Early best available antibiotic therapy for multidrug-resistant gram-negative bloodstream infections: a target trial emulation

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.

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EClinicalMedicine
Published
2026-10-29
DOI
https://doi.org/10.1016/j.eclinm.2026.104302
Primary Topic
Antibiotic Resistance in Bacteria
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article
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article

Early best available antibiotic therapy for multidrug-resistant gram-negative bloodstream infections: a target trial emulation

Xun Ting Tiong, Gabriel Zherong Yan, Suwatthiya Kitsaran, Azizullah Khan Dhiloo et al.
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EClinicalMedicine
Antibiotic Resistance in Bacteria
article

Early best available antibiotic therapy for multidrug-resistant gram-negative bloodstream infections: a target trial emulation

Xun Ting Tiong, Gabriel Zherong Yan, Suwatthiya Kitsaran, Azizullah Khan Dhiloo, Samanmalee Gunasekara, Hendri Wijaya, Darunee Chotiprasitsakul, Yohei Doi, Damdindorj Boldbaatar, Jinlan Lin, Sasheela S L Ponnampalavanar, Phan Vinh Tho, Ratiporn Bansong, Giri Shan Rajahram, Rosmonaliza Asli, H. Rogier van Doorn, David Leslie Paterson, Wei Cong Tan, Seanghuoy Ho, Sadia Shakoor, 秦晓华, Yin Mo, Lowell Ling, Cybéle Lara R. Abad, Arthur Dessi Roman, Andrea Lay‐Hoon Kwa, Siew Pei Ong, Ashesh Dhungana, Rina Yunita, Jia Rhou Lai, Abhilasha Karkey, Muhammad Osama Rehman Khalid, Louise Thwaites, Suvaporn Anugulruengkitt, Abi Manesh S, Po‐Yu Liu, Basudha Khanal, R. Lia Kusumawati, Shiau Hui Diong, Shogo Hanai, Hitoshi Honda, Chien-Hao Tseng, Shyam Prasad Kafle, Siriluck Anunnatsiri, Sotharith Bory, Gazi Md. Salahuddin Mamun, Joshua Francis, Bayaraa Baljin, Rongpong Plongla, Pope Kosalaraksa, Syed Faisal Mahmood, Raph L Hamers, Soo Nee Tang, Pitak Santanirand, Hock Hin Chua, Suchart Booraphun, Ngoc Thach Pham, Joan Quah, Robert Sinto, Luca Mezzadri, Md Ali Amin Nabin, Mohd Zaki Bin Mohd Zaili, Ambreen Fatima, Ping Shen, Merlin Moni, Trần Văn Giang, Anh T. K. Nguyen, Sheng Ping Wu, Zeti Norfidiyati Salmuna, Inke N. D. Lubis, Huynh Ngoc Hon, Thi Kim Anh Nguyen, Xinxin Hao, Mohd Zulfakar Mazlan, Ying Ding, Ke Juin Wong, Alisa Hanum Arba'eni, Ya-Ting Chang, Amanda Wei Ping Ling, Li-Yang Hsu, Minggui Wang, Ruth Tsin En Cheng, Bidhya Sharma Sharma, N. Lakshmi Priya, Cecilia C. Maramba Lazarte, Yulia R. Saharman, Sumudu Withanage, Ulziijargal Gurav, Nicole Bernadette Terre, Shweta Rajkumar Singh, May Gee Ong, Sophany Koy, Helmi Bin Sulaiman, Kee Mee Tan, Chithra Tomy, T. Palaniappan, Helio Gutierres, Madiha Hashmi, Yonghong Xiao, Jie Su
article en

Abstract

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.

EClinicalMedicineVol. 101
Ministry of Health (MY), Amrita Institute of Medical Sciences and Research Centre (IN), University Malaya Medical Centre (MY), Thai Red Cross Society (TH), Universiti Sains Malaysia (MY), Fujita Health University (JP), Kaohsiung Medical University (TW), Chulalongkorn University (TH), National University of Singapore (SG), Christian Medical College, Vellore (IN), Chinese University of Hong Kong (HK), Khon Kaen University (TH), Hanoi Medical University (VN), International Centre for Diarrhoeal Disease Research (BD), Singapore General Hospital (SG), Fudan University (CN), Mahidol University (TH), Universitas Sumatera Utara (ID), Bir Hospital (NP), Calmette Hospital (KH), Sarawak General Hospital (MY), Raja Isteri Pengiran Anak Saleha Hospital (BN), Patan Hospital (NP), Philippine General Hospital (PH), King Chulalongkorn Memorial Hospital (TH), Kaohsiung Medical University Chung-Ho Memorial Hospital (TW), Aga Khan University Hospital (PK), University of Indonesia (ID), University of Malaya (MY), Dow University of Health Sciences (PK), University of Oxford (GB), Taichung Veterans General Hospital (TW), Mongolian National University of Medical Sciences (MN), Sappasithiprasong Hospital (TH), Mahidol Oxford Tropical Medicine Research Unit (TH), National Cancer Institute of Sri Lanka (LK), Ramathibodi Hospital (TH), Ziauddin Hospital (PK), National University Hospital (SG), Oxford University Clinical Research Unit (VN), National University Health System (SG), Beijing Tsinghua Chang Gung Hospital (CN), Rumah Sakit Umum Pusat Nasional Dr. Cipto Mangunkusumo (ID), Hospital for Tropical Diseases (VN), Huashan Hospital (CN), Queen Elizabeth Hospital (MY), First Affiliated Hospital Zhejiang University (CN), Oxford University Clinical Research Unit Indonesia (ID), Oxford University Clinical Research Unit Nepal (NP), University of the Philippines Manila (PH), University of Milano-Bicocca (IT), B.P. Koirala Institute of Health Sciences (NP), Amrita Vishwa Vidyapeetham (IN)
Wellcome Trust, Saw Swee Hock School of Public Health, National University of Singapore
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Antibiotic Resistance in Bacteria
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