Journal Article

Low-Dose Nitric Oxide as Targeted Anti-biofilm Adjunctive Therapy to Treat Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis

Allan, Raymond N., Sukhtankar, Priya S., Daniels, Thomas, Howlin, Robert P., Carroll, Mary, Jefferies, Johanna, Feelisch, Martin, Webb, Jeremy S., Rice, Scott A., Stoodley, Paul, Cornelius, Victoria, Fernandez, Bernadette O., Kjelleberg, Staffan, Faust, Saul N., Duignan, Caroline, Clarke, Stuart C., Hall-Stoodley, Luanne, Smith, Caroline, Salib, Rami, Cathie, Katrina, Rogers, Geraint B., Kelso, Michael, Barraud, Nicolas, Legg, Julian, Bruce, Ken D., Connett, Gary, Pink, Sandra

2017

Overview

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. This paper reports the first example of targeted anti-biofilm therapy in human disease. We have demonstrated that using low-dose nitric oxide as a non-bactericidal signaling molecule to induce biofilm dispersal may be useful as a novel adjunctive therapy to treat chronic pseudomonal biofilm infection in cystic fibrosis.

• Publisher: Elsevier Inc,Elsevier Limited,American Society of Gene & Cell Therapy
• Subject: Adolescent / Adult / Anti-Bacterial Agents - administration & dosage / Antibiotic tolerance / Antibiotics / Bacteria / Bacterial Load / Biofilms / Biofilms - drug effects / Biomass / Blood pressure / Ceftazidime / Chronic infection / Clinical trials / Colonization / Cystic fibrosis / Cystic Fibrosis - complications / Dispersal / Dose-Response Relationship, Drug / Humans / Inhalation / Laboratories / Middle Aged / Morbidity / Nitric oxide / Nitric Oxide - administration & dosage / Nitric Oxide - metabolism / Original / Pseudomonas aeruginosa / Pseudomonas aeruginosa - drug effects / Pseudomonas Infections - blood / Pseudomonas Infections - drug therapy / Pseudomonas Infections - microbiology / Randomized Controlled Trials as Topic / Sputum / Sputum - microbiology / Statistical analysis / Time Factors / Tobramycin / Young Adult