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dc.contributor.authorThwaites, Guy E
dc.contributor.authorScarborough, Matthew
dc.contributor.authorSzubert, Alexander
dc.contributor.authorSaramago Goncalves, Pedro
dc.contributor.authorSoares, Marta
dc.contributor.authorBostock, Jennifer
dc.contributor.authorNsutebu, Emmanuel
dc.contributor.authorTilley, Robert
dc.contributor.authorCunningham, Richard
dc.contributor.authorGreig, Julia
dc.contributor.authorWyllie, Sarah A
dc.contributor.authorWilson, Peter
dc.contributor.authorAuckland, Cressida
dc.contributor.authorCairns, Janet
dc.contributor.authorWard, Denise
dc.contributor.authorLal, Pankaj
dc.contributor.authorGuleri, Achyut
dc.contributor.authorJenkins, Neil
dc.contributor.authorSutton, Julian
dc.contributor.authorWiselka, Martin
dc.contributor.authorArmando, Gonzalez-Ruiz
dc.contributor.authorGraham, Clive
dc.contributor.authorChadwick, Paul R
dc.contributor.authorBarlow, Gavin
dc.contributor.authorGordon, N Claire
dc.contributor.authorYoung, Bernadette
dc.contributor.authorMeisner, Sarah
dc.contributor.authorMcWhinney, Paul
dc.contributor.authorPrice, David A
dc.contributor.authorHarvey, David
dc.contributor.authorNayar, Deepa
dc.contributor.authorJeyaratnam, Dakshika
dc.contributor.authorPlanche, Timothy
dc.contributor.authorMinton, Jane
dc.contributor.authorHudson, Fleur
dc.contributor.authorHopkins, Susan
dc.contributor.authorWilliams, John
dc.contributor.authorTörök, M Estee
dc.contributor.authorLlewelyn, Martin J
dc.contributor.authorEdgeworth, Jonathan D
dc.contributor.authorWalker, A Sarah
dc.date.accessioned2018-11-28T13:14:07Z
dc.date.available2018-11-28T13:14:07Z
dc.date.issued2018-10
dc.identifier.issn1366-5278
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286018
dc.description.abstractBACKGROUND: 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.
dc.description.sponsorshipNIHR HTA Programme
dc.format.mediumPrint
dc.languageeng
dc.publisherNational Institute for Health and Care Research (NIHR)
dc.subjectHumans
dc.subjectStaphylococcus aureus
dc.subjectBacteremia
dc.subjectStaphylococcal Infections
dc.subjectRifampin
dc.subjectAnti-Bacterial Agents
dc.subjectDrug Therapy, Combination
dc.subjectModels, Econometric
dc.subjectDouble-Blind Method
dc.subjectDrug Resistance, Bacterial
dc.subjectQuality-Adjusted Life Years
dc.subjectQuality of Life
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectCost-Benefit Analysis
dc.subjectHealth Expenditures
dc.subjectFemale
dc.subjectMale
dc.subjectUnited Kingdom
dc.titleAdjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT.
dc.typeArticle
prism.endingPage148
prism.issueIdentifier59
prism.publicationDate2018
prism.publicationNameHealth Technol Assess
prism.startingPage1
prism.volume22
dc.identifier.doi10.17863/CAM.33338
dcterms.dateAccepted2018-07-05
rioxxterms.versionofrecord10.3310/hta22590
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-10
dc.contributor.orcidThwaites, Guy E [0000-0002-2858-2087]
dc.contributor.orcidScarborough, Matthew [0000-0002-0455-0785]
dc.contributor.orcidSaramago Goncalves, Pedro [0000-0001-9063-8590]
dc.contributor.orcidSoares, Marta [0000-0003-1579-8513]
dc.contributor.orcidBostock, Jennifer [0000-0001-9261-9350]
dc.contributor.orcidCunningham, Richard [0000-0002-6081-2153]
dc.contributor.orcidYoung, Bernadette [0000-0001-6071-6770]
dc.contributor.orcidHopkins, Susan [0000-0001-5179-5702]
dc.contributor.orcidTörök, M Estee [0000-0001-9098-8590]
dc.contributor.orcidLlewelyn, Martin J [0000-0002-6811-1124]
dc.identifier.eissn2046-4924
dc.publisher.urlhttps://www.journalslibrary.nihr.ac.uk/hta/hta22590#/abstract
rioxxterms.typeJournal Article/Review
pubs.funder-project-idAcademy of Medical Sciences (unknown)
cam.issuedOnline2018-10


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