A course of oral antibiotics is noninferior to prolonged intravenous antibiotic therapy in managing complex orthopedic infections for some patients, according to results published online today in the New England Journal of Medicine.
"In this trial, with regard to treatment failure assessed at 1 year, oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks of treatment for bone and joint infection; our results thereby challenge a widely accepted standard of care," write Ho‑Kwong Li, MRCP, of Oxford University Hospitals NHS Foundation Trust and colleagues.
"Oral antibiotic therapy was associated with a shorter length of hospital stay and with fewer complications than intravenous therapy."
Because prolonged use of intravenous antibiotics is associated with inconvenience, substantial risks, and higher costs than oral antibiotics, the researchers conducted an open-label, randomized noninferiority trial comparing the two delivery routes. The trial was unblinded to avoid exposing participants to the risks of intravenous placebo.
The researchers recruited adults being treated for bone or joint infection at 26 centers in the United Kingdom. Diagnoses were native osteomyelitis of the extraaxial skeleton, native joint infection requiring excision arthroplasty, prosthetic joint infection, orthopedic fixation device infection, or vertebral osteomyelitis with or without associated diskitis or soft-tissue infection.
Participants were randomly assigned to receive either intravenous or oral antibiotics for the first 6 weeks of therapy, beginning within 7 days after surgery or within 7 days after the start of antibiotic treatment for nonsurgical management. Patients in both groups could continue oral antibiotics after the assessment period.
Rifampin was allowed in both groups. This is a common adjunctive treatment for certain biofilm-associated infections.
Of the 1054 recruited participants, 1015 remained for the modified intention-to-treat group and 909 for the per-protocol analysis. Median total duration of therapy was 78 days (interquartile range, 42-99) in the intravenous group and 71 days (interquartile range, 43-94) in the oral group (P = .63).
Definitive treatment failure within 1 year, which was the primary endpoint for the trial, occurred in 74 of the 506 participants (14.6%) in the intravenous antibiotics group and for 67 of the 509 participants (13.2%) in the oral antibiotics group. Treatment failure was defined as meeting at least one criterion that was clinical (eg, a draining sinus tract arising from bone or a prosthesis or nearby pus), microbiologic (eg, bacteria in biopsy or aspirate), or histologic (eg, inflammatory infiltrate or microorganisms).
The difference in the risk of definitive treatment failure (oral group vs intravenous group) in the intention-to-treat population was −1.4 percentage points (90% confidence interval [CI], −4.9 to 2.2; 95% CI, −5.6 to 2.9), which was within the prespecified boundary for noninferiority criteria of 7.5 percentage points (90% CI) or 5 percentage points (95% CI).
The secondary outcomes of probable or possible treatment failures occurred in 6 of 506 participants (1.2%) in the intravenous group and 10 of 509 participants (2.0%) in the oral group, putting the combined difference of any treatment failure at −0.7 percentage points (90% CI,−4.4 to 3.1; 95% CI, −5.1 to 3.8).
Members of the intravenous group were more likely to discontinue treatment early than those receiving oral treatment (99/523 participants [18.9%] vs 67/523 [12.8%]; P = .006). In addition, complications associated with the intravenous catheter were more common in the intravenous group (49/523 [9.4%] vs 5/523 [1.0%], P < .001).
Incidence of Clostridium difficile–associated diarrhea and/or serious adverse events did not differ between the groups. The median hospital stay was 14 days for the intravenous group compared with 11 days for the oral group. Rifampin use did not affect the groups differently.
Patient-reported hip pain improved with time and did not differ in the two groups, but knee pain was better in the oral antibiotic group.
Among patients administering their own medications, medium to high adherence to treatment (the Morisky score) at 42 days was reported from 75 of the 80 patients receiving intravenous antibiotics (93.8%) compared with 283 of 323 participants (87.6%) in the oral group. Among 62 patients in the oral group whose adherence was monitored with a medication event monitoring system, 56 (90.3%) had higher than 95% adherence, with only 3.8% of doses missed.
Helen W. Boucher, MD, from the Tufts Center for Integrated Management of Antimicrobial Resistance, points out limitations of the study in an accompanying editorial. These include the open-label design, infections by multiple pathogens, use of different treatment regimens, heterogeneous infections, and inclusion of few antibiotic-resistant organisms.
"It is noteworthy that oral therapy was associated with as many serious adverse events as intravenous therapy. Close monitoring of outpatients who are taking oral therapy may be warranted; indeed, it may be time to update outpatient parenteral antimicrobial therapy guidelines to include some oral antibiotic regimens," Boucher writes.
Bejon and Walker report support from NIHR Oxford Biomedical Research Center; Li, Briggs, Hemsley, and Romback from NIHR Health Technology Assessment; and Cooke from NIHR Imperial College Biomedical Research Center. Boucher serves as editor of Antimicrobial Agents and Chemotherapy and Infectious Disease Clinics of North America, infectious diseases board member of the American Board of Internal Medicine, and treasurer of the Infectious Diseases Society of America.
N Engl J Med. 2019;380:425-436, 487-489.
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Cite this: Ricki Lewis. Bone, Joint Infections Treatable With Oral Antibiotics - Medscape - Jan 30, 2019.
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