ceftobiprole and Gram-Positive-Bacterial-Infections

Ceftobiprole is a novel broad-spectrum cephalosporin with activity against a wide range of Gram-positive and Gram-negative bacteria, including several resistant species such as methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. Ceftobiprole is administered intravenously as the prodrug ceftobiprole medocaril, which is almost immediately converted to the active form. It is currently under review by the US Food and Drug Administration (FDA) and is approved in Canada under the trade name Zeftera. The pharmacokinetics of ceftobiprole are non-complex as it displays a two-compartment model, dose proportionality, linear plasma protein binding and negligible accumulation. The volume of distribution is approximately equal to the extracellular fluid volume and it is cleared primarily by glomerular filtration, resulting in a half-life of approximately 3-4h. Ceftobiprole displays a low plasma protein binding of approximately 22%. The efficacy of ceftobiprole was demonstrated in two pivotal studies in patients with complicated skin and skin-structure infections (cSSSIs) that compared ceftobiprole with vancomycin in Gram-positive infections in one study and ceftobiprole with vancomycin plus ceftazidime in Gram-positive and Gram-negative infections in the other. The clinical cure rates were similar for ceftobiprole vs. comparator treatments: 93.3% vs. 93.5% with vancomycin only and 90.5% vs. 90.2% with vancomycin plus ceftazidime. The pharmacokinetic/pharmacodynamic profile supports the use of ceftobiprole to treat a wide range of cSSSIs.

Topics: Anti-Bacterial Agents; Canada; Cephalosporins; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Methicillin-Resistant Staphylococcus aureus; Treatment Outcome; United States

Ceftobiprole, formerly designated BAL9141/Ro 63-9141, is a pyrrolidinone-3-ylidene-methyl cephalosporin with demonstrated in vitro activity against MRSA, Enterococcus faecalis, Enterobacteriaceae and Pseudomonas aeruginosa. Ceftobiprole has a low potential for inducing chromosomal AmpC beta-lactamases but it is hydrolyzed by most extended spectrum beta-lactamases and metallo-beta-lactamases. Glomerular filtration is predominantly responsible for removal of the free drug from the systemic circulation. The efficacy of ceftobiprole in the treatment of complicated skin and ski-structure infections has been recently demonstrated in two Phase III randomized clinical trials involving 1600 patients. Two other Phase III clinical trials to assess ceftobiprole's efficacy in community-acquired pneumonia and nosocomial pneumonia have also concluded. While the drug met the noninferiority criteria for community-acquired pneumonia and nosocomial pneumonia involving non-ventilator associated pneumonia, ceftobiprole was less effective than the comparator in ventilator associated pneumonia subjects. Ceftobiprole was well tolerated with a safety profile consistent with the cephalosporin class of antibiotic. The most frequent drug-related adverse event was dysgeusia. Ceftobiprole is intended for use in the hospital for the treatment of infections that frequently involve beta-lactam-resistant Gram-negative and Gram-positive organisms.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Cephalosporins; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Cross Infection; Drug Interactions; Enterococcus faecalis; Gram-Positive Bacterial Infections; Humans; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Treatment Outcome

Ceftobiprole is among the first of a new generation of cephalosporins with activity against aerobic Gram-negative bacilli, which extends to cefepime-sensitive Pseudomonas aeruginosa, and activity against Gram-positive organisms, which includes methicillin-resistant Staphylococcus aureus. Ceftobiprole is currently undergoing evaluation by the US FDA for the treatment of complicated skin and skin structure infections, with a decision pending further evaluation of study site monitoring. It is also being evaluated for the treatment of community-acquired and healthcare-associated pneumonia. Two Phase III multicenter trials have demonstrated noninferiority in complicated skin and skin structure infections when tested against vancomycin in primarily Gram-positive bacterial infections, and when tested against vancomycin plus ceftazidime in Gram-positive and Gram-negative bacterial infections. It is well tolerated, with the most common side effects being nausea and dysgeusia. Ceftobiprole is likely to prove useful as an empiric as well as directed monotherapy in patients with complicated skin and skin structure infections, in which both Gram-positive pathogens including methicillin-resistant S. aureus and Gram-negative pathogens including cefepime-sensitive P. aeruginosa may be involved.

Topics: Anti-Bacterial Agents; Cephalosporins; Clinical Trials, Phase III as Topic; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Multicenter Studies as Topic; Skin Diseases, Bacterial; Treatment Outcome

Several new antimicrobials demonstrate in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and other Gram-positive bacteria. Data from large surveys indicate that linezolid, daptomycin, and tigecycline are almost universally active against MRSA. Linezolid and tigecycline inhibit both Enterococcus faecium and Enterococcus faecalis at low concentrations; daptomycin is somewhat more potent against the latter. The investigational agents dalbavancin and telavancin are more potent than vancomycin against vancomycin-susceptible organisms. Dalbavancin inhibits vanB type VRE at low concentrations, but is not active against vanA type VRE. Telavancin is less active against VRE than against vancomycin-susceptible enterococci, but minimum inhibitory concentrations are lower than those of vancomycin against VRE. With continued careful use of available antimicrobials, the vast majority of these organisms should remain susceptible to 1 or more of the agents discussed for the foreseeable future.

Topics: Aminoglycosides; Anti-Bacterial Agents; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Teicoplanin; Vancomycin

Since the 1970s, resistance to antimicrobial agents has become an escalating problem. In the last 25 years, treatment of infections caused by Gram-positive bacteria has been more problematical than ever, with infections being caused by multidrug-resistant organisms, particularly methicillin-resistant staphylococci, penicillin- and erythromycin-resistant pneumococci, and vancomycin-resistant enterococci. There is a continuing effort in the pharmaceutical industry to develop new antimicrobial agents for the treatment of resistant infections. Linezolid, quinupristin-dalfopristin, daptomycin, tigecyline, new glycopeptides and ceftobiprole are the main agents recently introduced or under clinical development. This review summarises their major properties, the results of recent studies with these agents, and future treatment possibilities.

Topics: Acetamides; Anti-Infective Agents; Cephalosporins; Daptomycin; Glycopeptides; Gram-Positive Bacterial Infections; Linezolid; Minocycline; Oxazolidinones; Tigecycline; Virginiamycin

Complicated skin and skin structure infections (cSSSIs) are common and are associated with significant health and economic costs. These infections are predominantly characterized by infection with Staphylococcus aureus, and SENTRY Surveillance data indicate that the occurrence of this pathogen in cSSSIs has increased and that almost half of the isolated pathogens are methicillin-resistant S. aureus (MRSA). Surveillance data also indicate that Gram-negative isolates are not uncommon in cSSSIs. In the past, empiric antimicrobial coverage of both Gram-positive and Gram-negative infections has generally necessitated the use of at least 2 antimicrobial agents. Ceftobiprole, a novel advanced-generation pyrrolidinone cephalosporin, is currently under review by the Food and Drug Administration as therapy for cSSSIs. This article presents a summary of the results of 2 recently published multicenter noninferiority trials involving approximately 1600 patients with a variety of cSSSIs. In the 1st trial, which included patients with Gram-positive cSSSI, the clinical cure rate at the test-of-cure (TOC) visit (the primary end point) among patients receiving ceftobiprole was 93.3%. The 2nd trial included a broad range of cSSSIs of varying pathogenicity. In this trial, the clinical cure rate among patients receiving ceftobiprole for S. aureus and MRSA infection was 94.6% and 91.8%, respectively. Ceftobiprole's capacity as a broad-spectrum agent was demonstrated in the 2nd trial, in which the clinical cure rate at TOC was 90.5% against a variety of infections and pathogens (including Gram negatives). In addition, the cure rate among patients with moderate to severe diabetic foot infection who received ceftobiprole was 86.2%, and these patients experienced a shorter length of stay in the hospital than those who received a comparator. This article also addresses the results of these trials in the context of the current medical need for safe broad-spectrum antimicrobial agents with MRSA coverage.

Topics: Cephalosporins; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Skin Diseases, Bacterial; Treatment Outcome

Ceftobiprole, an investigational beta-lactam antibiotic, has been shown to have a broad spectrum of activity against Gram-positive and Gram-negative pathogens. Unlike currently available beta-lactams, ceftobiprole has been shown to be active against methicillin-resistant staphylococci because of its high affinity for penicillin-binding protein (PBP) 2' (2a). Ceftobiprole has undergone extensive evaluation in phase I studies to characterise dose, pharmacokinetics, and safety/tolerability. In an early phase II study, all 35 clinically evaluable patients (n = 40) with complicated skin and skin structure infections (cSSSIs) receiving intravenous ceftobiprole 750 mg twice-daily were cured, including four of four patients with methicillin-resistant Staphylococcus aureus (MRSA). Microbiological eradication was achieved in 91% (21/23) of evaluable patients. On the basis of these results, phase III studies of ceftobiprole for the treatment of cSSSIs were initiated. One study compared intravenous ceftobiprole (500 mg every 12 h) to intravenous vancomycin (1 g every 12 h) in patients with cSSSIs due to Gram-positive bacteria. Staphylococci were the predominant pathogens, and more than 25% of the microbiologically evaluable patients had infections caused by MRSA. In the clinically evaluable population, efficacy and adverse events were comparable between treatment arms. Additional clinical trials in cSSSI and pneumonia patients are underway to evaluate ceftobiprole for the treatment of infections due to both Gram-positive and Gram-negative bacteria. Ceftobiprole is the first cephalosporin to demonstrate clinical efficacy in patients with infections due to methicillin-resistant staphylococci and, if approved by regulatory authorities, is expected to be a useful addition to the armamentarium of agents for the treatment of complicated skin infections and pneumonia.

Topics: Anti-Bacterial Agents; Cephalosporins; Clinical Trials as Topic; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Skin Diseases, Bacterial; Staphylococcal Infections; Staphylococcal Skin Infections

Ceftobiprole is the first broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) to be assessed in late-stage clinical trials. As a pivotal step in the clinical development of ceftobiprole, a multicenter, global, randomized, double-blind trial was conducted to compare the efficacy of ceftobiprole to that of vancomycin in patients with complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria. The primary objective was to assess noninferiority on the basis of the cure rates 7 to 14 days after the completion of therapy in patients administered ceftobiprole 500 mg every 12 h or vancomycin 1 g every 12 h. Of 784 patients randomized, 282 receiving ceftobiprole and 277 receiving vancomycin were clinically evaluable. Of these patients, 93.3% treated with ceftobiprole and 93.5% treated with vancomycin were cured (95% confidence interval of difference, -4.4%, 3.9%). The cure rates for patients with MRSA infections were 91.8% (56/61) with ceftobiprole treatment and 90.0% (54/60) with vancomycin treatment (95% confidence interval of difference, -8.4%, 12.1%). At least one adverse event (AE) was reported by 52% of the ceftobiprole-treated patients and 51% of the vancomycin-treated patients. The most common AEs reported by the ceftobiprole-treated patients were nausea (14%) and taste disturbance (8%). Discontinuation of the study drug because of treatment-emergent AEs occurred in 4% (n = 17) of the ceftobiprole-treated patients and 6% (n = 22) of the vancomycin-treated patients. The results of this trial support the use of ceftobiprole as an effective and well-tolerated treatment option for patients with cSSSIs caused by a spectrum of gram-positive bacteria.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cephalosporins; Double-Blind Method; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Male; Middle Aged; Skin Diseases, Bacterial; Treatment Outcome; Vancomycin

In phase 3 clinical trials for ceftobiprole treatment of complicated skin and skin structure infections, 1,219 gram-positive and 276 gram-negative aerobic baseline pathogens were identified. Ceftobiprole inhibited all staphylococcal isolates, including methicillin-resistant strains, at MICs of

Topics: Anti-Bacterial Agents; Cephalosporins; Enterobacteriaceae; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Skin Diseases, Bacterial; Staphylococcus

Complicated skin and skin structure infections (cSSSIs) are common and are associated with significant health and economic costs. These infections are predominantly characterized by infection with Staphylococcus aureus, and SENTRY Surveillance data indicate that the occurrence of this pathogen in cSSSIs has increased and that almost half of the isolated pathogens are methicillin-resistant S. aureus (MRSA). Surveillance data also indicate that Gram-negative isolates are not uncommon in cSSSIs. In the past, empiric antimicrobial coverage of both Gram-positive and Gram-negative infections has generally necessitated the use of at least 2 antimicrobial agents. Ceftobiprole, a novel advanced-generation pyrrolidinone cephalosporin, is currently under review by the Food and Drug Administration as therapy for cSSSIs. This article presents a summary of the results of 2 recently published multicenter noninferiority trials involving approximately 1600 patients with a variety of cSSSIs. In the 1st trial, which included patients with Gram-positive cSSSI, the clinical cure rate at the test-of-cure (TOC) visit (the primary end point) among patients receiving ceftobiprole was 93.3%. The 2nd trial included a broad range of cSSSIs of varying pathogenicity. In this trial, the clinical cure rate among patients receiving ceftobiprole for S. aureus and MRSA infection was 94.6% and 91.8%, respectively. Ceftobiprole's capacity as a broad-spectrum agent was demonstrated in the 2nd trial, in which the clinical cure rate at TOC was 90.5% against a variety of infections and pathogens (including Gram negatives). In addition, the cure rate among patients with moderate to severe diabetic foot infection who received ceftobiprole was 86.2%, and these patients experienced a shorter length of stay in the hospital than those who received a comparator. This article also addresses the results of these trials in the context of the current medical need for safe broad-spectrum antimicrobial agents with MRSA coverage.

Topics: Cephalosporins; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Skin Diseases, Bacterial; Treatment Outcome

Ceftobiprole is a relatively new cephalosporin with broad-spectrum activity and good tolerability. Despite its promising characteristics, to our knowledge, only two case reports, previously published also by some of us, is available concerning its administration for the treatment of infective endocarditis. Hereby we report our experience in this field.. All the patients with infective endocarditis treated with ceftobiprole were enrolled.. 12 cases of endocarditis were treated with ceftobiprole, 11/12 in combination with daptomycin and 1/12 as monotherapy. Gram-positive bacteria were isolated in 12/12 patients; 3 cases were polymicrobial. Cure rate was 83% (10/12 patients). In 9/12 (75%) cases, patients were switched to ceftobiprole following failure of previous antimicrobial regimen. In 3/3 patients in which ceftobiprole was administered because of persistently positive blood culture, bacteraemia clearance was rapidly achieved.. Ceftobiprole, especially in combination, could be a promising alternative treatment for infective endocarditis.

Topics: Adult; Aged; Aged, 80 and over; Cephalosporins; Daptomycin; Drug Therapy, Combination; Endocarditis; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Male; Middle Aged; Treatment Outcome

Ceftobiprole medocaril, the prodrug of ceftobiprole, is an advanced-generation cephalosporin that is approved in many European and non-European countries for the treatment of adults with hospital-acquired pneumonia (excluding ventilator-associated pneumonia) and community-acquired pneumonia and is currently being evaluated in a global phase 3 clinical trial of patients with Staphylococcus aureus bacteremia. This study investigated the in vitro activity of ceftobiprole and comparators against a total of 5466 gram-positive and -negative isolates from bloodstream infections (BSIs) that were collected in the United States during 2016 and 2017 as part of the SENTRY Antimicrobial Surveillance Program. Ceftobiprole was highly active (isolates were >99% susceptible) against S. aureus (including methicillin-resistant S. aureus), coagulase-negative staphylococci, Enterococcus faecalis, streptococci, and non-extended-spectrum β-lactamase (non-ESBL) phenotype Enterobacteriaceae. As expected, lower activities were observed against Enterococcus faecium, ESBL-phenotype Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. These results support further clinical evaluation of ceftobiprole for the treatment of BSIs caused by susceptible organisms.

Topics: Anti-Bacterial Agents; Bacteremia; Cephalosporins; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; United States

to assess the in vitro activity of ceftobiprole and comparators against a recent collection of Gram-positive and Gram-negative pathogens, in order to detect potential changes in susceptibility patterns, and to evaluate the Etest assay for ceftobiprole susceptibility testing.. contemporary Gram-positive and Gram-negative isolates (excluding extended-spectrum β-lactamase-producing isolates) from across Europe and the Middle East were collected, and their susceptibility to ceftobiprole, vancomycin, teicoplanin, linezolid, ceftazidime and cefepime was assessed using the Etest method. Quality testing [using Etest and broth microdilution (BMD)] was conducted at a central reference laboratory.. some 5041 Gram-positive and 4026 Gram-negative isolates were included. Against Gram-positive isolates overall, ceftobiprole had the lowest MIC50 (0.5 mg/L), compared with 1 mg/L for its comparators (vancomycin, teicoplanin and linezolid). Against methicillin-resistant Staphylococcus aureus, all four agents had a similar MIC90 (2 mg/L), but ceftobiprole had a 4-fold better MIC90 (0.5 mg/L) against methicillin-susceptible strains. Only 38 Gram-positive isolates were confirmed as ceftobiprole resistant. Among Gram-negative strains, 86.9%, 91.7% and 95.2% were susceptible to ceftobiprole, ceftazidime and cefepime, respectively. Pseudomonas aeruginosa was less susceptible to all three antimicrobials than any other Gram-negative pathogen. There was generally good agreement between local Etest results and those obtained at the reference laboratory (for ceftobiprole: 86.8% with Gram-negatives; and 94.7% with Gram-positives), as well as between results obtained by BMD and Etest methods (for ceftobiprole: 98.2% with Gram-negatives; and 98.4% with Gram-positives).. ceftobiprole exhibits in vitro activity against a wide range of Gram-positive and Gram-negative pathogens, including multidrug-resistant strains. No changes in its known susceptibility profile were identified.

Topics: Anti-Bacterial Agents; Cephalosporins; Drug Resistance, Multiple, Bacterial; Europe; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Middle East

The in vitro activity of ceftobiprole was evaluated against 15 011 clinical isolates obtained from patients in Canadian hospitals between 2007 and 2009. All Staphylococcus aureus were susceptible to ceftobiprole (MIC(90)'s for methicillin-susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus of ≤ 1 μg/mL and 2 μg/mL, respectively). Ceftobiprole was active against penicillin-susceptible Streptococcus pneumoniae (MIC(90), ≤ 0.06 μg/mL), penicillin-resistant Streptococcus pneumoniae (MIC(90), 0.5 μg/mL), Streptococcus pyogenes (MIC(90), ≤ 0.06 μg/mL), Staphylococcus epidermidis (MIC(90), ≤ 1 μg/mL), and Enterococcus faecalis (MIC(90), ≤ 1 μg/mL). Over 90% of Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Citrobacter freundii, Proteus mirabilis, and Serratia marcescens isolates were inhibited by a ceftobiprole concentration of ≤ 1 μg/mL. Ceftobiprole was not active against extended-spectrum β-lactamase-producing Escherichia coli and K. pneumoniae. The in vitro activity of ceftobiprole versus Pseudomonas aeruginosa was similar to that of cefepime (MIC(90), 16 μg/mL). The broad spectrum of activity by ceftobiprole would support further study of this agent in the treatment of hospital-acquired infections.

Topics: Anti-Bacterial Agents; Canada; Cephalosporins; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests

Ceftobiprole (BAL9141) is an investigational cephalosporin with broad in vitro activity against gram-positive cocci, including enterococci. Ceftobiprole MICs were determined for 93 isolates of Enterococcus faecalis (including 16 beta-lactamase [Bla] producers and 17 vancomycin-resistant isolates) by an agar dilution method following the Clinical and Laboratory Standards Institute recommendations. Ceftobiprole MICs were also determined with a high inoculum concentration (10(7) CFU/ml) for a subset of five Bla producers belonging to different previously characterized clones by a broth dilution method. Time-kill and synergism studies (with either streptomycin or gentamicin) were performed with two beta-lactamase-producing isolates (TX0630 and TX5070) and two vancomycin-resistant isolates (TX2484 [VanB] and TX2784 [VanA]). The MICs of ceftobiprole for 50 and 90% of the isolates tested were 0.25 and 1 microg/ml, respectively. All Bla producers and vancomycin-resistant isolates were inhibited by concentrations of

Topics: Anti-Bacterial Agents; beta-Lactamases; Cephalosporins; Drug Synergism; Enterococcus faecalis; Gentamicins; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Streptomycin; Vancomycin Resistance