Abstract
Background: People with cystic fibrosis are susceptible to pulmonary infection with Pseudomonas aeruginosa. This may become chronic and lead to increased mortality and morbidity. If treatment is commenced promptly, infection may be eradicated through prolonged antibiotic treatment.
Objective: To compare the clinical effectiveness, cost-effectiveness and safety of two eradication regimens.
Design: This was a Phase IV, multicentre, parallel-group, randomised controlled trial. Setting Seventy UK and two Italian cystic fibrosis centres.
Participants: Participants were individuals with cystic fibrosis aged> 28 days old who had never had a P. aeruginosa infection or who had been infection free for 1 year.
Interventions: Fourteen days of intravenous ceftazidime and tobramycin or 3 months of oral ciprofloxacin. Inhaled colistimethate sodium was included in both regimens over 3 months. Consenting patients were randomly allocated to either treatment arm in a 1:1 ratio using simple block randomisation with random variable block length.
Main outcome measures: The primary outcome was eradication of P. aeruginosa at 3 months and remaining free of infection to 15 months. Secondary outcomes included time to reoccurrence, spirometry, anthropometrics, pulmonary exacerbations and hospitalisations. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who had received at least one dose of any of the study drugs. Cost-effectiveness analysis explored the cost per successful eradication and the cost per quality-adjusted life-year.
Results: Between 5 October 2010 and 27 January 2017, 286 patients were randomised: 137 patients to intravenous antibiotics and 149 patients to oral antibiotics. The numbers of participants achieving the primary outcome were 55 out of 125 (44%) in the intravenous group and 68 out of 130 (52%) in the oral group. Participants randomised to the intravenous group were less likely to achieve the primary outcome; although the difference between groups was not statistically significant, the clinically important difference that the trial aimed to detect was not contained within the confidence interval (relative risk 0.84, 95% confidence interval 0.65 to 1.09; p = 0.184). Significantly fewer patients in the intravenous group (40/129, 31%) than in the oral group (61/136, 44.9%) were hospitalised in the 12 months following eradication treatment (relative risk 0.69, 95% confidence interval 0.5 to 0.95; p = 0.02). There were no clinically important differences in other secondary outcomes. There were 32 serious adverse events in 24 participants [intravenous: 10/126 (7.9%); oral: 14/146 (9.6%)]. Oral therapy led to reductions in costs compared with intravenous therapy (-£5938.50, 95% confidence interval -£7190.30 to-£4686.70). Intravenous therapy usually necessitated hospital admission, which accounted for a large part of this cost.
Limitations: Only 15 out of the 286 participants recruited were adults-partly because of the smaller number of adult centres participating in the trial. The possibility that the trial participants may be different from the rest of the cystic fibrosis population and may have had a better clinical status, and so be more likely to agree to the uncertainty of trial participation, cannot be ruled out.
Conclusions: Intravenous antibiotics did not achieve sustained eradication of P. aeruginosa in a greater proportion of cystic fibrosis patients. Although there were fewer hospitalisations in the intravenous group during follow-up, this confers no advantage over the oral therapy group, as intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P. aeruginosa in cystic fibrosis.
Future work: Future research studies should combine long-term follow-up with regimens to reduce reoccurrence after eradication.
| Original language | English |
|---|---|
| Number of pages | 158 |
| Journal | Health Technology Assessment |
| Volume | 25 |
| Issue number | 65 |
| DOIs | |
| Publication status | Published - 01 Nov 2021 |
| Externally published | Yes |
Bibliographical note
Funding Information:Declared competing interests of authors: Alan R Smyth reports grants from Vertex Pharmaceuticals, Inc. (Boston, MA, USA), personal fees from Vertex Pharmaceuticals, Inc., non-financial support from Teva Pharmaceuticals (Petah Tikva, Israel) and non-financial support from Novartis International AG (Basel, Switzerland) outside the submitted work. In addition, Alan R Smyth has a patent for alkyl quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof issued and was a member of the Health Technology Assessment (HTA) Clinical Evaluation and Trials Committee (from 1 April 2011 to 1 April 2016). Deborah Ashby has been a member of various National Institute for Health Research (NIHR) Committees from 2008 to 2018 [HTA Commissioning Sub-Board (Expression of Interest) 1 April 2016 to 31 March 2017; HTA Funding Teleconference Members 31 May 2016 to 1 October 2016; NIHR Clinical Trials Unit Standing Advisory Committee 1 May 2008 to 1 May 2014; HTA Board Recruitment 1 January 2016 to 31 December 2018; HTA Remit and Competitiveness Group 1 May 2018 to 30 November 2018; HTA Funding Committee Policy Group (formerly Commissioning Strategy Group) 1 November 2015 to 30 November 2018, Imperial College London; and HTA Commissioning Committee, 1 November 2015 to 31 December 2018, all while at Imperial College London]. In additon, Deborah Ashby is supported by NIHR Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. Paula R Williamson was Director of Liverpool Clinical Trials Centre (April 2005–December 2018; formerly Medicines for Children Clinical Trials Unit), which received funding from NIHR (end date 31 August 2021), and reports grants from the University of Liverpool, during the conduct of the study. We would like to thank the European Cystic Fibrosis Society Clinical Trial Network for its help and financial support in setting up the trial in Italy.
Funding Information:
The research reported in this issue of the journal was funded by the HTA programme as project number 07/51/01. The contractual start date was in December 2009. The draft report began editorial review in August 2019 and was accepted for publication in December 2020. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.
Funding Information:
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 65. See the NIHR Journals Library website for further project information.
Funding Information:
T his project was funded by the UK NIHR Health Technology Assessment programme, project number 07/51/01 and trial registration number EudraCT 2009-012575-10. The trial sponsor was University Hospitals Bristol NHS Foundation Trust and co-sponsor for the Italian sites was the University of Liverpool, a member of Liverpool Health Partners.
Publisher Copyright:
© Queen’s Printer and Controller of HMSO 2021.
ASJC Scopus subject areas
- Health Policy
Access to Document
- Intravenous or oral antibiotic treatment in adults and children with cystic fibrosis and Pseudomonas aeruginosa infection: the TORPEDO-CF RCT
© Queen’s Printer and Controller of HMSO 2021. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.