Abstract
Pneumonia continually ranks in the top ten causes of death in the United States, despite continual development of new antibiotics and streamlined therapeutic treatment of patients. One approach to the treatment of pneumonia that has recently once again gained prominence is inhaled delivery of antibiotics to the lungs, with the development of new drug formulations. Despite the development of new products and potential for improved therapy, inhaled antibiotics, especially for the treatment of pneumonias, are under-utilized. This is mainly due to the poor correlation between in vitro and in vivo/ex vivo studies. Current methods to do not evaluate drug deposition and aerodynamic properties in conjunction with pharmacokinetic and pharmacodynamics studies. Therefore, there is a need for an improved tool to evaluate aerosol testing. |Building off the work done by a previous graduate student, the development of an in vitro model to evaluate antibiotic drug formulation efficacy was created and validated, utilizing large volume liquid impaction surfaces (LVLIS) incorporated into the Next Generation Impactor (NGI). This model allowed for the correlation of deposition and aerodynamic parameters of an antibiotic solution and antibacterial effects. Amberlite® beads were incorporated into the model to absorb the antibiotic so that time kill studies could be performed. Ceftazidime was chosen as the aerosolized antibiotic formulation due to its broad spectrum of activity as a third generation cephalosporin and its use clinically to treat pneumonias, specifically hospital-acquired pneumonias. ‘Laboratory’ strains of both E. coli and Klebsiella pneumoniae were incorporated into the LVLIS modified NGI. Time-kill studies showed decreased bacteria counts over an eight hour time period, and in some strains, complete eradication of the organism was seen. Clinically relevant, susceptible and non-susceptible strains with various resistance mechanisms, of both E. coli and Klebsiella pneumoniae were incorporated into the LVLIS modified NGI. Killing was observed in the susceptible strains and at least a two-log killing was not observed in the non-susceptible strains. A laboratory strain of Pseudomonas aeruginosa was unsuccessfully incorporated into the model. Studies were performed to determine the reason why killing was not observed that suggest that this could have been due to the production of a biofilm by a P. aeruginosa when exposed to the nebulized antibiotic in the LVLIS modified NGI. |The modification to the NGI allowed the correlation of both deposition and aerodynamic parameters with antibacterial effects, which was seen in several bacteria strains. However, further studies need to be completed to widen the scope of the usefulness of this model by incorporating additional clinically relevant bacteria strains, gram negative and gram positive, and characterizing and testing additional antibiotic formulations appropriate for patients with pneumonia.