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. 2023 Jul 5:61:102064.
doi: 10.1016/j.eclinm.2023.102064. eCollection 2023 Jul.

Repeated antibiotic exposure and risk of hospitalisation and death following COVID-19 infection (OpenSAFELY): a matched case-control study

Ya-Ting Yang  1 , David Wong  2 , Darren M Ashcroft  3   4 , Jon Massey  5 , Brian MacKenna  5 , Louis Fisher  5 , Amir Mehrkar  5 , Sebastian Cj Bacon  5 ; OpenSAFELY collaborative; Kieran Hand  6 , Xiaomin Zhong  1 , Ali Fahmi  1 , Ben Goldacre  5 , Tjeerd van Staa  1 , Victoria Palin  1   7
Affiliations

Repeated antibiotic exposure and risk of hospitalisation and death following COVID-19 infection (OpenSAFELY): a matched case-control study

Ya-Ting Yang et al. EClinicalMedicine. .

Abstract

Background: Identifying potential risk factors related to severe COVID-19 outcomes is important. Repeated intermittent antibiotic use is known be associated with adverse outcomes. This study aims to examine whether prior frequent antibiotic exposure is associated with severe COVID-19 outcomes.

Methods: With the approval of NHS England, we used the OpenSAFELY platform, which integrated primary and secondary care, COVID-19 test, and death registration data. This matched case-control study included 0.67 million patients (aged 18-110 years) from an eligible 2.47 million patients with incident COVID-19 by matching with replacement. Inclusion criteria included registration within one general practice for at least 3 years and infection with incident COVID-19. Cases were identified according to different severity of COVID-19 outcomes. Cases and eligible controls were 1:6 matched on age, sex, region of GP practice, and index year and month of COVID-19 infection. Five quintile groups, based on the number of previous 3-year antibiotic prescriptions, were created to indicate the frequency of prior antibiotic exposure. Conditional logistic regression used to compare the differences between case and control groups, adjusting for ethnicity, body mass index, comorbidities, vaccination history, deprivation, and care home status. Sensitivity analyses were done to explore potential confounding and the effects of missing data.

Findings: Based on our inclusion criteria, between February 1, 2020 and December 31, 2021, 98,420 patients were admitted to hospitals and 22,660 died. 55 unique antibiotics were prescribed. A dose-response relationship between number of antibiotic prescriptions and risk of severe COVID-19 outcome was observed. Patients in the highest quintile with history of prior antibiotic exposure had 1.80 times greater odds of hospitalisation compared to patients without antibiotic exposure (adjusted odds ratio [OR] 1.80, 95% Confidence Interval [CI] 1.75-1.84). Similarly, the adjusted OR for hospitalised patients with death outcomes was 1.34 (95% CI 1.28-1.41). Larger number of prior antibiotic type was also associated with more severe COVID-19 related hospital admission. The adjusted OR of quintile 5 exposure (the most frequent) with more than 3 antibiotic types was around 2 times larger than quintile 1 (only 1 type; OR 1.80, 95% CI 1.75-1.84 vs. OR 1.03, 95% CI 1.01-1.05).

Interpretation: Our observational study has provided evidence that antibiotic exposure frequency and diversity may be associated with COVID-19 severity, potentially suggesting adverse effects of repeated intermittent antibiotic use. Future work could work to elucidate causal links and potential mechanisms. Antibiotic stewardship should put more emphasis on long-term antibiotic exposure and its adverse outcome to increase the awareness of appropriate antibiotics use.

Funding: Health Data Research UK and National Institute for Health Research.

Keywords: Antibiotics; COVID-19; Primary care; Severe outcome.

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Conflict of interest statement

All authors declare the following: BG and OpenSAFELY has received research funding from the Laura and John Arnold Foundation, the NHS National Institute for Health Research (NIHR), the NIHR School of Primary Care Research, NHS England, the NIHR Oxford Biomedical Research Centre, the Mohn-Westlake Foundation, NIHR Applied Research Collaboration Oxford and Thames Valley, the Wellcome Trust, the Good Thinking Foundation, Health Data Research UK, the Health Foundation, the World Health Organisation, UKRI MRC, Asthma UK, the British Lung Foundation, and the Longitudinal Health and Wellbeing strand of the National Core Studies programme; he is a Non-Executive Director at NHS Digital; he also receives personal income from speaking and writing for lay audiences on the misuse of science. AM has received consultancy fees (from https://inductionhealthcare.com) and is member of RCGP health informatics group and the NHS Digital GP data Professional Advisory Group that advises on access to GP Data for Pandemic Planning and Research (GDPPR). For the latter, he received payment for the GDPPR role.

Figures

Fig. 1
Fig. 1
Study design (A) andpatient selection (B).
Fig. 2
Fig. 2
Adjusted ORs for COVID-19 outcomes (A. admitted to hospitals; B. death) stratified by number of antibiotic types in the 3 years by quintile (Q1–Q5) of total number of prior antibiotic prescription.
See this image and copyright information in PMC

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