ceftobiprole-medocaril and Pneumonia--Bacterial

Ceftobiprole is a novel broad-spectrum cephalosporin with excellent activity against a broad range of pathogens that are important in community-acquired pneumonia (CAP), including drug-resistant pneumococci, methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa. Areas covered: This article reviews the spectrum of activity, the main pharmacological and pharmacodynamic characteristics of ceftobiprole as well its clinical efficacy and safety in the treatment of CAP in adult patients. Expert opinion: Taking into account that the current treatment guidelines for CAP recommend the use of an adequate empirical therapy to improve its prognosis, ceftobiprole shows a profile of antimicrobial activity that would cover most etiological agents in patients with risk factors for infection caused by multidrug resistant organisms. The results of the pivotal clinical trial of patients hospitalized with CAP treated with ceftobiprole showed a high rate of clinical cure. The clinical tolerance of ceftobiprole in clinical trials was generally very good. These findings make ceftobiprole a good parenteral therapeutic alternative for the empirical treatment of CAP that requires hospitalization, especially in patients with risk factors for CAP caused by resistant microorganisms.

Topics: Anti-Bacterial Agents; Cephalosporins; Community-Acquired Infections; Humans; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial

Ceftobiprole medocaril is a fifth-generation cephalosporin approved in Europe as single-agent therapy for hospital-acquired pneumonia (HAP), excluding ventilator-associated pneumonia (VAP). It is rapidly converted to the active metabolite ceftobiprole following intravenous administration. Ceftobiprole has a broad spectrum of activity, notably against methicillin-resistant Staphylococcus aureus, ampicillin-susceptible enterococci, penicillin-resistant pneumococci and Enterobacteriaceae not producing extended-spectrum β-lactamase. Ceftobiprole is primarily excreted renally by glomerular filtration, with minimal propensity for interaction with co-administered drugs. Normal dose is ceftobiprole 500 mg, administered by 2-h intravenous infusion every 8 h, with dose adjustment according to renal function. In a pivotal Phase III trial in patients with HAP, ceftobiprole monotherapy was as efficacious as ceftazidime/linezolid for clinical and microbiological cure and was noninferior to ceftazidime/linezolid in the subgroup of patients with HAP excluding VAP. Ceftobiprole and ceftazidime/linezolid were similarly well tolerated. Ceftobiprole is an efficacious and well-tolerated option for empirical treatment of patients with HAP (excluding VAP).

Topics: Anti-Bacterial Agents; Cephalosporins; Clinical Trials as Topic; Cross Infection; Drug-Related Side Effects and Adverse Reactions; Enterobacteriaceae; Enterococcus; Europe; Humans; Microbial Sensitivity Tests; Pneumonia, Bacterial; Staphylococcus aureus; Treatment Outcome

Ceftobiprole, the active metabolite of the prodrug ceftobiprole medocaril (Zevtera(®)), is a new generation broad-spectrum intravenous cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Ceftobiprole exhibits potent in vitro activity against a number of Gram-positive and Gram-negative pathogens associated with hospital-acquired pneumonia (HAP) and community-acquired pneumonia (CAP). It is the first cephalosporin monotherapy approved in the EU for the treatment of both HAP (excluding ventilator associated-pneumonia [VAP]) and CAP. In phase III trials, ceftobiprole medocaril was noninferior, in terms of clinical cure rates at the test-of-cure visit, to ceftazidime plus linezolid in patients with HAP and to ceftriaxone ± linezolid in patients with CAP severe enough to require hospitalization. In patients with HAP, noninferiority of ceftobiprole medocaril to ceftazidime plus linezolid was not demonstrated in a subset of patients with VAP. In patients with CAP, ceftobiprole medocaril was effective in those at risk for poor outcomes (pneumonia severity index ≥91, Pneumonia Patient Outcomes Research Team score IV-V or bacteraemic pneumonia). In the phase III trials, ceftobiprole medocaril was generally well tolerated, with ≈10 % of patients discontinuing the treatment because of adverse events. The most common treatment-related adverse events occurring in ceftobiprole recipients in the trials in patients with HAP or CAP included nausea, diarrhoea, infusion site reactions, vomiting, hepatic enzyme elevations and hyponatraemia. Therefore, ceftobiprole medocaril monotherapy offers a simplified option for the initial empirical treatment of patients with HAP (excluding VAP) and in those with CAP requiring hospitalization.

Topics: Anti-Bacterial Agents; Cephalosporins; Community-Acquired Infections; Cross Infection; Drug Approval; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Pneumonia, Bacterial; Prodrugs

Ceftobiprole is a cephalosporin with activity against methicillin-resistant Staphylococcus aureus, Enterobacteriaceae, and Pseudomonas aeruginosa with a promising role in the treatment of hospital-acquired pneumonia (HAP). Cure rates, however, with ceftobiprole at the doses studied may be inferior to conventional treatment in the ventilator-acquired subset of HAP.. Literature was sought using PubMed and through abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy (2006 - 2012) and the European Congress of Clinical Microbiology and Infectious Diseases (2007 - 2012). The authors used the search terms "ceftobiprole," "BAL9141," "RO63-9141," "BAL5788," and 'RO5788." The article discusses the activity, mechanism of action, pharmacokinetics (PK), pharmacodynamics (PD), and clinical trials of ceftobiprole in HAP. The article also provides discussion of how PK/PD parameters play a role in the outcome of HAP treatment and how dosing in ventilator-associated pneumonia (VAP) should be reconsidered in light of altered PK/PD.. In patients with normal PK and non-VAP, ceftobiprole is effective for the treatment of HAP in the recommended doses, ceftobiprole is unlikely to achieve the desired PD targets when PK parameters are altered in VAP (e.g., increased volume of distribution and clearance). In these settings, off-label use at higher doses may overcome these limitations; but in the presence of alternative therapies, it cannot be currently recommended.

Topics: Anti-Bacterial Agents; Cephalosporins; Clinical Trials as Topic; Cross Infection; Dose-Response Relationship, Drug; Humans; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Treatment Outcome

Ceftobiprole, the active moiety of ceftobiprole medocaril, is a novel broad-spectrum cephalosporin, with bactericidal activity against a wide range of gram-positive bacteria, including Staphylococcus aureus (including methicillin-resistant strains) and penicillin- and ceftriaxone-resistant pneumococci, and gram-negative bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa.. This was a double-blind, randomized, multicenter study of 781 patients with hospital-acquired pneumonia (HAP), including 210 with ventilator-associated pneumonia (VAP). Treatment was intravenous ceftobiprole 500 mg every 8 hours, or ceftazidime 2 g every 8 hours plus linezolid 600 mg every 12 hours; primary outcome was clinical cure at the test-of-cure visit.. Overall cure rates for ceftobiprole vs ceftazidime/linezolid were 49.9% vs 52.8% (intent-to-treat [ITT], 95% confidence interval [CI] for the difference, -10.0 to 4.1) and 69.3% vs 71.3% (clinically evaluable [CE], 95% CI, -10.0 to 6.1). Cure rates in HAP (excluding VAP) patients were 59.6% vs 58.8% (ITT, 95% CI, -7.3 to 8.8), and 77.8% vs 76.2% (CE, 95% CI, -6.9 to 10.0). Cure rates in VAP patients were 23.1% vs 36.8% (ITT, 95% CI, -26.0 to -1.5) and 37.7% vs 55.9% (CE, 95% CI, -36.4 to 0). Microbiological eradication rates in HAP (excluding VAP) patients were, respectively, 62.9% vs 67.5% (microbiologically evaluable [ME], 95% CI, -16.7 to 7.6), and in VAP patients 30.4% vs 50.0% (ME, 95% CI, -38.8 to -0.4). Treatment-related adverse events were comparable for ceftobiprole (24.9%) and ceftazidime/linezolid (25.4%).. Ceftobiprole is a safe and effective bactericidal antibiotic for the empiric treatment of HAP (excluding VAP). Further investigations are needed before recommending the use of ceftobiprole in VAP patients. Clinical Trials Registration. NCT00210964, NCT00229008.

Topics: Acetamides; Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftazidime; Cephalosporins; Cross Infection; Double-Blind Method; Drug Therapy; Female; Humans; Linezolid; Male; Middle Aged; Oxazolidinones; Pneumonia, Bacterial; Treatment Outcome; Young Adult

Community-acquired pneumonia (CAP) is a serious infection requiring hospitalisation in 20% of cases. The novel cephalosporin ceftobiprole has microbiological activity against the major bacterial pathogens causing CAP, including Streptococcus pneumoniae, Haemophilus influenzae and Klebsiella pneumoniae, as well as against Staphylococcus aureus, including meticillin-resistant S. aureus (MRSA). This was a multicentre, double-blind study in which 706 patients with CAP severe enough to require hospitalisation were randomised to ceftobiprole or to an expert-recommended course of ceftriaxone ± linezolid (comparator group). Clinical and microbiological outcomes were determined 7-14 days after completion of therapy (test-of-cure visit). For the 469 clinically evaluable patients, cure rates were 86.6% vs. 87.4% for ceftobiprole and comparator, respectively [95% confidence interval (CI) of the difference, -6.9% to 5.3%]; in the intention-to-treat (ITT) analysis of 638 CAP patients, these cure rates were 76.4% vs. 79.3%, respectively (95% CI of the difference, -9.3% to 3.6%). A typical bacterial pathogen was identified in 29% of the ITT population. Microbiological eradication rates in the 144 microbiologically evaluable patients were 88.2% and 90.8% for the respective treatment groups (95% CI of the difference, -12.6% to 7.5%). Both study drugs were well tolerated, with but a minority of patients requiring premature discontinuation due to an adverse event (6% in the ceftobiprole group and 4% in the comparator group). The overall incidence of treatment-related adverse events was higher in the ceftobiprole group, primarily owing to differences in rates of self-limited nausea (7% vs. 2%) and vomiting (5% vs. 2%). In summary, ceftobiprole was non-inferior to the comparator (ceftriaxone ± linezolid) in all clinical and microbiological analyses conducted, suggesting that ceftobiprole has a potential role in treating hospitalised patients with CAP. [ClinicalTrials.gov identifier: NCT00326287].

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Disease Eradication; Double-Blind Method; Drug Therapy, Combination; Female; Hospitalization; Humans; Linezolid; Male; Middle Aged; Oxazolidinones; Pneumonia, Bacterial; Treatment Outcome; Young Adult

Topics: Administration, Intravenous; Anti-Bacterial Agents; Cephalosporins; Humans; Pneumonia, Bacterial