Oral antibiotics are equivalent to IV (again) – the OVIVA trial (Li 2019)

Complex orthopedic infections are traditionally managed with long courses of intravenous antibiotics. I have previously discussed, in the context of skin and soft tissue infection, that as long as the antibiotic is absorbed through the GI tract, there is no physiologic reason to think that IV antibiotics would be superior to oral. This assertion is backed up by numerous RCTs, but the idea that IV antibiotics are somehow “stronger” is still prevalent among clinicians and patients alike. Therefore, although not looking at emergency department patients, it is worth reviewing one of the biggest RCTs comparing oral and IV antibiotics to date.

The paper

Li HK, Rombach I, Zambellas R, et al. Oral versus Intravenous Antibiotics for Bone and Joint Infection. The New England journal of medicine. 2019; 380(5):425-436. PMID: 30699315

The Methods

This is a multicenter, open label, parallel-group, randomized, controlled noninferiority trial. It was not blinded because of the difficulty of exposing patients to multiple weeks of IV placebo.

Patients

Adult patients (18 and older) who, in the opinion of the treating physician, needed 6 weeks of IV antibiotics for a complicated orthopedic infection, including osteomyelitis, septic arthritis, prosthetic joint infection, and vertebral osteomyelitis/discitis.

Intervention

A 6 week oral antibiotics strategy.

Comparison

A 6 week IV antibiotics strategy.

Outcome

The primary outcome was definitive treatment failure 1 year after randomization, based on a range of clinical, microbiological, and histological criteria.

The Results

They include 1015 patients in their final analysis.

The target was to get people to their assigned antibiotic regimens as soon as possible, but about 10% of both groups started their randomly assigned treatment more than 7 days after the definitive diagnosis or surgery. Furthermore, there was a lot of crossover between the two groups, and 76% of the population had their treatment extended beyond 6 weeks (at which point care wasn’t protocolized).

Definitive treatment failure occured in 14.6% of the intravenous group and 13.2% of the oral antibiotics group (ARR 1.4% 95% C −5.6% to 2.9%). Oral antibiotics were statistically non-inferior to IV treatment.  

Early discontinuation was more common in the IV group (18.9% vs 12.8%, P = 0.006).  IV catheter complications were also more common (9.4% vs 1.0%, P<0.001).

There was no difference in the incidence of C. diff (1.7% vs 1.0%, p=0.3), nor in the overall rate of adverse events (27.7% vs 26.2%, P = 0.58).

Unsurprisingly, hospital stay was significantly longer in the IV group (14 days vs. 11 days, P<0.001).

Although they don’t present the statistics, all cause mortality was much higher in the IV group (7.7% vs 2.7%), but the total numbers were small (17 vs 6 total patients).

My thoughts

This study is far from perfect. It is not blinded. The outcome of treatment failure combines some truly patient oriented outcomes with others (such as repeat cultures) which may be less relevant for the patient. There was significant cross over between the groups, and large numbers of patients received unprotolized care both before and after the 6 week trial period.

However, it is widely taught that these complex orthopedic infection absolutely need IV antibiotics, and this trial clearly counters that dogma. In fact, much like in the trials for cellulitis, the oral group actually came out a little bit better.

Although it is true that some antibiotics can only be given intravenously, it is actually rare for a an appropriate oral regimen to be unavailable. Out of 2077 patients screened for this trial, only 80 were excluded because there was no appropriate oral antibiotic.

Although this trial is imperfect, it adds to a long list of trials demonstrating that oral antibiotics are at least as good as IV. In the same issue of NEJM, the POET trial demonstrated non-inferiority of partial oral therapy for endocarditis. (Iversen 2019)  There are 8 large RCTs demonstrating equivalence between oral and IV antibiotics in pneumonia. (Addo-Yobo 2004; Atkinson 2007; Hazir 2008; Agweyu 2015; Vogel 1991; Siegel 1996; Castro-Guardiola 2001; Oosterheert 2006) There are also Cochrane reviews that conclude that oral antibiotics are as good as IV in febrile neutropenia, chronic osteomyelitis, cellulitis, and pediatric pyelonephritis. (Conterno 2013; Vidal 2013; Kilburn 2010, Strohmeier 2014)

However, despite offering no benefit, IV antibiotics and more expensive, inconvenient, and carry potential harm. In this trial, almost 10% of the IV antibiotics group had some IV catheter complication.

We need to dispel the myth the IV antibiotics are somehow stronger. For the vast majority of our patients, PO is the way to go.

Bottom line

In this trial of complex orthopedic infections, a primarily oral treatment regimen was non-inferior to an IV treatment approach, but had fewer complications. Oral therapy is probably the best approach.

Other FOAMed

None yet (that I could find).

References

Addo-Yobo E, Chisaka N, Hassan M. Oral amoxicillin versus injectable penicillin for severe pneumonia in children aged 3 to 59 months: a randomised multicentre equivalency study. Lancet (London, England). ; 364(9440):1141-8. PMID: 15451221

Agweyu A, Gathara D, Oliwa J. Oral amoxicillin versus benzyl penicillin for severe pneumonia among kenyan children: a pragmatic randomized controlled noninferiority trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2015; 60(8):1216-24. PMID: 25550349

Atkinson M, Lakhanpaul M, Smyth A. Comparison of oral amoxicillin and intravenous benzyl penicillin for community acquired pneumonia in children (PIVOT trial): a multicentre pragmatic randomised controlled equivalence trial. Thorax. 2007; 62(12):1102-6. PMID: 17567657

Castro-Guardiola A, Viejo-Rodríguez AL, Soler-Simon S. Efficacy and safety of oral and early-switch therapy for community-acquired pneumonia: a randomized controlled trial. The American journal of medicine. 2001; 111(5):367-74. PMID: 11583639

Conterno LO, Turchi MD. Antibiotics for treating chronic osteomyelitis in adults. The Cochrane database of systematic reviews. 2013; PMID: pubmed

Haran JP, Hayward G, Skinner S. Factors influencing the development of antibiotic associated diarrhea in ED patients discharged home: risk of administering IV antibiotics. The American journal of emergency medicine. 2014; 32(10):1195-9. PMID: 25149599

Hazir T, Fox LM, Nisar YB. Ambulatory short-course high-dose oral amoxicillin for treatment of severe pneumonia in children: a randomised equivalency trial. Lancet (London, England). 2008; 371(9606):49-56. PMID: 18177775

Iversen K, Ihlemann N, Gill SU, et al. Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis. The New England journal of medicine. 2019; 380(5):415-424. PMID: 30152252

Kilburn SA, Featherstone P, Higgins B, Brindle R. Interventions for cellulitis and erysipelas. The Cochrane database of systematic reviews. 2010; PMID: 20556757

MacGregor RR, Graziani AL. Oral administration of antibiotics: a rational alternative to the parenteral route. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1997; 24(3):457-67. PMID: 9114201

Oosterheert JJ, Bonten MJ, Schneider MM. Effectiveness of early switch from intravenous to oral antibiotics in severe community acquired pneumonia: multicentre randomised trial. BMJ (Clinical research ed.). 2006; 333(7580):1193. PMID: 17090560

Siegel RE, Halpern NA, Almenoff PL, Lee A, Cashin R, Greene JG. A prospective randomized study of inpatient iv. antibiotics for community-acquired pneumonia. The optimal duration of therapy. Chest. 1996; 110(4):965-71. PMID: 8874253

Strohmeier Y, Hodson EM, Willis NS, Webster AC, Craig JC. Antibiotics for acute pyelonephritis in children. The Cochrane database of systematic reviews. 2014; PMID: 25066627

Vidal L, Ben Dor I, Paul M. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients. The Cochrane database of systematic reviews. 2013; PMID: 24105485

Vogel F, Lode H. The use of oral temafloxacin compared with a parenteral cephalosporin in hospitalized patients with pneumonia. The Journal of antimicrobial chemotherapy. 1991; 28 Suppl C:81-6. PMID: 1664833