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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)975-986
Number of pages12
JournalThe Lancet Respiratory Medicine
Volume8
Issue number10
DOIs
Publication statusPublished - Oct 2020

Bibliographical note

Funding Information:
SCLH reports grants from National Institute for Health Research Health Technology Assessment award, and speaker fees and expenses from Vertex Pharmaceuticals. ARS reports grants from National Institute for Health Research Health Technology Assessment award and Vertex; and speaker fees and expenses from TEVA and Novartis; and personal fees from Vertex. ARS has a patent for alkyl quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof issued (European Patents Office, EP2997382A1). MB, APJ, HH, DK, DA, AT, and PRW report grants from National Institute for Health Research Health Technology Assessment award.

Funding Information:
AS is supported by the Nottingham National Institute for Health Research (NIHR) Biomedical Research Centre. DA is supported by the NIHR Biomedical Research Centre based at Imperial College Healthcare National Health Service (NHS) Trust and Imperial College London, London, UK. This project was funded by the UK NIHR HTA programme, project number 07/51/01. The trial sponsor was University Hospitals Bristol NHS Foundation Trust and co-sponsor for Italian sites was University of Liverpool. We thank the European Cystic Fibrosis Society Clinical Trial Network for their help and financial support in setting up the trial in Italy. We thank all the participants and their families who took part in this trial and the staff from all participating centres. We thank the independent members of the trial steering committee (Jonathan Grigg [chair], Dominic Kavanagh, Ranjit Lall, Sophie Lewis, Barry Plant, David Stableforth, Jennifer Wederell, and Duncan Geddes [until November 2011], and the independent data and safety monitoring committee (Robert Dinwiddie [chair], Christiane De Boeck, and Mrs Enid Hennessy) for their contributions. We thank Barbara Arch, Vladislav Berdunov, Dannii Clayton, Laura Sutton, and ?ukasz Tanajewski for their contributions in the analyses of the data for the trial. The views expressed in this Article are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Funding Information:
AS is supported by the Nottingham National Institute for Health Research (NIHR) Biomedical Research Centre. DA is supported by the NIHR Biomedical Research Centre based at Imperial College Healthcare National Health Service (NHS) Trust and Imperial College London, London, UK. This project was funded by the UK NIHR HTA programme, project number 07/51/01. The trial sponsor was University Hospitals Bristol NHS Foundation Trust and co-sponsor for Italian sites was University of Liverpool. We thank the European Cystic Fibrosis Society Clinical Trial Network for their help and financial support in setting up the trial in Italy. We thank all the participants and their families who took part in this trial and the staff from all participating centres. We thank the independent members of the trial steering committee (Jonathan Grigg [chair], Dominic Kavanagh, Ranjit Lall, Sophie Lewis, Barry Plant, David Stableforth, Jennifer Wederell, and Duncan Geddes [until November 2011], and the independent data and safety monitoring committee (Robert Dinwiddie [chair], Christiane De Boeck, and Mrs Enid Hennessy) for their contributions. We thank Barbara Arch, Vladislav Berdunov, Dannii Clayton, Laura Sutton, and Łukasz Tanajewski for their contributions in the analyses of the data for the trial. The views expressed in this Article are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Publisher Copyright:
© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

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