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

journal contribution
posted on 2023-06-08, 14:27 authored by Guy Thwaites, Cressida Auckland, Gavin Barlow, Richard Cunningham, Gerry Davies, Jonathan Edgeworth, Julia Greig, Susan Hopkins, Dakshika Jeyaratnam, Neil Jenkins, Martin LlewelynMartin Llewelyn, Sarah Meisner, Emmanuel Nsutebu, Tim Planche, Robert C Read, Matthew Scarborough, Marta Soares, Robert Tilley, M Estée Török, John Williams, Peter Wilson, Sarah Wyllie, A Sarah Walker
UNLABELLED 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.

History

Publication status

  • Published

Journal

Trials

ISSN

1745-6215

Volume

13

Page range

241

Department affiliated with

  • Clinical and Experimental Medicine Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2013-02-14

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