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Bacteremias por Staphylococcus aureus meticilina resistentes em um hospital terciário : análise clínica, microbiológica e molecularCechinel, Angélica Bauer January 2014 (has links)
Introdução: Staphylococcus aureus é um patógeno que causa uma variedade de infecções nosocomiais e comunitárias. Bacteremia por Staphylococcus aureus meticilina resistente (MRSA) está associada com uma elevada morbidade e mortalidade. Alguns autores consideram uma maior taxa de mortalidade em bacteremia por MRSA em comparação aos observados em bacteremia causada por Staphylococcus aureus sensível a meticilina. O uso da vancomicina no tratamento de infecções por MRSA tem estado sobre crescente vigilância nos últimos anos, já que existe uma grande preocupação sobre a redução de sua eficácia no tratamento de pacientes com bacteremia por MRSA. Estudos sugerem que a vancomicina tem atividade reduzida contra infecções por MRSA quando os valores da concentração inibitória mínima (CIM) se aproximam do valor máximo considerável como susceptível. O locus (acessory gene regulator) regula a expressão de vários genes de virulência, de aderência e produção de biofilme, e pode estar envolvido com a diminuição da sensibilidade a vancomicina. O staphylococcal cassette chromosome (SCCmec) carreia o gene mecA que caracteriza o fenótipo clássico de MRSA e confere resistência aos antibióticos β-lactâmicos. Objetivos: Avaliar as CIMs dos antibióticos: vancomicina, por microdiluição em caldo, e daptomicina, linezolida, tigeciclina e quinopristina/dalfopristina e teicoplanina pela metodologia de Etest®; caracterizar o polimorfismo do locus agr e os tipos de SCCmec de isolados de MRSA de pacientes internados em um hospital, terciário e acadêmico, no sul do Brasil. Métodos: Estudo retrospectivo de coorte no qual foram avaliados todos os episódios de bacteremia causada por MRSA nos Centros de Terapia Intensiva (CTIs) durante o período de junho de 2009 a dezembro de 2011. A detecção dos grupos agr (agr tipo I, II, III e IV) e SCCmec (SCCmec I, II, III, IV e V) foi realizada a partir da técnica da reação em cadeia da polimerase (PCR). Resultados: Foram incluídos no total 21 pacientes. Os isolados de MRSA testados se apresentaram sensíveis a todos os antibióticos testados. O locus agr foi determinado em todos os isolados, sendo que onze pertencem ao grupo agr I (52,4%) e dez ao grupo agr II (27,6%). Já a caracterização dos tipos de SCCmec, não foi possível para onze isolados; para o restante, foi encontrado dois isolados SCCmec tipo I, cinco SCCmec tipo III e três SCCmec tipo IV. Conclusão: Apesar do pequeno número de pacientes e da necessidade de maiores estudos em nosso meio, nossos resultados sugerem que a vancomicina continua a ser a primeira opção de escolha para o tratamento de infecções por MRSA, como recomendado pela Infectious Diseases Society of America. No entanto, a publicação de uma série de estudos sugerindo a susceptibilidade reduzida à vancomicina, mesmo com CIMs próximas ou no ponte de corte, a terapia com vancomicina não seria recomendada a estes pacientes, sendo necessário a avaliação de um novo esquema terapêutico. / Background: Staphylococcus aureus is a versatile pathogen that cause a variety of nosocomial and community infections. Bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) is associated with high morbidity and mortality. Some authors consider a higher rate of mortality in MRSA bacteremia compared to those observed in bacteremia caused by methicillin-sensitive Staphylococcus aureus. The use of vancomycin to treat infection due to MRSA has been under increased vigilance in recent years, since there is great concern about reducing their effectiveness in treating patients with MRSA bacteremia. Studies suggest that reduced activity against vancomycin has MRSA when the values of the minimum inhibitory concentration (MIC) approach the upper end of the range of susceptibility. The agr locus (acessory regulator gene) and regulates the expression of several virulence genes, adherence and biofilm production and can be involved in reduced sensitivity to vancomycin. The staphylococcal cassette chromosome (SCCmec) carries the mecA gene that characterizes the classic phenotype of MRSA and confers resistance to β-lactam antibiotics. Objectives: Evaluate MICs of antibiotics: vancomycin, by broth microdilution, and daptomycin, linezolid, tigecycline and quinopristina / dalfopristin and teicoplanin by Etest® methodology; characterize the polymorphism of the agr locus and SCCmec types of MRSA isolates from patients in a hospital, tertiary and academic, in southern Brazil. Methods: A retrospective cohort study which evaluated all episodes of bacteremia caused by MRSA in intensive care units (ICUs) during the period June 2009 to December 2011. The detection of agr groups (agr type I, II, III and IV) and SCCmec (SCCmec I, II, III, IV and V) were performed using the technique of polymerase chain reaction (PCR). Results: We included a total twenty one patients. The MRSA isolates tested were susceptible to all antibiotics tested. The agr locus was determined in all isolates, eleven belong to agr group I (52.4%) and ten to agr group II (27.6%). Already characterization of SCCmec types, it was not possible to eleven isolates; for the remaining two isolates found was SCCmec type I, five SCCmec type III and three SCCmec type IV. Conclusions: Despite the small number of patients and the need for further studies in this area, our results suggest that vancomycin remains the first choice option for the treatment of MRSA infections, as recommended by the Infectious Diseases Society of America. However, the publication of a series of studies suggesting reduced susceptibility to vancomycin, even with MICs near or on cut off, with vancomycin therapy would not be recommended for these patients, the evaluation of a new regimen is necessary.
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Uso de clorexidina e vancomicina na inibiÃÃo de streptococcus mutans salivares em crianÃas com cÃrie: um ensaio clÃnico duplo-cego, randomizado / Use of chlorhexidine and vancomycin in inhibition of Mutans streptococci in children with dental caries: a clinical trial, double-blind, randomizedPatrÃcia Leal Dantas Lobo 05 February 2007 (has links)
CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Objetivo: Comparar a eficÃcia de quatro diferentes substÃncias: clorexidina 1%, vancomicina 3%, vancomicina 10% e fluoreto de sÃdio 1,23%, na reduÃÃo de Streptococcus mutans (SM) em crianÃas com cÃrie.
MÃtodos: Setenta e uma crianÃas, entre 4 e 8 anos de idade, foram distribuÃdas aleatoriamente em quatro grupos. Os antimicrobianos foram manipulados na forma de gel e aplicados, durante seis dias consecutivos, por meio de moldeiras individuais previamente confeccionadas. Foi coletada saliva antes do inÃcio do tratamento (D1), apÃs seis dias (D6), apÃs quinze dias (D15) e apÃs trinta dias do inÃcio das aplicaÃÃes (D30). Para anÃlise microbiolÃgica as amostras foram cultivadas sobre Agar MSB, incubadas em estufa a 37oC, com atmosfera de microaerofilia, durante 48 horas. As contagens das colÃnias foram entÃo realizadas e confirmadas a partir de provas bioquÃmicas, expressa em Unidades Formadoras de ColÃnias (UFC)/mL.
Resultados: Quando comparado D6 com D1 encontramos os seguintes resultados: Vancomicina 10% (p = 0,0008) e clorexidina (p = 0,0001) expressaram as menores contagens bacterianas. Comparando D30 com D1: flÃor e clorexidina demonstraram um retorno aos valores iniciais encontrados em D1; enquanto a vancomicina 3% (p = 0,004) e 10% (p = 0,003) tiveram significativo aumento nas contagens bacterianas. No D6, vancomicina 10% (p = 0,0001) e clorexidina (p = 0,000) expressaram menores contagens que o flÃor (Teste Mann-Whitney ), com nenhuma diferenÃa entre ambos os grupos (p = 0,24).
ConclusÃes: No presente trabalho apÃs 6 dias consecutivos de administraÃÃo tÃpica, a clorexidina gel a 1% demonstrou-se tÃo eficaz quanto a vancomicina gel a 10% na reduÃÃo de SM salivares em crianÃas com cÃrie. O fluoreto de sÃdio a 1,23 % e a vancomicina a 3%, entretanto, demonstraram-se igualmente ineficazes. Em conclusÃo, o uso da clorexidina na forma de gel a 1%, por 10 minutos, durante seis dias consecutivos demonstrou grande eficÃcia na reduÃÃo de SM salivares em crianÃas com cÃrie, nÃo tendo ocasionado, apÃs 30 dias, contagens bacteriolÃgicas superiores Ãs observadas inicialmente. / Aim: Compare the effectiveness of four different substances, e.g., 1% chlorhexidine, 3% vancomycin, 10% vancomycin and 1,23 % sodium fluoride, in the reduction of Mutans streptococci (MS) in children with dental caries.
Methods: Seventy one children, with ages between 4 and 8 years, were randomly assigned to one of four groups. The antimicrobial agents were prepared as gels and applied during 6 consecutive days, in previously fabricated custom trays. Saliva samples were collected before treatment application (D1), on the last day of treatment (D6), 15 (D15) and 30 days from day 1 (D30). For microbiological analysis samples were placed on MSB Agar medium, incubated at 37o C, under microaerophilic condition for 48 hours and then reading was performed in order to identify number of colony forming units (CFU)/mL.
Results: When comparing D6 and D1 the following results were observed: Vancomycin 10% (p = 0.0008) and Chlorhexidine (p = 0.0001) expressed significantly lower bacterial counts. Comparisons between D30 and D1 revealed that Fluoride and Chlorhexidine demonstrated a return to baseline values (D1), while Vancomycin 3% (p = 0.004) and 10% (p = 0.003) generated significantly higher counts in D30 than baseline. At D6 Vancomycin 10% (p = 0.0001) and Chlorhexidine (p = 0.000) expressed the lowest bacterial counts when compared to Fluoride (Mann-Whitney test), with no statistically significant difference between these two groups (p = 0.24) being observed.
Conclusions: In the present study, after 6 consecutive days of topical administration, 1% Chlorhexidine gel demonstrated to be as effective as 10% Vancomycin gel in salivary MS reduction in children with dental caries. However, 1.23% Sodium Fluoride and 3% Vancomycin gel demonstrated to be equally ineffective. In conclusion, the use of a 1% Chlorhexidine gel during 10 minutes, for 6 consecutive days demonstrated a great efficacy in salivary MS reduction in children with caries, not leading to bacterial counts higher than what was initially observed.
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Farmacocinética da vancomicina em pacientes no período pós-operatório cardíaco / Vancomycin pharmacokinetics in patients during the cardiac post operative periodCarla Viotto Belli 28 July 2000 (has links)
Investigaram-se 108 pacientes, entre 20 a 85 anos, com internação no pós-operatório em unidades de recuperação cardíaca. Pacientes submetidos a procedimentos cirúrgicos e portadores de quadros infecciosos diversos - broncopneumonia, endocardite, mediastinite e sepse - causados por agentes etiológicos sensíveis à terapia com vancomicina, foram selecionados para este estudo retrospectivo. A vancomicina é um antibiótico muito utilizado, principalmente na terapia de infecções hospitalares graves, predominantemente causadas por Staphylococcus aureus, microorganismo gram positivo resistente à meticilina e oxacilina. Na primeira fase do estudo realizou-se o desenvolvimento e validação da metodologia analítica para dosagem das concentrações plasmáticas da vancomicina pela técnica de cromatografia líquida de alta eficiência (CLAE). O método consiste em simples purificação das amostras biológicas em acetonitrila e detecção em ultravioleta (UV 230 nm). Empregou-se, para a quantificação do fármaco, coluna analítica Shimpack® CLC-ODS, 150 x 6 mm, 5 µm e fase móvel constituída por tampão fosfato 0,05 M, pH 4,5, metanol e acetonitrila, na proporção 80:15:5, pH da fase móvel entre 4,0-4,5, em sistema isocrático de diluição, fluxo 0,8 ml/minuto. Solução metanólica de b-etil-hidroxiteofilina foi utilizada como padrão interno no ensaio. Na fase seguinte da investigação, coletaram-se 2 amostras de sangue de cada paciente, em níveis de pico (Css MÁX), 2 horas após o início da infusão e vale (Css MÍN), imediatamente antes da infusão subsequente, na terapia de manutenção - \"steady state\". As concentrações plasmáticas da vancomicina foram determinadas e utilizadas para estimativa dos parâmetros farmacocinéticos, por meio de modelagem cinética monocompartimental. Determinou-se a meia-vida biológica de eliminação (t(1/2)b) pelo método gráfico e calcularam-se a depuração plasmática ou ?clearance? total (ClT) e o volume de distribuição (Vd) do fármaco no organismo. Estimou-se o índice de acúmulo da vancomicina, pela razão vale/pico (V/P). Efetuou-se, na última etapa do protocolo, o estudo comparativo da cinética da vancomicina, com a população dividida em grupos, classificados de acordo com a idade, função renal, tipo de infecção e dose total diária. Utilizou-se a estatística não paramétrica para análise de significância (teste de Kruskall Wallis). A função renal é o fator determinante da farmacocinética da vancomicina e das doses da antibioticoterapia, sendo responsável pelo acúmulo do fármaco em pacientes no pós-operatório cardíaco. Idade e tipo de infecção não demonstram influência significativa na disposição cinética da vancomicina nos indivíduos estudados. / In this study, 108 patients were investigated, aged 20 to 85 years old, admitted in the intensive care units during the post-operative period. Patients submitted to surgical procedures and with several infectious - bronchopneumonia, endocarditis, mediastinitis, and sepsis - caused by agents sensitive to vancomycin therapy, were selected for this retrospective study. The vancomycin is a widely prescribed antibiotic, mainly for therapy of serious hospital infections caused by Staphylococcus aureus, gram positive microorganism resistant to meticilin and oxacilin. Firstly, the analytic methodology was developed and validated for dosage of the vancomycin plasmatic concentrations by the technique of high efficiency liquid chromatography (HPLC). The method consists of biological samples simple purification in acetonitrile and detection in ultraviolet (UV 230 nm). It was used for quantification of the drug analytical column Shimpack® CLC-ODS, 150 x 6 mm, 5 mm and mobile phase constituted by phosphate buffer 0,05 M, pH 4,5, methanol and acetonitrile, proportion 80:15:5, mobile phase pH 4,0-4,5, in isocratic dilution system, flow 0,8 ml/min. Solution of b-ethil-hydroxitheophylline in methanol was used as internal standard. In the following investigation phase, 2 blood samples from each patient were collected, at peak levels (Css MÁX - 2 hours after the infusion beginning), and at trough (Css MÍN - immediately before the subsequent infusion) in the maintenance therapy - steady state. Plasmatic vancomycin concentrations were used to estimate pharmacokinetics parameters, by monocompartimental kinetic model. Biological half-life of elimination (t(1/2)b) was determined by graphic method. The plasmatic purification or total clearance (ClT) and drug distribution volume (Vd) in the organism were calculated. It was estimated the vancomycin accumulation index, the reason trough/peak (V/P). Comparative study of vancomycin kinetics was performed with groups of patients, classified according to their age, renal function, infection type and daily total dose. Non parametric statistic were used for significancy analysis (Kruskall Wallis test). Renal function is a decisive factor of the vancomycin kinetics disposition and therapy doses, being responsible for drug accumulation in cardiac post-operative patients. Age and infection type did not demonstrate significant influence in the vancomycin pharmacokinetics in this study.
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Farmacovigilância: monitorização intensiva de vancomicina em pacientes hospitalizados / Pharmacovigilance: intensive monitoring of vancomycin in hospitalized patientsMaira Umezaki de Queiroz Netto 17 August 2010 (has links)
Os eventos adversos, devido à grande ocorrência, são considerados um importante problema de saúde pública além de elevarem os custos com a saúde. Dessa forma, existe a necessidade de um sistema eficiente de farmacovigilância para prevení-los sendo a monitorização intensiva uma excelente estratégia para se alcançar este objetivo, pois permite a identificação e o conhecimento dos eventos adversos, além de medir sua incidência e melhorar as notificações voluntárias. Por esta razão, o presente estudo propôs a avaliação deste método em eventos adversos relacionados ao antimicrobiano vancomicina. As informações coletadas, provenientes dos bancos de dados e dos prontuários do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP-USP), são referentes aos pacientes internados no hospital em tratamento com vancomicina no período de 01/09/2008 a 31/08/2009. Identificou-se 1719 tratamentos de 1302 usuários. Destes tratamentos, 521 foram excluídos por serem profiláticos. A idade média dos 1198 pacientes monitorados foi de 39,33 (± 27,66) anos e 58,68% pertenciam ao gênero masculino. Os diagnósticos infecciosos prevalentes para o tratamento com vancomicina foram pneumonia (18,95%), sepse (11,19%) e infecção relacionada a cateter (10,27%) com período médio de duração do tratamento de 11,47 (±7,79) dias geralmente na dose de 2000 mg ao dia (35,98%). Foram identificados indicadores de eventos adversos em 85,81% dos tratamentos, sendo a incidência de eventos adversos de 7,18%. A incidência de reações adversas (RAM) foi de 5,93% e de erros de medicação 2,57%. A causalidade das RAM foi prevalentemente provável (49,29%) e a gravidade moderada (54,93%). As RAM foram essencialmente do tipo B (81,69%) e os erros de medicação relativos à prescrição (87,10%). A comparação entre os grupos controle e estudo não apresentou diferenças significativas, demonstrando a necessidade de monitorização de todos os parâmetros relacionados a eventos adversos com a vancomicina. Dessa forma, fica evidente a importância da monitorização intensiva e da presença dos farmacêuticos clínicos na equipe de saúde para melhorar a eficiência da farmacovigilância, como demonstrado por este estudo. Diante dos resultados, conclui-se que o método de monitorização intensiva utilizando base de dados e prontuários, além da participação de um farmacêutico clínico, promove o conhecimento, a avaliação e a compreensão dos eventos adversos presentes em uma instituição, permitindo a esquematização de estratégias para a sua prevenção. / Adverse events, due to the high occurrence, are considered an important public health problem in addition to driving up health care costs. There is therefore a need for an efficient system of pharmacovigilance to prevent them being the intensive monitoring an excellent strategy for achieving this goal because it allows the identification and knowledge of the adverse events, in addition to measuring its incidence and improve spontaneous reports. For this reason, the present study evaluated this method in adverse events related to antibiotic vancomycin. The informations collected from databases and records of the Hospital of the Medical School of Ribeirão Preto-SP (USP-HCFMRP), refers to hospital patients treated with vancomycin for the period 01/09/2008 to 31/08/2009. We evaluated 1719 treatments in 1302 users, of which 521 were excluded because they were prophylactic. The average age of 1198 patients was 39.33 years (±27.66) and 58.68% were males. Prevalent infectious diagnoses for treatment with vancomycin were pneumonia (18.95%), sepsis (11.19%) and catheter-related infection (10.27%) with mean duration of treatment of 11.47 days (± 7.79) usually at a dose of 2000 mg daily (35.98%). We identified indicators of adverse events in 85.81% of treatments, and the incidence of adverse events was 7.18%. The adverse drug reactions (ADR) incidence was 5.93% and 2.57% of medication errors. The causality of ADR was probable (49.29%) and severity was moderate (54.93%). The ADR were mainly of type B (81.69%) and medication errors related to prescription (87.10%). Comparisons between the study and control groups showed no significant differences, demonstrating the need for monitoring of all parameters related to adverse events with vancomycin. Thus, it is clear the importance of the intensive monitoring and the presence of clinical pharmacists in the health team to improve the efficiency of pharmacovigilance, as demonstrated by this study. Before the results, we conclude that the method of intensive monitoring using the database and records, plus the involvement of a clinical pharmacist, promotes knowledge, assessment and understanding of adverse events presents in an institution, enabling the layout of strategies to prevention.
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O papel da monitorização das concentrações de vancomicina e amicacina no plasma e no dialisato de pacientes com peritonite associada à diálise peritonealReis, Pâmela Falbo January 2020 (has links)
Orientador: Daniela Ponce / Resumo: Introdução: Peritonite é complicação grave nos pacientes em diálise peritoneal (DP) e a principal causa de transição para hemodiálise. O uso intraperitoneal (IP) de aminoglicosídeo e vancomicina é opção para o tratamento empírico. No entanto, a absorção sistêmica dessas drogas é controversa e pouco estudada. Objetivo: Descrever os níveis plasmáticos e do dialisato de amicacina e vancomicina administrados IP em pacientes com peritonite em DP nos momentos de 30 e 120 min após administração, após 24h da administração da amicacina e 48h da vancomicina e associá-los com o desfecho da peritonite. Metodologia: Estudo observacional realizado de novembro/2017 a abril/2019, que incluiu 32 episódios de peritonites. Análise de amostras foi realizada no 1º, 3º e 5º dias. No momento de pico, foram consideradas concentrações terapêuticas de amicacina valores entre 25 e 35 mg/L e no vale (antes da infusão do dialisato) concentrações de 4-8 mg/L ; e de vancomicina no vale de 15–20 mg/L. Resultados: A idade foi de 60 ± 11,3 anos, a principal causa da doença renal foi diabetes (42,4%) e 63,3% eram homens. Entre as culturas 39,4% foram gram negativos, 36,3% gram positivos e 21,2% negativas. Houve cura em 84,8% dos episódios. Vancomicina foi administrada IP a cada 72h e amicacina diariamente. Avaliando-se os períodos antes e depois da peritonite, não houve mudanças no tipo de transporte peritoneal (p=0,76), mas houve diferenças na função renal residual (p=0,05) e redução do débito urinário (p=0,0... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Peritonitis is a serious complication in patients on peritoneal dialysis and the main cause of transition to hemodialysis. The intraperitoneal use of aminoglycoside and vancomycin is an option for empiric treatment. However, the systemic absorption of these drugs is controversial and little studied. Objectives: Describe intraperitoneal amikacin and vancomycin dialysate levels in patients with peritonitis on peritoneal dialysis at 30 and 120 minutes after administration, 48 hours after vancomycin and 24 hours after amikacin and associating them with the peritonitis outcome. Methodology: Observational study conducted from August 2017 to April 2019, which included 32 episodes of peritonitis. Samples were analyzed on the 1st, 3rd and 5th days. At peak moment, therapeutic concentrations of amikacin were considered to be between 25 and 35 mg/L and at baseline concentrations of 4-8 mg/L; and vancomycin at the valley moment of 15-20 mg/L. Results: Age was 60 ± 11.3 years, the main cause of kidney disease was diabetes (42.4%) and 63.3% were men. Among the cultures 39.4% were gram negative, 36.3% gram positive and 21.2% negative. There was cure in 84.8% of the episodes. Vancomycin was administered intraperitoneal every 72 hours and amikacin daily. There were no changes in the peritoneal transport type (p = 0.76), but there were differences in residual renal function (p = 0.05) and reduction in urinary output (p = 0.02). Regarding the outcomes of cure and non-cure, there w... (Complete abstract click electronic access below) / Mestre
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Pharmacokinetic modeling of vancomycin in children, pre-adolescent, and adolescent patients : development, assessment, and applicationAsiri, Yousif Abdu 01 January 1998 (has links) (PDF)
The development and evaluation of a vancomycin population pharmacokinetic model in children, pre-adolescent, and adolescent patients was performed via non linear mixed effects modeling (NONMEM) in 2 phases. In phase I, a vancomycin population pharmacokinetic model was developed based on data from 200 children (aged 2-17 years) using a two-compartment model. Variables tested for inclusion in the model were serum creatinine (SCR), age (AGE), weight (WT), height (HT), sex (SEX), and body surface area (BSA). Variables were included at the p $
In phase II, the performance of the derived model was evaluated in a naive tested population and then compared to the Schaad, et al. model via prediction error techniques (PE). The predictability of 159 measured concentrations was assessed in 68 new patients. In predicting all concentrations types, the mean prediction error (MPE) with a 95% confidence interval (CI) for both the current study model and Schaad, et al model were: $-$1.42 ($-$3.38, 0.54), and 6.01 (4.46, 7.56) mg/L, respectively. When considering only peaks, a MPE with 95% CI were 1.72 ($-$0.94, 4.38), and 7.61 (5.13, 10.09) mg/L, respectively. Finally, MPE with 95% CI for the troughs were $-$1.45 ($-$3.42, 0.52), and 3.84 (2.98, 4.70) mg/L, respectively.
Maintenance dose (MD) tables were designed, based on the relationship of height and serum creatinine to clearance. In addition, a loading dose (LD) was also recommended, which was 5 mg/cm. It is recommended that the current study model be used for dosing the pediatric population while setting an initial target peak of 30 mg/L and a trough of 5-10 mg/L. This should frequently result in optimal serum vancomycin concentrations within the therapeutic window. Individualization of therapy should then be done, once the measured concentrations are available.
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Synthesis and Evaluation of Radiopharmaceuticals for Imaging Bacterial InfectionBeiraghi, Omid January 2016 (has links)
Despite recent advances, radiopharmaceuticals to detect and characterize bacterial infections have a number of limitations. Many of the clinically approved radiopharmaceutical agents are not specific to bacterial infections and accumulate at lesions of inflammation. Hence, new approaches are necessary to detect bacteria with high specificity and selectivity. A library of desferrioxamine B (DFO) derivatives were prepared to create radiolabeled siderophores to create a bacteria-specific imaging probe by exploiting the mechanism bacteria use to scavenge iron, which plays a key role in bacterial growth and biofilm formation Compounds were synthesized using two convenient carbamate forming strategies in 30% to 92% yield. The cold and radioactive gallium (67Ga) complexes were prepared and characterized and their uptake by S. aureus bacteria were assessed in vitro and in vivo. In vivo studies revealed that 67GaDFOethoxycarbamate had uptake comparable to GaDFO that was blockable, showing the compound was actively taken up via the siderophore pathway. In vivo studies in a mouse model resulted in a good infected to non-infected thigh ratio (11:1) and non-specific uptake by the GI tract.
Bioorthogonal chemistry was also explored as an approach for imaging infection using trans-cyclooctene (TCO) functionalized vancomycin and a tetrazine functionalized 67GaDFO (67GaDFO-Tz) complex.2,3 In vitro results revealed that allowing vancomycin-TCO to bind S. aureus prior to the addition of 67GaDFO-Tz (pretargeting) showed higher (63%) uptake than with a conjugate formed prior to incubation with the bacteria (direct targeting, 28%). For the bioorthogonal approach, the distribution of the 67GaDFO-Tz was assessed in a S. aureus infection murine model, which showed significant uptake of 67GaDFO-Tz in the GI tract 1 h post intravenous injection. However, uptake in the infected joint was evident at 71 h post infection. The data suggests targeting bacteria using TCO-labeled antibiotics and radiolabeled tetrazines is a feasible strategy, but that further optimization of the vancomycin injection dose and injection time are necessary. / Thesis / Master of Science (MSc)
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STUDIES TOWARDS THE TOTAL SYNTHESIS OF VANCOMYCIN AGLYCONBasu, Shubhamita 03 July 2007 (has links)
No description available.
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Studies Towards the Total Synthesis of Ristocetin A and Orienticin C AglyconesCiurea, Diana Victoria January 2008 (has links)
No description available.
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Evading Glycopeptide Antibiotic ResistanceBack, Jason 04 1900 (has links)
<p> Glycopeptide Antibiotics (GPAs) such as vancomycin are often used clinically as antibiotics of last resort against infections due to Gram-positive bacteria that are resistant to more commonly used antibiotics such as methicillin. The clinical emergence of vancomycin resistant enterococci (VRE) and vancomycin resistantS. aureus (VRSA) necessitates methods to evade this resistance. </p> <p> GP As consist ofa heptapeptide backbone that is cross-linked to create a pocket that binds the D-Alanyl-D-Alanine terminus of peptidoglycan intermediates, inhibiting strengthening ofthe cell wall and resulting in susceptibility to osmotic stress. Resistance to GPAs occurs when D-Ala-D-Lactate replaces D-Ala-D-Ala and the GPA pocket can no longer bind effectively. In order to create novel binding pockets, we must understand the specificity ofthe P450 monooxygenase enzymes that have been shown to catalyze the cross-links. The 4 P450-encoding genes ofthe GPA A47934 biosynthetic cluster of Streptomyces toyocaensis as well as genes encoding electron transport proteins necessary for P450 function from Streptomyces coelicolor were cloned in Escherichia coli for heterologous expression and characterization. One P450, StaJ was purified and shown to bind CO as expected using spectrophotometric tests. </p> <p> The genes responsible for GP A resistance are regulated by a two component regulatory system consisting ofa sensor kinase (VanS) and a response regulator (V an.R). In order to probe the events leading to VanS autophosphorylation and ultimately resistance activation we utilize a series of GP A derivatives harbouring the photo labile group benzophenone as well as the fluorescent and affinity moieties BODIPY and biotin. Benzophenone permits light controlled covalent binding of the GP A to proteins that bind them while BODIPY allows fluorescence detection and biotin allows enrichment and detection by Western analysis. We report that this system was insufficient to clearly identify vancomycin binding proteins due to background signals despite multiple rounds of troubleshooting. It must be our conclusion that under the conditions tested, there are no proteins that bind the GP A derivative used in this study. </p> / Thesis / Master of Science (MSc)
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