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

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

Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study

Background Staphylococcus aureus persistent bacteraemia is only vaguely defined and the effect of different durations of bacteraemia on mortality is not well established. Our primary aim was to analyse mortality according to duration of bacteraemia and to derive a clinically relevant definition for persistent bacteraemia. Methods We did a secondary analysis of a prospective observational cohort study at 17 European centres (nine in the UK, six in Spain, and two in Germany), with recruitment between Jan 1, 2013, and April 30, 2015. Adult patients who were consecutively hospitalised with monomicrobial S aureus bacteraemia were included. Patients were excluded if no follow-up blood culture was taken, if the first follow-up blood-culture was after 7 days, or if active antibiotic therapy was started more than 3 days after first blood culture. The primary outcome was 90-day mortality. Univariable and time-dependent multivariable Cox regression analysis were used to assess predictors of mortality. Duration of bacteraemia was defined as bacteraemic days under active antibiotic therapy counting the first day as day 1. Findings Of 1588 individuals assessed for eligibility, 987 were included (median age 65 years [IQR 51–75]; 625 [63%] male). Death within 90 days occurred in 273 (28%) patients. Patients with more than 1 day of bacteraemia (315 [32%]) had higher Charlson comorbidity index and sequential organ failure assessment scores and a longer interval from first symptom to first blood culture. Crude 90-day mortality increased from 22% (148 of 672) with 1 day of bacteraemia, to 39% (85 of 218) with 2–4 days, 43% (30 of 69) with 5–7 days, and 36% (10 of 28) with more than 7 days of bacteraemia. Metastatic infections developed in 39 (6%) of 672 patients with 1 day of bacteraemia versus 40 (13%) of 315 patients if bacteraemia lasted for at least 2 days. The second day of bacteraemia had the highest HR and earliest cutoff significantly associated with mortality (adjusted hazard ratio 1·93, 95% CI 1·51–2·46; p<0·0001). Interpretation We suggest redefining the cutoff duration for persistent bacteraemia as 2 days or more despite active antibiotic therapy. Our results favour follow-up blood cultures after 24 h for early identification of all patients with increased risk of death and metastatic infection