BALANCE – 7 vs 14 days of antibiotics

Antibiotic Treatment for 7 versus 14 Days in Patients with Bloodstream Infections

BALANCE Investigators. NEJM 2024; DOI: 10.1056/NEJMoa2404991

Clinical Question

  • In hospitalised patients with bloodstream infections (BSI), is antibiotic treatment for 7 days, compared to treatment for 14 days, non-inferior with respect to mortality at 90 days?

Background

  • BSI are common and a leading cause of mortality and morbidity, accounting for 2.9 million deaths per year worldwide
  • Early appropriate antibiotic therapy improves survival, but there are limited studies assessing duration of antibiotic therapy 
  • Shorter duration of therapy would confer benefits such as decreased antimicrobial exposure, complications, antimicrobial resistance, and costs
  • Conversely, insufficient duration of antibiotic therapy could result in treatment failure, relapse, or selection of resistance
  • Prior trials comparing antibiotic duration:
    • Yahav et al. 2019 – Individualised, CRP-guided or 7 days fixed duration non-inferior compared with 14 days for gram-negative BSI
    • von Dach et al. 2020 – 7 days non-inferior to 14 days in uncomplicated gram-negative BSI
    • Molina et al. 2022 – 7 days is non-inferior to 14 days antibiotic duration for Enterbacterales BSI

Design

  • Multicentre, investigator-initiated, open-label, randomised, non-inferiority trial
    • Whilst open-label, allocation of antibiotic treatment group concealed until day 7 of adequate antibiotic therapy
  • Initially only for ICU patients but extended to include all hospital patients after successful parallel trial of ward patients
  • Eligible patients were assigned (1:1) via web-based randomization with variable block sizes, stratified according to hospital site and whether admitted to the ICU or hospital ward
  • Sample size 3626 based on non-inferiority margin of 4% (assuming a baseline 90-day mortality of 22%) and accounting for maximum 5% loss to follow-up would achieve 80% power, at a one-sided alpha level of 2.5%
  • Primarily intention-to-treat analysis, however modified intention to treat and per-protocol analysis also conducted
    • Modified intention-to-treat analysis to exclude patients who died before day-7 of treatment (where the groups diverge).
    • Per-protocol excluded all those who had more than a 2-day difference (+ or -) in assigned duration
  • Daily assessment of adherence and reason for non adherence reported
  • Pre-specified subgroup analyses based on source of infection, location of enrolment (ICU vs not), gram stain, vasopressor use and APACHE II score
  • Trial protocol published a priori
  • Informed consent obtained from patients or substitute decision maker prior to enrolment

Setting

  • Conducted in 74 hospital sites across 7 countries
    • Canada, Australia, New Zealand, Saudi Arabia, Israel, Switzerland, United States
  • Oct 17, 2014 to May 5, 2023

Population

  • Inclusion:
    • Adult patients admitted to hospital with a positive blood culture with a pathogenic bacterium
  • Exclusion:
    • Severely immunocompromised (i.e. absolute neutrophil count < 0.5×10^9/L, or receiving immunosuppressive therapy for solid organ or bone marrow or stem cell transplant)
    • Prosthetic heart valves or endovascular grafts
    • Documented or suspected infectious syndrome for which prolonged antibiotics treatment was necessary (i.e. endocarditis, osteomyelitis, septic arthritis, undrained abscess, unremoved prosthesis-associated infection)
    • Blood culture positive with a common contaminant (e.g. Coagulase-negative Staphylococci)
    • Staphylococcus aureus or Staphylococcus lugdunensis bacteraemia
    • Bacteraemia from rare organisms requiring prolonged treatment
    • Fungaemia
  • 36637 assessed for eligibility → 13,597 eligible → 3631 patients randomised
    • 1824 patients assigned to 7-day group, and 1807 patients to 14-day group
  • Comparing baseline characteristics of 7 day vs. 14 day group
    • Male sex: 54% vs 53%
    • Median age (yrs): 70 vs 70
    • Median SOFA score day 0: 4 vs 5
    • Enrolled in ICU: 55% vs 55%
    • Mechanical ventilation: 21% vs 22%
    • Coexisting conditions:
      • Diabetes mellitus: 33% vs 31%
      • Solid organ cancer: 22% vs 21%
      • Glucocorticoid or immunosuppressant: 13% vs 12%
    • Source control procedure: 44% vs 46%
    • Source of bacteraemia
      • UTI: 42% vs 43%
      • Intra-abdominal or hepatobiliary: 19% vs 19%
      • Lung: 13% vs 13%
      • Vascular catheter: 6% vs 6%
      • Skin, soft tissues, both: 6% vs 5%
      • Other: 2% vs 2%
      • Unidentified: 13% vs 12%
    • Most commonly isolated pathogen
      • Ecoli: 44% vs 43%
      • Klebsiella spp.: 15% vs 16%
      • Enterococcus spp.: 7% vs 7%

Intervention

  • 7 days adequate antibiotic therapy
    • Median duration received 8 days

Control

  • 14 days adequate antibiotic therapy
    • Median duration received 14 days

Management common to both groups

  • Selection of antibiotics, duration and route was at discretion of treating clinician
  • Adequate antibiotics was defined as per local laboratory susceptibilities

Outcome

  • Primary outcome:
    • Death from any cause at 90 days from the date of collection of index positive blood culture
    • 7-day group was non-inferior
      • Difference: -1.6% (95% CI, -4.0 to 0.8)
    • No difference in pre-specified subgroups

 

  • Secondary outcomes:
    • Comparing 7 vs 14 days
    • Significant difference in:
      • Median hospital length of stay (days): 10 vs 11
        • Difference: −1 days (95% CI, −1.5 to −0.5)
      • Median hospital-free days by day 28: 17 vs 15
        • Difference: 2 days (95% CI, 0.8 to 3.2)
      • Median number of antibiotic free days by day 28: 19 vs 14
        • Difference: 5 days (95% CI, 4.6 to 5.4)
    • No significant difference in:
      • Hospital mortality: 9.3% vs 10.3%
      • Median ICU length of stay (days): 5 vs 5
      • Median days of vasopressor use: 3 vs 3
      • Median days on mechanical ventilation: 6 vs 5
      • Relapse rates of bacteraemia with same organism: 2.6 vs 2.2%
      • C difficile infection: 1.7 vs 2.0 %
      • Secondary infection/colonisation with antimicrobial-resistant organisms: 9.5 vs 8.5%

Authors’ Conclusions

Among hospitalized patients with bloodstream infection, antibiotic treatment for 7 days was noninferior to treatment for 14 days

Strengths

  • Pragmatic design with patient centred outcomes:
    • Inclusion of ward patients increases generalisability; conversely the inclusion of ward patients may make the overall cohort more heterogenous and less unwell
  • Multicentre, international RCT
  • Largest trial looking at antibiotic duration and included wide variety of pathogenic bacteria
    • However some common bacteria not included such as Staph aureus, which represents a large proportion of BSI with high morbidity and mortality
  • Minimal attrition: 0.5% withdrew consent (7 in intervention group, 10 in control group), 0.7% lost to follow-up (12 in intervention group, 15 in control group).
  • Similar baseline characteristics, disease severity and frailty scores
  • Intention-to-treat analysis supported by per-protocol and modified-ITT analysis to mitigate non-adherence/protocol deviation
  • Clinicians blinded to allocation up until 7 days before being instructed to continue or cease antibiotics to avoid influencing antibiotic choices and clinical decision-making
  • Objective primary outcome measures partly mitigates open-label design
    • Central adjudication committee blinded to treatment allocation to look at secondary outcome such as relapse and secondary infection/colonisation

Weaknesses

  • Predominantly Canadian hospitals (75%, 2712/3608) may not be representative of all practices
  • Whilst 4% non-inferiority margin is lower than other similar trials and ultimately the point estimate favoured the 7-day group, given antimicrobials are one of the most important tools to treat patients within ICU some may view a 4% margin as too high for a non-inferiority trial
  • Not powered to examine whether some subgroups benefit from prolonged durations such as differing sources of infection
    • In particular, UTIs made up 40% of study population, one would expect clinical stability would be quickly achieved with appropriate antibiotics and extended antibiotic regimens would be uncommon for most
  • Non-adherence rate was high
    • 24% in 7-day group (23% received antibiotics for longer duration) and 17 % in 14-day group (including 6% receiving antibiotics for shorter duration and 11 % receiving antibiotics for longer duration)
    • Per-protocol analysis similar to overall results
    • It would be interesting to see the reasons for this
  • No mention of whether there were patients who were already on antibiotics prior to index positive blood culture; and if they were, whether these would have ultimately treated the BSI
  • Daily visits by research team could potentially introduce performance bias / Hawthorne effect

The Bottom Line

  • This well-executed multi-centre trial provides solid evidence that a 7-day course of appropriate antibiotics is sufficient to treat most bloodstream infections, although it was not powered to examine different sources of BSI
  • It highlights the importance of further research into antibiotic duration and antimicrobial stewardship

External Links

Metadata

Summary author: Tim Law
Summary date: 19th December 2024
Peer-review editor: George Walker

Picture by: Pixabay / Pexels

 

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