By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: A six-week course of antibiotic therapy was “not noninferior” to a 12-week course in patients with prosthetic joint infection, at least in those who had undergone debridement and implant retention.

SOURCE: Bernard L, Arvieux C, Brunschweiler B, et al. Antibiotic therapy for 6 or 12 weeks for prosthetic joint infection. N Engl J Med 2021;384:1991-2001.

In this open-label noninferiority trial, 410 patients who had undergone appropriate surgical management of prosthetic joint infections were randomized to receive antibiotic therapy for either six or 12 weeks. Debridement and implant retention (DAIR) was performed in 81.3%, single-stage implant was performed in 31.7%, and a two-stage implant exchange was performed in 21.5%.

The groups were well-balanced at baseline, although there were somewhat more infections due to Staphylo-coccus aureus and fewer due to coagulase-negative staphylococci in those assigned six weeks of therapy. Antibiotics initially were administered intravenously for a median of nine days in each group, after which a variety of orally administered antibiotics were used to complete the assigned treatment course. Chronic suppressive antibiotics were not prescribed. The most frequently administered oral antibiotics were rifampin and fluoroquinolones, which were prescribed to 70.3% and 68.4%, respectively, and 51.1% received both antibiotics.

The primary outcome was persistent or recurrent infection within two years of follow-up, defined as recovery of an isolate phenotypically indistinguishable (including by antibiogram) from their original isolate. This outcome occurred in 35/193 patients (18.1%) in the six-week group and in 18/191 patients (9.4%) in the 12-week group (risk difference, 8.7 percentage points; 95% confidence interval [CI], 1.8 to 15.6). Thus, since the a priori definition of noninferiority in this trial was an upper bound of the 95% CI of the difference of 10%, the 15.6% upper limit in this study demonstrated that a six-week course of therapy was “not noninferior” to a 12-week course — 12 weeks is preferred. The results were similar in patients with knee or hip infections. There also were no significant differences in the proportions with new infections, probable treatment failure, or serious adverse events.

A deeper examination indicates that the benefit of more prolonged antibiotic therapy was most apparent in those undergoing DAIR in whom failure occurred in 25/175 (30.7%) of those treated for six weeks and in 11/76 (14.5%) with a 95% CI around the 16.2% difference of 2.9% to 29.5%. For those who underwent two-stage procedures, the failure rates were 6/40 (15.0%) and 2/41 (4.9%), respectively, with a 95% CI for the 10.1% difference of -3.1% to 23.3%. Finally, the failure rate after six weeks of therapy in those who had undergone a one-stage procedure was 3/75 (4.0%), while it was 2/71 (2.8%) in the 12-week group (95% CI, -4.8% to 7.1%).

COMMENTARY

An earlier underpowered study involving a much smaller number of patients found no significant difference in outcomes with six weeks vs. 12 weeks of treatment.1 The current study by Bernard and colleagues, in contrast, clearly provides evidence of significantly improved outcomes in patients who have undergone DAIR for prosthetic joint infections in association with 12 weeks of treatment when compared to those who received treatment for only six weeks. There appeared to be no such benefit in those who, instead, had undergone a one-stage procedure, and the results for patients with two-stage procedures were equivocal — although the power in these subgroups was limited. As a consequence, the investigators stated that this “remains to be explored in a randomized trial.”

Patients in this study did not receive continued suppressive therapy after their assigned study duration. Although recommended by some clinicians, the evidence in support of this approach, in the absence of chronic incurable suppurative periprosthetic infection, is limited at best.

It is of note that the median duration of intravenous antibiotic administration in this study was nine days, a duration shorter than many clinicians use. It should be noted that no information is provided concerning the antibiotic doses used. However, a recent retrospective study also performed in France found high success rates in patients with S. aureus prosthetic bone and joint or orthopedic metalware-associated infection whose therapy was switched to the intravenous route after a median of just 4.4 days.2 In a randomized trial in which patients with a variety of bone and joint infections, including some involving prosthetic devices, switched to orally administered antibiotics within seven days of therapy initiation or surgery was found to be noninferior to continued intravenous administration for six weeks.3

In summary, 12 weeks of therapy is preferred to six weeks in patients who have undergone DAIR for periprosthetic joint infections, while the optimal duration is uncertain after other procedures. This study and others also indicate that most of that therapy can be administered orally.

REFERENCES

  1. Chaussade H, Uçkay I, Vuagnat A, et al. Antibiotic therapy duration for prosthetic joint infections treated by Debridement and Implant Retention (DAIR): Similar long-term remission for 6 weeks as compared to 12 weeks. Int J Infect Dis 2017;63:37-42.
  2. Boclé H, Lavigne JP, Cellier N, et al. Effectiveness of early switching from intravenous to oral antibiotic therapy in Staphylococcus aureus prosthetic bone and joint or orthopedic metalware-associated infections. BMC Musculoskelet Disord 2021;22:315.
  3. Li HK, Rombach I, Zambellas R, et al; OVIVA Trial Collaborators. Oral versus intravenous antibiotics for bone and joint infection. N Engl J Med 2019;380:425-436.