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

Thwaites, Guy E, Scarborough, Matthew, Szubert, Alexander, Nsutebu, Emmanuel, Tilley, Robert, Greig, Julia, Wyllie, Sarah A, Wilson, Peter, Auckland, Cressida, Cairns, Janet, Ward, Denise, Lal, Pankaj, Guleri, Achyut, Jenkins, Neil, Sutton, Julian, Wiselka, Martin, Armando, Gonzalez-Ruiz, Graham, Clive, Chadwick, Paul R, Barlow, Gavin, Gordon, N Claire, Young, Bernadette, Meisner, Sarah, McWhinney, Paul, Price, David A, Harvey, David, Nayar, Deepa, Jeyaratnam, Dakshika, Planche, Tim, Minton, Jane, Hudson, Fleur, Hopkins, Susan, Williams, John, Török, M Estee, Llewelyn, Martin J, Edgeworth, Jonathan D, on behalf of the UK Clinical Infection Research Grou, and Cole, Kevin (2018) Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet, 391 (10121). pp. 668-678. ISSN 0140-6736

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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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Global Health and Infection
Subjects: R Medicine
R Medicine > R Medicine (General)
Depositing User: Sandy Gray
Date Deposited: 15 Jan 2018 14:23
Last Modified: 26 Feb 2018 11:13
URI: http://sro.sussex.ac.uk/id/eprint/72827

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