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Despite aggressive antibiotic therapy, bronchopulmonary colonization by Pseudomonas aeruginosa causes persistent morbidity and mortality in cystic fibrosis (CF). Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms. We have demonstrated the effects of non-bactericidal, low-dose nitric oxide (NO), a signaling molecule that induces biofilm dispersal, as a novel adjunctive therapy for P. aeruginosa biofilm infection in CF in an ex vivo model and a proof-of-concept double-blind clinical trial. Submicromolar NO concentrations alone caused disruption of biofilms within ex vivo CF sputum and a statistically significant decrease in ex vivo biofilm tolerance to tobramycin and tobramycin combined with ceftazidime. In the 12-patient randomized clinical trial, 10 ppm NO inhalation caused significant reduction in P. aeruginosa biofilm aggregates compared with placebo across 7 days of treatment. Our results suggest a benefit of using low-dose NO as adjunctive therapy to enhance the efficacy of antibiotics used to treat acute P. aeruginosa exacerbations in CF. Strategies to induce the disruption of biofilms have the potential to overcome biofilm-associated antibiotic tolerance in CF and other biofilm-related diseases.

Despite aggressive antibiotic therapy, bronchopulmonary colonization by Pseudomonas aeruginosa causes persistent morbidity and mortality in cystic fibrosis (CF). Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms. We have demonstrated the effects of non-bactericidal, low-dose nitric oxide (NO), a signaling molecule that induces biofilm dispersal, as a novel adjunctive therapy for P. aeruginosa biofilm infection in CF in an ex vivo model and a proof-of-concept double-blind clinical trial. Submicromolar NO concentrations alone caused disruption of biofilms within ex vivo CF sputum and a statistically significant decrease in ex vivo biofilm tolerance to tobramycin and tobramycin combined with ceftazidime. In the 12-patient randomized clinical trial, 10 ppm NO inhalation caused significant reduction in P. aeruginosa biofilm aggregates compared with placebo across 7 days of treatment. Our results suggest a benefit of using low-dose NO as adjunctive therapy to enhance the efficacy of antibiotics used to treat acute P. aeruginosa exacerbations in CF. Strategies to induce the disruption of biofilms have the potential to overcome biofilm-associated antibiotic tolerance in CF and other biofilm-related diseases.

Biofilms are sessile communities of microbial cells contained within a self-produced exopolymeric matrix. Bacteria encased in biofilms exhibit upwards of 10–1000-fold higher resistance to biocides and traditional antibiotics than their planktonic counterparts (i.e. floating, unattached), and they are less susceptible to host immune defenses.[1, 2] Accordingly, chronic antimicrobial-tolerant bacterial infections are often biofilmbased (e.g. infections on indwelling medical devices and incurable Pseudomonas aeruginosa respiratory infections in cystic fibrosis (CF) sufferers).[3] Currently there are few effective therapeutics for clearing biofilm-based infections, and a critical need exists for new agents and treatment strategies

Biofilms are sessile communities of microbial cells contained within a self-produced exopolymeric matrix. Bacteria encased in biofilms exhibit upwards of 10–1000-fold higher resistance to biocides and traditional antibiotics than their planktonic counterparts (i.e. floating, unattached), and they are less susceptible to host immune defenses.[1, 2] Accordingly, chronic antimicrobial-tolerant bacterial infections are often biofilmbased (e.g. infections on indwelling medical devices and incurable Pseudomonas aeruginosa respiratory infections in cystic fibrosis (CF) sufferers).[3] Currently there are few effective therapeutics for clearing biofilm-based infections, and a critical need exists for new agents and treatment strategies

Biofilms are sessile communities of microbial cells contained within a self-produced exopolymeric matrix. Bacteria encased in biofilms exhibit upwards of 10–1000-fold higher resistance to biocides and traditional antibiotics than their planktonic counterparts (i.e. floating, unattached), and they are less susceptible to host immune defenses.[1, 2] Accordingly, chronic antimicrobial-tolerant bacterial infections are often biofilmbased (e.g. infections on indwelling medical devices and incurable Pseudomonas aeruginosa respiratory infections in cystic fibrosis (CF) sufferers).[3] Currently there are few effective therapeutics for clearing biofilm-based infections, and a critical need exists for new agents and treatment strategies

Biofilms are sessile communities of microbial cells contained within a self-produced exopolymeric matrix. Bacteria encased in biofilms exhibit upwards of 10–1000-fold higher resistance to biocides and traditional antibiotics than their planktonic counterparts (i.e. floating, unattached), and they are less susceptible to host immune defenses.[1, 2] Accordingly, chronic antimicrobial-tolerant bacterial infections are often biofilmbased (e.g. infections on indwelling medical devices and incurable Pseudomonas aeruginosa respiratory infections in cystic fibrosis (CF) sufferers).[3] Currently there are few effective therapeutics for clearing biofilm-based infections, and a critical need exists for new agents and treatment strategies