PMID- 30382016 OWN - NLM STAT- MEDLINE DCOM- 20190409 LR - 20210109 IS - 2046-4924 (Electronic) IS - 1366-5278 (Print) IS - 1366-5278 (Linking) VI - 22 IP - 59 DP - 2018 Oct TI - Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT. PG - 1-148 LID - 10.3310/hta22590 [doi] AB - BACKGROUND: Staphylococcus aureus bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early S. aureus 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 S. aureus 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 S. 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 of S. aureus bacteraemia costs an average of pound12,197 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 with S. aureus 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 Health Technology Assessment; Vol. 22, No. 59. See the NIHR Journals Library website for further project information. FAU - Thwaites, Guy E AU - Thwaites GE AD - Nuffield Department of Medicine, University of Oxford, Oxford, UK. AD - Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam. FAU - Scarborough, Matthew AU - Scarborough M AD - Nuffield Department of Medicine, University of Oxford, Oxford, UK. FAU - Szubert, Alexander AU - Szubert A AD - Medical Research Council Clinical Trials Unit, University College London, London, UK. FAU - Saramago Goncalves, Pedro AU - Saramago Goncalves P AD - Centre for Health Economics, University of York, York, UK. FAU - Soares, Marta AU - Soares M AD - Centre for Health Economics, University of York, York, UK. FAU - Bostock, Jennifer AU - Bostock J AD - Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. FAU - Nsutebu, Emmanuel AU - Nsutebu E AD - Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, Liverpool, UK. FAU - Tilley, Robert AU - Tilley R AD - Department of Microbiology, Plymouth Hospitals NHS Trust, Plymouth, UK. FAU - Cunningham, Richard AU - Cunningham R AD - Department of Microbiology, Plymouth Hospitals NHS Trust, Plymouth, UK. FAU - Greig, Julia AU - Greig J AD - Department of Infectious Diseases, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. FAU - Wyllie, Sarah A AU - Wyllie SA AD - Microbiology Department, Portsmouth Hospitals NHS Trust, Portsmouth, UK. FAU - Wilson, Peter AU - Wilson P AD - Centre for Clinical Microbiology, University College London Hospital NHS Foundation Trust, London, UK. FAU - Auckland, Cressida AU - Auckland C AD - Microbiology Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. FAU - Cairns, Janet AU - Cairns J AD - Medical Research Council Clinical Trials Unit, University College London, London, UK. FAU - Ward, Denise AU - Ward D AD - Medical Research Council Clinical Trials Unit, University College London, London, UK. FAU - Lal, Pankaj AU - Lal P AD - Microbiology Department, Aintree University Hospital NHS Foundation Trust, Liverpool, UK. FAU - Guleri, Achyut AU - Guleri A AD - Microbiology Department, Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, UK. FAU - Jenkins, Neil AU - Jenkins N AD - Department of Infectious Diseases and Tropical Medicine, Heart of England NHS Foundation Trust, Birmingham, UK. FAU - Sutton, Julian AU - Sutton J AD - Department of Microbiology and Virology, University Hospital Southampton NHS Foundation Trust, Southampton, UK. FAU - Wiselka, Martin AU - Wiselka M AD - Department of Infection and Tropical Medicine, University Hospitals of Leicester NHS Trust, Leicester, UK. FAU - Armando, Gonzalez-Ruiz AU - Armando GR AD - Microbiology Department, Darent Valley Hospital, Dartford, UK. FAU - Graham, Clive AU - Graham C AD - Microbiology Department, North Cumbria University Hospitals NHS Trust, Cumbria, UK. FAU - Chadwick, Paul R AU - Chadwick PR AD - Microbiology Department, Salford Royal NHS Foundation Trust, Salford, UK. FAU - Barlow, Gavin AU - Barlow G AD - Department of Infection, Hull and East Yorkshire Hospitals NHS Trust, Hull, UK. FAU - Gordon, N Claire AU - Gordon NC AD - Nuffield Department of Medicine, University of Oxford, Oxford, UK. FAU - Young, Bernadette AU - Young B AD - Nuffield Department of Medicine, University of Oxford, Oxford, UK. FAU - Meisner, Sarah AU - Meisner S AD - Microbiology Department, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK. FAU - McWhinney, Paul AU - McWhinney P AD - Microbiology Department, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK. FAU - Price, David A AU - Price DA AD - Department of Infectious Diseases, Newcastle Upon Tyne Hospital NHS Foundation Trust, Newcastle, UK. FAU - Harvey, David AU - Harvey D AD - Microbiology Department, Wirral University Teaching Hospital NHS Foundation Trust, Birkenhead, UK. FAU - Nayar, Deepa AU - Nayar D AD - Microbiology Department, County Durham and Darlington NHS Foundation Trust, Durham, UK. FAU - Jeyaratnam, Dakshika AU - Jeyaratnam D AD - Department of Microbiology, King's College Hospital NHS Foundation Trust, London, UK. FAU - Planche, Timothy AU - Planche T AD - Department of Infectious Diseases and Tropical Medicine, St George's University Hospitals NHS Foundation Trust, London, UK. FAU - Minton, Jane AU - Minton J AD - Department of Infectious Diseases, Leeds Teaching Hospitals NHS Trust, Leeds, UK. FAU - Hudson, Fleur AU - Hudson F AD - Medical Research Council Clinical Trials Unit, University College London, London, UK. FAU - Hopkins, Susan AU - Hopkins S AD - Infectious Diseases Unit, Royal Free London NHS Foundation Trust, London, UK. FAU - Williams, John AU - Williams J AD - Department of Infectious Diseases, South Tees Hospitals NHS Foundation Trust, Middlesbrough, UK. FAU - Torok, M Estee AU - Torok ME AD - Department of Medicine, University of Cambridge, Cambridge, UK. FAU - Llewelyn, Martin J AU - Llewelyn MJ AD - Department of Infectious Diseases, Brighton and Sussex Medical School, Brighton, UK. FAU - Edgeworth, Jonathan D AU - Edgeworth JD AD - Department of Immunology, Infectious and Inflammatory diseases, King's College London, London, UK. FAU - Walker, A Sarah AU - Walker AS AD - Nuffield Department of Medicine, University of Oxford, Oxford, UK. AD - Medical Research Council Clinical Trials Unit, University College London, London, UK. LA - eng SI - EudraCT/2012-000344-10 SI - ISRCTN/ISRCTN37666216 GR - 10/104/25/DH_/Department of Health/United Kingdom GR - MC_UU_12023/22/MRC_/Medical Research Council/United Kingdom GR - MR/K023985/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - England TA - Health Technol Assess JT - Health technology assessment (Winchester, England) JID - 9706284 RN - 0 (Anti-Bacterial Agents) RN - VJT6J7R4TR (Rifampin) SB - IM MH - Aged MH - Anti-Bacterial Agents/adverse effects/economics/*therapeutic use MH - Bacteremia/*drug therapy/microbiology/*mortality MH - Cost-Benefit Analysis MH - Double-Blind Method MH - Drug Resistance, Bacterial/drug effects MH - Drug Therapy, Combination MH - Female MH - Health Expenditures/statistics & numerical data MH - Humans MH - Male MH - Middle Aged MH - Models, Econometric MH - Quality of Life MH - Quality-Adjusted Life Years MH - Rifampin/adverse effects/economics/*therapeutic use MH - Staphylococcal Infections/*drug therapy/*mortality MH - Staphylococcus aureus MH - United Kingdom PMC - PMC6231058 COIS- Alexander Szubert reports grants from National Institute for Health Research (NIHR) and the Medical Research Council (MRC) during the conduct of the study. Robert Tilley reports personal fees from NIHR Clinical Research Network outside the submitted work. Peter Wilson reports personal fees from 3M Advisory Panel, Roche Drug Safety Monitoring Board and Merck Sharp & Dohme Corp. (MSD; Hoddesdon, UK) outside the submitted work. Achyut Guleri reports receiving fees from Novartis as a member of advisory boards and speaker panels, and consultancy fees from Astellas (Chertsey, UK), AstraZeneca (Cambridge, UK), MSD and Schering-Plough (Hoddesdon, UK); he also received support to attend scientific conferences, including accommodation and travel payments from Becton Dickinson (Winnersh Triangle, UK), Carefusion UK (Winnersh Triangle, UK), Janssen-Cilag (High Wycombe, UK) and MSD. Paul R Chadwick reports non-financial support from Novartis (Frimley, UK), and grants and personal fees from NIHR outside the submitted work. Bernadette Young reports grants from the Wellcome Trust outside the submitted work. M Estee Torok reports grants from Academy of Medical Sciences/The Health Foundation, grants from Medical Research Council (MRC), grants from NIHR Cambridge Biomedical Research Centre, grants from MRC/Department of Biotechnology Partnership Grant, and personal fees from Oxford University Press outside the submitted work. Martin J Llewelyn reports personal fees from Pfizer (Walton Oaks, UK) outside the submitted work and is a member of the panel that develops the European Society of Clinical Microbiology and Infectious Diseases/Infectious Diseases Society of America clinical practice guideline on Staphylococcus aureus bacteraemia. EDAT- 2018/11/02 06:00 MHDA- 2019/04/10 06:00 PMCR- 2018/11/12 CRDT- 2018/11/02 06:00 PHST- 2018/11/02 06:00 [entrez] PHST- 2018/11/02 06:00 [pubmed] PHST- 2019/04/10 06:00 [medline] PHST- 2018/11/12 00:00 [pmc-release] AID - 10.3310/hta22590 [doi] PST - ppublish SO - Health Technol Assess. 2018 Oct;22(59):1-148. doi: 10.3310/hta22590.