Inhalation of an immunomodulatory adjuvant to treat drug-resistant bacterial pneumonia

Introduction Bacterial pneumonia is a major cause of morbidity and mortality worldwide. Antibiotics constitute the standard of care but face the emergence of antimicrobial resistance and curative failure. Moreover, antimicrobial agents are often administered orally or intravenously (I.V.) regardless the site of infection, as they are expected to distribute to this site. Inhalation is the obvious way of matching the delivery route to the target's location to treat pneumonia. It is suitable for protein therapeutics [1], and usually improves the therapeutic index of drugs. Here, we investigated inhalation of FLAMOD, a Toll-Like receptor 5 agonist, which enhances airway innate immune defenses. It improves the therapeutic outcome relative to antibiotic alone [2] and has synergic effect when combined with antibiotics, in pneumonia. Evidences showing that the FLAMOD-mediated immune protective effectors are regionally compartmentalized in the lungs further support the relevance of developing inhalation. Methods FLAMOD has been delivered either by nebulization into the lungs of macaques (Aerogen Solo®) or I.V. blood and bronchoalveolar lavages were collected to analyze innate immune response induced by the FLAMOD, in the systemic and local compartments and assess the potential immunogenicity of the inhaled formulation. Results Our results demonstrate that inhalation resulted in a local response, associated with a transient peak in cytokine secretion 2 to 70-fold lower than systemic response, as compared to the I.V. route. Moreover, the inhalation route led to lower anti-drug antibody (ADA) production than I.V. route. Conclusion Overall, our findings indicate that inhalation is better to achieve and restrict the immunomodulatory activity of FLAMOD into the lung compartment.