283 research outputs found

    Understanding central nervous system efficacy of antimicrobials

    Get PDF
    The requirements for antimicrobial treatment to reach the central nervous system (CNS) are of maximal importance, for two major reasons: (i) the brain is an immuno-privileged site, with virtually no leukocytes in the brain parenchyma or cerebrospinal fluid (CSF) at baseline; (ii) the blood–brain barrier (BBB) drastically reduces the diffusion of antimicrobials into the CNS [1]. Treatment of CNS infections has been a major area of research since the discovery of the first antimicrobials. Treatment regimens recommended for encephalitis [2, 3], meningitis [4], and brain abscess [5], have to comply with the pharmacokinetic (PK), and pharmacodynamic (PD) characteristics of available antibacterial, antiviral, antifungal, and antiparasitic agents [6]. Due to the numerous constraints created by the BBB, therapeutic options are quite limited, so that current practices for treatment of CNS infections are remarkably similar worldwide, with much less heterogeneity than for other major infectious diseases (e.g. pneumonia, abdominal, or skin and skin structure infections). This paper summarizes the main parameters that must be taken into account to ensure efficacy of antimicrobial agents in the CNS, with an emphasis on antibacterial drugs

    Genetic Variation in the β2-Adrenocepter Gene Is Associated with Susceptibility to Bacterial Meningitis in Adults

    Get PDF
    Recently, the biased β2-adrenoceptor/β-arrestin pathway was shown to play a pivotal role in crossing of the blood brain barrier by Neisseria meningitidis. We hypothesized that genetic variation in the β2-adrenoceptor gene (ADRB2) may influence susceptibility to bacterial meningitis. In a prospective genetic association study we genotyped 542 patients with CSF culture proven community acquired bacterial meningitis and 376 matched controls for 2 functional single nucleotide polymorphisms in the β2-adrenoceptor gene (ADRB2). Furthermore, we analyzed if the use of non-selective beta-blockers, which bind to the β2-adrenoceptor, influenced the risk of bacterial meningitis. We identified a functional polymorphism in ADRB2 (rs1042714) to be associated with an increased risk for bacterial meningitis (Odds ratio [OR] 1.35, 95% confidence interval [CI] 1.04–1.76; p = 0.026). The association remained significant after correction for age and was more prominent in patients with pneumococcal meningitis (OR 1.52, 95% CI 1.12–2.07; p = 0.007). For meningococcal meningitis the difference in genotype frequencies between patients and controls was similar to that in pneumococcal meningitis, but this was not statistically significant (OR 1.43, 95% CI 0.60–3.38; p = 0.72). Patients with bacterial meningitis had a lower frequency of non-selective beta-blockers use compared to the age matched population (0.9% vs. 1.8%), although this did not reach statistical significance (OR 1.96 [95% CI 0.88–4.39]; p = 0.09). In conclusion, we identified an association between a genetic variant in the β2-adrenoceptor and increased susceptibility to bacterial meningitis. The potential benefit of pharmacological treatment targeting the β2-adrenoceptor to prevent bacterial meningitis in the general population or patients with bacteraemia should be further studied in both experimental studies and observational cohorts

    Second-Generation Everolimus-Eluting Stents Versus First-Generation Sirolimus-Eluting Stents in Acute Myocardial Infarction 1-Year Results of the Randomized XAMI (XienceV Stent vs. Cypher Stent in Primary PCI for Acute Myocardial Infarction) Trial

    Get PDF
    ObjectivesThe goal of this study was to compare the efficacy and safety of second-generation everolimus-eluting stents (EES) with first-generation sirolimus-eluting stents (SES) in primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI).BackgroundDrug-eluting stents (DES) in AMI are still feared for possible late and very late stent thrombosis (ST). Newer-generation DES, with more hemocompatible polymers and improved healing, may show promise regarding increased efficacy of DES with improved safety. However, no randomized trials in AMI are available.MethodsA total of 625 patients with AMI were randomized (2:1) to receive EES or SES in the XAMI (XienceV Stent vs Cypher Stent in Primary PCI for Acute Myocardial Infarction) trial. Primary endpoint was major adverse cardiac events (MACE) at 1 year consisting of cardiac death, nonfatal AMI, or any target vessel revascularization. The study was powered for noninferiority of EES. Secondary endpoints comprised ST rates and MACE rate up to 3 years.ResultsThe MACE rate was 4.0% for EES and 7.7% for SES; the absolute difference was −3.7% (95% confidence interval: −8.28 to −0.03; p = 0.048) and relative risk was 0.52 (95% confidence interval: 0.27 to 1.00). One-year cardiac mortality was low at 1.5% for EES versus 2.7% for SES (p = 0.36), and 1-year incidence of definite and/or probable ST was 1.2% for EES versus 2.7% for SES (p = 0.21).ConclusionsIn this all-comer, randomized, multicenter AMI trial, second-generation EES was noninferior to SES, and superiority for MACE was suggested. ST rate in EES at 1-year was low, but long-term follow-up and larger studies will have to show whether very late ST rates will also be improved in newer DES. (XienceV Stent vs Cypher Stent in Primary PCI for Acute Myocardial Infarction [XAMI]; NTR1123

    V-akt murine thymoma viral oncogene homolog 3 (AKT3) contributes to poor disease outcome in humans and mice with pneumococcal meningitis

    Get PDF
    Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Here, we have performed a prospective nationwide genetic association study using the Human Exome BeadChip and identified gene variants in encoding dynactin 4 (DCTN4), retinoic acid early transcript 1E (RAET1E), and V-akt murine thymoma viral oncogene homolog 3 (AKT3) to be associated with unfavourable outcome in patients with pneumococcal meningitis. No clinical replication cohort is available, so we validated the role of one of these targets, AKT3, in a pneumococcal meningitis mouse model. Akt3 deficient mice had worse survival and increased histopathology scores for parenchymal damage (infiltration) and vascular infiltration (large meningeal artery inflammation) but similar bacterial loads, cytokine responses, compared to wild-type mice. We found no differences in cerebrospinal fluid cytokine levels between patients with risk or non-risk alleles. Patients with the risk genotype (rs10157763, AA) presented with low scores on the Glasgow Coma Scale and high rate of epileptic seizures. Thus, our results show that AKT3 influences outcome of pneumococcal meningiti

    Infection of zebrafish embryos with live fluorescent Streptococcus pneumoniae as a real-time pneumococcal meningitis model

    Get PDF
    Background: Streptococcus pneumoniae is one of the most important causes of bacterial meningitis, an infection where unfavourable outcome is driven by bacterial and host-derived toxins. In this study, we developed and characterized a pneumococcal meningitis model in zebrafish embryos that allows for real-time investigation of early host-microbe interaction. Methods: Zebrafish embryos were infected in the caudal vein or hindbrain ventricle with green fluorescent wild-type S. pneumoniae D39 or a pneumolysin-deficient mutant. The kdrl:mCherry transgenic zebrafish line was used to visualize the blood vessels, whereas phagocytic cells were visualized by staining with far red anti-L-plastin or in mpx:GFP/mpeg1:mCherry zebrafish, that have green fluorescent neutrophils and red fluorescent macrophages. Imaging was performed by fluorescence confocal and time-lapse microscopy. Results: After infection by caudal vein, we saw focal clogging of the pneumococci in the blood vessels and migration of bacteria through the blood-brain barrier into the subarachnoid space and brain tissue. Infection with pneumolysin-deficient S. pneumoniae in the hindbrain ventricle showed attenuated growth and migration through the brain as compared to the wild-type strain. Time-lapse and confocal imaging revealed that the initial innate immune response to S. pneumoniae in the subarachnoid space mainly consisted of neutrophils and that pneumolysin-mediated cytolytic activity caused a marked reduction of phagocytes. Conclusions: This new meningitis model permits detailed analysis and visualization of host-microbe interaction in pneumococcal meningitis in real time and is a very promising tool to further our insights in the pathogenesis of pneumococcal meningitis

    Large scale genomic analysis shows no evidence for pathogen adaptation between the blood and cerebrospinal fluid niches during bacterial meningitis.

    Get PDF
    Recent studies have provided evidence for rapid pathogen genome diversification, some of which could potentially affect the course of disease. We have previously described such variation seen between isolates infecting the blood and cerebrospinal fluid (CSF) of a single patient during a case of bacterial meningitis. Here, we performed whole-genome sequencing of paired isolates from the blood and CSF of 869 meningitis patients to determine whether such variation frequently occurs between these two niches in cases of bacterial meningitis. Using a combination of reference-free variant calling approaches, we show that no genetic adaptation occurs in either invaded niche during bacterial meningitis for two major pathogen species, Streptococcus pneumoniae and Neisseria meningitidis. This study therefore shows that the bacteria capable of causing meningitis are already able to do this upon entering the blood, and no further sequence change is necessary to cross the blood-brain barrier. Our findings place the focus back on bacterial evolution between nasopharyngeal carriage and invasion, or diversity of the host, as likely mechanisms for determining invasiveness

    Validation of a Dutch Risk Score Predicting Poor Outcome in Adults with Bacterial Meningitis in Vietnam and Malawi

    Get PDF
    We have previously developed and validated a prognostic model to predict the risk for unfavorable outcome in Dutch adults with bacterial meningitis. The aim of the current study was to validate this model in adults with bacterial meningitis from two developing countries, Vietnam and Malawi. Demographic and clinical characteristics of Vietnamese (n = 426), Malawian patients (n = 465) differed substantially from those of Dutch patients (n = 696). The Dutch model underestimated the risk of poor outcome in both Malawi and Vietnam. The discrimination of the original model (c-statistic [c] 0.84; 95% confidence interval 0.81 to 0.86) fell considerably when re-estimated in the Vietnam cohort (c = 0.70) or in the Malawian cohort (c = 0.68). Our validation study shows that new prognostic models have to be developed for these countries in a sufficiently large series of unselected patients

    Disruptions of Anaerobic Gut Bacteria Are Associated with Stroke and Post-stroke Infection : a Prospective Case-Control Study

    Get PDF
    In recent years, preclinical studies have illustrated the potential role of intestinal bacterial composition in the risk of stroke and post-stroke infections. The results of these studies suggest that bacteria capable of producing volatile metabolites, including trimethylamine-N-oxide (TMAO) and butyrate, play opposing, yet important roles in the cascade of events leading to stroke. However, no large-scale studies have been undertaken to determine the abundance of these bacterial communities in stroke patients and to assess the impact of disrupted compositions of the intestinal microbiota on patient outcomes. In this prospective case-control study, rectal swabs from 349 ischemic and hemorrhagic stroke patients (median age, 71 years; IQR: 67-75) were collected within 24 h of hospital admission. Samples were subjected to 16S rRNA amplicon sequencing and subsequently compared with samples obtained from 51 outpatient age- and sex-matched controls (median age, 72 years; IQR, 62-80) with similar cardiovascular risk profiles but without active signs of stroke. Plasma protein biomarkers were analyzed using a combination of nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS). Alpha and beta diversity analyses revealed higher disruption of intestinal communities during ischemic and hemorrhagic stroke compared with non-stroke matched control subjects. Additionally, we observed an enrichment of bacteria implicated in TMAO production and a loss of butyrate-producing bacteria. Stroke patients displayed two-fold lower plasma levels of TMAO than controls (median 1.97 vs 4.03 mu M, Wilcoxonp <0.0001). Finally, lower abundance of butyrate-producing bacteria within 24 h of hospital admission was an independent predictor of enhanced risk of post-stroke infection (odds ratio 0.77,p = 0.005), but not of mortality or functional patient outcome. In conclusion, aberrations in trimethylamine- and butyrate-producing gut bacteria are associated with stroke and stroke-associated infections.Peer reviewe

    Key Intervention Characteristics in e-Health: Steps Towards Standardized Communication

    Get PDF
    PURPOSE: This paper reports expert opinion on e-health intervention characteristics that enable effective communication of characteristics across the diverse field of e-health interventions. The paper presents a visualization tool to support communication of the defining characteristics. METHODS: An initial list of e-health intervention characteristics was developed through an iterative process of item generation and discussion among the 12 authors. The list was distributed to 123 experts in the field, who were emailed an invitation to assess and rank the items. Participants were asked to evaluate these characteristics in three separate ways. RESULTS: A total of 50 responses were received for a response rate of 40.7%. Six respondents who reported having little or no expertise in e-health research were removed from the dataset. Our results suggest that 10 specific intervention characteristics were consistently supported as of central importance by the panel of 44 e-intervention experts. The weight and perceived relevance of individual items differed between experts; oftentimes, this difference is a result of the individual theoretical perspective and/or behavioral target of interest. CONCLUSIONS: The first iteration of the visualization of salient characteristics represents an ambitious effort to develop a tool that will support communication of the defining characteristics for e-health interventions aimed to assist e-health developers and researchers to communicate the key characteristics of their interventions in a standardized manner that facilitates dialog
    • …
    corecore