The syntheses of the cephalosporin analogs cis-N-(2'-hydroxyphenyl)-3-phenylacetamido-4-hydroxymethyl-2-azetidinone (37), cis-N-(2'-hydroxy-5'-nitrophenyl)-3-phenylacetamido-4-hydroxymethyl-2-azetidinone (59) and 7-(beta)-phenylacetamido-3'-hydroxybenzo{3,4}-0,2-isocephem (77) are described. Compounds 37 and 59 were devoid of antibacterial activity, while (beta)-lactam 77 showed weak activity against two micoorganisms. / Two new ring systems, 2-phenylcarbapenams 146 and 157 have been prepared. These are key intermediates in the syntheses of phosphonic acid carbapenam 148 and the carboxylic acid derivative 158, respectively. / The one carbon homologation of (beta)-trimethylsilyl-(alpha),(beta)-unsaturated esters with diazomethane was extended to the corresponding (beta)-trimethylsilyl or (beta)-t-butyldimethylsilyl aldehydes.

Thesis (M. Med. Sc.)--University of Hong Kong, 2004. / Also available in print.

Thesis (M. Med. Sc.)--University of Hong Kong, 2004. / Also available in print.

Thesis supervisor: John R. Kirby. Includes bibliographic references (p. 63-67).

Thesis (M. Med. Sc.)--University of Hong Kong, 2005.

Thesis (M. Phil.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

Made available in DSpace on 2015-12-06T23:46:57Z (GMT). No. of bitstreams: 0 Previous issue date: 2007 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Objetivo: Avaliar a acuracia de diferentes testes fenotipicos para a deteccao da producao de MBL entre amostras produtoras de IMP, VIM, SPM, GIM, ou SIM, incluindo Pseudomonas, Acinetobacter spp. e enterobacterias. Metodos: Foram testadas 46 bacterias nao relacionadas geneticamente e produtoras de diferentes tipos de MBL. Dezenove amostras nao produtoras de MBL foram incluidas como controles negativos. Foi avaliada a capacidade do inibidor de MBL (IMBL) em inibir o crescimento bacteriano e em realizar a hidrolise do substrato. Os isolados foram submetidos aos testes de disco aproximacao e disco combinado para adeteccao da producao de MBL, utilizando imipenem e ceftazidima em combinacao com diferentes IMBLs. Resultados: Foi obtido 100 por cento de sensibilidade e especificidade para a deteccao da producao de MBL por disco aproximacao utilizando acido mercaptopropionico como IMBL, em combinacao com ceftazidima e imipenem, para P. aeruginosa e Acinetobacter spp., respectivamente. A tecnica de disco combinado utilizando imipenem e EDT A apresentou os mesmos resultados para detectar enterobacterias produtoras de MBL, considerando-se como ponto de corte o aumento de pelo menos 5,0 mm na zona de inibicao do crescimento bacteriano. Conclusoes: Nossos resultados indicam que ambos os metodos fenotipicos para a deteccao de MBL, disco aproximacao e disco combinado, devem ser escolhidos apos a identificacao da bacteria-teste. Adicionalmente, devem ser considerados a prevalencia local de bacterias que apresentem este determinante de resistencia, assim como a habilidade de tecnicos especializados em interpretar corretamente a inibicao de MBL / The emergence of metallo-β-lactamase (MBL)-producing isolates is a challenge to routine microbiology laboratories, since there are no standardized methods for detecting such isolates. The aim of this study was to evaluate the accuracy of different phenotypic methods to detect MBL production among Pseudomonas, Acinetobacter spp and enterobacterial isolates, including GIM-, IMP-, SIM-, SPM-, and VIM- variants. A total of 46 genetically unrelated P. aeruginosa, P. putida, Acinetobacter spp. and enterobacterial strains producing distinct MBLs were tested. Nineteen strains were included as negative controls. The inhibition of bacterial growth and β-lactam hydrolysis caused by MBL-inhibitors (IMBL) were also evaluated. The isolates were tested for MBL production by both double disk synergy test (DDST) and combined disk (CD) using imipenem and ceftazidime as substrates in combination with distinct IMBL. One hundred percent sensitivity and specificity was achieved by DDST using 2-mercaptopropionic acid in combination with ceftazidime and imipenem for detection of MBL production among P. aeruginosa and Acinetobacter spp. isolates, respectively. CD showed the same results for detecting MBL-producing enterobacteria by combining imipenem and EDTA with a 5.0 mm breakpoint increase in the inhibition zone. Our results indicate that both phenotypic methods to detect MBL-producing isolates should be based on the genera to be tested regardless of the enzyme produced by such isolates as well as the local prevalence of MBL producers and on the ability of specialized technicians to correctly interpret MBL inhibition. / FAPESP: 2006/07197-0 / BV UNIFESP: Teses e dissertações

Made available in DSpace on 2015-12-06T23:47:06Z (GMT). No. of bitstreams: 0 Previous issue date: 2007 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / No Hospital São Paulo, um hospital terciario de 600 leitos, a presenca de P. aeruginosa produtora de metalo-β-lactamase tem sido encontrada desde 2000 (a primeira, SPM-1, foi isolada em 1997). Durante a periodo entre 2000 e 2001, 25 das 128 amostras avaliadas produziam SPM au IMP (88 por cento e 12 por cento das P. aeruginosa resistentes a imipenem, respectivamente). Durante o ano de 2004, as 10 primeiras amostras consecutivas de P. aeruginosa isoladas par mes foram selecionadas para a producao de MβL. Um total de 120 isolados foram submetidas ao teste de hidro1ise contra imipenem, PCR para a identificacao do gene de MβL seguido de sequenciamento de DNA. Todos as isolados produtores de IMP foram avaliados para a presenca de integrons de c1asse 1. A similaridade genetica dos isolados produtores de MβL foram avaliados pelo PFGE. Entre os 120 isolados de P. aeruginosa, 46 (38,1 por cento) foram capazes de hidrolizar imipenem. 0 sequenciamento dos amplicons demonstrou que 20 por cento dos 80 por cento dos isolados de P. aeruginosa carreavam blaIMP-1 e blaSPM-1, respectivamente. Todos os isolados produtores de IMP-1 pertenciam ao mesmo clone, enquanto os isolados produtores de SPM-1 apresentaram uma grande diversidade genetica. A analise dos dados c1inicos dos pacientes que apresentaram infeccao por P. aeruginosa mostrou que a urina parece ter um papel importante na aquisicao de P. aeruginosa resistentes a carbapenemicos no Hospital São Paulo e que o uso previa de carbapenemicos e um fator de risco importante na aquisicao de amostras produtoras de MI3L. Os dados sugerem que as medidas de prevencao de disseminacao de P. aeruginosa carreadoras de MβL no Hospital São Paulo no ano de 2004 foram ineficazes / At Hospital São Paulo, a 600-bed tertiary care university hospital, the presence of metallo-β-lactamase producing P. aeruginosa has been detected since 2000 (the first strain, a SPM producer, was isolated in 1997). During the 2000-2001 period, 25 of 183 evaluated strains produced SPM or IMP (88% and 12% of the imipenem-resistant P. aeruginosa, respectively). During 2004, the 10 first consecutive imipenem resistant P. aeruginosa strains isolated monthly were screened for the production of MβL. A total of 120 isolates were submitted to hydrolysis test against imipenem, PCR for described MßL genes, and DNA sequencing. IMP-producing isolates were further evaluated with primers targeting class 1 integrons. The genetic relatedness of MßL-producing isolates was evaluated by PFGE. Among the 120 P. aeruginosa isolates, 46 (38,1%) were able to hydrolyze imipenem. Sequencing of the amplicons showed that 20% and 80% of the P. aeruginosa isolates carried blaIMP-1 and blaSPM-1, respectively. All IMP-1-producingisolates belonged to the same genotype, while the SPM-1-producing isolates showed a great genetic diversity. Analysis of the clinical data of patients with P. aeruginosa infections reveals that the urinary site seems to be important in the acquisition of carbapenem-resistant P. aeruginosa at Hospital São Paulo and that the previous use of carbapenens is an important risk factor for the acquisition of MßL-producing strains. These data show that the nosocomial infection control measures for prevention of dissemination of P. aeruginosa carring MßL in patients hospitalized at Hospital São Paulo in 2004 were not effective. / BV UNIFESP: Teses e dissertações

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