A pilot randomized controlled trial of 7 versus 14 days of antibiotic treatment for bloodstream infection on non-intensive care versus intensive care wards
Nick Daneman,
Asgar H. Rishu,
Ruxandra Pinto,
Yaseen Arabi,
Emilie P. Belley-Cote,
Robert Cirone,
Mark Downing,
Deborah J. Cook,
Richard Hall,
Shay McGuinness,
Lauralyn McIntyre,
John Muscedere,
Rachael Parke,
Steven Reynolds,
Benjamin A. Rogers,
Yahya Shehabi,
Phillip Shin,
Richard Whitlock,
Robert A. Fowler,
on behalf of the Canadian Critical Care Trials Group
Affiliations
Nick Daneman
Division of Infectious Diseases & Clinical Epidemiology, Department of Medicine Sunnybrook Health Sciences Centre, University of Toronto and Adjunct Scientist, Institute for Clinical Evaluative Sciences, Sunnybrook Health Sciences Centre
Asgar H. Rishu
Department of Critical Care Medicine, Sunnybrook Health Sciences Center
Ruxandra Pinto
Department of Critical Care Medicine, Sunnybrook Health Sciences Center
Yaseen Arabi
College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Intensive Care Department, Ministry of National Guard Health Affairs
Emilie P. Belley-Cote
Division of Cardiology, Department of Medicine, McMaster University
Robert Cirone
Division of Critical Care, St. Joseph’s Health Centre
Mark Downing
Division of Infectious Diseases, St. Joseph’s Health Centre
Deborah J. Cook
Division of Critical Care Medicine, Department of Medicine, McMaster University
Richard Hall
Departments of Critical Care Medicine and Anesthesiology, Pain Management and Perioperative Medicine, Dalhousie University
Shay McGuinness
Cardiothoracic and Vascular Intensive Care Unit, Auckland City Hospital
Lauralyn McIntyre
Division of Critical Care, Department of Medicine, The Ottawa Hospital
John Muscedere
Department of Critical Care Medicine, Queen’s University
Rachael Parke
Cardiothoracic and Vascular Intensive Care Unit, Auckland City Hospital
Steven Reynolds
Department of Biophysiology and Kinesiology, Simon Fraser University
Benjamin A. Rogers
Centre for Inflammatory Diseases, Monash University School of Clinical Sciences, Clayton, Victoria, Australia; Monash Infectious Diseases, Monash Health
Yahya Shehabi
Critical Care and Perioperative Medicine, School of Clinical Sciences, Monash University and Monash Health, Clayton, Victoria, Australia and the Clinical School of Medicine, University of New South Wales
Phillip Shin
Department of Medicine and Critical Care, North York General Hospital
Richard Whitlock
Department of Surgery, McMaster University
Robert A. Fowler
Departments of Medicine and Critical Care Medicine, Sunnybrook Health Sciences Center, Adjunct Scientist, Institute for Clinical Evaluative Sciences, Institute of Health Policy, Management and Evaluation, University of Toronto
on behalf of the Canadian Critical Care Trials Group
Abstract Background The optimal treatment duration for patients with bloodstream infection is understudied. The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) pilot randomized clinical trial (RCT) determined that it was feasible to enroll and randomize intensive care unit (ICU) patients with bloodstream infection to 7 versus 14 days of treatment, and served as the vanguard for the ongoing BALANCE main RCT. We performed this BALANCE-Ward pilot RCT to examine the feasibility and impact of potentially extending the BALANCE main RCT to include patients hospitalized on non-ICU wards. Methods We conducted an open pilot RCT among a subset of six sites participating in the ongoing BALANCE RCT, randomizing patients with positive non-Staphylococcus aureus blood cultures on non-ICU wards to 7 versus 14 days of antibiotic treatment. The co-primary feasibility outcomes were recruitment rate and adherence to treatment duration protocol. We compared feasibility outcomes, patient/pathogen characteristics, and overall outcomes among those enrolled in this BALANCE-Ward and prior BALANCE-ICU pilot RCTs. We estimated the sample size and non-inferiority margin impacts of expanding the BALANCE main RCT to include non-ICU patients. Results A total of 134 patients were recruited over 47 site-months (mean 2.9 patients/site-month, median 1.0, range 0.1–4.4 patients/site-month). The overall recruitment rate exceeded the BALANCE-ICU pilot RCT (mean 1.10 patients/site-month, p < 0.0001). Overall protocol adherence also exceeded the adherence in the BALANCE-ICU pilot RCT (125/134, 93% vs 89/115, 77%, p = 0.0003). BALANCE-Ward patients were older, with lower Sequential Organ Failure Assessment scores, and higher proportions of infections caused by Escherichia coli and genito-urinary sources of bloodstream infection. The BALANCE-Ward pilot RCT patients had an overall 90-day mortality rate of 17/133 (12.8%), which was comparable to the 90-day mortality rate in the ICU pilot RCT (17/115, 14.8%) (p = 0.65). Simulation models indicated there would be minimal sample size and non-inferiority margin implications of expanding enrolment to increasing proportions of non-ICU versus ICU patients. Conclusion It is feasible to enroll non-ICU patients in a trial of 7 versus 14 days of antibiotics for bloodstream infection, and expanding the BALANCE RCT hospital-wide has the potential to improve the timeliness and generalizability of trial results. Trial registration Clinicaltrials.gov, NCT02917551. Registered on September 28, 2016.
