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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
31

Novel Double-Deposited-Aluminum (DDA) Process for Improving Al Void and Refresh Characteristics of DRAM

Hong, Seok-Woo, Kang, Seung-Mo, Choi, In-Hyuk, Jung, Seung-Uk, Park, Dong-Sik, Kim, Kyoung-Ho, Choi, Yong-Jin, Lee, Tae-Woo, Lee, Haebum, Cho, In-Soo 22 July 2016 (has links)
In order to resolve the Al void formation originated from the severe stress issues in dynamic random access memory (DRAM), double-deposited-aluminum (DDA) layer process was proposed. This novel metallization process can be effectively and simply performed with the native oxide such as Al 2 O 3 between upper and lower Al metal layer by ex-situ deposition technique. We could effectively control the Al void by adapting the DDA layers with different grain structure. From this novel metallization process, we have confirmed the optimal thickness of Al barrier metal to 100Å to be free from Al voids, which makes it possible to improve the static refresh characteristics of DRAM by 17%.
32

Luminescence induite par microscopie à effet tunnel et étude des propriétés électroniques, chimiques et optiques de la surface de carbure de silicium 6H-SiC(0001)3x3

Baffou, Guillaume 28 September 2007 (has links) (PDF)
Le microscope à effet tunnel (STM) permet une analyse spatiale et spectroscopique de surfaces à l'échelle atomique. Mise en évidence peu après l'invention du STM, la lumière émise par la jonction tunnel contient des informations pertinentes sur les propriétés électroniques et optiques de surfaces ou de nano-objets.<br /><br />La thématique dans laquelle s'inscrit cette thèse est la luminescence induite par STM sur substrat semiconducteur à large bande interdite. Les travaux ont porté sur la reconstruction de surface SiC(0001)3x3 du carbure de silicium (SiC) et s'articulent autour de trois parties.<br /><br />La première partie est consacrée à l'étude de la luminescence de la jonction tunnel métal/vide/SiC(0001)3x3. Cette étude, en parallèle à des mesures de spectroscopie tunnel, a mis en évidence les mécanismes et propriétés de transport électronique le long des états de surface du SiC.<br /><br />Une deuxième partie est dédiée à l'adsorption de molécules organiques sur la surface SiC(0001)3x3. La fonctionnalisation organique du SiC est une étape indispensable pour l'étude de molécules individuelles mais aussi pour la conception de matériaux hybrides organique/inorganique. La résolution submoléculaire du STM associée à des calculs ab initio en collaboration ont dégagé un modèle de chimisorption détaillé de la phthalocyanine hydrogénée.<br /><br />La dernière partie décrit des simulations numériques, basées sur le formalisme des tenseurs de Green, de la lumière émise par la jonction tunnel. Ces travaux ont permis de modéliser d'une part l'influence de la forme de la pointe du STM sur le spectre de la lumière émise, d'autre part l'inhibition de la fluorescence de molécules individuelles excitées par STM.
33

Détermination de la distribution de taille des nanoparticules de suie par analyse du spectre d'extinction et de diffusion angulaire de la lumière

Caumont-Prim, Chloé 15 January 2013 (has links) (PDF)
Le but de ce travail est de déterminer par méthodes optiques la distribution de taille (pdf) des nanoparticules de suie, agrégats de morphologie fractale. Après des études préliminaires qui utilisent DDSCAT pour valider la théorie RDG-FA et permettent de convertir un rayon de giration en rayon de mobilité, deux diagnostics optiques sont étudiés. Le premier consiste à exploiter une mesure d'extinction spectrale de la lumière. Nous montrons que pour exploiter ce signal, il faut connaître les propriétés optiques des suies, leur préfacteur et dimension fractale, la loi de distribution et le diamètre des sphérules primaires. Le second diagnostic tire parti de la mesure angulaire de la diffusion de la lumière. Nous montrons qu'il est possible de déterminer la pdf à l'aide de la mesure de diffusion à trois angles. Il faut supposer la loi de distribution et la dimension fractale. Cette deuxième approche, in-situ, est plus appropriée que la première pour déterminer optiquement la pdf des suies.
34

Interaktivní webové výukové aplikace z oblasti vektorové grafiky / Interactive apps for education of vector graphics theory

Lipa, Matúš January 2019 (has links)
This work deals with the creation of several interactive web applets for education of vector graphics. Described is the image signal, his discretization, vector and bitmap types of image record. Further they describe selected vector curves, their properties, algorithms for their construction and usage. The principles of rasterization of basic vector objects are explained. Using the Figma tool, graphical user interfaces for each applet are designed. These applets are implemented using HTML and Javascript. The implemented applets are placed on web pages that are used in computer graphics education.
35

Étude des mécanismes d'adhésion entre une surface d'oxyde et hydroxyde métallique (modèle et industrielle) et un polymère type époxy. Caractérisation de l'interface et de l'interphase / Study of adhesion mechanisms between surfaces oxides and hydroxides and epoxy polymer. Interfaces and interphase’s characterization

Pélissier, Krystel 04 June 2014 (has links)
La nouvelle génération de revêtement métallique à base de zinc, aluminium et magnésium (ZM) développée par ArcelorMittal permet une meilleure résistance à la corrosion pour une épaisseur plus faible que les aciers galvanisés standard du type GI. Toutefois, leur homologation pour l’utilisation dans des assemblages collés dans le secteur automobile pose problème car, contrairement au système adhésif crash/GI, des ruptures adhésives sont observées lors du test de traction-cisaillement d’un assemblage adhésif crash/ZM. Ce travail a visé à comprendre la ou les raison(s) de ces ruptures adhésives afin de proposer des solutions industrielles pour y remédier. Pour cela, une stratégie multi-technique et multi-échelle (XPS, IRRAS, Raman, AFM, …) a été mise au point afin de caractériser la surface métallique et ses oxydes, les interactions de ces derniers et les composants réactifs de l’adhésif à savoir la résine (DGEBA) et le durcisseur (DDA), et le système complet adhésif/ZM. Nous avons montré que la chimie de surface du ZM est bien plus complexe que celle du GI et est dominée par des phases riches en magnésium et très peu par des oxydes/hydroxydes de zinc contrairement au GI d’où une réactivité différente vis-à-vis de la DGEBA et la DDA. En particulier le piégeage de la DDA par interaction avec le magnésium perturbe la réticulation dans une interphase chimique ainsi que l’interaction du réseau polymérique avec la silice colloïdale et les charges à base de calcium dans une interphase mécanique affaiblissant la mécanique d’ancrage de l’adhésif. Divers solutions telles que l’application d’un traitement de surface sont proposées pour remédier à cet effet négatif du magnésium / New generation of metallic coatings based on zinc, aluminum and magnesium chemistry (ZM) developed by ArcelorMittal allows a higher corrosion resistance with a thinner layer than standard galvanized steel GI. However, its homologation for bonding structure application in automobile sector is a problem because of observation of adhesive failure after lap shear test with crash adhesive unlike GI coatings. This work’s aim is to understand the reason(s) behind the adhesive failure in order to resolve this problem by proposing industrial solutions. Thus, a multi-technical and multi-scale strategy (XPS, IRRAS, Raman, AFM,… ) was developed to characterize the metallic surface and its oxides, interactions between these oxides and the reactive components of the adhesive, namely the epoxide resin (DGEBA) and the hardener (DDA) and finally the whole system, i.e. ZM/adhesive. It was demonstrated that ZM surface chemistry is far more complex than GI surface chemistry and is dominated by rich magnesium phases and low in zinc oxides/hydroxides unlike GI leading to a different reactivity towards DGEBA and DDA. In particular, the DDA trapping by interaction with magnesium disrupts reticulation process in a chemical interphase and interaction of the polymeric network with colloidal silica and mineral fillers (calcium types) in a mechanical interphase which is weakening the adhesive mechanical anchoring. Several solutions like application of surface treatments can be proposed to solve the negative effect of magnesium
36

Modeling Optical Properties of Combustion Soot emitted in the Troposphere / Modélisation de la réponse optique des particules de suie émises dans la Troposphère

Garcia Fernandez, Carlos 26 November 2015 (has links)
Ce travail concerne la modélisation, à l’échelle moléculaire, de l’interaction entre des nanoparticules carbonées et le rayonnement électromagnétique. Le but est d’aider à la compréhension des propriétés optiques des particules de suie afin de mieux quantifier l’influence des suies sur l’atmosphère et le climat. L’étude de l’interaction rayonnement/particules de suie fraîche a été effectuée par la méthode PDI ; il a été montré que : i) le coefficient d’absorption massique (MAC) des particules de suie dépend de la répartition des atomes dans la particule et de leurs liaisons, en particulier entre 200 et 350 nm ; ii) le MAC diffère selon que le cœur de la particule carbonée est occupé ou non par des plans graphitiques ; iii) un modèle analytique n’est pas adapté pour calculer le MAC d’une nanoparticule carbonée présentant des défauts structuraux. De plus, des méthodes de chimie quantique ont été utilisées pour caractériser le vieillissement des suies. Les résultats montrent que : i) NO, Cl, et HCl sont physisorbées sur une surface carbonée parfaite alors que sur une surface défective, ces espèces sont chimisorbées et conduisent à une modification de la surface ; ii) la présence de Cl conduit à un piégeage fort des molécules d’eau supérieur à celui obtenu lorsqu’un site oxygéné est présent sur la surface carbonée, expliquant ainsi le caractère hydrophile des suies émises lors d’incendies dans des milieux industriels. Enfin, la méthode PDI a été appliquée au calcul de la polarisabilité de HAP afin d’interpréter des spectres d’absorption des grains carbonés du milieu interstellaire, en incluant des molécules pour lesquelles aucune donnée n’était actuellement disponible. / This work concerns the modeling, at the molecular level, of the interaction between carbonaceous particles of nanometric size and the electromagnetic radiation. The goal is to improve our understanding of the optical properties of soot particles, to better quantify the influence of soot on the atmosphere and on climate change. The study of the interaction between radiation and fresh soot particles was carried out using the point dipole interaction method; it has been shown that: i) the mass absorption coefficient (MAC) of these soot nanoparticles may significantly depend on their atomistic details, especially between 200 and 350 nm; ii) the MAC depends on whether the heart of the carbonaceous particle is occupied or not by graphite planes; iii) an analytical model is not suitable for calculating the MAC of carbonaceous nanoparticles having structural defects. In addition, quantum chemical methods have been used to characterize the ageing of soot. The results obtained are i) NO, Cl, and HCl are physisorbed on a perfect carbonaceous surface whereas on a defective surface, these species are chemisorbed and lead to a modification of the surface; ii) on a carbonaceous surface, the presence of adsorbed Cl atoms leads to a strong trapping of the surrounding water molecules. This may be related to the highly hydrophilic nature of soot emitted during fires in industrial environments. Finally, the PDI method was applied to calculate the polarizability of PAHs to help at interpreting the absorption spectra of carbonaceous grains in the interstellar medium, including molecules for which no data was currently available.
37

Fusion de données hyperspectrales, polarimétriques et angulaires de diffusion : application au diagnostic optique de milieux denses et complexes / Data fusion system for hyperspectral, polarimetric, and angular scattering : application to optical diagnostic of dense and complex media

Ceolato, Romain 08 November 2013 (has links)
Ces travaux de recherche portent sur le développement d'un système original de fusion de données de diffusion électromagnétique et optique par des milieux denses et complexes. La méthode, à la fois théorique, numérique et expérimentale, permet la fusion des signatures de diffusion hyperspectrales, polarimétriques et angulaires d'un milieu d'étude. Un système expérimental multi-capteurs comprenant une source laser supercontinuum est présenté pour mesurer les signatures de diffusion de différentes cibles. Des modèles directs de simulation physique ont aussi été développés via : (i) une approche dite « top-down » qui modélise les signatures à partir de paramètres macroscopiques (ex. rugosité, indices optiques effectifs) ou (ii) une approche dite « bottom-up » qui modélise les signatures à partir de paramètres microscopiques (ex. distribution en taille, géométrie, concentration, indices optiques et structuration des diffuseurs) en résolvant soit l'équation de transfert radiatif ou directement les équations de Maxwell. Des méthodes inverses appliquées sur les signatures mesurées sont développées pour retrouver simultanément les paramètres d’intérêt du milieu analysé. Les avancées de ces travaux permettent une amélioration de la compréhension des phénomènes de diffusion électromagnétiques et optiques par des milieux denses et complexes tels que les surfaces rugueuses, les revêtements, les nanomatériaux, les suspensions colloïdales ou les agrégats fractals d'aérosols ultrafins. Les domaines d'applications de ces travaux sont l'aéronautique (ex. peintures d'aéronefs), l'imagerie aéroportée ou satellite (ex. imagerie active hyperspectrale ou polarimétrique), la sécurité et la défense (ex. matériaux pour la furtivité) ou bien les sciences de l'atmosphère (ex. systèmes LiDAR, suivi de pollution, suies), l'industrie chimique (ex. suspensions colloïdales) ou le biomédical (ex. diagnostic de tumeurs et mélanomes). / This work reports the development of an original data fusion system dedicated to electromagnetic and light scattering by dense and complex media. The dissertation encompasses the theoretical, numerical and experimental studies. The output of the data fusion system is a fused hyperspectral, polarimetric and angular scattering signature. An experimental multi-sensor and supercontinuum laser-based system is presented to measure the scattering signatures for various targets. Direct physical simulation models were developed using a two-level modelling scheme: (i) a top-down approach is used to model signatures from macro-physical parameters, e.g. the surface roughness or the effective refractive index and, (ii) a bottom-up approach is used to model signatures from microphysical parameters, e.g. the size distribution, the geometry, the concentration, the refractive index and the structuration of the scatterers, by solving the radiative transfer equation or directly the Maxwell's equations. Inversion schemes are deployed to retrieve these parameters by inverting the experimental signatures. The advancements described throughout this dissertation will serve to improve understanding of electromagnetic and light scattering by dense and complex media such as rough surfaces, coatings, nanomaterials, colloidal suspension and fractal aggregates of ultrafine aerosols. This study has relevant applications in fields as diverse as aeronautics (e.g. aircraft paint coatings), remote-sensing (e.g. hyperspectral, polarimetric, active or passive imaging), security and defense (e.g. furtive materials), atmospheric science (e.g. black carbon or soot characterization, LiDAR systems), chemical engineering (e.g. colloidal suspensions), or biomedical (e.g. tumor and melanoma diagnostic).
38

Outils statistiques pour le positionnement optimal de capteurs dans le contexte de la localisation de sources / Statistical tool for the array geometry optimization in the context of the sources localization

Vu, Dinh Thang 19 October 2011 (has links)
Cette thèse porte sur l’étude du positionnement optimale des réseaux de capteurs pour la localisation de sources. Nous avons étudié deux approches: l’approche basée sur les performances de l’estimation en termes d’erreur quadratique moyenne et l’approche basée sur le seuil statistique de résolution (SSR).Pour le première approche, nous avons considéré les bornes inférieures de l’erreur quadratique moyenne qui sont utilisés généralement pour évaluer la performance d’estimation indépendamment du type d’estimateur considéré. Nous avons étudié deux types de bornes: la borne Cramér-Rao (BCR) pour le modèle où les paramètres sont supposés déterministes et la borne Weiss-Weinstein (BWW) pour le modèle où les paramètres sont supposés aléatoires. Nous avons dérivé les expressions analytiques de ces bornes pour développer des outils statistiques afin d’optimiser la géométrie des réseaux de capteurs. Par rapport à la BCR, la borne BWW peut capturer le décrochement de l’EQM des estimateurs dans la zone non-asymptotique. De plus, les expressions analytiques de la BWW pour un modèle Gaussien général à moyenne paramétré ou à covariance matrice paramétré sont donnés explicitement. Basé sur ces expressions analytiques, nous avons étudié l’impact de la géométrie des réseaux de capteurs sur les performances d’estimation en utilisant les réseaux de capteurs 3D et 2D pour deux modèles des observations concernant les signaux sources: (i) le modèle déterministe et (ii) le modèle stochastique. Nous en avons ensuite déduit des conditions concernant les propriétés d’isotropie et de découplage.Pour la deuxième approche, nous avons considéré le seuil statistique de résolution qui caractérise la séparation minimale entre les deux sources. Dans cette thèse, nous avons étudié le SSR pour le contexte Bayésien moins étudié dans la littérature. Nous avons introduit un modèle des observations linéarisé basé sur le critère de probabilité d’erreur minimale. Ensuite, nous avons présenté deux approches Bayésiennes pour le SSR, l’une basée sur la théorie de l’information et l’autre basée sur la théorie de la détection. Ces approches pourront être utilisée pour améliorer la capacité de résolution des systèmes. / This thesis deals with the array geometry optimization problem in the context of sources localization. We have considered two approaches for the array geometry optimization: the performance estimation in terms of mean square error approach and the statistical resolution limit (SRL) approach. In the first approach, the lower bounds on the mean square error which are usually used in array processing to evaluate the estimation performance independently of the considered estimator have been considered. We have investigated two kinds of lower bounds: the well-known Cramér-Rao bound (CRB) for the deterministic model in which the parameters are assumed to be deterministic, and the Weiss-Weinstein bound (WWB) which is less studied, for the Bayesian model, in which, the parameters are assumed to be random with some prior distributions. We have proposed closed-form expressions of these bounds, which can be used as a statistical tool for array geometry design. Compared to the CRB, the WWB can predict the threshold effect of the MSE in the non-asymptotic area. Moreover, the closed-form expressions of the WWB proposed for a general Gaussian model with parameterized mean or parameterized covariance matrix can also be useful for other problems. Based on these closed-form expressions, the 3D array geometry and the classical planar array geometry have been investigated under (i) the conditional observation model in which the source signal is modeled as a deterministic sequence and under (ii) the unconditional observation model in which the source signal is modeled as a Gaussian random process. Conditions concerning the isotropic and uncoupling properties were then derived.In the second approach, we have considered the statistical resolution limit which characterizes the minimal separation between the two closed spaced sources which still allows to determine correctly the number of sources. In this thesis, we are interested in the SRL in the Bayesian context which is less studied in the literature. Based on the linearized observation model with the minimum probability of error, we have introduced the two Bayesian approaches of the SRL based on the detection and information theories which could lead to some interesting tools for the system design.
39

Análise de texto literário em Língua Inglesa no curso de Letras: uma perspectiva dialógico-pragmática

Júnior, Orison Marden Bandeira de Melo 29 August 2014 (has links)
Made available in DSpace on 2016-04-28T18:22:55Z (GMT). No. of bitstreams: 1 Orison Marden Bandeira de Melo Junior.pdf: 5418428 bytes, checksum: 84bf1841112fead6609a0f0bd2716b78 (MD5) Previous issue date: 2014-08-29 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / In general, the teaching of literature written in foreign languages at Brazilian universities faces a big challenge: Letras freshmen with limited knowledge of the foreign language find it difficult to analyze literary works in the original texts. Therefore, this research is justified by the need to discursively and pragmatically help students better analyze literature works. In order to do that, the theoretical discussion was based upon the works of the Bakhtin Circle [Bakhtin (2002, 2003, 2010), Bakhtin/Volochínov (2010), Voloshinov/Bajtin (1997), Voloshinov (1983), Medviédev (2012)] and of the pragmaticist Jacob Mey (2000, 2001, 2007). 68 Letras undergraduate students from a private university in the Eastern area of São Paulo were invited to participate in the research, which was approved by the Ethics Committee of PUC-SP under protocol number 054/2011 and whose data were generated in three different phases: The first one was related to literary analyses based on concepts from Pragmatics, such as from Micropragmatics (reference, verb tenses, presuppositions, implicatures and speech acts), from Macropragmatics (pragmatic presuppositions and pragmatic acts) and from Literary Pragmatics (speech and voice); the second phase involved literary analyses based on concepts from the Dialogical Discourse Analysis (DDA), such as utterance, genre, text, understanding, and dialogism; in the the third and last phase students did literary analyses based on the concepts from Pragmatics and DDA. The research corpus comprised three sets: (1) Letras DCN (National Curriculum Guidelines); (2) literary analysis activities done throughout the three phases, and (3) students stimulated recall reports. As to the literary works analyzed, they were nine short stories by Alice Walker. They were chosen by the researcher, who was also the students professor, due to their short length, their social role, and the dialogic relations there could be established between them. Based on the notion that texts are not autonomous, the only literary activities analyzed were the ones done by the students who had done the stimulated recall reports. Based on the understanding that the contextualized meanings produced by the students could not go beyond the fixity of meaning of the utterances, it was necessary to verify if students answers were potencially coherent with the plots and with the discourses that penetrate them. Moreover, as the research focused on students with limited knowledge of the target language, i.e., English, only the results of basic and intermediate level students were verified. It was possible to find that in the first phase, basic and intermediate students were able to coherently answer one fourth of the questions of the literary activities and, in the second phase, one third. However, in the third phase, this number significantly increased to two thirds. It was possible to conclude, thus, that the study of Pragmatics as the first step to the study of the concepts from DDA helped students with a limited knowledge of the English language to better understand and analyze literary works written in English and, consequently, to develop their linguistic skills / O ensino de literatura em língua estrangeira (LE) em universidades brasileiras, em geral, tem enfrentado um grande desafio: alunos ingressantes no curso de Letras com conhecimento limitado de LE, o que dificulta a execução de análises de objetos literários na língua original. Essa pesquisa justifica-se, portanto, pela necessidade de auxiliar o aluno a analisar textos literários discursiva e pragmaticamente. Para tal, buscamos, nos estudos do Círculo [Bakhtin (2002, 2003, 2010), Bakhtin/Volochínov (2010), Voloshinov/Bajtin (1997), Voloshinov (1983), Medviédev (2012)] e do pragmaticista Jacob Mey (2000, 2001, 2007), uma discussão teórica referente à linguagem e ao discurso. Para participar da pesquisa, foram convidados, em diferentes momentos, 68 alunos do curso de Letras de uma universidade particular na zona leste de São Paulo. A geração de dados da pesquisa, aprovada pelo Comitê de Ética em Pesquisa da PUC-SP, sob o número de protocolo 054/2011, compreendeu três fases: a primeira envolveu análises literárias a partir do estudo dos conceitos da Pragmática, como os da Micropragmática (referência, tempos verbais, pressupostos, subentendidos e atos de fala), da Macropragmática (pressupostos pragmáticos e atos pragmáticos) e da Pragmática Literária (discurso e voz); a segunda, análises literárias a partir do estudo dos conceitos da Análise Dialógica do Discurso (ADD), como enunciado, gênero, texto, compreensão e dialogismo; a terceira, por fim, análises literárias a partir do estudo dos conceitos da Pragmática e da ADD. O corpus da pesquisa é formado de três conjuntos: (1) as Diretrizes Curriculares Nacionais de Letras, (2) exercícios de análise literária (exercícios AL) feitos durante as três fases da pesquisa e (3) relatos escritos finais (stimulated recall). Quanto aos textos literários analisados pelos alunos, nove contos da autora afro-americana Alice Walker foram escolhidos pelo pesquisador, que também era professor dos alunos pesquisados, devido à sua pequena extensão, ao seu papel social e às relações dialógicas que pudessem ser estabelecidas entre eles. Diante da concepção de texto como não autônomo adotada nesta pesquisa, somente os exercícios AL dos alunos que fizeram o relato final foram analisados. A partir do entendimento de que os sentidos construídos pelos alunos nas suas respostas não poderiam extrapolar a estabilidade de significação dos enunciados sob análise, buscamos determinar se as respostas dadas nos exercícios AL eram potencialmente coerentes com os enredos dos contos e com os discursos que os perpassam. Ademais, por ser o foco da pesquisa alunos com conhecimento limitado da língua-alvo, i.e., a Língua Inglesa, atentamos para os resultados dos alunos em nível básico e intermediário. Percebemos que, na primeira fase, os alunos em nível básico e intermediário conseguiram responder a cerca de um quarto das perguntas e na segunta fase, a um terço. No entanto, na terceira fase, esse número aumentou substancialmente, já que os alunos nesses níveis responderam a cerca de dois terços de todas as perguntas. É possível concluir, portanto, que o estudo dos conceitos da Pragmática como um primeiro passo para os da ADD possibilitou uma melhor compreensão e análise de textos literários escritos em Língua Inglesa por alunos com conhecimento limitado dessa língua estrangeira e, consequentemente, o desenvolvimento de seu conhecimento do idioma
40

Avaliação in vitro e in vivo de efeitos sinérgicos de antibacterianos para o tratamento de infecções por Acinetobacter baumannii multirresistentes produtoras de carbapenemases tipo OXA endêmicas no Brasil / In vitro and in vivo synergistic effects of antibacterial agents for the treatment of multidrug-resistant OXA-type carbapenemase-producing Acinetobacter baumannii infections endemic in Brazil

Medeiros, Micheli 06 February 2013 (has links)
As infecções relacionadas à assistência à saúde (IRAS) são um grave problema de saúde pública cujo prognóstico tem sido desfavorecido pela emergência e endemicidade de bactérias multirresistentes (MRs). Neste cenário, seguindo uma tendência mundial, no Brasil, infecções por cepas de Acinetobacter baumannii MRs produtoras de carbapenemases do tipo OXA são atualmente consideradas uma emergência clínica e epidemiológica. Na falta de alternativas terapêuticas efetivas para infecções relacionadas, este trabalho objetivou avaliar efeitos sinérgicos (utilizando checkerboard e time-kill) decorrentes da combinação de 10 antimicrobianos de diferentes classes, contra 8 cepas MRs de A. baumannii, clonalmente não relacionadas, produtoras de carbapenemases do tipo OXA-23, OXA-72, OXA-58 e OXA-143, representativas de diferentes centros hospitalares do Brasil. Como resultado, a combinação amicacina/tigeciclina apresentou atividade sinérgica (S= &#931;CIF &#8804; 0,5) e parcialmente sinérgica (PS= &#931CIF ;0,5-0,75) contra 4 (50%) cepas produtoras de OXA-143 ou OXA-72, e 2 cepas (25%) produtoras de OXA-23, respectivamente. Por outro lado, a combinação polimixina B/imipenem apresentou atividade S e PS contra 3 (37,5%) isolados OXA-143, OXA-23 ou OXA-72 positivos, e 1 (12,5%) isolado produtor de OXA-58, respectivamente. Já, a combinação amicacina/ampicilina-sulbactam foi S contra 2 (25%) A. baumannii OXA-143 ou OXA-23 positivos, sendo PS contra dois (25%) A. baumannii OXA-58 ou OXA-143/23 positivos. De interesse, foi o efeito S da combinação polimixina B/vancomicina, contra 2 cepas (25%) produtoras de OXA-72 ou OXA-23. Por outro lado, a combinação ampicilina-sulbactam/rifampicina apresentou atividade PS contra 6 (75%) cepas produtoras das variantes OXA-23, OXA-143, OXA-72 ou OXA-58. Da mesma forma, rifampicina combinada com polimixina B foi sinérgica para uma cepa OXA-23 (12,5%) e PS para 5/8 (62,5%) cepas produtoras de OXA-72, OXA-58, OXA-23/-OXA143 ou OXA-143. O efeito sinérgico da combinação polimixina B/imipenem foi confirmado, in vivo, no modelo murino de infecção, tanto por avaliação histopatológica como por redução das UFC/g pulmão ou baço (p &#8804; 0,05). Finalmente, foi avaliada a atividade, in vitro, do lípide catiônico brometo de dioctadecildimetilamônio (DDA), individualmente e em combinação com tigeciclina. DDA possui efeito bactericida, e potencializou sinergicamente a tigeciclina contra 2 (25%) cepas OXA-143 ou OXA-23 positivas. A atividade do DDA, assim como a atividade da sua combinação com tigeciclina foram efetivas já na segunda hora de interação, como avaliado pelas curvas de morte. Em resumo, o efeito sinérgico decorrente do uso combinado de amicacina, tigeciclina, polimixina B, imipenem, rifampicina ou ampicilina/sulbactam, pode constituir uma alternativa terapêutica para o tratamento de infecções produzidas por cepas de A. baumannii MRs produtoras de oxacilinases, sendo que nanofragmentos catiônicos de bicamada do lipídeo sintético de DDA tem potencial para consolidar um produto de aplicação clínica. / Healthcare-associated infections (HAIs) are a serious public health issue, which have been related with an unfavorable prognosis due to the emergence and endemicity of multidrug-resistant (MDR) bacteria. In this scenario, following a worldwide trend, in Brazil, infections produced by MDR OXA-type carbapenemase-producing Acinetobacter baumannii are currently considered a clinical and epidemiological urgency. In the absence of effective therapeutic alternatives for related infections, this study aimed to evaluate synergistic effects (by using time-kill and checkerboard assays) achieved by the combination of 10 different classes of antimicrobial against 8 strains of MDR, clonally unrelated, A. baumannii strains producing OXA-23, OXA-72, OXA-58 and OXA-143 carbapenemases, being representatives of different medical centers in Brazil. As a result, the combination of amikacin / tigecycline showed synergistic (S = &#931;FIC &#8804; 0.5) and partially synergistic (PS = 0.5 to 0.75 &#931;FIC) activity against 4 (50%) OXA-72 or OXA-143 producing A. baumannii strains, and two strains (25%) producing OXA-23, respectively. Moreover, the combination of polymyxin B / imipenem showed S and PS activity against 3 (37.5%) OXA-143, OXA-23 and OXA-72 positive isolates, and 1 (12.5%) OXA-58 producer, respectively. On the other hand, the combination amikacin / ampicillin-sulbactam was S against 2 (25%) OXA-143 and OXA-23 positive strains, being PS against two (25%) OXA-58- and OXA-143/23-producing A. baumannii. Of interest was the synergistic effect achieved by polymyxin B plus vancomycin against two strains (25%) producing OXA-72 and OXA-23, respectively. Furthermore, the ampicilina-sulbactam / rifampicin combination displayed a PS activity against six (75%) strains producing OXA-23, OXA-143, OXA-72 or OXA-58-type enzymes. Likewise, rifampicin combined with polymyxin B was S against 1 (25%) OXA-23-positive A. baumannii being PS to 5/8 (62.5%) strains producing OXA-72, OXA-58, OXA-23/-OXA143 or OXA-143. The synergistic effect of the combination polymyxin B / imipenem was confirmed, in vivo, in the murine model of infection, by using both histopathological studies and bacterial clearance from the lungs and spleen (CFU/g, p&#8804; 0.05). Finally, we evaluated the in vitro activity of the cationic lipid dioctadecyldimethylammonium bromide (DDA), alone and in combination with tigecycline. DDA display a bactericidal effect, enhancing synergistically the activity of tigecycline against 2 (25%) OXA-143 and OXA-23 positive strains, respectively. DDA activity alone and in combination with tigecycline was effective on the second hour of interaction, as evaluated by time-kill assays. In summary, the synergistic effect resulting from the combined use of amikacin, tigecycline, polymyxin B, imipenem, rifampicin or ampicillin / sulbactam, could be an alternative therapy for the treatment of infections caused by MDR A. baumannii strains producing oxacilinases. On the other hand, cationic bilayer nanofragments of DDA has potential for consolidating a product for medical application.

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