Open Access Study protocol

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia (ARREST): study protocol for a randomised controlled trial

Guy Thwaites1*, Cressida Auckland2, Gavin Barlow3, Richard Cunningham4, Gerry Davies56, Jonathan Edgeworth1, Julia Greig7, Susan Hopkins8, Dakshika Jeyaratnam9, Neil Jenkins10, Martin Llewelyn11, Sarah Meisner12, Emmanuel Nsutebu6, Tim Planche13, Robert C Read14, Matthew Scarborough15, Marta Soares16, Robert Tilley4, M Estée Török17, John Williams18, Peter Wilson19, Sarah Wyllie20, A Sarah Walker2122 and on behalf of the United Kingdom Clinical Infection Research Group

Author Affiliations

1 Department of Infectious Diseases/Centre for Clinical Infection and Diagnostics Research, Kings College London/Guy’s and St. Thomas’ Hospitals NHS Foundation Trust, London, England, United Kingdom

2 Department of Microbiology, Royal Devon and Exeter NHS Foundation Trust, Exeter, England, United Kingdom

3 Department of Infection and Tropical Medicine, Hull and East Yorkshire Hospitals NHS Trust, Hull, England, United Kingdom

4 Department of Microbiology, Plymouth Hospitals NHS Trust, Plymouth, England, United Kingdom

5 Institutes of Infection and Global Health and Translational Medicine, University of Liverpool, Liverpool, England, United Kingdom

6 Department of Infection and Tropical Medicine, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, England, United Kingdom

7 Department of Infectious Diseases, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, England, United Kingdom

8 Department of Infectious Diseases and Microbiology, Royal Free London NHS Foundation Trust, London, England, United Kingdom

9 Department of Medical Microbiology, King’s College Hospital NHS Foundation Trust, London, England, United Kingdom

10 Department of Infection and Tropical Medicine, Birmingham Heart of England NHS Foundation Trust, Birmingham, England, United Kingdom

11 Department of Infectious Diseases and Microbiology, Brighton and Sussex University Hospitals NHS Trust, Brighton, England, United Kingdom

12 Department of Microbiology, Royal United Hospital Bath NHS Trust, Bath, England, United Kingdom

13 Department of Infectious Diseases and Microbiology, St. Georges Healthcare NHS Trust, London, England, United Kingdom

14 Department of Infectious Diseases, University Hospitals Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, England, United Kingdom

15 Department of Infectious Diseases, Oxford University Hospitals NHS Trust, Oxford, England, United Kingdom

16 Centre for Health Economics, York University, York, England, United Kingdom

17 Departments of Infectious Diseases and Microbiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England, United Kingdom

18 Department of Infectious Diseases and Microbiology, South Tees Hospitals NHS Foundation Trust, Middlesbrough, England, United Kingdom

19 Department of Microbiology, University College London Hospitals NHS Foundation Trust, London, England, United Kingdom

20 Department of Microbiology, Portsmouth Hospitals NHS Trust, Portsmouth, England, United Kingdom

21 Infections Theme, MRC Clinical Trials Unit, London, United Kingdom

22 NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom

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Trials 2012, 13:241  doi:10.1186/1745-6215-13-241

Published: 18 December 2012

Abstract

Background

Staphylococcus aureus bacteraemia is a common and serious infection, with an associated mortality of ~25%. Once in the blood, S. aureus can disseminate to infect almost any organ, but bones, joints and heart valves are most frequently affected. Despite the infection’s severity, the evidence guiding optimal antibiotic therapy is weak: fewer than 1,500 patients have been included in 16 randomised controlled trials investigating S. aureus bacteraemia treatment. It is uncertain which antibiotics are most effective, their route of administration and duration, and whether antibiotic combinations are better than single agents. We hypothesise that adjunctive rifampicin, given in combination with a standard first-line antibiotic, will enhance killing of S. aureus early in the treatment course, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. Our aim is to determine whether adjunctive rifampicin reduces all-cause mortality within 14 days and bacteriological failure or death within 12 weeks from randomisation.

Methods

We will perform a parallel group, randomised (1:1), blinded, placebo-controlled trial in NHS hospitals across the UK. Adults (≥18 years) with S. aureus (meticillin-susceptible or resistant) grown from at least one blood culture who have received ≤96 h of active antibiotic therapy for the current infection and do not have contraindications to the use of rifampicin will be eligible for inclusion. Participants will be randomised to adjunctive rifampicin (600-900mg/day; orally or intravenously) or placebo for the first 14 days of therapy in combination with standard single-agent antibiotic therapy. The co-primary outcome measures will be all-cause mortality up to 14 days from randomisation and bacteriological failure/death (all-cause) up to 12 weeks from randomisation. 940 patients will be recruited, providing >80% power to detect 45% and 30% reductions in the two co-primary endpoints of death by 14 days and bacteriological failure/death by 12 weeks respectively.

Discussion

This pragmatic trial addresses the long-standing hypothesis that adjunctive rifampicin improves outcome from S. aureus bacteraemia through enhanced early bacterial killing. If proven correct, it will provide a paradigm through which further improvements in outcome from S. aureus bacteraemia can be explored.

Trial registration

Current Controlled Trial ISRCTN 37666216

Keywords:
Staphylococcus aureus; Bacteraemia; Rifampicin; Mortality