1,588 research outputs found
High susceptibility to zoliflodacin and conserved target (GyrB) for zoliflodacin among 1209 consecutive clinical Neisseria gonorrhoeae isolates from 25 European countries, 2018
No full textRandomized Controlled TrialEuropean Collaborative Group: Raquel Abad Torreblanca, Lena Rós Ásmundsdóttir, Eszter Balla, Irith De Baetselier, Beatrice Bercot, Anna Carannante, Dominique Caugant, Maria José Borrego, Susanne Buder, Robert Cassar, Michelle Cole, Alje van Dam, Claudia Eder, Steen Hoffmann, Blazenka Hunjak, Samo Jeverica, Vesa Kirjavainen, Panayiota Maikanti-Charalambous, Vivi Miriagou, Beata Mlynarczyk-Bonikowska, Gatis Pakarna, Lynsey Patterson, Peter Pavlik, Monique Perrin, Jill Shepherd, Paola Stefanelli, Magnus Unemo, Jelena Viktorova, Hana ZákouckáEuropean Collaborative Group: Portugal - Maria José Borrego, INSA.Objectives: Novel antimicrobials for treatment of gonorrhoea are imperative. The first-in-class spiropyrimidinetrione zoliflodacin is promising and currently in an international Phase 3 randomized controlled clinical trial (RCT) for treatment of uncomplicated gonorrhoea. We evaluated the in vitro activity of and the genetic conservation of the target (GyrB) and other potential zoliflodacin resistance determinants among 1209 consecutive clinical Neisseria gonorrhoeae isolates obtained from 25 EU/European Economic Area (EEA) countries in 2018 and compared the activity of zoliflodacin with that of therapeutic antimicrobials currently used.
Methods: MICs of zoliflodacin, ceftriaxone, cefixime, azithromycin and ciprofloxacin were determined using an agar dilution technique for zoliflodacin or using MIC gradient strip tests or an agar dilution technique for the other antimicrobials. Genome sequences were available for 96.1% of isolates.
Results: Zoliflodacin modal MIC, MIC50, MIC90 and MIC range were 0.125, 0.125, 0.125 and ≤0.004-0.5 mg/L, respectively. The resistance was 49.9%, 6.7%, 1.6% and 0.2% to ciprofloxacin, azithromycin, cefixime and ceftriaxone, respectively. Zoliflodacin did not show any cross-resistance to other tested antimicrobials. GyrB was highly conserved and no zoliflodacin gyrB resistance mutations were found. No fluoroquinolone target GyrA or ParC resistance mutations or mutations causing overexpression of the MtrCDE efflux pump substantially affected the MICs of zoliflodacin.
Conclusions: The in vitro susceptibility to zoliflodacin was high and the zoliflodacin target GyrB was conserved among EU/EEA gonococcal isolates in 2018. This study supports further clinical development of zoliflodacin. However, additional zoliflodacin data regarding particularly the treatment of pharyngeal gonorrhoea, pharmacokinetics/pharmacodynamics and resistance selection, including suppression, would be valuable.The present work was funded by grants from the O¨rebro County Council
Research Committee and the Foundation for Medical Research at O¨rebro
University Hospital, Sweden. Work at the WHO Collaborating Centre for
Gonorrhoea and Other STIs is additionally supported by grants to M.U.
from the WHO and the Global Antibiotic Research and Development
Partnership (GARDP). L.S.-B. was supported by the Li Ka Shing Foundation
(Big Data Institute, University of Oxford, UK) and the Centre for Genomic Pathogen Surveillance (CGPS; http://pathogensurveillance.net) when this
work was conceived. Currently, L.S.-B. is funded by Plan GenT (CDEI-06/
20-B), Conselleria de Sanitat Universal i Salut Pu´blica, Generalitat
Valenciana, Valencia, Spain.info:eu-repo/semantics/publishedVersio
Recommendations for the optimal introduction of novel antibiotics to treat uncomplicated gonorrhoea in the face of increasing antimicrobial resistance : a case study with zoliflodacin
No full textNew, first-in-class oral antibiotics like zoliflodacin, developed in a public-private partnership, require an optimal introduction strategy while ensuring antibiotic stewardship. Zoliflodacin, given as a single dose for uncomplicated urogenital gonorrhoea, recently demonstrated non-inferiority to ceftriaxone plus azithromycin and safety in a phase 3 randomised controlled trial. Following regulatory approval, zoliflodacin could improve sexually transmitted infection (STI) management and help address the threat of untreatable gonorrhoea, as levels of resistance to current first-line treatments increase. The Global Antibiotic Research & Development Partnership (GARDP) convened an expert meeting during the 2023 STI and HIV World Congress to discuss key questions about the introduction of zoliflodacin in low- and middle-income countries (LMICs). The questions included: which patients to treat in which situations, the timing of introduction, and what additional evidence is needed to change policy for the use of new antibiotics for gonorrhoea. Recommendations from the expert group included: the generation of evidence for the role of a drug like zoliflodacin in clinical treatment failures; the need for additional antimicrobial resistance surveillance; investigation of the role of novel diagnostic approaches, such as point-of-care tests, to improve stewardship; study of preferences and values among the population in need; and modelling of the emergence of N. gonorrhoeae resistance and transmission in different scenarios. Forthcoming World Health Organization (WHO) global guidelines could outline recommendations for a new oral antibiotic like zoliflodacin based on existing evidence, and rational approaches for certain populations or use cases, while the evidence base is further strengthened.</p
Efficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections : A Phase 3, double-blind, randomized study
No full textFunding Information: This work was funded by Melinta Therapeutics. In addition the editorial assistance (see below) was funded by Melinta Therapeutics. Publisher Copyright: © The Author 2017.Background: Delafloxacin is an investigational anionic fluoroquinolone in development for oral or intravenous administration for the treatment of infections caused by Gram-positive (including MRSA), Gram-negative, atypical and anaerobic organisms. Objectives: To establish the non-inferiority of delafloxacin compared with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections and to compare the safety of the two antimicrobials. Patients and methods: A Phase 3, multicentre, randomized, double-blind, active-controlled study with 660 patients compared delafloxacin 300mg or vancomycin 15 mg/kg plus aztreonam2 g each administered twice daily intravenously for 5-14 days. Non-inferiority was evaluated by objective response ( ≥ 20% erythema reduction) at 48-72 h after initiation of study drug, investigator subjective assessment of outcome and microbiological responses. Clinical Trials Registration: NCT01811732. EudraCT number: 2012-001767-71. Results: In the ITT analysis set, the objective response was 78.2% in the delafloxacin arm and 80.9% in the vancomycin/aztreonam arm (mean treatment difference, -2.6%; 95% CI, -8.78% to 3.57%). Investigatorassessed cure was similar between the two groups at follow-up (52.0% versus 50.5%) and late follow-up (70.4% versus 66.6%). Bacterial eradication of MRSA was 100% and 98.5% in the delafloxacin group and the vancomycin/ aztreonamgroup, respectively. Frequency of treatment-emergent adverse events in the delafloxacin and vancomycin/aztreonam groups was similar. Treatment-emergent adverse events leading to study drug discontinuation were higher in the vancomycin/aztreonam group compared with the delafloxacin group (4.3% versus 0.9%). Conclusions: Delafloxacin, an anionic fluoroquinolone, was statistically non-inferior to vancomycin/aztreonam at 48-72 h following the start of therapy and was well tolerated as monotherapy in the treatment of acute bacterial skin and skin structure infections.Peer reviewe
Efficacy and Safety of Sarilumab in patients with COVID19 Pneumonia : A Randomized, Phase III Clinical Trial (SARTRE Study)
No full textPublisher Copyright: © 2021, The Author(s).Introduction: SARS-CoV-2 pneumonia is often associated with hyper-inflammation. The cytokine-storm-like is one of the targets of current therapies for coronavirus disease 2019 (COVID-19). High Interleukin-6 (IL6) blood levels have been identified in severe COVID-19 disease, but there are still uncertainties regarding the actual role of anti-IL6 antagonists in COVID-19 management. Our hypothesis was that the use of sarilumab plus corticosteroids at an early stage of the hyper-inflammatory syndrome would be beneficial and prevent progression to acute respiratory distress syndrome (ARDS). Methods: We randomly assigned (in a 1:1 ratio) COVID-19 pneumonia hospitalized patients under standard oxygen therapy and laboratory evidence of hyper-inflammation to receive sarilumab plus usual care (experimental group) or usual care alone (control group). Corticosteroids were given to all patients at a 1 mg/kg/day of methylprednisolone for at least 3 days. The primary outcome was the proportion of patients progressing to severe respiratory failure (defined as a score in the Brescia-COVID19 scale ≥ 3) up to day 15. Results: A total of 201 patients underwent randomization: 99 patients in the sarilumab group and 102 patients in the control group. The rate of patients progressing to severe respiratory failure (Brescia-COVID scale score ≥ 3) up to day 15 was 16.16% in the Sarilumab group versus 15.69% in the control group (RR 1.03; 95% CI 0.48–2.20). No relevant safety issues were identified. Conclusions: In hospitalized patients with Covid-19 pneumonia, who were under standard oxygen therapy and who presented analytical inflammatory parameters, an early therapeutic intervention with sarilumab plus standard of care (including corticosteroids) was not shown to be more effective than current standard of care alone. The study was registered at EudraCT with number: 2020-002037-15.Peer reviewe
Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
No full textGenetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10<sup>−11</sup>; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28–1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
No full textUsing the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10−4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10−8), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals
Efficacy and Safety of Budesonide Orodispersible Tablets for Eosinophilic Esophagitis up to 3 Years: An Open-Label Extension Study
No full textBudesonide orodispersible tablets (BOT) have been shown to be safe and effective in phase III double-blind trials of induction and 48-week maintenance therapy of eosinophilic esophagitis (EoE). We now analyzed the long-term efficacy and safety of BOT in a 96-week open-label extension (OLE) study.
All patients with EoE in the 48-week double-blind maintenance study were eligible to receive BOT treatment for up to 96 weeks. Dosage was 0.5 or 1.0 mg BOT, twice daily, at investigator's discretion. Clinical, histologic, endoscopic, quality of life, and safety measures were assessed.
A total of 186 patients participated in the OLE up to 96 weeks. At week 96, 81.9% of patients had clinical remission, defined as an EoE Symptom Activity Index (EEsAI) score of ≤20 vs 77.7% at OLE baseline. A further 80.1% of patients were in histologic remission, defined as peak eosinophils per high-power field of <5, at week 96 vs 91.8% at OLE baseline. Mean EoE endoscopic reference scores (EREFS) were 1 at all time points measured. Mean EoE Quality of Life (EoE-QoL-A) Scale scores improved from 3.3 at OLE baseline to 3.5 at week 96. No new safety concerns were observed across 96 weeks of treatment. Suspected symptomatic candidiasis occurred at similar rates to prior BOT studies and was predominantly mild and resolved with treatment.
Clinical and histologic remission of EoE could be maintained with BOT in a large majority of patients for up to 96 weeks, and for up to 144 weeks in patients with uninterrupted BOT therapy across all trials. No additional safety concerns were identified with long-term BOT treatment (ClinicalTrials.gov, Number: NCT02493335).
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved
The Dantu blood group prevents parasite growth in vivo: Evidence from a controlled human malaria infection study
No full textBackground: The long co-evolution of Homo sapiens and Plasmodium falciparum has resulted in the selection of numerous human genetic variants that confer an advantage against severe malaria and death. One such variant is the Dantu blood group antigen, which is associated with 74% protection against severe and complicated P. falciparum malaria infections in homozygous individuals, similar to that provided by the sickle haemoglobin allele (HbS). Recent in vitro studies suggest that Dantu exerts this protection by increasing the surface tension of red blood cells, thereby impeding the ability of P. falciparum merozoites to invade them and reducing parasite multiplication. However, no studies have yet explored this hypothesis in vivo.
Methods: We investigated the effect of Dantu on early phase P. falciparum (Pf) infections in a controlled human malaria infection (CHMI) study. 141 sickle-negative Kenyan adults were inoculated with 3.2 × 103 aseptic, purified, cryopreserved Pf sporozoites (PfSPZ Challenge) then monitored for blood-stage parasitaemia for 21 days by quantitative polymerase chain reaction (qPCR)analysis of the 18S ribosomal RNA P. falciparum gene. The primary endpoint was blood-stage P. falciparum parasitaemia of ≥500/μl while the secondary endpoint was the receipt of antimalarial treatment in the presence of parasitaemia of any density. On study completion, all participants were genotyped both for Dantu and for four other polymorphisms that are associated with protection against severe falciparum malaria: α+-thalassaemia, blood group O, G6PD deficiency, and the rs4951074 allele in the red cell calcium transporter ATP2B4.
Results: The primary endpoint was reached in 25/111 (22.5%) non-Dantu subjects in comparison to 0/27 (0%) Dantu heterozygotes and 0/3 (0.0%) Dantu homozygotes (p=0.01). Similarly, 49/111 (44.1%) non-Dantu subjects reached the secondary endpoint in comparison to only 7/27 (25.9%) and 0/3 (0.0%) Dantu heterozygotes and homozygotes, respectively (p=0.021). No significant impacts on either outcome were seen for any of the other genetic variants under study.
Conclusions: This study reveals, for the first time, that the Dantu blood group is associated with high-level protection against early, non-clinical, P. falciparum malaria infections in vivo. Learning more about the mechanisms involved could potentially lead to new approaches to the prevention or treatment of the disease. Our study illustrates the power of CHMI with PfSPZ Challenge for directly testing the protective impact of genotypes previously identified using other methods.
Funding: The Kenya CHMI study was supported by an award from Wellcome (grant number 107499). SK was supported by a Training Fellowship (216444/Z/19/Z), TNW by a Senior Research Fellowship (202800/Z/16/Z), JCR by an Investigator Award (220266/Z/20/Z), and core support to the KEMRI-Wellcome Trust Research Programme in Kilifi, Kenya (203077), all from Wellcome. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
Clinical trial number: NCT0273976
Short-interval observational data to inform clinical trial design in Huntington's disease.
No full textOBJECTIVES: To evaluate candidate outcomes for disease-modifying trials in Huntington's disease (HD) over 6-month, 9-month and 15-month intervals, across multiple domains. To present guidelines on rapid efficacy readouts for disease-modifying trials. METHODS: 40 controls and 61 patients with HD, recruited from four EU sites, underwent 3 T MRI and standard clinical and cognitive assessments at baseline, 6 and 15 months. Neuroimaging analysis included global and regional change in macrostructure (atrophy and cortical thinning), and microstructure (diffusion metrics). The main outcome was longitudinal effect size (ES) for each outcome. Such ESs can be used to calculate sample-size requirements for clinical trials for hypothesised treatment efficacies. RESULTS: Longitudinal changes in macrostructural neuroimaging measures such as caudate atrophy and ventricular expansion were significantly larger in HD than controls, giving rise to consistently large ES over the 6-month, 9-month and 15-month intervals. Analogous ESs for cortical metrics were smaller with wide CIs. Microstructural (diffusion) neuroimaging metrics ESs were also typically smaller over the shorter intervals, although caudate diffusivity metrics performed strongly over 9 and 15 months. Clinical and cognitive outcomes exhibited small longitudinal ESs, particularly over 6-month and 9-month intervals, with wide CIs, indicating a lack of precision. CONCLUSIONS: To exploit the potential power of specific neuroimaging measures such as caudate atrophy in disease-modifying trials, we propose their use as (1) initial short-term readouts in early phase/proof-of-concept studies over 6 or 9 months, and (2) secondary end points in efficacy studies over longer periods such as 15 months
Improving the energy efficient of manufactured lightweight housing: Integrating phase-change material with passive solar design
No full textImproving the energy efficiency of the built environment is fundamental to slowing the current increase in atmospheric greenhouse gases and hence global warming. Thermal energy storage in buildings is a key component of energy conservation and the use of phase change materials is now regarded as one of the most efficient and cost-effective ways of achieving this. Space conditioning systems using integrated phase-change materials exhibit significantly higher thermal capacities than conventional systems and are therefore able to reduce and normalize extremes of high and low temperatures within the home. Various techniques have been used over time and this thesis describes the results of spring and summer trials using microencapsulated phase-change material plasterboard to improve thermal performance in lightweight buildings.
The author assisted in the design, supervision of construction, commissioning and thermal performance monitoring of a prototype lightweight manufactured park home in the warm temperate climate of Mandurah, 65 kms south of Perth, Western Australia. The microencapsulated phasechange material plasterboard was used as an integrated active and passive space heating and cooling system within the prototype. The summer trials involved the combination of using the plasterboard together with a fan assisted ventilation system; the spring trials described the use of the plasterboard together with a natural gas fire as a sensible heat source. Under cool conditions the fan
ventilation system was also used to heat the building.
This prototype indicates that innovative use of the new technology is a cost-effective way to improve the thermal performance and energy efficiency of housing under both summer and winter conditions. The thesis reports on the findings that have emerged from various planning, design, construction and preliminary monitoring activities. The project has verified that the costs of adding phase-change
materials are viable when integrated in volume manufactured lightweight housing with the added benefits of ignificantly reduced heating cooling costs and reduced greenhouse emissions. In fact, the benefits at this early stage have proven significant enough for the village development company to incorporate the new plasterboard within the design specification of all 415 homes in their next lifestyle village currently under construction
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