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dc.contributor.authorThwaites, Guy Een
dc.contributor.authorScarborough, Matthewen
dc.contributor.authorSzubert, Alexanderen
dc.contributor.authorSaramago Goncalves, Pedroen
dc.contributor.authorSoares, Martaen
dc.contributor.authorBostock, Jenniferen
dc.contributor.authorNsutebu, Emmanuelen
dc.contributor.authorTilley, Roberten
dc.contributor.authorCunningham, Richarden
dc.contributor.authorGreig, Juliaen
dc.contributor.authorWyllie, Sarah Aen
dc.contributor.authorWilson, Peteren
dc.contributor.authorAuckland, Cressidaen
dc.contributor.authorCairns, Janeten
dc.contributor.authorWard, Deniseen
dc.contributor.authorLal, Pankajen
dc.contributor.authorGuleri, Achyuten
dc.contributor.authorJenkins, Neilen
dc.contributor.authorSutton, Julianen
dc.contributor.authorWiselka, Martinen
dc.contributor.authorArmando, Gonzalez-Ruizen
dc.contributor.authorGraham, Cliveen
dc.contributor.authorChadwick, Paul Ren
dc.contributor.authorBarlow, Gavinen
dc.contributor.authorGordon, N Claireen
dc.contributor.authorYoung, Bernadetteen
dc.contributor.authorMeisner, Sarahen
dc.contributor.authorMcWhinney, Paulen
dc.contributor.authorPrice, David Aen
dc.contributor.authorHarvey, Daviden
dc.contributor.authorNayar, Deepaen
dc.contributor.authorJeyaratnam, Dakshikaen
dc.contributor.authorPlanche, Timothyen
dc.contributor.authorMinton, Janeen
dc.contributor.authorHudson, Fleuren
dc.contributor.authorHopkins, Susanen
dc.contributor.authorWilliams, Johnen
dc.contributor.authorTörök, M Esteeen
dc.contributor.authorLlewelyn, Martin Jen
dc.contributor.authorEdgeworth, Jonathan Den
dc.contributor.authorWalker, A Sarahen
dc.date.accessioned2018-11-28T13:14:07Z
dc.date.available2018-11-28T13:14:07Z
dc.date.issued2018-10en
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.mediumPrinten
dc.languageengen
dc.publisherNational Coordinating Centre for Health Technology Assessment
dc.subjectHumansen
dc.subjectStaphylococcus aureusen
dc.subjectBacteremiaen
dc.subjectStaphylococcal Infectionsen
dc.subjectRifampinen
dc.subjectAnti-Bacterial Agentsen
dc.subjectDrug Therapy, Combinationen
dc.subjectModels, Econometricen
dc.subjectDouble-Blind Methoden
dc.subjectDrug Resistance, Bacterialen
dc.subjectQuality-Adjusted Life Yearsen
dc.subjectQuality of Lifeen
dc.subjectAgeden
dc.subjectMiddle Ageden
dc.subjectCost-Benefit Analysisen
dc.subjectHealth Expendituresen
dc.subjectFemaleen
dc.subjectMaleen
dc.subjectUnited Kingdomen
dc.titleAdjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT.en
dc.typeArticle
prism.endingPage148
prism.issueIdentifier59en
prism.publicationDate2018en
prism.publicationNameHealth technology assessment (Winchester, England)en
prism.startingPage1
prism.volume22en
dc.identifier.doi10.17863/CAM.33338
dcterms.dateAccepted2018-07-05en
rioxxterms.versionofrecord10.3310/hta22590en
rioxxterms.versionVoR*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-10en
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
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idAcademy of Medical Sciences (unknown)


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