The BALANCE Program

ANTIBIOTIC OVERUSE IS A GLOBAL HEALTH THREAT

The World Health Organization, U.S. Centers for Disease Control, Association of Medical Microbiology and Infectious Diseases (AMMI) Canada, and Canadian Federal Health Minister have all declared antimicrobial resistance a global threat to health, based on rapidly increasing resistance rates and declining new antimicrobial drug development.
 

PROLONGED TREATMENT DURATIONS ARE THE GREATEST CONTRIBUTOR TO ANTIBIOTIC OVERUSE

Up to 30-50% of antibiotic use is inappropriate, and excessive durations of antibiotic treatment are the greatest contributor to inappropriate use. Unnecessarily prolonged antibiotic use is contributing to preventable complications, C. difficile infections, and antimicrobial resistance among patients, and preventable costs for the healthcare system.  Large numbers of studies have confirmed that shorter duration treatment (≤ 7 days) is as effective as longer duration treatment for a range of infections, including lung, skin and soft tissue, intra-abdominal, and urinary tract infections.

EVIDENCE IS LACKING FOR THE OPTIMAL TREATMENT DURATION FOR BLOODSTREAM INFECTIONS

Bloodstream infections are among the most common and serious infections in critically ill patients, affecting 50,000 Canadians per year, and more than 600,000 patients per year in North America, and 1,200,000 per year in Europe.  Yet, the optimal duration of treatment for these patients has not been studied.

OVERALL GOAL OF THE BALANCE RESEARCH PROGRAM

The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE). Research Program seeks to define the optimal treatment duration for patients with bloodstream infection. The goal is to maximize the benefits while minimizing the harms of these treatments, including antibiotic resistance, C. difficile, and other drug-related side effects.

SYSTEMATIC REVIEW OF THE MEDICAL LITERATURE

We systematically reviewed the medical literature, and found no prior dedicated trials of shorter versus longer antibiotic treatment duration for non-newborn patients with bloodstream infection.  We did find two dozen prior studies of more than 7000 patients treated with shorter versus longer antibiotic courses for conditions commonly complicated by bloodstream infection (lung infection, urine infection, skin and soft tissue infection, intra-abdominal infection).   Very few of these studies reported on the outcomes of the subgroup of patients that had bloodstream infection.  In these small subgroups, shorter and longer duration treatment had similar cure rates.

→  VIEW ABSTRACT
 

NATIONAL PRACTICE SURVEY OF CANADIAN INFECTIOUS DISEASES AND CRITICAL CARE PHYSICIANS

We conducted a national survey of Canadian Infectious Diseases and Critical Care Physicians, and learned that 14 days is the most commonly recommended treatment duration for patients with bloodstream infection, but that there are major variations in recommendations, and general agreement that a trial of 7 versus 14 days of treatment is needed.

→  VIEW ABSTRACT
 

CROSS-CANADA MULTICENTRE OBSERVATIONAL STUDY

We studied actual treatment practices among more than 1200 patients with bloodstream infection across ICUs in 14 hospitals, in 10 Canadian cities and 6 Provinces.  This study confirmed that longer treatment durations are being used, irrespective of the bug or the source of the bloodstream infection.

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BALANCE PILOT RANDOMIZED CONTROLLED TRIAL

In a pilot randomized controlled trial of 7 versus 14 days of antibiotic treatment for bloodstream infection we have confirmed the feasibility of this trial design. Our recruitment rates and protocol adherence rates have exceeded expectations, and we are ready now to embark on the main trial.

→  VIEW ABSTRACT 1

→  VIEW ABSTRACT 2

BALANCE WARD PILOT RANDOMIZED CONTROLLED TRIAL

→ VIEW ABSTRACT
 

BALANCE MAIN RANDOMIZED CONTROLLED TRIAL

The BALANCE Main trial randomized hospitalized patients with bloodstream infection to 7 versus 14 days of antibiotics. The trial included 3626 patients, of which 2/3 were enrolled in participating Canadian sites within the Canadian Critical Care Trials Group, and 1/3 were enrolled in collaborating sites in United States, Australia, New Zealand (ANZICS), Israel and Saudi Arabia. The primary aim is to determine whether shorter duration antibiotic treatment (7 days) for patients with bloodstream infection is associated with non-inferior survival rates (at 90 days) to those achieved with longer duration treatment (14 days). The secondary aims are to determine whether shorter course treatment is associated with non-inferior secondary clinical outcomes (hospital mortality, ICU mortality, relapse rates of bacteremia, ICU length of stay, hospital length of stay, mechanical ventilation duration, vasopressor duration) while leading to improvements in antibiotic-free days, C. difficile infection, antibiotic allergy and adverse events, and colonization/infection with antibiotic-resistant organisms.

BALANCE completed recruitment in May 2023.

BALANCE +

BALANCE+ is a perpetual platform trial to answer multiple questions that are important for patients with the most common kind of bloodstream infections – caused by “Gram negative” bacteria. This trial provides a platform upon which to answer three questions looking at best ways to ‘de-escalate’ and ‘step-down’ antibiotic treatment (going from a broad to more specific antibiotic). We will answer the question about what to do when the infection is caused by bacteria on an intravenous catheter – should we remove and replace the catheter or just treat with antibiotics. We will also answer some key antibiotic selection controversies for some difficult to treat pathogens. As each question is answered, optimal therapies will be adopted into usual care, and new questions will be introduced into the platform of the trial. The evidence generated by BALANCE+ will improve cures for this vulnerable patient population while decreasing potential harms from using too many antibiotics for too long.

PROGRAM FIGURE

Implementing knowledge gained from BALANCE will not require new equipment, technology or advanced training of personnel. Instead, implementing shorter course treatment, if proven non-inferior, would be a simple intervention that could be widely implemented with cost-savings rather than cost increases. The result would be rapid large-scale reductions in antibiotic days of treatment across ICUs in Canada and across the globe. 

Reductions in C. difficile infections, and antibiotic resistant organisms would then follow.  If shorter course treatment is sufficient for critically ill patients with bloodstream infections, then it might also be sufficient for less ill populations with bloodstream infections.  Therefore, the BALANCE trial findings could lead to very broad global reductions in antimicrobial use and pressure.

Implementing knowledge gained from BALANCE will not require new equipment, technology or advanced training of personnel.  Instead, implementing shorter course treatment, if proven non-inferior, would be a simple intervention that could be widely implemented with cost-savings rather than cost increases.  The result would be rapid large-scale reductions in antibiotic days of treatment across ICUs in Canada and across the globe.  Reductions in C. difficile infections, and antibiotic resistant organisms would then follow.  If shorter course treatment is sufficient for critically ill patients with bloodstream infections, then it might also be sufficient for less ill populations with bloodstream infections.  Therefore, the BALANCE trial findings could lead to very broad global reductions in antimicrobial use and pressure.

The involvement of the knowledge users and leaders in the Canadian Critical Care Trials Group (CCCTG) will lead to rapid national knowledge dissemination, since its members include over 350 clinicians and researchers who work in ICUs across Canada at all major teaching hospitals and many community hospitals. A major mandate of the CCCTG is translating knowledge into practice and advancing the science of Knowledge Translation (KT) in the critically ill.

BALANCE

BALANCE+

Congratulations to Royal Victoria McGill for enrolling the 2000th BALANCE patient | March 25, 2021

 

Australian National Health and Medical Research Council Awarded | February 10, 2020

The New Zealand Health Research Council Awarded | February 10, 2020

CIHR Project Grant | February 19, 2016

INNOVATION AWARD  | February 19, 2016