Is the effectiveness of mannitol (Allison et al. 2011) due to elimination of persisters?

Allison et al. (2011) claims that aminoglycosides given in combination with specific metabolites like glucose, fructose, mannitol or pyruvate can be used to treat biofilm-related infections. They demonstrated that catheters colonized with E. coli biofilms, implanted in the urinary tract of mice, had reduced biofilm viability and lower kidney bacterial load when gentamicin was given in combination with mannitol than with gentamicin alone. Based on their findings, it is also proposed that inhaled tobramycin along with mannitol can be effective in treating Pseudomonas aeruginosa infection in cystic fibrosis (CF) (Cain 2011).

However, it is already reported that inhaled mannitol can improve the lung function in CF (Robinson et al. 1999; Jaques et al. 2008). The background information in the abstract of Jaques et al. (2008) is reproduced below.

“The airways in patients with cystic fibrosis (CF) are characterized by the accumulation of tenacious, dehydrated mucus that is a precursor for chronic infection, inflammation, and tissue destruction. The clearance of mucus is an integral component of daily therapy. Inhaled mannitol is an osmotic agent that increases the water content of the airway surface liquid, and improves the clearance of mucus with the potential to improve lung function and respiratory health”.

If mannitol along with aminoglycosides is effective in reducing the bacterial load in CF patients, is it due to the osmotic activity of mannitol or is it due to the ability of mannitol to eliminate persisters? It is already reported that antibiotics may not be effective without clearing mucus and other secretions in the airway.

Similarly, the choice of using mannitol in mouse urinary tract infection model (Allison et al. 2011) raises some questions. Mannitol at 1.5g/kg is an osmotic diuretic, which increases the urinary output. Can the reduction in the number of persisters be due to the increased urine flow that wash away some of the bacteria in the biofilm attached to the urinary catheter? Washing away some of the bacteria not only reduce the bacterial number but also exposes some of the deep seated bacteria, otherwise protected by the biofilm, to the antibiotic more effectively. If I am guessing it correctly, use of other diuretics with aminoglycosides may also give same results (although some combinations are contraindicatory).

In conclusion, it is predictable that

1. administration of glucose with aminoglycosides may not have any effect in reducing bacterial load in CF (on the other hand, it is possible that it may actually worsen the condition)

2. administration of mannitol along with aminoglycosides may reduce bacterial load (but it may not be due to metabolite-enabled eradication of persisters, but due to the osmotic activity of mannitol that improves the clearance of mucus, thus improving the  lung function).

3. even the above combination may not be able to kill the persisters completely.

Allison et al. (2011). Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 473: 216-220.

Cain, C. (2011). Sweetening antibiotic treatments. SciBX 4(23): doi:10.1038/scibx.2011.647.

Baker et al. (2008). Inhaled mannitol improves lung function in cystic fibrosis. Chest 133(6): 1388-1396.

Robinson et al. (1999). The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study. European Respiratory Journal 14(3): 678-685.