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

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.

Figure 1

Trial profile *Reasons are not mutually exclusive; therefore, total is more than the number of participants not randomly assigned. †Seven participants with predicted drug interaction, two misdiagnosed (S aureus not grown from blood but only other samples), rifampicin considered mandatory in one, one other clinician considered participant should not have been assigned because of acute kidney injury, one other clinician considered participant should not have been randomly assigned because they were in another study (not of an investigational medicinal product). ‡Final 12-week visit could occur any time from 11 weeks onwards according to the protocol. Consent withdrawals not included in these numbers. §Time-to-event analyses included all time at risk from randomisation to the earliest of the event or last clinical follow-up if the event had not occurred.

Figure 2

Treatment failure, disease recurrence, and death from randomisation to 12 weeks Kaplan-Meier curves of bacteriologically confirmed treatment failure or disease recurrence, or death, (A), clinically defined treatment failure or disease recurrence, or death, (C), and mortality (D) from randomisation to 12 weeks; and Forest plot of three priority subgroup analyses for bacteriological treatment failure or disease recurrence, or death from randomisation to 12 weeks (primary endpoint; B). The p value for interaction is presented in (B). HR=hazard ratio. MSSA=meticillin-susceptible Staphylococcus aureus. MRSA=meticillin-resistant S aureus.

Figure 3

Long-term mortality Dashed line indicates end of formal trial follow-up. HR=hazard ratio.