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

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

doi:10.1016/j.ymthe.2017.06.021

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

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

College of Medicine and Public Health

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Abstract

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.

Original language	English
Pages (from-to)	2104-2116
Number of pages	13
Journal	MOLECULAR THERAPY
Volume	25
Issue number	9
DOIs	https://doi.org/10.1016/j.ymthe.2017.06.021
Publication status	Published - 6 Sept 2017

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Under a Creative Commons License.
You are free to:
Share — copy and redistribute the material in any medium or format
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This license is acceptable for Free Cultural Works.
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Keywords

Pseudomonas aeruginosa
cystic fibrosis
nitric oxide

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Howlin_Low-dose_P2017Final published version, 3.1 MBLicence: CC BY

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Howlin, R. P., Cathie, K., Hall-Stoodley, L., Cornelius, V., Duignan, C., Allan, R. N., Fernandez, B. O., Barraud, N., Bruce, K. D., Jefferies, J., Kelso, M., Kjelleberg, S., Rice, S. A., Rogers, G. B., Pink, S., Smith, C., Sukhtankar, P. S., Salib, R., Legg, J., ... Webb, J. S. (2017). Low-Dose Nitric Oxide as Targeted Anti-biofilm Adjunctive Therapy to Treat Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis. MOLECULAR THERAPY, 25(9), 2104-2116. https://doi.org/10.1016/j.ymthe.2017.06.021

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abstract = "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.",

keywords = "Pseudomonas aeruginosa, cystic fibrosis, nitric oxide",

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

note = "Under a Creative Commons License. You are free to: Share — copy and redistribute the material in any medium or format Adapt — remix, transform, and build upon the material for any purpose, even commercially. This license is acceptable for Free Cultural Works. The licensor cannot revoke these freedoms as long as you follow the license terms. Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits. ",

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doi = "10.1016/j.ymthe.2017.06.021",

language = "English",

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Howlin, RP, Cathie, K, Hall-Stoodley, L, Cornelius, V, Duignan, C, Allan, RN, Fernandez, BO, Barraud, N, Bruce, KD, Jefferies, J, Kelso, M, Kjelleberg, S, Rice, SA, Rogers, GB, Pink, S, Smith, C, Sukhtankar, PS, Salib, R, Legg, J, Carroll, M, Daniels, T, Feelisch, M, Stoodley, P, Clarke, SC, Connett, G, Faust, SN & Webb, JS 2017, 'Low-Dose Nitric Oxide as Targeted Anti-biofilm Adjunctive Therapy to Treat Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis', MOLECULAR THERAPY, vol. 25, no. 9, pp. 2104-2116. https://doi.org/10.1016/j.ymthe.2017.06.021

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AU - Howlin, Robert P

AU - Cathie, Katrina

AU - Hall-Stoodley, Luanne

AU - Cornelius, Victoria

AU - Duignan, Caroline

AU - Allan, Raymond N

AU - Fernandez, Bernadette O

AU - Barraud, Nicolas

AU - Bruce, Ken D

AU - Jefferies, Johanna

AU - Kelso, Michael

AU - Kjelleberg, Staffan

AU - Rice, Scott A

AU - Rogers, Geraint B

AU - Pink, Sandra

AU - Smith, Caroline

AU - Sukhtankar, Priya S

AU - Salib, Rami

AU - Legg, Julian

AU - Carroll, Mary

AU - Daniels, Thomas

AU - Feelisch, Martin

AU - Stoodley, Paul

AU - Clarke, Stuart C

AU - Connett, Gary

AU - Faust, Saul N

AU - Webb, Jeremy S

N1 - Under a Creative Commons License. You are free to: Share — copy and redistribute the material in any medium or format Adapt — remix, transform, and build upon the material for any purpose, even commercially. This license is acceptable for Free Cultural Works. The licensor cannot revoke these freedoms as long as you follow the license terms. Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.

PY - 2017/9/6

Y1 - 2017/9/6

N2 - 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.

AB - 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.

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DO - 10.1016/j.ymthe.2017.06.021

M3 - Article

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JO - MOLECULAR THERAPY

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

Abstract

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