ceftobiprole and Gram-Negative-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 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

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 novel, broad-spectrum cephalosporin with in-vitro activity against common Gram-positive and Gram-negative organisms. It forms a stable inhibitory complex with Staphylococcus aureus penicillin-binding protein (PBP) 2' (2a), resulting in enhanced activity against methicillin-resistant S. aureus (MRSA). In recent studies of methicillin-susceptible S. aureus, the ceftobiprole MIC(90) value was most frequently < or =1.0 mg/L (MIC range < or =0.25-1.0 mg/L). For MRSA, MIC(90) values were generally 2.0 mg/L (MIC range < or =0.06-4.0 mg/L). MICs for all streptococcal species, except penicillin-resistant Streptococcus viridans but including penicillin-resistant Streptococcus pneumoniae, ranged from < or =0.008 to 2.0 mg/L. Ceftobiprole is active against Enterococcus faecalis (MIC(90) = 4 mg/L), but not generally active against Enterococcus faecium (MIC(90) > 16 mg/L). Ceftobiprole displayed bactericidal activity against Gram-negative pathogens comparable to that of cefepime, ceftazidime or piperacillin-tazobactam in early studies. However, recent data show activity against Pseudomonas aeruginosa similar to that of cefepime but less than that of ceftazidime. Ceftobiprole, like cefepime, is stable in the presence of most class A non-extended spectrum beta-lactamases and inducible class C beta-lactamases. Ceftobiprole is a poor inducer of AmpC beta-lactamase and a poor substrate for hydrolysis by AmpC beta-lactamase. Studies of ceftobiprole in several animal models have demonstrated potent in-vivo efficacy against infections caused by MRSA, including strains intermediately resistant to vancomycin. It was also efficacious in murine infections caused by Gram-negative bacteria with MIC values < or =2 mg/L. The broad spectrum of activity demonstrated by ceftobiprole in vitro and in vivo suggests that it may have potential for empirical treatment of suspected Gram-negative and Gram-positive infections, including those caused by MRSA.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Cephalosporins; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus

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

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

The purpose of the present study was to investigate the in vitro activity of ceftobiprole in combination with other antimicrobials against 27 selected Gram-negative isolates, including ESBL-producing E. coli and KPC-OXA-48-producing K. pneumoniae. Ceftobiprole activity in combination with amikacin, colistin, levofloxacin, piperacillin/tazobactam and rifampin was evaluated by time-kill curves and gradient-cross method (except colistin). Among the 27 strains tested with gradient strips most were resistant to ceftobiprole. Synergy was observed in some cases with piperacillin/tazobactam. There was at least one synergistic combination towards 9 isolates belonging to different species. No antagonism was observed with any of the antibiotic tested. In time-kill curves, performed for 12 selected isolates, synergistic interaction was more frequent, occurring with 32/60 combinations. The most interesting results of our study are the bactericidal effects of ceftobiprole in combination with colistin or piperacillin/tazobactam tested against Gram-negative isolates, including KPC and OXA-48-producing K. pneumoniae.

Topics: Anti-Bacterial Agents; beta-Lactamases; Cephalosporins; Drug Resistance, Multiple, Bacterial; Drug Synergism; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Microbial Viability

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 medocaril is the parenteral prodrug of ceftobiprole, a novel pyrrolidinone broad-spectrum cephalosporin with in vitro and in vivo bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). We have used murine thigh and lung infection models in neutropenic and normal mice to characterize the in vivo pharmacokinetic (PK)-pharmacodynamic (PD) activities of ceftobiprole against multiple strains of S. aureus (including MRSA), S. pneumoniae (including PRSP), and gram-negative bacilli. Serum levels of ceftobiprole following the administration of multiple doses were determined by a microbiological assay. In vivo bactericidal activities and postantibiotic effects (PAEs) of ceftobiprole against MRSA and PRSP strains were determined from serial CFU/thigh values following single doses of ceftobiprole (40 and 160 mg/kg of body weight). Dose fractionation studies were used to determine which PK-PD index correlated best with activity. Magnitudes of the PK-PD indices were calculated from MICs and PK parameters. A sigmoid dose-response model was used to estimate the dose (mg/kg/24 h) required to achieve a static and 2-log(10) kill effects over 24 h. PK results showed area under the concentration-time curve/dose values of 1.8 to 2.8 and half-lives of 0.29 to 0.51 h. MICs ranged from 0.015 to 2 microg/ml. Ceftobiprole demonstrated time-dependent killing; its in vivo PAEs varied from 3.8 h to 4.8 h for MRSA and from 0 to 0.8 h for PRSP. The time above MIC (T > MIC) correlated best with efficacy for both MRSA and PRSP. The T > MIC values required for the static doses were significantly longer (P < 0.001) for Enterobacteriaceae (36 to 45%) than for S. aureus (14 to 28%) and S. pneumoniae (15 to 22%). The drug showed activities in the lung model similar to those in the thigh model. The presence of neutrophils significantly enhanced the activity of ceftobiprole against S. pneumoniae but only slightly against Klebsiella pneumoniae. Based on its PD profile, ceftobiprole is a promising new beta-lactam agent with activity against gram-negative and gram-positive organisms including MRSA and PRSP.

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Cephalosporin Resistance; Cephalosporins; Disease Models, Animal; Dose-Response Relationship, Drug; Enterobacteriaceae Infections; Extremities; Female; Gram-Negative Bacterial Infections; Lung Diseases; Methicillin Resistance; Mice; Mice, Inbred ICR; Neutropenia; Penicillin Resistance; Pneumococcal Infections; Staphylococcal Infections; Staphylococcus aureus