Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT.

Background: bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death.

Objectives: To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin.

Design: Parallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial.

Setting: UK NHS trust hospitals.

Participants: Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin.

Interventions: Adjunctive rifampicin (600-900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation).

Main Outcome Measures: The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation.

Results: Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50-76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant . A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18-45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference -1.4%, 95% confidence interval (CI) -7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35;  = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures ( = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences ( = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence ( = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death ( = 0.84), all-cause mortality ( = 0.60), serious ( = 0.17) or grade 3/4 ( = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs ( = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions ( = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs ( = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs).

Conclusions: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with bacteraemia.

Future Work: Given the substantial mortality, other antibiotic combinations or improved source management should be investigated.

Trial Registrations: Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 22, No. 59. See the NIHR Journals Library website for further project information.