By Jake Scott, MD

Synopsis: In this multinational, noninferiority trial that included more than 3,600 hospitalized patients with bloodstream infections from various pathogens and infectious syndromes, seven days of antibiotic therapy was noninferior to 14 days with respect to death from any cause by 90 days. Patients were excluded if they had severe immunosuppression or foci requiring prolonged treatment, or if their blood cultures yielded Staphylococcus aureus or possible contaminants. Various secondary outcomes were similar between the two groups.

Source: BALANCE Investigators, for the Canadian Critical Care Trials Group, the Association of Medical Microbiology and Infectious Disease Canada Clinical Research Network, the Australian and New Zealand Intensive Care Society Clinical Trials Group, and the Australasian Society for Infectious Diseases Clinical Research Network; Daneman N, Rishu A, Pinto R, et al. Antibiotic treatment for 7 versus 14 days in patients with bloodstream infections. N Engl J Med. 2024;Nov 20. doi:10.1056/NEJMoa2404991. [Online ahead of print].

The BALANCE trial was an open-label, randomized, controlled, noninferiority trial that assessed seven vs. 14 days of antibiotic treatment for hospitalized patients with bloodstream infections.¹ The trial was investigator-initiated and conducted at 74 hospitals in seven countries between October 2014 and May 2023. Patients were excluded if they were severely immunocompromised (i.e., had neutropenia or were receiving immunosuppressive treatment after solid-organ transplantation or hematopoietic stem-cell transplantation); had prosthetic heart valves or endovascular grafts; had an infectious syndrome for which prolonged antibiotic treatment was indicated; had a positive blood culture with a suspected contaminant (e.g., coagulase-negative staphylococci); had bacteremia caused by Staphylococcus aureus, S. lugdunensis, or rare organisms that required prolonged treatment; or had fungemia. Participants were randomized in a 1:1 ratio to receive either seven days or 14 days of adequate antibiotic treatment. The type, dose, frequency, and route of antibiotics were at the discretion of the treating clinicians. To minimize bias, group assignments were concealed until day 7 of adequate treatment.

The primary outcome was death from any cause by 90 days after diagnosis of the bloodstream infection, with a noninferiority margin of four percentage points. Several various secondary outcomes were included, such as death in the hospital, relapse of bacteremia, and length of stay. Among the 3,608 patients in the intention-to-treat group, 1,814 patients were randomly assigned to seven days and 1,794 patients were assigned to 14 days of antibiotic treatment. Patient characteristics were similar between the two groups. Overall, 1,922 (53%) were male, the median age was 70 years (interquartile range [IQR], 59 to 80), and 1,986 (55%) were enrolled in the intensive care unit (ICU) at the time of enrollment. The majority of bloodstream infections (75%) were classified as community-onset and 25% were nosocomial. The most common source of bacteremia was the urinary tract (42%), followed by intra-abdominal or hepatobiliary (19%), lung (13%), vascular catheter (6%), and skin and soft tissue (5%). The source was undefined or unknown in 13% of patients. The most commonly isolated pathogens were Escherichia coli (43.8%), followed by Klebsiella species (15.3%), Enterococcus species (6.9%), coagulase-negative staphylococci (4.8%), Pseudomonas species (4.7%), Streptococcus pneumoniae (4.5%), Enterobacter species (4.4%), and various others. Overall, 2,562 patients (71.0%) had monomicrobial gram-negative bacteremia, 625 (17.3%) had monomicrobial gram-positive bacteremia, and 421 (11.7%) had polymicrobial bacteremia.

By 90 days, death occurred in 261 patients (14.5%) in the seven-day group and in 286 patients (16.1%) in the 14-day group. In the intention-to-treat (ITT) analysis, seven days of treatment was found to be noninferior to 14 days (difference, -1.6 percentage points [95.7% confidence interval {CI}, -4.0 to 0.8). Nonadherence to the protocol (i.e., antibiotics given for a shorter or longer duration than the assigned number of days ± 2 days) occurred in 23.9% of patients in the seven-day group and in 16.5% in the 14-day group. The median duration of treatment was eight days (IQR, 7 to 11) in the seven-day group and 14 days (IQR, 14 to 15) in the 14-day group. Noninferiority of seven days of treatment also was shown in the per-protocol analysis (difference, -2.0 percentage points [95% CI, -4.5 to 0.6]) and in the modified ITT analysis that excluded patients who died before day 7 of treatment (difference, -1.6 percentage points [95% CI, -3.9 to 0.7]).

Seven days of treatment also was shown to be noninferior with respect to the primary outcome in prespecified subgroup analyses stratified according to the underlying source of infection, although confidence intervals were wide around the estimate of treatment effect in multiple subgroups. There were no significant differences found between the two groups with respect to secondary outcomes. The difference between the seven-day group and the 14-day group regarding bacteremia relapse was 0.4 percentage points (95% CI, -0.6 to 1.4). There was a higher median number of antibiotic-free days by day 28 among patients in the seven-day group (19 days [IQR, 11 to 21]) than in the 14-day group (14 days [IQR, 11 to 21]). There were no significant differences in percentages of patients with antimicrobial-related adverse outcomes, Clostridioides difficile infection, or secondary infection or colonization with antibiotic-resistant organisms.

Commentary

The BALANCE trial is the largest randomized clinical trial to date that showed noninferiority of seven days of antibiotic treatment as compared with 14 days for hospitalized patients with bloodstream infections, regardless of severity of illness. Three smaller trials that used a larger noninferiority margin of 10% also showed noninferiority with a shorter duration of treatment. Yahav and colleagues conducted a randomized, multicenter trial that included 604 patients hospitalized with gram-negative bacteremia (68% of which originated from the urinary tract) and found no significant difference with respect to the primary outcome at 90 days, which was a composite of all-cause mortality; relapse, suppurative, or distant complications; and readmission or extended hospitalization.² In a trial performed by von Dach and colleagues, a fixed seven-day antibiotic treatment duration was noninferior to a fixed 14-day duration in patients hospitalized with uncomplicated gram-negative bacteremia for a variety of clinical outcomes at day 30, although the study was limited by low event rates and low rates of adherence.³ The most recent trial, which was conducted by Molina and colleagues, demonstrated that a seven-day course of antibiotics for Enterobacterales bloodstream infections was noninferior to a 14-day course for clinical cure.⁴ However, these three smaller trials enrolled very few ICU patients, or excluded them altogether, unlike the BALANCE trial. They also only focused on patients with gram-negative bacteremia, whereas the BALANCE trial included patients with bloodstream infections caused by a wide variety of pathogens, including gram-positive organisms.

A fundamental element of antimicrobial stewardship is ensuring that antibiotic treatment be administered for the minimum duration required for maximum efficacy. Multiple randomized clinical trials have demonstrated that shorter courses of antibiotics are noninferior to longer courses for a variety of infectious syndromes, such as pneumonia, uncomplicated intra-abdominal infection, pyelonephritis, cellulitis, and others.^5-9 The findings from the large and well-conducted BALANCE trial make a significant contribution to the growing body of evidence in support of a shorter course of antibiotics.

Jake Scott, MD, is Clinical Associate Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley.

References

1. BALANCE Investigators, for the Canadian Critical Care Trials Group, the Association of Medical Microbiology and Infectious Disease Canada Clinical Research Network, the Australian and New Zealand Intensive Care Society Clinical Trials Group, and the Australasian Society for Infectious Diseases Clinical Research Network; Daneman N, Rishu A, Pinto R, et al. Antibiotic treatment for 7 versus 14 days in patients with bloodstream infections. N Engl J Med. 2024;Nov 20. doi:10.1056/NEJMoa2404991. [Online ahead of print].

2. Yahav D, Franceschini E, Koppel F, et al. Seven versus 14 days of antibiotic therapy for uncomplicated gram-negative bacteremia: A noninferiority randomized controlled trial. Clin Infect Dis. 2019;69(7):1091-1098.

3. von Dach E, Albrich WC, Brunel AS, et al. Effect of C-reactive protein-guided antibiotic treatment duration, 7-day treatment, or 14-day treatment on 30-day clinical failure rate in patients with uncomplicated gram-negative bacteremia: A randomized clinical trial. JAMA. 2020;323(21):2160-2169.

4. Molina J, Montero-Mateos E, Praena-Segovia J, et al. Seven- versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: A randomized, controlled trial. Clin Microbiol Infect. 2022;28(4):550-557.

5. Uranga A, España PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: A multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257-1265.

6. Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: A randomized trial. JAMA. 2003;290(19):2588-2598.

7. Sawyer RG, Claridge JA, Nathens AB, et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med. 2015;372(21):1996-2005.

8. Sandberg T, Skoog G, Hermansson AB, et al. Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: A randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. Lancet. 2012;380(9840):484-490.

9. Hepburn MJ, Dooley DP, Skidmore PJ, et al. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med. 2004;164(15):1669-1674.