sodium-nitrite and Cystic-Fibrosis

CF airway mucus can be infected by opportunistic microorganisms, notably Pseudomonas aeruginosa. Once organisms are established as biofilms, even the most potent antibiotics have little effect on their viability, especially during late-stage chronic infections. Better understanding of the mechanisms used by P. aeruginosa to circumvent host defenses and therapeutic intervention strategies is critical for advancing novel treatment strategies.. Inflammatory injury in CF lung, role of neutrophils in pathogenesis, P. aeruginosa biofilms, mucoidy and its relationship with poor airway oxygenation, mechanisms by which P. aeruginosa biofilms in the CF airway can be killed.. An understanding of the processes that P. aeruginosa undergoes during CF airway disease and clues to better treat such infections in future.. The course of CF airway disease is a process involving host and microbial factors that often dictate frequency of pulmonary exacerbations, thus affecting the overall course. In the past decade significant discoveries have been made regarding the pathogenic processes used by P. aeruginosa to bypass the immune system. Many new and exciting features of P. aeruginosa now illuminate weaknesses in the organism that may render it susceptible to inexpensive compounds that force its own destruction.

Topics: Biofilms; Cystic Fibrosis; Fimbriae, Bacterial; Flagella; Humans; Lung; Neutrophils; Pseudomonas aeruginosa; Pseudomonas Infections; Quorum Sensing; Sodium Nitrite

Sodium nitrite inhibits bacterial respiration and is in development as an antimicrobial for chronic bacterial infections associated with cystic fibrosis. The goal of the current study was to investigate the interaction between nitrite and ciprofloxacin. Using liquid culture killing assays and a biotic biofilm model, we observed that nitrite induces tolerance of ciprofloxacin.

Topics: Anti-Bacterial Agents; Biofilms; Ciprofloxacin; Cystic Fibrosis; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Sodium Nitrite

A hallmark of airways in patients with cystic fibrosis (CF) is highly refractory, chronic infections by several opportunistic bacterial pathogens. A recent study demonstrated that acidified sodium nitrite (A-NO(2)(-)) killed the highly refractory mucoid form of Pseudomonas aeruginosa, a pathogen that significantly compromises lung function in CF patients (S. S. Yoon et al., J. Clin. Invest. 116:436-446, 2006). Therefore, the microbicidal activity of A-NO(2)(-) (pH 6.5) against the following three major CF pathogens was assessed: P. aeruginosa (a mucoid, mucA22 mutant and a sequenced nonmucoid strain, PAO1), Staphylococcus aureus USA300 (methicillin resistant), and Burkholderia cepacia, a notoriously antibiotic-resistant organism. Under planktonic, anaerobic conditions, growth of all strains except for P. aeruginosa PAO1 was inhibited by 7.24 mM (512 μg ml(-1) NO(2)(-)). B. cepacia was particularly sensitive to low concentrations of A-NO(2)(-) (1.81 mM) under planktonic conditions. In antibiotic-resistant communities known as biofilms, which are reminiscent of end-stage CF airway disease, A-NO(2)(-) killed mucoid P. aeruginosa, S. aureus, and B. cepacia; 1 to 2 logs of cells were killed after a 2-day incubation with a single dose of ∼15 mM A-NO(2)(-). Animal toxicology and phase I human trials indicate that these bactericidal levels of A-NO(2)(-) can be easily attained by aerosolization. Thus, in summary, we demonstrate that A-NO(2)(-) is very effective at killing these important CF pathogens and could be effective in other infectious settings, particularly under anaerobic conditions where bacterial defenses against the reduction product of A-NO(2)(-), nitric oxide (NO), are dramatically reduced.

Topics: Anaerobiosis; Anti-Bacterial Agents; Biofilms; Burkholderia cepacia; Cystic Fibrosis; Microbial Sensitivity Tests; Microscopy, Confocal; Plankton; Pseudomonas aeruginosa; Sodium Nitrite