Flagellin aerosol therapy safe against antibiotic-resistant pneumonia: Study

In the fight against antibiotic-resistant pneumonia, new research published in the Antimicrobial Agents and Chemotherapy highlighted the use of aerosolized flagellin which is delivered directly to the lungs and could enhance the immune response and help antibiotic treatments. With increasing rates of resistance in Streptococcus pneumoniae there is a dire need for therapies that can bolster treatment outcomes when standard antibiotics are less effective.

Flagellin, a Toll-like receptor 5 (TLR5) agonist, has shown promise in previous studies as an enhancer of lung immunity. When delivered intranasally, flagellin helped activate lung defenses by leading to reduced bacterial loads and improved outcomes when used along with antibiotics. However, translating this therapeutic strategy to clinical applications requires a delivery method that is not only effective but also non-invasive and easy to implement in a healthcare setting. Thus, this recent study tested a novel delivery approach using a vibrating mesh nebulizer to aerosolize flagellin directly into the airways of mice.

The findings of this study outlined in an in-depth table when compared to two delivery methods which is the traditional intranasal administration and aerosolized delivery via nebulization. The table detailed lung deposition rates, with intranasal delivery achieving approximately 40% of the administered flagellin dose in the lungs. Also, nebulization was significantly lower, with less than 1% lung deposition. Despite the low lung uptake through nebulization, the approach still triggered a robust immune response, including the production of cytokines and chemokines, as well as the recruitment of neutrophils into the airways.

This immune activation was transient, suggesting that nebulized flagellin induces a controlled and time-bound inflammatory response in the lung which is a characteristic crucial for avoiding excessive lung inflammation. The study also showed that aerosolized flagellin not only activated local lung defenses but also accelerated the reduction of systemic pro-inflammatory responses, an important factor in the overall health outcomes of pneumonia patients.

In a therapeutic trial, combining nebulized flagellin with the antibiotic amoxicillin was found to be effective against antibiotic-resistant strains of S. pneumoniae in mice. This combination therapy could represent a breakthrough for patients where conventional antibiotics alone may fail due to resistance. The study suggest that this inhaled approach could be an important addition to the arsenal against bacterial pneumonia, particularly in the context of rising antimicrobial resistance. Overall, the findings suggest that nebulized flagellin may serve as an adjunct therapy by improving the effectiveness of antibiotics while leveraging the the own immune defenses to combat severe pneumonia.

Source:

Baldry, M., Costa, C., Zeroual, Y., Cayet, D., Pardessus, J., Soulard, D., Wallet, F., Beury, D., Hot, D., MacLoughlin, R., Heuzé-Vourc’h, N., Sirard, J.-C., & Carnoy, C. (2024). Targeted delivery of flagellin by nebulization offers optimized respiratory immunity and defense against pneumococcal pneumonia. In B. P. Howden (Ed.), Antimicrobial Agents and Chemotherapy. American Society for Microbiology. https://doi.org/10.1128/aac.00866-24