title: Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia (ARREST): study protocol for a randomised controlled trial.
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 (600-900 mg/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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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. guy.thwaites@btinternet.com
authors.forename: Guy
authors.initials: G
authors.lastname: Thwaites
authors.forename: Cressida
authors.initials: C
authors.lastname: Auckland
authors.forename: Gavin
authors.initials: G
authors.lastname: Barlow
authors.forename: Richard
authors.initials: R
authors.lastname: Cunningham
authors.forename: Gerry
authors.initials: G
authors.lastname: Davies
authors.forename: Jonathan
authors.initials: J
authors.lastname: Edgeworth
authors.forename: Julia
authors.initials: J
authors.lastname: Greig
authors.forename: Susan
authors.initials: S
authors.lastname: Hopkins
authors.forename: Dakshika
authors.initials: D
authors.lastname: Jeyaratnam
authors.forename: Neil
authors.initials: N
authors.lastname: Jenkins
authors.forename: Martin
authors.initials: M
authors.lastname: Llewelyn
authors.forename: Sarah
authors.initials: S
authors.lastname: Meisner
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Nsutebu
authors.forename: Tim
authors.initials: T
authors.lastname: Planche
authors.forename: Robert C
authors.initials: RC
authors.lastname: Read
authors.forename: Matthew
authors.initials: M
authors.lastname: Scarborough
authors.forename: Marta
authors.initials: M
authors.lastname: Soares
authors.forename: Robert
authors.initials: R
authors.lastname: Tilley
authors.forename: M Estée
authors.initials: ME
authors.lastname: Török
authors.forename: John
authors.initials: J
authors.lastname: Williams
authors.forename: Peter
authors.initials: P
authors.lastname: Wilson
authors.forename: Sarah
authors.initials: S
authors.lastname: Wyllie
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy* / Q000401:mortality; D002985:Clinical Protocols; D006801:Humans; D012293:Rifampin / Q000009:adverse effects / Q000627:therapeutic use*; D018401:Sample Size; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000900:Anti-Bacterial Agents; D012293:Rifampin