Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial

Langton Hewer, Simon C.; Smyth, Alan R.; Brown, Michaela; Jones, Ashley P.; Hickey, Helen; Kenna, Dervla; Ashby, Deborah; Thompson, Alexander; Williamson, Paula R.

Abstract

Background: Chronic pulmonary infection with Pseudomonas aeruginosa is one of the most important causes of mortality and morbidity in cystic fibrosis. If antibiotics are commenced promptly, infection can be eradicated. The aim of the trial was to compare the effectiveness and safety of intravenous ceftazidime and tobramycin versus oral ciprofloxacin in the eradication of P aeruginosa. Methods: We did a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic fibrosis centres (70 in the UK and two in Italy). Eligible participants were older than 28 days with an isolate of P aeruginosa (either the first ever isolate or a new isolate after at least 1 year free of infection). Participants were excluded if the P aeruginosa was resistant to, or they had a contraindication to, one or more of the trial antibiotics; if they were already receiving P aeruginosa suppressive therapy; if they had received any P aeruginosa eradication therapy within the previous 9 months; or if they were pregnant or breastfeeding. We used web-based randomisation to assign patients to 14 days intravenous ceftazidime and tobramycin or 12 weeks oral ciprofloxacin. Both were combined with 12 weeks inhaled colistimethate sodium. Randomisation lists were generated by a statistician, who had no involvement in the trial, using a computer-generated list. Randomisation was stratified by centre and because of the nature of the interventions, blinding was not possible. Our primary outcome was eradication of P aeruginosa at 3 months and remaining free of infection to 15 months. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who received at least one dose of study drug. TORPEDO-CF was registered on the ISRCTN register, ISRCTN02734162, and EudraCT, 2009-012575-10. Findings: Between Oct 5, 2010, and Jan 27, 2017, 286 patients were randomly assigned to treatment: 137 to intravenous antibiotics and 149 to oral antibiotics. 55 (44%) of 125 participants in the intravenous group and 68 (52%) of 130 participants in the oral group achieved the primary outcome. Participants randomly assigned to the intravenous group were less likely to achieve the primary outcome, although the difference between groups was not statistically significant (relative risk 0·84, 95% CI 0·65–1·09; p=0·18). 11 serious adverse events occurred in ten (8%) of 126 participants in the intravenous antibiotics group and 17 serious adverse events in 12 (8%) of 146 participants in the oral antibiotics group. Interpretation: Compared with oral therapy, intravenous antibiotics did not achieve sustained eradication of P aeruginosa in a greater proportion of patients with cystic fibrosis and was more expensive. Although there were fewer hospitalisations in the intravenous group than the oral group during follow-up, this confers no advantage over oral treatment because intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P aeruginosa in cystic fibrosis. Funding: National Institute for Health Research Health Technology Assessment Programme.

Citation

Langton Hewer, S. C., Smyth, A. R., Brown, M., Jones, A. P., Hickey, H., Kenna, D., …Williamson, P. R. (2020). Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial. Lancet Respiratory Medicine, 8(10), 975-986. https://doi.org/10.1016/S2213-2600%2820%2930331-3

• Journal Article Type: Article
• Acceptance Date: Jun 9, 2020
• Publication Date: 2020-10
• Deposit Date: Jun 10, 2020
• Publicly Available Date: May 1, 2021
• Journal: The Lancet Respiratory Medicine
• Print ISSN: 2213-2600
• Electronic ISSN: 2213-2619
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 10
• Pages: 975-986
• DOI: https://doi.org/10.1016/S2213-2600%2820%2930331-3
• Keywords: Pulmonary and Respiratory Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/4619414
• Publisher URL: https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30331-3/fulltext
• Related Public URLs: https://www.sciencedirect.com/science/article/pii/S2213260020303313
• Additional Information: This article is maintained by: Elsevier; Article Title: Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial; Journal Title: The Lancet Respiratory Medicine; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/S2213-2600(20)30331-3; Content Type: article; Copyright: © 2020 The Author(s). Published by Elsevier Ltd.