Diffusion Retardation by Binding of Tobramycin in an Alginate Biofilm Model

Abstract

Microbial cells embedded in a self-produced extracellular biofilm matrix cause chronic infections, e. g. by Pseudomonas aeruginosa in the lungs of cystic fibrosis patients. The antibiotic killing of bacteria in biofilms is generally known to be reduced by 100–1000 times relative to planktonic bacteria. This makes such infections difficult to treat. We have therefore proposed that biofilms can be regarded as an independent compartment with distinct pharmacokinetics. To elucidate this pharmacokinetics we have measured the penetration of the tobramycin into seaweed alginate beads which serve as a model of the extracellular polysaccharide matrix in P. aeruginosa biofilm. We find that, rather than a normal first order saturation curve, the concentration of tobramycin in the alginate beads follows a power-law as a function of the external concentration. Further, the tobramycin is observed to be uniformly distributed throughout the volume of the alginate bead. The power-law appears to be a consequence of binding to a multitude of different binding sites. In a diffusion model these results are shown to produce pronounced retardation of the penetration of tobramycin into the biofilm. This filtering of the free tobramycin concentration inside biofilm beads is expected to aid in augmenting the survival probability of bacteria residing in the biofilm.

Efficacy of Aerosolized Rifaximin versus Tobramycin for Treatment of Pseudomonas aeruginosa Pneumonia in Mice

“…Screen of NIH drug library for inhibition of alginate production by P. aeruginosa identified RFX. Treatment with TOB cannot completely eradicate P. aeruginosa lung infections in CF, as shown by various recent studies (5,7,9,10,18,19). To identify an alternative treatment strategy, we screened a NIH drug library (16,17), consisting of the 1,171 pharmacologically active compounds currently used in pharmaceuticals and/or clinical trials for inhibition of alginate production, as well as growth inhibition activity against P. aeruginosa.…”

A new mathematical model of bacterial interactions in two-species oral biofilms

“…The decrease of diffusion could be a consequence of the production of specific biofilm extracellular matrix molecules in P. gingivalis biofilms, which would interfere with diffusion [39]. The nature and/or composition of matrix molecules was not studied in this work but would be of interest to better characterize the effect of bacterial species on biofilms.…”

Control of the Lung Residence Time of Highly Permeable Molecules after Nebulization: Example of the Fluoroquinolones

“…These biofilms, mainly present in the conductive area of the lungs [57], are aggregates of PA (50-100 µm large) entrapped in a selfproduced matrix of anionic polymers (polysaccharides, proteins, eDNA, …), and surrounded by the patient's thick mucus (also composed of anionic polymer) and polymorphonuclear leukocyte. One of the proposed mechanisms that contribute to the decrease in the susceptibility of PA to inhaled cationic antimicrobials, such as tobramycin, is the binding and sequestration of positively charged antibiotics by these anionic polymers [47,[58][59][60]. The sustained pulmonary concentration of CIP in the presence copper is due to the formation of a positively charged complex (CIP-Cu) 2+ that reduces the CIP Papp and lung-blood absorption rate.…”