Overall, 30-day mortality and clinical failure were 20% (18 of 89) and 36% (32 of 89), respectively. Independent predictors of 30-day mortality were: increasing age (OR for 1 year increase 1.0, 95% CI 1.0-1.1, P 0.043), presence of solid neoplasm (OR 4.0, 95% CI 1.0-15.1, P 0.044) and concomitant therapy with oseltamivir (OR 8.5, 95% CI 1.2°57.3, P 0.029). The only independent predictor of clinical failure was the time elapsing from SCAP diagnosis to ceftaroline therapy (OR for each passing day 1.5, 95% CI 1.1-1.9, P 0.003). The clinical success rate was 64% (57 of 89). In the subgroups of patients with proven Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) infection, clinical success was 83% (10 of 12), 75% (three of four) and 56% (five of nine), respectively.. Considering its spectrum of activity, ceftaroline could represent an important therapeutic option for SCAP. Further studies are needed to identify the precise clinical success rate against MRSA in a larger cohort of patients with SCAP.

Topics: Aged; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Female; Humans; Italy; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Oseltamivir; Pneumococcal Infections; Pneumonia; Retrospective Studies; Spain; Staphylococcal Infections; Streptococcus pneumoniae

We report Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) program data for ceftaroline and comparators against isolates collected from identified lower respiratory tract sources in 2015 and 2016. MICs and susceptibility were determined using CLSI broth microdilution methodology and EUCAST breakpoints. Ceftaroline susceptibility among penicillin-resistant Streptococcus pneumoniae (MIC≥4 mg/L [nonmeningitis breakpoint]) ranged from 77.4% (Asia, 72/93) to 100% (Oceania, 16/16; Latin America, 15/15). Among MRSA, ceftaroline susceptibility ranged from 72.3% (Asia, 553/765) to 100% (Oceania, 39/39). Among β-lactamase-positive Haemophilus influenzae, ceftaroline susceptibility ranged from 69.2% (Asia, 36/52) to 100% (Oceania, 19/19). Susceptibility to ceftaroline against non-ESBL-producing Klebsiella pneumoniae was between 91.4% (Europe, 659/721) and 100% (Oceania, 55/55) and for Escherichia coli between 85.7% (Africa/Middle East, 42/49) and 92.1% (Oceania, 35/38). Ceftaroline is not active against ESBL producers. In this study, susceptibility to ceftaroline was high among the S. pneumoniae, Staphylococcus aureus, β-lactamase-negative H. influenzae, and ESBL-negative K. pneumoniae and E. coli collected.

Topics: Anti-Bacterial Agents; Bacteria; Ceftaroline; Cephalosporins; Community-Acquired Infections; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Pneumonia; Public Health Surveillance

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

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with broad-spectrum in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), and common Gram-negative pathogens. This study investigated the in vivo activity of ceftaroline fosamil compared with clindamycin, linezolid, and vancomycin in a severe pneumonia model due to MRSA-producing Panton-Valentine leukocidin (PVL). A USA300 PVL-positive clone was used to induce pneumonia in rabbits. Infected rabbits were randomly assigned to no treatment or simulated human-equivalent dosing with ceftaroline fosamil, clindamycin, linezolid, or vancomycin. Residual bacterial concentrations in the lungs and spleen were assessed after 48 h of treatment. PVL expression was measured using a specific enzyme-linked immunosorbent assay (ELISA). Ceftaroline, clindamycin, and linezolid considerably reduced mortality rates compared with the control, whereas vancomycin did not. Pulmonary and splenic bacterial titers and PVL concentrations were greatly reduced by ceftaroline, clindamycin, and linezolid. Ceftaroline, clindamycin, and linezolid were associated with reduced pulmonary tissue damage based on significantly lower macroscopic scores. Ceftaroline fosamil, clindamycin, and, to a lesser extent, linezolid were efficient in reducing bacterial titers in both the lungs and spleen and decreasing macroscopic scores and PVL production compared with the control.

Topics: Animals; Anti-Bacterial Agents; Bacterial Toxins; Ceftaroline; Cephalosporins; Exotoxins; Leukocidins; Male; Methicillin-Resistant Staphylococcus aureus; Pneumonia; Rabbits; Staphylococcal Infections

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

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

Topics: Ceftaroline; Cephalosporins; Community-Acquired Infections; Guidelines as Topic; Humans; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Pneumonia; Staphylococcal Infections