Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis

Matthew N Hurley, Sherie Smith, Douglas L Forrester, Alan R Smyth, Matthew N Hurley, Sherie Smith, Douglas L Forrester, Alan R Smyth

Abstract

Background: Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. This leads to lung destruction and eventually death through respiratory failure. There are no antibiotics in development that exert a new mode of action and many of the current antibiotics are ineffective in eradicating the bacteria once chronic infection is established. Antibiotic adjuvants - therapies that act by rendering the organism more susceptible to attack by antibiotics or the host immune system, by rendering it less virulent or killing it by other means, would be a significant therapeutic advance. This is an update of a previously published review.

Objectives: To determine if antibiotic adjuvants improve clinical and microbiological outcome of pulmonary infection in people with cystic fibrosis.

Search methods: We searched the Cystic Fibrosis Trials Register which is compiled from database searches, hand searches of appropriate journals and conference proceedings. Date of most recent search: 16 January 2020. We also searched MEDLINE (all years) on 14 February 2019 and ongoing trials registers on 06 April 2020.

Selection criteria: Randomised controlled trials and quasi-randomised controlled trials of a therapy exerting an antibiotic adjuvant mechanism of action compared to placebo or no therapy for people with cystic fibrosis.

Data collection and analysis: Two of the authors independently assessed and extracted data from identified trials.

Main results: We identified 42 trials of which eight (350 participants) that examined antibiotic adjuvant therapies are included. Two further trials are ongoing and five are awaiting classification. The included trials assessed β-carotene (one trial, 24 participants), garlic (one trial, 34 participants), KB001-A (a monoclonal antibody) (two trials, 196 participants), nitric oxide (two trials, 30 participants) and zinc supplementation (two trials, 66 participants). The zinc trials recruited children only, whereas the remaining trials recruited both adults and children. Three trials were located in Europe, one in Asia and four in the USA. Three of the interventions measured our primary outcome of pulmonary exacerbations (β-carotene, mean difference (MD) -8.00 (95% confidence interval (CI) -18.78 to 2.78); KB001-A, risk ratio (RR) 0.25 (95% CI 0.03 to 2.40); zinc supplementation, RR 1.85 (95% CI 0.65 to 5.26). β-carotene and KB001-A may make little or no difference to the number of exacerbations experienced (low-quality evidence); whereas, given the moderate-quality evidence we found that zinc probably makes no difference to this outcome. Respiratory function was measured in all of the included trials. β-carotene and nitric oxide may make little or no difference to forced expiratory volume in one second (FEV1) (low-quality evidence), whilst garlic probably makes little or no difference to FEV1 (moderate-quality evidence). It is uncertain whether zinc or KB001-A improve FEV1 as the certainty of this evidence is very low. Few adverse events were seen across all of the different interventions and the adverse events that were reported were mild or not treatment-related (quality of the evidence ranged from very low to moderate). One of the trials (169 participants) comparing KB001-A and placebo, reported on the time to the next course of antibiotics; results showed there is probably no difference between groups, HR 1.00 (95% CI 0.69 to 1.45) (moderate-quality evidence). Quality of life was only reported in the two KB001-A trials, which demonstrated that there may be little or no difference between KB001-A and placebo (low-quality evidence). Sputum microbiology was measured and reported for the trials of KB001-A and nitric oxide (four trials). There was very low-quality evidence of a numerical reduction in Pseudomonas aeruginosa density with KB001-A, but it was not significant. The two trials looking at the effects of nitric oxide reported significant reductions in Staphylococcus aureus and near-significant reductions in Pseudomonas aeruginosa, but the quality of this evidence is again very low.

Authors' conclusions: We could not identify an antibiotic adjuvant therapy that we could recommend for treating of lung infection in people with cystic fibrosis. The emergence of increasingly resistant bacteria makes the reliance on antibiotics alone challenging for cystic fibrosis teams. There is a need to explore alternative strategies, such as the use of adjuvant therapies. Further research is required to provide future therapeutic options.

Trial registration: ClinicalTrials.gov NCT01983774 NCT00633191 NCT00742092 NCT02453789 NCT00928135 NCT02157922.

Conflict of interest statement

Dr Matthew Hurley Dr Hurley has no conflicts of interest to declare.

Sherie Smith Sherie Smith has no conflicts of interest to declare.

Dr Doug Forrester Dr Doug Forrester declares he has received support from Wellcome Trust as a Wellcome Trust Clinical Research Training Fellow, travel support from Vertex Pharmaceuticals and GSK and consultancy fees from Mologic.

Professor Alan Smyth Professor Smyth is lead investigator on one of the trials included in the review (Smyth 2010). He further declares relevant activities of lectures paid for by Teva and Novartis. He is affiliated to a research group which holds a patent: "ALKYL QUINOLONES AS BIOMARKERS OF PSEUDOMONAS AERUGINOSA INFECTION AND USES THEREOF".

Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Figures

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Study flow diagram.
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Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
1.1. Analysis
1.1. Analysis
Comparison 1: Chronic infection: β‐carotene supplementation versus placebo, Outcome 1: Days of antibiotic consumption
1.2. Analysis
1.2. Analysis
Comparison 1: Chronic infection: β‐carotene supplementation versus placebo, Outcome 2: Respiratory function absolute FEV1 % predicted up to 3 months
1.3. Analysis
1.3. Analysis
Comparison 1: Chronic infection: β‐carotene supplementation versus placebo, Outcome 3: Mortality
2.1. Analysis
2.1. Analysis
Comparison 2: Chronic infection: garlic supplementation versus placebo, Outcome 1: Respiratory function (% change FEV1)
2.2. Analysis
2.2. Analysis
Comparison 2: Chronic infection: garlic supplementation versus placebo, Outcome 2: Mortality
2.3. Analysis
2.3. Analysis
Comparison 2: Chronic infection: garlic supplementation versus placebo, Outcome 3: Mild adverse events
3.1. Analysis
3.1. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 1: Pulmonary exacerbations
3.2. Analysis
3.2. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 2: Decrease in respiratory function (FEV1)
3.3. Analysis
3.3. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 3: Number of participants experiencing an adverse event
3.4. Analysis
3.4. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 4: Serious adverse events
3.5. Analysis
3.5. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 5: Ear and labyrinth adverse effects
3.6. Analysis
3.6. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 6: Gastrointestinal adverse events
3.7. Analysis
3.7. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 7: General adverse events
3.8. Analysis
3.8. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 8: Infections and infestations
3.9. Analysis
3.9. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 9: Injury, poisoning and procedural complications
3.10. Analysis
3.10. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 10: Investigative adverse events
3.11. Analysis
3.11. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 11: Nervous system adverse events
3.12. Analysis
3.12. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 12: Psychiatric adverse events
3.13. Analysis
3.13. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 13: Respiratory, thoracic and mediastinal adverse events
3.14. Analysis
3.14. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 14: Skin and subcutaneous tissue adverse events
3.15. Analysis
3.15. Analysis
Comparison 3: Chronic infection: KB001‐A versus placebo, Outcome 15: Vascular adverse events
4.1. Analysis
4.1. Analysis
Comparison 4: Chronic infection: nitric oxide versus placebo, Outcome 1: Change from baseline in FEV1 % predicted
4.2. Analysis
4.2. Analysis
Comparison 4: Chronic infection: nitric oxide versus placebo, Outcome 2: Change from baseline in FVC % predicted
5.1. Analysis
5.1. Analysis
Comparison 5: Chronic infection: zinc supplementation versus placebo, Outcome 1: Pulmonary exacerbations (number of participants requiring IV antibiotics)
5.2. Analysis
5.2. Analysis
Comparison 5: Chronic infection: zinc supplementation versus placebo, Outcome 2: Respiratory function (FVC %predicted)
5.3. Analysis
5.3. Analysis
Comparison 5: Chronic infection: zinc supplementation versus placebo, Outcome 3: Antibiotic consumption (days oral antibiotics)
5.4. Analysis
5.4. Analysis
Comparison 5: Chronic infection: zinc supplementation versus placebo, Outcome 4: Antibiotic consumption (days IV antibiotics)
5.5. Analysis
5.5. Analysis
Comparison 5: Chronic infection: zinc supplementation versus placebo, Outcome 5: Antibiotic consumption (days of oral and IV antibiotics)
5.6. Analysis
5.6. Analysis
Comparison 5: Chronic infection: zinc supplementation versus placebo, Outcome 6: Respiratory function (FEV1 % predicted)
5.7. Analysis
5.7. Analysis
Comparison 5: Chronic infection: zinc supplementation versus placebo, Outcome 7: Adverse events (number of participants hospitalised in the study period)

Source: PubMed

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