Paper of the week: Oral versus Intravenous Antibiotics for Bone and Joint Infection

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.


  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.



Paper of the week: Continuous Antibiotic Therapy Can Reduce Recurrence of Prosthetic Joint Infection in Patients Undergoing 2-Stage Exchange.

Paper of the week: Continuous Antibiotic Therapy Can Reduce Recurrence of Prosthetic Joint Infection in Patients Undergoing 2-Stage Exchange. Ascione T, Balato G, Mariconda M, Rotondo R, Baldini A, Pagliano P. J Arthroplasty. 2018 Dec 20. pii: S0883-5403(18)31218-X. doi: 10.1016/j.arth.2018.12.017

Summary and editorial by Sreeram Penna

The main aim of this observational cohort study is to compare infection recurrence in patients who had continuous antibiotic therapy versus antibiotic holiday period prior to reimplantation following two-stage revision for periprosthetic joint infection (PJI). Researchers also analyzed factors associated with poor outcome in patients undergoing two-stage revision procedure who had normalization of serum markers and improvement of symptoms prior to reimplantation. All patients in the study had two weeks of intravenous antibiotics followed by six weeks targeted oral antibiotics.

A total of 196 patients were included in the study. 110 patients had continuous antibiotic therapy prior to reimplantation, and 82 patients had an antibiotic holiday. Overall 169 (86%) patients had a favorable outcome, and 14% had PJI recurrence. In the group that had continuous antibiotics, the cure rate was 91% (104/110) versus 79% (65/82) in patients who had antibiotic holiday prior to reimplantation, and this result was statistically significant (p=0.029). Further analysis revealed that the cure rate was significantly (p=0.02) better in immunocompromised patients receiving continuous antibiotics (41/46, 89%) versus patients who had an antibiotic holiday (20/31, 65%). Immunocompromised patients included those with diabetes, liver cirrhosis, autoimmune disease, and those who were on immunosuppressive medication.

The study also found that serum markers, body mass index, and positive microbiology at reimplantation did not affect the overall outcome. Immunocompromised patients and culture-negative cases were associated with poor outcome following a two-stage procedure. Of the culture positive cases, patients with Gram-positive cultures had a better outcome compared to Gram-negative cases. In another study done by Herman et al., researchers found that CRP and other classic markers like synovial white cell count and PMN % performed poorly in identifying residual infection prior to reimplantation.[1] In addition as researchers noted in this study that antibiotic holiday was shown to have poor outcomes especially in immunocompromised patients, as conditions for bacterial regrowth are still present. This paper puts forth an important argument to continue antibiotic treatment until reimplantation. However further research is needed to identify the optimal time and predictive factors to calculate the success of reimplantation.


[1] Herman A, Albers A, Garbuz DS, Duncan CP, Masri BA. Classic Markers for Infection Perform Poorly in Predicting Residual Infection Prior to Reimplantation. Orthopedics 2019;42:34–40. doi:10.3928/01477447-20190103-03.


Paper of the week: Mortality During Total Hip Periprosthetic Joint Infection.

Paper of the week. Mortality During Total Hip Periprosthetic Joint Infection. Natsuhara KM, Shelton TJ, Meehan JP, Lum ZC. J Arthroplasty. 2018 Dec 24. pii: S0883-5403(18)31225-7. doi: 10.1016/j.arth.2018.12.024.

Summary and Editorial by Sreeram Penna

This publication is a systemic review of the literature and its main aim is to identify the mortality rate following two-stage procedure for total hip periprosthetic joint infection (PJI). The review included 23 studies on 19169 patients. Average weighted age of the patients was 65 years and average follow up was 3.7 years. Researchers showed that average overall mortality after total hip PJI was 5.4% and mortality per year increased 4.22% year after year following total hip PJI. This data translates to around 21.12% five-year mortality for total hip PJI. This pooled data result is similar to big studies included in this review. [1,2] Among the issues highlighted by researchers include underreported mortality and inadequate follow up in the studies included in the systemic review. Researchers also noticed no change in trends of mortality rate over time. Although some studies show that a substantial decline in PJI mortality rate without changes in PJI risk over time.[3] Overall this research highlights fact that PJI has considerable mortality and morbidity and considerable research needed to be done in this respect.


[1] Zmistowski B, Karam JA, Durinka JB, Casper DS, Parvizi J. Periprosthetic Joint Infection Increases the Risk of One-Year Mortality. The Journal of Bone and Joint Surgery-American Volume 2013;95:2177–2184. doi:10.2106/JBJS.L.00789.

[2] Cancienne JM, Werner BC, Bolarinwa SA, Browne JA. Removal of an Infected Total Hip Arthroplasty: Risk Factors for Repeat Debridement, Long-term Spacer Retention, and Mortality. J Arthroplasty 2017;32:2519–22. doi:10.1016/j.arth.2017.03.018.

[3] Kurtz SM, Lau EC, Son M-S, Chang ET, Zimmerli W, Parvizi J. Are We Winning or Losing the Battle With Periprosthetic Joint Infection: Trends in Periprosthetic Joint Infection and Mortality Risk for the Medicare Population. J Arthroplasty 2018;33:3238–45. doi:10.1016/j.arth.2018.05.042.


Paper of the week: Failure after two-stage exchange arthroplasty for treatment of periprosthetic joint infection: the role of antibiotics in the cement spacer

Paper of the week: Failure after two-stage exchange arthroplasty for treatment of periprosthetic joint infection: the role of antibiotics in the cement spacer. Wouthuyzen-Bakker M, Kheir MM, Moya I, Rondon AJ, Kheir M, Lozano L, Parvizi J, Soriano A.Clin Infect Dis. 2018 Oct 3. doi: 10.1093/cid/ciy851.

Summary and Editorial by Sreeram Penna

This retrospective multicenter trial looked at the incidence of positive cultures at the time of reimplantation and their relation to antibiotics in the spacer and also at failure following reimplantation. All patients who had a two-stage revision as a primary procedure for periprosthetic joint infection (PJI) or as salvage therapy following failed surgical irrigation debridement for acute PJIs were included in the study. Researchers excluded culture-negative PJIs, cases where no cultures were obtained during reimplantation and cases with no data on cement spacers. The final cohort consists of 344 patients.

Results showed that forty cases (11.6%) had positive cultures at reimplantation. Based on the results positive cultures consists of coagulase-negative Staphylococcus (CoNS) (35%), followed by Gram-negative rods (25.0%) and S. aureus (17.5%). Results based antibiotics in cement spacers showed 9.5% for cement spacers containing a glycopeptide (27/284) either monotherapy or combined with aminoglycoside versus 21.7% for those containing monotherapy with an aminoglycoside (13/60) (p 0.008). Also, the lower incidence of positive cultures in the glycopeptide group at reimplantation was mostly attributed to a decrease of spacer infections with CoNS (17% versus 2%, p < 0.001).

Researchers identified that failure was, significantly higher in those patients with positive cultures during reimplantation (40.0% [16/40]) compared to 15.8% [48/304] with negative cultures, p < 0.001) despite the use of post-operative antibiotics in positive cases. This study notes that use of a glycopeptide in the cement spacer was not associated with a lower failure rate after reimplantation. However, it was noted that in cases where glycopeptide was added to the spacer, had a lower failure rate due to CoNS compared to those without a glycopeptide (2.5% versus 13.3%, respectively, p < 0.001).

This study highlights the importance of adding glycopeptide antibiotic into spacer in addition to an aminoglycoside. In cases where only monotherapy of aminoglycoside was used, there was a higher incidence of positive infections with CoNS and the resulting failure of reimplantation procedure. Another study by Corona et al. showed that increase in resistance against aminoglycosides in the bacteria that commonly cause chronic PJI, particularly in gram-positive cocci.[1] The current study further provides evidence to combining glycopeptide antibiotic along with aminoglycoside in the cement spacer.

[1] Corona PS, Espinal L, Rodríguez-Pardo D, Pigrau C, Larrosa N, Flores X. Antibiotic Susceptibility in Gram-Positive Chronic Joint Arthroplasty Infections: Increased Aminoglycoside Resistance Rate in Patients With Prior Aminoglycoside-Impregnated Cement Spacer Use. The Journal of Arthroplasty 2014;29:1617–21. doi:10.1016/j.arth.2014.03.029.


Paper of the Week: Salvage Debridement, Antibiotics and Implant Retention (“DAIR”) With Local Injection of a Selected Cocktail of Bacteriophages: Is It an Option for an Elderly Patient With Relapsing Staphylococcus aureus Prosthetic-Joint Infection?

Paper of the week: Salvage Debridement, Antibiotics and Implant Retention (“DAIR”) With Local Injection of a Selected Cocktail of Bacteriophages: Is It an Option for an Elderly Patient With Relapsing Staphylococcus aureus Prosthetic-Joint Infection? Tristan Ferry, Gilles Leboucher, Cindy Fevre, Yannick Herry, Anne Conrad, Jérôme Josse, Cécile Batailler, Christian Chidiac, Mathieu Medina, S Lustig, Frédéric Laurent, and Lyon BJI Study Group. Open Forum Infect Dis. 2018 Nov; 5(11): ofy269. Published online 2018 Oct 24. doi: 10.1093/ofid/ofy269

Summary and editorial by Sreeram Penna

This publication is about the use of bacteriophage treatment in a patient with relapsing poly microbial periprosthetic joint infection. The study case is an 80-year-old patient with a known history of type 2 diabetes and mild chronic renal failure. The patient had multiple procedures for PJI and grew methicillin-susceptible Staphylococcus aureus (MSSA), fluoroquinolone-resistant Escherichia coli (E. coli) and multi-drug resistant Pseudomonas aeruginosa. During her DAIR procedure, she had a cocktail of four bacteriophages targeting Pseudomonas and MSSA, which was grown preop. Operative specimens grew MSSA and E. coli and Staphylococcus lugdunensis. The patient had a course of Daptomycin and amoxicillin post op. The patient required further DAIR procedure for Citrobacter koseri infection eight months later. Eighteen months post-procedure with bacteriophage treatment patient was without signs of infection but was on long-term amoxicillin.

Bacteriophages are natural viruses that target bacteria. Bacteriophages were used in the past in treatment of osteomyelitis where they were injected through the fistula.[1] Bacteriophages are particularly interesting because they act synergistically with antibiotics. [2] In addition bacteriophages amplify during treatment due to their replication in bacteria.[3] Phages are being used in multidrug-resistant life-threatening infections with authorization from Food and Drug Administration (FDA) to administer the cocktails as an emergency investigational new drug (eIND) as seen in case of a patient with multidrug-resistant Acinetobacter baumannii infection.[4] The phase treatment thus shows promise as a viable treatment in multidrug-resistant PJIs.


[1] Kutateladze M, Adamia R. Bacteriophages as potential new therapeutics to replace or supplement antibiotics. Trends in Biotechnology 2010;28:591–595. doi:10.1016/j.tibtech.2010.08.001.

[2] Oechslin F, Piccardi P, Mancini S, Gabard J, Moreillon P, Entenza JM, et al. Synergistic Interaction Between Phage Therapy and Antibiotics Clears Pseudomonas Aeruginosa Infection in Endocarditis and Reduces Virulence. The Journal of Infectious Diseases 2017;215:703–712. doi:10.1093/infdis/jiw632.

[3] Clokie MR, Millard AD, Letarov AV, Heaphy S. Phages in nature. Bacteriophage 2011;1:31–45. doi:10.4161/bact.1.1.14942.

[4] Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J, Lessor L, et al. Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection. Antimicrob Agents Chemother 2017;61. doi:10.1128/AAC.00954-17.