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Lancet. 2018 Feb 17;391(10121):668-678. doi: 10.1016/S0140-6736(17)32456-X. Epub 2017 Dec 14.

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

Collaborators (452)

Scarborough M, Kamfose M, de Veciana A, Gordon NC, Peto L, Pill G, Clarke T, Watson L, Young B, Griffiths D, Vaughn A, Anson L, Liu E, Perera S, Rylance-Knight L, Cantell C, Moroney R, Edgeworth JD, Thwaites G, Bisnauthsing K, Querol-Rubiera A, Gibbs C, Patel A, Hemsley C, Goodman AL, Wyncoll D, Biswas J, Fitzpatrick J, Roberts L, Millard J, Stone N, Cape A, Hurley L, Tam CK, Nsutebu E, Hoyle MC, Maitland K, Trainor L, Reynolds H, Harrison J, Anson J, Lewis J, Folb J, Goodwin L, Beeching N, Dyas S, Winslow H, Foote E, Roberts P, Natarajan P, Chrdle A, Fenech M, Allsop H, Tilley R, Austin-Hutchison R, Barrett L, Brookes K, Carwithen L, Conbeer A, Cunningham R, Eglinton C, Fok R, Gott H, Hughes S, Jones L, Kalita M, King A, March L, Marner M, Mynes T, Plant A, Price S, Sercombe J, Stolton A, Wallis M, West MC, Westcott J, Williams C, Wosley R, Yabsley L, Greig J, Butland L, Sorrell J, Mitchell T, Alli A, Meiring J, Masake B, Rowson C, Smart L, Makey L, Moll S, Cunningham J, Ryalls K, Birchall K, Middle J, Jackson Y, Swift D, Cole J, Subramanian B, Okhuoya F, Edwards M, Bailey C, Warren R, Islam G, Ankcorn M, Birchall S, Jones P, Humphries J, Booth S, Evan C, Wyllie S, Flatt A, Strakova L, Hayes M, Valentine S, James C, Wands M, Cortes N, Khan N, Porter R, Martin Z, Yip K, Preedy H, Chesterfield H, Dobson T, Walker C, Llewelyn M, Dunne A, Latter L, Porges A, Price J, Paul J, Behar L, Robinson L, Murray A, Fitzpatrick J, Sargent T, Ridley C, de Gordoa LO, Gilliam D, McPherson C, Matthews S, Foreman E, Jarghese R, Beddoe A, Martin S, Shaw S, Wlazly D, Cole M, Gihawi A, Cole K, Török ME, Gouliouris T, Bedford L, Saunderson RB, Mariolis I, Bousfield R, Ramsay I, Greaves D, Aliyu S, Cox K, Mlemba L, Whitehead L, Vyse N, Bolton M, Williams J, Lambert P, Chadwick D, Baillie K, Cain M, Bellamy R, Wong J, Thompson J, Vassallo H, Skotnicka A, Boyce A, Donnelly A, Wilson P, FitzGerald G, Dean V, Warnes K, Reyes A, Rahman S, Tsang L, Williams J, Morris-Jones S, Hopkins S, Witness E, Brady O, Woodford E, Pettifer T, McCadden A, Marks B, Collier S, Mack D, Warren S, Brown C, Lyons A, Taiyari S, Mepham S, Sweeney A, Brown LA, Auckland C, Potter A, Mandiza J, Hough M, Williams S, Renton C, Walters F, Nadolski M, Evans A, Tarrant P, Curley K, Whiteley S, Halpin J, Hutchings M, Todd S, Lohan C, Chapter T, Folland E, Colville A, Marden K, Morgan M, Fok R, Porter R, Baxter M, Minton J, Rippon S, Cevik M, Chapman J, Kemp T, Vincent R, Osborne D, Platt T, Calderwood J, Cook B, Bedford C, Galloway-Browne L, Abberley N, Attack K, Allen J, Lal P, Harrison M, Stevenson S, Brooks C, Harlow P, Ewing J, Cooper S, Balancio-Tolentino R, O'Neil L, Tagney R, Shackcloth D, Planche T, Fellows J, Millett R, Studham J, de Souza C, Howell G, Greaves H, Foncel E, Kurup R, Briggs J, Smith M, Suarez C, Sorrentino G, Scobie A, Houston A, Ahmad F, Breathnach A, Chahuan R, Wilkins K, Guleri A, Waddington N, Sharma R, Flegg P, Kollipara V, Alam M, Potter A, Donaldson S, Armer C, Frudd J, Jeyaratnam D, Joy M, Mathews A, Glass SK, Ajayi A, Fife A, Qaiser S, Sheehan S, Muñoz-Villaverde S, Yogo N, De Abreu I, Notcheva G, Flanagan J, Watson C, Sais E, Adedayo A, Chu V, Shaw G, Graver MA, Palmer R, Palmer D, Haile S, Gordon J, Tam CK, Mandar K, Szypura W, Jenkins N, Marange J, Shabangu V, Moore K, Lyons J, Munang M, Sangombe M, Moran E, Hussain A, Wiselka M, Lewszuk A, Batham S, Ellis K, Bahadur L, White H, Pareek M, Sahota A, Coleman S, Pateman H, Kotecha A, Sim C, Rosser A, Deane J, Nendick R, Aldridge C, Clarke A, Wood M, Marshall A, Stephenson L, Matheson-Smith T, Sloss J, Potts K, Malkin J, Ftika L, Raviprakash V, Sutton J, Malachira A, Kean M, Criste K, Gladas K, Andrews C, Hutchison C, Adams E, Andrews J, Romans B, Ridley N, Ekani M, Mitchell J, Smith N, Clark T, Glover S, Reed R, Yam T, Burton H, Said R, Harvey D, Janvier A, Jacob R, Smalley C, Fair A, Lord S, Ripalda K, Wooldridge H, Cotter L, Cardoso G, Strachan E, Kaler G, Mohamoodally A, Lawrence E, Prime Z, Abrahams R, Price DA, Rigden L, Shewan L, Cullen K, Emmerson I, Martin K, Wilson H, Higham C, Taylor KL, Ong E, Patel B, Bond H, Gradwell J, Widdrington J, Graham C, Thornthwaite S, Prentice S, Poultney U, Crowther H, Fairlamb H, Hetherington E, Brewer C, Banerjee S, Hamson C, McSkeane A, McWhinney P, Sharratt P, Thorpe J, Kimachia S, Wilson H, Jeffs B, Masters L, Wilson J, Platt J, Burgess L, Chadwick P, Jeans A, Keatley C, Moran A, Swann Z, Pagett K, Peel A, Howard J, Meisner S, Maloney K, Masdin A, Wright L, Barlow G, Crossman S, Lowthorpe V, Moore E, Moss P, Parkin A, Wolstencroft A, Warner B, Tarbotton C, Eyre A, Anderson A, Burdett T, Driffill A, Walker AS, Hudson F, Szubert A, Cairns J, Ward D, Webb H, Russell C, Jackson B, Otiko D, Borg C, Masters L, Islam Z, Díaz-Montaña C, Johnson D.

Author information

1
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam. Electronic address: gthwaites@oucru.org.
2
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
3
Medical Research Council Clinical Trials Unit, University College London, London, UK.
4
Royal Liverpool University Hospital, Liverpool, UK.
5
Plymouth Hospitals National Health Service (NHS) Trust, Plymouth, UK.
6
Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
7
Portsmouth Hospitals NHS Trust, Portsmouth, UK.
8
University College London Hospital National Health Service Foundation Trust, London, UK.
9
Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
10
Aintree University Hospital NHS Foundation Trust, Aintree, UK.
11
Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, UK.
12
Heart of England NHS Foundation Trust, Birmingham, UK.
13
University Hospital Southampton NHS Foundation Trust, Southampton, UK.
14
Department of Infection and Tropical Medicine, University Hospitals of Leicester NHS Trust, Leicester, UK.
15
Microbiology Department, Darent Valley Hospital, Dartford, UK.
16
North Cumbria University Hospitals NHS Trust, Carlisle, UK.
17
Salford Royal NHS Foundation Trust, Salford, UK.
18
Hull and East Yorkshire Hospitals NHS Trust, Hull, UK.
19
Royal United Hospitals Bath NHS Foundation Trust, Bath, UK.
20
Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.
21
Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle, UK.
22
Wirral University Teaching Hospital NHS Foundation Trust, Birkenhead, UK.
23
County Durham and Darlington NHS Foundation Trust, Durham, UK.
24
King's College Hospital NHS Foundation Trust, London, UK.
25
St Georges University Hospitals NHS Foundation Trust, London, UK.
26
Leeds Teaching Hospitals NHS Trust, Leeds, UK.
27
Royal Free London NHS Foundation Trust, London, UK.
28
South Tees Hospitals NHS Foundation Trust, Middlesbrough, UK.
29
University of Cambridge, Department of Medicine, Cambridge, UK.
30
Brighton and Sussex Medical School, Brighton, UK.
31
King's College London, London, UK.
32
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Medical Research Council Clinical Trials Unit, University College London, London, UK.

Abstract

BACKGROUND:

Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.

METHODS:

In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.

FINDINGS:

Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).

INTERPRETATION:

Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.

FUNDING:

UK National Institute for Health Research Health Technology Assessment.

PMID:
29249276
PMCID:
PMC5820409
DOI:
10.1016/S0140-6736(17)32456-X
[Indexed for MEDLINE]
Free PMC Article

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