OVIVA

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Li HK, et al. "Oral versus Intravenous Antibiotics for Bone and Joint Infection". The New England Journal of Medicine. 2019. 380(5):425-436.
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Clinical Question

In adult patients with bone or joint infection requiring at least 6-weeks of antibiotic therapy without sepsis or bacteremia, is treatment with oral antibiotics non-inferior to intravenous therapy for the first 6 weeks of therapy.

Bottom Line

Following initial therapy with intravenous antimicrobials, 6 weeks of oral therapy was non-inferior to intravenous therapy with susceptible antibiotics

Major Points

Penetrating and managing bone and joint infections usually require weeks of antibiotics and the standard of care often is to manage these with intravenous (IV) therapy. Meta-analysis [1] demonstrated no advantage of IV over oral therapy and IV is over far more expensive and logistically challenging to deliver.[2][3] The oral versus intravenous antibiotics for bone and joint infection (OVIVA) trial was a multi-centred, parallel group, 1:1 randomized, open label, non-inferiority trial comparing IV to oral therapy. Randomizing 1054 patients from 26 National Health System hospitals in the UK between 2010 and 2015. The investigators followed patients out to one year looking for treatment failure and accepting an inferiority margin of 7.5%. Randomizing patients with an expected majority of gram-positive infections, there was no statistical difference in the rate of treatment failure between groups; IV with 14.6% compared to oral with 13.2% (95% CI -5.6 to 2.9). Probably or possible treatment failure was similar between groups along with rates of diarrhea associated with C. Diff and other adverse events. Therapy with IV antibiotics were associated with a longer hospital length of stay (14 days vs. 11 days, P < 0.001) with more early therapy discontinuation (18.9% vs. 12.8%, P = 0.006, NNH 16) and more IV catheter complications (9.4% vs. 1.0%, P < 0.001, NNT 12). There are a number of limitations with this trial, the high rate of complication and adverse events may be of some concern. The specific antibiotics were not compared in this trial and the greater application of rifampin in the oral group may indicate bias in the trial. The practical application of this trial is potentially practice changing. With only had 4% lost to follow-up the robustness of the findings hold merit. Depending on the delivery of the IV therapy, the oral therapy group may have had far less monitoring and allocation of resources and trended to do better than the IV group. The take away from this is that in many patients with definitive sensitivities, oral therapy may be a suitable treatment for bone and joint infections.

Guidelines

As of February 2019, no guidelines have been published that reflect the results of this trial.

Design

  • Multi-center, parallel group, randomized, open label, non-inferiority trial
  • N=1054
    • Intravenous Antibiotics (n=527)
    • Oral Antibiotics (n=527)
  • Setting: 26 centers in the UK
  • Enrollment: 2010-2015
  • Follow-up: 1 year
  • Analysis: Intention-to-treat
  • Primary Outcome: Definite treatment failure within 1 year after randomization

Population

Inclusion Criteria

  • ≥18 years old
  • Bone or joint infection requiring 6 weeks of antibiotics
    • Specific infections include one of the following:
      • Osteomyelitis of the extraaxial native skeleton
      • Native joint infection requiring excision arthroplasty
      • Prosthetic joint infection
      • Orthopedic fixation-device infection
      • Vertebral osteomyelitis +/- associated discitis or soft-tissue infection
  • Received ≤7 days of IV therapy from the date of definitive surgery or the start of planned curative treatment in patients managed non-operatively
  • Life expectancy >1 year

Exclusion Criteria

  • Staphylococcus aureus bacteraemia or any bacterial endocarditis on presentation or within prior month
  • Mild osteomyelitis not requiring 6 weeks of therapy per judgement of clinician
  • Septic Shock
  • Infection where no oral option is a viable option
  • Non-bacterial infection

Baseline Characteristics

  • Demographics: median age 60 years, 64.3% male
  • Baseline surgical procedure: No prosthetic present and underwent debridement 31%, no prosthetic and no debridement 5%, debridement and implant retention 23%, orthopedic device removal 16%, prosthetic joint removal 13%, prosthetic joint revision 8%, spinal debridement 1%, spinal surgery 2%
  • Deep tissue histology: Infected 52%, equivocal 3%, Uninfected 6%, not available or missing 40%
  • Microbiological diagnostic sample: ≥2 samples of same organism 66%, 1 of 2 samples positive for likely organism causing infection 5%, no sample positive 15%, not available or missing 5%
  • Organism: Staphylococcus aureus 38%, Coagulase-negative staphylococcus (CoNS) 27%, Streptococcus species 15%, Pseudomonas species 5%, Other gram-negative organisms 17%, culture negative 16%
  • Antimicrobials:[4] Glycopeptides IV (e.g., vancomycin) 23%, Penicillins IV 5%, Cephalosporins IV 17%, Carbapenems IV 4%, Penicillins PO 9%, Quinolones PO 22%, Macrolides PO 8%,
    • Rifampin: None 51%, <2 weeks 5%, 2-6 weeks 16%, >6 weeks 27%

Interventions

  • Within initiated within 7 days of definitive therapy (e.g., following surgical intervention and after microbiological sensitivities available), participants were randomized to a group:
    • IV antibiotics - Continued for 6 weeks
    • PO antibiotics - Continued for 6 weeks
  • Limited (up to 5 days) IV or oral adjunctive therapy was allowed based on local practice patterns
  • Adjunctive rifampin was allowed at investigator discretion
  • Therapy beyond 6 weeks was allowed at investigator discretion

Outcomes

Comparisons are Intravenous therapy vs. oral therapy.

Primary Outcomes

Definite treatment failure within 1 year after randomization
Missing data were imputed.
14.6% vs. 13.2% (risk difference oral vs. IV -1.4%; 95% CI -5.6 to 2.9)

Secondary Outcomes

Probably or possible treatment failure
1.2% vs. 2.0%
Early discontinuation of therapy
18.9% vs. 12.8% (ARR 6.1, P = 0.006) NNT 16
Median hospital length of stay
14 days vs. 11 days, P < 0.001

Subgroup Analysis

Adherence at Day 14
High 68.1% vs. 68.3%
Low 2.8% vs. 5.9%
Adherence at Day 42
High 67.5% vs. 51.4%
Low 3.6 vs. 7.7%

Adverse Events

Complications from the IV catheter
9.4% vs. 1.0% (ARR 8.4%, P < 0.001) NNT 12
C. Diff diarrhea
1.7% vs. 1.0%, P = 0.30
At least one serious adverse event
27.7% vs. 26.2%, P = 0.58

Criticisms

  • Incidence of serious adverse events was very high
  • Open-label design, while improved practicality of conducting the trial complicates the potential for bias
  • Depending on the delivery of the IV therapy, the oral group may have had significantly less monitoring
  • No comparison of antimicrobial regiments was made and bias may have been present
  • Rifampin was more commonly utilized in the oral group

Funding

  • NIHR Health Technology Assessment Programme (Project number 11/36/29)

Further Reading

  1. Conterno LO & Turchi MD Antibiotics for treating chronic osteomyelitis in adults. Cochrane Database Syst Rev 2013. :CD004439.
  2. Spellberg B & Lipsky BA Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin. Infect. Dis. 2012. 54:393-407.
  3. Rangel SJ et al. Intravenous Versus Oral Antibiotics for the Prevention of Treatment Failure in Children With Complicated Appendicitis: Has the Abandonment of Peripherally Inserted Catheters Been Justified?. Ann. Surg. 2017. 266:361-368.
  4. Supplemental appendix