Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT
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 whethe...
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| Format: | Article |
| Language: | English |
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NIHR Journals Library
2018-10-01
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| Series: | Health Technology Assessment |
| Subjects: | |
| Online Access: | https://doi.org/10.3310/hta22590 |
| _version_ | 1818477896390410240 |
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| author | Guy E Thwaites Matthew Scarborough Alexander Szubert Pedro Saramago Goncalves Marta Soares Jennifer Bostock Emmanuel Nsutebu Robert Tilley Richard Cunningham Julia Greig Sarah A Wyllie Peter Wilson Cressida Auckland Janet Cairns Denise Ward Pankaj Lal Achyut Guleri Neil Jenkins Julian Sutton Martin Wiselka Gonzalez-Ruiz Armando Clive Graham Paul R Chadwick Gavin Barlow N Claire Gordon Bernadette Young Sarah Meisner Paul McWhinney David A Price David Harvey Deepa Nayar Dakshika Jeyaratnam Timothy Planche Jane Minton Fleur Hudson Susan Hopkins John Williams M Estee Török Martin J Llewelyn Jonathan D Edgeworth A Sarah Walker |
| author_facet | Guy E Thwaites Matthew Scarborough Alexander Szubert Pedro Saramago Goncalves Marta Soares Jennifer Bostock Emmanuel Nsutebu Robert Tilley Richard Cunningham Julia Greig Sarah A Wyllie Peter Wilson Cressida Auckland Janet Cairns Denise Ward Pankaj Lal Achyut Guleri Neil Jenkins Julian Sutton Martin Wiselka Gonzalez-Ruiz Armando Clive Graham Paul R Chadwick Gavin Barlow N Claire Gordon Bernadette Young Sarah Meisner Paul McWhinney David A Price David Harvey Deepa Nayar Dakshika Jeyaratnam Timothy Planche Jane Minton Fleur Hudson Susan Hopkins John Williams M Estee Török Martin J Llewelyn Jonathan D Edgeworth A Sarah Walker |
| author_sort | Guy E Thwaites |
| collection | DOAJ |
| description | 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 £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 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. |
| first_indexed | 2024-12-10T09:42:12Z |
| format | Article |
| id | doaj.art-6ed53dee06594dd7824bb5a8cdc31e4b |
| institution | Directory Open Access Journal |
| issn | 1366-5278 2046-4924 |
| language | English |
| last_indexed | 2024-12-10T09:42:12Z |
| publishDate | 2018-10-01 |
| publisher | NIHR Journals Library |
| record_format | Article |
| series | Health Technology Assessment |
| spelling | doaj.art-6ed53dee06594dd7824bb5a8cdc31e4b2022-12-22T01:53:58ZengNIHR Journals LibraryHealth Technology Assessment1366-52782046-49242018-10-01225910.3310/hta2259010/104/25Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCTGuy E Thwaites0Matthew Scarborough1Alexander Szubert2Pedro Saramago Goncalves3Marta Soares4Jennifer Bostock5Emmanuel Nsutebu6Robert Tilley7Richard Cunningham8Julia Greig9Sarah A Wyllie10Peter Wilson11Cressida Auckland12Janet Cairns13Denise Ward14Pankaj Lal15Achyut Guleri16Neil Jenkins17Julian Sutton18Martin Wiselka19Gonzalez-Ruiz Armando20Clive Graham21Paul R Chadwick22Gavin Barlow23N Claire Gordon24Bernadette Young25Sarah Meisner26Paul McWhinney27David A Price28David Harvey29Deepa Nayar30Dakshika Jeyaratnam31Timothy Planche32Jane Minton33Fleur Hudson34Susan Hopkins35John Williams36M Estee Török37Martin J Llewelyn38Jonathan D Edgeworth39A Sarah Walker40Nuffield Department of Medicine, University of Oxford, Oxford, UKNuffield Department of Medicine, University of Oxford, Oxford, UKMedical Research Council Clinical Trials Unit, University College London, London, UKCentre for Health Economics, University of York, York, UKCentre for Health Economics, University of York, York, UKInstitute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UKTropical and Infectious Diseases Unit, Royal Liverpool University Hospital, Liverpool, UKDepartment of Microbiology, Plymouth Hospitals NHS Trust, Plymouth, UKDepartment of Microbiology, Plymouth Hospitals NHS Trust, Plymouth, UKDepartment of Infectious Diseases, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UKMicrobiology Department, Portsmouth Hospitals NHS Trust, Portsmouth, UKCentre for Clinical Microbiology, University College London Hospital NHS Foundation Trust, London, UKMicrobiology Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UKMedical Research Council Clinical Trials Unit, University College London, London, UKMedical Research Council Clinical Trials Unit, University College London, London, UKMicrobiology Department, Aintree University Hospital NHS Foundation Trust, Liverpool, UKMicrobiology Department, Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, UKDepartment of Infectious Diseases and Tropical Medicine, Heart of England NHS Foundation Trust, Birmingham, UKDepartment of Microbiology and Virology, University Hospital Southampton NHS Foundation Trust, Southampton, UKDepartment of Infection and Tropical Medicine, University Hospitals of Leicester NHS Trust, Leicester, UKMicrobiology Department, Darent Valley Hospital, Dartford, UKMicrobiology Department, North Cumbria University Hospitals NHS Trust, Cumbria, UKMicrobiology Department, Salford Royal NHS Foundation Trust, Salford, UKDepartment of Infection, Hull and East Yorkshire Hospitals NHS Trust, Hull, UKNuffield Department of Medicine, University of Oxford, Oxford, UKNuffield Department of Medicine, University of Oxford, Oxford, UKMicrobiology Department, Royal United Hospitals Bath NHS Foundation Trust, Bath, UKMicrobiology Department, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UKDepartment of Infectious Diseases, Newcastle Upon Tyne Hospital NHS Foundation Trust, Newcastle, UKMicrobiology Department, Wirral University Teaching Hospital NHS Foundation Trust, Birkenhead, UKMicrobiology Department, County Durham and Darlington NHS Foundation Trust, Durham, UKDepartment of Microbiology, King’s College Hospital NHS Foundation Trust, London, UKDepartment of Infectious Diseases and Tropical Medicine, St George’s University Hospitals NHS Foundation Trust, London, UKDepartment of Infectious Diseases, Leeds Teaching Hospitals NHS Trust, Leeds, UKMedical Research Council Clinical Trials Unit, University College London, London, UKInfectious Diseases Unit, Royal Free London NHS Foundation Trust, London, UKDepartment of Infectious Diseases, South Tees Hospitals NHS Foundation Trust, Middlesbrough, UKDepartment of Medicine, University of Cambridge, Cambridge, UKDepartment of Infectious Diseases, Brighton and Sussex Medical School, Brighton, UKDepartment of Immunology, Infectious and Inflammatory diseases, King’s College London, London, UKNuffield Department of Medicine, University of Oxford, Oxford, UKBackground: 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 £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 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.https://doi.org/10.3310/hta22590staphylococcus aureusbacteraemiarifampicinmortality |
| spellingShingle | Guy E Thwaites Matthew Scarborough Alexander Szubert Pedro Saramago Goncalves Marta Soares Jennifer Bostock Emmanuel Nsutebu Robert Tilley Richard Cunningham Julia Greig Sarah A Wyllie Peter Wilson Cressida Auckland Janet Cairns Denise Ward Pankaj Lal Achyut Guleri Neil Jenkins Julian Sutton Martin Wiselka Gonzalez-Ruiz Armando Clive Graham Paul R Chadwick Gavin Barlow N Claire Gordon Bernadette Young Sarah Meisner Paul McWhinney David A Price David Harvey Deepa Nayar Dakshika Jeyaratnam Timothy Planche Jane Minton Fleur Hudson Susan Hopkins John Williams M Estee Török Martin J Llewelyn Jonathan D Edgeworth A Sarah Walker Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT Health Technology Assessment staphylococcus aureus bacteraemia rifampicin mortality |
| title | Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT |
| title_full | Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT |
| title_fullStr | Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT |
| title_full_unstemmed | Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT |
| title_short | Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT |
| title_sort | adjunctive rifampicin to reduce early mortality from staphylococcus aureus bacteraemia the arrest rct |
| topic | staphylococcus aureus bacteraemia rifampicin mortality |
| url | https://doi.org/10.3310/hta22590 |
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