Dakshika Jeyaratnam, Achyut Guleri, Denise Ward, Gonzalez-Ruiz Armando, Martin Wiselka, Julia Greig, Clive Graham, R. Cunningham, Bernadette C. Young, David Harvey, Jonathan D. Edgeworth, Paul R. Chadwick, Matthew Scarborough, Janet Cairns, Guy E. Thwaites, Robert Tilley, Julian Sutton, M. Estée Török, Paul McWhinney, John Williams, Peter R. Wilson, A. Sarah Walker, Deepa Nayar, Pankaj Lal, Gavin Barlow, Emmanuel Nsutebu, Marta Soares, Neil Jenkins, Alexander J. Szubert, Pedro Saramago Goncalves, Sarah A Wyllie, Jennifer Bostock, Cressida Auckland, David Price, Jane Minton, N. Claire Gordon, Susan Hopkins, Sarah Meisner, T. Planche, Fleur Hudson, Martin J. Llewelyn, Thwaites, Guy E [0000-0002-2858-2087], Scarborough, Matthew [0000-0002-0455-0785], Saramago Goncalves, Pedro [0000-0001-9063-8590], Soares, Marta [0000-0003-1579-8513], Bostock, Jennifer [0000-0001-9261-9350], Cunningham, Richard [0000-0002-6081-2153], Young, Bernadette [0000-0001-6071-6770], Hopkins, Susan [0000-0001-5179-5702], Török, M Estee [0000-0001-9098-8590], Llewelyn, Martin J [0000-0002-6811-1124], and Apollo - University of Cambridge Repository
BackgroundStaphylococcus 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.ObjectivesTo 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.DesignParallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial.SettingUK NHS trust hospitals.ParticipantsAdult inpatients (≥ 18 years) with meticillin-resistant or susceptibleS. aureusgrown from one or more blood cultures, who had received InterventionsAdjunctive 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 measuresThe primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation.ResultsBetween 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).ConclusionsAdjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults withS. aureusbacteraemia.Future workGiven the substantial mortality, other antibiotic combinations or improved source management should be investigated.Trial registrationsCurrent Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001.FundingThis 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.