Two studies today in the New England Journal of Medicine suggest that partial oral antibiotic therapy may be appropriate for certain patients with bone and joint infections and infective endocarditis.
The studies report the results of two randomized controlled trials comparing intravenous (IV) versus oral antibiotic therapy for serious bacterial infections. In one trial, UK investigators found that oral antibiotic treatment was noninferior to IV treatment when used during the first 6 weeks of management of complex bone and joint infections. In the other trial, conducted in Denmark, switching patients with infective endocarditis on the left side of the heart from IV to oral antibiotics during treatment was found to be noninferior to continuous IV therapy.
The findings are noteworthy because, while guidelines for both infections recommend IV antibiotic therapy, IV treatment is associated with increased risk of complications, longer hospital stays, and higher costs than oral therapy. In addition, switching from IV to oral antibiotics when clinically appropriate is considered an important strategy for combatting antimicrobial resistance.
Complex bone, joint infections
In the OVIVA (Oral Versus Intravenous Antibiotics for Bone and Joint Infection) trial, patients from 26 UK hospitals were randomly assigned on a 1:1 basis, within 7 days after surgery (or 7 days after the start of antibiotic treatment if no surgery was involved), to receive either standard IV therapy or oral antibiotics to complete the first 6 weeks of treatment. Antibiotic therapies were tailored for each patient, and follow-up oral antibiotics were allowed in each group.
The primary endpoint was definitive treatment failure (defined as the presence of at least one clinical, microbiologic, or histologic criterion) within 1 year after randomization. The noninferiority margin for the risk of treatment failure was 7.5 percentage points.
Altogether, 1,054 patients were enrolled in the study (527 in each group), with endpoint data available for 1,015. Of the 1,054 participants, 639 (60.1%) had metalware-related infections. The most frequently identified organisms were Staphylococcus aureus (37.7%), coagulase-negative Staphylococcus (27.1%), and Streptococcus species (14.5%). The median total duration of treatment was 78 days in the IV group and 71 days in the oral group (P = 0.63).
Definitive treatment failure occurred in 74 of 506 patients in the IV group (14.6%) and 67 of 509 patients in the oral group (13.2%). The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral vs IV) of -1.4 percentage points (90% confidence interval [CI], -4.9 to 2.2; 95% CI, -5.6 to 2.9), indicating noninferiority. These results were consistent across all subgroups analyzed.
Incidence of Clostridioides difficile–related infection (1.7% in the IV group vs 1.0% in the oral group, P < 0.001) and serious adverse events (27.7% in the IV group vs 26.2% in the oral group, P = 0.30) was not significantly different between the two groups. The median hospital stay, however, was significantly longer among patients in the IV group (14 days vs 11 days, P < 0.001).
"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," the authors of the study write.
Endocarditis in Danish patients
In the POET (Partial Oral Treatment of Endocarditis) trial, investigators at cardiac centers in Denmark randomly assigned 400 patients who had endocarditis on the left side of the heart caused by Enterococcus faecalis, S aureus, or coagulase-negative Staphylococcus and who had been treated with IV antibiotics for at least 10 days to continue IV treatment or switch to oral antibiotics (201 patients). Only patients in stable condition were enrolled in the trial.
The primary outcome was a composite of all-cause mortality, unplanned cardiac surgery, clinically evident embolic events, or relapse of bacteremia with the primary pathogen 6 months after antibiotic treatment was completed. The noninferiority margin was 10 percentage points
After randomization, the IV group (199 patients) received a median of 19 days of antibiotic therapy and the oral group (201 patients) received a median of 17 days of treatment.
The primary composite outcome occurred in 24 of 199 patients in the IV group (12.1%) and 18 of 201 patients in the oral antibiotics group (9.0%), for a between-group difference of 3.1 percentage points (95% CI, -3.4 to 9.6, P = 0.40) in favor of oral treatment, which met noninferiority criteria.
The results were consistent across prespecified subgroups. Adverse events occurred in 6% of the IV group and 5% of the oral group (P = 0.66).
The results also showed that 160 patients (80%) in the oral group were partially or completely treated as outpatients, and that the median length of stay after randomization was 19 days in the IV group versus 3 days in the orally treated group (P < 0.001).
Findings have limits
In an accompanying editorial, Helen Boucher, MD, an infectious disease and antimicrobial resistance expert with Tufts University School of Medicine, writes that while the results need to be confirmed in further studies, the data from the two trials indicate that targeted oral therapy "may have a role in the treatment of selected patients who have osteomyelitis or infective endocarditis on the left side of the heart and the health care infrastructure to support close monitoring."
But Boucher also notes that the generalizability of the findings are limited by the open-label design of the two studies, the heterogeneous populations in both trials, the inclusion of few antibiotic-resistant organisms, and the use of treatments that are not available or used in the United States. As a result, she argues, it is premature to recommend a widespread early switch to oral therapy for bone and joint infection or step down to combination oral therapy for infective endocarditis on the left side of the heart.
Boucher says more studies like these are needed to address the role that oral antibiotics can play in serious infections.
"I hope that U.S. research leaders working with both government agencies and private research foundations will find ways to execute similar trials or to collaborate with colleagues abroad to study therapies available to our patients," she writes.
Jan 30 N Engl J Med bone and joint infection study
Jan 30 N Engl J Med endocarditis study
Jan 30 N Engl J Med editorial