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Effects of a comprehensive antibiotic stewardship program on antibiotic prescribing for acute respiratory infections in rural facilities: a cluster randomized trial

Nature Medicine (2026)Cite this article

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Abstract

Antimicrobial resistance is driven by inappropriate use of antibiotics for acute respiratory infections (ARIs), which is a major challenge in primary care in low- and middle-income countries. Here we conducted a pragmatic, cluster randomized controlled trial in 34 township hospitals in two rural counties of Guangdong, China, to evaluate whether a digitally enabled stewardship program could reduce antibiotic prescribing. The intervention combined training and guidelines for doctors; concise, evidence-based guidelines embedded in the electronic medical record with point-of-care prompts; monthly prescribing peer review feedback for doctors; and patient education delivered through a smartphone app. Control is usual care with no inputs. During the 12-month implementation period (1 March 2020 to 28 February 2021), we analyzed 97,239 eligible consultations for ARIs. The primary outcome was whether a consultation resulted in any antibiotics being prescribed. This outcome was met: antibiotics were prescribed in 26% (14,521/54,799) of intervention consultations compared to 71% (30,340/42,440) of control consultations, yielding an adjusted risk difference of –39 percentage points (95% confidence interval: –47 to –29; P < 0.001). There was no evidence of increased harm, as 30-day hospitalization rates for respiratory illness or sepsis did not differ between groups (adjusted risk difference, 0.2 percentage points; 95% confidence interval: –0.3 to 0.6). A comprehensive stewardship program can substantially reduce inappropriate antibiotic prescribing for ARIs in rural primary care facilities in China without compromising patient safety. Trial registration: ISRCTN96892547.

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Fig. 1: CONSORT trial flow diagram.
Fig. 2: Daily total number of eligible patient consultations per treatment group.
Fig. 3: Antibiotic prescribing rate by month (actual timeline) and treatment group.

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Data availability

Anonymized patient-level data underlying the results of this study are held at the Guangzhou Institute of Respiratory Health. Data will be made available for non-commercial research purposes to qualified investigators upon submission of a data access application, which must include a brief study protocol and a signed data use agreement compliant with China’s Public Data Safety Law. Applications should be sent to the corresponding author (N.Z., nanshan@vip.163.com) and will be reviewed by the institutional data access committee. Decisions on access will be provided within 2 months of application, as approvals are required from both the academic institute and the Shaoguan Health Bureau to ensure compliance with current legal and regulatory requirements. Approved applicants will be granted secure access to the data repository for a time-limited period.

Code availability

The statistical code used for the analyses in this study is available for non-commercial research purposes upon submission of a request to the first author (X.W., xiaolin.wei@utoronto.ca) and the chief biostatistician (J.P.H., j.p.hicks@leeds.ac.uk). Applicants must provide a brief description of the intended use and agree to a code-sharing agreement. Requests will be reviewed within 2 weeks, and approved applicants will be provided with the relevant R scripts via a secure repository.

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Acknowledgements

The authors acknowledge the support provided by the 36 township hospitals, including 34 in the trial and two in the pilot, in Shaoguan Prefecture, China, which were directly involved in the pilot and endline periods. We thank all patients and/or caregivers and healthcare providers who were involved in the trial. The study was funded by the China Primary Health Care Foundation (awarded to C.Z., X.W. and J.Z.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Xiaolin Wei, Chao Zhuo.

Authors and Affiliations

  1. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

    Xiaolin Wei, Zhitong Zhang, Shishi Wu, Hongyu Huang & Adalsteinn Brown

  2. National Center for Respiratory Diseases, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, Laboratory of Guangdong-Hong Kong-Macao Great Bay, Guangzhou Medical University, Guangzhou, China

    Chao Zhuo & Nanshan Zhong

  3. Nuffield Centre for International Health and Development, University of Leeds, Leeds, UK

    Joseph P. Hicks & John D. Walley

  4. Yuebei People’s Hospital, Shaoguan, China

    Jinkun Zheng & Wei Guo

  5. School of Medicine, University of St. Andrews, St. Andrews, UK

    Frank Sullivan

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Contributions

X.W., J.P.H., C.Z., Z.Z. and N.Z. contributed to the study design. X.W., C.Z., J.D.W., Z.Z., J.Z., W.G. and H.H. contributed to guideline development, training and implementation. X.W. and J.P.H. drafted the manuscript, with support from Z.Z. and S.W., and N.Z., C.Z., F.S. and A.B. commented on the manuscript. Z.Z. prepared and cleaned the data. J.P.H. analyzed the data and provided substantial scientific input in statistical methods and interpretation of results. N.Z. is the overall lead of the research consortium. The corresponding authors attest that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Corresponding authors

Correspondence to Xiaolin Wei or Nanshan Zhong.

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Nature Medicine thanks Rainer Tan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. Primary Handling Editor: Ming Yang, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Endline antibiotic prescription rate per intervention-group township hospital.

Bars indicate the antibiotic prescription rate (the percentage of eligible consultations where any acute respiratory infection[s] were diagnosed that resulted in any antibiotics being prescribed) across the endline period for each township hospital in the intervention group only. The 10th percentile (18%), mean (26.5%) and 90th (35%) percentile of those values are also illustrated (interquartile range = 10.3). Township hospitals are ordered by their endline antibiotic prescription rate.

Extended Data Fig. 2 Percentage point change in antibiotic prescription rate between baseline and endline per cluster.

APR = antibiotic prescription rate. Bars and values indicate the percentage point change in the antibiotic prescription rate between the baseline period and the endline period for each cluster, where the antibiotic prescription rate is the percentage of eligible patient consultations (where an acute respiratory infection was diagnosed) that resulted in any antibiotics.

Extended Data Fig. 3 Hospitalisation rate within 30 days after an eligible patient consultation in a township hospital by month (actual timeline) and treatment group.

Diamonds/squares and values represent the percentage of eligible patient consultations (where an acute respiratory infection was diagnosed) where the patient was subsequently hospitalised in any hospital within the Shaoguan Prefecture within 30 days of that consultation for the indicated treatment group and month relative to when the intervention started being implemented. The suspended period occurred when COVID-19 pandemic restrictions closed township hospitals and the trial was suspended.

Supplementary information

Supplementary Information

CONSORT checklist, Trial protocol and Statistical analysis plan.

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Peer Review File

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Wei, X., Zhuo, C., Hicks, J.P. et al. Effects of a comprehensive antibiotic stewardship program on antibiotic prescribing for acute respiratory infections in rural facilities: a cluster randomized trial. Nat Med (2026). https://doi.org/10.1038/s41591-026-04222-y

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