Aplicación de modelos econométricos para cuantificar la evolución de la resistencia a antibióticos en pacientes hospitalarios de Europa y su asociación con la legislación europea

Las infecciones que tienen lugar en pacientes hospitalizados (infecciones nosocomiales) constituyen una seria amenaza para la salud humana, pues existen cuadros concomitantes y un sistema inmune debilitado que ponen en riesgo su recuperación. Los agentes causantes pueden ser ubicuos en la naturaleza o estar presentes de forma natural en el ser humano, pero en determinadas condiciones algunas cepas de estos microrganismos presentan una elevada patogenicidad. Normalmente acompafia a este carácter patógeno una extraordinaria capacidad adquirida de resistencia a los tratamientos antibióticos. Tres de los microorganismos más frecuentemente aislados como responsables de estos cuadros son Escherichia coli, Klebsiella pneumoniae y Pseudomonas aeruginosa. Por ello existen protocolos de prevención en los hospitales encargados de dificultar la selección, aparición y diseminación de estas cepas. Asimismo, se documentan los brotes aparecidos aislándose e identificándose el microorganismo causante, así como las resistencias. Para su determinación y cuantificación se emplean pruebas laboratoriales. De esta forma para cada hospital y territorio se puede disponer de estadísticas de resistencias referenciadas a un lapso de tiempo determinado. Esta tesis doctoral disefta un modelo estadístico permitiendo estudiar retrospectivamente la evolución de los patrones de resistencia de diferentes microorganismos responsables de infecciones nosocomiales en Europa, desde que su emergencia hizo necesario recoger datos hasta la actualidad. El modelo está basado en la información recogida en EARS-Net, la base de datos de resistencia a antibióticos en hospitales de mayor implantación en la Unión Europea. Los grupos de antibióticos aquí estudiados son carbapenemas, cefalosporinas de tercera generación (C3G) y fluoroquinolonas, todos ellos arsenal terapéutico reservados a condiciones donde no se ha observado una mejoría clínica con antibióticos de amplio espectro, infecciones complicadas o nosocomiales..

Small-Plasmid-Mediated Antibiotic Resistance Is Enhanced by Increases in Plasmid Copy Number and Bacterial Fitness

Plasmids play a key role in the horizontal spread of antibiotic resistance determinants among bacterial pathogens. When an antibiotic resistance plasmid arrives in a new bacterial host, it produces a fitness cost, causing a competitive disadvantage for the plasmid-bearing bacterium in the absence of antibiotics. On the other hand, in the presence of antibiotics, the plasmid promotes the survival of the clone. The adaptations experienced by plasmid and bacterium in the presence of antibiotics during the first generations of coexistence will be crucial for the progress of the infection and the maintenance of plasmid-mediated resistance once the treatment is over. Here we developed a model system using the human pathogen Haemophilus influenzae carrying the small plasmid pB1000 conferring resistance to β-lactam antibiotics to investigate host and plasmid adaptations in the course of a simulated ampicillin therapy. Our results proved that plasmid-bearing clones compensated for the fitness disadvantage during the first 100 generations of plasmid-host adaptation. In addition, ampicillin treatment was associated with an increase in pB1000 copy number. The augmentation in both bacterial fitness and plasmid copy number gave rise to H. influenzae populations with higher ampicillin resistance levels. In conclusion, we show here that the modulations in bacterial fitness and plasmid copy number help a plasmid-bearing bacterium to adapt during antibiotic therapy, promoting both the survival of the host and the spread of the plasmid

Small-plasmid-mediated antibiotic resistance is enhanced by increases in plasmid copy number and bacterial fitness

Plasmids play a key role in the horizontal spread of antibiotic resistance determinants among bacterial pathogens. When an antibiotic resistance plasmid arrives in a new bacterial host, it produces a fitness cost, causing a competitive disadvantage for the plasmid-bearing bacterium in the absence of antibiotics. On the other hand, in the presence of antibiotics, the plasmid promotes the survival of the clone. The adaptations experienced by plasmid and bacterium in the presence of antibiotics during the first generations of coexistence will be crucial for the progress of the infection and the maintenance of plasmid-mediated resistance once the treatment is over. Here we developed a model system using the human pathogen Haemophilus influenzae carrying the small plasmid pB1000 conferring resistance to β-lactam antibiotics to investigate host and plasmid adaptations in the course of a simulated ampicillin therapy. Our results proved that plasmid-bearing clones compensated for the fitness disadvantage during the first 100 generations of plasmid-host adaptation. In addition, ampicillin treatment was associated with an increase in pB1000 copy number. The augmentation in both bacterial fitness and plasmid copy number gave rise to H. influenzae populations with higher ampicillin resistance levels. In conclusion, we show here that the modulations in bacterial fitness and plasmid copy number help a plasmid-bearing bacterium to adapt during antibiotic therapy, promoting both the survival of the host and the spread of the plasmid