Efficacy of ceftobiprole in a murine model of bacteremia and disseminated infection.

Introduction. Ceftobiprole is an advanced-generation broad-spectrum parenteral cephalosporin with activity against MSSA and MRSA.Gap Statement. Ceftobiprole is not currently approved for use to treat S. aureus bacteremia and phase three clinical trials are taking place. Drug approval requires further pre-clinical evidence to support this new indication.Aim. The aim of this study was to evaluate the efficacy of ceftobiprole at the human equivalent efficacious exposure (considering a 500 mg q8h dosing regimen infused over 2 h) against MSSA and MRSA strains in a neutropenic murine model of bacteremia and disseminated infection.Methodology. Two bioluminescent-tagged strains (one MSSA and one MRSA strain) were selected based on their in vitro susceptibility and in vivo growth profiles. Bacterial c.f.u. counts in the blood, lung, kidney, and liver were determined 48 h post-infection or after death. The bioluminescent-tag allowed the visualization of the real-time effects of ceftobiprole therapy compared to the natural progression of the infection in untreated controls.Results. Treatment with ceftobiprole resulted in a significant reduction of the bacterial load with the bioluminescence reduced by 2-log units and bacterial c.f.u. counts reduced by 3- to 6-log units, depending on the organ and bacterial strain. Survival was 100 % in the ceftobiprole-treated group compared to only 0-20 % survival in the untreated control animals for both strains tested.Conclusion. These results suggest that treatment with ceftobiprole using a 500 mg q8h dosing regimen studied in several successful phase three trials, has potential as an antibiotic therapy to treat bacteremia and associated disseminated infections caused by either methicillin-susceptible or methicillin-resistant strains of S. aureus.

Ceftobiprole for Treatment of Complicated Staphylococcus aureus Bacteremia.

BACKGROUND: Ceftobiprole is a cephalosporin that may be effective for treating complicated Staphylococcus aureus bacteremia, including methicillin-resistant S. aureus. METHODS: In this phase 3, double-blind, double-dummy, noninferiority trial, adults with complicated S. aureus bacteremia were randomly assigned in a 1:1 ratio to receive ceftobiprole at a dose of 500 mg intravenously every 6 hours for 8 days and every 8 hours thereafter, or daptomycin at a dose of 6 to 10 mg per kilogram of body weight intravenously every 24 hours plus optional aztreonam (at the discretion of the trial-site investigators). The primary outcome, overall treatment success 70 days after randomization (defined as survival, bacteremia clearance, symptom improvement, no new S. aureus bacteremia-related complications, and no receipt of other potentially effective antibiotics), with a noninferiority margin of 15%, was adjudicated by a data review committee whose members were unaware of the trial-group assignments. Safety was also assessed. RESULTS: Of 390 patients who underwent randomization, 387 (189 in the ceftobiprole group and 198 in the daptomycin group) had confirmed S. aureus bacteremia and received ceftobiprole or daptomycin (modified intention-to-treat population). A total of 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], -7.1 to 11.1). Findings appeared to be consistent between the ceftobiprole and daptomycin groups in key subgroups and with respect to secondary outcomes, including mortality (9.0% and 9.1%, respectively; 95% CI, -6.2 to 5.2) and the percentage of patients with microbiologic eradication (82.0% and 77.3%; 95% CI, -2.9 to 13.0). Adverse events were reported in 121 of 191 patients (63.4%) who received ceftobiprole and 117 of 198 patients (59.1%) who received daptomycin; serious adverse events were reported in 36 patients (18.8%) and 45 patients (22.7%), respectively. Gastrointestinal adverse events (primarily mild nausea) were more frequent with ceftobiprole. CONCLUSIONS: Ceftobiprole was noninferior to daptomycin with respect to overall treatment success in patients with complicated S. aureus bacteremia. (Funded by Basilea Pharmaceutica International and the U.S. Department of Health and Human Services; ERADICATE ClinicalTrials.gov number, NCT03138733.).

Ceftobiprole Medocaril Is an Effective Post-Exposure Treatment in the Fischer 344 Rat Model of Pneumonic Tularemia.

Francisella tularensis subspecies tularensis is a category-A biothreat agent that can cause lethal tularemia. Ceftobiprole medocaril is being explored as a medical countermeasure for the treatment of pneumonic tularemia. The efficacy of ceftobiprole medocaril against inhalational tularemia was evaluated in the Fischer 344 rat model of infection. The dose was expected to be effective against F. tularensis isolates with ceftobiprole minimum inhibitory concentrations ≤0.5 µg/mL. Animals treated with ceftobiprole medocaril exhibited a 92% survival rate 31 days post-challenge, identical to the survival of levofloxacin-treated rats. By comparison, rats receiving placebo experienced 100% mortality. Terminally collected blood, liver, lung, and spleen samples confirmed disseminated F. tularensis infections in most animals that died prior to completing treatments (placebo animals and a rat treated with ceftobiprole medocaril), although levels of bacteria detected in the placebo samples were significantly elevated compared to the ceftobiprole-medocaril-treated group geometric mean. Furthermore, no evidence of infection was detected in any rat that completed ceftobiprole medocaril or levofloxacin treatment and survived to the end of the post-treatment observation period. Overall, survival rates, body weights, and bacterial burdens consistently demonstrated that treatment with ceftobiprole medocaril is efficacious against otherwise fatal cases of pneumonic tularemia in the rat model.

Iridium complexes of an ortho-trifluoromethylphenyl substituted PONOP pincer ligand.

The synthesis and iridium coordination chemistry of a new pyridine-based phosphinito pincer ligand 2,6-(ArF2PO)2C5H3N (PONOP-ArF; ArF = 2-(CF3)C6H4) are described, where the P-donors have ortho-trifluoromethylphenyl substituents. The iridium(III) 2,2'-biphenyl (biph) derivative [Ir(PONOP-ArF)(biph)Cl] was obtained by reaction with [Ir(biph)(COD)Cl]2 (COD = 1,5-cyclooctadiene) and subsequent halide ion abstraction enabled isolation of [Ir(PONOP-ArF)(biph)]+ which features an Ir ← F-C bonding interaction in the solid state. Hydrogenolysis of the biphenyl ligand and formation of [Ir(PONOP-ArF)(H)2]+ was achieved by prolonged reaction of [Ir(PONOP-ArF)(biph)]+ with dihydrogen. This transformation paved the way for isolation and crystallographic characterisation of low valent iridium derivatives through treatment of the dihydride with tert-butylethylene (TBE). The iridium(I) π-complex [Ir(PONOP-ArF)(TBE)]+ is thermally stable but substitution of TBE can be achieved by reaction with carbon monoxide. The solid-state structure of the mono-carbonyl product [Ir(PONOP-ArF)(CO)]+ is notable for an intermolecular anagostic interaction between the metal centre and a pentane molecule which co-crystallises within a cleft defined by two aryl phosphine substituents.

Ceftobiprole activity against Gram-positive and Gram-negative pathogens causing bone and joint infections in the United States from 2016 to 2020.

Bone and joint infections (BJIs) present significant treatment challenges. Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus, is approved in many European and other countries for the treatment of adults with community- and hospital-acquired pneumonia, excluding ventilator-associated pneumonia. In this study, the in vitro activity of ceftobiprole and comparators was evaluated against clinical isolates collected from BJIs in the USA from 2016 to 2020. Gram-positive pathogens made up 70.6% of all BJI isolates and included S. aureus (47.4% of all isolates), ß-hemolytic streptococci, coagulase-negative staphylococci, and Enterococcus faecalis. Ceftobiprole was highly active against S. aureus (MIC50/90 values, 0.5/1 mg/L; 99.6% susceptible using the European Committee on Antimicrobial Susceptibility Testing susceptibility breakpoint of ≤2 mg/L for the treatment of pneumonia patients) and exhibited potent activity against the other Gram-positive cocci and the predominant BJI Gram-negative groups. These results support the further evaluation of ceftobiprole for this potential indication.

A Phase 3, Randomized, Investigator-blinded Trial Comparing Ceftobiprole With a Standard-of-care Cephalosporin, With or Without Vancomycin, for the Treatment of Pneumonia in Pediatric Patients.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Ceftobiprole Compared With Vancomycin Plus Aztreonam in the Treatment of Acute Bacterial Skin and Skin Structure Infections: Results of a Phase 3, Randomized, Double-blind Trial (TARGET).

BACKGROUND: The development of novel broad-spectrum antibiotics, with efficacy against both gram-positive and gram-negative bacteria, has the potential to enhance treatment options for acute bacterial skin and skin structure infections (ABSSSIs). Ceftobiprole is an advanced-generation intravenous cephalosporin with broad in vitro activity against gram-positive (including methicillin-resistant Staphylococcus aureus) and gram-negative pathogens. METHODS: TARGET was a randomized, double-blind, active-controlled, parallel-group, multicenter, phase 3 noninferiority study that compared ceftobiprole with vancomycin plus aztreonam. The Food and Drug Administration-defined primary efficacy endpoint was early clinical response 48-72 hours after treatment initiation in the intent-to-treat (ITT) population and the European Medicines Agency-defined primary endpoint was investigator-assessed clinical success at the test-of-cure (TOC) visit. Noninferiority was defined as the lower limit of the 95% CI for the difference in success rates (ceftobiprole minus vancomycin/aztreonam) >-10%. Safety was assessed through adverse event and laboratory data collection. RESULTS: In total, 679 patients were randomized to ceftobiprole (n = 335) or vancomycin/aztreonam (n = 344). Early clinical success rates were 91.3% and 88.1% in the ceftobiprole and vancomycin/aztreonam groups, respectively, and noninferiority was demonstrated (adjusted difference: 3.3%; 95% CI: -1.2, 7.8). Investigator-assessed clinical success at the TOC visit was similar between the 2 groups, and noninferiority was demonstrated for both the ITT (90.1% vs 89.0%) and clinically evaluable (97.9% vs 95.2%) populations. Both treatment groups displayed similar microbiological success and safety profiles. CONCLUSIONS: TARGET demonstrated that ceftobiprole is noninferior to vancomycin/aztreonam in the treatment of ABSSSIs, in terms of early clinical response and investigator-assessed clinical success at the TOC visit. CLINICAL TRIALS REGISTRATION: NCT03137173.

Diet Quality and Urbanization in Mozambique.

Robust income growth combined with the highest urban population growth in the world is driving rapid changes in the food system of sub-Saharan Africa. Demand is increasing for higher quality as well as more processed foods. Countries are increasingly experiencing a double burden of over and under nutrition as the overweight and obesity epidemic spreads. In this context, we seek to understand the key drivers and likely evolution of diet quality in Mozambique, in both its positive and negative dimensions, while specifically examining the role of farm ownership among increasingly urban populations. We use national household expenditure survey data and a set of ordinary least square and analysis of variance regressions to observe patterns of current diet quality across city size categories, household income, household education, and other demographic variables. We then anticipate the likely directions of change in diet quality over these same dimensions based on expected income growth and expenditure elasticities developed for several alternative nutrients. We find that growing incomes and the consumption of processed foods are associated with a worsening of negative factors in the diet. Furthermore, urbanization, controlling for income, is associated more strongly with a worsening of negative factors than with an improvement in positive factors in the diet. The effect on diet quality of farm ownership, however, is positive and significant, primarily driven by these households purchasing fewer unhealthy foods. African cities need to consider what mix of policies will counteract the negative effects of continued urbanization and rising incomes on diets.

Ceftobiprole Activity against Bacteria from Skin and Skin Structure Infections in the United States from 2016 through 2018.

Ceftobiprole medocaril is an advanced-generation cephalosporin prodrug that has qualified infectious disease product status granted by the US FDA and is currently being evaluated in phase 3 clinical trials in patients with acute bacterial skin and skin structure infections (ABSSSIs) and in patients with Staphylococcus aureus bacteremia. In this study, the activity of ceftobiprole and comparators was evaluated against more than 7,300 clinical isolates collected in the United States from 2016 through 2018 from patients with skin and skin structure infections. The major species/pathogen groups were S. aureus (53%), Enterobacterales (23%), Pseudomonas aeruginosa (7%), beta-hemolytic streptococci (6%), Enterococcus spp. (4%), and coagulase-negative staphylococci (2%). Ceftobiprole was highly active against S. aureus (MIC50/90, 0.5/1 mg/liter; 99.7% susceptible by EUCAST criteria; 42% methicillin-resistant S. aureus [MRSA]). Ceftobiprole also exhibited potent activity against other Gram-positive cocci. The overall susceptibility of Enterobacterales to ceftobiprole was 84.8% (>99.0% susceptible for isolate subsets that exhibited a non-extended-spectrum ß-lactamase [ESBL] phenotype). A total of 74.4% of P. aeruginosa, 100% of beta-hemolytic streptococci and coagulase-negative staphylococci, and 99.6% of Enterococcus faecalis isolates were inhibited by ceftobiprole at ≤4 mg/liter. As expected, ceftobiprole was largely inactive against Enterobacterales that contained ESBL genes and Enterococcus faecium Overall, ceftobiprole was highly active against most clinical isolates from the major Gram-positive and Gram-negative skin and skin structure pathogen groups collected at U.S. medical centers participating in the SENTRY Antimicrobial Surveillance Program during 2016 to 2018. The broad-spectrum activity of ceftobiprole, including potent activity against MRSA, supports its further evaluation for a potential ABSSSI indication.

The Effect of Varying Test Administration and Scoring Procedures on Three Tests of (Central) Auditory Processing Disorder.

BACKGROUND: There is currently no widely accepted objective method used to identify (central) auditory processing disorder ([C]APD). Audiologists often rely on behavioral test methods to diagnose (C)APD, which can be highly subjective. This is problematic in light of relevant literature that has reported a lack of adequate graduate-level preparation related to (C)APD. This is further complicated when exacerbated by the use of inconsistent test procedures from those used to standardize tests of (C)APD, resulting in higher test variability. The consequences of modifying test administration and scoring methods for tests of (C)APD are not currently documented in the literature. PURPOSE: This study aims to examine the effect of varying test administration and scoring procedures from those used to standardize tests of (C)APD on test outcome. RESEARCH DESIGN: This study used a repeated-measures design in which all participants were evaluated in all test conditions. The effects of varying the number of test items administered and the use of repetitions of missed test items on the test outcome score were assessed for the frequency patterns test (FPT), competing sentences test (CST), and the low-pass filtered speech test (LPFST). For the CST only, two scoring methods were used (a strict and a lax criterion) to determine whether or not scoring method affected test outcome. STUDY SAMPLE: Thirty-three native English-speaking adults served as participants. All participants had normal hearing (as defined by thresholds of 25-dB HL or better) at all octave band frequencies from 500 to 4000 Hz, with thresholds of 55-dB HL or better at 8000 Hz. All participants had normal cognitive function as assessed by the Mini-Mental State Examination. DATA COLLECTION AND ANALYSIS: Paired samples t-tests were used to evaluate the differences in test outcome when varying the CST scoring method. A 3 × 2 × 2 repeated-measures factorial analysis of variance (ANOVA) was used to determine the effects of test, length, and repetitions on outcome score for all three tests of auditory processing ability. Individual 2 × 2 repeated-measures two-way ANOVAs were subsequently conducted for each test to further evaluate interactions. RESULTS: There was no effect of scoring method on the CST outcome. There was a significant main effect of repetition use for the FPT and LPFST, in that test scores were greater when corrected for repetitions. An interaction between test length and repetitions was found for the LPFST only, such that there was a greater effect of repetition use when a shorter test was administered compared with a longer test. CONCLUSIONS: Test outcome may be affected when test administration procedures are varied from those used to standardize the test, lending itself to the broader possibility that the overall diagnosis of (C)APD may be subsequently affected.

Ceftobiprole activity when tested against contemporary bacteria causing bloodstream infections in the United States (2016-2017).

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 ß-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.

Assessment of the efferent auditory system in children with suspected auditory processing disorder: the Middle ear muscle reflex and contralateral inhibition of OAEs.

OBJECTIVE: To determine whether children aged 7 to 12 years with listening difficulties show objective evidence for efferent auditory function based on measurements of medial olivo-cochlear and middle ear muscle reflexes. DESIGN: Click-evoked otoacoustic emissions recorded with and without contralateral broadband noise and ipsilateral and contralateral tonal (1000, 2000 Hz) middle ear muscle reflex thresholds were examined. STUDY SAMPLE: 29 children diagnosed with suspected auditory processing disorder (APD) and a control group of 34 typically developing children participated in this study. RESULTS: Children with suspected APD had poorer performance on auditory processing tests than the control group. Middle ear muscle reflex thresholds were significantly higher at 2000 Hz in the suspected APD group for contralateral stimulation. MOC inhibition effects did not differ between APD and control groups. CONCLUSIONS: This research supports earlier studies showing altered acoustic reflexes in children with APD. No group differences were found for the MOC reflex measures, consistent with some earlier studies in children with APD.

Ceftobiprole Activity against Gram-Positive and -Negative Pathogens Collected from the United States in 2006 and 2016.

Ceftobiprole is an advanced cephalosporin with potent activity against Gram-positive and Gram-negative bacteria that has been approved in many European and non-European countries to treat community- and hospital-acquired pneumonia (excluding ventilator-associated pneumonia). This study reports on the activity of ceftobiprole against a large set of clinical isolates obtained from hospitalized patients in the United States in 2016 that caused serious infections, including pneumonia, bacteremia, and skin and skin structure infections. To assess any potential temporal changes in ceftobiprole activity, the 2016 results were compared to corresponding MIC data from a 2006 U.S. survey that included key target pathogens. Ceftobiprole exhibited potent activity against Staphylococcus aureus (including methicillin-resistant S. aureus isolates, which were 99.3% susceptible), coagulase-negative staphylococci (100% susceptible), Enterococcus faecalis (100% susceptible), Streptococcus pneumoniae (99.7% susceptible), and other tested streptococci. Similarly, ceftobiprole was highly active against Enterobacteriaceae isolates that did not exhibit an extended-spectrum ß-lactamase (ESBL) phenotype, including Escherichia coli (99.8% susceptible) and Klebsiella pneumoniae (99.6% susceptible). A total of 99.6% of all Haemophilus influenzae and Moraxella catarrhalis isolates were inhibited at ≤1 mg/liter ceftobiprole, and 72.7% of the Pseudomonas aeruginosa isolates were susceptible to ceftobiprole. With the exception of decreased cephalosporin susceptibility among Enterobacteriaceae isolates, which correlates with an increased prevalence of ESBL-producing isolates, ceftobiprole had similar activities against the isolate sets collected in 2006 and 2016. Therefore, ceftobiprole remains highly active when tested in vitro against a large number of current Gram-positive or Gram-negative pathogens that cause serious infections.

Susceptibility to ceftobiprole of respiratory-tract pathogens collected in the United Kingdom and Ireland during 2014-2015.

PURPOSE: Lower respiratory tract infections (LRTIs) can cause significant morbidity and mortality and are becoming increasingly difficult to treat because of the growing prevalence of resistance to conventional antimicrobial agents. This study aimed to assess the current in vitro susceptibility of respiratory tract pathogens collected from the UK and Ireland to ceftobiprole, an advanced-generation cephalosporin, as compared with other antibiotics. METHODS: Pathogens isolated from patients with LRTIs were analyzed as part of the British Society for Antimicrobial Chemotherapy Antimicrobial Resistance Surveillance Programme during 2014-2015. Antibiotic susceptibility was evaluated using European Committee on Antimicrobial Susceptibility Testing breakpoints, including the ceftobiprole pharmacokinetic/pharmacodynamic non-species-specific breakpoint when species-specific breakpoints were not available. RESULTS: One thousand one hundred and sixty-eight isolates from community-onset LRTIs and 1,264 isolates from hospital-onset LRTIs were analyzed. The ceftobiprole susceptibility rate was 99.8% (428/429) for Streptococcus pneumoniae, 100% (502/502) for Haemophilus influenzae, and 99.6% (236/237) for Moraxella catarrhalis. All Staphylococcus aureus isolates, including methicillin-susceptible S. aureus (MSSA; N=181) and methicillin-resistant S. aureus (MRSA; N=35), were susceptible to ceftobiprole. Overall, ceftobiprole susceptibility was observed in 88.1% (215/244) of Escherichia coli isolates, 83.4% (156/187) of Klebsiella pneumoniae isolates and 86.7% (98/113) of Enterobacter spp. isolates. CONCLUSION: Ceftobiprole had in vitro activity against all S. aureus (both MSSA and MRSA) isolates, and almost all S. pneumoniae isolates, as well as against Gram-negative bacteria associated with community-onset or hospital-onset LRTIs. Based on this analysis, ceftobiprole is a good treatment option when broad-spectrum antibiotic coverage is needed for LRTIs.

Impact of Personal Frequency Modulation Systems on Behavioral and Cortical Auditory Evoked Potential Measures of Auditory Processing and Classroom Listening in School-Aged Children with Auditory Processing Disorder.

BACKGROUND: Personal frequency modulation (FM) systems are often recommended for children diagnosed with auditory processing disorder (APD) to improve their listening environment in the classroom. Further evidence is required to support the continuation of this recommendation. PURPOSE: To determine whether personal FM systems enhance auditory processing abilities and classroom listening in school-aged children with APD. RESEARCH DESIGN: Two baseline assessments separated by eight weeks were undertaken before a 20-week trial of bilateral personal FM in the classroom. The third assessment was completed immediately after the FM trial. A range of behavioral measures and speech-evoked cortical auditory evoked potentials (CAEPs) in quiet and in noise were used to assess auditory processing and FM outcomes. Perceived listening ability was assessed using the Listening Inventory for Education-United Kingdom version (LIFE-UK) questionnaire student and teacher versions, and a modified version of the LIFE-UK questionnaire for parents. STUDY SAMPLE: Twenty-eight children aged 7-12 years were included in this intervention study. Of the 28 children, there were 22 males and six females. DATA COLLECTION AND ANALYSIS: APD Tests scores and CAEP peak latencies and amplitudes were analyzed using repeated measures analysis of variance to determine whether results changed over the two baseline assessments and after the FM trial. The LIFE-UK was administered immediately before and after the FM trial. Student responses were analyzed using paired t-tests. Results are described for the (different) pre- and post-trial teacher versions of the LIFE-UK. RESULTS: Speech in spatial noise (SSN) scores improved by 13% on average when participants wore the FM system in the laboratory. Noise resulted in increased P1 and N2 latencies and reduced N2 amplitudes. The impact of noise on CAEP latencies and amplitudes was significantly reduced when participants wore the FM. Participants' LIFE-UK responses indicated significant improvements in their perceived listening after the FM trial. Most teachers (74%) reported the trial as successful, based on LIFE-UK ratings. Teachers' and parents' questionnaire ratings indicated good agreement regarding the outcomes of the FM trial. There was no change in compressed and reverberated words, masking level difference, and sustained attention scores across visits. Gaps in noise, dichotic digits test, and SSN (hard words) showed practice effects. Frequency pattern test and SSN easy word scores did not change between baseline visits, and improved significantly after the FM trial. CAEP N2 latencies and amplitudes changed significantly across visits; changes occurred across the baseline and the FM trial period. CONCLUSIONS: Personal FM systems produce immediate speech perception benefits and enhancement of speech-evoked cortical responses in noise in the laboratory. The 20-week FM trial produced significant improvements in behavioral measures of auditory processing and participants' perceptions of their listening skills. Teacher and parent questionnaires also indicated positive outcomes.

Comparative activity of ceftobiprole against coagulase-negative staphylococci from the BSAC Bacteraemia Surveillance Programme, 2013-2015.

Coagulase-negative staphylococci (CoNS) are a significant cause of bacteraemia, the treatment of which is becoming increasingly complex due to the emergence of multidrug-resistant strains. This study aimed to evaluate the in vitro activity of ceftobiprole, an advanced-generation cephalosporin, as compared with other antimicrobial agents against CoNS from patients with bacteraemia. As part of the British Society for Antimicrobial Chemotherapy (BSAC) Bacteraemia Surveillance Programme, 650 blood isolates of CoNS were obtained from patients with bacteraemia at 74 centres throughout the UK and Ireland for the years 2013-2015. Minimum inhibitory concentrations (MICs) of ceftobiprole and other antimicrobial agents were determined using the BSAC agar dilution method. Susceptibility was assessed by European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. The majority of the isolates (63.2%) were Staphylococcus epidermidis. Overall, methicillin resistance, as determined by oxacillin susceptibility testing, was observed in 64.2% of isolates. The MIC50/90 of ceftobiprole was 1/2 mg/L, and 100% of CoNS isolates were inhibited at the EUCAST ceftobiprole non-species-specific pharmacokinetic/pharmacodynamic breakpoint of 4 mg/L. Only one isolate was resistant to vancomycin. Overall rates of resistance to ciprofloxacin, clindamycin, erythromycin and teicoplanin were 50.5, 25.1, 68.2 and 20.9%, respectively. In S. epidermidis, resistance to oxacillin was associated with increased resistance to other antimicrobials. Ceftobiprole demonstrated in vitro activity against all CoNS species isolated from patients with bacteraemia and was active against species resistant to other antistaphylococcal antimicrobials. The collection of clinical data regarding the efficacy of ceftobiprole in treating CoNS bacteraemia is warranted.

A review of predation as a limiting factor for bird populations in mesopredator-rich landscapes: a case study of the UK.

The impact of increasing vertebrate predator numbers on bird populations is widely debated among the general public, game managers and conservationists across Europe. However, there are few systematic reviews of whether predation limits the population sizes of European bird species. Views on the impacts of predation are particularly polarised in the UK, probably because the UK has a globally exceptional culture of intensive, high-yield gamebird management where predator removal is the norm. In addition, most apex predators have been exterminated or much depleted in numbers, contributing to a widely held perception that the UK has high numbers of mesopredators. This has resulted in many high-quality studies of mesopredator impacts over several decades. Here we present results from a systematic review of predator trends and abundance, and assess whether predation limits the population sizes of 90 bird species in the UK. Our results confirm that the generalist predators Red Fox (Vulpes vulpes) and Crows (Corvus corone and C. cornix) occur at high densities in the UK compared with other European countries. In addition, some avian and mammalian predators have increased numerically in the UK during recent decades. Despite these high and increasing densities of predators, we found little evidence that predation limits populations of pigeons, woodpeckers and passerines, whereas evidence suggests that ground-nesting seabirds, waders and gamebirds can be limited by predation. Using life-history characteristics of prey species, we found that mainly long-lived species with high adult survival and late onset of breeding were limited by predation. Single-brooded species were also more likely to be limited by predation than multi-brooded species. Predators that depredate prey species during all life stages (i.e. from nest to adult stages) limited prey numbers more than predators that depredated only specific life stages (e.g. solely during the nest phase). The Red Fox and non-native mammals (e.g. the American Mink Neovison vison) were frequently identified as numerically limiting their prey species. Our review has identified predator-prey interactions that are particularly likely to result in population declines of prey species. In the short term, traditional predator-management techniques (e.g. lethal control or fencing to reduce predation by a small number of predator species) could be used to protect these vulnerable species. However, as these techniques are costly and time-consuming, we advocate that future research should identify land-use practices and landscape configurations that would reduce predator numbers and predation rates.

Nest trampling and ground nesting birds: Quantifying temporal and spatial overlap between cattle activity and breeding redshank.

Conservation grazing for breeding birds needs to balance the positive effects on vegetation structure and negative effects of nest trampling. In the UK, populations of Common redshank Tringa totanus breeding on saltmarshes declined by >50% between 1985 and 2011. These declines have been linked to changes in grazing management. The highest breeding densities of redshank on saltmarshes are found in lightly grazed areas. Conservation initiatives have encouraged low-intensity grazing at <1 cattle/ha, but even these levels of grazing can result in high levels of nest trampling. If livestock distribution is not spatially or temporally homogenous but concentrated where and when redshank breed, rates of nest trampling may be much higher than expected based on livestock density alone. By GPS tracking cattle on saltmarshes and monitoring trampling of dummy nests, this study quantified (i) the spatial and temporal distribution of cattle in relation to the distribution of redshank nesting habitats and (ii) trampling rates of dummy nests. The distribution of livestock was highly variable depending on both time in the season and the saltmarsh under study, with cattle using between 3% and 42% of the saltmarsh extent and spending most their time on higher elevation habitat within 500 m of the sea wall, but moving further onto the saltmarsh as the season progressed. Breeding redshank also nest on these higher elevation zones, and this breeding coincides with the early period of grazing. Probability of nest trampling was correlated to livestock density and was up to six times higher in the areas where redshank breed. This overlap in both space and time of the habitat use of cattle and redshank means that the trampling probability of a nest can be much higher than would be expected based on standard measures of cattle density. Synthesis and applications: Because saltmarsh grazing is required to maintain a favorable vegetation structure for redshank breeding, grazing management should aim to keep livestock away from redshank nesting habitat between mid-April and mid-July when nests are active, through delaying the onset of grazing or introducing a rotational grazing system.

In Vitro Activity of Telavancin Against Clinically Important Gram-Positive Pathogens from 69 U.S. Medical Centers (2015): Potency Analysis by U.S. Census Divisions.

A total of 8,072 gram-positive isolates collected from 69 medical centers among all 9 U.S. Census Divisions during the 2015 SENTRY Antimicrobial Surveillance Program were included. Telavancin had minimal inhibitory concentration (MIC)50 and MIC90 values of 0.03/0.06 µg/mL, respectively, against methicillin-susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). Similar activity was also observed among coagulase-negative staphylococci (MIC50/90, 0.03/0.06 µg/ml; 100.0% inhibited by ≤0.12 µg/ml). Telavancin was active against vancomycin-susceptible Enterococcus faecalis (MIC50/90, 0.12/0.12 µg/ml) and Enterococcus faecium (MIC50/90, 0.03/0.06 µg/ml), but was less active against vancomycin-resistant E. faecium (MIC90, >2 µg/ml) and E. faecalis (MIC90, >2 µg/ml). Streptococci showed modal MIC results of 0.008 µg/ml (Streptococcus pneumoniae) to 0.015 µg/ml (ß-hemolytic streptococci and viridans group streptococci). Potency variations for telavancin within Census Divisions were not observed. Telavancin remains potent in vitro against indicated pathogens recovered from U.S. medical centers (2015).