Abstract

Pulmonary administration of antibiotics presents potential clinical use to treat chronic lung infections, as it may allow for higher drug concentrations at the site of infection while reducing systemic exposure compare to i.v. administration. This is mainly true for antibiotics having low lung-blood barrier permeability, such as tobramycin or colistin methansulfonate. However; this approach is less enabled for molecules that readily diffuse through the barrier to equilibrate with the blood, such as ciprofloxacin (CIP). In order to increase CIP lung residency time after its aerosolization, we recently developed positively charged complexes of CIP with calcium or copper. In fact, a 1/1 molar complex of CIP-Cu showed a decrease in CIP apparent permeability of 90% across a model of pulmonary epithelium. Also, the pulmonary delivery of this complex as dry microparticle provided and maintained CIP concentrations in the lung epithelial lining fluid 148-fold higher during 6h than those obtained after nebulization of a CIP solution in rats. Additionally, the antibacterial activity of CIP and CIP-Cu, studied on planktonic P. aeruginosa (PA - the main pathogen in chronic lung infection) by measure of minimum inhibitory concentration (MIC), were equivalent. However, one of the main challenges associated with the therapy against PA chronic pulmonary infections is the formation in the lung of PA communities submerged into a negatively charged extracellular polymeric substance (EPS), called biofilm. The principal problem with biofilms is the increased resistance to antimicrobials compared to the resistance of planktonic bacteria. A proposed mechanism that contributes to this increased resistance is binding and sequestration of positively charged antimicrobials by negatively charged EPS. Thus, the aim of this study was to evaluate the effect of positively charged CIP-Cu complex on biofilm formed by different PA stains.