ceftobiprole and Cross-Infection

Ceftobiprole is a fifth-generation cephalosporin with potent antimicrobial activity against Gram positive and Gram-negative bacteria. It has been approved in major European countries for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP), excluding ventilator-associated pneumonia (VAP). Ceftobiprole is currently in a phase 3 clinical program for registration in the U.S. In 2015, it was designated as an infectious disease product qualified for the treatment of lung and skin infections by the FDA. The efficacy of ceftobiprole in pneumonia has been demonstrated in two-phase III clinical trials conducted in patients with CAP and HAP. The recommended dose in the adult with pneumonia is 500 mg every 8 h infused in 2 h; in case of renal failure, the regimen of administration must be adjusted according to the patient's renal function. It is not necessary to adjust the dose according to gender, age, body weight or liver failure. In case of hyperfiltration, an extension to 4 h infusion of the 500mg TID is required.

Topics: Anti-Bacterial Agents; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Critical Illness; Cross Infection; Drug Administration Schedule; Humans; Pneumonia, Bacterial; Renal Insufficiency

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

Ceftobiprole is a fifth generation cephalosporin with a series of characteristics differentiating it from other beta-lactams, including its antibacterial activity, mainly against methicillin-resistant Staphylococcus aureus, resistant Streptococcus pneumoniae and also Gram-negative microorganisms such as Pseudomonas aeruginosa. This antibiotic has been subjected to various clinical trials and the results of these have led to its approval in Spain for the treatment of nosocomial pneumonia, excluding that associated with mechanical ventilation, and community-acquired pneumonia. The results of various ceftobiprole clinical studies provide consistent information on efficacy and tolerability. Ceftobiprole as monotherapy has been shown to be non-inferior to comparator antibiotics in different settings. Information is available on its compatibility with other drugs in Y-site administration, important from the point of view of the intravenous treatment of patients who present venous access limitation. On the other hand, and in contrast to other cephalosporins, ceftobiprole presents a low risk of infection due to Clostridium difficile and, in comparison with ceftaroline, neutropenia has not been reported to present any significant issues.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Cephalosporins; Clinical Trials, Phase I as Topic; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Cross Infection; Humans; Methicillin-Resistant Staphylococcus aureus; Neutropenia; Pneumonia, Bacterial; Pseudomonas aeruginosa; Streptococcus pneumoniae

Methicillin-resistant Staphylococcus aureus (MRSA), while decreasing in overall incidence, is still a prominent concern world-wide. New agents coming to market in the last 10 years allow practitioners to optimize treatment for MRSA infections. Ceftobiprole is a cephalosporin agent with MRSA activity, currently approved in selected countries for the treatment of community-acquired pneumonia and hospital-acquired pneumonia. Areas covered: Relevant literature regarding spectrum of activity, pharmacokinetics, pharmacodynamics, and clinical trials will be discussed. Expert opinion: Ceftobiprole is an addition to a growing number of antimicrobials with activity against MRSA. Concern for appropriate dosing in critically ill patients remains due to its ineffectiveness for the treatment of ventilator-associated pneumonia (VAP). While ceftobiprole has activity against gram-negative organisms, the allowance for use of an additional agent for gram-negative infections in clinical trials limits recommendations for monotherapy for empirical treatment of HAP. Ceftobiprole's place in therapy will lie in its activity against gram positive organisms, such as Streptococcus spp. and Staphylococcus spp.

Topics: Anti-Bacterial Agents; Cephalosporins; Community-Acquired Infections; Critical Illness; Cross Infection; Humans; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Staphylococcal Infections

Ceftobiprole, a new broad spectrum, parenteral cephalosporin, exhibits potent in vitro activity against a number of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae, and Gram-negative pathogens associated with hospital-acquired pneumonia (HAP) and community-acquired pneumonia (CAP). Ceftobiprole has demonstrated noninferiority in two large-scale pivotal studies comparing it to ceftriaxone with or without linezolid in CAP, with clinical cure rates 86.6% versus 87.4%, or ceftazidime in HAP, with clinical cure rates of 77% versus 76%, respectively. However, ceftobiprole was inferior in the subgroup of patients undergoing mechanical ventilation. Ceftobiprole has so far demonstrated a good safety profile in preliminary studies, with similar tolerability to comparators. The most commonly observed adverse events of ceftobiprole included headache and gastrointestinal upset. It is the first cephalosporin monotherapy approved in the EU for the treatment of both CAP and HAP (excluding ventilator-associated pneumonia).

Topics: Anti-Bacterial Agents; Cephalosporins; Community-Acquired Infections; Cross Infection; Europe; Humans; Pneumonia, Bacterial; Treatment Outcome

Current antibiotics available for the treatment of healthcare-associated pneumonia (HCAP) may result in clinical failure due to resistance development, side effect intolerance, or poor pharmacokinetic-pharmacodynamic profiles. New agents active against common HCAP pathogens are needed. The mechanism of action, spectrum of activity, pharmacokinetics, adverse effects, and clinical efficacy of seven new agents in clinical development or recently approved with either methicillin-resistant Staphylococcus aureus (MRSA) or pseudomonal activity are reviewed. They include doripenem, a new antipseudomonal carbapenem; ceftobiprole and ceftaroline, two anti-MRSA cephalosporins; iclaprim, a selective dihydrofolate reductase antagonist; and three glycopeptides, dalbavancin, telavancin, and oritavancin.

Topics: Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Ceftaroline; Cephalosporins; Cross Infection; Doripenem; Glycopeptides; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Pseudomonas Infections; Pyrimidines; Staphylococcal Infections; Teicoplanin

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

Traditionally, pneumonia is categorized by epidemiologic factors into community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP). Microbiologic studies have shown that the organisms which cause infections in HAP and VAP differ from CAP in epidemiology and resistance patterns. Patients with HAP or VAP are at higher risk for harboring resistant organisms. Other historical features that potentially place patients at a higher risk for being infected with resistant pathogens and organisms not commonly associated with CAP include history of recent admission to a health care facility, residence in a long-term care or nursing home facility, attendance at a dialysis clinic, history of recent intravenous antibiotic therapy, chemotherapy, and wound care. Because these "risk factors" have health care exposure as a common feature, patients presenting with pneumonia having these historical features have been more recently categorized as having health care-associated pneumonia (HCAP). This publication was prepared by the HCAP Working Group, which is comprised of nationally recognized experts in emergency medicine, infectious diseases, and pulmonary and critical care medicine. The aim of this article is to create awareness of the entity known as HCAP and to provide knowledge of its identification and initial management in the emergency department.

Topics: Acetamides; Age Distribution; Aged; Aged, 80 and over; Anti-Infective Agents; beta-Lactams; Cephalosporins; Cross Infection; Emergency Treatment; Ertapenem; Female; Humans; Length of Stay; Linezolid; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Oxazolidinones; Patient Care Team; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Practice Guidelines as Topic; Respiration, Artificial; Risk Factors; Severity of Illness Index; Tigecycline

A new addition to our therapeutic armamentarium against antimicrobial-resistant pathogens is ceftobiprole, a novel broad-spectrum cephalosporin currently undergoing investigation for the treatment of complicated skin and skin structure infections (cSSSIs) and nosocomial pneumonia. Several qualities make ceftobiprole uniquely suited for early empiric use. A major advance from contemporary beta-lactams, ceftobiprole has a high affinity for the altered penicillin-binding protein (PBP) 2' (2a), making it active against methicillin-resistant staphylococci. It also binds avidly to the relevant PBPs of most Gram-positive and Gram-negative pathogens, and is resistant to hydrolysis by many beta-lactamases, making it uniquely suited for infections caused by Gram-positive and mixed Gram-negative organisms. This review summarizes the pharmacokinetic and pharmacodynamic profile of ceftobiprole and addresses in detail the population pharmacokinetic and Monte Carlo simulation analyses used to determine the candidate doses for the cSSSI and nosocomial pneumonia phase 3 clinical trials. This review will also address the ability of the selected dosing regimens in providing adequate free drug concentrations in excess of the MICs against a contemporary group of bacterial isolates from a global resistance surveillance study.

Topics: Anti-Bacterial Agents; Cephalosporins; Cross Infection; Humans; Monte Carlo Method; Pneumonia; Skin Diseases, Bacterial

The prevalence of antimicrobial resistance for both Gram-positive and Gram-negative pathogens is escalating worldwide. Outbreaks of community- and hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) are being reported more frequently. Although antimicrobial resistance is well recognised as a global problem, decisions about appropriate intervention and treatment should be made at the level of the local hospital or healthcare system. Thus, local surveillance to identify prevalent pathogens, detect bacterial resistance and identify particular strains is necessary for selecting optimal treatment regimens. In addition, bactericidal antimicrobial agents with novel mechanisms of action and activity against multidrug-resistant bacteria, together with improved infection control measures, are needed to address this growing medical problem more effectively.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Cephalosporins; Cross Infection; Humans; Methicillin Resistance; Staphylococcal Infections; Staphylococcus aureus

Ceftobiprole, the active moiety of the prodrug ceftobiprole medocaril, is an advanced-generation, broad-spectrum, intravenous cephalosporin, which is currently approved for the treatment of adults with hospital-acquired or community-acquired pneumonia.. Noncompartmental pharmacokinetics and safety were analyzed from 2 recently completed pediatric studies, a single-dose, phase 1 study in neonates and infants up to 3 months of age (7.5 mg/kg) and a phase 3 study in patients 3 months to 17 years of age with pneumonia (10-20 mg/kg with a maximum of 500 mg per dose every 8 hours for up to 14 days).. Total ceftobiprole plasma concentrations peaked at the end of infusion. Half life (median ranging from 1.9 to 2.9 hours) and overall exposure (median AUC ranging from 66.6 to 173 μg•h/mL) were similar to those in adults (mean ± SD, 3.3 ± 0.3 hours and 102 ± 11.9 μg•h/mL, respectively). Calculated free-ceftobiprole concentrations in the single-dose study remained above a minimum inhibitory concentration (MIC) of 4 mg/L (fT > MIC of 4 mg/L) for a mean of 5.29 hours after dosing. In the pneumonia study, mean fT > MIC of 4 mg/L was ≥5.28 hours in all dose groups. Ceftobiprole was well tolerated in both studies.. Pharmacokinetic parameters of ceftobiprole characterized in the pediatric population were within the range of those observed in adults. In the pneumonia study, the lowest percentage of the dosing interval with fT > MIC of 4 mg/L was 50.8%, which suggests that pharmacokinetic-pharmacodynamic target attainment can be sufficient in pediatric patients. Ceftobiprole was well tolerated.

Topics: Administration, Intravenous; Adolescent; Anti-Bacterial Agents; Cephalosporins; Child; Child, Preschool; Community-Acquired Infections; Cross Infection; Data Analysis; Female; Humans; Infant; Infant, Newborn; Male; Microbial Sensitivity Tests; Pneumonia

The advanced-generation, broad-spectrum, intravenous (IV) cephalosporin, ceftobiprole, is an effective and well-tolerated treatment for adults with hospital-acquired pneumonia (HAP) or community-acquired pneumonia (CAP), but its effects in pediatric patients have not been established.. In this multicenter, investigator-blinded, active-controlled, phase 3 study, patients 3 months to <18 years old with HAP or CAP requiring hospitalization were randomized (2:1) to ceftobiprole versus standard-of-care (SoC) IV cephalosporin treatments (ceftazidime or ceftriaxone), with or without vancomycin. After at least 3 days' IV treatment, patients demonstrating clinical improvement could be switched to an oral antibiotic, to complete a minimum of 7 days' treatment.. Overall, 138 patients were randomized to ceftobiprole (n = 94) or a SoC cephalosporin (n = 44). Median time to oral switch was 6.0 days in the ceftobiprole group and 8.0 days in the SoC cephalosporin group. While on IV therapy, adverse events and treatment-related adverse events were reported by 20.2% and 8.5% of ceftobiprole-treated patients and 18.2% and 0% of SoC cephalosporin-treated patients. Early clinical response rates at day 4 in the intention-to-treat population were 95.7% and 93.2% (between-group difference, 2.6%; 95% confidence interval, -5.5% to 14.7%) in the ceftobiprole and comparator groups, and clinical cure rates at the test-of-cure visit were 90.4% and 97.7% (between-group difference, -7.3%; 95% confidence interval, -15.7% to 3.6%), respectively.. Ceftobiprole was well tolerated and, in this small phase 3 study, demonstrated similar efficacy to SoC cephalosporins in pediatric patients with HAP or CAP requiring hospitalization.

Topics: Adolescent; Anti-Bacterial Agents; Cephalosporins; Child; Child, Preschool; Cross Infection; Female; Hospitalization; Humans; Infant; Infusions, Intravenous; Male; Pneumonia, Bacterial; Treatment Outcome; Vancomycin

Lay abstract Pneumonia is a major cause of morbidity and mortality in East Asia and treatment is complicated by increasing rates of antibiotic resistance in this region. This study analyzed results from two clinical trials that assessed the benefits of the novel antibiotic ceftobiprole in patients from mainland China, Hong Kong, Taiwan and South Korea. In East Asian patients with either community- or hospital-acquired pneumonia, outcomes following ceftobiprole treatment were similar to those achieved with established antibiotics. There was also an indication that ceftobiprole may improve the rate at which causative bacteria were eradicated and may potentially reduce mortality rates compared with other antibiotics. Ceftobiprole was well tolerated in this population and will be a useful option for the treatment of pneumonia in East Asia.

Topics: Asia, Eastern; Cephalosporins; Community-Acquired Infections; Cross Infection; Humans; Pneumonia, Bacterial

Patients with pneumonia who are elderly or severely ill are at a particularly high risk of mortality. This post hoc retrospective analysis of data from two Phase III studies evaluated early improvement outcomes in subgroups of high-risk patients with community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP, excluding ventilator-associated pneumonia [VAP]).. One study included hospitalised CAP patients randomised to ceftobiprole or ceftriaxone ± linezolid treatment. The other study included HAP patients, who were randomised to ceftobiprole or ceftazidime plus linezolid treatment. The primary outcome was rate of early clinical response (Day 3 in CAP and Day 4 in HAP patients). Additional outcome measures included clinical cure at a test-of-cure visit, 30-day all-cause mortality and safety.. The overall high-risk group comprised 398 CAP patients and 307 HAP patients with risk factors present at baseline. The rate of early response was numerically higher in ceftobiprole-treated patients vs comparator-treated patients in the following high-risk groups: CAP patients aged ≥75 years (16.3% difference, 95% confidence interval [CI]: 1.8, 30.8); CAP patients with COPD (20.1% difference, 95% CI: 8.8, 31.1); all high-risk HAP patients (12.5% difference, 95% CI: 3.5, 21.4); HAP patients with >10 baseline comorbidities (15.3% difference, 95% CI: 0.3, 30.4).. Previous studies show that ceftobiprole is an efficacious therapy for patients with pneumonia who are at high risk of poor outcomes. This post hoc analysis provides preliminary evidence that ceftobiprole treatment may have advantages over other antibiotics in terms of achieving early improvement in high-risk patients with HAP (excluding VAP) and in some subgroups of high-risk CAP patients.. NCT00210964 : registered September 21, 2005; NCT00229008 : registered September 29, 2005; NCT00326287 : registered May 16, 2006.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftazidime; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Cross Infection; Female; Humans; Linezolid; Male; Middle Aged; Pneumonia; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Ceftobiprole is approved in Europe for treatment of community-acquired pneumonia and non-ventilator-associated hospital-acquired pneumonia (HAP) in adults. Real-world data are limited.. This multi-centre, observational, ambispective investigator-initiated study was undertaken in Italy from January 2018 to December 2019 in order to evaluate the use of ceftobiprole in a real-world setting.. Overall, 195 patients from 10 centres were evaluated (68% retrospectively). Male sex was prevalent (n=121, 62%). Median age was 67 [interquartile range (IQR) 53-75] years. Median Charlson Comorbidity Index score was 5 (IQR 3-7). The most common indication was pneumonia (151/195, 77%), especially HAP. Other uses were skin and soft tissue infections (5%), endocarditis (4%) and bone infections (4%). Ceftobiprole was usually an empiric choice (65%), in combination with other drugs (66%) and as second-line therapy (58%). A causative agent was found in 39% of cases. A diagnosis of sepsis was made in 59 cases (30%). Success in the clinically evaluable population (excluding 12 cases due to isolation of pathogens outside ceftobiprole's spectrum of activity) was obtained in 79% of cases, with all-cause mortality of 20%. On multi-level analysis, three predictors were positively associated with clinical success: male gender, pneumonia and detection of causal agent. Sepsis was a negative predictor. Nine factors were independently associated, favourably or unfavourably, with fatal outcome.. Ceftobiprole is a safe and effective therapeutic choice, even in a real-world setting. More data are needed to establish its efficacy in patients with sepsis.

Topics: Adult; Aged; Anti-Bacterial Agents; Cephalosporins; Cross Infection; Humans; Italy; Male; Middle Aged; Pneumonia; Retrospective Studies; Sepsis

Topics: Cephalosporins; Cross Infection; Healthcare-Associated Pneumonia; Humans

To determine the prevalence of Staphylococcus aureus from hospital-acquired pneumonia (HAP) in Italy and the susceptibility to ceftobiprole and comparators of MSSA and MRSA isolates. A secondary objective was to characterize the clonality and acquired resistance and virulence genes of MRSA.. Consecutive non-replicate isolates from HAP were collected from 13 laboratories distributed across Italy, from January to May 2016. Antimicrobial susceptibility testing was performed by broth microdilution, and results were interpreted according to the EUCAST breakpoints. All MRSA isolates were subjected to WGS using an Illumina platform. Clonality and resistance and virulence gene content were investigated with bioinformatics tools.. Among 333 isolates from HAP, S. aureus was the third most common pathogen (18.6%). The proportion of MRSA was 40.3%. Susceptibility to ceftobiprole was 100% for MSSA and 95.5% for MRSA. Lower susceptibility rates of 78.4% and 94.6% in MSSA and 36.4% and 12.1% in MRSA isolates were observed for erythromycin and levofloxacin, respectively. The MRSA from HAP mostly belonged to clonal complex (CC) 22 (47.0%), CC5 (25.8%) and CC8 (15.2%), with a minority of other lineages (ST1, ST6, ST7, ST30, ST152 and ST398). Acquired resistance and virulence genes in most cases exhibited a clonal distribution. The three ceftobiprole-resistant isolates exhibited an MIC of 4 mg/L and belonged to ST228-MRSA-I of CC5.. S. aureus is an important cause of HAP in Italy. Ceftobiprole exhibited good in vitro activity against S. aureus isolated from HAP, including MRSA. A trend to replacement of ST228 with ST22 was noticed compared with previous studies.

Topics: Anti-Bacterial Agents; Bacterial Typing Techniques; Cephalosporins; Cross Infection; DNA, Bacterial; Humans; Italy; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Epidemiology; Multilocus Sequence Typing; Pneumonia, Bacterial; Prevalence; Public Health Surveillance; Staphylococcal Infections; Staphylococcus aureus; Virulence; Whole Genome Sequencing

Baseline methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients with nosocomial and community-acquired pneumonia collected during Phase 3 trials for ceftobiprole were characterized. Eighty-four unique isolates from patients enrolled in Europe (50.0%), Asia-Western Pacific region (APAC; 20.2%), North America (19.0%), Latin America (8.3%), and South Africa (2.4%) were included. Antimicrobial susceptibility testing was performed by broth microdilution and isolates screened for Panton-Valentine leukocidin. SCCmec and agr types were determined. Strains were subjected to pulsed-field gel electrophoresis and spa typing. Clonal complexes (CCs) were assigned based on spa and/or multilocus sequence typing. Most isolates were CC5-MRSA-I/II/IV (44.0%; 37/84), followed by CC8-MRSA-IV (22.6%; 19/84) and CC239-MRSA-III (21.4%; 18/84). Other MRSA formed seven clonal clusters. Isolates from North America were associated with USA100, while those from South America belonged to the Cordobes/Chilean CC. A greater clonal diversity was observed in Europe; however, each country had CC5, CC8, or CC239 as prevalent lineages. Isolates from APAC were CC5-MRSA-II (47.1%; 8/17) or CC239-MRSA-III (47.1%; 8/17). Isolates carrying SCCmec I and III had ceftobiprole MIC50 values of 2 μg/ml, while those isolates with SCCmec II and IV had MIC50 values of 1 μg/ml. Ceftobiprole inhibited 96% and 100.0% of the isolates at ≤ 2 and ≤ 4 μg/ml, respectively. These isolates represented common circulating MRSA clones. Ceftobiprole demonstrated in vitro activity with a slight variation of minimum inhibitory concentrations (MICs) according to SCCmec or clonal type.

Topics: Anti-Bacterial Agents; Asia; Bacterial Toxins; Cephalosporins; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Cross Infection; Europe; Exotoxins; Genotype; Humans; Leukocidins; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Multilocus Sequence Typing; North America; Pneumonia; South Africa; South America; Staphylococcal Infections

The aim of the present study was to compare the potential of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin to achieve their requisite pharmacokinetic/pharmacodynamic (PK/PD) targets against methicillin-resistant Staphylococcus aureus isolates collected from intensive care unit (ICU) settings. Monte Carlo simulations were carried out to simulate the PK/PD indices of the investigated antimicrobials. The probability of target attainment (PTA) was estimated at minimum inhibitory concentration values ranging from 0.03 to 32 μg/mL to define the PK/PD susceptibility breakpoints. The cumulative fraction of response (CFR) was computed using minimum inhibitory concentration data from the Canadian National Intensive Care Unit study. Analysis of the simulation results suggested the breakpoints of 4 μg/mL for ceftobiprole (500 mg/2 h t.i.d.), 0.25 μg/mL for dalbavancin (1000 mg), 0.12 μg/mL for daptomycin (4 mg/kg q.d. and 6 mg/kg q.d.) and tigecycline (50 mg b.i.d.), and 2 μg/mL for linezolid (600 mg b.i.d.) and vancomycin (1 g b.i.d. and 1.5 g b.i.d.). The estimated CFR were 100, 100, 70.6, 88.8, 96.5, 82.4, 89.4, and 98.3% for ceftobiprole, dalbavancin, daptomycin (4 mg/kg/day), daptomycin (6 mg/kg/day), linezolid, tigecycline, vancomycin (1 g b.i.d.) and vancomycin (1.5 g b.i.d.), respectively. In conclusion, ceftobiprole and dalbavancin have the highest probability of achieving their requisite PK/PD targets against methicillin-resistant Staphylococcus aureus isolated from ICU settings. The susceptibility predictions suggested a reduction of the vancomycin breakpoint to 1 μg/mL.

Topics: Acetamides; Anti-Bacterial Agents; Cephalosporins; Computer Simulation; Cross Infection; Daptomycin; Dose-Response Relationship, Drug; Humans; Intensive Care Units; Linezolid; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Minocycline; Models, Biological; Monte Carlo Method; Oxazolidinones; Staphylococcal Infections; Teicoplanin; Tigecycline; Vancomycin

Monte Carlo simulation (MCS) of antimicrobial dosage regimens during drug development to derive predicted target attainment values is frequently used to choose the optimal dose for the treatment of patients in phase 2 and 3 studies. A criticism is that pharmacokinetic (PK) parameter estimates and variability in healthy volunteers are smaller than those in patients. In this study, the initial estimates of exposure from MCS were compared with actual exposure data in patients treated with ceftobiprole in a phase 3 nosocomial-pneumonia (NP) study (NTC00210964). Results of MCS using population PK data from ceftobiprole derived from 12 healthy volunteers were used (J. W. Mouton, A. Schmitt-Hoffmann, S. Shapiro, N. Nashed, N. C. Punt, Antimicrob. Agents Chemother. 48:1713-1718, 2004). Actual individual exposures in patients were derived after building a population pharmacokinetic model and were used to calculate the individual exposure to ceftobiprole (the percentage of time the unbound concentration exceeds the MIC [percent fT > MIC]) for a range of MIC values. For the ranges of percent fT > MIC used to determine the dosage schedule in the phase 3 NP study, the MCS using data from a single phase 1 study in healthy volunteers accurately predicted the actual clinical exposure to ceftobiprole. The difference at 50% fT > MIC at an MIC of 4 mg/liter was 3.5% for PK-sampled patients. For higher values of percent fT > MIC and MICs, the MCS slightly underestimated the target attainment, probably due to extreme values in the PK profile distribution used in the simulations. The probability of target attainment based on MCS in healthy volunteers adequately predicted the actual exposures in a patient population, including severely ill patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cephalosporins; Clinical Trials, Phase I as Topic; Clinical Trials, Phase III as Topic; Cross Infection; Drug Dosage Calculations; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Pneumonia, Bacterial

Topics: Anti-Bacterial Agents; Carbapenems; Cephalosporins; Critical Illness; Cross Infection; Doripenem; Humans; Kidney; Metabolic Clearance Rate; Pneumonia; Pneumonia, Ventilator-Associated; Randomized Controlled Trials as Topic

Topics: Anti-Bacterial Agents; Bacterial Typing Techniques; Cephalosporins; Colony Count, Microbial; Community-Acquired Infections; Cross Infection; DNA Fingerprinting; DNA, Bacterial; Electrophoresis, Gel, Pulsed-Field; Genotype; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Microbial Viability; Staphylococcal Infections

This study compared the pharmacodynamics of ceftobiprole and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) using an in vitro model.. Two methicillin-susceptible S. aureus (MSSA), two community-associated (CA)-MRSA, one healthcare-associated (HA)-MRSA, three VISA and two VRSA were studied. The pharmacodynamic model was inoculated with a concentration of 1 x 10(6) cfu/mL and ceftobiprole dosed every 8 h (at 0, 8 and 16 h) to simulate the fC(max) and t(1/2) obtained after 500 mg intravenous (iv) every 8 h dosing (fC(max,) 30 mg/L; t(1/2,) 3.5 h). Vancomycin was dosed every 12 h (at 0 and 12 h) to simulate fC(max) and t(1/2) obtained after 1 g iv every 12 h dosing (fC(max), 20 mg/L; t(1/2), 8 h). Samples were collected over 24 h to assess viable growth.. Ceftobiprole T > MIC of > or =100% (ceftobiprole MICs, < or =2 mg/L) was bactericidal (> or =3 log(10) killing) against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h. Vancomycin fAUC(24)/MIC of 340 (vancomycin MIC, 1 mg/L for MSSA and MRSA) resulted in a 1.8-2.6 log(10) reduction in colony count at 24 h. Vancomycin fAUC(24)/MIC of 85-170 (vancomycin MIC, 2-4 mg/L for VISA) resulted in a 0.4-0.7 log(10) reduction at 24 h. Vancomycin fAUC(24)/MIC of 5.3 (vancomycin MIC, 64 mg/L for VRSA) resulted in a limited effect.. Ceftobiprole T > MIC of > or =100% (ceftobiprole MICs, < or =2 mg/L) was bactericidal (> or =3 log(10) killing) against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h. Vancomycin was bacteriostatic against MSSA, MRSA and VISA, while demonstrating no activity against VRSA.

Topics: Anti-Bacterial Agents; Cephalosporins; Colony Count, Microbial; Community-Acquired Infections; Cross Infection; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Microbial Viability; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Vancomycin Resistance

Ceftobiprole (BPR) is an investigational cephalosporin with activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) strains. The pharmacodynamic (PD) profile of BPR against S. aureus strains with a variety of susceptibility phenotypes in an immunocompromised murine pneumonia model was characterized. The BPR MICs of the test isolates ranged from 0.25 to 2 mug/ml. Pharmacokinetic (PK) studies were conducted with infected neutropenic BALB/c mice; and the BPR concentrations were measured in plasma, epithelial lining fluid (ELF), and lung tissue. PD studies with these mice were undertaken with eight S. aureus isolates (two methicillin-susceptible S. aureus strains, three hospital-acquired MRSA strains, and three community-acquired MRSA strains). Subcutaneous BPR doses of 2 to 125 mg/kg of body weight/day were administered, and the change in the number of log(10) CFU/ml in lungs was evaluated after 24 h of therapy. The PD profile was characterized by using the free drug exposures (f) determined from the following parameters: the percentage of time that the concentration was greater than the MIC (T > MIC), the maximum concentration in serum/MIC, and the area under the concentration-time curve/MIC. The BPR PK parameters were linear over the dose range studied in plasma, and the ELF concentrations ranged from 60 to 94% of the free plasma concentration. fT > MIC was the parameter that best correlated with efficacy against a diverse array of S. aureus isolates in this murine pneumonia model. The 80% effective dose (ED(80)), ED(50), and stasis exposures appeared to be similar among the isolates studied. BPR exerted maximal antibacterial effects when fT > MIC ranged from 6 to 22%, regardless of the phenotypic profile of resistance to beta-lactam, fluoroquinolone, erythromycin, clindamycin, or tetracycline antibiotics.

Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Community-Acquired Infections; Cross Infection; Disease Models, Animal; Drug Resistance, Bacterial; Female; Humans; Methicillin Resistance; Mice; Mice, Inbred BALB C; Phenotype; Pneumonia, Staphylococcal; Staphylococcus aureus

We evaluated the activity of ceftobiprole against 100 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and 100 hospital-associated MRSA (HA-MRSA) isolates. Eight isolates were evaluated by time-kill studies for kill rate and potential for synergy with tobramycin. Ceftobiprole MIC(50) and MIC(90) values were 1 and 2 microg/ml, respectively, against CA-MRSA and HA-MRSA. In time-kill analysis, ceftobiprole was bactericidal at all concentrations tested.

Topics: Acetamides; Anti-Bacterial Agents; Cephalosporins; Community-Acquired Infections; Cross Infection; Daptomycin; Drug Synergism; Humans; Linezolid; Methicillin Resistance; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Topics: Anti-Bacterial Agents; Canada; Cephalosporins; Cross Infection; Humans; Intensive Care Units; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections