Orientador: Carlos Magno Castelo Branco Fortaleza / Resumo: A resistência microbiana causa grande número de mortes todos os anos. Sua emergência e disseminação são fenômenos complexos, que devem ser compreendidos no contexto de redes de assistência. Entre os microrganismos multidroga-resistentes (MDR), causam especial preocupação os bacilos Gram-negativos, especialmente Acinetobacter baumannii e Enterobactérias (Escherichia coli, Klebsiella spp e Enterobacter spp) resistentes aos carbapenêmicos (CRAB e CRE, respectivamente). Nós realizamos dois estudos com o objetivo de descrever o comportamento espaço-temporal de CRAB e CRE. O primeiro deles teve delineamento ecológico e se baseou em notificações de agentes de infecção da corrente sanguínea em Unidades de Terapia Intensiva do Estado de São Paulo. O segundo foi uma revisão sistemática de literatura científica e “literatura cinzenta” para identificar relatos de ocorrência de infecções por CRAB e CRE no Brasil. Nossos resultados no Estado de São Paulo demonstraram tendências temporais opostas para CRAB (redução) e CRE (crescimento). Em ambos os casos a incidência é maior nas Regiões Metropolitanas de São Paulo e Campinas, a partir de onde os microrganismos parecem espalhar-se para outras áreas. Infecções foram mais frequentes em hospitais públicos e naqueles com menor proporção de leitos de UTI. Fatores socio-econômicos e demográficos apresentaram associações variáveis, porém plausíveis, com a incidência dos microrganismos de interesse. Os resultados da revisão sistemática apontam para ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Antimicrobial resistance causes great numbers of deaths every year. Its emergence and dissemination are complex phenomena, which must be understood in the context of healthcare networks. Among multidrug-resistant microorganisms (MDR), carbapenem-resistant Gram-negative bacilli, especially Acinetobacter baumannii (CRAB) and Enterobacteriaceae (Escherichia coli, Klebsiella spp and Enterobacter spp; CRE) are of special concern. We performed two studies with the objective of describing the space-time behavior of CRAB and CRE. The first study had an ecological design and was based on reports of microorganisms causing bloodstream infections in Intensive Care Units in the São Paulo State, Brazil. The second was a systematic review of scientific literature and "gray literature" to identify reports of CRAB and CRE infections in Brazil. Our results in the State of São Paulo showed opposite temporal trends for CRAB (reduction) and CRE (growth). In both cases the incidence is higher in the Metropolitan Regions of São Paulo and Campinas, from where the microorganisms seem to spread to other areas. Infections were more frequent in public hospitals and in those with a lower proportion of ICU beds. Socio-economic and demographic factors presented variable but plausible associations with the incidence of microorganisms of interest. Results of the systematic review point to an initial concentration of CRAB and CRE reports in the Brazilian Southeast, followed by a dispersion in the country. The... (Complete abstract click electronic access below) / Doutor

La détection, la surveillance et la diffusion de la résistance des bactéries aux antibiotiques est un enjeu majeur au niveau mondial depuis la découverte et la diffusion de bactéries multi résistantes, en particulier la résistance aux carbapénèmes, spécifiquement chez les Entérobactéries et les bactéries du genre Pseudomonas et Acinetobacter. L’émergence et la dissémination des pathogènes Gram- résistants aux carbapénèmes est un contributeur significatif de la morbidité et la mortalité du patient. Malgré les efforts radicaux dans le contrôle de l’infection et les améliorations dans le diagnostique moléculaire, les bacilles Gram- résistants aux carbapénèmes demeurent une formidable menace vue que quelques agents antimicrobiens sont actifs et très peu devraient être disponibles dans le futur proche.L’origine et la source des gènes de résistance dans le monde sont mal connues et des travaux récents suggèrent que les animaux domestiques et sauvages, l’environnement mais également le tube digestif des mammifères et des humains pourraient représenter un réservoir et une source importante de gènes de résistance susceptibles d’être transmissibles à l’homme. C’est dans cette optique que ce projet de thèse s’articule avec comme objectifs : (i) la réalisation d’études épidémiologiques moléculaires d’isolats cliniques et animales résistants aux carbapénèmes isolés dans le basin Méditerranéen et la caractérisation des supports moléculaires de cette résistance ; (ii) la description de nouveaux mécanismes de résistance a l’imipenème ; et enfin (iii) le séquençage de génomes d’isolats cliniques résistants aux carbapénèmes et l’analyse de ces derniers. / The detection, monitoring and dissemination of bacterial resistance to antibiotics are a major issue worldwide since the discovery and spread of multi-resistant bacteria, in particular resistance to carbapenems, specifically among Enterobacteriaceae and bacteria of the genus Pseudomonas and Acinetobacter.The emergence and dissemination of carbapenem-resistant Gram-negative pathogens is a significant contributor to patient morbidity and mortality. Despite radical efforts in infection control and improvements in molecular diagnostics, carbapenem-resistant Gram-negative bacilli remain a formidable threat as few antimicrobial agents are reliably active and very little is expected to be available in the near future.The origin and source of resistance genes in the world are not well known and recent works suggest that domestic and wild animals, the environment (soil, water, rivers ..) but also the digestive tract of mammals and humans could represent a reservoir and an important source of resistance genes that may be transmissible to humans.It is in this context that this thesis project articulates with the following objectives: (i) The achievement of molecular epidemiological studies on carbapenem-resistant clinical and animal isolates collected from countries in the Mediterranean basin (Lebanon, Libya, France) and the characterization of the genetic determinants of this resistance; (ii) the description of new resistance mechanisms to imipenem; and finally (iii) The genome sequencing of clinical isolates resistant to carbapenems, the analysis of these genomes and the identification of mechanisms and genetic supports of the resistance to carbapenems and other antibiotics.