BALANCE: 7 vs. 14 Days of Antibiotics for Bloodstream Infection (2024)

“Among hospitalized patients with bloodstream infection, antibiotic treatment for 7 days was noninferior to treatment for 14 days.” — The BALANCE Investigators

1. Publication Details

  • Trial Title: Antibiotic Treatment for 7 versus 14 Days in Patients with Bloodstream Infections
  • Citation: The BALANCE Investigators. Antibiotic Treatment for 7 versus 14 Days in Patients with Bloodstream Infections. N Engl J Med 2025;392:1065-78. (Published online Nov 20, 2024)
  • Published: March 13/20, 2025, in The New England Journal of Medicine
  • Author: The BALANCE Investigators
  • Funding: Canadian Institutes of Health Research; National Health and Medical Research Council of Australia; Health Research Council of New Zealand, and others.

2. Keywords

  • Sepsis, Bloodstream Infection, Bacteremia, Antibiotic Duration, Antimicrobial Stewardship, Non-inferiority Trial

3. The Clinical Question

  • In hospitalized patients with a bloodstream infection (Population), is a 7-day course of antibiotic treatment (Intervention) non-inferior to a 14-day course (Comparison) with respect to death from any cause by 90 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: While early and appropriate antibiotics are crucial for bloodstream infections, the optimal duration is unknown. Shorter courses may reduce adverse events and resistance, but concerns about treatment failure have led to traditionally longer courses.
  • Knowledge Gap: Previous randomized trials comparing shorter vs. longer antibiotic durations for bacteremia were small, used large non-inferiority margins, and often excluded critically ill patients, limiting their generalizability.
  • Proposed Hypothesis: The investigators hypothesized that 7 days of antibiotic treatment would be non-inferior to 14 days of treatment with respect to 90-day mortality.

5. Study Design and Methods

  • Design: Multicenter, investigator-initiated, open-label, randomized, controlled, non-inferiority trial.
  • Setting: 74 hospitals in seven countries.
  • Trial Period: October 2014 to May 2023.
  • Population:
    • Inclusion Criteria: Hospitalized adult patients (in ICU or on wards) with a positive blood culture with a pathogenic bacterium.
    • Exclusion Criteria: Severe immunosuppression (neutropenia, transplant), prosthetic heart valves, suspected infections requiring prolonged therapy (e.g., endocarditis, osteomyelitis, undrained abscess), or bacteremia with Staphylococcus aureus.
  • Intervention: 7 days of adequate, pathogen-directed antibiotic therapy.
  • Control: 14 days of adequate, pathogen-directed antibiotic therapy.
  • Management Common to Both Groups: The specific antibiotic, dose, and route of administration were at the discretion of the treating clinicians. Group assignment was concealed until day 7 of adequate therapy.
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days after the index blood culture.
    • Secondary Outcomes: Hospital and ICU mortality, relapse of bacteremia, C. difficile infection, secondary infection with resistant organisms, and days free of hospital, ICU, and antibiotic use.

6. Key Results

  • Enrollment and Baseline: 3,608 patients were included in the intention-to-treat analysis (1814 in the 7-day group; 1794 in the 14-day group). The groups were well-matched. The median age was 70, 55% were in the ICU, and the most common source was the urinary tract (42.2%).
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: Death by 90 days occurred in 261 of 1802 patients (14.5%) in the 7-day group and in 286 of 1779 patients (16.1%) in the 14-day group. The absolute difference was -1.6 percentage points (95.7% confidence interval [CI], −4.0 to 0.8), meeting the pre-specified criteria for non-inferiority.
  • Secondary Outcomes: Patients in the 7-day group had a median of 5 more antibiotic-free days by day 28. There were no significant differences in other clinical outcomes, including bacteremia relapse or C. difficile infection.
  • Adverse Events: The rates of antimicrobial-related adverse events were similar between the two groups.

7. Medical Statistics

  • Analysis Principle: The primary analysis was intention-to-treat.
  • Statistical Tests Used: The primary outcome was evaluated by calculating the absolute risk difference and its confidence interval.
  • Primary Outcome Analysis: Comparison of 90-day mortality rates to assess non-inferiority against a margin of 4 percentage points.
  • Key Statistic(s) Reported: Absolute risk difference in 90-day mortality: -1.6 percentage points; 95.7% CI, -4.0 to 0.8.
  • Interpretation of Key Statistic(s):
    • Confidence Interval (CI):
      • Calculation: 95.7% CI, -4.0 to 0.8 percentage points.
      • Clinical Meaning: The upper boundary of the confidence interval was 0.8 percentage points. Since this is less than the pre-specified non-inferiority margin of 4 percentage points, the trial concluded that the 7-day antibiotic course was non-inferior to (not unacceptably worse than) the 14-day course.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR): The point estimate was a 1.6% absolute risk reduction with the 7-day course, though the CI includes the possibility of a small harm (0.8% absolute risk increase).
    • Number Needed to Treat (NNT): Not applicable in the traditional sense for a non-inferiority trial.
  • Subgroup Analyses: The finding of non-inferiority was generally consistent across all prespecified subgroups, including by source of infection, location (ICU vs. ward), and pathogen type.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, pragmatic, multicenter international RCT, which increases the generalizability of the findings.
  • Generalizability: The inclusion of both critically ill and ward patients with a variety of pathogens and infection sources makes the results widely applicable.
  • Statistical Power: The large sample size and a strict non-inferiority margin (4%) provide a high degree of confidence in the results.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The open-label design could have introduced bias, although the primary outcome of all-cause mortality is objective and less susceptible to bias.
  • Adherence: A notable number of patients did not adhere to the assigned duration; 23.1% of the 7-day group received antibiotics for a longer duration. However, per-protocol analyses confirmed the primary findings.
  • Other: The trial was underpowered to assess for differences in rare secondary outcomes like infection with antimicrobial-resistant organisms.

10. Conclusion of the Authors Among hospitalized patients with bloodstream infection, antibiotic treatment for 7 days was non-inferior to treatment for 14 days.

11. To Summarize

  • Impact on Current Practice: This landmark trial provides strong evidence to support using a 7-day course of antibiotics for many common bloodstream infections, challenging the traditional longer-duration approach.
  • Specific Recommendations:
    • Patient Selection: For hospitalized patients with bloodstream infections (excluding S. aureus and those with undrainable sources), a 7-day course of appropriate antibiotics is a reasonable standard of care.
    • Actionable Intervention: Clinicians can confidently shorten antibiotic courses to 7 days for patients who are clinically improving.
  • What This Trial Does NOT Mean: The results do not apply to patients with S. aureus bacteremia, endocarditis, osteomyelitis, or other deep-seated infections that require prolonged therapy. Individual clinical judgment remains paramount.

12. Context and Related Studies

  • Building on Previous Evidence: This trial provides much-needed, high-quality evidence that builds upon smaller, less definitive studies which had suggested that shorter courses might be adequate. BALANCE is the largest and most generalizable trial to date on this topic.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal duration for specific, less common pathogens or in severely immunocompromised patient populations (who were largely excluded) remains an area for further study.
  • Future Directions: Further research is needed to test individualized and potentially even shorter treatment durations to better balance the benefits and harms of antibiotic therapy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: Highly relevant and important question for antimicrobial stewardship and patient care.
  • Methods: The non-inferiority design was appropriate, and the trial was well-conducted with a large, diverse population.
  • Results: The results are clear and statistically robust, convincingly demonstrating non-inferiority for the primary outcome.
  • Conclusions and Applicability: The authors’ conclusions are well-supported by the data. The findings are highly applicable to a large proportion of hospitalized patients with bacteremia.

16. Disclaimer and Contact This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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