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Oral Tx Sufficient in Joint Infections

The use of oral antibiotic therapy during the first 6 weeks of treatment for complex bone and joint infections was non-inferior to intravenous antibiotic treatment, a pragmatic open-label study found.

Treatment failure by 1 year was reported in 14.6% of patients receiving intravenous therapy and 13.2% of those given oral antibiotics, according to Matthew Scarborough, MBBCh, PhD, of John Radcliffe Hospital in Oxford, England, and colleagues.

The difference in treatment failure between the intravenous and oral groups was -1.4 percentage points (95% CI -5.6 to 2.9), which met the prespecified noninferiority margin, the investigators reported online in the New England Journal of Medicine.

Complex bone and joint infections have routinely been treated with initial surgery followed by a long course of intravenous antibiotics, which “reflects a broadly held belief that parenteral therapy is inherently superior to oral therapy,” despite the risks, costs, and inconvenience of intravenous treatments, the researchers explained. “Our results thereby challenge a widely accepted standard of care.”

In an accompanying editorial, Helen W. Boucher, MD, of Tufts University School of Medicine in Boston, said that on the basis of the data, targeted oral therapy may have a role in the treatment of selected patients who have osteomyelitis.

The researchers noted that an earlier meta-analysis had found no significant advantage for intravenous treatment of chronic osteomyelitis, but the data were insufficient for definitive conclusions to be drawn. The team, therefore, enrolled 1,054 patients from 26 sites from 2010 to 2015, with conditions ranging from osteomyelitis of the extra-axial skeleton to prosthetic joint infections.

“The trial hypothesis was based on the pharmacokinetic principle that appropriately selected oral agents provide adequate antibiotic concentrations at the site of infection,” Scarborough and co-authors explained.

Participants were randomly assigned to have either oral or intravenous treatment to begin no more than 7 days after surgery or treatment initiation and to be given for 6 weeks, with follow-on oral treatment permitted. The choice of antibiotics was made by specialists based on factors such as susceptibility, local epidemiologic patterns, previous infections, and potential drug interactions.

Treatment failure (possible, probable, or definite) was evaluated according to clinical criteria, such as the presence of a draining sinus tract, or by microbiologic or histologic criteria.

Patients randomized to the oral therapy group could receive intravenous treatment for up to 5 days for an intercurrent infection.

The initial study protocol called for a five percentage point margin for noninferiority, but following an interim analysis, the margin was adjusted to 7.5 percentage points.

Patients’ median age was 60, and almost two-thirds were men. Initial surgical procedures included debridement and removal of joint implant or device, and in more than half of the patients, deep-tissue histologic analysis identified an infection.

The most common organisms were Staphylococcus aureus and coagulase-negative staphylococcus.

Possible or probable treatment failures occurred in 1.2% of the intravenous-treatment group and 2% of the oral group, and the difference in risk of any treatment failure was -0.7 percentage points (95% CI -5.1 to 3.8).

More patients in the intravenous group discontinued treatment early (18.9% vs 12.8%, P=0.006) and had complications from the intravenous catheter (9.4% vs 1%, P<0.001). These patients also had significantly longer hospital stays -- 14 compared with 11 days (P<0.001).

There were no differences between the groups in the rates of Clostridium difficile diarrhea or serious adverse events, the researchers reported.

Adjunctive oral rifampin was used by 15.6% of the intravenous group and 51.5% of the oral group; no difference in outcome was seen according to planned use of this additional agent, which is intended for biofilm-associated infections, the team explained.

For patient-reported outcomes, similar improvements were seen in both groups on the European Quality of Life 5 Dimensions scale and the Oxford Hip Score, but the oral group had greater improvements on the Oxford Knee Score.

Scarborough and co-authors noted that the trial was not designed to be selective in terms of pathogens, surgical procedures, or site of infection, and the agents used were the choice of the treating infectious disease specialists. “Although the resulting trial population was heterogeneous, the advantages of generalizability outweigh the disadvantages of heterogeneity,” the researchers said, adding that a more selective trial design would have limited the utility of the results.

In her editorial, Boucher sounded a note of caution: “At this time, it is premature to recommend a widespread early switch to oral therapy for bone and joint infection,” she wrote. “Further studies are needed to confirm these findings and will further inform these strategies and advance stewardship to decrease antimicrobial resistance.”

A limitation of the study, the researchers said, was its open-label design.

The study and the investigators were supported by the National Institute for Health Research.

Several investigators also reported financial relationships with Gilead, Biocomposites, Merck Sharp & Dohme, Cubist Pharmaceuticals, Bonesupport AB, and Novartis.