Optimización de una formulación farmacológica para tratar infecciones recurrentes causadas por C. difficile
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Fecha
2017
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es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
Clostridium difficile es un bacilo Gram positivo, anaerobio estricto, formador de endoesporas y el principal agente de transmisión nosocomial causante de diarrea asociada al uso de antibióticos. Los síntomas clínicos de una infección por C. difficile (ICD) van desde diarrea leve a colitis pseudomembranosa pudiendo llegar hasta megacolon tóxico y la muerte. Las esporas de C. difficile tienen un rol importante en la patogénesis, contribuyendo a la infección, persistencia y transmisión del patógeno en el hospedero. La evidencia ha demostrado que el uso de metronidazol y/o vancomicina frente a ICD no logra ser completamente efectivo y se estima que entre un 20% a 35% de los pacientes que parecen estar aliviados por el tratamiento inicial desarrollan un segundo episodio de la enfermedad (ICD Recurrente). La tasa de aparición de un nuevo episodio en un paciente que ya ha tenido una recurrencia puede ser mayor al 50% y un subconjunto de pacientes tendrá múltiples recurrencias. Debido a la importancia y la alta frecuencia que presenta la ICDR es necesario encontrar un tratamiento adecuado para reducir las tasas de recurrencia de la infección. En esta Tesis se evaluó la eficacia de nistatina e indometacina, dos inhibidores farmacológicos de la endocitosis mediada por caveolina y taurocolato como germinante de esporas de C. difficile, utilizando diferentes modelos murinos. Para esto se utilizaron animales de la cepa C57BL/6 a los cuales se les indujo una disbiosis para hacerlos susceptibles a la infección por C. difficile. Posterior a la infección los animales fueron tratados con los distintos fármacos por si solos y en forma de formulación farmacológica. De acuerdo a los resultados obtenidos en un modelo murino de recurrencia, la administración de un tratamiento con vancomicina, por un periodo de 7 días genera una mayor tasa de recurrencia que al ser administrado por un periodo de 4 días. El uso de indometacina en episodios de ICD exacerba la condición clínica asociada a la infección, aumentando de forma drástica la tasa de muerte en modelo murino, por lo tanto no se recomienda su uso bajo ninguna circunstancia en casos de ICD. Finalmente, la adición de taurocolato en una formulación farmacológica de vancomicina-nistatina reduce la recurrencia de la ICD.
Clostridium difficile is an anaerobic, gram-positive bacillus, endospore-forming and important nosocomial pathogen and the major infectious cause of nosocomial antibiotic-associated diarrhea and colitis. The clinical symptoms of a C. difficile infection (CDI) range from mild diarrhea to pseudomembranous colitis and may reach toxic megacolon even death. C. difficile spores have an important role in pathogenesis, contributing to the infection, persistence and transmission of the pathogen in the host. Evidence has shown that the use of metronidazole and/or vancomycin against C. difficile infections isn´t completely effective and it is estimated that between 20% and 35% of patients who appear to be relieved by the initial treatment develop a second episode of the disease. The rate of relapse of a new episode in a patient who has already had a recurrence may be higher than 50% and a subset of patients will have multiple recurrences. Due to the importance and high frequency of recurrence of C. difficile infection, it is necessary to find an adequate novel treatment to reduce the recurrence rates of the infection. This Thesis evaluated the efficacy of nistatin and indomethacin, two pharmacological inhibitors of endocytosis mediated by caveolin and taurocholate as spore germinant of C. difficile, using different murine models. Here we use animals of strain C57BL/6 where dysbiosis is induced to make them susceptible to C. difficile infection. Post-infection, the animals were treated with the different drugs alone and in form of a pharmacological formulation. According to the results, treatment with vancomycin in a murine model of recurrence for a period of 7 days generated a higher rate of recurrence than the observed when the tratment was applied for a period of 4 days. The use of indomethacin in CDI episodes exacerbates the clinical condition associated with the infection, drastically increasing the death rate in the murine model and therefore its use is not recommended under any circumstances in cases of CDI. Finally, the addition of taurocholate in a vancomycin-nystatin pharmacological formulation reduces the recurrence of CDI.
Clostridium difficile is an anaerobic, gram-positive bacillus, endospore-forming and important nosocomial pathogen and the major infectious cause of nosocomial antibiotic-associated diarrhea and colitis. The clinical symptoms of a C. difficile infection (CDI) range from mild diarrhea to pseudomembranous colitis and may reach toxic megacolon even death. C. difficile spores have an important role in pathogenesis, contributing to the infection, persistence and transmission of the pathogen in the host. Evidence has shown that the use of metronidazole and/or vancomycin against C. difficile infections isn´t completely effective and it is estimated that between 20% and 35% of patients who appear to be relieved by the initial treatment develop a second episode of the disease. The rate of relapse of a new episode in a patient who has already had a recurrence may be higher than 50% and a subset of patients will have multiple recurrences. Due to the importance and high frequency of recurrence of C. difficile infection, it is necessary to find an adequate novel treatment to reduce the recurrence rates of the infection. This Thesis evaluated the efficacy of nistatin and indomethacin, two pharmacological inhibitors of endocytosis mediated by caveolin and taurocholate as spore germinant of C. difficile, using different murine models. Here we use animals of strain C57BL/6 where dysbiosis is induced to make them susceptible to C. difficile infection. Post-infection, the animals were treated with the different drugs alone and in form of a pharmacological formulation. According to the results, treatment with vancomycin in a murine model of recurrence for a period of 7 days generated a higher rate of recurrence than the observed when the tratment was applied for a period of 4 days. The use of indomethacin in CDI episodes exacerbates the clinical condition associated with the infection, drastically increasing the death rate in the murine model and therefore its use is not recommended under any circumstances in cases of CDI. Finally, the addition of taurocholate in a vancomycin-nystatin pharmacological formulation reduces the recurrence of CDI.
Notas
Tesis (Magíster en Biotecnología)
Proyecto Fondecyt Regular N° 1151025
Proyecto Fondecyt Regular N° 1151025
Palabras clave
Clostridium Difficile, Enfermedades Infecciosas, Medicamentos, Administración y Dosis