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We previously showed that respiratory administration of flagellin, a potent TLR5 agonist, in combination with amoxicillin (AMX) improves the treatment of primary pneumonia or superinfection caused by AMX-sensitive or AMX-resistant Streptococcus pneumoniae. Here, the impact of adjunct flagellin therapy on antibiotic dose\/regimen and the selection of antibiotic-resistant S. pneumoniae was investigated using superinfection with isogenic antibiotic-sensitive and antibiotic-resistant bacteria and population dynamics analysis. Our findings demonstrate that flagellin allows for a 200-fold reduction in the antibiotic dose, achieving the same therapeutic effect observed with antibiotic alone. Adjunct treatment also reduced the selection of antibiotic-resistant bacteria in contrast to the antibiotic monotherapy. A mathematical model was developed that captured the population dynamics and estimated a 20-fold enhancement immune-modulatory factor on bacterial clearance. This work paves the way for the development of host-directed therapy and refinement of treatment by modeling.<\/jats:p>","DOI":"10.1093\/infdis\/jiae239","type":"journal-article","created":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T10:18:21Z","timestamp":1715163501000},"page":"e1126-e1135","source":"Crossref","is-referenced-by-count":9,"title":["Triggering Toll-Like Receptor 5 Signaling During Pneumococcal Superinfection Prevents the Selection of Antibiotic Resistance"],"prefix":"10.1093","volume":"230","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7651-8832","authenticated-orcid":false,"given":"Charlotte","family":"Costa","sequence":"first","affiliation":[{"name":"Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille , Lille ,","place":["France"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9854-4652","authenticated-orcid":false,"given":"Jean-Claude","family":"Sirard","sequence":"additional","affiliation":[{"name":"Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille , Lille ,","place":["France"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7563-9824","authenticated-orcid":false,"given":"Paddy S","family":"Gibson","sequence":"additional","affiliation":[{"name":"Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne , Lausanne ,","place":["Switzerland"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3162-6634","authenticated-orcid":false,"given":"Jan-Willem","family":"Veening","sequence":"additional","affiliation":[{"name":"Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne , Lausanne ,","place":["Switzerland"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0493-3102","authenticated-orcid":false,"given":"Erida","family":"Gjini","sequence":"additional","affiliation":[{"name":"Center for Computational and Stochastic Mathematics, Instituto Superior T\u00e9cnico, Universidade de Lisboa , Lisbon ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6005-1078","authenticated-orcid":false,"given":"Mara","family":"Baldry","sequence":"additional","affiliation":[{"name":"Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille , Lille ,","place":["France"]}]}],"member":"286","published-online":{"date-parts":[[2024,5,8]]},"reference":[{"key":"2024111514560374500_jiae239-B1","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/S1473-3099(18)30310-4","article-title":"Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990\u20132016: a systematic analysis for the global burden of disease study 2016","volume":"18","author":"GBD 2016 Lower Respiratory Infections Collaborators","year":"2018","journal-title":"Lancet Infect Dis"},{"key":"2024111514560374500_jiae239-B2","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1016\/j.cmi.2018.02.004","article-title":"Aetiology of lower respiratory tract infection in adults in primary care: a prospective study in 11 European 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