title: Oral versus intravenous antibiotic treatment for bone and joint infections (OVIVA): study protocol for a randomised controlled trial.
abstract: BACKGROUND
  Bone and joint infection in adults arises most commonly as a complication of joint replacement surgery, fracture fixation and diabetic foot infection. The associated morbidity can be devastating to patients and costs the National Health Service an estimated £20,000 to £40,000 per patient. Current standard of care in most UK centres includes a prolonged course (4-6 weeks) of intravenous antibiotics supported, if available, by an outpatient parenteral antibiotic therapy service. Intravenous therapy carries with it substantial risks and inconvenience to patients, and the antibiotic-related costs are approximately ten times that of oral therapy. Despite this, there is no evidence to suggest that oral therapy results in inferior outcomes. We hypothesise that, by selecting oral agents with high bioavailability, good tissue penetration and activity against the known or likely pathogens, key outcomes in patients managed primarily with oral therapy are non-inferior to those in patients treated by intravenous therapy.
  
  
  METHODS
  The OVIVA trial is a parallel group, randomised (1:1), un-blinded, non-inferiority trial conducted in thirty hospitals across the UK. Eligible participants are adults (>18 years) with a clinical syndrome consistent with a bone, joint or metalware-associated infection who have received ≤7 days of intravenous antibiotic therapy from the date of definitive surgery (or the start of planned curative therapy in patients treated without surgical intervention). Participants are randomised to receive either oral or intravenous antibiotics, selected by a specialist infection physician, for the first 6 weeks of therapy. The primary outcome measure is definite treatment failure within one year of randomisation, as assessed by a blinded endpoint committee, according to pre-defined microbiological, histological and clinical criteria. Enrolling 1,050 subjects will provide 90 % power to demonstrate non-inferiority, defined as less than 7.5 % absolute increase in treatment failure rate in patients randomised to oral therapy as compared to intravenous therapy (one-sided alpha of 0.05).
  
  
  CONCLUSIONS
  If our results demonstrate non-inferiority of orally administered antibiotic therapy, this trial is likely to facilitate a dramatically improved patient experience and alleviate a substantial financial burden on healthcare services.
  
  
  BACKGROUND
  ISRCTN91566927 - 14/02/2013.
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK. ho-kwong.li@ouh.nhs.uk.
authors.forename: Ho Kwong
authors.initials: HK
authors.lastname: Li
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK. matthew.scarborough@ouh.nhs.uk.
authors.forename: Matthew
authors.initials: M
authors.lastname: Scarborough
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK. rhea.zambellas@ndorms.ox.ac.uk.
authors.forename: Rhea
authors.initials: R
authors.lastname: Zambellas
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK. cushla.cooper@ndorms.ox.ac.uk.
authors.forename: Cushla
authors.initials: C
authors.lastname: Cooper
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK. ines.rombach@ndorms.ox.ac.uk.
authors.forename: Ines
authors.initials: I
authors.lastname: Rombach
authors.affiliation: MRC Clinical Trials Unit, University College London, London, UK. rmjlasw@ucl.ac.uk.
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.affiliation: Division of Medical Sciences, University of Oxford, Oxford, UK. dblipsky@hotmail.com.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Lipsky
authors.affiliation: Health Economics and Health Technology Assessment, University of Glasgow, Glasgow, UK. andrew.briggs@glasgow.ac.uk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Briggs
authors.affiliation: Gartnavel General Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK. andrew.seaton@ggc.scot.nhs.uk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Seaton
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK. bridget.atkins@ouh.nhs.uk.
authors.forename: Bridget
authors.initials: B
authors.lastname: Atkins
authors.affiliation: Heart of England NHS Foundation Trust, Birmingham, UK. andrew.woodhouse@heartofengland.nhs.uk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Woodhouse
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK. tony.berendt@ouh.nhs.uk.
authors.forename: Anthony
authors.initials: A
authors.lastname: Berendt
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK. ivor.byren@ouh.nhs.uk.
authors.forename: Ivor
authors.initials: I
authors.lastname: Byren
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK. brian.angus@ndm.ox.ac.uk.
authors.forename: Brian
authors.initials: B
authors.lastname: Angus
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK. hemant.pandit@ouh.nhs.uk.
authors.forename: Hemant
authors.initials: H
authors.lastname: Pandit
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK. david.stubbs@ouh.nhs.uk.
authors.forename: David
authors.initials: D
authors.lastname: Stubbs
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK. martin.mcnally@ouh.nhs.uk.
authors.forename: Martin
authors.initials: M
authors.lastname: McNally
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust, Ho Chi Minh, Vietnam. gthwaites@oucru.org.
authors.forename: Guy
authors.initials: G
authors.lastname: Thwaites
authors.affiliation: Kenya Medical Research Institute, Wellcome Trust, Kilifi, Kenya. pbejon@kemri-wellcome.org.
authors.forename: Philip
authors.initials: P
authors.lastname: Bejon
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001424:Bacterial Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D001850:Bone Diseases, Infectious / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D002985:Clinical Protocols; D004334:Drug Administration Schedule; D006801:Humans; D007592:Joint Diseases / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D000900:Anti-Bacterial Agents