No description available.

No description available.

The purpose of this study was to investigate the prevalence and mechanisms of extended-spectrum cephalosporin- (ESC) and carbapenem-resistance in Escherichia coli from the GTA. A total of 526 non-duplicate E. coli clinical isolates were collected during March 1-5, 2010 from 13 participant hospitals. Among these, 71 isolates showed reduced susceptibility (rS, intermediate, and/or resistant phenotype) to cefoxitin (FOX) and/or ESC. No carbapenem resistance was detected. Extended-spectrum ß-lactamase genes detected (n=37; 52.1%) belong to the CTX-M-family, including blaCTX-M-15 (78.4%), blaCTX-M-23 (2.7%), blaCTX-M-14 (18.9%). The only plasmid-mediated ampC gene identified among FOXrS isolates (n=49; 69%) was blaCMY-2 (n=7; 14.3%). Seventeen strains (24%) were negative for all ß-lactamase genes tested. Analysis of the chromosomal ampC promoter revealed mutations associated with AmpC hyperproduction. Other mechanisms of resistance (e.g. impermeability and/or unidentified ß-lactamases) cannot be discarded. The most prevalent clone detected was ST131. IncFIA, FIB and Frep were the most common plasmid replicon types detected.

The purpose of this study was to investigate the prevalence and mechanisms of extended-spectrum cephalosporin- (ESC) and carbapenem-resistance in Escherichia coli from the GTA. A total of 526 non-duplicate E. coli clinical isolates were collected during March 1-5, 2010 from 13 participant hospitals. Among these, 71 isolates showed reduced susceptibility (rS, intermediate, and/or resistant phenotype) to cefoxitin (FOX) and/or ESC. No carbapenem resistance was detected. Extended-spectrum ß-lactamase genes detected (n=37; 52.1%) belong to the CTX-M-family, including blaCTX-M-15 (78.4%), blaCTX-M-23 (2.7%), blaCTX-M-14 (18.9%). The only plasmid-mediated ampC gene identified among FOXrS isolates (n=49; 69%) was blaCMY-2 (n=7; 14.3%). Seventeen strains (24%) were negative for all ß-lactamase genes tested. Analysis of the chromosomal ampC promoter revealed mutations associated with AmpC hyperproduction. Other mechanisms of resistance (e.g. impermeability and/or unidentified ß-lactamases) cannot be discarded. The most prevalent clone detected was ST131. IncFIA, FIB and Frep were the most common plasmid replicon types detected.

Orientador: Maria Lucia Gonsales da Costa Araujo / Banca: Oswaldo Garcia Junior / Banca: Alberto Colli Baldino Junior / Resumo: Os grupos de antibióticos mais importantes clinicamente são os dos b-lactâmicos, aminoglicosídeos e tetraciclinas. Streptomyces clavuligerus produz vários compostos b- lactâmicos, com destaque para os antibióticos envolvidos na rota biossintética da cefalosporina C (penicilina N, deacetoxicefalosporina C e cefamicina C) e o ácido clavulânico (AC) que, embora não tenha atividade biológica significativa, é um potente inibidor de b-lactamases (penicilinases e cefalosporinases). A cefamicina C (CefC) é uma 7-metoxi-cefalosporina que apresenta maior atividade que a cefalosporina C (CPC), produzida somente por fungos, por ser resistente a b-lactamases. Apesar das rotas biossintéticas de AC e CefC serem completamente independentes em S. clavuligerus, são controladas pelo mesmo elemento multifuncional (ccaR), o que dificulta a indução da produção de um ou outro composto durante o processo fermentativo. No presente trabalho, procurou-se obter maiores concentrações de CefC manipulando-se componentes em meio solúvel de cultivo de S. clavuligerus, selecionados dentre compostos que, segundo a literatura, atuam como agentes reguladores da síntese daquele antibiótico. As fermentações foram realizadas em frascos agitados (28ºC, 260 rpm) para selecionar fontes de C e de N e, então, avaliar o processo no melhor meio-padrão, variando-se concentrações combinadas de L-lisina (10 a 108 mM) e -cetoglutarato (3 a 110 mM) através de metodologia de planejamento experimental. A presença de -cetoglutarato acarretou em aumento indesejável de pH, afetando negativamente o processo e os melhores resultados (entre 300 e 400 mg CPC totais/L após 72 horas de fermentação) foram obtidos no meio adotado como meio-controle, contendo amido e extrato protéico de semente de algodão como principais fontes de C e N, respectivamente, e L-lisina. / Abstract: The most important groups of antibiotics, from a clinical standpoint, are -lactams, aminoglycosides and tetracyclines. Streptomyces clavuligerus produces several -lactam compounds, primarily the antibiotics involved in the biosynthetic route of cephalosporin C (penicillin N, deacetoxycephalosporin C and cephamycin C) and clavulanic acid (CA), which, despite its slight biological activity, is a potent inhibitor of -lactamases (penicillinases and cephalosporinases). Cephamycin C (CMC) is a 7-methoxycephalosporin with higher bioactivity than cephalosporin C (CPC) because it is more resistant to -lactamases. Although the biosynthetic routes of CA and CMC are completely independent in S. clavuligerus, they are controlled by a common multi-functional element (ccaR), which hinders induction of the production of one or the other compound during the fermentation process. In this work, we sought to obtain higher concentrations of CMC by handling compounds in a soluble medium of S. clavuligerus, which were selected from compounds that, according to the literature, act as regulating agents in the synthesis of that antibiotic. Fermentation was carried out in flasks under shaking (28ºC, 260 rpm), in order to select sources of C and N. The process was then evaluated in the best standard medium, by varying combined concentrations of lysine (10 to 108 mM) and -ketoglutarate (3 to 110 mM) using an experimental planning methodology. The presence of -ketoglutarate caused an undesirable increase in pH, negatively affecting the process. The best results (between 300 and 400 mg/L of total CPC after 72 h of fermentation) were obtained in the medium used as the control, which contained starch and cottonseed protein extract as main sources, respectively, of C and N, and L-lysine. / Mestre

Orientador: Ronilson Agnaldo Moreno / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-05T05:47:22Z (GMT). No. of bitstreams: 1 Maluly_HellenDeaBarros_M.pdf: 7988282 bytes, checksum: 2d5724c0002bc95aaec9c7de5cbd35bd (MD5) Previous issue date: 2005 / Resumo: O Objetivo deste estudo foi comparar a bioequivalência do Cefadroxil - cápsula (500mg) da Apotex do Brasil Ltda (formulação teste) and Cemmox@do Laboratório Bristol-Myers Squibb (formulação de referencia) em voluntários sadios de ambos os sexos. Este estudo foi necessário para comercialização deste medicamento. O estudo foi aleatorizado, cruzado, com dois períodos e duas seqüências (2x2) e com uma semana de intervalo entre as doses (wash out), onde os mesmos voluntários receberam, em cada período a formulação teste e a formulação de referência. A seqüência de tratamento foi determinada por uma lista de aleatorização, automaticamente produzida pela Medicines Clinical Trials Control System. As amostras de plasma foram coletadas num intervalo de 36 horas. As concentrações de Cefadroxil foram analisadas por cromatografia líquida de alta eficiência acoplada a um detector de UV-visível. A partir da curva da concentração de Cefadroxil no plasma vs tempo foram obtidos os parâmetros farmacocinéticos: 'ASC IND. 0-t¿, 'ASC IND. 0-INFINITO¿ e 'C IND. max¿. As médias geométricas de CefadroxiI / 'Cefamox MARCA REGISTRADA¿ 500 mg em porcentagem foram: 105.58% (90% CI=102.17%; 109.10%) para 'ASC IND. 0-t¿, 104.74% (90% CI= 101.55%; 108.02%), para 'ASC IND. 0-INFINITO¿ 112.08% (90% CI=10S.59%; 118.97%) para 'C IND. max¿.Sendo 90% o intervalo de confiança para 'C IND. max¿, 'ASC IND. 0-t¿, 'ASC IND. 0-INFINITO¿ estiverem entre 80-125% do intervalo proposto pela RDC 135 (ANVISA/mai 2003), conclui-se que o Cefadroxil - cápsulas (500 mg) foi bioequivalente ao Cefamox MARCA REGISTRADA¿ ,de acordo com as porcentagens e extensão da absorção / Abstract: The objective of this study is to compare the bioequivalence of Cefadroxil- capsule 500 mg ¿ formulated by Apotex of Brazil Ltda (test formulation) and Cefamox by LaboratoryBristol-Myers Squibb (reference formulation) in volunteers of both sexes. This study was necessary for the commercialization of medicines. The study was conducted with a randomized two-period crossover design (2x2) and a one-week washout period, the same volunteers received, in each period, a test formulation or a reference formulation. The treatment sequence was determined by a randomization list, automatically produced by Medicines Clinical Trials Control System. Plasma samples were obtained over a 36-hour interval. Cefadroxil concentrations were analyzed by combined high pressure liquid chromatography and UV-visible detection (HPLC-UV). From the Cefadroxil plasma concentration vs time curves the following pharmacokinetic parameters were obtained: 'AUC IND. 0-t ', 'AUC IND. 0-INFINITO¿ and 'C IND. max¿. The Geometric mean of Cefadroxil / Cefamox 500 mg for individual percentage ratio was 105.58% (90% CI=102.17%; 109.10%) for an area under the cefadroxil plasma concentration versus time curves (0-t), 104.74% (90% CI= 101.55%; 108.02%), for an area under the cefadroxil plasma concentration versus time curves ('0-INFINITO¿), and 112.08% (90% CI=105.59%; 118.97%) for maximum observed plasma concentration. Conclusion: Since 90% CI for both 'C IND. max¿, 'AUC IND. 0-t ', and 'AUC IND. 0-INFINITO¿ were within the 80-125% interval proposed by the RDC 135 (ANVISA/may 2003), it was conc1uded that Cefadroxil - capsule 500 mg was bioequivalent to Cefamox, according to both the rate and the extension of absorption / Mestrado / Mestre em Farmacologia

No description available.

Made available in DSpace on 2014-06-11T19:23:06Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-12-12Bitstream added on 2014-06-13T19:08:57Z : No. of bitstreams: 1 antonio_t_me_araiq.pdf: 609701 bytes, checksum: da17caf99f88297148973c0dd3d64e83 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Os grupos de antibióticos mais importantes clinicamente são os dos b-lactâmicos, aminoglicosídeos e tetraciclinas. Streptomyces clavuligerus produz vários compostos b- lactâmicos, com destaque para os antibióticos envolvidos na rota biossintética da cefalosporina C (penicilina N, deacetoxicefalosporina C e cefamicina C) e o ácido clavulânico (AC) que, embora não tenha atividade biológica significativa, é um potente inibidor de b-lactamases (penicilinases e cefalosporinases). A cefamicina C (CefC) é uma 7-metoxi-cefalosporina que apresenta maior atividade que a cefalosporina C (CPC), produzida somente por fungos, por ser resistente a b-lactamases. Apesar das rotas biossintéticas de AC e CefC serem completamente independentes em S. clavuligerus, são controladas pelo mesmo elemento multifuncional (ccaR), o que dificulta a indução da produção de um ou outro composto durante o processo fermentativo. No presente trabalho, procurou-se obter maiores concentrações de CefC manipulando-se componentes em meio solúvel de cultivo de S. clavuligerus, selecionados dentre compostos que, segundo a literatura, atuam como agentes reguladores da síntese daquele antibiótico. As fermentações foram realizadas em frascos agitados (28ºC, 260 rpm) para selecionar fontes de C e de N e, então, avaliar o processo no melhor meio-padrão, variando-se concentrações combinadas de L-lisina (10 a 108 mM) e -cetoglutarato (3 a 110 mM) através de metodologia de planejamento experimental. A presença de -cetoglutarato acarretou em aumento indesejável de pH, afetando negativamente o processo e os melhores resultados (entre 300 e 400 mg CPC totais/L após 72 horas de fermentação) foram obtidos no meio adotado como meio-controle, contendo amido e extrato protéico de semente de algodão como principais fontes de C e N, respectivamente, e L-lisina. / The most important groups of antibiotics, from a clinical standpoint, are -lactams, aminoglycosides and tetracyclines. Streptomyces clavuligerus produces several -lactam compounds, primarily the antibiotics involved in the biosynthetic route of cephalosporin C (penicillin N, deacetoxycephalosporin C and cephamycin C) and clavulanic acid (CA), which, despite its slight biological activity, is a potent inhibitor of -lactamases (penicillinases and cephalosporinases). Cephamycin C (CMC) is a 7-methoxycephalosporin with higher bioactivity than cephalosporin C (CPC) because it is more resistant to -lactamases. Although the biosynthetic routes of CA and CMC are completely independent in S. clavuligerus, they are controlled by a common multi-functional element (ccaR), which hinders induction of the production of one or the other compound during the fermentation process. In this work, we sought to obtain higher concentrations of CMC by handling compounds in a soluble medium of S. clavuligerus, which were selected from compounds that, according to the literature, act as regulating agents in the synthesis of that antibiotic. Fermentation was carried out in flasks under shaking (28ºC, 260 rpm), in order to select sources of C and N. The process was then evaluated in the best standard medium, by varying combined concentrations of lysine (10 to 108 mM) and -ketoglutarate (3 to 110 mM) using an experimental planning methodology. The presence of -ketoglutarate caused an undesirable increase in pH, negatively affecting the process. The best results (between 300 and 400 mg/L of total CPC after 72 h of fermentation) were obtained in the medium used as the control, which contained starch and cottonseed protein extract as main sources, respectively, of C and N, and L-lysine.

The medicare system within the Taiwanese government has been cutting public hospitals' purchasing budget on antibiotic drugs year after year, making antibiotic suppliers less profitable. This essay takes a close look at how the medicare is minimizing aitibiotic supplier's profit, and the right sales strategies needed for suppliers to survive in this hostile environment.

Bacterial resistance to antibiotics is an emerging epidemic throughout the world and there is a desperate need for new antibiotics and new strategies to maintain the effectiveness of current agents. ??-Lactams, such as the penicillins and cephalosporins, have been the most important class of antibiotic for several decades and represent half of the global antibacterial market, but the continued use of ??-lactams is threatened by ??-lactamases, enzymes that efficiently inactivate ??-lactams through hydrolysis. Class A, C, and D ??-lactamases use an active-site serine residue for hydrolysis and achieve turnover through an acylenzyme intermediate while the class B metallo-??-lactamases (MBLs) use a zinc-bound hydroxide as the active-site nucleophile. Two successful approaches to combat ??-lactamase-mediated resistance have involved the development of ??-lactam antibiotics which bind poorly to ??-lactamases and the combination of ??-lactams with ??-lactamase inhibitors. These strategies have been effective for overcoming resistance due to class A ??-lactamases, but the ever-increasing prevalence of extended-spectrum ??-lactamases (ESBLs), metallo-??-lactamases, and carbapenemases compromises the effectiveness of current penicillins, cephalosporins, carbapenems, and mechanism-based ??-lactamase inhibitors. Cyclobutanone analogues of ??-lactam antibiotics were explored in the early 1980s as potential inhibitors of ??-lactamases and D-Ala-D-Ala transpeptidases, but simple analogues showed only weak inhibitory activity and this approach was subsequently abandoned. The increasing threat of multidrug-resistant ??-lactamase-producing organisms in recent years, however, has inspired a re-evaluation of these inhibitors since cyclobutanones have the potential to exhibit broad-spectrum inhibition of both serine- and metallo-??-lactamases through the formation of enzyme-bound hemiketals or hydrates. 7,7-Dichloro-2-thia-bicyclo[3.2.0]heptan-6-one-4-carboxylic acid (65), a dichlorocyclobutanone that had shown modest inhibition of the class B and D ??-lactamases IMP-1 and OXA-10 in earlier work in this laboratory, was prepared in an efficient seven-step sequence from triethyl phosphonoacetate (103) with an overall yield of 28%. Initial efforts to improve upon the potency of the cyclobutanones involved functionalization at C3 and a highly stereoselective chlorination with sulfuryl chloride provided the 3??-chloro derivative 117?? in nearly quantitative yield. Elimination of HCl from 117?? was achieved under a variety of conditions and 3-alkoxy derivatives were prepared from 117?? through diastereoselective substitution reactions with alcohols. Cyclobutanones with 3??-OR substituents were found to favour an endo envelope conformation while the 3??-OR derivatives adopt the exo envelope conformation. Evidence from X-ray crystal structures and ab initio molecular orbital calculations suggests that an anomeric effect contributes to the large conformational preference of the tetrahydrothiophene ring that favours the 3-alkoxy substituent in an axial orientation. In addition, the conformation of the bicyclic system was found to have a dramatic effect on the tendency of the cyclobutanone to undergo hemiketal formation. Cyclobutanone analogues of penicillins, including 3-alkoxy derivatives, and cyclobutanone analogues of penems were evaluated against class A, B, C, and D ??-lactamases and found to be moderate inhibitors of KPC-2, IMP-1, GC1, and OXA-10. The cyclobutanones found to be most potent were those which are hydrated to a larger extent in aqueous solution. Dichlorocyclobutanones were found to be better inhibitors than dechlorinated cyclobutanones and a 3??-methoxy derivative 152??, which favours the exo envelope conformation in which the C4 carboxylate is equatorial, was found to be a better inhibitor than cyclobutanones that favour the endo envelope conformation. A 3,4-unsaturated penem analogue, 153, showed comparable potency to that of 152?? and molecular models of enzyme-inhibitor complexes indicate that an equatorial carboxylate is required for binding to ??-lactamases. An X-ray crystal structure of 152?? bound to the class D ??-lactamase OXA-10 confirms that a serine hemiketal is formed in the active site and that the inhibitor adopts the exo envelope. The biochemical data described above demonstrate that cyclobutanones can indeed act as inhibitors of serine- and metallo-??-lactamases and these cyclobutanones represent the first class of reversible inhibitors to show moderate inhibition of all four classes of ??-lactamase. Although the inhibitory potency of these compounds is modest (low micromolar IC50 values), penem analogue 153 was able to enhance the potency of meropenem against carbapenem-resistant MBL-producing clinical isolates of Chryseobacterium meningosepticum and Stenotrophomonas maltophilia and the synergy demonstrated in these antimicrobial assays is encouraging. Synthetic studies toward other C3-alkyl and C3-thioalkyl-substituted inhibitors are described and the design and synthesis of C7-monochloro- and 7??-hydroxymethyl-7??-chloro cyclobutanone derivatives is presented.