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Imagenología de las infecciones por Enterobacterales a través del estudio por Tomografía por Emisión de Positrones con 18F-Fluorodeoxisorbitol

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dc.contributor.advisorGranados Oliveros, Ulises
dc.contributor.otherUniversidad Johns Hopkins
dc.creatorWintaco Martinez, Luz Maira
dc.creator.degreeDoctor en Ciencias Biomédicas y Biológicases
dc.creator.degreeLevelDoctorado
dc.creator.degreetypeFull timees
dc.date.accessioned2022-09-21T16:54:18Z
dc.date.available2022-09-21T16:54:18Z
dc.date.created2022-09-13
dc.descriptionLos Enterobacterales son un amplio grupo de bacterias Gram negativas, algunas especies forman parte del microbioma intestinal de los humanos y algunos animales. Actualmente, representan un problema para la salud pública y un reto en la práctica clínica diaria, debido al aumento de la resistencia a los antibióticos disponibles para su tratamiento y las altas tasas de morbilidad y mortalidad reportadas en todo el mundo. Este tipo de infecciones están íntimamente relacionadas con la Infecciones Asociadas Atención en Salud (IAAS) y representa un gran número de las mismas. Hasta el momento, el diagnóstico para estas infecciones bacterianas continúa siendo la identificación microbiológica que puede tardar entre 3 o 4 días, desde la obtención de la muestra biológica del sitio donde se sospecha la infección hasta su identificación. Sin embargo, esta metodología presenta algunas limitaciones como la necesidad de obtener una muestra clínica para aislar e identificar el agente causal de la infección, lo cual no siempre es posible o fácil de obtener; ya sea por desconocer la localización exacta del lugar de infección o por requerir procedimientos invasivos que representar más riesgos que beneficios para el paciente. Teniendo en cuenta lo anterior, urge la necesidad de desarrollar nuevos métodos de diagnóstico rápidos y específicos que permitan identificar las infecciones causadas por los Enterobacterales en un menor tiempo y con mayor sensibilidad. Por esta razón un grupo de investigadores identificó el radiotrazador 18F- Fluorodeoxisorbitol conocido como (18F-FDS); substrato metabólico específico para los Enterobacterales, el cual a través del operón srl conformado por 3 subunidades constituyen el sistema de fosfotransferasa dependiente de sorbitol, el cual permite el ingreso del sorbitol al interior de la bacteria para ser metabolizado vía glicolisis (1). Posteriormente experimentos (in vitro) utilizando diferentes familias de bacterias y líneas celulares eucariotas, permitieron determinar su absorción y establecer la especificidad para este tipo de bacterias, al igual que experimentos (in vivo) en un modelo de infección murino, permitieron distinguir correctamente los focos de infección causados por Enterobacterales de sitios con inflamación estéril e infecciones causadas por otros tipos de bacterias (2) . Posteriormente realizaron estudios de Tomografía por Emisión de Positrones (PET) y Tomografía Computarizada (TC) con 18F-FDS en personas sanas sin focos de infección para analizar su biodistribución y dosimétrica, obteniendo excelentes resultados que permitieron determinar la actividad radioactiva que se debe inyectar de 18F-FDS y garantizar el uso seguro en humanos (3). A partir de los anteriores resultados se planteó como un posible radiotrazador PET candidato para identificar focos de infección específicos originados por los Enterobacterales. Razón por la cual; el objetivo principal de esta investigación fue evaluar la utilidad diagnóstica del radiotrazador 18F-FDS utilizando la técnica PET/TC en 13 pacientes hospitalizados mayores de edad, con alta sospecha clínica de infecciones causadas por Enterobacterales, atendidos en la Fundación Cardiovascular de Colombia (FCV) entre los años 2018-2020, además evaluar la respuesta a la antibioticoterapia una vez finalizaran el tratamiento, mediante un segundo estudio de control PET/CT con 18F-FDS. Este estudio inicio con la estandarización de la síntesis del radiotrazador del 18F-FDS, a partir de la reducción química de 18- Fluorodexosiglucosa (18F-FDG); radiotrazador ampliamente utilizado en la práctica clínica diaria de la Medicina Nuclear, una vez culminada esta etapa se da inicio a la búsqueda de los participantes con alta sospecha de infección causada por Enterobacterales que cumplieran con los criterios de inclusión previamente definidos por el grupo de investigadores y aprobados por el Comité de Ética de la Fundación Cardiovascular de Colombia (FCV) para realizar los estudios PET/TC con 18F-FDS y finalmente, analizar cada una de las imágenes moleculares obtenidas de los participantes que permitiera localizar el lugar exacto de la infección junto con la confirmación microbiológica. Además, realizar un segundo estudio de control PET/TC con 18F-FDS post antibioticoterapia que evaluará la evolución de la misma. La correcta estandarización de la síntesis del 18F-FDS y el análisis preciso de las imágenes moleculares obtenidas mediante PET/TC permitieron identificar de manera rápida y específica los focos de infección formados por los Enterobacterales en los 13 participantes junto con la confirmación microbiológica y adicionalmente evaluar la respuesta al tratamiento antibiótico mediante un segundo estudio de control PET/TC con 18F-FDS que permitió ver el efecto de la antibioticoterapia y evolución de los focos de infección identificados inicialmente. Además, analizar en qué casos puede ser de mayor utilidad clínica la realización del estudio PET/CT con 18F-FDS para que en un futuro pueda ser implementado durante la práctica de la Medicina Nuclear (4). Los resultados producto de esta tesis permitieron (I) realizar la correcta síntesis de 18F-FDS a partir de 18F-FDG de manera rápida, segura con alta calidad radioquímica y microbiológica (II) Evaluar la utilidad clínica del radiotrazador 18F-FDS el cual mostró selectividad bacterial para identificar de manera rápida focos de infección causados por Enterobacterales en diferentes tejidos y microambientes del cuerpo, sin que se vea afectada su absorción por la localización de la infección, (III) Analizar mediante imágenes moleculares (in vivo) la evolución de los focos de infección causados por Enterobacterales después de la antibioticoterapia. Además, evaluar sus posibles aplicaciones clínicas tanto para el diagnóstico como para el seguimiento de las infecciones, (4) Describir la importancia clínica de las Infecciones Asociadas Atención en Salud y su relación con los Enterobacterales. Por último, es importante resaltar que este estudio es el primero en su clase realizado en el mundo; en donde se está evaluando la utilidad clínica del estudio PET/TC con 18F-FDS en humanos infectados por Enterobacterales, el cual será de referencia en el futuro para el desarrollo nuevos estudios clínicos con 18F-FDS y su implementación en Medicina Nuclear.es
dc.description.abstractEnterobacterales are a large group of Gram-negative bacteria some species are part of the intestinal microbiome of humans and some animals. Currently, it represents a public health problem and a challenge in daily clinical practice due to the increased resistance to antibiotics available for treatment and the high rates of morbidity and mortality reported throughout the world. These infections are related to Health Care-Associated Infections (HAI) and represent many of them. To date, the diagnosis of these bacterial infections continues to be microbiological identification, which can take between 3 or 4 days, from obtaining the biological sample from the site where the infection is suspected to its identification. However, this methodology has some limitations, such as the need to obtain a clinical sample to isolate and identify the causal agent of the infection, which is not always possible or easy to get; either because the exact location of the infection site is unknown or because invasive procedures are required that represent more risks than benefits for the patient. Taking the above into account, it is urgent to develop new rapid and specific diagnostic methods that allow the identification of infections caused by Enterobacterales in less time and with greater sensitivity. Therefore, a group of researchers identified the radiotracer 18F-Fluorodeoxysorbitol known as (18F-FDS); a specific metabolic substrate for Enterobacterales, which through the srl operon made up of 3 subunits that constitute the sorbitol-dependent phosphotransferase system, which allows sorbitol to enter the interior of the bacterium to be metabolized via glycolysis (1). Subsequently, experiments (in vitro) with different families of bacteria and eukaryotic cell lines made it possible to determine their absorption and establish the specificity for this type of bacteria, just as experiments (in vivo) in a murine infection model made it possible to correctly determine the foci of infection caused by Enterobacterales from sites with sterile inflammation and infections caused by other types of bacteria (2). Subsequently, they carried out Positron Emission Tomography (PET) and Computed Tomography (CT) studies with 18F-FDS in healthy people without foci of infection to analyze their biodistribution and dosimetry, obtaining excellent results that allowed determining the radioactive activity that should be injected from 18F-FDS and ensure safe use in humans (3). Based on the above results, a PET radiotracer is recommended as a possible candidate to identify specific foci of infection caused by Enterobacterales. The reason why; The main objective of this research was to evaluate the diagnostic utility of the 18F-FDS radiotracer using the PET/CT technique in 13 hospitalized patients of legal age with high clinical suspicion of infections caused by Enterobacterales, treated at the Fundación Cardiovascular de Colombia ( FCV). Between 2018-2020, in addition to evaluating the response to antibiotic therapy once treatment was completed, through a second PET/CT control study with 18F-FDS. This study began with the standardization of the synthesis of the 18F-FDS radiotracer from the chemical reduction of 18-Fluorodeoxyglucose (18F-FDG), a radiotracer widely used in the daily clinical practice of Nuclear Medicine once this stage is completed, the search begins for participants with a high suspicion of infection caused by Enterobacterales. They meet the inclusion criteria previously defined by the group of researchers and approved by the Ethics Committee of the Fundación Cardiovascular de Colombia (FCV) to carry out the PET/CT studies with 18F-FDS and finally, to analyze each of the molecular images obtained from the participants that would allow locating the exact place of the infection together with the microbiological confirmation. In addition, perform a second PET/CT control study with 18F-FDS post-antibiotic therapy to evaluate its evolution. The correct standardization of the synthesis of 18F-FDS and the precise analysis of the molecular images obtained using PET/CT allowed us to quickly and precisely identify the foci of infection formed by the Enterobacterales in the 13 participants together with the microbiological confirmation and further evaluate the response to antibiotic treatment through a second PET/CT control study with 18F-FDS that made it possible to see the effect of antibiotic therapy and the evolution of the initially identified sources of infection. In addition, analyze in which cases the performance of the PET/CT study with 18F-FDS can be of greater clinical utility so that in the future it can be implemented during the practice of Nuclear Medicine (4). The results of this thesis allowed (I) to carry out the correct synthesis of 18F-FDS from 18F-FDG in a fast, safe manner with high radiochemical and microbiological quality (II) To evaluate the clinical utility of the 18F-FDS radiotracer, which is showed bacterial selectivity to quickly identify foci of infection caused by Enterobacterales in different tissues and microenvironments of the body, without its absorption being affected by the location of the infection, (III) Analyze by molecular imaging (in vivo ) the evolution of foci of infection caused by Enterobacterales after antibiotic therapy. In addition, evaluate its possible clinical applications for both diagnosis and monitoring of infections, (4) Describe the clinical importance of Health Care-Associated Infections and their relationship with Enterobacterales. Finally, it is important to highlight that this study is the first of its kind carried out in the world; where the clinical utility of the PET/CT study with 18F-FDS in humans damaged by Enterobacterales is being evaluated, which will be a reference in the future for the development of new clinical studies with 18F-FDS and its implementation in Nuclear Medicine.es
dc.description.sponsorshipMinisterio de Ciencias Tecnología e Innovaciónes
dc.format.extent108 ppes
dc.format.mimetypeapplication/pdfes
dc.identifier.doihttps://doi.org/10.48713/10336_36026
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/36026
dc.language.isospaes
dc.publisherUniversidad del Rosario
dc.publisher.departmentEscuela de Medicina y Ciencias de la Salud
dc.publisher.programDoctorado en Ciencias Biomédicas y Biológicas
dc.relation.urihttps://stm.sciencemag.org/content/13/589/eabe9805es
dc.rightsAtribución-NoComercial-SinDerivadas 2.5 Colombia*
dc.rights.accesRightsinfo:eu-repo/semantics/openAccesses
dc.rights.accesoAbierto (Texto Completo)es
dc.rights.licenciaPARGRAFO: En caso de presentarse cualquier reclamación o acción por parte de un tercero en cuanto a los derechos de autor sobre la obra en cuestión, EL AUTOR, asumirá toda la responsabilidad, y saldrá en defensa de los derechos aquí autorizados; para todos los efectos la universidad actúa como un tercero de buena fe.
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/2.5/co/*
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dc.source.instnameinstname:Universidad del Rosario
dc.source.reponamereponame:Repositorio Institucional EdocUR
dc.subjectInfecciónes
dc.subjectTomografía por emisión de Positroneses
dc.subjectEnterobacteraleses
dc.subject[18F]- Fluorodeoxisorbitoles
dc.subject.ddcCiencias médicas, Medicinaes
dc.subject.keywordInfectiones
dc.subject.keywordEnterobacteraleses
dc.subject.keywordFDSes
dc.subject.keywordPET imaginges
dc.titleImagenología de las infecciones por Enterobacterales a través del estudio por Tomografía por Emisión de Positrones con 18F-Fluorodeoxisorbitoles
dc.title.TranslatedTitleImaging of Enterobacterales infections through positron emission tomography study with 2-deoxy-2-[18F]fluoro-d-sorbitoles
dc.typemasterThesises
dc.type.documentTesises
dc.type.hasVersioninfo:eu-repo/semantics/acceptedVersion
dc.type.spaTesises
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