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

Abstract

BackgroundStaphylococcus 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.MethodsWe 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.DiscussionThis 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 registrationCurrent Controlled Trial ISRCTN 37666216

Infective endocarditis

“…For staphylococcal PVIE, weak evidence supports the use of both gentamicin and rifampin 156 . A large trial examining the role of adjunctive rifampin for S. aureus bacteraemia has recently completed enrollment 157 .…”

Microbiological characteristics of acute osteoarticular infections in children

“…If bacteraemia is indeed associated with worse outcomes then future clinical trials should consider this and investigate whether these children should be treated differently. Given the prevalence of Staphylococcus aureus bacteraemia amongst bacteraemic children with SA and OM, it is interesting to note that adjunctive rifampicin may be associated with better outcomes than beta-lactam or glycopeptide monotherapy, and this is currently being investigated by the ARREST trial (Russell et al, 2014;Thwaites et al, 2012).…”

Northern Hemisphere temperature patterns in the last 12 centuries

“…Based on the Levine et al 110 aureus bacteraemia [ARREST] study). 113 In a review of four previously published RCTs, 110,112,114,115 Thwaites et al determined that adjunctive rifampin for serious staphylococcal infections was associated with a reduction in infection-related deaths by 55% (p ¼ 0.02). 113 Notably, two of these studies principally focused on MSSA infections treated with oxacillin, 114,115 and the combined findings in this systematic review probably do not apply to MRSA and vancomycin therapy.…”