Oral versus intravenous antibiotics for bone and joint infections: the OVIVA non-inferiority RCT.

BACKGROUND

Management of bone and joint infection commonly includes 4-6 weeks of intravenous (IV) antibiotics, but there is little evidence to suggest that oral (PO) therapy results in worse outcomes.

OBJECTIVE

To determine whether or not PO antibiotics are non-inferior to IV antibiotics in treating bone and joint infection.

DESIGN

Parallel-group, randomised (1 : 1), open-label, non-inferiority trial. The non-inferiority margin was 7.5%.

SETTING

Twenty-six NHS hospitals.

PARTICIPANTS

Adults with a clinical diagnosis of bone, joint or orthopaedic metalware-associated infection who would ordinarily receive at least 6 weeks of antibiotics, and who had received ≤ 7 days of IV therapy from definitive surgery (or start of planned curative treatment in patients managed non-operatively).

INTERVENTIONS

Participants were centrally computer-randomised to PO or IV antibiotics to complete the first 6 weeks of therapy. Follow-on PO therapy was permitted in either arm.

MAIN OUTCOME MEASURE

The primary outcome was the proportion of participants experiencing treatment failure within 1 year. An associated cost-effectiveness evaluation assessed health resource use and quality-of-life data.

RESULTS

Out of 1054 participants (527 in each arm), end-point data were available for 1015 (96.30%) participants. Treatment failure was identified in 141 out of 1015 (13.89%) participants: 74 out of 506 (14.62%) and 67 out of 509 (13.16%) of those participants randomised to IV and PO therapy, respectively. In the intention-to-treat analysis, using multiple imputation to include all participants, the imputed risk difference between PO and IV therapy for definitive treatment failure was -1.38% (90% confidence interval -4.94% to 2.19%), thus meeting the non-inferiority criterion. A complete-case analysis, a per-protocol analysis and sensitivity analyses for missing data each confirmed this result. With the exception of IV catheter complications [49/523 (9.37%) in the IV arm vs. 5/523 (0.96%) in the PO arm)], there was no significant difference between the two arms in the incidence of serious adverse events. PO therapy was highly cost-effective, yielding a saving of £2740 per patient without any significant difference in quality-adjusted life-years between the two arms of the trial.

LIMITATIONS

The OVIVA (Oral Versus IntraVenous Antibiotics) trial was an open-label trial, but bias was limited by assessing all potential end points by a blinded adjudication committee. The population was heterogenous, which facilitated generalisability but limited the statistical power of subgroup analyses. Participants were only followed up for 1 year so differences in late recurrence cannot be excluded.

CONCLUSIONS

PO antibiotic therapy is non-inferior to IV therapy when used during the first 6 weeks in the treatment for bone and joint infection, as assessed by definitive treatment failure within 1 year of randomisation. These findings challenge the current standard of care and provide an opportunity to realise significant benefits for patients, antimicrobial stewardship and the health economy.

FUTURE WORK

Further work is required to define the optimal total duration of therapy for bone and joint infection in the context of specific surgical interventions. Currently, wide variation in clinical practice suggests significant redundancy that likely contributes to the excess and unnecessary use of antibiotics.

TRIAL REGISTRATION

Current Controlled Trials ISRCTN91566927.

FUNDING

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in

Treatment of bone and joint infection usually requires a long course of antibiotics. Doctors usually give these by injection through a vein (intravenously) for the first 4–6 weeks, rather than by mouth (orally). Although intravenous (IV) administration is more expensive and less convenient for patients, most doctors believe that it is more effective. However, there is little evidence to support this. The OVIVA (Oral Versus IntraVenous Antibiotics) trial set out to challenge this assumption. A total of 1054 patients from 26 UK hospitals were randomly allocated to receive the first 6 weeks of antibiotic therapy either intravenously or orally. Irrespective of the route of administration, the choice of antibiotic was left to an infection specialist so as to ensure that the most appropriate antibiotics were given. Patients were followed up for 1 year. Thirty-nine participants were lost to follow-up. Among the remaining 1015 participants, treatment failure occurred in 14.6% of those treated intravenously and 13.2% of those treated with PO antibiotics. This difference could easily have occurred by chance. Even if it was not by chance, the difference does not suggest that PO therapy is associated with worse outcomes than IV therapy and is too small to conclude that PO therapy is better than IV therapy. Participants in the IV group stayed in hospital longer and 10% of them had complications related to the IV line used for administering the antibiotics. In addition, their treatment was, overall, more expensive. We conclude that PO antibiotic therapy has no disadvantages for the early management of bone and joint infection. It is also cheaper and associated with fewer complications.

Déclaration de conflit d'intérêts

Adrian Taylor reports personal fees from Zimmer Inc., Corin Group and DePuy Synthes Companies outside the submitted work. Martin McNally reports personal fees from Bonesupport AB outside the submitted work. R Andrew Seaton reports personal fees from previous consultancy and funding for speaking at educational meetings (Novartis Pharma) and consultancy for Merck Sharp & Dohme Corp. (MSD) outside the submitted work. Harriet Hughes reports other competing interests from Gilead Sciences Inc., MSD, Biocomposites, and personal fees from Biocomposites and Cubist Pharmaceuticals outside the submitted work. Jennifer Bostock was a member of the Health Services and Delivery Research Commissioned Panel Members during this project.