Accounting for non-adherence to assigned antibiotic treatment duration for bloodstream infection (BALANCE): a post-hoc analysis of a randomised clinical trial - 12/11/25

Doi : 10.1016/S1473-3099(25)00592-4

Sean W X Ong, MBBS ^a,^b,^c,^d,⁎ , Ruxandra Pinto, PhD ^a,^c, Robert K Mahar, PhD ^e,^f,^g, Asgar Rishu, MBBS ^c, Joshua S Davis, ProfPhD ^h,^i,^j, Robert A Fowler, ProfMDCM ^a,^c, Steven Y C Tong, ProfPhD ^b,^d,^{*
Senior authors who contributed equally}, Nick Daneman, ProfMD ^a,^c,^{*
Senior authors who contributed equally}
for the
BALANCE trial consortium^†
Members listed in the Supplementary Material (pp 4–6)
Benjamin Rogers, Yahya Shehabi, Rachael Parke, Deborah J. Cook, Yaseen Arabi, John Muscedere, Steven Reynolds, Richard Hall, Dhiraj Bhatia Dwivedi, Colin McArthur, Shay McGuinness, Dafna Yahav, Bryan Coburn, Anna Geagea, Pavani Das, Phillip Shin, Michael Detsky, Andrew Morris, Michael Fralick, Jeff Powis, Christopher Kandel, Wendy Sligl, Sean M. Bagshaw, Nishma Singhal, Emilie Belley-Cote, Richard Whitlock, Kosar Khwaja, Susan Morpeth, Alex Kazemi, Tony Williams, Derek MacFadden, Lauralyn McIntyre, Jennifer LY Tsang, Francois Lamontagne, Alex Carignan, John Marshall, Jan O. Friedrich, Rob Cirone, Mark Downing, Christopher Graham, Erick Duan, John Neary, Gerald Evans, Basem Alraddadi, Sameera Aljohani, Claudio Martin, Sameer Elsayed, Ian Ball, François Lauzier, Alexis F. Turgeon, Henry Thomas Stelfox, John Conly, Todd C. Lee, Emily G. McDonald, 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 L. 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, Abhijit Duggal, Abdulaziz Dawood, Adam Stewart, Aditee Parab, Adrian Regli, Aidan Findlater, Alicia Sarabia, Amalie Wilkie, Anna Rozenberg, Andre Poirier, Andrew Burke, Andrew Cheung, Baldwin Toye, Burcu Isler, Cameron Knott, Charles St-Arnaud, Chin-Yen Yeo, Christian Lavallee, Craig Hourigan, Dan Perri, Daniel Ovakim, David Knight, David Brewster, David Maslove, David McCullagh, Debbie Marriott, Deirdre Murphy, Donald Griesdale, Ebrahim Mahmoud, Edward Raby, Elaine Cheong, Elliott Owen, François Lellouche, François Marquis, Frederick D'Aragon, Genevieve McKew, Gloria Vazquez-Grande, Gopal Taori, Gururaj Nagaraj, Hatim Hasser Arishi, Han Ting Wang, Hilary Lee, Gordon Boyd, Jean-Luc Pagani, Jeffrey M. Singh, Jennie Johnstone, Jessica Triay, Jill Parkes-Smith, Joanne Meyer, Josh Douglas, Janos Pataki, John McNamara, Jonathan Albrett, Karen Doucette, Karim Ali, Kevin Woodward, Kristi Kozierowski, Linda R. Taggart, Lolowa M. Al Swaidan, Lorenzo Del Sorbo, M. Elizabeth Wilcox, Majed Mousa Al Shamrani, Manoj Saxena, Mathieu Simon, Marjoree Sehu, Miriam Torchinsky, Mark Kubicki, Max Bloomfield, Michael Mayette, Muhammed Moneer Farahat Hegazy, Najib Ayas, Nava Maham, Navdeep Mehta, Neal Irfan, Osama Loubani, Pamela Konecny, Philippe Eggimann, Philippe Lagacé-Wiens, Philippe Morency-Potvin, Pranesh Jogia, Radu Postelnicu, Raquel Cowan, Reem Abanamy, Robert Coke, Roger Sandre, Ross Freebairn, Salman Qureshi, Sam Rudham, Sarah Metcalf, Sai Rupa Baskar, Stephanie Sibley, Steve Webb, Stephanie Smith, Syeda Naqvi, Terence Wuerz, Tiffany Chan, Thomas Szakacs, Umesh Kadam, Valérie Martel-Laferrière, Victor Leung, Vikramjit Mukherjee, Vineet Sarode, Waleed Alhazzani, Ying Tung Sia

^a Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada
^b Department of Infectious Diseases, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
^c Sunnybrook Health Sciences Centre, Toronto, ON, Canada
^d Victorian Infectious Diseases Service, Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
^e Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville, VIC, Australia
^f Clinical Epidemiology and Biostatistics Unit, Murdoch Children’s Research Institute, Parkville, VIC, Australia
^g Methods and Implementation Support for Clinical and Health Research Hub, University of Melbourne, Parkville, VIC, Australia
^h School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
ⁱ Department of Immunology and Infectious Diseases, John Hunter Hospital, Newcastle, NSW, Australia
^j Global and Tropical Health Division, Menzies School of Health and Research, Darwin, NT, Australia

^*Correspondence to: Dr Sean W X Ong, Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON M5T 3M6, CanadaInstitute of Health Policy, Management and EvaluationUniversity of TorontoTorontoONM5T 3M6Canada

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Wednesday 12 November 2025

Summary

Background

The BALANCE trial (NCT03005145) showed non-inferiority of 7-day versus 14-day antibiotic duration for treatment of patients with non-Staphylococcus aureus uncomplicated bloodstream infection (BSI). Non-adherence to assigned duration occurred in 728 (20·3%) of 3581 patients. This post-hoc analysis aimed to identify factors associated with this non-adherence, and evaluate its effect on validity of trial results.

Methods

We identified factors associated with non-adherence using generalised linear mixed models. Adherence was defined as receiving antibiotic duration up to 2 days longer or shorter than assigned duration, measured using a trial-specific adherence variable (assessed daily by research staff) and a separate variable capturing total antibiotic duration. We estimated the effect of antibiotic duration on the primary outcome of 90-day all-cause mortality, accounting for confounding introduced by non-adherence, in adjusted per-protocol and as-treated populations (using two different adherence definitions: first, using an adherence variable as assessed daily by site research staff, and second, using a total antibiotic duration variable recording the total cumulative antibiotic duration received), using inverse probability of treatment weighting (IPTW) and instrumental variable methods. We compared these adjusted estimates to the primary effect estimates in BALANCE and used the same 4% non-inferiority margin to determine non-inferiority of 7-day duration.

Findings

3581 patients with complete outcome data were included. Non-adherence was higher in the 7-day group (432 [24·0%] of 1802 patients) versus 14-day group (296 [16·6%] of 1779). Disease severity, intra-abdominal and skin or soft tissue source of infection, persistent fever, and persistent bacteraemia were associated with treatment prolongation, whereas vascular catheter source and antimicrobial resistance were associated with treatment shortening. Adjusted risk differences for the primary outcome of 90-day all-cause mortality were similar to the primary results in BALANCE: (1) IPTW per-protocol analysis (definition one): –1·61% (95% CI –4·13 to 0·87); IPTW per-protocol analysis (definition two): –1·91% (95% CI –4·61 to 0·93); and IPTW as-treated analysis: –0·75% (95% CI –3·36 to 1·86); and (2) instrumental variable analysis (definition one): –2·68% (95% CI –6·65 to 1·29) and instrumental variable analysis (definition two): –2·80% (95% CI –5·98 to 0·37).

Interpretation

Non-adherence in BALANCE was significantly associated with a range of important prognostic factors, which might have introduced bias. Causal inference methods addressing this bias showed a consistent conclusion of non-inferiority, strengthening the validity of this finding. 7-day antibiotic duration should be the standard of care for patients with uncomplicated BSI.

Funding

The BALANCE trial was funded by the Canadian Institutes of Health Research, Health Research Council of New Zealand, Australian National Medical Research Council, Physicians Services Incorporated Ontario, and Ontario Ministry of Health and Long-term Care Innovation Fund.

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