Tobramycin Efficacy Decreased by Human Airway Mucus

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Investigators demonstrated results supporting the likelihood that mucus environment and biofilm formation might be highly relevant in anti-infective drug development.
Investigators demonstrated results supporting the likelihood that mucus environment and biofilm formation might be highly relevant in anti-infective drug development.

Human airway mucus alters the susceptibility of Pseudomonas aeruginosa biofilms to tobramycin but not to colistin, according to a study published in the Journal of Antimicrobial Chemotherapy.

Normal airway epithelium enables continuous clearance of inhaled pathogens and pollutants by constant mucus secretion into the airway lumen and the coordinated beating of epithelial cell cilia. In diseases like asthma and cystic fibrosis (CF), the mucociliary machinery is compromised, reducing the mucus clearance rate and providing an optimal environment for bacterial infections.

P aeruginosa is one of the most prevalent pathogens found in patients with CF. Inhaled antibiotic therapies for pseudomonal infections such as tobramycin, colistin, levofloxacin, and aztreonam, are relatively effective in early stages of P aeruginosa infection. In the lungs of individuals living with CF, P aeruginosa forms structured bacterial communities (biofilms) that are surrounded by a self-produced extracellular matrix known to evade antibacterial treatment. 

Further, P aeruginosa biofilms are often embedded in mucus, representing an additional barrier to the diffusion of inhaled drugs. Therefore, an effective antibiotic therapy must overcome both the extracellular matrix of the biofilms and mucus layer. These barriers are barely addressed in the currently available in vitro models used during pre-clinical development stages of anti-infective candidates. This study aimed to investigate the impact of airway mucus on P aeruginosa biofilm susceptibility to antibiotic treatment.

P aeruginosa biofilms were grown in vitro in the presence or absence of human tracheal mucus and the antibacterial efficacy of colistin and tobramycin — a process termed P aeruginosa biofilm susceptibility (PBS) by the researchers — was investigated in a total of 85 independent mucus samples. The efficacy of antibiotics is typically assessed by determining the minimum inhibitory concentration (MIC) using in vitro assays; however, this technique does not take into account either bacterial biofilm formation or the influence of mucus, both of which may act as diffusion barriers, potentially limiting antibiotic efficacy.

Biofilms grown in PBS required a concentration 900 times higher than the MIC to be eradicated, irrespective of the antibiotic used. In biofilms grown in a mucus environment, a concentration-dependent decrease in viable bacterial load could still be seen for both antibiotics. However, tobramycin efficacy was significantly impaired in the presence of mucus, leading to a shift of the IC50 value from 100 mg/L without mucus to >900 mg/L with mucus. In contrast, colistin treatment efficacy was not affected by the mucus environment, with IC50 values of 170 and 190 mg/L for biofilms grown in PBS and in mucus, respectively. Furthermore, diffusion studies revealed significantly retarded and decreased diffusion of tobramycin through mucus compared with diffusion through pure mucus or biofilm formed in PBS. This reduction was more pronounced in biofilm/mucus mixtures, suggesting biofilms in the presence of mucus respond differently to antibiotic treatment. Alternatively, no differences in mucus permeability of colistin were observed.

Overall, results suggest the mucus environment and biofilm formation may be of high relevance for anti-infective drug development. The study investigators concluded that, “[A] model considering mucus as the natural microenvironment for P aeruginosa biofilms in human lungs has been successfully developed, suggesting that the mucus environment should be considered as a key factor for in vivo biofilm formation.”

Reference

Müller L, Murgia X, et al. Human airway mucus alters susceptibility of Pseudomonas aeruginosa biofilms to tobramycin, but not colistin [published online July 5, 2018]. J Antimicrob Chemother. doi:10.1093/jac/dky241

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