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

Guy E. Thwaites*, Matthew Scarborough, Alexander Szubert, Emmanuel Nsutebu, Robert Tilley, Julia Greig, Sarah A. Wyllie, Peter Wilson, Cressida Auckland, Janet Cairns, Denise Ward, Pankaj Lal, Achyut Guleri, Neil Jenkins, Julian Sutton, Martin Wiselka, Gonzalez Ruiz Armando, Clive Graham, Paul R. Chadwick, Gavin BarlowN. Claire Gordon, Bernadette Young, Sarah Meisner, Paul McWhinney, David A. Price, David Harvey, Deepa Nayar, Dakshika Jeyaratnam, Tim Planche, Jane Minton, Fleur Hudson, Susan Hopkins, John Williams, M. Estee Török, Martin J. Llewelyn, Jonathan D. Edgeworth, A. Sarah Walker, Matthew Scarborough, Musa Kamfose, Ana de Veciana, Leon Peto, Gemma Pill, Tiphanie Clarke, Laura Watson, Bernadette Young, Dai Griffiths, Ali Vaughn, Luke Anson, Elian Liu, Pauline Lambert, United Kingdom Clinical Infection Research Group (UKCIRG)

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

86 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)668-678
Number of pages11
JournalThe Lancet
Volume391
Issue number10121
DOIs
Publication statusPublished - 17 Feb 2018

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