Article Citation: Daneman N, Rishu A, Pinto R, Rogers BA, Shehabi Y, Parke R, Cook D, Arabi Y, Muscedere J, Reynolds S, Hall R, Dwivedi DB, McArthur C, McGuinness S, Yahav D, Coburn B, Geagea A, Das P, Shin P, Detsky M, Morris A, Fralick M, Powis JE, Kandel C, Sligl W, Bagshaw SM, Singhal N, Belley-Cote E, Whitlock R, Khwaja K, Morpeth S, Kazemi A, Williams A, MacFadden DR, McIntyre L, Tsang J, Lamontagne F, Carignan A, Marshall J, Friedrich JO, Cirone R, Downing M, Graham C, Davis J, Duan E, Neary J, Evans G, Alraddadi B, Al Johani S, Martin C, Elsayed S, Ball I, Lauzier F, Turgeon A, Stelfox HT, Conly J, McDonald EG, Lee TC, Sullivan R, Grant J, Kagan I, Young P, Lawrence C, O'Callaghan K, Eustace M, Choong K, Aslanian P, Buehner U, Havey T, Binnie A, Prazak J, Reeve B, Litton E, Lother S, Kumar A, Zarychanski R, Hoffman T, Paterson D, Daley P, Commons RJ, Charbonney E, Naud JF, Roberts S, Tiruvoipati R, Gupta S, Wood G, Shum O, Miyakis S, Dodek P, Kwok C, Fowler RA; The BALANCE Investigators. Antibiotic Treatment for 7 versus 14 Days in Patients with Bloodstream Infections. N Engl J Med. 2025 Mar 13;392(11):1065-1078.

Background

The optimal duration of antibiotic therapy for bloodstream infections remains uncertain. Prolonged courses of antibiotics may increase iatrogenic adverse effects, resistance, and costs, while shorter courses may increase the risk of treatment failure. The BALANCE trial aimed to determine whether 7 days of antibiotic treatment was non-inferior to 14 days of treatment in patients with bloodstream infections.

Methods:

This was a multicenter, randomized, non-inferiority trial with a delayed open-label design (investigators were blinded to treatment protocol until the 7^th day) enrolling patients from both the ICU and hospital wards. Choice and dosing of antibiotics were determined by patients’ clinical teams. Notable exclusion criteria included infection with S. aureus or S. lugdunensis, severe immunosuppression, infections expected to require longer treatment times (e.g., osteomyelitis, endocarditis), patients with cultures thought to be positive due to contaminants, and fungemia.

The primary outcome was all-cause mortality at 90 days from diagnosis of bloodstream infection. Secondary outcomes included death in the hospital, death in the ICU, relapse of bacteremia with the originally cultured organism, allergies and adverse events related to antibiotic use, C. difficile infections while in the hospital, secondary infections with antimicrobial-resistant organisms while in the hospital, length of stay in the ICU, ICU-free days, hospital-free days, duration of invasive mechanical ventilation, invasive mechanical ventilation-free days, antibiotic-free days, duration of vasopressor use, and vasopressor-free days. No correction was made for multiple comparisons as these secondary outcomes were considered exploratory. In prespecified secondary analyses, the investigators also accounted for clustering by center in a generalized linear mixed model, and they conducted a meta-analysis with three similar, smaller trials (which included only patients with gram-negative infection).

Results

The trial enrolled 3608 patients from 74 hospitals in 7 countries, with 1814 patients assigned to the 7-day treatment course and 1794 to the 14-day course. At the time of enrollment, 55% of these patients were in an ICU and 45% were on a non-intensive floor. Among all infections, 75.4% were acquired in the community, 13.4% on a non-intensive floor, and 11.2% in an ICU, while suspected sources of infection were mixed (42.2% urinary tract, 18.8% abdominal, 13% respiratory, 6.3% vascular catheter-related, and 5.2% skin/soft tissue). Adherence to the treatment timelines was good overall: median treatment length for the 7-day group was 8 days (IQR 7-11) and for the 14-day group was 14 days (IQR 14-15). However, 23.1% of the 7-day group received treatment for longer than 9 days.

In terms of 90-day mortality, the primary intention-to-treat analysis revealed non-inferiority of antibiotic treatment for 7 versus 14 days (14.5% vs. 16.1%; mean difference -1.6% [95% CI -4.0, 0.8]). This finding was replicated in both the per-protocol and modified intention-to-treat analyses. Non-inferiority was also preserved in subgroup analyses based on Clinical Frailty Scale, APACHE II score, source of bacteremia, and pathogen type. Secondary outcomes between the two groups were similar, though overall trends favored the 7-day treatment course. Antimicrobial-related adverse events were relatively rare (32 in the 7-day group and 41 in the 14-day group), and rates of secondary infection with C. difficile or resistant organisms were similar between the two groups. The generalized linear mixed model and meta-analysis supported the primary findings.

Commentary:

The authors concluded that, in patients with a bloodstream infection, a 7-day course of antibiotic treatment was non-inferior to a 14-day course in terms of 90-day mortality. Mortality was lower by 1.6% in the 7-day group, though both groups experienced significantly lower mortality than the anticipated 22%. Because of the study’s large sample size, its non-inferiority margin was stringent (4%) compared to similar studies (typically 10%) with mortality as a primary outcome. Other strengths of this trial include consistent findings across intention-to-treat, per-protocol, and generalized linear mixed model analyses, strong representation of ICU patients, and inclusion of gram-positive bacteria (except for S. aureus and S. lugdunensis). The exclusion of S. aureus is of great significance, however, since it is the second most common cause of bloodstream infections.

The authors note that the impetus for a study aimed at justifying shorter durations of antibiotic treatment is a presumed decrease in drug-related adverse events, C. difficile infections, bacterial resistance, and costs. However, as the prevalence of adverse events was low overall in both groups, this study does not provide strong support for an increase in safety by switching from a 14-day to a 7-day treatment plan. Still, a shorter duration of treatment may be preferable if equally effective.

Overall, this large-scale trial supports the notion that shorter antibiotic courses can be as effective as longer ones, reducing treatment duration without compromising outcomes. As evidenced by the greater deviation from protocol in the 7-day treatment group, it is also likely that clinician acumen will play a role in determining treatment timeframe when a persistent infection is suspected. The findings do, however, provide support for a more conservative approach to treatment when deemed clinically appropriate. As the authors note, this bimodal treatment model is non-specific, and more research will be needed to increase the precision of individualized treatment options.