ceftobiprole and Bacterial-Infections

Ceftobiprole is a fifth-generation cephalosporin approved for the treatment of adult community-acquired pneumonia and non-ventilator associated hospital-acquired pneumonia. However, its microbiological and pharmacokinetic profile is very attractive as armamentarium for empirical monotherapy treatment in other infections too. Among these, the following scenarios could be considered complicated skin and soft tissue infections, moderate-severe diabetic foot infections without bone involvement, vascular-catheter-associated-bloodstream infections, and fever without apparent focus in the hospitalized patient without septic shock or profound immunosuppression.

Topics: Anti-Bacterial Agents; Bacterial Infections; Catheter-Related Infections; Cephalosporins; Cross Infection; Diabetic Foot; Fever of Unknown Origin; Humans; Inpatients; Pneumonia, Bacterial; Skin Diseases, Bacterial; Soft Tissue Infections

The development of resistance to antibiotics has been ignored for a long time. But nowadays, increasing resistance is an important topic. For a decade no new antibiotics had been developed and it is not possible to quickly close this gap of new resistance and no new drugs. This work presents six new antibiotics (ceftaroline, ceftobiprole, solithromycin, tedizolid, ceftolozane/tazobactam, ceftazidime/avibactam). In part, only expert opinions are given due to lack of study results.The two 5th generation cephalosporins ceftaroline and ceftobiprole have beside their equivalent efficacy to ceftriaxone (ceftaroline) and cefipim (ceftobiprole) high activity against MRSA. The fluoroketolide solithromycin should help against macrolide-resistant pathogens and has been shown to be noninferior to the fluorochinolones. The oxazolidinone tedizolid is effective against linezolid-resistant MRSA. The two cephalosporins ceftolozane/tazobactam and ceftazidime/avibactam are not only effective against gram-negative pathogens, but they have a very broad spectrum. Due to the efficacy against extended-spectrum β‑lactamases, they can relieve the selection pressure of the carbapenems. We benefit from all new antibiotics which can take the selection pressure from other often used antibiotics. The increasing number of resistant gram-negative pathogens worldwide is alarming. Thus, focusing on the development of new drugs is extremely important.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Infections; Ceftaroline; Ceftazidime; Cephalosporins; Clinical Trials as Topic; Drug Approval; Drug Combinations; Drug Resistance, Multiple, Bacterial; Ephedrine; Humans; Macrolides; Methicillin-Resistant Staphylococcus aureus; Organophosphates; Oxazoles; Penicillanic Acid; Phenobarbital; Staphylococcal Infections; Tazobactam; Theophylline; Triazoles

Ceftobiprole, an investigational cephalosporin, is currently in phase III clinical development. Ceftobiprole is a broad-spectrum cephalosporin with demonstrated in vitro activity against Gram-positive cocci, including meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-resistant S. epidermidis, penicillin-resistant S. pneumoniae, Enterococcus faecalis, Gram-negative bacilli including AmpC-producing Escherichia coli and Pseudomonas aeruginosa, but excluding extended-spectrum beta-lactamase-producing strains. Like cefotaxime, ceftriaxone, ceftazidime, and cefepime, ceftobiprole demonstrates limited activity against anaerobes such as Bacteroides fragilis and non-fragilis Bacteroides spp. In single-step and serial passage in vitro resistance development studies, ceftobiprole demonstrated a low propensity to select for resistant subpopulations. Ceftobiprole, like cefepime, is a weak inducer and a poor substrate for AmpC beta-lactamases.Ceftobiprole medocaril, the prodrug of ceftobiprole, is converted by plasma esterases to ceftobiprole in <30 minutes. Peak serum concentrations of ceftobiprole observed at the end of a single 30-minute infusion were 35.5 mug/mL for a 500-mg dose and 59.6 mug/mL for a 750-mg dose. The volume of distribution of ceftobiprole is 0.26 L/kg ( approximately 18 L), protein binding is 16%, and its serum half-life is approximately 3.5 hours. Ceftobiprole is renally excreted ( approximately 70% in the active form) and systemic clearance correlates with creatinine clearance, meaning that dosage adjustment is required in patients with renal dysfunction. Ceftobiprole has a modest post-antibiotic effect (PAE) of approximately 0.5 hours for MRSA and a longer PAE of approximately 2 hours for penicillin-resistant pneumococci. Ceftobiprole, when administered intravenously at 500 mg once every 8 hours (2-hour infusion), has a >90% probability of achieving f T(>MIC) (free drug concentration exceeds the minimum inhibitory concentration [MIC]) for 40% and 60%, respectively, of the dosing interval for isolates with ceftobiprole MIC < or =4 and < or =2 mg/L, respectively.Currently, only limited clinical trial data are published for ceftobiprole. In a phase III trial, 784 patients with Gram-positive skin infections were randomized to treatment with either ceftobiprole 500 mg or vancomycin 1 g, each administered twice daily for 7-14 days; 93.3% of patients were clinically cured with ceftobiprole compared with 93.5% receiving vancomycin, and t

Topics: Anti-Bacterial Agents; Bacterial Infections; Cephalosporins; Drugs, Investigational; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus

Despite increasing antimicrobial resistance and multiple drug resistance in clinical isolates of both Gram-positive and Gram-negative bacteria, there are few novel antimicrobial agents in development. The few new agents that have been recently licensed have tended to have narrow spectra of activity, focused on Gram-positive pathogens, especially methicillin-resistant Staphylococcus aureus (MRSA). This situation is rightly causing concern among clinicians and public health authorities worldwide. This article reviews available data on three new antibacterials currently in development. The cephalosporin ceftobiprole is active against MRSA, Enterococcus faecalis and penicillin-resistant Streptococcus pneumoniae, but otherwise has a spectrum of activity similar to that of other recent cephalosporins. In a clinical trial, ceftobiprole was non-inferior to vancomycin for the treatment of MRSA-associated complicated skin and skin structure infections (cSSSIs). Doripenem, a new carbapenem, has some activity against MRSA, but otherwise has an anti-Gram-positive spectrum of activity similar to that of imipenem and an anti-Gram-negative spectrum similar to that of meropenem. In a clinical trial, it was non-inferior to meropenem for the treatment of complicated intra-abdominal infections. Iclaprim is a dihydrofolate reductase inhibitor with greatly enhanced activity, as compared with trimethoprim, against a range of Gram-positive and Gram-negative pathogens. The limited literature concerning this agent has concentrated on its potential role in the treatment of infections with Gram-positive bacteria. A clinical trial has demonstrated the non-inferiority of iclaprim, as compared with linezolid, in the treatment of cSSSIs, including those associated with MRSA.

Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Carbapenems; Cephalosporins; Doripenem; Drug Resistance, Multiple, Bacterial; Humans; Pyrimidines; Research

Resistance to antimicrobials is a significant and growing problem, limiting treatment options, especially for serious Gram-positive infections. Ceftobiprole is a novel broad-spectrum cephalosporin that is active in vitro against streptococci and staphylococci, including penicillin-resistant strains of pneumococci and methicillin-resistant Staphylococcus aureus (MRSA). It maintains the activity of extended-spectrum cephalosporins against Gram-negative bacteria, including Enterobacteriaceae. The in-vivo activity of ceftobiprole has been demonstrated in mouse sepsis and subcutaneous abscess models of infection. Its activity also has been examined in several discriminative models of infection that mimic specific diseases in humans and permit testing of antimicrobial activity under a variety of defined pharmacokinetic conditions. These include experimental pneumonia in mice, a tissue cage model of foreign body infection in rats, and endocarditis models in rats and rabbits. In these models, ceftobiprole exhibits activity equivalent or superior to that of comparators against MRSA, including vancomycin-intermediate strains. These models also confirm the in-vivo activity of ceftobiprole against Gram-negative bacteria that are susceptible in vitro. The results from animal models support the evaluation of the clinical efficacy of ceftobiprole in humans and also predict clinical efficacy in the empirical treatment of severe infections. The broad spectrum of activity may allow ceftobiprole to be used as monotherapy for serious hospital-acquired infections where combination therapy would otherwise be required.

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Cephalosporins; Disease Models, Animal; Drug Resistance, Bacterial; Humans; Mice; Rabbits; Rats

Ceftobiprole medocaril is a newly approved drug in Europe for the treatment of hospital-acquired pneumonia (HAP) (excluding patients with ventilator-associated pneumonia but including ventilated HAP patients) and community-acquired pneumonia in adults. The aim of this study was to evaluate the in vitro antimicrobial activity of ceftobiprole against prevalent Gram-positive and -negative pathogens isolated in Europe, Turkey, and Israel during 2005 through 2010. A total of 60,084 consecutive, nonduplicate isolates from a wide variety of infections were collected from 33 medical centers. Species identification was confirmed, and all isolates were susceptibility tested using reference broth microdilution methods. Ceftobiprole had high activity against methicillin-susceptible Staphylococcus aureus (MSSA) (100.0% susceptible), methicillin-susceptible coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci, and Streptococcus pneumoniae (99.3% susceptible), with MIC90 values of 0.25, 0.12, ≤ 0.06, and 0.5 μg/ml, respectively. Ceftobiprole was active against methicillin-resistant S. aureus (MRSA) (98.3% susceptible) and methicillin-resistant CoNS, having a MIC90 of 2 μg/ml. Ceftobiprole was active against Enterococcus faecalis (MIC50/90, 0.5/4 μg/ml) but not against most Enterococcus faecium isolates. Ceftobiprole was very potent against the majority of Enterobacteriaceae (87.3% susceptible), with >80% inhibited at ≤ 0.12 μg/ml. The potency of ceftobiprole against Pseudomonas aeruginosa (MIC50/90, 2/>8 μg/ml; 64.6% at MIC values of ≤ 4 μg/ml) was similar to that of ceftazidime (MIC50/90, 2/>16 μg/ml; 75.4% susceptible), but limited activity was observed against Acinetobacter spp. and Stenotrophomonas maltophilia. High activity was also observed against all Haemophilus influenzae (MIC90, ≤ 0.06 μg/ml) and Moraxella catarrhalis (MIC50/90, ≤ 0.06/0.25 μg/ml) isolates. Ceftobiprole demonstrated a wide spectrum of antimicrobial activity against this very large longitudinal sample of contemporary pathogens.

Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Cephalosporins; Europe; Humans; Israel; Microbial Sensitivity Tests; Public Health Surveillance; Reference Standards; Turkey

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

Topics: Anti-Bacterial Agents; Bacterial Infections; Cephalosporins; Drug Approval; Humans; Methicillin-Resistant Staphylococcus aureus; Pseudomonas aeruginosa; United States; United States Food and Drug Administration; Vancomycin

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

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

Ceftobiprole is a 1st-in-class anti-methicillin-resistant Staphylococcus aureus (MRSA) extended-spectrum cephalosporin currently in clinical trials for the treatment of complicated skin and skin structure infections (cSSSIs) and nosocomial pneumonia. This agent is also active against other prominent Gram-positive and Gram-negative pathogens, making it an attractive candidate for broad-spectrum therapy. We evaluated the in vitro potency of ceftobiprole tested against the most commonly occurring bacterial pathogens as part of a global surveillance study for the years 2005 to 2006 (>60 medical centers in North America, Latin America, and Europe). All isolates (40 675) were susceptibility tested using reference broth microdilution methods. Ceftobiprole inhibited 100% and >99% of tested S. aureus and coagulase-negative staphylococci at < or =4 and < or =8 microg/mL, respectively, although MIC90 values for oxacillin-resistant strains were 4-fold and 8-fold higher than oxacillin-susceptible isolates for the 2 groups. Ceftobiprole was also broadly active against Streptococcus pneumoniae, beta-hemolytic and viridans group streptococci, inhibiting >98% of isolates at < or =0.5 microg/mL. Although ceftobiprole was generally inactive against Enterococcus faecium, the majority of Enterococcus faecalis strains (95.7%) were inhibited at < or =4 microg/mL. This agent was similar in potency to the "3rd- and 4th-generation" cephems (MIC50 values, < or =0.06 microg/mL) for all tested Enterobacteriaceae. Although cefepime provided enhanced coverage against Klebsiella spp. (86.5% at < or =8 microg/mL versus 76.9-81.7% for ceftobiprole and ceftazidime), ceftobiprole and cefepime were superior to ceftazidime against Enterobacter spp. and Citrobacter spp. Against Pseudomonas aeruginosa, ceftobiprole was equal in potency to ceftazidime (MIC50, 2 microg/mL) and 2-fold more potent than cefepime. None of these agents inhibited >45% of Acinetobacter spp. at 8 mug/mL. Ceftobiprole is a new anti-MRSA beta-lactam with recognized activity against the most commonly occurring Enterobacteriaceae and P. aeruginosa, similar to that of extended-spectrum cephems. These characteristics warrant continued evaluation of the agent as empiric therapy for cSSSIs, and in pneumonia, especially in those institutions/regions where MRSA and P. aeruginosa may be prevalent.

Topics: Anti-Bacterial Agents; Bacterial Infections; Cephalosporins; Europe; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Latin America; Microbial Sensitivity Tests; North America

The relentless emergence and spread of antimicrobial resistance warrant an increased awareness of the problem and improved coordination and standardisation of surveillance systems, as well as resistance control strategies. Moreover, this underscores the urgent need for new antibiotics active against the emerging resistant pathogens. Ceftobiprole is a new beta-lactam molecule engineered for bactericidal activity against methicillin-resistant staphylococci that also exhibits an extended broad spectrum of activity covering the most clinically important Gram-positive (methicillin-susceptible staphylococci, penicillin-susceptible and -resistant pneumococci, other streptococci and ampicillin-susceptible enterococci) and Gram-negative (Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp., Haemophilus spp. and Moraxella spp.) pathogens. Results from studies with experimental infections and from clinical trials support a role for ceftobiprole in treating complicated skin and skin structure infections caused by Gram-positive pathogens, including methicillin-resistant staphylococci, and suggest a potential role for this drug in treating other types of serious infection caused by Gram-positive and Gram-negative pathogens.

Topics: Anti-Bacterial Agents; Bacterial Infections; beta-Lactam Resistance; Cephalosporins; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Methicillin Resistance; Staphylococcal Infections; Staphylococcus aureus

Topics: Amidohydrolases; Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Cephalosporins; Clinical Trials as Topic; Daptomycin; Drug Design; Drug Evaluation, Preclinical; Drug Resistance; Drug Resistance, Multiple, Bacterial; Humans; Ketolides; Marketing; Mice; Protein Synthesis Inhibitors; Ribosomes; Structure-Activity Relationship; Topoisomerase II Inhibitors