Discover Portal

Oral antibiotics

NIHR Signal Switching to oral antibiotics early for bone and joint infections gave similar results to continuing intravenous therapy

Published on 16 April 2019

doi: 10.3310/signal-000760

For adults with bone or joint infection, many of whom had metal implants, beginning six weeks of oral antibiotics within seven days of intravenous treatment, was no worse than a regimen delivered wholly intravenously (IV). After one year, around 14% of both groups still had an infection, showing the difficulty of treatment, irrespective of the route of administration.

Although current practice suggests antibiotics should be given IV for bone and joint infections, for at least six weeks, this large NIHR-funded UK trial challenges this assumption. Participants were randomised to oral antibiotics seven days after initial surgical or IV antibiotic treatment.

Using oral antibiotics has the potential to reduce complications and give patients greater freedom while undergoing treatment, and costs less. This study strengthens evidence from an existing Cochrane review of smaller diverse trials, and may potentially lead to a shift in practice.

Share your views on the research.

Why was this study needed?

Bone infection in adults can occur as a serious complication of joint replacement surgery, or when infection travels through the bloodstream from another source, or a side effect of diabetes.

IV antibiotics for four to six weeks or longer are the usual treatment. The prolonged intravenous access carries its own risk and can pose a considerable inconvenience to patients due to long hospital stays or therapy at home. Costs are approximately 10 times that of oral therapy.

IV antibiotics continue to be used, in part because of a long-standing assumption and prior research that this mode of delivery is more effective. However, a recent Cochrane review of small trials did not demonstrate that IV antibiotics were any better than those given orally, but the evidence was uncertain. This large trial aimed to see if there were any long term differences.

What did this study do?

The OVIVA randomised controlled trial had 1,015 participants from 26 UK centres. Patients were enrolled within seven days of either surgery or IV antibiotics to treat infection in the bone or joint. Causes ranged from a joint replacement infection to diabetes complications. Most had Staphylococcus aureus infections, and over 90% had initial surgical treatment.

Both the IV and the oral group received antibiotics for at least six weeks. In accordance with usual practice, the IV group could also be given oral antibiotics, such as rifampicin. Similarly, the oral group could have up to five consecutive days of IV antibiotics for unrelated infections; over 80% of the oral group started with IV antibiotics. The primary outcome was treatment failure within one year.

What did it find?

  • A similar proportion of people in each group still had an infection at one year: 67/509 (13.2%) of the oral group and 74/506 (14.6%) in the IV group (risk difference ‑1.5, 95% confidence interval [CI] ‑5.7 to 2.8).
  • Adverse events, ranging from trips and falls to allergic reactions, happened to just over a quarter of participants in both groups: 138/527 (26.2%) in the oral group and 146/527 (27.7%) in the IV group.
  • Patients in the oral group had a median length of stay three days shorter than patients in the IV group (11 days [interquartile range, 8 to 20] vs 14 days [interquartile range, 11 to 21]).

What does current guidance say on this issue?

There is currently no national guidance on the management of bone and joint infection, but several local NHS guidance documents exist. For example, NHS Bolton recommends that the infection is confirmed either through bone, blood or deep tissue samples before initiation of antibiotic therapy.

Although the nature of the infection impacts upon the exact antibiotic regime, IV antibiotics are always the first line treatment. However, the type of antibiotic and duration of treatment does differ according to the exact indication.

For example, acute bone infection will be treated with IV antibiotics for four to six weeks, although after two weeks a switch to oral antibiotics may be considered.

What are the implications?

This research provides good evidence that bone and joint infections can be treated with predominantly oral regimens. This could have several benefits, not least the greater freedom afforded to patients and reduced costs.

The importance of taking the medication and potential treatment side effects need to be explained so that patients can seek medical support to modify the treatment when necessary.

Also, staff perceptions surrounding the effectiveness of oral antibiotics for this indication also need to be addressed to enable a shift in practice.

Citation and Funding

Li HK, Rombach I, Zambellas R, Walker AS et al.; OVIVA Trial Collaborators. Oral Versus Intravenous Antibiotics for bone and joint infection. N Engl J Med. 2019; 380(5):425-36.

This project was funded by the NIHR Health Technology Assessment Programme (project number 11/36/29), the NIHR Biomedical Research Centre at Imperial College and the NIHR Biomedical Research Centre at Oxford.

Bibliography

Boucher HW. Partial oral therapy for osteomyelitis and endocarditis — is it time? N Engl J Med 2019;380:487-9.

Conterno LO, Turchi MD. Antibiotics for treating chronic osteomyelitis in adults. Cochrane Database Syst Rev. 2013;9:CD004439.

NHS website. Osteomyelitis. London: Department of Health and Social Care; updated 2017.

Patel S, Chu C, Subudhi P. Empirical treatment of bone and joint infection in adults. Bolton: NHS Bolton; 2017.

Why was this study needed?

Bone infection in adults can occur as a serious complication of joint replacement surgery, or when infection travels through the bloodstream from another source, or a side effect of diabetes.

IV antibiotics for four to six weeks or longer are the usual treatment. The prolonged intravenous access carries its own risk and can pose a considerable inconvenience to patients due to long hospital stays or therapy at home. Costs are approximately 10 times that of oral therapy.

IV antibiotics continue to be used, in part because of a long-standing assumption and prior research that this mode of delivery is more effective. However, a recent Cochrane review of small trials did not demonstrate that IV antibiotics were any better than those given orally, but the evidence was uncertain. This large trial aimed to see if there were any long term differences.

What did this study do?

The OVIVA randomised controlled trial had 1,015 participants from 26 UK centres. Patients were enrolled within seven days of either surgery or IV antibiotics to treat infection in the bone or joint. Causes ranged from a joint replacement infection to diabetes complications. Most had Staphylococcus aureus infections, and over 90% had initial surgical treatment.

Both the IV and the oral group received antibiotics for at least six weeks. In accordance with usual practice, the IV group could also be given oral antibiotics, such as rifampicin. Similarly, the oral group could have up to five consecutive days of IV antibiotics for unrelated infections; over 80% of the oral group started with IV antibiotics. The primary outcome was treatment failure within one year.

What did it find?

  • A similar proportion of people in each group still had an infection at one year: 67/509 (13.2%) of the oral group and 74/506 (14.6%) in the IV group (risk difference ‑1.5, 95% confidence interval [CI] ‑5.7 to 2.8).
  • Adverse events, ranging from trips and falls to allergic reactions, happened to just over a quarter of participants in both groups: 138/527 (26.2%) in the oral group and 146/527 (27.7%) in the IV group.
  • Patients in the oral group had a median length of stay three days shorter than patients in the IV group (11 days [interquartile range, 8 to 20] vs 14 days [interquartile range, 11 to 21]).

What does current guidance say on this issue?

There is currently no national guidance on the management of bone and joint infection, but several local NHS guidance documents exist. For example, NHS Bolton recommends that the infection is confirmed either through bone, blood or deep tissue samples before initiation of antibiotic therapy.

Although the nature of the infection impacts upon the exact antibiotic regime, IV antibiotics are always the first line treatment. However, the type of antibiotic and duration of treatment does differ according to the exact indication.

For example, acute bone infection will be treated with IV antibiotics for four to six weeks, although after two weeks a switch to oral antibiotics may be considered.

What are the implications?

This research provides good evidence that bone and joint infections can be treated with predominantly oral regimens. This could have several benefits, not least the greater freedom afforded to patients and reduced costs.

The importance of taking the medication and potential treatment side effects need to be explained so that patients can seek medical support to modify the treatment when necessary.

Also, staff perceptions surrounding the effectiveness of oral antibiotics for this indication also need to be addressed to enable a shift in practice.

Citation and Funding

Li HK, Rombach I, Zambellas R, Walker AS et al.; OVIVA Trial Collaborators. Oral Versus Intravenous Antibiotics for bone and joint infection. N Engl J Med. 2019; 380(5):425-36.

This project was funded by the NIHR Health Technology Assessment Programme (project number 11/36/29), the NIHR Biomedical Research Centre at Imperial College and the NIHR Biomedical Research Centre at Oxford.

Bibliography

Boucher HW. Partial oral therapy for osteomyelitis and endocarditis — is it time? N Engl J Med 2019;380:487-9.

Conterno LO, Turchi MD. Antibiotics for treating chronic osteomyelitis in adults. Cochrane Database Syst Rev. 2013;9:CD004439.

NHS website. Osteomyelitis. London: Department of Health and Social Care; updated 2017.

Patel S, Chu C, Subudhi P. Empirical treatment of bone and joint infection in adults. Bolton: NHS Bolton; 2017.

Oral versus Intravenous Antibiotics for Bone and Joint Infection

Published on 31 January 2019

H.. Li, I. Rombach, R. Zambellas, A. Walker, M. McNally, B. Atkins,B Lipsky, H. Hughes, D. Bose, M. Kümin, C. Scarborough, P. Matthews,A. Brent, J. Lomas, R. Gundle, M. Rogers, A. Taylor, B. Angus, I. Byren,A. Berendt, S. Warren, F. Fitzgerald, D. Mack, S. Hopkins, J. Folb,H. Reynolds, E. Moore, J. Marshall, N. Jenkins, C. Moran, A. Woodhouse,S. Stafford, R. Seaton, C. Vallance, C. Hemsley, K. Bisnauthsing, J. Sandoe,I. Aggarwal, S. Ellis, D. Bunn, R. Sutherland, G. Barlow, C. Cooper, C. Geue,N. McMeekin, A. Briggs, P. Sendi, E. Khatamzas, T. Wangrangsimakul,T. Wong, L. Barrett, A. Alvand, C. Old, J. Bostock, J. Paul, G. Cooke,G. Thwaites, P. Bejon, and M. Scarborough

New England Journal of Medicine , 2019

BACKGROUND The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. METHODS We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. RESULTS Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of −1.4 percentage points (90% confidence interval [CI], −4.9 to 2.2; 95% CI, −5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P = 0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.3% vs. 1.0%). CONCLUSIONS Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927.)

Expert commentary

Bone and joint infections carry a risk to life and limb. The OVIVA Trial challenges the deeply held beliefs that intravenous antibiotics ‘are best’ for patients with these serious infections. This study found that 12 months after initial treatment, patients who were given carefully selected oral antibiotics did as well as those who had intravenous treatment.

These findings are potentially game-changing for patients and the NHS. Oral antibiotics are cheaper, more patient-friendly, come with fewer complications and with lower demands on other NHS resources. The potential cost savings to the NHS are therefore significant.

Jonathan Rees, Professor of Orthopaedic Surgery and Musculoskeletal Science, University of Oxford; Honorary Consultant Orthopaedic Surgeon, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust

Professor Rees has previously published research papers with trial investigators Dr Scarborough, Dr Rombach and Mr Alvand