Novel Antimicrobial Agents and Therapeutic Approaches for Nosocomial pneumonia Caused by Pseudomonas aeruginosa
[eng] INTRODUCTION: Nosocomial pneumonia caused by Pseudomonas aeruginosa is associated with high mortality and morbidity. Furthermore, the high incidence of multi-resistance to antimicrobials makes both empirical and targeted treatment a complex decision for clinicians. Various strategies have been...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/209621 |
| Acceso en línea: | https://hdl.handle.net/2445/209621 http://hdl.handle.net/10803/690518 |
| Access Level: | acceso abierto |
| Palabra clave: | Malalties infeccioses Pneumònia Infeccions nosocomials Pseudomonas Communicable diseases Pneumonia Nosocomial infections |
| Sumario: | [eng] INTRODUCTION: Nosocomial pneumonia caused by Pseudomonas aeruginosa is associated with high mortality and morbidity. Furthermore, the high incidence of multi-resistance to antimicrobials makes both empirical and targeted treatment a complex decision for clinicians. Various strategies have been proposed, including optimization of the concentration of antimicrobials via nebulization or through a better study of penetration at the lung level; as well as the use of new antimicrobial combinations such as ceftolozane-tazobactam, meropenem-nacubactam. OBJECTIVES: The key objectives were to: (i) clarify whether pharmacokinetic models constructed with locally comprehensive profiles (ELF) can lead to more precise estimates; (ii) elucidate the benefits of appropriate empiric antimicrobial treatment with ceftolozane- tazobactam compared to inappropriate empiric treatment; (iii) evaluate the efficacy of the antimicrobial combination of meropenem-nacubactam in P. aeruginosa strains that express KPC and overproduce AmpC; (iv) analyze the role of nebulized amikacin/fosfomycin as adjuvant therapy, compared to intravenous administration of meropenem in nosocomial pneumonia caused by P. aeruginosa. MATERIALS AND METHODS: The studies included in this doctoral thesis were primarily based on a porcine model of severe pneumonia and a lung infection model in neutropenic mice. The animals were inoculated with different strains of P. aeruginosa, to subsequently be randomized and treated depending on the design of each study. Microbiological, histological, inflammatory results and clinical parameters were analyzed. In addition, pharmacokinetic and pharmacodynamic analyzes were performed. MAIN RESULTS AND CONCLUSIONS: The main findings were that: (i) ELF models built with concentrations at dispersed points result in estimates similar to those built from concentrated profiles; (ii) appropriate initial treatment with ceftolozane- tazobactam decreased the bacterial load in respiratory secretions, prevented the development of resistance and achieved the therapeutic objective at the pharmacodynamic level; (iii) the addition of nacubactam to meropenem resulted in a substantial bacterial reduction in P. aeruginosa counts; (iv) and it was confirmed that nebulized amikacin/fosfomycin reduces the presence of P. aeruginosa in tracheal secretions and limits the development of resistance, but has negligible efficacy in lung tissue. |
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