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Life sciences · Journal article
Eclinicalmedicine · October 29, 2026
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Background The effect of timely appropriate antibiotics in multidrug-resistant Gram-negative bacteria (MDR-GNB) bloodstream infections (BSIs) remains uncertain. Robust evidence is needed to inform diagnostic and treatment strategies, especially across settings with high antimicrobial resistance (AMR) and varying access to effective preventive and treatment therapeutics. Methods Using data from the prospective ACORN-HAI cohort across 19 Asian countries between September 2022 and February 2025, we emulated a target trial comparing early guideline-recommended best available therapy (BAT) initiated within 24 h of blood culture collection (early BAT), versus no early BAT among adults with monomicrobial BSIs due to third-generation cephalosporin-resistant Enterobacterales (3GCRE), carbapenem-resistant Enterobacterales (CRE), or carbapenem-resistant Acinetobacter spp. (CRA). Confounding was addressed using inverse probability weighting. The primary outcome was 14-day all-cause mortality. Whether mortality benefit differed according to disease severity was assessed using relative excess risk due to interaction (RERI). Findings Among 1412 adults (706 3GCRE, 442 CRE, and 264 CRA BSIs), early BAT was associated with lower 14-day mortality (18.5% versus 25.6% without early BAT; risk difference [RD] −7.1%; 95% CI −11.3%, −3.0%). In 3GCRE BSIs, the mortality reduction was 7.4% (RD −7.4%; 95% CI −12.2, −2.5). Among carbapenem-resistant Gram-negative bacteria (CR-GNB) BSIs, where early BAT predominantly consisted of polymyxin-based regimens (81.7%, 147/180), the estimated RDs were −3.3% (95% CI −13.8, 10.4) for CRE and −7.5% (95% CI −19.1, 4.0) for CRA. Interaction analyses showed a greater mortality benefit of early BAT in severe 3GCRE infections (RERI 2.06, 95% CI 0.47, 4.41), but not in CR-GNB BSIs. Interpretation Early BAT was associated with reduced mortality in MDR-GNB BSIs overall. By pathogen group, a mortality reduction was observed in 3GCRE BSIs, whereas findings for CR-GNB BSIs were uncertain. In the context of predominantly polymyxin-based therapy, reducing treatment delays alone may therefore be insufficient to improve outcomes in CR-GNB BSIs, highlighting the need to develop and optimise prevention and therapeutic strategies, especially across AMR-prevalent settings. Funding Wellcome Trust, National University of Singapore, Yong Loo Lin School of Medicine, Duke-NUS Medical School, Nanyang Technological University (Lee Kong Chian School of Medicine), Singapore National Centre for Infectious Diseases, and Singapore Medical Research Council.