Publicação
Assessing optimal treatments for intracellular infection: host immunity, heterogeneity, and the antibiotic resistance challenge
| Resumo: | Mathematical models have been used as tools to study the dynamics of infectious diseases for a long time and to design successful control interventions, both at within-host and at the epidemiological level. Models can provide estimates of biological parameters which are difficult or expensive to obtain through experiments. Currently, in infection diseases, the growing antimicrobial resistance of pathogens poses great challenges. Recently, aggressive and moderate approaches are being debated as therapeutic strategies to deal with antibiotic resistance. The discussion is still open, as the field is becoming aware of the risks, due to higher and longer antibiotic prescriptions, not only considering the infection pathogen but also non-target resistance in resident microbiota. In this work, we study intracellular infection dynamics combining effects of antibiotic treatment and adaptive immune responses. The ODE models are based on infection processes for acute and chronic bacterial infections. We find the critical parameter combination in macrophage-bacteria-immunity interaction, dividing regimes of clearance and persistence of infection. Moreover, we study the consequences of antimicrobial treatment on many infection measures, including duration, bacterial burden, pathology and resistance. We notice that different combination of treatment duration and antibiotic doses can lead to the same infection outcomes and that the same treatment can have different effects if applied early or later during the infection course. Moreover, treatment is not always beneficial, as longer durations often select more resistant bacteria. We compare short (3 days) versus long (7 days) treatment duration in-depth. Long treatment duration is overall more efficient, with higher infection resolution. However, there are regimes where short treatment is non-inferior or even superior. Our results highlight the potential of new targeted treatments of intracellular infection, with lower antibiotic doses and duration, combined with sufficient immune action. From this, we extract optimization principles for infection over a range of scenarios and we discuss future directions for the improvement of this area, namely the importance of infection and immunity biomarkers at treatment onset. |
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| Autores principais: | Paupério, Francisco Ferreira da Silva |
| Assunto: | Infecção Imunidade Modelos matemáticos Tratamento antibiótico Interacção bactéria-macrófagos Teses de mestrado - 2019 |
| Ano: | 2019 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Mathematical models have been used as tools to study the dynamics of infectious diseases for a long time and to design successful control interventions, both at within-host and at the epidemiological level. Models can provide estimates of biological parameters which are difficult or expensive to obtain through experiments. Currently, in infection diseases, the growing antimicrobial resistance of pathogens poses great challenges. Recently, aggressive and moderate approaches are being debated as therapeutic strategies to deal with antibiotic resistance. The discussion is still open, as the field is becoming aware of the risks, due to higher and longer antibiotic prescriptions, not only considering the infection pathogen but also non-target resistance in resident microbiota. In this work, we study intracellular infection dynamics combining effects of antibiotic treatment and adaptive immune responses. The ODE models are based on infection processes for acute and chronic bacterial infections. We find the critical parameter combination in macrophage-bacteria-immunity interaction, dividing regimes of clearance and persistence of infection. Moreover, we study the consequences of antimicrobial treatment on many infection measures, including duration, bacterial burden, pathology and resistance. We notice that different combination of treatment duration and antibiotic doses can lead to the same infection outcomes and that the same treatment can have different effects if applied early or later during the infection course. Moreover, treatment is not always beneficial, as longer durations often select more resistant bacteria. We compare short (3 days) versus long (7 days) treatment duration in-depth. Long treatment duration is overall more efficient, with higher infection resolution. However, there are regimes where short treatment is non-inferior or even superior. Our results highlight the potential of new targeted treatments of intracellular infection, with lower antibiotic doses and duration, combined with sufficient immune action. From this, we extract optimization principles for infection over a range of scenarios and we discuss future directions for the improvement of this area, namely the importance of infection and immunity biomarkers at treatment onset. |
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