Carbapenemase-producing Enterobacteriaceaein Europe: assessment by national experts from 38 countries, May 2015

European Survey of Carbapenemase-Producing Enterobacteriaceae (EuSCAPE) working group collaborators: Koraqi A, Bino S, Hartl R, Apfalter P, Glupczynski Y, Jans B, Marković T, Dedeić- Ljubović A, Kojić D, Strateva T, Sabtcheva S, Butić I, Andrašević AT, Pieridou-Bagatzouni D, Panayiota M, Hrabák J, Žemličková H, Hammerum AM, Skov R, Ivanova M, Jalava J, Dortet L, Vaux S, Kaase M, Eckmanns T, Vatopoulos A, Giamarellou H, Tóth Á, Kurcz A, Hardarson H, Kristinsson K, Boo TW, Burns K, Carmeli Y, Pantosti A, Kurti A, Raka L, Balode A, Miciulevičienė J, Valintėlienė R, Perrin-Weniger M, Nestorova N, Borg M, Mijović G, Mugosa B, Meessen N, de Greeff S, Samuelsen Ø, Simonsen GS, Żabicka D, Hryniewicz W, Caniça M, Paiva JA, Kaftandzieva A, Memeti S, Damian M, Codita I, Jelesić Z, Stevanovic G, Nikš M, Schréterová E, Pirš M, Kolman J, Oteo J, Campos J, Giske CG, Sjöström K, Gür D, Ekmekci E, Wiuff C, Hopkins K, Woodford N, Cantón R, Friedrich AW, Gniadkowski M, Poirel L, Rossolini GM, Seifert H, Walsh T, Livermore D, Nordmann P.In 2012, the European Centre for Disease Prevention and Control (ECDC) launched the 'European survey of carbapenemase-producing Enterobacteriaceae (EuSCAPE)' project to gain insights into the occurrence and epidemiology of carbapenemase-producing Enterobacteriaceae (CPE), to increase the awareness of the spread of CPE, and to build and enhance the laboratory capacity for diagnosis and surveillance of CPE in Europe. Data collected through a post-EuSCAPE feedback questionnaire in May 2015 documented improvement compared with 2013 in capacity and ability to detect CPE and identify the different carbapenemases genes in the 38 participating countries, thus contributing to their awareness of and knowledge about the spread of CPE. Over the last two years, the epidemiological situation of CPE worsened, in particular with the rapid spread of carbapenem-hydrolysing oxacillinase-48 (OXA-48)- and New Delhi metallo-beta-lactamase (NDM)-producing Enterobacteriaceae. In 2015, 13/38 countries reported inter-regional spread of or an endemic situation for CPE, compared with 6/38 in 2013. Only three countries replied that they had not identified one single case of CPE. The ongoing spread of CPE represents an increasing threat to patient safety in European hospitals, and a majority of countries reacted by establishing national CPE surveillances systems and issuing guidance on control measures for health professionals. However, 14 countries still lacked specific national guidelines for prevention and control of CPE in mid-2015

European Antibiotic Awareness Day: a five-year perspective of Europe-wide actions to promote prudent use of antibiotics.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Following the European Union (EU) Council Recommendation on prudent use of antimicrobial agents in human medicine in 2001, and the success of national campaigns, i.e. Belgium and France, the European Centre for Disease Prevention and Control (ECDC) decided to establish the European Antibiotic Awareness Day (EAAD) on 18 November as platform to support national campaigns across Europe. This article provides an overview of EAAD tools, materials, and activities developed during the first five years. It shows that EAAD has been successful due to good cooperation between ECDC and national institutions, strong political and stakeholder support and evidence-based development of campaign materials. EAAD has provided a platform for pre-existing national campaigns and encouraged similar campaigns to develop where neither political support had been secured, nor financial support had been available. As a result, participating countries have continuously expressed strong support for ECDC to continue its work on EAAD. This has been endorsed by a steadily increasing number of countries participating and the growing interest of varied professional and stakeholder organisations. We conclude that EAAD should continue to act as catalyst for discussion and as mechanism to raise awareness of the public and prescribers about prudent use of antibiotics

Pneumolysin Activates Macrophage Lysosomal Membrane Permeabilization and Executes Apoptosis by Distinct Mechanisms without Membrane Pore Formation

Intracellular killing of Streptococcus pneumoniae is complemented by induction of macrophage apoptosis. Here, we show that the toxin pneumolysin (PLY) contributes both to lysosomal/phagolysosomal membrane permeabilization (LMP), an upstream event programing susceptibility to apoptosis, and to apoptosis execution via a mitochondrial pathway, through distinct mechanisms. PLY is necessary but not sufficient for the maximal induction of LMP and apoptosis. PLY’s ability to induce both LMP and apoptosis is independent of its ability to form cytolytic pores and requires only the first three domains of PLY. LMP involves TLR (Toll-like receptor) but not NLRP3/ASC (nucleotide-binding oligomerization domain [Nod]-like receptor family, pyrin domain-containing protein 3/apoptosis-associated speck-like protein containing a caspase recruitment domain) signaling and is part of a PLY-dependent but phagocytosis-independent host response that includes the production of cytokines, including interleukin-1 beta (IL-1β). LMP involves progressive and selective permeability to 40-kDa but not to 250-kDa fluorescein isothiocyanate (FITC)-labeled dextran, as PLY accumulates in the cytoplasm. In contrast, the PLY-dependent execution of apoptosis requires phagocytosis and is part of a host response to intracellular bacteria that also includes NO generation. In cells challenged with PLY-deficient bacteria, reconstitution of LMP using the lysomotrophic detergent LeuLeuOMe favored cell necrosis whereas PLY reconstituted apoptosis. The results suggest that PLY contributes to macrophage activation and cytokine production but also engages LMP. Following bacterial phagocytosis, PLY triggers apoptosis and prevents macrophage necrosis as a component of a broad-based antimicrobial strategy. This illustrates how a key virulence factor can become the focus of a multilayered and coordinated innate response by macrophages, optimizing pathogen clearance and limiting inflammation

Antimicrobial use and microbiological testing in district general hospital ICUs of the Veneto region of north-east Italy

International - predominantly American - studies undertaken in the ICUs of teaching centres show that inadequate antibiotic therapy increases mortality and length of stay. We sought to ascertain whether this also pertains to smaller ICUs in the Veneto region of north-east Italy. To the best of our knowledge, this is the first such survey in the Veneto area or in Italy as a whole. A retrospective, observational study was performed across five general-hospital ICUs to examine appropriateness of microbiological sampling, empirical antibiotic adequacy, and outcomes. Among 911 patients (mean age, 65.8 years ± 16.2 SD; median ICU stay, 17.0 days [IQR, 8.0–29.0]), 757 (83.1 %) were given empirical antibiotics. Treatment adequacy could be fully assessed in only 212 patients (28.0 %), who received empirical treatment and who had a relevant clinical sample collected at the initiation of this antibiotic (T0). Many other patients only had delayed microbiological investigation of their infections between day 1 and day 10 of therapy. Mortality was significantly higher among the 34.9 % of patients receiving inadequate treatment (48.6 % vs 18.80 %; p < 0.001). Only 32.5 % of combination regimens comprised a broad-spectrum Gram-negative β-lactam plus an anti-MRSA agent, and many combinations were irrational. Inadequate treatment was frequent and was strongly associated with mortality; moreover, there was delayed microbiological investigation of many infections, precluding appropriate treatment modification and de-escalation. Improvements in these aspects and in antibiotic stewardship are being sought

Interaction of Pattern Recognition Receptors with Mycobacterium Tuberculosis.

Tuberculosis (TB) is considered a major worldwide health problem with 10 million new cases diagnosed each year. Our understanding of TB immunology has become greater and more refined since the identification of Mycobacterium tuberculosis (MTB) as an etiologic agent and the recognition of new signaling pathways modulating infection. Understanding the mechanisms through which the cells of the immune system recognize MTB can be an important step in designing novel therapeutic approaches, as well as improving the limited success of current vaccination strategies. A great challenge in chronic disease is to understand the complexities, mechanisms, and consequences of host interactions with pathogens. Innate immune responses along with the involvement of distinct inflammatory mediators and cells play an important role in the host defense against the MTB. Several classes of pattern recognition receptors (PRRs) are involved in the recognition of MTB including Toll-Like Receptors (TLRs), C-type lectin receptors (CLRs) and Nod-like receptors (NLRs) linked to inflammasome activation. Among the TLR family, TLR1, TLR2, TLR4, and TLR9 and their down-stream signaling proteins play critical roles in the initiation of the immune response in the pathogenesis of TB. The inflammasome pathway is associated with the coordinated release of cytokines such as IL-1β and IL-18 which also play a role in the pathogenesis of TB. Understanding the cross-talk between these signaling pathways will impact on the design of novel therapeutic strategies and in the development of vaccines and immunotherapy regimes. Abnormalities in PRR signaling pathways regulated by TB will affect disease pathogenesis and need to be elucidated. In this review we provide an update on PRR signaling during M. tuberculosis infection and indicate how greater knowledge of these pathways may lead to new therapeutic opportunities

Cyclic Cushing's syndrome: an overview

Cyclic Cushing's syndrome (CS) is a disorder in which glucocorticoid levels are alternately normal and high, the latter occurring in episodes that can last from a few days to several months. It is more common in children than in adults. Cyclic CS may be either of the two different forms of CS (ACTH-dependent or -independent CS). Clinically, it may present with one or many symptoms, depending on the duration of disease activity and the timing of the fluctuations. A serotoninergic influence, cyclic changes in central dopaminergic tone, spontaneous episodic hemorrhage in the tumor, and the action of inflammatory cytokines with antitumor properties are some of the mechanisms suggested to explain the physiopathology of this phenomenon but the exact mechanism remains to be clarified. The cyclic pattern of hypercortisolism can delay the final diagnosis of CS and make it difficult to interpret the results of dynamic tests. Patients may have paradoxical responses to dexamethasone that can reflect increasing or decreasing levels of endogenous activity. Hormone assessments have to be repeated periodically when a diagnosis of CS is suspected. The cyclic pattern can also interfere with medical treatment because patients may show unexpected clinical and biochemical signs of hypocortisolism when cortisol secretion cyclically returns to normal, so an accurate follow-up is mandatory in these patients

Structure-Activity Studies and Therapeutic Potential of Host Defense Peptides of Human Thrombin

Peptides of the C-terminal region of human thrombin are released upon proteolysis and identified in human wounds. In this study, we wanted to investigate minimal determinants, as well as structural features, governing the antimicrobial and immunomodulating activity of this peptide region. Sequential amino acid deletions of the peptide GKYGFYTHVFRLKKWIQKVIDQFGE (GKY25), as well as substitutions at strategic and structurally relevant positions, were followed by analyses of antimicrobial activity against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive bacterium Staphylococcus aureus, and the fungus Candida albicans. Furthermore, peptide effects on lipopolysaccharide (LPS)-, lipoteichoic acid-, or zymosan-induced macrophage activation were studied. The thrombin-derived peptides displayed length-and sequence-dependent antimicrobial as well as immunomodulating effects. A peptide length of at least 20 amino acids was required for effective anti-inflammatory effects in macrophage models, as well as optimal antimicrobial activity as judged by MIC assays. However, shorter (> 12 amino acids) variants also displayed significant antimicrobial effects. A central K14 residue was important for optimal antimicrobial activity. Finally, one peptide variant, GKYGFYTHVFRLKKWIQKVI (GKY20) exhibiting improved selectivity, i.e., low toxicity and a preserved antimicrobial as well as anti-inflammatory effect, showed efficiency in mouse models of LPS shock and P. aeruginosa sepsis. The work defines structure-activity relationships of C-terminal host defense peptides of thrombin and delineates a strategy for selecting peptide epitopes of therapeutic interest

Windenergie-Nutzung

Innerhalb des Gesamtrahmens des Projektes "Klimaverträgliche Energieversorgung in Baden-Württemberg" ist es das Ziel des Gutachtens über die Windenergienutzung, die Möglichkeiten und Grenzen einer windtechnischen Stromerzeugung in Baden-Württemberg darzustellen und zu diskutieren. Gleichzeitig sollen die notwendigen technischen, ökonomischen, ökologischen und sonstigen Eckdaten für die in der zweiten Projektphase geplante Szenarioanalyse, deren Ausgangspunkt die politische Orientierung der CO2-Emissionsminderung um 30% im Zeitraum von 1987 bis 2005 ist, zur Verfügung gestellt werden

The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of gsp(-) somatotropinomas

Glucose-dependent insulinotropic polypeptide receptor (GIPR) overexpression has been recently described in a proportion of gsp(-) somatotropinomas and suggested to be associated with the paradoxical increase of GH (GH-PI) during an oral glucose load