Abstract
AbstractNovel therapeutic strategies are urgently needed to combat pneumonia caused byStreptococcus pneumoniaestrains resistant to standard-of-care antibiotics. Previous studies have shown that targeted stimulation of lung innate immune defenses through intranasal administration of the Toll-like receptor 5 agonist flagellin, improves the treatment of pneumonia when combined with antibiotics. To promote translation to the clinic application, this study assessed the direct delivery of flagellin to the airways through nebulization using a vibrating mesh nebulizer in mice. Intranasal delivery achieved approximately 40% lung deposition of the administered flagellin dose, whereas nebulization yielded less than 1%. Despite these differences, nebulized flagellin induced a transient activation of lung innate immunity characterized by cytokine/chemokine production and neutrophil infiltration into airways analogous to intranasal administration. Furthermore, inhalation by nebulization resulted in an accelerated resolution of systemic pro-inflammatory responses. Lastly, adjunct therapy combining nebulized flagellin and amoxicillin proved effective against antibiotic-resistant pneumococcal pneumonia in mice. We posit that flagellin aerosol therapy represents a safe and promising approach to address bacterial pneumonia within the context of antimicrobial resistance.
Publisher
Cold Spring Harbor Laboratory
Reference55 articles.
1. https://www.who.int/news/item/09-12-2020-who-reveals-leading-causes-of-death-and-disability-worldwide-2000-2019, (2019).
2. C. Scelfo , F. Menzella , M. Fontana , G. Ghidoni , C. Galeone , N.C. Facciolongo , Pneumonia and Invasive Pneumococcal Diseases: The Role of Pneumococcal Conjugate Vaccine in the Era of Multi-Drug Resistance, Vaccines (Basel), 9 (2021).
3. Impact of vaccination on carriage of and infection by antibiotic-resistant bacteria: a systematic review and meta-analysis;Clin Exp Vaccine Res,2021
4. Divergent serotype replacement trends and increasing diversity in pneumococcal disease in high income settings reduce the benefit of expanding vaccine valency
5. Changes in antimicrobial resistance, serotypes and genotypes in Streptococcus pneumoniae over a 30-year period