The University of Southampton
University of Southampton Institutional Repository

G385 RATNO–Reducing Antibiotic Tolerance using Nitric Oxide in Cystic Fibrosis: report of a proof of concept clinical trial

G385 RATNO–Reducing Antibiotic Tolerance using Nitric Oxide in Cystic Fibrosis: report of a proof of concept clinical trial
G385 RATNO–Reducing Antibiotic Tolerance using Nitric Oxide in Cystic Fibrosis: report of a proof of concept clinical trial
Aims: to investigate whether low dose Nitric Oxide (NO) enhances antibiotic therapy through disruption of Pseudomonas aeruginosa (PA) bacteria in biofilms in patients with Cystic Fibrosis (CF).BackgroundBacterial biofilms present a major challenge due to their antimicrobial tolerance. In CF, chronic PA infection cannot be eradicated with conventional antibiotics, leading to increased hospitalisation, intravenous (IV) antibiotic use, more rapid decline in lung function and reduced survival.PA biofilms are dispersed in ex vivo samples by nanomolar, non-toxic concentrations of NO. Biofilm dispersal is signalled by NO via cyclic-di-GMP leading to increased susceptibility of PA to tobramycin and ceftazidime.

Method: we carried out a participant blind, placebo controlled, randomised trial to investigate whether low dose NO enhances antibiotic therapy through disruption of PA bacteria in biofilms in patients with CF (EudraCT 2010–023529–39). 12 patients received 7 days of NO gas or placebo (air) via nasal cannula for 8 h alongside standard IV antibiotics during a pulmonary exacerbation. Primary outcome was microbiological quantification of PA measured using Fluorescent In Situ Hybridisation (FISH), Quantitative-Polymerase Chain Reaction (Q-PCR) and Colony Forming Units (CFUs). Clinical parameters including lung function and quality of life were secondary outcome measures to monitor safety.
Result: generalised estimating equation analyses of FISH data demonstrated significant reduction in PA biofilm from day 0 to 7 [mean Ln difference between groups 3.49 (95% CI: 0.32, 6.67; p = 0.031) for > 20 bacterial cell aggregates and 4.47 (95% CI: 0.04, 8.98; p = 0.052) for biofilm volume]. CFU and Q-PCR analyses were also consistent with the primary hypothesis (data not shown). The treatment group showed some benefit in FEV1 and FVC during the period of treatment. Mean percentage predicted FEV1 increased by 15.6% (95% CI –5.76–36.96) in the treatment group, compared to 6.67% (95% CI: 1.99–11.3) for placebo. Mean percentage predicted FVC increased by 16% (95% CI –8.94–40.942) in the treatment group and 4.8% (95% CI –2.24–11.90) in the placebo group.
Conclusion: these data show preliminary evidence of benefit using low dose NO as adjunctive therapy with ceftazidime and tobramycin during a 7 day treatment period. Novel targeted NO-donor antimicrobial therapies are being investigated that may enable long term biofilm control and the reduction of PA-related morbidity.
0003-9888
Webb, Jeremy
ec0a5c4e-86cc-4ae9-b390-7298f5d65f8d
Cathie, K.
0aefad71-334f-4938-b896-3572147555ef
Howlin, Robert
f3c84990-6196-47d4-ad8a-80954ea46c7f
Carroll, M.
03b8cfe1-8070-432c-9a7d-c7c7811a94b9
Connett, Gary
55d5676c-90d8-46bf-a508-62eded276516
Cornelius, V.
4b800ab8-820b-4681-ae6f-f52ef8852350
Daniels, T.
f52926d7-b757-4f37-9266-dc5ded38429b
Duignan, Ciara
06c12eb5-d705-4b56-acac-9c7ad80337d3
Hall Stoodley, L.
664c12bf-9dbf-49e9-9f05-d57d6f190481
Jefferies, J.
2d2de9a5-c181-4a86-8166-85cd86acfae9
Kelso, Michael J.
6afd2b75-c893-44cf-8b86-93e89e21f894
Kjelleberg, Staffan
043b66b5-130c-42f2-99b3-ec3eecf3248e
Legg, J.
d448a24c-1dca-40d8-a031-6a04a9a22b1b
Pink, S.
d08a73a0-e7e7-4103-8ee5-e7e001cd5c51
Rogers, G.
fabda4cb-636a-4441-bcf7-050203c4bd3f
Salib, R.
962f24b6-1828-47e7-9827-4a627c63b18b
Stoodley, Paul
08614665-92a9-4466-806e-20c6daeb483f
Sukhtankar, P.
ec2c0290-1c31-4c8e-bf70-9bc1187e16ee
Faust, Saul
f97df780-9f9b-418e-b349-7adf63e150c1
Webb, Jeremy
ec0a5c4e-86cc-4ae9-b390-7298f5d65f8d
Cathie, K.
0aefad71-334f-4938-b896-3572147555ef
Howlin, Robert
f3c84990-6196-47d4-ad8a-80954ea46c7f
Carroll, M.
03b8cfe1-8070-432c-9a7d-c7c7811a94b9
Connett, Gary
55d5676c-90d8-46bf-a508-62eded276516
Cornelius, V.
4b800ab8-820b-4681-ae6f-f52ef8852350
Daniels, T.
f52926d7-b757-4f37-9266-dc5ded38429b
Duignan, Ciara
06c12eb5-d705-4b56-acac-9c7ad80337d3
Hall Stoodley, L.
664c12bf-9dbf-49e9-9f05-d57d6f190481
Jefferies, J.
2d2de9a5-c181-4a86-8166-85cd86acfae9
Kelso, Michael J.
6afd2b75-c893-44cf-8b86-93e89e21f894
Kjelleberg, Staffan
043b66b5-130c-42f2-99b3-ec3eecf3248e
Legg, J.
d448a24c-1dca-40d8-a031-6a04a9a22b1b
Pink, S.
d08a73a0-e7e7-4103-8ee5-e7e001cd5c51
Rogers, G.
fabda4cb-636a-4441-bcf7-050203c4bd3f
Salib, R.
962f24b6-1828-47e7-9827-4a627c63b18b
Stoodley, Paul
08614665-92a9-4466-806e-20c6daeb483f
Sukhtankar, P.
ec2c0290-1c31-4c8e-bf70-9bc1187e16ee
Faust, Saul
f97df780-9f9b-418e-b349-7adf63e150c1

Webb, Jeremy, Cathie, K., Howlin, Robert, Carroll, M., Connett, Gary, Cornelius, V., Daniels, T., Duignan, Ciara, Hall Stoodley, L., Jefferies, J., Kelso, Michael J., Kjelleberg, Staffan, Legg, J., Pink, S., Rogers, G., Salib, R., Stoodley, Paul, Sukhtankar, P. and Faust, Saul (2014) G385 RATNO–Reducing Antibiotic Tolerance using Nitric Oxide in Cystic Fibrosis: report of a proof of concept clinical trial. Archives of Disease in Childhood, 99 (Suppl 1), [A159]. (doi:10.1136/archdischild-2014-306237.367).

Record type: Article

Abstract

Aims: to investigate whether low dose Nitric Oxide (NO) enhances antibiotic therapy through disruption of Pseudomonas aeruginosa (PA) bacteria in biofilms in patients with Cystic Fibrosis (CF).BackgroundBacterial biofilms present a major challenge due to their antimicrobial tolerance. In CF, chronic PA infection cannot be eradicated with conventional antibiotics, leading to increased hospitalisation, intravenous (IV) antibiotic use, more rapid decline in lung function and reduced survival.PA biofilms are dispersed in ex vivo samples by nanomolar, non-toxic concentrations of NO. Biofilm dispersal is signalled by NO via cyclic-di-GMP leading to increased susceptibility of PA to tobramycin and ceftazidime.

Method: we carried out a participant blind, placebo controlled, randomised trial to investigate whether low dose NO enhances antibiotic therapy through disruption of PA bacteria in biofilms in patients with CF (EudraCT 2010–023529–39). 12 patients received 7 days of NO gas or placebo (air) via nasal cannula for 8 h alongside standard IV antibiotics during a pulmonary exacerbation. Primary outcome was microbiological quantification of PA measured using Fluorescent In Situ Hybridisation (FISH), Quantitative-Polymerase Chain Reaction (Q-PCR) and Colony Forming Units (CFUs). Clinical parameters including lung function and quality of life were secondary outcome measures to monitor safety.
Result: generalised estimating equation analyses of FISH data demonstrated significant reduction in PA biofilm from day 0 to 7 [mean Ln difference between groups 3.49 (95% CI: 0.32, 6.67; p = 0.031) for > 20 bacterial cell aggregates and 4.47 (95% CI: 0.04, 8.98; p = 0.052) for biofilm volume]. CFU and Q-PCR analyses were also consistent with the primary hypothesis (data not shown). The treatment group showed some benefit in FEV1 and FVC during the period of treatment. Mean percentage predicted FEV1 increased by 15.6% (95% CI –5.76–36.96) in the treatment group, compared to 6.67% (95% CI: 1.99–11.3) for placebo. Mean percentage predicted FVC increased by 16% (95% CI –8.94–40.942) in the treatment group and 4.8% (95% CI –2.24–11.90) in the placebo group.
Conclusion: these data show preliminary evidence of benefit using low dose NO as adjunctive therapy with ceftazidime and tobramycin during a 7 day treatment period. Novel targeted NO-donor antimicrobial therapies are being investigated that may enable long term biofilm control and the reduction of PA-related morbidity.

Full text not available from this repository.

More information

Published date: April 2014

Identifiers

Local EPrints ID: 442671
URI: http://eprints.soton.ac.uk/id/eprint/442671
ISSN: 0003-9888
PURE UUID: da349a0d-d351-4e8e-ac02-4737f55c846f
ORCID for Jeremy Webb: ORCID iD orcid.org/0000-0003-2068-8589
ORCID for Gary Connett: ORCID iD orcid.org/0000-0003-1310-3239
ORCID for Paul Stoodley: ORCID iD orcid.org/0000-0001-6069-273X
ORCID for Saul Faust: ORCID iD orcid.org/0000-0003-3410-7642

Catalogue record

Date deposited: 23 Jul 2020 16:30
Last modified: 18 Feb 2021 17:36

Export record

Altmetrics

Contributors

Author: Jeremy Webb ORCID iD
Author: K. Cathie
Author: Robert Howlin
Author: M. Carroll
Author: Gary Connett ORCID iD
Author: V. Cornelius
Author: T. Daniels
Author: Ciara Duignan
Author: L. Hall Stoodley
Author: J. Jefferies
Author: Michael J. Kelso
Author: Staffan Kjelleberg
Author: J. Legg
Author: S. Pink
Author: G. Rogers
Author: R. Salib
Author: Paul Stoodley ORCID iD
Author: P. Sukhtankar
Author: Saul Faust ORCID iD

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×