INTRODUÇÃO: Os aminoglicosídeos são freqüentemente usados no berçário e podem ser tóxicos para as células ciliadas cócleo-vestibulares, especialmente para as células ciliadas externas da base da cóclea. As emissões ototacústicas produto de distorção permitem avaliar porções específicas da cóclea, antes mesmo que a sensação auditiva seja alterada, sendo ideais para análise precoce da integridade dessa estrutura auditiva, além de ser indicada para recém-nascidos por serem objetivas. O objetivo deste estudo prospectivo longitudinal é pesquisar a amplitude das emissões otoacústicas produto de distorção, causadas pelo uso de drogas ototóxicas, entre o término da administração e de 15 a 40 dias após seu uso. MÉTODOS: A população foi de recém-nascidos a termo e pré-termo provenientes de berçário e maternidade de um hospital público em Santo André, no período de julho de 2003 a setembro de 2004. A primeira avaliação ocorreu no dia da alta hospitalar. Foram avaliados três grupos: grupo controle com 33 recém-nascidos saudáveis e de termo; grupo de estudo a termo exposto a amicacina e /ou vancomicina com 19 recém-nascidos com mais de 37 semanas e grupo de estudo pré-termo exposto aos mesmos ototóxicos, com 15 recém-nascidos de 32 a 37 semanas. Os recém-nascidos não apresentavam indicadores de risco para deficiência auditiva preconizados pelo JCIH,2000 concomitante à infecção neonatal. Todos os recém-nascidos foram avaliados com idade gestacional corrigida maior que 37 semanas. As amplitudes das emissões otoacústicas dos recém-nascidos em fase de alta hospitalar foram comparadas às obtidas de 15 a 40 dias após a alta. RESULTADOS: As amplitudes das emissões otoacústicas dos recém-nascidos do grupo de estudo pré-termo foram menores que as amplitudes do grupo controle e do grupo de estudo a termo nos dois momentos de teste. As amplitudes das emissões dos recém-nascidos dos três grupos aumentaram no segundo momento de teste. As amplitudes das emissões dos recém-nascidos foram maiores na freqüência de 6.000 Hz e na orelha direita para a freqüência f2 3.000 Hz. As amplitude das emissões do grupo controle no segundo momento de teste foram semelhantes as do grupo de estudo à termo no primeiro momento da pesquisa. CONCLUSÔES: Houve aumento da amplitude das emissões otoacústicas produto de distorção desde a fase de alta até 15 a 40 dias após. A exposição a amicacina e vancomicina nas doses preconizadas pelo Neofax®, 2003/2004 não alterou as amplitudes das emissões nos recém-nascidos sem indicadores de risco concomitante à infecção neonatal. / The amynoglicosides are frequently used in nurseries and may be toxic for the cochleo-vestibular hair cells, specially for the outer cells of the cochlear base. The distortion product otoacoustic emissions allow to evaluate specific portions of the cochlea even before the hearing sensation is altered, and are ideal for the early analysis of this auditory structure integrity, besides being indicated for newborns once they are objective. The aim of this prospective longitudinal study is to research the amplitude of distortion product otoacoustic emissions caused by the ototoxic drugs use, between the end of the administration and from 15 to 40 days after its use. The population studied was composed by term and preterm newborns from a nursery and maternity of a Santo André city hospital, in the period from July 2003 to September 2004. The first evaluation occurred on the hospital discharge day. Three groups were evaluated: control group with 33 term and healthy newborns; term study group with 19 term newborns with more than 37 weeks exposed to amicacin and/or vancomycin; and preterm study group with 15 preterm newborns from 32 to 37 weeks exposed to the same ototoxic. The newborns did not present risk factors for hearing loss according to the JCIH, 2000 concomitant to the neonatal infection. All newborns were evaluated at a corrected gestational age greater than 37 weeks. The otoacoustic emissions amplitudes obtained at the hospital discharge were compared to the ones obtained from 15 to 40 days after the discharge. The results showed that the otoacoustic emissions amplitudes of the preterm study group were smaller than the amplitudes of the control group and the term study group in both moments of the test. The amplitude of the newborns’ otoacoustic emissions increased in the second moment of the test. The amplitudes were higher in the frequency of 6.000Hz and, in the right ear in the frequency f2 3.000 Hz. The otoacoustic emissions amplitudes of the control group in the second moment of the test were similar to the term study group in the first moment of the research. It was concluded that there is an increase of the distortion product otoacoustic emissions amplitude from the discharge moment until 15 to 40 days after, suggesting a maturation of the cochlear structures in the post-natal period, and that the exposure to amicacin and vancomycin on the recommended dose by Neofax®, 2003/2004 did not alter the amplitude of the emissions in the newborns without risk indicators concomitant with neonatal infection.

INTRODUÇÃO: Os aminoglicosídeos são freqüentemente usados no berçário e podem ser tóxicos para as células ciliadas cócleo-vestibulares, especialmente para as células ciliadas externas da base da cóclea. As emissões ototacústicas produto de distorção permitem avaliar porções específicas da cóclea, antes mesmo que a sensação auditiva seja alterada, sendo ideais para análise precoce da integridade dessa estrutura auditiva, além de ser indicada para recém-nascidos por serem objetivas. O objetivo deste estudo prospectivo longitudinal é pesquisar a amplitude das emissões otoacústicas produto de distorção, causadas pelo uso de drogas ototóxicas, entre o término da administração e de 15 a 40 dias após seu uso. MÉTODOS: A população foi de recém-nascidos a termo e pré-termo provenientes de berçário e maternidade de um hospital público em Santo André, no período de julho de 2003 a setembro de 2004. A primeira avaliação ocorreu no dia da alta hospitalar. Foram avaliados três grupos: grupo controle com 33 recém-nascidos saudáveis e de termo; grupo de estudo a termo exposto a amicacina e /ou vancomicina com 19 recém-nascidos com mais de 37 semanas e grupo de estudo pré-termo exposto aos mesmos ototóxicos, com 15 recém-nascidos de 32 a 37 semanas. Os recém-nascidos não apresentavam indicadores de risco para deficiência auditiva preconizados pelo JCIH,2000 concomitante à infecção neonatal. Todos os recém-nascidos foram avaliados com idade gestacional corrigida maior que 37 semanas. As amplitudes das emissões otoacústicas dos recém-nascidos em fase de alta hospitalar foram comparadas às obtidas de 15 a 40 dias após a alta. RESULTADOS: As amplitudes das emissões otoacústicas dos recém-nascidos do grupo de estudo pré-termo foram menores que as amplitudes do grupo controle e do grupo de estudo a termo nos dois momentos de teste. As amplitudes das emissões dos recém-nascidos dos três grupos aumentaram no segundo momento de teste. As amplitudes das emissões dos recém-nascidos foram maiores na freqüência de 6.000 Hz e na orelha direita para a freqüência f2 3.000 Hz. As amplitude das emissões do grupo controle no segundo momento de teste foram semelhantes as do grupo de estudo à termo no primeiro momento da pesquisa. CONCLUSÔES: Houve aumento da amplitude das emissões otoacústicas produto de distorção desde a fase de alta até 15 a 40 dias após. A exposição a amicacina e vancomicina nas doses preconizadas pelo Neofax®, 2003/2004 não alterou as amplitudes das emissões nos recém-nascidos sem indicadores de risco concomitante à infecção neonatal. / The amynoglicosides are frequently used in nurseries and may be toxic for the cochleo-vestibular hair cells, specially for the outer cells of the cochlear base. The distortion product otoacoustic emissions allow to evaluate specific portions of the cochlea even before the hearing sensation is altered, and are ideal for the early analysis of this auditory structure integrity, besides being indicated for newborns once they are objective. The aim of this prospective longitudinal study is to research the amplitude of distortion product otoacoustic emissions caused by the ototoxic drugs use, between the end of the administration and from 15 to 40 days after its use. The population studied was composed by term and preterm newborns from a nursery and maternity of a Santo André city hospital, in the period from July 2003 to September 2004. The first evaluation occurred on the hospital discharge day. Three groups were evaluated: control group with 33 term and healthy newborns; term study group with 19 term newborns with more than 37 weeks exposed to amicacin and/or vancomycin; and preterm study group with 15 preterm newborns from 32 to 37 weeks exposed to the same ototoxic. The newborns did not present risk factors for hearing loss according to the JCIH, 2000 concomitant to the neonatal infection. All newborns were evaluated at a corrected gestational age greater than 37 weeks. The otoacoustic emissions amplitudes obtained at the hospital discharge were compared to the ones obtained from 15 to 40 days after the discharge. The results showed that the otoacoustic emissions amplitudes of the preterm study group were smaller than the amplitudes of the control group and the term study group in both moments of the test. The amplitude of the newborns’ otoacoustic emissions increased in the second moment of the test. The amplitudes were higher in the frequency of 6.000Hz and, in the right ear in the frequency f2 3.000 Hz. The otoacoustic emissions amplitudes of the control group in the second moment of the test were similar to the term study group in the first moment of the research. It was concluded that there is an increase of the distortion product otoacoustic emissions amplitude from the discharge moment until 15 to 40 days after, suggesting a maturation of the cochlear structures in the post-natal period, and that the exposure to amicacin and vancomycin on the recommended dose by Neofax®, 2003/2004 did not alter the amplitude of the emissions in the newborns without risk indicators concomitant with neonatal infection.

A membrane protein VanZTei which is encoded by the gene vanZ from the vanA glycopeptide resistance gene cluster is a part of the large family of VanZ proteins. VanZTei confers resistance to teicoplanin in Enterococcus faecalis without the presence of other proteins encoded by the cluster. The aim of my work was to compare the ability of two orthologous proteins VanZTei and VanZg (from the genome of Enterococcus faecium) to confer resistance to glycopeptides in Staphylococcus aureus RN4220 and Enterococcus faecium. We have shown that VanZg increases resistance to teicoplanin (Tei) 8 to 16 times the and also to dalbavancin (Dalb) 8 times. VanZTei also confers resistance to Tei and Dalb, but the increase is only twofold. Conversely VanZTei confers resistance to newly synthetized glycopeptides more effectively than VanZg (fourfold increase of resistance confered by VanZTei and two to fourfold increase of resistance confered by VanZg). It suggests that both proteins have different specificity to antibiotics. In despite the mutants of S. aureus RN4220 VanZTei pRMC2 with increased resistance to teicoplanin (MICTei> 8 µg/ml) in which the resistance is dependent on vanZTei expression were selected. These resistant mutants do not carry mutation in a gene vanZTei or in its ribosomal binding site. Neither of the...

L’étude de la structure de complexes non-covalents présente un intérêt fondamental dans la recherche en chimie des protéines. Le premier objectif est de caractériser les interactions physico-chimiques sur lesquelles repose l’adoption d’une structure tridimensionnelle fonctionnelle par un édifice multimoléculaire. Le second objectif est de mettre en évidence les changements structuraux induits par le phénomène de complexation, et leur influence sur la fonction du système. Le couplage entre la spectrométrie de masse et la mobilité ionique (IM/MS) est une technique d’étude structurale en phase gazeuse, dont le principe repose sur la séparation d’ions selon leur forme et leur rapport masse sur charge, et qui permet en outre de mesurer leurs sections efficaces de diffusion. Grâce à cette technique, nous avons réalisé l’étude structurale de trois complexes non-covalents : l’agrégation de molécules de tanin sur la protéine salivaire humaine IB5, la fixation du ligand Ac2KAA sur la vancomycine, et la complexation de cations métalliques sur des polymères poly-lactide. L’évolution des sections efficaces en fonction de la taille du système ou de l’état de complexation met en évidence la présence de transitions structurales. De plus, utilisé avec de la modélisation moléculaire ou de la spectroscopie laser, le couplage IM/MS s’avère pertinent pour caractériser les interactions responsables de la stabilisation de tels complexes. Ces travaux de thèse montrent que cette technique , au-delà du simple aspect analytique (séparation d’isomères), peut également être utilisée au sein d’études plus globales, mettant en jeu plusieurs techniques afin de résoudre la structure de systèmes complexes / Knowing the structure of non-covalent complexes is essential to understand many biological processes. The first step is the characterization of the interactions leading to the adoption of a functional tridimensional structure by a multimeric assembly. The second step consists of underlining the structural modifications induced by the complexation, and their influence on the system’s function. The Ion Mobility/Mass Spectrometry (IM/MS) is a gas-phase method that is used to separate ions according to their geometry and their masse-to-charge ratio. IM/MS also provides insights on their intrinsic properties, by measuring their collision cross sections. Using this method, we have studied the structure of three different non-covalent complexes: the aggregation of tannins on the human salivary protein IB-5, the fixation of a small ligand (Ac2KAA) on vancomycin, and the complexation between metallic cations and poly-lactid polymers. The evolution of the collision cross-sections as a function of the size of the system or the complexation state clearly shows structural transitions. Moreover, combined with molecular modeling or laser spectroscopy, the IM/MS technique reveals to be a powerful tool to characterize the relevant interactions in such systems. This work proves that IM/MS, besides a powerful analytical aspect, can also be used in global studies that involve several structural methods to resolve the structure of large multimeric assemblies

A sepse após a injúria térmica é a maior causa de morbidade e mortalidade em pacientes queimados, uma vez que profundas alterações ocorrem na farmacocinética de agentes antimicrobianos. Investigaram-se trinta e um pacientes, portadores de sepse documentada e apresentando lesões ativas; utilizou-se o tratamento empírico conforme seguem os regimes de dose: 1 g, 12/12 h para a vancomicina, 1 g, 6/6 h para o imipenem e 2 g, 8/8 h para o cefepime. Sete coletas seriadas de sangue foram realizadas através de cateter venoso (2 mL/cada); o plasma foi obtido pela centrifugação e armazenado no congelador (-80o C) até o ensaio. A concentração plasmática dos antimicrobianos foi determinada simultaneamente pela aplicação do método bioanalítico desenvolvido no estudo. O método de cromatografia líquida de alta eficiência demonstrou boa linearidade, precisão e exatidão para a determinação simultânea da vancomicina, cefepime e imipenem plasmáticos; a plicação desse método bioanalítico permitiu o monitoramento plasmático terapêutico e o estudo farmacocinético. Com base nos resultados obtidos de concentração plasmática versus tempo, aplicou-se a modelagem para investigar a farmacocinética desses agentes antimicrobianos nos pacientes queimados. Os parâmetros cinéticos foram estimados com base no modelo aberto de um compartimento pela aplicação do programa PK Solutions v. 2.0; a estatística foi realizada pela utilização do programa GraphPad Prism v. 4.0. Com base na farmacocinética alterada, as concentrações obtidas para a vancomicina e imipenem se mostraram abaixo dos valores recomendados para atingir eficácia; por outro lado, as concentrações obtidas para o cefepime se mostraram dentro da faixa recomendada para atingir eficácia, uma vez que não se registrou alteração da farmacocinética deste antimicrobiano nos pacientes queimados. Desta forma, o monitoramento plasmático terapeutico se mostrou importante, permitindo o ajuste de dose para a vancomicina e para o imipenem, uma vez que a concentração minima efetiva (CME) não foi atingida para ambos pela utilização do regime de dose empírica nos pacientes queimados. Por outro lado, o monitoramento do cefepime plasmático também se mostrou de relevância, uma vez que os pacientes queimados com longa permanência na terapia intensiva podem apresentar disfunção renal em alguma fase da internação; consequentemente, a individualização de dose será recomendada para esses pacientes. Adicionalmente, investigou-se a disposição cinética da vancomicina em nove pacientes queimados após duas diferentes intervenções cirúrgicas. Comparou-se a farmacocinética da vancomicina pós-desbridamento versus pos-enxerto com base no monitoramento plasmático após o regime de dose empírica (1 g, 12/12 h). Após multiplas infusões, o vale da vancomicina plasmática foi obtido pela coleta de sangue imediatamente antes da infusão subsequente e está relacionado ao acúmulo no estado de equilíbrio. Em conseqüência da depuração aumentada e meia-vida biológica reduzida pós-desbridamento comparado ao pós-enxerto, registrou-se para a vancomicina vale abaixo da concentração efetiva mínima nos pacientes queimados. Finalmente, os resultados obtidos no presente estudo permitem concluir que a farmacocinética da vancomicina e do imipenem está alterada nos pacientes queimados com sepse, e recomenda-se o monitoramento das concentrações plasmáticas para garantir a eficácia de forma a previnir a emergência bacteriana. / Sepsis after thermal injury is the major cause of morbidity and mortality in burn patients, once deep changes on the pharmacokinetics of antimicrobials agents are expected. Thirty one burn patients were investigated, all of them had documented sepsis and presented active lesions; they were treated with empirical dose regimen as follows: 1 g, 12/12 h for vancomycin, 1 g, 6/6 h for imipenem and 2 g, 8/8 h for cefepime. A serial of seven blood samples were collected from the venous catheter (2 mL/each); plasma was obtained by centrifugation and storaged in an ultra-low freezer (-80o C) until assay. Drug plasma concentration was determined simultaneously by application of a bioanalytical method described previously. High performance liquid chromatographic method showed good linearity, precision and accuracy for vancomycin, cefepime and imipenem plasma measurements; its application permitted therapeutic drug monitoring and pharmacokinetic studies. Pharmacokinetic modeling was applied to data obtained based on drug plasma concentrations versus time, to investigate those antimicrobial agents in burn patients. Estimated kinetic parameters were based on the one compartment open model by application the software PK Solutions v. 2.0; statistics was performed by using the software GraphPad Prism v. 4.0. Based on altered pharmacokinetics, obtained plasma concentrations to reach drug efficacy were below the recommended values for vancomycin and imipenem; on the other hand, cefepime plasma concentrations to reach drug efficacy were in the recommended range, once its pharmacokinetics didnt change in burn patients. Then, therapeutic plasma monitoring was cost-effective permitting dose adjustment for vancomycin and imipenem, once the minimum effective concentration (MEC) wasnt reached for both antimicrobial agents by using the empirical dose regimen for burn patients. On the other hand, cefepime plasma monitoring was also cost-effective, since burn patients long term therapy can present renal dysfunction at the minimum one period in the intensive care unit; consequently, dose adjustment could be required for them. Additionally, vancomycin kinetic disposition was investigated in nine burn patients after two different surgical interventions. Vancomycin pharmacokinetics post-debridement versus post-skin grafting procedure was compared based on drug plasma monitoring by using the empirical dose regimen (1 g, 12/12 h). Trough vancomycin plasma level after multiple infusions, obtained by blood collection before de next dose, is related to drug accumulation at the steady state level; then, trough below the minimum effective concentration (MEC) were obtained after both surgical procedures performed in burn patients. Meanwhile, increased plasma clearance and reduced biological half-life were obtained after debridement compared skin grafting procedure. Finally, data obtained in the present study permit to conclude that the pharmacokinetics is altered for vancomycin and imipenem in burn patients with sepsis, and drug plasma monitoring is recommended to guarantee drug efficacy and to prevent the bacterial emergency.

INTRODUÇÃO: A combinação de sepse e insuficiência renal com necessidade de diálise é bastante comum nas Unidades de Terapia Intensiva e esta situação tem elevada mortalidade. Um desafio neste cenário é prescrever a dose correta dos antimicrobianos para o tratamento destas infecções. Em pacientes críticos e hemodinamicamente instáveis que necessitam de terapia renal substitutiva, um dos métodos mais utilizados é a diálise contínua, entretanto, recentemente, tem-se utilizado a diálise de baixa eficiência - conhecida como SLED, da abreviação do inglês \"sustained low-efficiency dialysis\". Esta modalidade de terapia renal substitutiva combina características da hemodiálise contínua com a intermitente, utilizando o equipamento da diálise intermitente, com menores fluxos sanguíneos e de dialisato, e com vantagem de menor custo. Apesar do fluxo mais baixo, por ser utilizado tempo mais prolongado, a SLED frequentemente resulta em maior clearance e especula-se que a remoção dos fármacos seria maior. Há escassez de estudos que avaliaram a farmacocinética e farmacodinâmica de antimicrobianos em pacientes submetidos à SLED.OBJETIVOS: Avaliar adequação farmacodinâmica de meropenem e vancomicina em pacientes submetidos a diálise estendida de baixa eficiência. Avaliar a depuração paramêtros farmacocinéticos durante a sessão de SLED. MÉTODOS: Foi realizado estudo prospectivo descritivo observacional com coleta de material biológico julho de 2012 a julho de 2014 HC-FMUSP. Foram incluídos pacientes submetidos à SLED em uso de vancomicina e/ou meropenem. Foram coletadas amostras de sangue seriadas (tempos: imediatamente antes do início da sessão de diálise, 0,5h, 1h, 2h, 4h após o início do tratamento e ao final da sessão). A quantificação dos antimicrobianos foi realizada através dos métodos analíticos de quantificação em Cromatografia Líquida de Alta Eficiência (CLAE). Os parâmetros farmacocinéticos foram calculados apenas durante a sessão de diálise utilizando-se o software WinNonlin. A área sob a curva foi determinada para a vancomicina. Para o meropenem, calculou-se o tempo acima da MIC. Resultados: Foram incluídos 24 pacientes tratados com vancomicina e 21 com meropenem eforam obtidas 170 amostras de plasma. As concentrações médias de vancomicina sérica e meropenem: antes da sessão de SLED foram 24,5 e 28,0 ?g / ml, respectivamente; e após SLED 14 e 6 ?g / ml, respectivamente. A depuração média foi de 41% para a vancomicina e 78% para o meropenem. Para vancomicina, 22 (96%), 19 (83%) e 16 (70%) pacientes teriam atingido o alvo (AUC0-24 > 400) considerando-se MIC 0,5; <= 1mg/l e <= 2 mg/l respectivamente. Para meropenem, 19 (95%), 18 (90%) e 11 (55%) pacientes teriam atingido a meta (70% de tempo acima da CIM) se infectados com isolados com MIC <= 1, <= 4 e <= 8 mg/l, respectivamente. Conclusões: Em pacientes críticos, meropenem evancomicina foram removidas durante o SLED. Entretando, a maioria dos pacientes alcançaria alvo PK-PD, excepto para CIMs mais altas. Sugerimos doses de manutenção de 1g a cada 12 ou 8 horaspara meropenem. Para a vancomicina, deve-se utilizar abordagem mais individualizada com monitorização sérica, uma vez que ensaios comerciais são disponíveis / Background: Antibiotic dosing is a challenge in critically ill patients undergoing renal replacement therapy. Our aim was to evaluate pharmacokinetics and pharmacodynamics of meropenem and vancomycin in patients undergoing SLED.Methods: ICU patients undergoing SLED, receiving meropenem and/or vancomycin, were prospectively evaluated. Blood samples were collected at the start of SLED and 0.5; 1; 2; 4 and 6 hours later. Antimicrobial levels were determined by HPLC. Noncompartimental pharmacokinetic analysis was performed. Area under the curve was determined for vancomycin. For meropenem, time above MIC was calculated. Results: 24 patients receiving vancomycin and 21 receiving meropenem were included; 170 plasma samples were obtained. Median serum vancomycin and meropenem concentrations: before SLED were 24.5 and 28.0 ?g/ml, respectively; and after SLED 14 and 6 ?g/ml, respectively. Mean removal was 41% for vancomycin and 78% for meropenem. For vancomycin, 22 (96%), 19(83%) and 16(70%) patients would have achieved the target (AUC0-24>400) considering MIC 0.5; <= 1mg/l and <= 2 mg/l, respectively. For meropenem, 19 (95%), 18 (90%) and 11(55%) patients would have achieved the target (70% of time above MIC) if infected with isolates with MIC <= 1, <= 4 and <= 8mg/l, respectively. Conclusions: In critically ill patients, meropenem and vancomycin were removed during SLED. Despite this, overall high PK/PD target attainment was obtained, except for higher MICs. We suggest maintenance doses of 1g tid or bid for meropenem. For vancomycin, more individualized approach using therapeutic drug monitoring should be used, as commercial assays are available

No description available.

Antibiotic resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci (VRE), are an increasing burden on healthcare systems. Hospital acquired infections with these organisms leads to higher morbidity and mortality compared with the sensitive strains of the same species and both VRE and MRSA are on the rise worldwide including in Australian hospitals. Emerging community infectious diseases are also having an impact on hospitals. The Severe Acute Respiratory Syndrome virus (SARS Co-V) was noted for its propensity to spread throughout hospitals, and was contained largely through social distancing interventions including hospital isolation. A detailed understanding of the transmission of these and other emerging pathogens is crucial for their containment. The statistical inference and mathematical models used in this thesis aim to improve understanding of pathogen transmission by estimating the transmission rates of contagions and predicting the impact of interventions. Datasets used for these studies come from the Princess Alexandra Hospital in Brisbane, Australia and Shanxi province, mainland China. Epidemiological data on infection outbreaks are challenging to analyse due to the censored nature of infection transmission events. Most datasets record the time on symptom onset, but the transmission time is not observable. There are many ways of managing censored data, in this study we use Bayesian inference, with transmission times incorporated into the augmented dataset as latent variables. Hospital infection surveillance data is often much less detailed that data collected for epidemiological studies, often consisting of serial incidence or prevalence of patient colonisation with a resistant pathogen without individual patient event histories. Despite the lack of detailed data, transmission characteristics can be inferred from such a dataset using structured HiddenMarkovModels (HMMs). Each new transmission in an epidemic increases the infection pressure on those remaining susceptible, hence infection outbreak data are serially dependent. Statistical methods that assume independence of infection events are misleading and prone to over-estimating the impact of infection control interventions. Structured mathematical models that include transmission pressure are essential. Mathematical models can also give insights into the potential impact of interventions. The complex interaction of different infection control strategies, and their likely impact on transmission can be predicted using mathematical models. This dissertation uses modified or novel mathematical models that are specific to the pathogen and dataset being analysed. The first study estimates MRSA transmission in an Intensive Care Unit, using a structured four compartment model, Bayesian inference and a piecewise hazard methods. The model predicts the impact of interventions, such as changes to staff/patient ratios, ward size and decolonisation. A comparison of results of the stochastic and deterministic model is made and reason for differences given. The second study constructs a Hidden Markov Model to describe longitudinal data on weekly VRE prevalence. Transmission is assumed to be either from patient to patient cross-transmission or sporadic (independent of cross-transmission) and parameters for each mode of acquisition are estimated from the data. The third study develops a new model with a compartment representing an environmental reservoir. Parameters for the model are gathered from literature sources and the implications of the environmental reservoir are explored. The fourth study uses a modified Susceptible-Exposed-Infectious-Removed (SEIR) model to analyse data from a SARS outbreak in Shanxi province, China. Infectivity is determined before and after interventions as well as separately for hospitalised and community symptomatic SARS cases. Model diagnostics including sensitivity analysis, model comparison and bootstrapping are implemented.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2008. / Härtill 6 uppsatser.

Orientador: Maria de Lourdes Ribeiro de Souza da Cunha / Resumo: A alta frequência de Estafilococos Coagulase-Negativa (CoNS) na pele de indivíduos saudáveis e em doenças associadas ao sangue, associados à seleção de cepas resistentes devido a uso indiscriminado de antimicrobianos, tornou mais estreitos os limites entre o ambiente hospitalar e o comunitário quanto à distribuição de cepas. Objetivou-se, com este estudo, caracterizar isolados de CoNS de origem hospitalar e comunitária da cidade de Botucatu-SP quanto ao perfil clonal, analisar os aspectos de resistência à oxacilina pela aferição de metodologia de detecção, e investigar os determinantes de heterorresistência à vancomicina nessas cepas. As espécies estudadas incluíram S. epidermidis, S. haemolyticus, S. warneri, S. hominis, S. lugdunensis, S. capitis, S. saprophyticus, S. pasteuri, S. simulans e S. xylosus. O teste de disco-difusão (TDD) com discos de oxacilina e cefoxitina, fitas de Etest impregnadas com oxacilina e pesquisa do gene mecA por PCR em tempo real foram realizadas. A triagem em ágar com 6 e 8 µg/ml de vancomicina, microdiluição em caldo para aferição da Concentração Inibirtória Mínima (MIC), microscopia eletrônica de transmissão para verificar espessamento da parede celular e alterações fenotípicas por testes bioquímicos foram realizadas. O perfil clonal foi determinado por PFGE (Pulsed-Field Gel Eletrophoresis) e para clones de S. epidermidis, o MLST (Multilocus Sequence Typing). S. epidermidis apresentou alta diversidade clonal, mas presença de clusters no ambien... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The high frequency of Coagulase-Negative Staphylococci (CoNS) on the skin of healthy individuals and in bloodstream infections, together with the selection of resistant strains, has narrowed the boundaries between the hospital and the community environment for the distribution of strains. This study aimed to characterize CoNS isolated from clinical and colonization specimens of patients and individuals from Botucatu-SP, to compare their clonal profile, to analyze the determination of oxacillin resistance by the evaluation of the methodology of detection, and to investigate the determinants of reduced susceptibility to vancomycin in those strains. CoNS species included S. epidermidis, S. haemolyticus, S. warneri, S. hominis, S. lugdunensis, S. capitis, S. saprophyticus, S. pasteuri, S. simulans and S. xylosus. The disc diffusion test (DDT) using oxacillin and cefoxitin discs was employed, Etest strips impregnated with oxacillin and mecA gene detection by real-time PCR were used. An agar screening with 6 and 8 µg/ml of vancomycin, the broth microdiluition method for the Minimal Inhibitory Concentration (MIC), the transmission eletronic microscopy for evaluation of cellwall thickening and phenotypic modifications by biochemical tests were performed. Clonal profile was determined by PFGE (Pulsed-Field Gel Eletrophoresis) and, for S. epidermidis clones, MLST (Multilocus Sequence Typing). S. epidermidis presented high clonal diversity, despite some clusters circulating within hospi... (Complete abstract click electronic access below) / Doutor