Paper of the Week: Oral versus Intravenous Antibiotics for Bone and Joint Infection. Ho-Kwong Li, M.R.C.P., Ines Rombach, D.Phil., Rhea Zambellas, M.Sc., A. Sarah Walker, Ph.D., Martin A. McNally, F.R.C.S.(Orth.), Bridget L. Atkins, F.R.C.P., Benjamin A. Lipsky, M.D., Harriet C. Hughes, M.A.(Cantab.), Deepa Bose, F.R.C.S., Michelle Kümin, Ph.D., Claire Scarborough, M.R.C.P., Philippa C. Matthews, D.Phil., et al., for the OVIVA Trial Collaborators. N Engl J Med 2019; 380:425-436. DOI: 10.1056/NEJMoa1710926

Summary and editorial by Dr. Katherine Belden, MD

The standard of care for the management of prosthetic joint infection, in particular, staphylococcal infection, includes surgery if indicated and extended parenteral antimicrobial therapy.^1,2 Parenteral therapy is used with the goal of achieving optimal plasma drug concentration in the shortest period of time and has traditionally been considered superior to oral therapy for the treatment of most bone and joint infections. Parenteral therapy requires an intravenous vascular access line that can be associated with infection and thromboembolic disease.³ Oral antimicrobial therapy is less invasive for patients, lowers costs and reduces hospital length of stay. Management of PJI with an initial short course of parenteral therapy followed by oral therapy to complete the course has been shown to be effective in observational studies.^4–6  Additionally, a 2013 meta-analysis of patients with chronic osteomyelitis showed no difference in outcome with parenteral or oral therapy.⁷

The Oral versus Intravenous Antibiotics for Bone and Joint Infection (OVIVA) trial, published in the New England Journal of Medicine on January 31, 2019, evaluated standard parenteral therapy compared with an early switch to oral therapy for the treatment of bone and joint infections, 60% involving hardware including prosthetic joints. 1054 patients were enrolled from 26 UK centers with the majority having a staphylococcal infection. Therapy was tailored for each patient by Infectious Diseases physicians and the primary composite endpoint was definite treatment failure at one year. Extended therapy after an initial 6-week course was allowed and the duration of therapy included a median of 78 days in the intravenous group and 71 days in the oral group. Adjunctive rifampin was used in 41% of parenteral regimens and 55.7% of oral regimens. Treatment failure occurred in 14.6% of the intravenous group and 13.2% of those in the oral group; oral therapy was found to be non-inferior to parenteral therapy when used during the first 6 weeks for treatment of bone and joint infection and was associated with decreased length of hospital stay.⁸

The OVIVA trial supports the use of oral antimicrobial therapy in select patients with PJI and osteomyelitis, challenging the standard of care. While specific pathogens and antibiotics were not compared and analysis according to surgical procedure was limited, the generalized findings of this study suggest that oral therapy has a role. There were no significant differences between groups in the incidence of serious adverse events including Clostridium difficile infection, highlighting the need for close monitoring of patients receiving both extended intravenous and oral therapy for PJI. New concerns as to the safety of fluoroquinolone antibiotics, known to have excellent bioavailability and the most common class of oral antibiotics used in this study, pose risk-benefit questions in antimicrobial selection.⁹ Given the advantages of oral rather than parenteral therapy to the patient, health care system and antimicrobial stewardship, the OVIVA study is an important contribution to the literature and our understanding of how to optimize antimicrobial selection for PJI. Additional well-designed studies will hopefully continue to shed light on this important topic.

References

1. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: Clinical practice guidelines by the infectious diseases Society of America. Clin Infect Dis. 2013;56(1):1-10.
2. Esposito S, Leone S, Bassetti M, et al. Italian guidelines for the diagnosis and infectious disease management of osteomyelitis and prosthetic joint infections in adults. Infection. 2009;37(6):478-496.
3. Norris AH, Shrestha NK, Allison GM, et al. 2018 IDSA Clinical Practice Guideline for the Management of OPAT. Clinical Infectious Diseases 2019;68(1):e1-35.
4. Darley ESR, Bannister GC, Blom AW, Macgowan AP, Jacobson SK, Alfouzan W. Role of early intravenous to oral antibiotic switch therapy in the management of prosthetic hip infection treated with one- or two-stage replacement. J Antimicrob Chemother. 2011;66(10):2405-2408.
5. Ascione T, Pagliano P, Balato G, Mariconda M, Rotondo R, Esposito S. Oral Therapy, Microbiological Findings, and Comorbidity Influence the Outcome of Prosthetic Joint Infections Undergoing 2-Stage Exchange. J Arthroplasty. 2017;32(7):2239-2243.
6. Cordero-Ampuero J, Esteban J, García-Cimbrelo E, Munuera L, Escobar R. Low relapse with oral antibiotics and two-stage exchange for late arthroplasty infections in 40 patients after 2-9 years. Acta Orthop. 2007;78(4):511-519.
7. Conterno LO, Da Silva Filho CR, Lo C. Antibiotics for treating chronic osteomyelitis in adults ( Review ). Cochrane Database Syst Rev. 2013;(9):CD004439.
8. Li H-K, Rombach I, Zambellas R, et al. Oral versus Intravenous Antibiotics for Bone and Joint Infection. N Engl J Med. 2019;380(5):425-436.
9. FDA warns about increase risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. fda.gov. https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm. 12/20/18.