Background: The proportion of nosocomial Staphylococcus infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has increased from 22% in 1995 to 63% in 2004. Blood stream infections, more commonly referred to as bacteremias, represented the majority (75.5%) of hospital-onset MRSA cases. The economic impact of Staphylococcus aureus bacteremia merits investigation. Methods: This was a retrospective cohort analysis within Cerner HealthFacts data warehouse. Eligible patients were those who had Staphylococcus aureus bacteremia and were discharged between January 1, 2000, and December 31, 2006. Inclusion criteria include age > 18 years old and onset of infection > 48 hours post admission. The crude association was measured by subtracting the total mean hospital charge for MSSA bacteremia from the MRSA charge. A generalized linear model using a gamma distribution and log link were used to determine the adjusted hospital charge and post-infection length of stay for the MRSA and MSSA groups. Path analysis was used to describe the relationships between infection susceptibility status, LOS and total hospital charge. Results: During the study period, 930 patients meet all the inclusion and exclusion criteria. The overall total hospital charge was $111,636 (MRSA = $121,713, MSSA = $97,307.) The crude difference in mean charge was $24,406. The multivariable model included predicted a MRSA patient would have an increased total charge of $22,889. MRSA had a higher total charge but when patients were more severely ill, MRSA charges decreased while MSSA charges increased. The second multivariable model predicted a MRSA patient would have an increased post-infection LOS of 1.3 days. However, the magnitude of increased post-infection LOS based on pre-infection LOS was different for MRSA and MSSA patients. The path analysis model indicated the direct and indirect effects of susceptibility status on both post-infection LOS and total charge were relatively small. Conclusion: This investigation was the first large multi-center investigation to examine the economic impact of MRSA and MSSA bacteremia. MRSA was associated with a higher total charge and longer post-infection LOS than MSSA patients. The path analysis model analyzed suggests the actually role of infection susceptibility status on post-infection LOS and total charge was minor.

Les conséquences des épidémies de grippe nosocomiale (GN) pour les patients en termes de morbidité et mortalité sont importantes. Cependant, la présentation clinique des cas, la fréquence de l’infection, le risque d’infection parmi les patients, la transmission et les mesures de contrôle les plus adaptées restent mal connues. Une analyse originale de la littérature nous a permis de synthétiser les connaissances sur la GN. Puis sur la base d’une étude prospective menée pendant 3 saisons de grippe de 2004 à 2007, nous avons présenté une description clinique des cas de grippe observés à l’hôpital Edouard Herriot de Lyon. Nous avons ensuite développé un modèle statistique d’analyse du risque de GN chez les patients et nous avons appliqué ce modèle sur des données concernant plus de 21500 patients. Les facteurs influençant la transmission ont été étudiés par simulation de la diffusion du virus grippal dans une unité de soin à l’aide d’un modèle biomathématique. Nous montrons qu’il était difficile d’identifier les cas de grippe dans l’hôpital sans réalisation systématique d’un test de dépistage. Le risque pour le patient de présenter un syndrome grippal était 2 fois plus important à l’hôpital que dans la communauté. De plus ce risque était 5 à 35 fois plus élevé lorsqu’un patient était exposé à un autre patient ou à un soignant contagieux au cours de son séjour. La transmission de patient à patient semblait une voie de transmission importante. La démarche de ce travail pourrait être adaptée et l’outil statistique étendu à l’étude de la dynamique et du contrôle des infections nosocomiales. / The consequences of outbreaks of nosocomial influenza (NI) for patients in terms of morbidity and mortality are an issue of concerned. However, clinical presentation of cases, frequency of infection, risk of infection among patients, transmission and the most adapted control measures remain poorly understood. An original analysis of the literature allowed synthesizing the knowledge on NI. Then on the basis of a prospective study conducted during 3 influenza seasons from 2004 to 2007, we report a description of clinical cases of NI observed at the Edouard Herriot hospital in Lyon. Then, we developed a statistical model to analyze the risk of NI among patients and we apply this model on data from over 21,500 patients. Factors influencing the transmission were studied by simulating the spread of influenza virus in a hospital unit using a mathematical model. We show that identifying cases of influenza in the hospital without a systematic virological screening is difficult. The risk for the patient to present influenza like illness was 2 times higher in hospital than in the community. Furthermore, the risk was 5 to 35 times higher when a patient was exposed to other contagious patients or health care workers during his hospitalization. Transmission from patient to patient seemed to be a major route of transmission. The approach used in this work could be adapted and the statistical tools could be extended to study of the dynamics and control of nosocomial infections

The thesis is focused on ventilator-associated pneumonia and its possible preventive measures during nursing care. In the theoretical part of the work we have included chapters on nosocomial infections emphasizing on the etiology and epidemiology of ventilator-associated pneumonia and its clinical manifestations. We have analyzed the issues of artificial airway management with a detailed focus on the peculiarities of nursing care of the ventilated patients. There, we focus primarily on the care of the patients oral cavity, respiratory tract and the ventilation circuit. A big chapter is dedicated to preventive measures and to the possibilities of prevention in the nursing practice. The empirical part includes research on preventive measures that are implemented in practice and comparative analysis of the measures between different facilities as well as their compliance to the guidelines. We have also determined the level of VAP awareness and its prevention among the nurses. KEYWORDS nosocomials infections, nursing care, prevention, ventilator-associated pneumonia

Nosokomiale Infektionen (NKI) gehören zu den häufigsten Komplikationen eines Krankenhausaufenthaltes, insbesondere auf Intensivstationen mit einer Prävalenz von rund 18,65%. Die Folgen sind eine längere Verweildauer, erhöhte Morbidität und Letalität sowie höhere Kosten für das Gesundheitssystem. Die Erfassung NKI stellt einen wichtigen Qualitäts- Parameter für Intensivstationen dar. Ziel dieser Arbeit war es, die Übereinstimmung von nur nach KISS (Krankenhaus-InfektionsSurveillance System)- Definitionen erfassten Infektionen mit der klinisch diagnostizierten nosokomialen Infektion zu prüfen und den Zusammenhang zwischen ärztlicher Diagnose und den laborchemischen und klinisch erhobenen Kriterien darzustellen. Hierfür wurden auf einer interdisziplinären operativen Intensivstation nosokomiale Infektionen sowohl nach ITS- KISS (VAP, ZVK- assoziierte Infektionen und HWI), als auch nach ärztlicher Diagnose plus Beginn oder Eskalation einer Antibiotikatherapie erfasst. Zusätzlich zu den KISS-Parametern wurden laborchemische Entzündungsparameter (CRP und PCT) registriert. Es traten 32 Infektionen nach ITS- KISS und 69 Infektionen nach ärztlicher Diagnose auf. Acht Infektionen wurden ausschließlich nach KISS und 45 ausschließlich nach der ärztlichen Diagnose erfasst. Die Infektionsrate nach KISS für VAP lag bei 20,6, für ZVK bei 5,9 und für HWI bei 2 Infektionen, jeweils pro 1000 Devicetage. Spezifität und positiv prädiktiver Wert hinsichtlich der Vorhersage einer ärztlich diagnostizierten Infektion waren gering. Auch durch Kombination verschiedener Parameter wurden keine höheren prädiktiven Werte erreicht. Die geringe Übereinstimmung der beiden Methoden legt nahe, dass KISS die klinisch relevanten Infektionen nicht wesentlich erfasst und relevante Infektfoci nicht berücksichtigt werden, beispielsweise abdominelle Infektionen. Zudem erlauben die erfassten Laborparameter keine zuverlässige Diagnose bzw. Prädiktion einer nosokomialen Infektion. Die ärztliche Diagnose in Verbindung mit dem Beginn oder der Eskalation einer Antibiotikatherapie könnte eine vereinfachte Methode zur Surveillance nosokomialer Infektionen darstellen.

Staphylococcus aureus é um patógeno versátil, capaz de causar uma grande variedade de infecções. Nos últimos anos, ocorreu um aumento da proporção de infecções causadas por S. aureus resistentes a meticilina (MRSA). A resistência a meticilina deve-se à presença do gene mecA, carreado no cassete cromossômico estafilocócico (SCCmec). Pacientes infectados ou colonizados por MRSA são reservatórios e fontes de disseminação deste microorganismo, em instituições de cuidado à saúde, principalmente através de profissionais transitoriamente colonizados. Freqüentemente, a infecção por MRSA é precedida por um período de colonização. Em 2003 foi observado um aumento das taxas de infecções hospitalares por S. aureus na Enfermaria de Dermatologia do Hospital das Clínicas (EDER), em relação aos cinco anos anteriores. Os objetivos do presente estudo foram avaliar a transmissão hospitalar de MRSA, entre os pacientes da EDER e caracterizar os isolados de MRSA, obtidos de pacientes e funcionários colonizados, presentes nessa unidade. Foi realizada a detecção dos pacientes colonizados por MRSA, através de culturas de vigilância das narinas e, quando possível, culturas de vigilância das lesões de pele, num período de seis meses. A identificação fenotípica foi confirmada por reação em cadeia da polimerase (PCR) multiplex para detecção dos genes mecA e coa. Posteriormente, os isolados de MRSA foram submetidos ao teste de sensibilidade aos antimicrobianos pelo método de microdiluição em caldo, PCR multiplex para determinação do tipo de SCCmec e tipagem molecular por eletroforese em campo pulsado (PFGE). Quarenta e cinco por cento dos pacientes eram portadores de MRSA. No início do estudo, 14% dos funcionários eram portadores de MRSA, no fim eram 18%. Foram obtidas 105 amostras de MRSA, sendo que 11 foram isoladas de funcionários da EDER e 94 isoladas de 64 pacientes que eram portadores deste microorganismo.Sessenta e um por cento dos pacientes classificados como portadores de MRSA, eram positivos na primeira coleta realizada e 39% foram identificados durante o seguimento, nas coletas posteriores. O gene da coagulase foi detectado em todas as 105 amostras e o gene mecA em 101. Todos os isolados foram sensíveis a vancomicina e resistentes a oxacilina e penicilina. Trinta e três por cento dos isolados eram multirresistentes, apresentaram SCCmec tipo IIIA e um perfil PFGE predominante. SCCmec tipo IV foi observado em 59% dos isolados. Não foi possível determinar o tipo de SCCmec de quatro isolados. Na PFGE, o perfil B1 foi o mais prevalente, apresentado por isolados de MRSA SCCmec tipo IV, obtidos de nove pacientes e de três funcionários. A transmissão hospitalar foi caracterizada em 39% dos pacientes portadores. Foi possível observar a participação dos funcionários, na transmissão cruzada de MRSA, na EDER. A colonização por MRSA, dos profissionais de cuidado à saúde, foi transitória. Além da transmissão hospitalar de MRSA, foi possível detectar pacientes que eram portadores de MRSA na admissão / Staphylococcus aureus is a versatile pathogen capable of causing a wide variety of infections. The proportion of nosocomial and community-acquired methicillinresistant Staphylococcus aureus (MRSA) infections has increased in the last years. Methicillin resistance is mediated by the mecA gene which is carried on the Staphylococcal Cassette Chromosome mec (SCCmec). In heath care settings, patients who are colonized or infected with MRSA constitute a reservoir and a source of spread of this microorganism, mainly through transiently colonized health care workers (HCWs). MRSA infections are usually preceded by a period of colonization. In 2003, an increase in the rates of MRSA nosocomial infection in the Dermatology ward of Hospital das Clínicas was observed, in comparison with the five previous years. The aims of this study were to evaluate the nosocomial transmission of MRSA in the Dermatology ward and to characterize MRSA isolates obtained from patients and HCWs. Surveillance cultures of the anterior nares and skin lesions were performed to identify patients who were MRSA carriers, during a period of six months. The phenotypic identification was confirmed by multiplex polymerase chain reaction (PCR), to detect mecA and coa genes. Subsequently, MRSA isolates were submitted to antimicrobial susceptibility testing by microdilution method, multiplex PCR for SCCmec typing and molecular typing by pulsed-field gel electrophoresis (PFGE). Forty-five percent of the patients were MRSA carriers. 14% of the HCWs were MRSA carriers at the beginning of the study and 18% at the end. One hundred and five MRSA isolates were obtained, 11 from HCWs and 94 from 64 patients who were MRSA carriers. Sixty-one percent of the patients, classified as MRSA carriers, were positive on the first culture and 39% were identified during the follow up period in the subsequent cultures. The coagulase gene was detected in all 105 isolates and the mecA gene in 101. All MRSA isolates were susceptible to vancomycin and resistant to oxacillin and penicillin. Thirty-three percent of the isolates were multiresistant, presented SCCmec Type IIIA and showed a predominant PFGE type. The SCCmec type IV was found in 59% of the isolates. It was not possible to determine the SCCmec type of four isolates. The B1 PFGE pattern was the most prevalent, presented by MRSA SCCmec type IV isolates, obtained from nine patients and three HCWs. Nosocomial transmission occurred in 39% of the MRSA carriers. It was possible to observe HCWs MRSA cross- transmission in the Dermatology ward. HCWs were transiently colonized. In addition to nosocomial transmission of MRSA, it was possible to detect patients who were MRSA carriers on admission

Este estudo avaliou a incidência e distribuição de Candida spp. isoladas de casos de infecção hospitalar no período entre 2005 to 2007, em um hospital público infantil, em São Paulo. Brasil. As amostras foram isoladas de sangue, urina e outros materiais biológicos (36,6%, 37,12% e 26,52%, respectivamente). As análises micromorfológicas e bioquímicas revelaram que a distribuição por espécie foi 62,12% Candida albicans, 37,88% não-albicans. Uma maior incidência de amostras de C. albicans foi observada em casos de candidúria (53,62%) enquanto espécies não-albicans foram mais prevalentes em candidemia (71,43%) (p < 0.05). A respeito da produção enzimática, 68,94%, 47,73%, 65,91% e 66,67% foram positivas para proteínase, fosfolipase, lipase e hemolisina. Em relação aos antifúngicos, para Anfotericina B, 96,97% dos isolados mostraram e para 5- fluorcitosina foi observado o maior índice de resistência. Os fatores de risco identificados para candidemia hospitalar foram as doenças pré-existentes, terapia antibiótica de largo espectro e a presença de cateter venoso central. / This study evaluated the incidence and distribution of Candida spp. identified from cases of nosocomial infection in the period from 2005 to 2007, in a public children\'s hospital in São Paulo, Brazil. The strains were isolated from the blood, urine and other biological specimens (36,6%, 37,12% and 26,52%, respectively). Micromorphological and biochemical analyses revealed that the overall distribution by species was 62,12% Candida albicans, 37,88% non-albicans. A higher incidence of C. albicans strains was observed in cases of candiduria (53,62%) while non-albicans species were more prevalent in cases of candidemia (71,43%) (p < 0.05). Concernig the production of enzymes, 68,94%, 47,73%, 65,91% and 66,67% presented positive proteinase, phospholipase, lipase and hemolin activity. In relation to antifungal for the Amphotericin B, 96,97% of isolates showed sensitivity and for 5- fluorocytosine was observed the biggest index of resistence. The Risk factors identified for nosocomial candidemia was underlying disease, therapy with broad-spectrum antibiotics and the presence of a central venous catheter.

S.aureus SCCmec type IV é prevalente em nosso hospital e mais de 10% das bacteremias nosocomiais por MRSA eram causadas por quatro clones diferentes de MRSA tipo IV. O objetivo deste trabalho foi identificar fatores associados à infecção de corrente sangüínea causada por MRSA tipo IV. O desenho do estudo foi de caso-controle não pareado (1:2). Os casos foram definidos como pacientes com infecção de corrente sangüínea intrahospitalar causada por MRSA tipo IV e os controles como pacientes com infecção de corrente sangüínea intra-hospitalar causada por MRSA multiresistente. Na análise univariada, idade < 1 ano, menor uso de antibióticos, menor freqüência de uso de cateter venoso central e procedimentos cirúrgicos, menor número de doenças de base e menor pontuação de APACHE II à admissão e no dia da hemocultura positiva para MRSA, foram associados aos casos. Na análise multivariada, idade < 1 ano (OR: 26.6; 95% IC: 2.6-274.1), menor número de doenças de base (OR: 0.13; 95% IC: 0.04-0.44), menor uso de antibióticos (OR: 0.05; 95% IC: 0.007-0.3) e menor freqüência na realização de procedimentos cirúrgicos (OR: 0.18; 95% IC:0.04-0.81), foram estatisticamente significantes. MRSA SCCmec tipo IV é uma causa expressiva de infecção de corrente sangüínea intrahospitalar e acomete uma população de pacientes menos doentes e submetidos a menos procedimentos invasivos e antibióticos, se comparados com os pacientes com MRSA multi-resistentes. Crianças menores de um ano de idade possuem maior risco e parecem ser uma fonte potencial de transmissão cruzada nesta população. / Staphylococcus aureus SCCmec type IV is prevalent in our hospital and more than 10% of the nosocomial MRSA bacteremias were caused by 4 different type IV MRSA clones. To identify factors associated with nosocomial bloodstream infections caused by MRSA SCCmec type IV, we conducted a case-control study (1:2). Cases were patients with a nosocomial bloodstream infection due to MRSA SCCmec type IV. Controls were patients with a nosocomial bloodstream infection due to multi-resistant MRSA. There were 33 cases and 66 controls. In the univariate analysis, age < one year, less frequent use of antibiotics, less frequent use of central venous catheters and surgical procedures, smaller number of underlying diseases, and lower APACHE II score on admission and on the day of MRSA isolation were significantly associated with cases. Although the mean length of hospitalization before the isolation of MRSA was shorter among cases (27.5 versus 36.9 days), this was not statistically significant (P = .15). In the multivariate analysis, age < one year (odds ratio [OR], 26.6; 95% confidence interval [CI], 2.6-274.1), smaller number of underlying diseases (OR, 0.13 per disease; 95% CI, 0.04-0.44), and less frequent use of antibiotics (OR, 0.05; 95% CI, 0.007-0.3) and surgical procedures (OR, 0.18; 95% CI, 0.04-0.81) were statistically significant.Type IV SCCmec MRSA is an expressive cause of nosocomial bloodstream infections and affects a patient population that is less ill and less frequently submitted to invasive procedures and antibiotics than multi-resistant MRSA. Children under one year are at higher risk and type IV MRSA seems to have the potential to spread through crosstransmission in this population.

A incidência de infecções hospitalares tem aumentado substancialmente, resultando no aumento de morbidade e mortalidade nas últimas décadas. Embora as infecções hospitalares estejam intimamente ligadas à assepsia e à higiene do ambiente nosocomial, não se pode deixar de considerar a susceptibilidade já instaurada dos doentes acometidos por estas infecções. Os avanços tecnológicos relacionados à procedimentos invasivos, diagnósticos ou terapêuticos, ajudaram na disseminação das infecções microbianas. Em decorrência desta evolução, surgiram micro-organismos multirresistentes ao atual arsenal de agentes farmacológicos utilizados rotineiramente na quimioterapia, tornando estas infecções grave problema de Saúde Pública. A necessidade de pesquisar novas alternativas para o combate destes micro-organismos é evidente, sendo que derivados nitro-heterocíclicos apresentam-se como alternativa bastante viável para estudos de novos compostos com potencial atividade antimicrobiana. Baseado nestes fatos o presente trabalho propõe o planejamento, síntese e avaliação da atividade antimicrobiana de derivados tiofilidênicos com estruturas azometínica e oxadiazolínica frente a micro-organismos responsáveis por algumas das principais infecções hospitalares instauradas em hospitais em todo o mundo. A escolha dos grupos substituintes dos compostos planejados foi baseada no digrama de Craig, tendo sido planejado e sintetizados vinte derivados tiofilidênicos, estruturalmente identificados e avaliados quanto à atividade antimicrobiana frente às cepas padrão de Staphylococcus aureus (ATCC 29213) e multirressitente (VISA 3), Escherichia coli (ATCC 25922), Candida albicans (ATCC 573Y), Klebsiella pneumoniae (ATCC 70060), Enterococcus faecalis (ATCC 29212), Enterobacter cloacae (ATCC 23355) e Serratia marcescens (ATCC 14756). Observou-se que os compostos sintetizados apresentaram atividade bastante promissora frente às bactérias Gram positivas (S. aureus ATCC 29213, S. aureus VISA 3 e E. faecalis ATCC 29212) e para o fungo (C. albicans ATCC 573Y), enquanto que para bactérias Gram negativas não foi observado atividade antibacteriana significativa. Estudos de Relação Estrutura Atividade (REA) foram realizados, com objetivo de determinar quais propriedades físico-químicas auxiliam na atividade biológica. Pode-se observar que o equilíbrio lipo-hidrofílico, juntamente com as propriedades eletrônicas, estereoquímicas e topológicas foram as propriedades que contribuíram para a atividade antimicrobiana dos compostos estudados. Revelando esta classe de compostos como promissora opção no delineamento de novos fármacos no combate às infecções hospitalares com caráter de multirresistência. / Incidence of nosocomial infections has increased substantially, resulting in increased morbidity and mortality in recent decades. Although nosocomial infections are closely connected to asepsis and hygiene of the nosocomial environment, one cannot fail to consider the already established susceptibility of patients affected by these infections. Technological progress related to invasive procedures, diagnostic or therapeutic, helped in spreading microbial infections. However, as a consequence of this advancement, microorganisms that are multidrug resistant to the current arsenal of pharmacologic agents used in antibiotic therapy emerged and these infections became a serious public health problem. The need for new alternatives to fight these microorganisms is evident and nitro-heterocyclic derivatives are considered as viable for studies of new compounds with potential antimicrobial activity. Based on those events the present study proposes the design, synthesis and antimicrobial activity of thiophylidene derivatives with azomethine and oxadiazole structures against microorganisms responsible for some of the main nosocomial infections observed in hospitals worldwide. The choice of the substituent groups of compounds was based on the Craig diagram, having been designed and synthesized twenty thiophylidene derivatives, structurally identified and evaluated for antimicrobial activity against the strains standard Staphylococcus aureus (ATCC 29213) and mutiresistant (VISA 3), Escherichia coli (ATCC 25922), Candida albicans (ATCC 573Y), Klebsiella pneumoniae (ATCC 70060), Enterococcus faecalis (ATCC 29212), Enterobacter cloacae (ATCC 23355) and Serratia marcescens (ATCC 14756). It was observed that the synthesized compounds show very promising activity on the Gram positive bacteria (S. aureus ATCC 29213, S. aureus VISA 3 and E. faecalis ATCC 29212) and against the fungus (C. albicans ATCC 573Y), while for Gram negative bacteria significant antibacterial activity was not observed. Structure Activity Relationship (SAR) Studies were performed with the objective of determining which physicochemical properties help in the biological activity. It can be observed that the lipophilic-hydrophilic balance, together with the stereochemistry, electronic and topological properties were contributed to the antimicrobial activity of the studied substances. Revealing this class of compounds as a promising option in designing of new drugs to fight nosocomial infections with multidrug resistance character.

Infecções hospitalares, causadas por fungos e bactérias, são responsáveis por milhares de mortes anuais e disseminam-se cada vez mais rápido em ambiente hospitalar. Estas infecções afetam principalmente pacientes que são submetidos a procedimentos invasivos ou que apresentam baixa imunidade. Este quadro tende a agravar-se devido ao surgimento de micro-organismos resistentes aos tratamentos atualmente disponíveis, decorrentes, principalmente, de excessivas prescrições, automedicação, pela utilização errônea de antibióticos bem como pela aplicação de métodos de profilaxia inadequados determinando, desta forma, a necessidade de pesquisar e de identificar novos medicamentos para esta finalidade. Neste contexto, ressalta-se que os nitrocompostos que vêm demonstrando bons resultados como agentes antimicrobianos e, sendo assim, este trabalho se propõe a planejar, sintetizar e avaliar duas séries de compostos análogos à nifuroxazida frente a bactérias Gram-positivas, Gram-negativas e fungos de importância em infecções hospitalares com caráter de multirresistência. O planejamento de modificações moleculares na estrutura da série de análogos à nifuroxazida foi auxiliado pelo diagrama de Craig, que se aplica à seleção dos grupos substituintes. A identificação dos compostos obtidos foi realizada por análise espectrofotométrica RMN 1H e RMN 13C e, como critério de pureza, foi realizado análise elementar de CHN. A melhor atividade dos análogos foi frente à S. aureus, onde 16 dos 23 compostos planejados apresentaram atividade superior aos fármacos de referência, estas quais, e composto protótipo. Vale salientar também que os compostos mais ativos foram os análogos 4-butil-N\'-[(5-nitrofuran-2-il) metileno] benzidrazida e 3-acetil-2-[5-nitro-furan-2-il]-5-[4-ciano-fenil]-2,3-diidro-1,3,4-oxadiazolínico com IC90 = 1,8 ± 0,04 &#181;M e 3,89 ± 0,07 &#181;M, respectivamente. Nos estudos de relações estrutura-atividade, a propriedade eletrônica se mostrou com importância fundamental para a atividade dos compostos frente aos micro-organismos considerados. Os resultados encontrados são bastantes promissores e sinalizam para a possibilidade de identificação de um novo candidato para fármaco antimicrobiano frente à infecções hospitalares com caráter de multirresistência. / Nosocomial infections are caused by bacteria and fungi and are the main reason for thousands of deaths every year in the hospital environment. The most susceptible individuals to these type of infection are the immunocompromised, highlighting old-aged and immunodeficiency people, as also patients who passed by invasive procedures. Not only do this situation is very serious, but also a huge number of multidrug-resistant microorganisms are reported worldwide, basically due to excess of prescription and wrong use of antibiotics. If this situation doesn\'t be maintained today, there will not be a bright sight in the future. In this context, there is the necessity for research and development of new antimicrobial agents, and the nitrocompounds, highlighting nifuroxazide\'s analogs, are showing excellent activity against several pathogens related to multidrug resistant nosocomial infections. Therefore, this work aims to design, to synthesize and to evaluate two series of nifuroxazide\'s analogs against strains of gram-positive and gram-negative bacteria, also fungi strains. The sets of analogs were designed based on the replacement of hydroxyl group of nifuroxazide by different substituent groups according to Craig\'s diagram, also a modification in the structure core; identification of these compounds was carried out through 1H and 13C NMR. Melting point and elementary analysis were analyzed for purity criteria. Until the moment, about 23 compounds were evaluated and the best observed activity was against S. aureus strains, which 16 analogs showed better activity than the lead compound and several other compounds, used as referential drug. It is noteworthy that the best activity were analogs 4-butyl-N\'-((5-nitrofuran-2-yl) methylene) benzohydrazide and 3-acetyl-2-[5-nitro-furan-2-yl]-5-[4-cyano-phenil]-2,3-dihydro-1,3,4 oxadiazole with IC90 = 1,8 ± 0,04 &#181;M and 3,89 ± 0,07 &#181;M, respectively. The chemometrics studies suggest that electronic properties are most related to the biological activity on these microorganisms. All the available results shows the potential of nitrofurans to be a new candidate for an antimicrobial drug against multidrug resistant nosocomial infections.

A surgimento de bactérias multirresistentes é uma ameaça global. Essas bactérias têm sido associadas com infecções hospitalares, no entanto, diversos casos de infecções multirresistentes adquiridas na comunidade vêm sendo relatadas, o que acendo um alerta quanto a propagação destes micro-organismos para além do ambiente hospitalar. Em todo o mundo o consumo indiscriminado de antibióticos tem aumentado significativamente, sendo este o principal fator para o surgimento e propagação de novas formas de resistência. Outro fator preocupante é a velocidade com que estas novas formas de resistência cruzam fronteiras internacionais se disseminando facilmente em todo o mundo. Este fato tem preocupado líderes mundiais, os quais consideram o aparecimento de \"superbactérias\" um pesadelo, o que pode vir a ser em um futuro próximo uma catástrofe mundial. Diante desse quadro preocupante, a necessidade de desenvolvimento de novos agentes antimicrobianos para combater essas infecções se torna iminente. Neste contexto, os compostos nitrofurânicos tem se destacado por sua atividade contra bactérias com caráter de multirresistência. Por isto, este trabalho teve como objetivo o desenvolvimento de novos compostos nitrofurânicos, tendo como composto-protótipo a nifuroxazida. O processo de desenvolvimento das estruturas análogas a nifuroxazida foi realizado a partir do planejamento da série de compostos 5-nitro-2-furfurilidênicos, com base nos parâmetros estabelecidos por Lipinski para obtenção de compostos com características farmacocinéticas e farmacodinâmicas que favorecem a biodisponibilidade, com vistas a administração por via oral. Os ensaios de avaliação da atividade antimicrobiana dos compostos foram realizados com base no método de teste de sensibilidade a agentes antimicrobianos por diluição para bactérias de crescimento aeróbio, norma M07-A9, e como base no método de padrões de crescimento para teste de suscetibilidade a antimicrobianos, vigésimo terceiro suplemento informativo, M100-S23, aprovados pelo Clinical and Laboratory Standards Institute. Os resultados de avaliação da atividade antimicrobiana indicam que o composto mais ativo c24, 6-amino-N\'-((5-nitrofurano-2-il)metileno)-2-naftohidrazida, teve atividade significativa frente a todas cepas, sendo superior a nifuroxazida, NF; nitrofurantoína, NTF; oxacilina, OXA; e vancomicina, VAN; [ (Staphylococcus aureus ATCC 29213, c24 - IC90 = 0.31 &#181;M ± 0.06; NF - IC90 = 2.39 &#181;M ± 0.08; NTF - IC90 = 5.26 &#181;M ± 0.39; OXA - IC90 = 1.14 &#181;M ± 0.18; VAN - IC90 = 0.31 &#181;M ± 0.06); (Staphylococcus aureus resistente à oxacilina, c24 - IC90 = 0.52 &#181;M ± 0.26; NF - IC90 = 5.37 &#181;M ± 0.67; NTF - IC90 = 8.20 &#181;M ± 1.66; OXA - IC90 = s. a.; VAN - IC90 = 0.50 &#181;M ± 0.20); (Staphylococcus aureus cepa heterogênea com resistência intermediária à vancomicina, hVISA-FCFHV36, c24 - IC90 = 0.82 &#181;M ± 0.07; NF - IC90 = 7.22 &#181;M ± 0.29; NTF - IC90 = 13.14 &#181;M ± 0.94; OXA - IC90 = s. a.; VAN - IC90 = 0.88 &#181;M ± 0.05); (Staphylococcus epidermidis com perfil de resistência a linezolida, c24 - IC90 = 0.74 &#181;M ± 0.02; NF - IC90 = 4.36 &#181;M ± 0.54; NTF - IC90 = 8.46 &#181;M ± 0.60; OXA - IC90 = 12.66 &#181;M ± 0.36; VAN - IC90 = 1.40 &#181;M ± 0.28); e (Enterococcus faecalis resistente à vancomicina fenótipo vanA, c24 - IC90 = 0.72 &#181;M ± 0.02; NF - IC90 = 5.09 &#181;M ± 0.08; NTF - IC90 = 9.28 &#181;M ± 0.32; OXA - IC90 = 12.26 &#181;M ± 0.72, VAN - IC90 = s. a.) ]. Entre as propriedades de maior influência na atividade do composto c24 estão ClogP e PSA. / The emergence of multidrug-resistant bacteria is a global threat. These bacteria have been associated with nosocomial infections, however, many cases of community-acquired multidrug resistant infections have been reported which light a warning about the spread of these microorganisms other than the hospital environment. Worldwide the indiscriminate use of antibiotics has increased significantly, which is the main factor for the emergence and spread of new forms of resistance. Another factor of concern is the speed with which these new forms of resistance cross international boundaries easily spreading worldwide. This has worried world leaders, who consider the emergence of \"superbugs\" a nightmare, which might be in the near future a global catastrophe. Faced with this alarming situation, the need for development of new antimicrobial agents to combat such infections becomes imminent. In this context, nitrofuran compounds has been noted for its activity against bacteria with multidrug resistance character. Therefore, this study aimed to develop new nitrofuran compounds, with the composite prototype to nifuroxazida. The process of developing similar structures nifuroxazida was performed using the designed series of substituted 5-nitro-2-furfurilidênicos, based on parameters set by Lipinski to obtain compounds with pharmacokinetic and pharmacodynamic properties that promote the bioavailability in order administration orally. The evaluation of the antimicrobial activity tests of the compounds were carried out based on the method of the antimicrobial susceptibility testing by dilution for bacterial aerobic growth, M07-A9 standard, and based on the method of growth standards for antimicrobial susceptibility testing , twenty-third informational supplement M100-S23, approved by the Clinical and Laboratory Standards Institute. The results of evaluation of the antimicrobial activity indicate that the compound more active c24, 6-amino-N\'-((5-nitrofuran-2-yl) methylene)-2-naftohidrazida had significant activity against all strains, exceeding nifuroxazida, NF; nitrofurantoin, NTF; oxacillin, OXA; and vancomycin, VAN; [(Staphylococcus aureus ATCC 29213, c24 - IC90 = 0:31 uM ± 12:06; NF - IC90 = 2.39 uM ± 12:08; NTF - IC90 = 5.26 uM ± 12:39; OXA - IC90 = 1.14 uM ± 00:18; VAN - IC90 = 0:31 uM ± 12:06); (Staphylococcus aureus resistant to methicillin, c24 - IC90 = 0:52 uM ± 00:26; NF - IC90 = 5:37 uM ± 0.67; NTF - IC90 = 8.20 uM ± 1.66; OXA - IC90 = s to .; VAN - IC90 = 0:50 uM ± 00:20.); (Staphylococcus aureus heterogeneous strain with intermediate resistance to vancomycin, hVISA-FCFHV36, c24 - IC90 = 0.82 uM ± 00:07; NF - IC90 = 7.22 uM ± 00:29; NTF - IC90 = 13:14 uM ± 0.94; OXA - IC90 = sa; VAN - IC90 = 0.88 ± 0.05 uM); (Staphylococcus epidermidis with linezolid resistance profile, c24 - IC90 = 0.74 uM ± 12:02; NF - IC90 = 4:36 uM ± 00:54; NTF - IC90 = 8:46 uM ± 0.60; OXA - IC90 = 12.66 uM ± 12:36; VAN - IC90 = uM 1:40 ± 0:28); and (Enterococcus faecalis Vancomycin-resistant vanA phenotype, c24 - IC90 = 0.72 uM ± 00:02; NF - IC90 = 9.5 uM ± 12:08; NTF - IC90 = 9.28 uM ± 00:32; OXA - IC90 = 12.26 uM ± 0.72, VAN - IC90 = sa)]. Among the most influential properties in the activity of the compound c24 are ClogP and PSA