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

United Kingdom Clinical Infection Research Group (UKCIRG)

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139 Scopus citations

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 (US)
Pages (from-to)668-678
Number of pages11
JournalThe Lancet
Volume391
Issue number10121
DOIs
StatePublished - Feb 17 2018

Bibliographical note

Funding Information:
ARREST was funded by the UK National Institutes of Health Research Health Technology Assessment (Project number 10/104/2). The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health. The Medical Research Council Clinical Trials Unit at University College London, UK, is supported by funding from the Medical Research Council (MC_UU_12023/22). We thank the participants and staff from all the centres who participated in the ARREST trial (listed in the appendix pp 2–3 ). We thank the Trial Steering Committee (Adrian Martineau [Chair], Geoff Scott, Achim Kaasch, and Jennifer Bostock [Public and Patient representative]); the Data Monitoring Committee (David Lalloo [Chair], Doug Altman, and Mark Wilcox); and the Endpoint Review Committee (Tim Peto and Graham Cooke).

Funding Information:
Acknowledgments ARREST was funded by the UK National Institutes of Health Research Health Technology Assessment (Project number 10/104/2). The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health. The Medical Research Council Clinical Trials Unit at University College London, UK, is supported by funding from the Medical Research Council (MC_UU_12023/22). We thank the participants and staff from all the centres who participated in the ARREST trial (listed in theappendix pp 2?3). We thank the Trial Steering Committee (Adrian Martineau [Chair], Geoff Scott, Achim Kaasch, and Jennifer Bostock [Public and Patient representative]); the Data Monitoring Committee (David Lalloo [Chair], Doug Altman, and Mark Wilcox); and the Endpoint Review Committee (Tim Peto and Graham Cooke).

Publisher Copyright:
© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

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