Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT
Authors: Thwaites Guy E , Scarborough Matthew , Szubert Alexander , Saramago Goncalves Pedro , Soares Marta , Bostock Jennifer , Nsutebu Emmanuel , Tilley Robert , Cunningham Richard , Greig Julia , Wyllie Sarah A , Wilson Peter , Auckland Cressida , Cairns Janet , Ward Denise , Lal Pankaj , Guleri Achyut , Jenkins Neil , Sutton Julian , Wiselka Martin , Armando Gonzalez-Ruiz , Graham Clive , Chadwick Paul R , Barlow Gavin , Gordon N Claire , Young Bernadette , Meisner Sarah , McWhinney Paul , Price David A , Harvey David , Nayar Deepa , Jeyaratnam Dakshika , Planche Timothy , Minton Jane , Hudson Fleur , Hopkins Susan , Williams John , Török M Estee , Llewelyn Martin J , Edgeworth Jonathan D , Walker A Sarah 
Published: November 2018

Background

Staphylococcus aureusbacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance earlyS. aureuskilling, 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 susceptibleS. aureusgrown 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-resistantS. aureus. 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;p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 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 (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode ofS. aureusbacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 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 withS. aureusbacteraemia.

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 inHealth Technology Assessment; Vol. 22, No. 59. See the NIHR Journals Library website for further project information.