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

BALANCE Investigators, for the Canadian Critical Care Trials Group, the Association of Medical Microbiology and Infectious Disease Canada Clinical Research Network, the Australian and New Zealand Intensive Care Society Clinical Trials Group, and the Australasian Society for Infectious Diseases Clinical Research Network; Nick Daneman; Asgar Rishu; Ruxandra Pinto; Benajmin A Rogers; Yahya Shehabi; Rachael Parke; Deborah Cook; Yaseen Arabi; John Muscedere; Steven Reynolds; Richard Hall; Dhiraj B Dwivedi; Colin McArthur; Shay McGuinness; Dafna Yahav; Bryan Coburn; Anna Geagea; Pavani Das; Phillip Shin; Michael Detsky; Andrew Morris; Michael Fralick; Jeff E Powis; Christopher Kandel; Wendy Sligl; Sean M Bagshaw; Nishma Singhal; Emilie Belley-Cote; Richard Whitlock; Kosar Khwaja; Susan Morpeth; Alex Kazemi; Anthony Williams; Derek R MacFadden; Lauralyn McIntyre; Jennifer Tsang; Francois Lamontagne; Alex Carignan; John Marshall; Jan O Friedrich; Robert Cirone; Mark Downing; Christopher Graham; Joshua Davis; Erick Duan; John Neary; Gerald Evans; Basem Alraddadi; Sameera Al Johani; Claudio Martin; Sameer Elsayed; Ian Ball; Francois Lauzier; Alexis Turgeon; Henry T Stelfox; John Conly; Emily G McDonald; Todd C Lee; Richard Sullivan; Jennifer Grant; Ilya Kagan; Paul Young; Cassie Lawrence; Kevin O'Callaghan; Matthew Eustace; Keat Choong; Pierre Aslanian; Ulrike Buehner; Tom Havey; Alexandra Binnie; Josef Prazak; Brenda Reeve; Edward Litton; Sylvain Lother; Anand Kumar; Ryan Zarychanski; Tomer Hoffman; David Paterson; Peter Daley; Robert J Commons; Emmanuel Charbonney; Jean-Francois Naud; Sally Roberts; Ravindranath Tiruvoipati; Sachin Gupta; Gordon Wood; Omar Shum; Spiros Miyakis; Peter Dodek; Clement Kwok; Robert A Fowler

doi:10.1056/NEJMoa2404991

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

N Engl J Med. 2024 Nov 20. doi: 10.1056/NEJMoa2404991. Online ahead of print.

Authors

BALANCE Investigators, for the Canadian Critical Care Trials Group, the Association of Medical Microbiology and Infectious Disease Canada Clinical Research Network, the Australian and New Zealand Intensive Care Society Clinical Trials Group, and the Australasian Society for Infectious Diseases Clinical Research Network; Nick Daneman¹, Asgar Rishu¹, Ruxandra Pinto¹, Benajmin A Rogers¹, Yahya Shehabi¹, Rachael Parke¹, Deborah Cook¹, Yaseen Arabi¹, John Muscedere¹, Steven Reynolds¹, Richard Hall¹, Dhiraj B Dwivedi¹, Colin McArthur¹, Shay McGuinness¹, Dafna Yahav¹, Bryan Coburn¹, Anna Geagea¹, Pavani Das¹, Phillip Shin¹, Michael Detsky¹, Andrew Morris¹, Michael Fralick¹, Jeff E Powis¹, Christopher Kandel¹, Wendy Sligl¹, Sean M Bagshaw¹, Nishma Singhal¹, Emilie Belley-Cote¹, Richard Whitlock¹, Kosar Khwaja¹, Susan Morpeth¹, Alex Kazemi¹, Anthony Williams¹, Derek R MacFadden¹, Lauralyn McIntyre¹, Jennifer Tsang¹, Francois Lamontagne¹, Alex Carignan¹, John Marshall¹, Jan O Friedrich¹, Robert Cirone¹, Mark Downing¹, Christopher Graham¹, Joshua Davis¹, Erick Duan¹, John Neary¹, Gerald Evans¹, Basem Alraddadi¹, Sameera Al Johani¹, Claudio Martin¹, Sameer Elsayed¹, Ian Ball¹, Francois Lauzier¹, Alexis Turgeon¹, Henry T Stelfox¹, John Conly¹, Emily G McDonald¹, Todd C Lee¹, Richard Sullivan¹, Jennifer Grant¹, Ilya Kagan¹, Paul Young¹, Cassie Lawrence¹, Kevin O'Callaghan¹, Matthew Eustace¹, Keat Choong¹, Pierre Aslanian¹, Ulrike Buehner¹, Tom Havey¹, Alexandra Binnie¹, Josef Prazak¹, Brenda Reeve¹, Edward Litton¹, Sylvain Lother¹, Anand Kumar¹, Ryan Zarychanski¹, Tomer Hoffman¹, David Paterson¹, Peter Daley¹, Robert J Commons¹, Emmanuel Charbonney¹, Jean-Francois Naud¹, Sally Roberts¹, Ravindranath Tiruvoipati¹, Sachin Gupta¹, Gordon Wood¹, Omar Shum¹, Spiros Miyakis¹, Peter Dodek¹, Clement Kwok¹, Robert A Fowler¹

Affiliation

¹ From the Division of Infectious Diseases, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto (N.D.), Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto (A.R.), the Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto (R. Pinto); the Department of Infectious Diseases, Monash University, Clayton, Melbourne, VIC, Australia (B.A.R.), the Department of Intensive Care, Monash Medical Centre, Melbourne, VIC, Australia (Y.S.); the Cardiothoracic and Vascular Intensive Care Unit, Auckland City Hospital, Auckland, New Zealand (R. Parke); the Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada (D.C.); the Intensive Care Department, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (Y.A.); the Department of Critical Care Medicine, Queen's University, Kingston, ON, Canada (J. Muscedere), the Department of Critical Care Medicine, Royal Columbian Hospital, Vancouver, BC, Canada (S. Reynolds), Critical Care Medicine, Capital District Health Authority, Dalhousie University, Halifax, NS, Canada (R.H.); Monash Medical Centre, Clayton, VIC, Australia (D.B.D.); Critical Care Medicine, Auckland City Hospital, New Zealand (C. McArthur), the Cardiothoracic and Vascular Intensive Care Unit, Auckland City Hospital, Auckland, New Zealand. (S. McGuinness); the Infectious Diseases Unit, Sheba Medical Center, Ramat-Gan, and Faculty of medicine, Ramat-Aviv, Tel-Aviv, Israel (D.Y.); Infectious Diseases, University Health Network, University of Toronto, Toronto (B.C.); Critical Care Medicine, North York General Hospital, Toronto (A.G., P.S.), Infectious Diseases, North York General Hospital, Toronto (P. Das), Critical Care Medicine, Mount Sinai Hospital, Unity Health Toronto, Toronto (M. Detsky), the Department of Medicine, University of Toronto, Toronto (A.M.); Sinai Health, Division of General Internal Medicine, Toronto, Toronto (M.F.), Infectious Diseases, Michael Garron Hospital, University of Toronto, Toronto (J.E.P.), Infectious Diseases, Michael Garron Hospital, Toronto (C. Kandel), Critical Care Medicine and Infectious Diseases, University of Alberta, Edmonton, Canada (W.S.), Department of Critical Care Medicine, University of Alberta and Alberta Health Services, Edmonton, Canada (S.M.B.), the Department of Medicine, Hamilton Health Sciences, McMaster University, Hamilton, ON, Canada (N.S.), the Department of Anaesthesia, Hamilton General Hospital, McMaster University, Hamilton, ON, Canada (E.B.-C.), the Faculty of Health Sciences, Hamilton General Hospital, McMaster University, Hamilton, ON, Canada (R.W.), the Departments of Surgery and Critical Care, McGill University Health Center, Montreal (K.K.); the Departments of Infectious Diseases and Pathology, Middlemore hospital, University of Auckland, New Zealand (S. Morpeth), Organ Donation New Zealand, New Zealand Blood Service, Auckland, New Zealand (A. Kazemi), Intensive Care Medicine, Middlemore Hospital, Auckland, New Zealand (A.W.); the Division of Infectious Diseases, Ottawa Hospital, Ottawa Hospital Research Institute, Ottawa (D.R.M.), the Department of Medicine, Ottawa Hospital, University of Ottawa, Ottawa (L.M.), Niagara Health Knowledge Institute, Niagara Health, St. Catharines, ON, Canada (J.T.), the Department of Medicine, Université de Sherbrooke, QC, Canada (F. Lamontagne); the Department of Microbiology and Infectious Diseases, Université de Sherbrooke, QC, Canada (A.C.), Surgery and Critical Care Medicine, Unity Health Toronto, University of Toronto, Toronto (J. Marshall); Critical Care and Medicine, Unity Health Toronto-St. Michael's Hospital, University of Toronto, Toronto (J.O.F.), Critical Care Medicine, Unity Health Toronto, Toronto (R.C.), the Department of Medicine, Unity Health Toronto, Toronto (M. Downing), the Department of Medicine, Infectious Diseases, Trillium Health Partners, University of Toronto, Toronto (C.G.); the School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia (J.D.); the Division of Critical Care, Department of Medicine, McMaster University, Hamilton, ON, Canada (E.D.), St. Joseph's Healthcare Hamilton, McMaster University, Hamilton, ON, Canada (J.N.), the Department of Medicine (Infectious Diseases), Queen's University, Kingston, ON, Canada (G.E.); the Department of Medicine, King Faisal Specialist Hospital and Research Center, Al Faisal University, Jeddah, Saudi Arabia (B.A.), the Department of Pathology and Laboratory Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (S.A.); the Department of Medicine, University of Western Ontario, London, Canada (C. Martin); the Department of Medicine, London Health Sciences Centre, London, ON, Canada (S.E.), the Department of Medicine, Western University, London, ON, Canada (I.B.), the Department of Medicine, Université Laval, Quebec, QC, Canada (F. Lauzier), the Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Université Laval, Quebec, QC, Canada (A.T.), the Population Health and Optimal Health Practice Research Unit, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec, QC, Canada (A.T.), the Department of Critical Care, University of Calgary Cumming School of Medicine, Calgary, AB, Canada (H.T.S.), the Department of Medicine, University of Calgary and Alberta Health Services (Calgary), Calgary, AB, Canada (J.C.), the Division of General Internal Medicine, Department of Medicine, McGill University Health Centre, Montreal (E.G.M.), the Division of Infectious Diseases, Department of Medicine, McGill University, Montreal (T.C.L.); the Department Infectious Diseases, St. George Hospital, UNSW Medicine and Health, Sydney (R.S.); the Divisions of Infectious Diseases and Medical Microbiology, University of British Columbia, Vancouver, Canada (J.G.); the Intensive Care Unit, Rabin Medical Centers, Tel Aviv University, Tel Aviv, Israel (I.K.); the Intensive Care Research Programme, Medical Research Institute of New Zealand, Wellington, New Zealand (P.Y.), Medical Research Institute of New Zealand, Wellington, New Zealand. (C.L.); the Department of Infectious Diseases, Redcliffe Hospital, Redcliffe, QLD, Australia (K.O.), Infectious Diseases, Redcliffe Hospital, University of Queensland, Redcliffe, Australia (M.E.), Infectious Diseases, Sunshine Coast University Hospital, Sunshine Coast University Hospital, Birtinya, QLD, Australia (K.C.); Medicine, Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montreal (P.A.); the Department of Anaesthesia, Rotorua Hospital, Rotorua, New Zealand (U.B.); Infectious Diseases, William Osler Health System, Brampton, ON, Canada (T. Havey), Critical Care Medicine, William Osler Health System, Brampton, ON, Canada (A.B.); the Department of Intensive Care Medicine, Bern University Hospital, University of Bern, Bern, Switzerland (J.P.); Brantford General Hospital, McMaster University, Brantford, ON, Canada (B.R.); the Intensive Care Unit, Fiona Stanley Hospital, University of Western Australia, Murdoch, WA, Australia (E.L.); the Department of Medicine, University of Manitoba, Winnipeg, Canada (S.L.), the Division of Critical Care Medicine and Infectious Diseases, Health Sciences Centre, University of Manitoba, Winnipeg, Canada (A. Kumar), the Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada (R.Z.); the Infectious Diseases Unit, Sheba Medical Center, Ramat Gan, Israel (T. Hoffman); the Infectious Diseases Unit, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia. (D.P.); Infectious Diseases, Memorial University, St. John's, NL, Canada (P. Daley); General and Subspecialty Medicine, Grampians Health Ballarat, Ballarat, VIC, Australia (R.J.C.); Service des soins intensifs, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal (E.C.), Critical Care Medicine, CIUSSS MCQ CHAUR, University of Montreal, Montreal (J.-F.N.); Clinical Microbiology and Infection Prevention and Control, Auckland Hospital, Auckland, New Zealand (S. Roberts); the Department of Intensive Care Medicine, Frankston Hospital, Frankston, VIC, Australia (R.T.), the Department of Intensive Care Medicine, Monash University, Melbourne, VIC, Australia (S.G.); the Department of Critical Care, Island Health Authority, Royal Jubilee Hospital, British Columbia, Victoria, Canada (G.W.); Infectious Diseases, Wollongong Hospital, Wollongong, NSW, Australia (O.S.), Infectious Diseases, Wollongong Hospital, University of Wollongong, Wollongong, NSW, Australia (S. Miyakis); the Department of Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, Canada (P. Dodek), Infectious Diseases, Richmond Hospital, Richmond, BC, Canada (C. Kwok), and the Interdepartmental Division of Critical Care Medicine, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto (R.A.F.).

PMID: 39565030
DOI: 10.1056/NEJMoa2404991

Abstract

Background: Bloodstream infections are associated with substantial morbidity and mortality. Early, appropriate antibiotic therapy is important, but the duration of treatment is uncertain.

Methods: In a multicenter, noninferiority trial, we randomly assigned hospitalized patients (including patients in the intensive care unit [ICU]) who had bloodstream infection to receive antibiotic treatment for 7 days or 14 days. Antibiotic selection, dosing, and route were at the discretion of the treating team. We excluded patients with severe immunosuppression, foci requiring prolonged treatment, single cultures with possible contaminants, or cultures yielding Staphylococcus aureus. The primary outcome was death from any cause by 90 days after diagnosis of the bloodstream infection, with a noninferiority margin of 4 percentage points.

Results: Across 74 hospitals in seven countries, 3608 patients underwent randomization and were included in the intention-to-treat analysis; 1814 patients were assigned to 7 days of antibiotic treatment, and 1794 to 14 days. At enrollment, 55.0% of patients were in the ICU and 45.0% were on hospital wards. Infections were acquired in the community (75.4%), hospital wards (13.4%) and ICUs (11.2%). Bacteremia most commonly originated from the urinary tract (42.2%), abdomen (18.8%), lung (13.0%), vascular catheters (6.3%), and skin or soft tissue (5.2%). By 90 days, 261 patients (14.5%) receiving antibiotics for 7 days had died and 286 patients (16.1%) receiving antibiotics for 14 days had died (difference, -1.6 percentage points [95.7% confidence interval {CI}, -4.0 to 0.8]), which showed the noninferiority of the shorter treatment duration. Patients were treated for longer than the assigned duration in 23.1% of the patients in the 7-day group and in 10.7% of the patients in the 14-day group. A per-protocol analysis also showed noninferiority (difference, -2.0 percentage points [95% CI, -4.5 to 0.6]). These findings were generally consistent across secondary clinical outcomes and across prespecified subgroups defined according to patient, pathogen, and syndrome characteristics.

Conclusions: Among hospitalized patients with bloodstream infection, antibiotic treatment for 7 days was noninferior to treatment for 14 days. (Funded by the Canadian Institutes of Health Research and others; BALANCE ClinicalTrials.gov number, NCT03005145.).

Associated data

ClinicalTrials.gov/NCT03005145