Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness
Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness
The World Health Organization, U.S. Centers for Disease Control and Prevention, Association
 of Medical Microbiology and Infectious Diseases (AMMI) Canada, and Health Canada have all
 declared antimicrobial resistance a global threat to health, based on rapidly increasing
 resistance rates and declining new drug development. Up to 30-50% of antibiotic use is
 inappropriate, and excessive durations of treatment are the greatest contributor to
 inappropriate use. Shorter duration treatment (≤7 days) has been shown in meta-analyses to be
 as effective as longer antibiotic treatment for a range of mild to moderate infections. A
 landmark trial in critically ill patients with ventilator-associated pneumonia showed that
 mortality and relapse rates were non-inferior in patients who received 8 vs 15 days of
 treatment. Similar adequately powered randomized trial evidence is lacking for the treatment
 of patients with bloodstream infections caused by a wide spectrum of organisms.
Bloodstream infections are a common and serious problem, increasing length of hospital stay
 by 2-3 weeks, adding $25,000-40,000 in excess hospital costs, and tripling the risk of death.
 At the same time, antibiotic overuse is also a common and serious problem, in that 30-50% of
 antibiotic use is unnecessary or inappropriate, and results in avoidable drug side effects
 such as kidney failure, Clostridioides difficile infection, increased costs, and spiralling
 antibiotic resistance rates. The greatest contributor to antibiotic overuse is excessive
 durations of treatment.

 Extensive research has demonstrated that shorter duration antibiotic treatment (less or equal
 to 7 days) is as effective as longer duration treatment for a variety of infectious diseases,
 but this question has not been directly studied in the setting of bloodstream infection.
 BALANCE team's systematic review of the medical literature, national survey of Canadian
 infectious diseases and critical care physicians, multicentre retrospective study and BALANCE
 pilot RCT, all support the need for a randomized controlled trial comparing shorter (7 days)
 versus longer (14 days) antibiotic therapy for bloodstream infections. Prior to performing
 the main trial, Investigators completed a pilot trial in ICU patients to establish the
 feasibility of the research design, and to optimize the definitive trial. Investigators also
 completed a pilot trial of non-ICUs patients to test the feasibility, compare the patient
 population in two settings and to assess the reasonableness of expanding the main BALANCE
 Trial to non-ICU wards. The overall recruitment rate of the non-ICU ward pilot RCT exceeded
 the recruitment rate in the BALANCE ICU pilot RCT with a protocol adherence of 90%. The
 results of this pilot were used to estimate the necessary sample size recalculation, after
 merging the BALANCE ward trial with the BALANCE main trial, with the principle of maintaining
 an equal to smaller non-inferiority margin by the trial's completion. With the completion of
 this pilot RCT, the eligibility criteria for the BALANCE trial are also modified to broaden
 the inclusion of all bacteremic patients admitted to hospital. By defining the duration of
 treatment for bloodstream infections, BALANCE research program will help maximize the
 clinical cure of individual patients, while minimizing their risk of drug side effects, C.
 difficile, and antibiotic resistance. Since this intervention would require no new
 technology, and would reduce (rather than increase) health care costs, it would offer
 immediate benefits to patients and the healthcare system.

 The BALANCE RCT will randomize hospitalized patients with bloodstream infection to 7 versus
 14 days of adequate antibiotic treatment; the antibiotic drugs, doses, routes and interval
 will be left to the discretion of the treating team. Although placebo controls are not
 feasible, prolonged allocation concealment to day 7 will be used to mitigate selection bias.
 The primary analysis will assess whether 7 days is associated with non-inferior 90 day
 survival as compared to 14 days of treatment. Participants from the vanguard BALANCE pilot
 RCTs will be included in the BALANCE main RCT, and participating Canadian sites will continue
 to enrol patients. BALANCE international collaborators include New Zealand, Australia, Saudi
 Arabia, the United States, Israel and Switzerland.
Inclusion Criteria:

 1. Patient is in ICU or non-ICU ward at the time the blood culture is drawn or reported
 as positive.

 2. Patient has a positive blood culture with pathogenic bacteria.

 Exclusion Criteria:

 1. Patient already enrolled in the trial

 2. Patient has severe immune system compromise, as defined by: absolute neutrophil count
 <0.5x109/L; or is receiving immunosuppressive treatment for solid organ or bone marrow
 or stem cell transplant

 3. Patient has a prosthetic heart valve or synthetic endovascular graft (post major
 vessel repair with synthetic material) (note: coronary artery stents are not an
 exclusion)

 4. Patient has documented or suspected syndrome with well-defined requirement for
 prolonged treatment:

 i) infective endocarditis; ii) osteomyelitis/septic arthritis; iii)
 undrainable/undrained abscess; iv) unremovable/unremoved prosthetic-associated
 infection (e.g. infected pacemaker, prosthetic joint infection, ventriculoperitoneal
 shunt infection etc.) (note: central venous catheters, including tunneled central
 intravenous catheter, and urinary catheters are not excluded unless the treating
 clinical team does not have equipoise for enrollment and randomization to either
 group)

 5. Patient has a single positive blood culture with a common contaminant organism
 according to Clinical Laboratory & Standards Institute (CLSI) Guidelines: coagulase
 negative staphylococci; or Bacillus spp.; or Corynebacterium spp.; or
 Propionobacterium spp.; or Aerococcus spp.; or Micrococcus spp.

 6. Patient has a positive blood culture with Staphylococcus aureus or Staphylococcus
 lugdunensis

 7. Patient has a positive blood culture with Candida spp. or other fungal species.

 8. Blood culture grows rare bacterial pathogens requiring prolonged treatment (e.g.
 Mycobacteria spp., Nocardia spp., Actinomyces spp., Brucella spp., Burkholderia
 pseudomallei)