Inhaled Sodium Nitrite as an Antimicrobial for Cystic Fibrosis

Pseudomonas aeruginosa infects the airways of 80% of adults with Cystic Fibrosis (CF). In these patients, P. aeruginosa forms extremely antibiotic resistant biofilm communities that accelerate progression of obstructive lung disease. Current treatment of airway infection focuses on monthly cycles of inhaled antibiotics. However up to 20% of adults are infected with multi drug resistant P. aeruginosa for which we have no effective inhaled treatments. These isolates are more common as patients age so with the increasing life expectancy of the CF population, MDR P. aeruginosa is likely to remain a clinical problem. Another 10% of patients are infected with other Gram-negative organisms such as Burkholderia cepacia and Achromobacter species, for which we have inadequate suppressive treatment. Following lung transplant, MDR airway infections remain a problem as the allografts are colonized by strains carried in the paranasal sinuses. Sodium nitrite may present a new antimicrobial approach to treating respiratory infection with Gram-negative organisms, because it is able to prevent biotic biofilm formation.

Within the CF lung, P. aeruginosa grows as a biotic biofilm in association with airway epithelial cells and mucous plaques. This environment has an acidic pH and low oxygen tension with many bacteria subsisting through denitrification (both conditions where traditional antibiotics are less effective). Because biotic biofilms can be up to 500-fold more resistant than biofilms grown on abiotic surfaces, with support from our CF Research Development Program (RDP) Cores, we showed that nitrite prevents biofilm formation on the surface of primary CF airway epithelial cells. Moreover, nitrite dose-dependently potentiates the effects of colistin sulfate in liquid culture, and in biotic biofilms on airway epithelial cells. These data support the hypothesis that nebulized sodium nitrite will inhibit growth of Pseudomonas aeruginosa in CF airways, and identify a potential therapeutic benefit for nitrite alone and cooperatively with colistin as a novel therapy to inhibit P. aeruginosa in CF airways. Nebulized nitrite has been through extensive animal toxicology, and is well tolerated by subjects with pulmonary arterial hypertension where it is being studied as a pulmonary vasodilator.

To determine the therapeutic potential of sodium nitrite for CF, we propose two specific aims:

Aim 1: Determine the safety of nebulized sodium nitrite administered in two doses to patients with CF.

Aim 2: Explore the effects of inhaled sodium nitrite on measures of lung function, exhaled airway nitric oxide, and bacterial burden as measured by quantitative sputum cultures.