Antibiotic resistance is a growing human health threat, making infections more difficult to treat and increasing fatalities from and cost of treatment of associated diseases. The rise of multidrug resistant pathogens threatens a return to the pre-antibiotic era where even the most common infections may be impossible to treat. It is estimated that the majority of global antibiotic use, and use in the U.S., is dedicated towards livestock, where they are used to promote growth, treat, or prevent disease. Given that exposure to antibiotics selects for antibiotic resistant bacteria (ARBs) and can stimulate the horizontal transfer of their associated antibiotic resistance genes (ARGs), it is important to examine livestock operations as a reservoir of resistance. Correspondingly, there is growing interest in identifying how agricultural practices can limit the potential for spread of antibiotic resistance through the "farm to fork continuum," starting with antibiotic use practices, manure management and land application and ending with the spread of ARBs and ARGs present onto edible crops and serving as a route of exposure to consumers. This study focused specifically on the effect of composting on the prevalence of ARBs and ARGs in cattle manure. Three composting trials were performed: small-scale, heat-controlled, and large-scale. The small-scale composting trial compared dairy and beef manures, with or without antibiotic treatment (treated beef cattle received chlortetracycline, sulfamethazine, and tylosin while treated dairy cattle received cephapirin and pirlimycin), subject to either static or turned composting. The heat-controlled composting trial examined only dairy manure, with or without antibiotic treatment, subject to static composting, but using external heat tape applied to the composting tumblers to extend the duration of the thermophilic (>55°C) temperature range. The large-scale composting trial examined dairy manure, with or without antibiotic treatment, subject to static composting at a much larger scale that is more realistic to typical farm practices. Samples were analyzed to assess phenotypic resistance using the Kirby Bauer disk diffusion method and by diluting and plating onto antibiotic-supplemented agar. Genetic markers of resistance were also assessed using quantitative polymerase chain reaction (qPCR) to quantify sul1 and tet(W) ARGs; metagenomic DNA sequencing and analysis were also performed to assess and compare total ARG abundance and types across all samples. Results indicate that composting can enrich indicators of phenotypic and genetic resistance traits to certain antibiotics, but that most ARGs are successfully attenuated during composting, as evidenced by the metagenomic sequencing. Maintaining thermophilic composting temperatures for adequate time is necessary for the effective elimination of enteric bacteria. This study suggests that indicator bacteria that survive composting tend to be more resistant than those in the original raw manure; however, extending the thermophilic stage of composting, as was done in the heat-controlled trial, can reduce target indicator bacteria below detection limits. Of the two ARGs specifically quantified via qPCR, prior administration of antibiotics to cattle only had a significant impact on tet(W). There was not an obvious difference in the final antibiotic resistance profiles in the finished beef versus dairy manure composts according to metagenomics analysis. Based on these results, composting is promising as a method of attenuating ARGs, but further research is necessary to examine in depth all of the complex interactions that occur during the composting process to maximize performance. If not applied appropriately, e.g., if time and temperature guidelines are not enforced, then there is potential that composting could exacerbate the spread of certain types of antibiotic resistance. / Master of Science

The reduced efficacy of antibiotics in treating common infections is one of the most pressing health concerns of the 21st Century. Increasing evidence links the widespread use of antibiotics in livestock production to the transfer of bacteria carrying antibiotic resistance genes to the broader environment. It is therefore critical to understand the persistence and dissemination of resistance in agricultural soils to understand potential threats to consumers. The goal of this large-scale agricultural field experiment was to identify the effects of crop (lettuce, radish) and fertilizer type (inorganic, compost, raw manure) on the incidence and persistence of antibiotic-resistant fecal coliforms, a common family of fecal indicator bacteria used to track the environmental spread of antibiotic resistance. Soil samples were collected eight times over a 120-day period and analyzed for fecal coliforms utlizing a suite of MacConkey agars supplemented with different antibiotics (ceftazidime, clindamycin, erythromycin, sulfamethoxazole, and tetracycline). Given the number of samples with resistant fecal coliform concentrations below the limit of detection, analyses to identify the effects of soil treatment and crop relied on Zero-inflated Poisson Regressions. Antibiotic-resistant culturable fecal coliforms were recoverable from soils across all treatments immediately following application, though persistence throughout the experiment varied by antibiotic. Sulfamethoxazole- and tetracycline-resistant fecal coliforms were nondetectable after Day 1; this was expected, as the cattle supplying the manure amendments were not treated with these antibiotics or similar analogs. Clindamycin- and erythromycin-resistant fecal coliforms were nondetectable after 42 days but rebounded on Day 90 in the soil; both of these drugs were of the same antibiotic class as the ones used to treat the dairy cattle during the manure collection period. Ceftazidime-resistant fecal coliform levels were consistently high throughout the duration of the growing season. No statistical differences were observed between root and aboveground crops. Results suggest that soils amended with raw or composted dairy manure are at risk of contamination with antibiotic resistant fecal coliforms; however, composting decreased the antibiotic resistant fecal coliform levels of the macrolide (erythromycin) and lincosamide (clindamycin) antibiotic classes administered to the dairy cattle (cephapirin and pirlimycin). / Master of Science

京都大学 / 新制・課程博士 / 博士(工学) / 甲第25270号 / 工博第5229号 / 京都大学大学院工学研究科都市環境工学専攻 / (主査)教授 西村 文武, 教授 松田 知成, 准教授 浅田 安廣, 准教授 井原 賢(高知大学) / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / The marketing of fish has shown substantial increase; however, their place of origin and ways of handling and storage may pose health risk. The microorganisms in the food chain and in capture environments cause concern over the risk of disease transmission and the multiple resistance to several drugs. This study aimed at characterizing the antimicrobial resistance of 191 strains of Escherichia coli isolated from 20 fish samples, ten saltwater samples: (5) mackerel (S. cavalla) and (5) snapper (L. purpureus) and ten freshwater samples: (5) curimatà (P. cearenses) and (5) tilapia (O. niloticus), sold in street markets of the city of Fortaleza (Cearà State), Brazil. The strains were isolated, identified and then subjected to susceptibility testing (20 antibiotics) in order to provide the resistance profile. Moreover, it was also performed: Multiple Resistance Index (MRI), the Antimicrobial Resistance Index (ARI), Minimum Inhibitory Concentration (MIC), plasmid "cure" and analysis of plasmid profile through DNA extraction. Strains isolated from marine and freshwater fish species showed distinct multidrug resistance profiles, but with broad resistance to penicillins and tetracyclines. There was high frequency of saltwater isolates resistant to chloramphenicol. Overall, low resistance to betalactamase inhibitors (ampicillin/sulbactam, and piperacillin/tazobactam) and aminoglycosides was observed, excepting streptomycin. The MRI has shown that about 50% of the isolates were resistant to five of the twenty tested antimicrobials, highlighting the strains from mackerel (55.5%). As for MIC, the percentage of isolates resistant to NAL, CIP, MFX, SUT and AMO stood out in saltwater fish strains. For bacteria from freshwater, greater resistance to high concentrations of antimicrobials were most significant for AMO, SUL and NAL. Chromosomal profiles in freshwater isolates were mostly composed of amoxicillin, ampicillin, streptomycin, and sulfametazol/trimethoprim. For saltwater fish, there was predominance of quinolones. Analysis of the plasmid DNA showed the occurrence of a heterogeneous population of small plasmids distributed in various profiles. The greater diversity and lower molecular weight were observed in strains of marine fish samples. Thus, it is emphasized that the circulation of pathogenic E. coli with antimicrobial resistance characteristics poses a risk to the aquatic ecosystem and the marketing environment, there being need for continued vigilance to contaminant bacterial to fish so that the safety of these foods is guaranteed. / A comercializaÃÃo de pescado tem indicado aumento substancial, contudo, seu local de origem e formas de manipulaÃÃo e armazenamento, podem representar risco sanitÃrio. Os micro-organismos presentes na cadeia produtiva de alimentos e nos ambientes de captura ocasionam preocupaÃÃo pelo risco de transmissÃo de doenÃas e pela mÃltipla resistÃncia apresentada a diversos fÃrmacos. Este trabalho objetivou caracterizar a resistÃncia antimicrobiana de 191 cepas de Escherichia coli isoladas de 20 amostras de pescado, sendo dez amostras de pescado de Ãgua salgada: (5) cavala (S. cavalla) e (5) pargo (L. purpureus) e dez amostras de Ãgua doce: (5) curimatà (P. cearenses) e (5) tilÃpia (O.niloticus), comercializadas em feiras livres da cidade de Fortaleza, CE. As cepas foram isoladas, identificadas e posteriormente submetidas a testes de susceptibilidade (20 antimicrobianos) a fim de conferir o perfil de resistÃncia. AlÃm disso, foram realizados: Ãndice de MÃltipla ResistÃncia (IMR), Ãndice de ResistÃncia a Antimicrobianos (IRA), ConcentraÃÃo InibitÃria MÃnina (CIM), âcuraâ plasmidial e anÃlise de perfil plasmidial, atravÃs de extraÃÃo de DNA. As cepas isoladas das espÃcies de pescado marinho e de Ãgua doce apresentaram perfis de multirresistÃncia distintos, porÃm com ampla resistÃncia Ãs penicilinas e Ãs tetraciclinas. Houve elevada frequÃncia de isolados de pescado marinho resistentes ao cloranfenicol. Foi observada, de forma geral, baixa resistÃncia para inibidores de betalactamases (ampicilina/ sulbactam e piperacilina/ tazobactam) e aminoglicosÃdeos, excetuando, estreptomicina. O IMR demonstrou que cerca de 50% dos isolados foram resistentes a cinco dos vinte antimicrobianos testados, destacando as cepas provenientes de cavala (55,5%). Nos testes de CIM observou-se que, cepas isoladas de pescados de Ãgua salgada apresentaram maiores percentuais de isolados resistentes a NAL, CIP, MFX, SUT e AMO. Maiores resistÃncias a elevadas concentraÃÃes de antimicrobianos, quando testadas bactÃrias oriundas de Ãgua doce, foram observadas para AMO, SUL e NAL. Os perfis cromossomiais em isolados de Ãgua doce foram na maioria compostos por amoxicilina, ampicilina, estreptomicina e sulfametazol ∕ trimetropim. Para o pescado de Ãgua salgada, foi verificado a predominÃncia de quinolonas. A anÃlise do DNA plasmidial mostrou a ocorrÃncia de uma populaÃÃo heterogÃnea de pequenos plasmÃdios distribuÃdos em vÃrios perfis. A maior diversidade e menor peso molecular foram observados em cepas de amostras de pescado de origem marinha. Dessa forma, destaca-se que a circulaÃÃo de E. coli patogÃnicas com caracterÃsticas de resistÃncia antimicrobiana representa um risco ao ecossistema aquÃtico e ao ambiente de comercializaÃÃo, havendo necessidade de vigilÃncia contÃnua a bactÃrias contaminantes do pescado, para que a seguranÃa desses alimentos seja garantida.

Bakgrund Antibiotikaresistens är rangeras idag som ett av de största hoten mot folkhälsan. Bärare av multiresistenta bakterier är ofta dåligt införstådda i vad det innebär att vara bärare vilket leder till ett minskat välbefinnande. Sjuksköterskor har en central roll i att informera patienter om deras hälsotillstånd och ska säkerställa att informationen är förstådd. Syfte Att undersöka sjuksköterskors upplevelse av att informera patienter som bär på multiresistenta bakterier om deras bärarskap. Metod Kvalitativ intervjustudie med induktiv ansats. Semistrukturerade intervjuer genomfördes med sju sjuksköterskor på ett sjukhus i Mellansverige. Data analyserades med kvalitativ innehållsanalys. Resultat Analysen resulterade i fyra kategorier: arbetsmiljö, sjuksköterskans roll, patientens förutsättningar och okunskap. Informanterna upplevde att det var otydliga rutiner kring vilken information som skulle ges till patienterna. Informanterna antog att patienter redan var införstådda i sitt bärarskap när de ankom avdelningen. Patientens tillstånd och språk var faktorer som påverkade informationsgivandet. Det fanns en okunskap hos patienter och anhöriga som ofta ledde till en rädsla och onödig förstorning av bärarskapet. Kunskapsbrister existerade även hos vårdutbildade och kunde leda till att patienter blev felbehandlade. Slutsats Informanterna upplevde att det förekom otydliga rutiner kring vilken information som skulle ges till bärare av MRB om deras bärarskap. Förförståelse om att patienten redan var införstådd i sitt bärarskap samt patientens förutsättning att kunna motta information påverkade givandet av information. Att ge korrekt information till patienten och säkerställa sig om att informationen är förstådd är viktiga faktorer som leder till minskat lidande hos patienten samt minskad spridning av MRB i samhället. / Background Antimicrobial resistance is an increasingly serious threat to public health. Carriers of multidrug-resistant bacteria are often poorly understood in what it implies to be a carrier. This can lead to a reduced sense of wellbeing. Nurses have a central role in informing patients about their health condition and also in ensuring that the information is apprehended. Aim To investigate nurses’ experience of informing patients who carry multidrug-resistant bacteria about their colonisation. Method Qualitative interview study. Semi structured interviews were conducted with 7 nurses at a university hospital in central Sweden. The interviews were analyzed using content analysis. Result The analyze resulted in four categories: work environment, role of the nurse, patients’ conditions and lack of knowledge. The informants experienced uncertain routines concerning what information they should distribute to the patients about multidrug-resistant bacteria. The informants often assumed that the patients were well informed and understood  about colonisation of multidrug-resistant bacteria prior to the hospital stay. The patients’ condition and language could affect the distributed information. The informants recognized a lack of knowledge in patients and relatives that could lead to fear and exaggeration of the colonisation. Lack of knowledge was also seen among health care professionals and could lead to patients being mistreated at the hospital. Conclusion The informants experienced uncertain guidelines about what information to give carriers of multidrug-resistant bacteria. The patients’ condition and the preunderstanding that the patient already was well informed about being a carrier were two factors affecting the distribution of information. It is essential that nurses distribute adequate information and ensure that patients understand their condition in order to reduce the patient suffering and the spreading of multidrug-resistant bacteria in the society.

Desde a primeira enzima ?-lactamase de espectro estendido (ESBL) detectada, na década de 1980, o número de diferentes enzimas ESBL têm aumentado exponencialmente. Houve também aumento no número de relatos de isolamento de bactérias resistentes presentes em alimentos de origem animal. O objetivo deste estudo foi avaliar enterobactérias de microbiota de frangos comerciais saudáveis, de granjas localizadas no interior do Estado de São Paulo (Brasil), quanto à resistência a antimicrobianos e ao potencial de virulência. Foram avaliadas todas as enterobactérias que apresentaram resistência à cefotaxima e/ou ceftazidima de 200 frangos comerciais para consumo humano. O teste de sensibilidade aos antimicrobianos foi realizado por disco de difusão para diferentes classes de antimicrobianos incluindo ?- lactâmicos e não ?-lactâmicos. Reação em cadeia da polimerase e sequenciamento foram utilizados para a pesquisa de genes codificadores de ESBL, ?-lactamases AmpC e determinantes de resistência às quinolonas mediada por plasmídeos (PMQR). A similaridade genética dos isolados foi caracterizada por eletroforese em campo pulsado (PFGE) e a localização cromossômica ou plasmideal de genes de resistência foi avaliada por I-Ceu IPFGE ou S1-PFGE. Além disso, experimentos de conjugação, tipagem de plasmídeos, investigação de filogenia e de virulência foram realizados. Em todas as amostras de cloaca coletadas foram identificados Enterobacteriaceae, incluindo Escherichia coli, Escherichia fergusonii, Klebsiella oxytoca e Klebsiella pneumoniae resistentes à cefotaxima e/ou ceftazidima. Salmonella sp não foi detectada. Foi encontrada ampla diversidade genômica entre todos os isolados classificados entre diferentes tipos de PFGE. Foram detectados diferentes genes codificadores de ?-lactamases, a maioria em diferentes plasmídeos, de diversos tamanhos, sendo alguns conjugativos, presentes em diferentes populações bacterianas. Foram identificados isolados de E. coli produtores de CTX-M-2, com inserção do gene blaCTX-M-2 no cromossomo bacteriano. Plasmídeo IncI (ST113/ST114) foi identificado carreando o gene blaCTX-M-8. Foram também encontrados os genes codificadores de ?- ii lactamase, blaCTX-M-2 e blaCTX-M-15, sendo carreados por plasmídeos. Foi identificado gene blaCMY-2 disseminado por plasmídeos de diferentes grupos de incompatibilidade, na população comensal de E. coli. Nos isolados que abrigavam gene PMQR, além das resistências às quinolonas, foi observado também resistência a outras importantes classes de antimicrobianos. Genes determinantes de PMQR abrigados em plasmídeos tipo ColE foram encontrados em E. coli, E. fergusonii, K. oxytoca e K. pneumoniae. Todas as aves comerciais de granjas localizadas no interior do Estado de São Paulo, incluídas nesse estudo, apresentaram isolados considerados multirresistentes a antimicrobianos e o trato intestinal destes frangos é reservatório dos genes de resistência em enterobactérias da microbiota normal. Além disso, alguns isolados demonstraram alto potencial de virulência, incluindo a capacidade de adesão e invasão em células epiteliais in vitro. / of commercial poultry in farms located at the countryside of São Paulo State (Brazil). All enterobacteria presenting cefotaxime and/or ceftazidime resistance from 200 commercial broiler chickens for human consumption were evaluated. Antimicrobial susceptibility testing was performed by disc diffusion for different classes of antimicrobials, including ?-lactams and non-?-lactams. The genes encoding ESBL, ampC ?-lactamases and determinants of plasmid mediated quinolone resistance (PMQR) were screened by polymerase chain reaction and sequencing. Genetic similarity of bacterial isolates was characterized by pulsed field gel electrophoresis (PFGE) and the location of the resistance genes in the chromosome or plasmids was evaluated by I-CeuI-PFGE or S1-PFGE. Additionally, experiments of conjugation, plasmid typing, phylogeny and virulence characterization were performed. Enterobacteriaceae were identified in all cloacal swab samples, including Escherichia coli, Escherichia fergusonii, Klebsiella oxytoca and Klebsiella pneumoniae resistant to cefotaxime and/or ceftazidime. Salmonella sp. was not detected. High genetic diversity was detected among all isolates, classified into diferent types of PFGE. Different genes coding for ?-lactamases were detected, harbored in diverse plasmids, of different sizes, some were conjugative and were present in different bacterial populations. E. coli isolates producing CTX-M-2 were identified, harbouring the blaCTX-M-2 gene inserted into the chromosome. IncI (ST113/ST114) plasmid was identified carrying the blaCTX-M-8 gene. The ?-lactamase coding genes, blaCTX-M-2 and blaCTX-M-15 were also found in plamids. The gene blaCMY-2 was found disseminated in different types of plasmid replicons in the commensal E. coli population. In isolates harbouring PMQR genes, in addition to the quinolones resistance, was observed resistance to other important antimicrobials classes was observed. PMQR determinant genes harbored in ColE-like plasmids were found in E. coli, E. fergusonii, K. oxytoca and K. pneumoniae. All commercial poultry from farms located at São Paulo State, evaluated in this study, carried isolates considered multidrug resistant and the intestinal tract of these chickens is reservoir of resistant genes blaCTX-M-2, blaCTX-M-8 and blaCTX-M-15 in enterobacteria from the normal microbiota. Moreover, some have demonstrated a high virulence potential, with adhesion and invasion capacity in epithelial cells cultured in vitro.

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 µM ± 0.06; NF - IC90 = 2.39 µM ± 0.08; NTF - IC90 = 5.26 µM ± 0.39; OXA - IC90 = 1.14 µM ± 0.18; VAN - IC90 = 0.31 µM ± 0.06); (Staphylococcus aureus resistente à oxacilina, c24 - IC90 = 0.52 µM ± 0.26; NF - IC90 = 5.37 µM ± 0.67; NTF - IC90 = 8.20 µM ± 1.66; OXA - IC90 = s. a.; VAN - IC90 = 0.50 µM ± 0.20); (Staphylococcus aureus cepa heterogênea com resistência intermediária à vancomicina, hVISA-FCFHV36, c24 - IC90 = 0.82 µM ± 0.07; NF - IC90 = 7.22 µM ± 0.29; NTF - IC90 = 13.14 µM ± 0.94; OXA - IC90 = s. a.; VAN - IC90 = 0.88 µM ± 0.05); (Staphylococcus epidermidis com perfil de resistência a linezolida, c24 - IC90 = 0.74 µM ± 0.02; NF - IC90 = 4.36 µM ± 0.54; NTF - IC90 = 8.46 µM ± 0.60; OXA - IC90 = 12.66 µM ± 0.36; VAN - IC90 = 1.40 µM ± 0.28); e (Enterococcus faecalis resistente à vancomicina fenótipo vanA, c24 - IC90 = 0.72 µM ± 0.02; NF - IC90 = 5.09 µM ± 0.08; NTF - IC90 = 9.28 µM ± 0.32; OXA - IC90 = 12.26 µM ± 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

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 µM ± 0.06; NF - IC90 = 2.39 µM ± 0.08; NTF - IC90 = 5.26 µM ± 0.39; OXA - IC90 = 1.14 µM ± 0.18; VAN - IC90 = 0.31 µM ± 0.06); (Staphylococcus aureus resistente à oxacilina, c24 - IC90 = 0.52 µM ± 0.26; NF - IC90 = 5.37 µM ± 0.67; NTF - IC90 = 8.20 µM ± 1.66; OXA - IC90 = s. a.; VAN - IC90 = 0.50 µM ± 0.20); (Staphylococcus aureus cepa heterogênea com resistência intermediária à vancomicina, hVISA-FCFHV36, c24 - IC90 = 0.82 µM ± 0.07; NF - IC90 = 7.22 µM ± 0.29; NTF - IC90 = 13.14 µM ± 0.94; OXA - IC90 = s. a.; VAN - IC90 = 0.88 µM ± 0.05); (Staphylococcus epidermidis com perfil de resistência a linezolida, c24 - IC90 = 0.74 µM ± 0.02; NF - IC90 = 4.36 µM ± 0.54; NTF - IC90 = 8.46 µM ± 0.60; OXA - IC90 = 12.66 µM ± 0.36; VAN - IC90 = 1.40 µM ± 0.28); e (Enterococcus faecalis resistente à vancomicina fenótipo vanA, c24 - IC90 = 0.72 µM ± 0.02; NF - IC90 = 5.09 µM ± 0.08; NTF - IC90 = 9.28 µM ± 0.32; OXA - IC90 = 12.26 µM ± 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

Antibiotic-resistant bacteria(ARB) is causing increased health risk and cost to society. Mathematical models have been developed to study the transmission of resistant bacteria and the efficacy of preventive measures to slow its spread within a hospital setting. The majority of these models have assumed a constant total hospital population with the admission and discharge rates being equal throughout the duration. But a typical hospital population varies from day to day and season to season. In this thesis, we apply variable admission and discharge daily rates to existing deterministic and stochastic models which examine the transmission of single and dual resistant bacteria. We perform stability and equilibrium analyses as well as a sensitivity analysis on the resulting model..

Smittsamma sjukdomar kostar det svenska samhället enorma summor varje år. Behandlingen av smittade patienter har tidigare uppskattats till 5-10 miljarder svenska kronor årligen. Vidare estimeras de förebyggande åtgärderna kosta samhället runt en miljard svenska kronor. Detta betyder att det finns en ekonomisk drivkraft för att reducera antalet smittade patienter inom vården, speciellt de fall som är orsakade av resistenta bakterier. Samtidigt pågår det en debatt om resistenta bakterier och antibiotikaförbrukningen i både forskning och media. Resistenta bakterier kan bli ett hot mot vår framtid om vi inte minskar antibiotikaförbrukningen och vidtar åtgärder för att förhindra smittspridning. Om antalet personer som blir smittade av resistenta bakterier kan reduceras minskar även antibiotikaförbrukningen som i sin tur leder till att färre bakterier utvecklar ett resistensmönster för antibiotika. Detta betyder att det är viktigt att studera och effektivisera hanteringen av smittsamma patienter.   För att reducera antalet smittade patienter måste förebyggande åtgärder vidtas och smittkällan måste kartläggas vid ett upptäckt fall av en smitta. Svensk sjukvård arbetar idag aktivt med smitthantering. Detta begrepp omfattar upptäckt, kontroll och spårning av smitta. Uppdragsgivaren till detta examensarbete, Cambio Healthcare Systems, saknar en fullständig bild över hur smitthanteringen egentligen går till på ett sjukhus. Deras målsättning är att utveckla ett IT-system som kan underlätta smitthanteringsprocessen. Denna studie syftar till att kartlägga informationsflödet vid smitthanteringsprocessen och identifiera de inblandade aktörernas ansvarsområden och skyldigheter enligt regelverket. Vidare syftar arbetet till att presentera åtgärdsförslag som kan minska de identifierade riskerna och effektivisera smitthanteringsprocessen av resistenta bakterier.   För att kartlägga smitthanteringsprocessen genomfördes en fallstudie av ett svenskt universitetssjukhus under våren 2013. Aktörer som studerades var det mikrobiologiska laboratoriet, vårdhygien, smittskyddsenheten, smittskyddsinstitutet samt läkare och sjuksköterskor vid två avdelningar på sjukhuset. Datainsamlingen består av intervjuer, observationer och dokument.   Resultatet av fallstudien visade att smitthanteringsprocessen är ett komplext system med ett omfattande informationsflöde. Huvudaktörerna är vårdhygien, sjukvårdspersonalen och det mikrobiologiska laboratoriet. De är viktiga eftersom deras praktiska handlande är avgörande för att smitthanteringen genomförs. Smittskyddsenheten är inblandad till viss del, men tillhör inte huvudaktörerna. Studien visade även att smittskyddsinstitutet inte hade någon framträdande roll i smitthanteringsprocessen av resistenta bakterier på sjukhuset.   Ansvarsfördelningen är till viss del styrd av smittskyddslagen och enligt denna lag har den behandlande läkaren en central roll i processen. I verkligheten är läkarens roll mindre framträdande vid smittspårningen, vanligtvis delegerar läkaren uppgifter till sjuksköterskor eller till vårdhygien. Mycket av kommunikationen mellan aktörerna är muntlig och detta innebär att ett flertal risker kan uppstå. Vid identifieringen av risker för hela processen konstaterades det att de flesta risker kan uppstå på grund av den mänskliga faktorn, ofta i kombination med användandet av ett otillräckligt datasystem. Åtgärdsförslagen för att effektivisera processen fokuserar därför på att minimera de identifierade riskerna med hjälp av framtida IT-system.   Slutsatsen av studien är att det finns ett stort behov av IT-lösningar för att effektivisera smitthanteringsprocessen av resistenta bakterier. Min rekommendation är att Cambio Healthcare Systems AB bör fokusera på att utveckla ett system för att digitalisera arkiveringen av beläggningslistorna och spåra patientflöden tillbaka i tiden i Cosmic då detta är ett starkt önskemål från kunderna. En annan viktig åtgärd är att utveckla smittspecifika checklistor som visas på datorn i samband med att läkaren får ett positivt provsvar. Slutligen rekommenderar jag Cambio Healthcare Systems AB att utveckla ett smittlarm som kan integreras med deras befintliga whiteboardtavla som nyligen lanserades. / Infectious diseases are a major cost item for the Swedish society. The treatment of infected patients has previously been estimated to 5-10 billion SEK annually and preventive actions cost the Swedish society around one billion SEK every year. Therefore, there are strong economic incentives to reduce the number of infected patients in care, particularly cases caused by resistant bacteria. There is an ongoing debate in both media and research about bacterial resistance and antibiotic consumption. Resistant bacteria can be a threat to our future if we do not reduce the consumption of antibiotics and take measure against infection spreading. If it is possible to reduce the number of resistant bacteria infected patients in the future it enables a decline in antibiotic consumption. This in turn leads to a decreased quantity of bacteria that is able to develop a resistance pattern to antibiotic. Thus, it is highly motivated to study and streamline the process of infection control.   Preventive measures must be taken and the source of the infection must be identified in order to reduce the number of infected patients. The Swedish health care sector is currently working actively with infection control. The concept of infection control encloses the detection, the control and the tracing of the infection. The requestor of this master thesis, Cambio Healthcare Systems AB, does not have a complete picture of the process of the infection control. Their goal is to develop an IT system to facilitate the process of infection control. This study aims to map the information flow of the process and to identify the involved actors’ field of responsibility and obligations according to the law. Further, this thesis aims to present action proposals that can reduce the identified risks and streamline the infection control of resistant bacteria.   A case study of a Swedish university hospital was performed in the spring of 2013 in order to map the process of infection control. The investigated actors were the microbiological laboratory, the local health protection unit (Vårdhygien), the unit of infection control at a regional level (Smittskyddsenheten), the Swedish Institute of Infectious Disease Control (Smittskyddsinstitutet) and physicians and nurses at two hospital departments. The data collection consists of interviews, observations and documents.   The result of this case study shows that the process of infection control is a complex system with an extensive flow of information. The main actors are the local health protection unit, the microbiological laboratory and the medical staff. Their practical actions are essential for the process of infection control. The unit of infection control at a regional level is involved to some extent, but does not belong to the main actors. Furthermore, the study showed that the Swedish Institute of Infectious Disease Control does not have a prominent role in the process at the hospital.   The division of responsibilities is to some extent controlled by the law. According to the law, the physician in charge has a central role in the process of infection control. However, the physician’s role in reality is less prominent. Usually, the physician delegates the tasks to the other actors such as nurses or to the local health protection unit. The communication between the actors is mainly oral and this can cause risks. Most of the identified risks occurred due to human error, often in combination with use of an insufficient IT-system. Therefore, the proposed actions to streamline the process focus on minimizing the identified risks with help of future IT solutions.   The conclusion of this study is that there is a strong demand for IT solutions to streamline the process of infection control of resistant bacteria. My recommendation is that Cambio Healthcare Systems AB should focus on developing a system to digitalize the archiving of the occupancy lists, which also enables tracing the flow of patients back in time. This is a request from several health care professionals. Another important proposed action is to develop a checklist that is specific for every infection disease. Simultaneously as the physician receives the positive test results, this checklist will appear on the physician’s screen. Finally, I recommend Cambio Healthcare Systems AB to develop an alarm to infection diseases that can be integrated with their existing whiteboards that were recently introduced to the market.