Determining the Optimal Duration of Antibiotic Treatment in Older Adults Living with Frailty with Bloodstream Infection
The Canadian Federal Government, United States Centres for Disease Control and the World Health Organization, have all identified antimicrobial resistance as an urgent, global public health threat given rising
rates of resistance among important bacterial pathogens and declining new antibiotic drug discovery. Antimicrobial resistance is being driven by high rates of inappropriate antimicrobial use, including unnecessarily
prolonged antibiotic treatment courses. The older patient living with frailty population is particularly susceptible to both community- and hospital-acquired infections, and to the untoward effects of factors prolonging lengths of stay in hospital.
The optimal length of treatment for bloodstream infections is undefined, and so the Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) research program seeks to learn whether shorter duration treatment is as effective as longer treatment for these infections. As part of the BALANCE clinical trial,we will include all older patients living with frailty admitted to the hospital with bloodstream infections, to measure frailty in these patients, and to learn whether being frail influences whether shorter duration antibiotics are as good as longer duration antibiotics for the cure of these infections. By defining the duration of treatment for bloodstream infections, our research program will provide best evidence for the cure of older patients living with frailty, potentially providing a mechanism for earlier liberation from acute care while lowering their risks of antibiotic-related harms, including side effects, C. difficile, and antibiotic resistance.
About the Project
Bloodstream infections affect more than 40,000 Canadians per year, and are associated with high morbidity, mortality and healthcare costs. At the same time, antibiotic overuse is 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, Clostridium difficile infection, increased costs, prolonged hospital stays and spiralling antibiotic resistance rates. The risks and benefits of antibiotic treatment are particularly difficult to balance in older patients living with frailty, given that they are at heightened risk of infection-related complications as well as antibiotic treatment-related complications.
Perhaps the best way to balance these benefits and risks is by optimizing duration of treatment. Shorter duration treatment (≤ 7 days) is as effective as longer treatment for infectious diseases such as urinary tract infection and pneumonia, but this question has not been directly studied for bloodstream infection. Our team’s systematic review of the medical literature, national clinician survey, multicentre retrospective study, and pilot randomized controlled trial (RCT) all supported the need for a trial comparing shorter versus longer antibiotic treatment for bloodstream infections. To this end we have recently launched the Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) RCT, aiming to enroll 3600 critically ill patients with bloodstream infection; in this current application we seek to extend enrolments beyond the critical care unit to include all older patients living with frailty admitted to hospital with bloodstream infection.
Over-arching objective: To maximize the benefits while minimizing the harms of antimicrobial treatment.
Main objective of Ongoing BALANCE Trial: To test whether shorter duration antibiotic treatment (7 days) for critically ill patients with bloodstream infection is associated with non-inferior survival rates (at 90 days) to those achieved with longer duration treatment (14 days). To expand BALANCE trial enrolments outside of the intensive care unit, to include all frail elderly patients admitted to the hospital with bloodstream infection.
The BALANCE RCT is currently being conducted across 28 Canadian hospitals, which have already enrolled 300 of a targeted 3600 critically ill patients. The trial is currently limited to patients admitted to the critical care unit, but our recently completed single-centre ward pilot study, suggests that expanding the BALANCE study hospital-wide would improve recruitment rates, protocol adherence rates, and generalizability of findings across all patients living with frailty with bloodstream infection.
The project will seek to expand hospital wide within 12 months. Critical milestones will include: (1) research ethics board amendments at all participating hospitals, (2) run-in piloting of hospital-wide expansion at each site, (3) full active hospital-wide enrolment at each site.
By defining the duration of treatment for bloodstream infections, our research program will help maximize the clinical cure of older patients living with frailty, 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.
Nick Daneman, MD, FRCPC, M.Sc., Scientist and Assistant Professor, Faculty of Medicine, Sunnybrook Health Sciences Centre
Robert Fowler, MD, MDCM, M.Sc., Scientist and Professor, Faculty of Medicine and and Critical Care Medicine, Sunnybrook Health Sciences Centre
Kenneth Rockwood, MD FRCPC FRCP, Professor, Divisionon of Geriatric Medicine, Dalhousie University
Barbara Liu, MD, Scientist and Associate Professor, Division of Geriatric Medicine, Sunnybrook Health Sciences Centre
Deborah Cook, MD, FRCPC, MSc(Epid), CRC, CAHS, FRS, Professor, Department of Medicine and Critical Care, McMaster University
Bryan Coburn, MD, PhD, FRCPC, Clinician-Scientist in the Division of Infectious Diseases, University Health Network, University of Toronto
Project Contact: Nick Daneman--Nick.Daneman@sunnybrook.ca
Key words: Bloodstream infection; bacteremia; frailty; antibiotic treatment; duration of therapy; mortality; antibiotic resistance; Clostridium difficile; adverse events; randomized controlled trial