Early trajectories of antibiotic exposure and colonization pressure and risk of ICU-acquired carbapenem-resistant Gram-negative bacteria: A prospective cohort study - 01/04/26

Doi : 10.1016/j.aicoj.2026.100063

Zhihui Chen ^a,^b,^{^{1
These authors contributed equally as co-first authors.}}, Xiangru Ye ^c,^{^{1
These authors contributed equally as co-first authors.}}, Jing Wu ^a,^{^{1
These authors contributed equally as co-first authors.}}, Zhonghua Li ^a,^d, Sen Wang ^a, Jing Wang ^e, Yueru Tian ^f, Shirong Li ^g, Lei Zhou ^a, Jie Ni ^g, Yue Qu ^h,⁎ , Jialin Jin ^a,⁎ , Wenhong Zhang ^a,^b,^i,^{^{2
These authors contributed equally as co-corresponding authors.},}⁎

^a Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, China

^b Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, China

^c Department of Neurocritical care unit, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

^d Department of Infectious Diseases, Taicang First People's Hospital, Taicang, China

^e Department of Infection Control, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

^f Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

^g Department of Intensive Care Unit, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

^h Department of infectious diseases, School of Translational Medicine, Monash University, Melbourne, VIC, Australia

ⁱ Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, 200052, China

^⁎ Corresponding authors.

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Abstract

Background

Carbapenem-resistant Gram-negative bacteria (CR-GNB) pose a critical threat in intensive care units (ICUs), with antibiotic exposure and colonization pressure identified as key associated factors. Prior studies have analyzed these two time-varying factors as static cumulative variables, obscuring heterogeneity in temporal patterns and their joint evolution. How distinct early trajectories of these factors jointly relate to CR-GNB acquisition risk remains unclear.

Methods

In this prospective cohort study conducted at four ICUs in a tertiary-care center in China from March 2024 to January 2025, we enrolled consecutive patients with systematic rectal surveillance cultures. We used group-based multi-trajectory modeling to identify distinct joint trajectories of daily antibiotic exposure (dose, duration, spectrum) and colonization pressure during the first five ICU days. Continuous-time Markov multi-state models with Day-5 landmark analysis were adopted to assess associations between trajectory groups and subsequent ICU-acquired CR-GNB, adjusting for baseline and cumulative covariates.

Results

Among 533 patients entering the Day-5 landmark analysis, three distinct trajectory groups were identified: Low exposure/low pressure (34.1%), escalating exposure/intermediate pressure (54.4%), and high exposure/high pressure (11.4%). CR-GNB acquisition occurred in 124 patients (23.3%), with rates of 9.3%, 26.2%, and 50.8% across trajectory groups, respectively. Compared with the low-exposure trajectory, adjusted hazard ratios were 1.68 (95% confidence interval [CI] 1.24–2.28) for escalating-exposure and 2.82 (95% CI, 1.53–5.19) for high-exposure trajectories (both P < 0.001).

Conclusions

This study identified distinct early trajectories of antibiotic exposure and colonization pressure that were associated with differential CR-GNB acquisition risk. This trajectory-based framework for early association-based risk stratification may inform targeted prevention strategies, but external validation is required before clinical implementation.

Trial registration

Chinese Clinical Trial Registry Identifier: ChiCTR2400081352. Registered 28 February 2024.

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Keywords : Carbapenem-resistant Gram-negative bacteria, Intensive care unit, Antibiotic exposure, Colonization pressure, Group-based multi-trajectory modeling