A randomized controlled trial involving more than 3,600 patients hospitalized with bloodstream infections found that 7 days of antibiotic treatment was noninferior to 14 days, an international team of researchers reported today in the New England Journal of Medicine.
The findings are from the BALANCE (Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness) trial, which was conducted in 74 hospitals in seven countries, among patients who had bloodstream infections caused by a variety of pathogenic bacteria. It's the latest in a series of trials that have found that shorter antibiotic treatments are noninferior for a range of common bacterial infections.
Bloodstream infections are among the most severe types of bacterial infection, causing an estimated 2.9 million deaths globally per year. Antibiotic treatment duration is typically 14 days or longer, but proper duration for bloodstream infections has been understudied. The concern about shorter antibiotic treatment is that it might result in clinical failure or recurrence of infection.
Given the limited of evidence to guide clinical practice, a team led by researchers with the University of Toronto set out to investigate whether death rates after 7 days of antibiotics are similar to those after 14 days. They also hypothesized that shorter antibiotic duration might reduce antibiotic exposure, adverse events, and infections with resistant organisms.
Noninferiority found across most outcomes
Across the 74 hospitals, the investigators enrolled 3,608 patients (median age, 70 years; 53.3% men) with positive blood cultures and randomized them 1:1 to receive 7 or 14 days of antibiotic treatment.
Fifty-five percent of the enrolled patients were in the intensive care unit (ICU), and 45% were on hospitals wards. The most common source of infection was the urinary tract (42.2% of patients), and gram-negative organisms accounted for 71% of positive cultures.
Patients with severe immunosuppression and cultures yielding Staphylococcus aureus were among those excluded from the trial. Antibiotic selection, dosing, and route were at the discretion of the treating team.
The primary outcome of the trial was death from any cause at 90 days, with a noninferiority margin of 4 percentage points. Secondary outcomes included death in the hospital, death in the ICU, Clostridioides difficile infections, and secondary infection or colonization with antibiotic-resistant organisms.
Results for the primary outcome were available for 1,802 patients (99.3%) in the 7-day treatment arm and 1,779 (99.2%) in the 14-day arm. By 90 days, 261 patients (14.5%) receiving 7 days of antibiotics had died, compared with 286 (16.1%) in the 14-day arm, for a treatment difference of –1.6 percentage points (95.7% confidence interval [CI], –4.0 to 0.8), which met the noninferiority criteria.
Adopting a 7-day treatment strategy requires no new expensive medications or technologies, could lead to large savings in drug-acquisition costs, and has the potential to generate downstream benefits in selection of antimicrobial resistance at an individual and population level.
There was some non-adherence to the treatment duration in the trial, with 23.1% of patients in the 7-day group and 10.7% in the 14-day group being treated for longer than the assigned duration. But the per-protocol analysis also showed that 7 days of treatment was non-inferior for the primary outcome (difference, –2.0 percentage points; 95% CI, –4.5 to 0.6).
The results were consistent across most secondary outcomes and prespecified subgroups. C difficile infections and infection or colonization with resistant bacteria were infrequent events in both treatment groups.
Potential for 'downstream benefits'
The study authors note that three similar trials have been conducted since enrollment for the BALANCE trial began, all of which also found 7-day treatment for bloodstream infections to be noninferior to 14 days. But all three trials were smaller, used larger noninferiority margins, and either excluded or enrolled very few patients in the ICU.
"The sample size and much smaller noninferiority margin (4 percentage points) in the BALANCE trial provide a stronger inference about the noninferiority of a 7-day treatment strategy," they wrote, adding that the inclusion of ICU patients "extends the evidence for shorter treatment duration to critically ill patients."
The authors say shorter antibiotic treatment for bloodstream infections could hold many benefits for patients and healthcare systems.
"Adopting a 7-day treatment strategy requires no new expensive medications or technologies, could lead to large savings in drug-acquisition costs, and has the potential to generate downstream benefits in selection of antimicrobial resistance at an individual and population level," they wrote.
They suggest that further research is needed to test individualized and potentially shorter treatment durations, "so that each patient receives just as long a course as is needed and to balance the benefits and possible harms of antibiotic treatment more fully."
