Early best available antibiotic therapy for multidrug-resistant gram-negative bloodstream infections: a target trial emulation
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.
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Authors: Luca Mezzadri, Wei Cong Tan, Xinxin Hao, Joan Quah, Abi Manesh S, Ya-Ting Chang, Anh T. K. Nguyen, Ying Ding, Suwatthiya Kitsaran, Hock Hin Chua, Sotharith Bory, Sasheela S L Ponnampalavanar, Siriluck Anunnatsiri, Mohd Zulfakar Mazlan, Azizullah Khan Dhiloo, Rongpong Plongla, Andrea Lay‐Hoon Kwa, Syed Faisal Mahmood, Arthur Dessi Roman, Louise Thwaites, Phan Vinh Tho, Sheng Ping Wu, Darunee Chotiprasitsakul, Ke Juin Wong, Hendri Wijaya, Cybéle Lara R. Abad, Muhammad Osama Rehman Khalid, Gazi Md. Salahuddin Mamun, Giri Shan Rajahram, Helio Gutierres, Huynh Ngoc Hon, Trần Văn Giang, Ngoc Thach Pham, Abhilasha Karkey, Samanmalee Gunasekara, Raph L Hamers, Robert Sinto, Inke N. D. Lubis, Minggui Wang, Merlin Moni, Po‐Yu Liu, Yonghong Xiao, Basudha Khanal, N. Lakshmi Priya, Yohei Doi, Hitoshi Honda, Bayaraa Baljin, Ulziijargal Gurav, Rosmonaliza Asli, Lowell Ling, Ashesh Dhungana, Li-Yang Hsu, David L. Paterson, Yin Mo, Jie Su, May Gee Ong, Kee Mee Tan, Amanda Wei Ping Ling, Shweta Rajkumar Singh, Siew Pei Ong, Jia Rhou Lai, Shiau Hui Diong, Suchart Booraphun, Ratiporn Bansong, Xun Ting Tiong, Alisa Hanum Arba'eni, Sophany Koy, Seanghuoy Ho, Helmi Bin Sulaiman, Soo Nee Tang, Pope Kosalaraksa, Zeti Norfidiyati Salmuna, Gabriel Zherong Yan, Ambreen Fatima, Suvaporn Anugulruengkitt, Sadia Shakoor, Cecilia C. Maramba Lazarte, Thi Kim Anh Nguyen, Jinlan Lin, Pitak Santanirand, Ruth Tsin En Cheng, Rina Yunita, Nicole Bernadette Terre, Madiha Hashmi, Md Ali Amin Nabin, Mohd Zaki Bin Mohd Zaili, Joshua Francis, H. Rogier van Doorn, Bidhya Sharma Sharma, Sumudu Withanage, Yulia R. Saharman, R. Lia Kusumawati, 秦晓华, Chithra Tomy, Chien-Hao Tseng, Ping Shen, Shyam Prasad Kafle, T. Palaniappan, Shogo Hanai, Damdindorj Boldbaatar
Institutions: First Affiliated Hospital Zhejiang University, Kaohsiung Medical University, Kaohsiung Medical University Chung-Ho Memorial Hospital, Fudan University, Hanoi Medical University, University of Oxford, Universitas Sumatera Utara, Khon Kaen University, Sappasithiprasong Hospital, Mahidol University, King Chulalongkorn Memorial Hospital, Ramathibodi Hospital, Universiti Sains Malaysia, National University of Singapore, Christian Medical College, Vellore, National University Health System, Chinese University of Hong Kong, Chulalongkorn University, Amrita Institute of Medical Sciences and Research Centre, University of Indonesia, Singapore General Hospital, University of the Philippines Manila, Amrita Vishwa Vidyapeetham, University of Milano-Bicocca, University of Malaya, Beijing Tsinghua Chang Gung Hospital, Dow University of Health Sciences, Mahidol Oxford Tropical Medicine Research Unit, Rumah Sakit Umum Pusat Nasional Dr. Cipto Mangunkusumo, Huashan Hospital, International Centre for Diarrhoeal Disease Research, Fujita Health University, Ministry of Health, National University Hospital, Taichung Veterans General Hospital, Hospital for Tropical Diseases, Mongolian National University of Medical Sciences, University Malaya Medical Centre, National Cancer Institute of Sri Lanka, Sarawak General Hospital, Philippine General Hospital, Thai Red Cross Society, B.P. Koirala Institute of Health Sciences, Aga Khan University Hospital, Patan Hospital, Bir Hospital, Oxford University Clinical Research Unit, Oxford University Clinical Research Unit Nepal, Ziauddin Hospital, Queen Elizabeth Hospital, Calmette Hospital, Oxford University Clinical Research Unit Indonesia, Raja Isteri Pengiran Anak Saleha Hospital