Grado de magíster en farmacología / Introducción: La neutropenia febril es la reacción adversa (RAM) más severa de los agentes quimioterapéuticos y que predispone a los pacientes con cáncer a infecciones graves1, siendo esencial la administración rápida de antimicrobianos.7-8 Las recomendaciones nacionales e internacionales incluyen el uso de aminoglucósidos.1,5-10 Sin embargo, para asegurar un correcto resultado, esta terapia antibiótica requiere una adecuada monitorización. En esta investigación, se pretende establecer el tiempo más adecuado de monitorización de amikacina en pacientes con neutropenia febril, para asegurar un régimen posológico seguro y eficaz que contribuya al manejo y recuperación de estos pacientes. Objetivo: Determinar el esquema más adecuado para monitorizar amikacina en pacientes con neoplasias y otras patologías hematológicas, que cursan con neutropenia febril en un hospital de alta complejidad, que es centro de referencia de pacientes hematoncológicos. Metodología: Se realizó un estudio prospectivo aleatorizado doble ciego, que comparó dos estrategias de monitoreo plasmático: uno mediante la toma de nivel en valle, contra uno a las 12 horas posterior al término de la infusión. Ambos grupos se caracterizaron y analizaron según sus parámetros farmacocinéticos y el cumplimiento de los parámetros Farmacocinético/Farmacodinámico (FC/FD), evaluándose además la correlación e influencia de ciertos factores como el clearence de amikacina y creatinina. Para el cálculo del régimen posológico de amikacina como indicación médica, se utilizó un modelo farmacocinético teórico del programa TDMS2000®. Resultados: Se incluyó un total de 42 pacientes, de los cuales 21 comprendieron a los que se les monitorizó en valle. El 81,0% de los pacientes que se les monitorizó en valle tuvieron niveles < 1, de los cuales 38,1% fueron en cero, en el caso de la monitorización a las 12 horas sólo en 9,5% tuvieron niveles < 1. Al individualizar las dosis hubo un aumento de 15 a 19 mg/Kg, siendo así el 85,7% de los pacientes cumplieron el Cmáx/CIM ≥ 8 en ambos grupos. Sin embargo, en el caso del ABC/CIM > 70, sólo 14,3% de los pacientes con niveles valle cumplieron con el parámetro objetivo versus aquellos que se les midió niveles a las 12 horas que fue un 42,3%, presentando diferencia estadística significativa. En el caso de la seguridad ningún paciente presentó disfunción renal en ambos grupos, objetivándose en 21 días de tratamiento. Por otra parte, se encontró una correlación directa entre el clearence de creatinina y el de amikacina. Conclusión: Finalmente, se puede concluir que la monitorización de amikacina a las 12 horas cuando se utiliza un programa farmacocinético con modelación bayesiana, es un método más adecuado y efectivo que la monitorización valle en el cumplimiento FC/FD. La monitorización farmacocinética de amikacina es un método seguro en la prevención de nefrotoxicidad en tratamientos prolongados.

Severe congenital neutropenia (SCN) is a rare blood disorder characterized by abnormally low levels of circulating neutrophils. Mutations in multiple genes like neutrophil elastase gene (ELANE) and granulocyte colony stimulating factor receptor (CSF3R) may cause SCN. The treatment of choice for SCN is the administration of granulocyte-colony stimulating factor (G-CSF) which elevates the neutrophil count and hence improves the survival and quality of life. Long term survivorship on G-CSF is however linked to development of MDS (myelodysplastic syndrome)/AML (acute myeloid leukemia). About 70% of MDS/AML patients acquire nonsense mutations affecting the cytoplasmic domain of CSF3R. In this project, we hypothesized that this coding region of CSF3R constitutes a hotspot, vulnerable to mutations resulting from excessive oxidative stress or endoplasmic reticulum (ER) stress. We used the murine Ba/F3 cell line to study the effect of induced oxidative or ER stress on the mutation rate in our hypothesized hotspot of the exogenous human CSF3R, the corresponding region in the endogenous Csf3r, and a leukemia-associated gene Runx1. Ba/F3 cells transduced with the cDNA for partial C-terminal of CSF3R fused in-frame with a Green Fluorescent Protein (GFP) tag was subjected to cellular stress inducing mutagen treatment for a prolonged period of time (30 days). The amplicon based targeted deep sequencing data for days 15 and 30 samples show that although there was increased mutagenesis observed in all genes, there were more mutations in the GFP region as compared to the GC-rich partial CSF3R region. Our findings also indicate that there is no correlation between the stress-inducing chemical treatments and mutagenesis in Ba/F3 cells. Thus, we conclude that there are other mechanisms to acquired mutations of CSF3R that help drive the evolution of SCN to MDS/AML. To test this hypothesis, further experiments using unique barcoding system are in progress to characterize the clonal competition between different mutant CSF3R and ELANE expressing cell lines. This study will shed further light on the selection advantage that is provided to cells because cooperativity between mutations in different genes.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Thesis (M.Med.Sc.)--University of Hong Kong, 2002. / Also available in print.

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Made available in DSpace on 2015-12-06T23:44:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2006 / Objetivos: analisar a aplicação de um componente específico para o diagnóstico das infecções relacionadas à assistência à saúde em pacientes com câncer durante o período de neutropenia; avaliar as variáveis associadas e determinar a mortalidade associada às infecções relacionadas à assistência à saúde nesta população. Métodos: foi realizado um estudo de coorte no Hospital Israelita Albert Einstein, hospital privado, com 430 leitos. Foram acompanhados os pacientes com câncer e neutropenia (definido como sendo a contagem absoluta de neutrófilos ≤ 500 células/mm3 de sangue) admitidos consecutivamente na Unidade Oncológica entre primeiro de fevereiro de 2001 e 31 de janeiro de 2005. A vigilância epidemiológica, realizada por enfermeiro epidemiologista utilizando formulário específico, consiste na busca ativa dos casos de infecção (segundo critérios diagnósticos do Centers for Disease Control and Prevention), fatores de risco associados e levantamento do número de granulócitos. Resultados: foram acompanhados 206 pacientes (6212 pacientes-dia e 3113 neutropenia-dia). A maioria pertencia ao sexo masculino (58,7%). A mediana de idade foi 53 anos (2 - 86 anos). As doenças hematológicas foram as mais freqüentemente encontradas, destacando-se os linfomas e leucemia. Houve predomínio de transplante de medula autólogo (86,6% dos transplantes incluídos). A maioria dos pacientes apresentou apenas um episódio de neutropenia, com uma média de 1,7 (1-9) episódios. O cateter venoso central esteve presente na maioria dos pacientes (82,5%). Foram diagnosticadas 169 infecções relacionadas à assistência à saúde em 104 pacientes. A taxa de densidade de infecção foi de 27,2 por 1000 pacientesdia e a taxa de densidade por neutropenia-dia foi de 54,3. Das infecções relacionadas à assistência à saúde, a mais freqüente foi a de corrente sangüínea associada á cateter venoso central, sendo a densidade de incidência de 22,3 por 1000 cateteres venosos central-dia. A mortalidade associada às infecções relacionadas à assistência à saúde nesta população foi 1,2%. Cinco variáveis associaram-se independentemente com o risco de Resumo x desenvolver infecção relacionada à assistência à saúde: ocorrência de dois ou mais episódios de neutropenia (OR 4,59; IC95%= 2,12 -9,95; p= 0,0001), ter sido submetido a transplante de medula óssea autólogo (OR 3,68; IC95%= 1,69 - 7,99; p= 0,05), ser paciente neutropênico grave no qual a contagem de neutrófilos foi ≤ 100 por mm3 de sangue (OR 5,59; IC95%= 1,28 - 24,28; p= 0,02), ter recebido tratamento quimioterápico no período prévio a neutropenia (OR 3,06; IC95%= 1,35 - 6,96; p= 0,0076) e ter utilizado antiviral (OR 2,31; IC95%= 2,13 - 4,75; p= 0,02) antes da infecção relacionada à assistência à saúde. Conclusões: o componente neutropeniadia foi importante para o diagnóstico das infecções relacionadas à assistência à saúde durante o período de neutropenia, mas a coleta do número de granulócitos demanda tempo. Os fatores de risco associados a aquisição de infecções relacionadas à assistência à saúde estão mais relacionados a doença de base do paciente, terapêutica e suas conseqüências. Observou-se baixa mortalidade nesta população. / Objectives: to evaluate a specific component for surveillance for healthcare associated infections in patients with cancer and neutropenia, and the variables associated with healthcare associated infections. To determine the mortality associated with healthcare associated infections. Methods: this study was done in a prospective cohort. All adults and children patient with cancer and neutropenia (defined as an absolute neutrophil count ≤ 500 cell/mm3 ) admitted to an Oncology unit of Albert Einstein hospital between February 1, 2001, and January 31, 2005 were included. Active surveillance was carried out by the infection control nurse using a specific formulary. The healthcare associated infections were classified according to Centers for Disease Control and Prevention’s criteria. Risk factors associated with healthcare associated infections and total number of neutrophils were also collected. Results: over the 48-months period, the 206 patients accounted for 6212 patient-days, and 3113 neutropenic-days. Of these patients, 58,7% was men. The median age was 53 years (range 2-86 years). Most patients had hematology diseases; leukemias and lymphomas were the most frequent diseases. The majority bone marrow transplantation was autologous (86,6%). More than half patients had one neutropenia episode only, with mean 1,7 episodes (range 1-9 episodes). During the study period, a total of 169 healthcare associated infections were identified in 104 patients. The incidence density of healthcare associated infections was 27, 2 per 1,000 patient-days and 54, 3 per 1,000 neutropenic days. The majority of the healthcare associated infections were catheter-associated bloodstream infection. The incidence density of catheter associated bloodstream infection was 22, 3 per 1,000 central venous catheter-days. The mortality associated with healthcare associated infections was 1, 2%. Five variables were predictive for healthcare associated infections: more than two neutropenia episodes, submitting to autologous bone marrow transplantation, profound neutropenia (absolute neutrophil count ≤ 100 cell/mm3 ), receive to chemotherapeutic regimens previous neutropenia and the use of antiviral previous infection. Conclusions: the neutropenia-days component was important to healthcare associated infection to diagnose during neutropenia period, but to collect the total number of neutrophil is time consuming. The risk factors associated with healthcare associated infections were related to the primary diagnosis, therapy and Abstract 105 its consequences. We observed smaller mortality associated with healthcare associated infections in this population than described in other studies. / BV UNIFESP: Teses e dissertações

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Foram incluídos no estudo 525 casos de fungemia causadas por Candida spp, Cryptocossus spp, Trichosporon spp, Rhodotorula spp, Histoplasma capsulatum, Saccharomyces cerevisiae e Pseudozyma aphidis, que constam nos arquivos do Laboratório de Micologia, Santa Casa-Complexo Hospitalar, Porto Alegre (RS) num período de 13 anos (1994-2007). Aspectos demográficos, doenças de base e fatores associadas aos episódios de fungemia foram estudados. Assim como, os agentes etiológicos e a mortalidade global entre os pacientes com fungemia. Os 525 casos foram classificados da seguinte maneira: candidemia (413/78,6%), subdivididos em: Candida albicans (151/36,5%), C. parapsilosis (91/22%), C. tropicalis (65/15,7%), C. glabrata (27/6,5%), C. pelliculosa (18/4,3%), C. guilliermondii (18/4,3%), C. humicola (7/1,7%), C. krusei (7/1,7%), C. famata (5/1,2%), C. lusitaniae (4/0,9%), C. sake (4/0,9%), C. lipolytica (3/0,7%), C. globosa (3/0,7%), C. intermedia (2/0,5%), C. kefyr (1/0,24%), C. colliculosa (1/0,24%) e Candida sp (8/1,9%); criptocococemia (77/14,6%), subdivididos em: Cryptococcus neoformans (72/93,5%), C. gattii (3/3,9%), C. laurentii (1/1,3%), Cryptococcus sp (1/1,3%); Histoplasma capsulatum (21/4%);Trichosporon spp (9/1,5%) subdivididos em: T. asahii (8/89%), T. mucoides (1/11%); Rhodotorula spp (5/0,9%) subdivididos, Rhodotorula sp (4/80%), R. mucilaginosa (1/20%); Saccharomyces cerevisiae (1/0,2%); Pseudozyma aphidis (1/0,2%)O sexo masculino foi o mais prevalente (288/55%), porém sem significância estatística, a idade variou de 12 dias à 97 anos, com uma mediana de 39,64 anos. A mortalidade nestes pacientes variou entre 22% e 52%. As doenças de base mais frequente foram câncer e Aids. Febre foi o sinal mais frequente. x Neste contexto, a fungemia deve ser incluída no diagnóstico diferencial destes pacientes com febre de origem desconhecida e prolongada. Utilizando-se de técnicas laboratoriais específicas para o diagnóstico etiológico. / We reviewd 525 cases of fungemia caused by Candida spp, Cryptocossus spp, Trichosporon spp, Rhodotorula spp, Histoplasma capsulatum, Saccharomyces cerevisiae and Pseudozyma aphidis. They have all been part of the files of the Mycology Laboratory at Santa Casa Hospital Complex in Porto Alegre (RS), during a thirteen-year period (1994 - 2007). Demographic aspects, underlying diseases and factors associated with the fungemia episodes were studied, as well as the etiologic agents and the global mortality among the patients having fungemia. The 525 cases included in the study were classified according to the following: candidemia (413/78,6%), subdivided in: Candida albicans (151/36,5%), C. parapsilosis (91/22%), C. tropicalis (65/15,7%), C glabrata (27/6,5%), C. pelliculosa (18/4,3%), C.guilliermondii (18/4,3%), C. humicola (7/1,7%), C. krusei (7/1,7%), C. famata (5/1,2%), C. lusitaniae (4/0,9%), C. sake (4/0,9%), C. lipolytica (3/0,7%), C. globosa (3/0,7%), C. intermedia (2/0,5%), C. kefyr (1/0,24%), C. colliculosa (1/0,24%) e Candida sp (8/1,9%); criptocococemia (77/14,6%), subdivided in: Cryptococcus neoformans (72/93,5%), C. gattii (3/3,9%), C. laurentii (1/1,3%), Cryptococcus sp (1/1,3%); Histoplasma capsulatum (21/4%);Trichosporon spp (9/1,5%) subdivided in: T. asahii (8/89%), T. mucoides (1/11%); Rhodotorula spp (5/0,9%) subdivided, Rhodotorula sp (4/80%), R. mucilaginosa (1/20%); Saccharomyces cerevisiae (1/0,2%); Pseudozyma aphidis (1/0,2%) The male gender was the most prevalent (288/55%), although no significance difference was observed. The age ranged from 12 days to 97 years old, with an average of 39,64 years. The mortality among these patients ranged between 22% and 52%. The most frequent underlying diseases were cancer and Aids. Fever was the most frequent sign. xii Within this context, fungemia must be included in the differential diagnosis of these patients presenting long-term fever with unknown cause. Making use of specific laboratorial techniques for the etiologic diagnosis.

Foram incluídos no estudo 525 casos de fungemia causadas por Candida spp, Cryptocossus spp, Trichosporon spp, Rhodotorula spp, Histoplasma capsulatum, Saccharomyces cerevisiae e Pseudozyma aphidis, que constam nos arquivos do Laboratório de Micologia, Santa Casa-Complexo Hospitalar, Porto Alegre (RS) num período de 13 anos (1994-2007). Aspectos demográficos, doenças de base e fatores associadas aos episódios de fungemia foram estudados. Assim como, os agentes etiológicos e a mortalidade global entre os pacientes com fungemia. Os 525 casos foram classificados da seguinte maneira: candidemia (413/78,6%), subdivididos em: Candida albicans (151/36,5%), C. parapsilosis (91/22%), C. tropicalis (65/15,7%), C. glabrata (27/6,5%), C. pelliculosa (18/4,3%), C. guilliermondii (18/4,3%), C. humicola (7/1,7%), C. krusei (7/1,7%), C. famata (5/1,2%), C. lusitaniae (4/0,9%), C. sake (4/0,9%), C. lipolytica (3/0,7%), C. globosa (3/0,7%), C. intermedia (2/0,5%), C. kefyr (1/0,24%), C. colliculosa (1/0,24%) e Candida sp (8/1,9%); criptocococemia (77/14,6%), subdivididos em: Cryptococcus neoformans (72/93,5%), C. gattii (3/3,9%), C. laurentii (1/1,3%), Cryptococcus sp (1/1,3%); Histoplasma capsulatum (21/4%);Trichosporon spp (9/1,5%) subdivididos em: T. asahii (8/89%), T. mucoides (1/11%); Rhodotorula spp (5/0,9%) subdivididos, Rhodotorula sp (4/80%), R. mucilaginosa (1/20%); Saccharomyces cerevisiae (1/0,2%); Pseudozyma aphidis (1/0,2%)O sexo masculino foi o mais prevalente (288/55%), porém sem significância estatística, a idade variou de 12 dias à 97 anos, com uma mediana de 39,64 anos. A mortalidade nestes pacientes variou entre 22% e 52%. As doenças de base mais frequente foram câncer e Aids. Febre foi o sinal mais frequente. x Neste contexto, a fungemia deve ser incluída no diagnóstico diferencial destes pacientes com febre de origem desconhecida e prolongada. Utilizando-se de técnicas laboratoriais específicas para o diagnóstico etiológico. / We reviewd 525 cases of fungemia caused by Candida spp, Cryptocossus spp, Trichosporon spp, Rhodotorula spp, Histoplasma capsulatum, Saccharomyces cerevisiae and Pseudozyma aphidis. They have all been part of the files of the Mycology Laboratory at Santa Casa Hospital Complex in Porto Alegre (RS), during a thirteen-year period (1994 - 2007). Demographic aspects, underlying diseases and factors associated with the fungemia episodes were studied, as well as the etiologic agents and the global mortality among the patients having fungemia. The 525 cases included in the study were classified according to the following: candidemia (413/78,6%), subdivided in: Candida albicans (151/36,5%), C. parapsilosis (91/22%), C. tropicalis (65/15,7%), C glabrata (27/6,5%), C. pelliculosa (18/4,3%), C.guilliermondii (18/4,3%), C. humicola (7/1,7%), C. krusei (7/1,7%), C. famata (5/1,2%), C. lusitaniae (4/0,9%), C. sake (4/0,9%), C. lipolytica (3/0,7%), C. globosa (3/0,7%), C. intermedia (2/0,5%), C. kefyr (1/0,24%), C. colliculosa (1/0,24%) e Candida sp (8/1,9%); criptocococemia (77/14,6%), subdivided in: Cryptococcus neoformans (72/93,5%), C. gattii (3/3,9%), C. laurentii (1/1,3%), Cryptococcus sp (1/1,3%); Histoplasma capsulatum (21/4%);Trichosporon spp (9/1,5%) subdivided in: T. asahii (8/89%), T. mucoides (1/11%); Rhodotorula spp (5/0,9%) subdivided, Rhodotorula sp (4/80%), R. mucilaginosa (1/20%); Saccharomyces cerevisiae (1/0,2%); Pseudozyma aphidis (1/0,2%) The male gender was the most prevalent (288/55%), although no significance difference was observed. The age ranged from 12 days to 97 years old, with an average of 39,64 years. The mortality among these patients ranged between 22% and 52%. The most frequent underlying diseases were cancer and Aids. Fever was the most frequent sign. xii Within this context, fungemia must be included in the differential diagnosis of these patients presenting long-term fever with unknown cause. Making use of specific laboratorial techniques for the etiologic diagnosis.

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