Sweetening Inhaled Antibiotic Treatment for Eradication of Chronic Respiratory Biofilm Infection.

PURPOSE: The failure of chronic therapy with antibiotics to clear persistent respiratory infection is the key morbidity and mortality factor for patients with chronic lung diseases, primarily due to the presence of biofilm in the lungs. It is hypothesised that carbon sources, such as mannitol, could stimulate the metabolic activity of persister cells within biofilms and restore their susceptibility to antibiotics. The aims of the current study are to: (1) establish a representative in vitro model of Pseudomonas aeruginosa biofilm lung infection, and (2) investigate the effects of nebulised mannitol on antibiotic efficacy, focusing on ciprofloxacin, in the eradication of biofilm. METHOD: Air interface biofilm was cultured onto Snapwell inserts incorporated into a modified pharmacopeia deposition apparatus, the Anderson Cascade Impactor (ACI). Three different formulations including mannitol only, ciprofloxacin only and combined ciprofloxacin and mannitol were nebulised onto the P. aeruginosa biofilm using the modified ACI. Antibacterial effectiveness was evaluated using colony-forming units counts, biofilm penetration and scanning electron microscopy. RESULTS: Nebulised mannitol promotes the dispersion of bacteria from the biofilm and demonstrated a synergistic enhancement of the antibacterial efficacy of ciprofloxacin compared to delivery of antibiotic alone. CONCLUSIONS: The combination of ciprofloxacin and mannitol may provide an important new strategy to improve antibiotic therapy for the treatment of chronic lung infections. Furthermore, the development of a representative lung model of bacterial biofilm could potentially be used as a platform for future new antimicrobial pre-clinical screening.

Is the cellular uptake of respiratory aerosols delivered from different devices equivalent?

The study focuses on the application of a cell integrated modified Andersen Cascade Impactor (ACI) as an in vitro lung model for the evaluation of aerosols' behaviour of different formulation devices, containing the same active drug, specifically nebuliser, pressurised metered dose inhaler (pMDI) and dry powder inhaler (DPI). Deposition and transport profiles of the three different inhaled salbutamol sulphate (SS) formulations with clinically relevant doses were evaluated using a modified ACI coupled with the air interface Calu-3 bronchial cell model. Reproducible amounts of SS were deposited on Snapwells for the different formulations, with no significant difference in SS deposition found between the standard ACI plate and modified plate. The transport of SS aerosols produced from pMDI formulation had similar transport kinetics to nebulised SS but significantly higher compared to the DPI, which could have led to the differences in clinical outcomes. Furthermore, drug absorption of different inhaled formulation devices of the same aerodynamic fraction was found not to be equivalent due to their physical chemical properties upon aerosolisation. This study has established an in vitro platform for the evaluation of the different inhaled formulations in physiologically relevant pulmonary conditions.