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Antibiotics for lower respiratory tract infection in children presenting in primary care: ARTIC-PC RCT

Antibiotics for lower respiratory tract infection in children presenting in primary care: ARTIC-PC RCT
Antibiotics for lower respiratory tract infection in children presenting in primary care: ARTIC-PC RCT

Background: Antimicrobial resistance is a global health threat. Antibiotics are commonly prescribed for children with uncomplicated lower respiratory tract infections, but there is little randomised evidence to support the effectiveness of antibiotics in treating these infections, either overall or relating to key clinical subgroups in which antibiotic prescribing is common (chest signs; fever; physician rating of unwell; sputum/rattly chest; shortness of breath). Objectives: To estimate the clinical effectiveness and cost-effectiveness of amoxicillin for uncomplicated lower respiratory tract infections in children both overall and in clinical subgroups. Design: Placebo-controlled trial with qualitative, observational and cost-effectiveness studies. Setting: UK general practices. Participants: Children aged 1-12 years with acute uncomplicated lower respiratory tract infections. Outcomes: The primary outcome was the duration in days of symptoms rated moderately bad or worse (measured using a validated diary). Secondary outcomes were symptom severity on days 2-4 (0 = no problem to 6 = as bad as it could be); symptom duration until very little/no problem; reconsultations for new or worsening symptoms; complications; side effects; and resource use. Methods: Children were randomised to receive 50 mg/kg/day of oral amoxicillin in divided doses for 7 days, or placebo using pre-prepared packs, using computer-generated random numbers by an independent statistician. Children who were not randomised could participate in a parallel observational study. Semistructured telephone interviews explored the views of 16 parents and 14 clinicians, and the data were analysed using thematic analysis. Throat swabs were analysed using multiplex polymerase chain reaction. Results: A total of 432 children were randomised (antibiotics, n = 221; placebo, n = 211). The primary analysis imputed missing data for 115 children. The duration of moderately bad symptoms was similar in the antibiotic and placebo groups overall (median of 5 and 6 days, respectively; hazard ratio 1.13, 95% confidence interval 0.90 to 1.42), with similar results for subgroups, and when including antibiotic prescription data from the 326 children in the observational study. Reconsultations for new or worsening symptoms (29.7% and 38.2%, respectively; risk ratio 0.80, 95% confidence interval 0.58 to 1.05), illness progression requiring hospital assessment or admission (2.4% vs. 2.0%) and side effects (38% vs. 34%) were similar in the two groups. Complete-case (n = 317) and per-protocol (n = 185) analyses were similar, and the presence of bacteria did not mediate antibiotic effectiveness. NHS costs per child were slightly higher (antibiotics, £29; placebo, £26), with no difference in non-NHS costs (antibiotics, £33; placebo, £33). A model predicting complications (with seven variables: baseline severity, difference in respiratory rate from normal for age, duration of prior illness, oxygen saturation, sputum/rattly chest, passing urine less often, and diarrhoea) had good discrimination (bootstrapped area under the receiver operator curve 0.83) and calibration. Parents found it difficult to interpret symptoms and signs, used the sounds of the child's cough to judge the severity of illness, and commonly consulted to receive a clinical examination and reassurance. Parents acknowledged that antibiotics should be used only when 'necessary', and clinicians noted a reduction in parents' expectations for antibiotics. Limitations: The study was underpowered to detect small benefits in key subgroups. Conclusion: Amoxicillin for uncomplicated lower respiratory tract infections in children is unlikely to be clinically effective or to reduce health or societal costs. Parents need better access to information, as well as clear communication about the self-management of their child's illness and safety-netting. Future work: The data can be incorporated in the Cochrane review and individual patient data meta-analysis. Trial registration: This trial is registered as ISRCTN79914298. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 9. See the NIHR Journals Library website for further project information.

ANTIBACTERIAL AGENTS, ANTIMICROBIAL DRUG RESISTANCE, COUGH, PRIMARY CARE, PUBLIC HEALTH, RESPIRATORY TRACT INFECTIONS
1366-5278
Little, Paul
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Francis, Nick A.
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Stuart, Beth
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O'Reilly, Gilly
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Thompson, Natalie
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Becque, Taeko
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Hay, Alastair D.
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Wang, Kay
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Sharland, Michael
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Harnden, Anthony
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Yao, Guiqing
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Raftery, James
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Zhu, Shihua
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Little, Joseph
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Hookham, Charlotte
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Rowley, Kate
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Euden, Joanne
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Harman, Kim
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Coenen, Samuel
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Read, Robert C.
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Woods, Catherine
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Butler, Christopher C.
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Faust, Saul N.
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Leydon, Geraldine
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Wan, Mandy
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Hood, Kerenza
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Whitehurst, Jane
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Richards-Hall, Samantha
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Smith, Peter
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Thomas, Michael
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Moore, Michael
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Verheij, Theo
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Little, Paul
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Francis, Nick A.
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Stuart, Beth
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O'Reilly, Gilly
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Thompson, Natalie
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Becque, Taeko
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Hay, Alastair D.
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Wang, Kay
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Sharland, Michael
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Harnden, Anthony
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Yao, Guiqing
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Raftery, James
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Zhu, Shihua
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Little, Joseph
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Hookham, Charlotte
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Rowley, Kate
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Euden, Joanne
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Harman, Kim
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Coenen, Samuel
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Read, Robert C.
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Woods, Catherine
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Butler, Christopher C.
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Faust, Saul N.
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Leydon, Geraldine
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Wan, Mandy
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Hood, Kerenza
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Whitehurst, Jane
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Richards-Hall, Samantha
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Smith, Peter
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Thomas, Michael
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Moore, Michael
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Verheij, Theo
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Little, Paul, Francis, Nick A., Stuart, Beth, O'Reilly, Gilly, Thompson, Natalie, Becque, Taeko, Hay, Alastair D., Wang, Kay, Sharland, Michael, Harnden, Anthony, Yao, Guiqing, Raftery, James, Zhu, Shihua, Little, Joseph, Hookham, Charlotte, Rowley, Kate, Euden, Joanne, Harman, Kim, Coenen, Samuel, Read, Robert C., Woods, Catherine, Butler, Christopher C., Faust, Saul N., Leydon, Geraldine, Wan, Mandy, Hood, Kerenza, Whitehurst, Jane, Richards-Hall, Samantha, Smith, Peter, Thomas, Michael, Moore, Michael and Verheij, Theo (2023) Antibiotics for lower respiratory tract infection in children presenting in primary care: ARTIC-PC RCT (Health technology assessment (Winchester, England), 27) 90pp. (doi:10.3310/DGBV3199).

Record type: Monograph (Project Report)

Abstract

Background: Antimicrobial resistance is a global health threat. Antibiotics are commonly prescribed for children with uncomplicated lower respiratory tract infections, but there is little randomised evidence to support the effectiveness of antibiotics in treating these infections, either overall or relating to key clinical subgroups in which antibiotic prescribing is common (chest signs; fever; physician rating of unwell; sputum/rattly chest; shortness of breath). Objectives: To estimate the clinical effectiveness and cost-effectiveness of amoxicillin for uncomplicated lower respiratory tract infections in children both overall and in clinical subgroups. Design: Placebo-controlled trial with qualitative, observational and cost-effectiveness studies. Setting: UK general practices. Participants: Children aged 1-12 years with acute uncomplicated lower respiratory tract infections. Outcomes: The primary outcome was the duration in days of symptoms rated moderately bad or worse (measured using a validated diary). Secondary outcomes were symptom severity on days 2-4 (0 = no problem to 6 = as bad as it could be); symptom duration until very little/no problem; reconsultations for new or worsening symptoms; complications; side effects; and resource use. Methods: Children were randomised to receive 50 mg/kg/day of oral amoxicillin in divided doses for 7 days, or placebo using pre-prepared packs, using computer-generated random numbers by an independent statistician. Children who were not randomised could participate in a parallel observational study. Semistructured telephone interviews explored the views of 16 parents and 14 clinicians, and the data were analysed using thematic analysis. Throat swabs were analysed using multiplex polymerase chain reaction. Results: A total of 432 children were randomised (antibiotics, n = 221; placebo, n = 211). The primary analysis imputed missing data for 115 children. The duration of moderately bad symptoms was similar in the antibiotic and placebo groups overall (median of 5 and 6 days, respectively; hazard ratio 1.13, 95% confidence interval 0.90 to 1.42), with similar results for subgroups, and when including antibiotic prescription data from the 326 children in the observational study. Reconsultations for new or worsening symptoms (29.7% and 38.2%, respectively; risk ratio 0.80, 95% confidence interval 0.58 to 1.05), illness progression requiring hospital assessment or admission (2.4% vs. 2.0%) and side effects (38% vs. 34%) were similar in the two groups. Complete-case (n = 317) and per-protocol (n = 185) analyses were similar, and the presence of bacteria did not mediate antibiotic effectiveness. NHS costs per child were slightly higher (antibiotics, £29; placebo, £26), with no difference in non-NHS costs (antibiotics, £33; placebo, £33). A model predicting complications (with seven variables: baseline severity, difference in respiratory rate from normal for age, duration of prior illness, oxygen saturation, sputum/rattly chest, passing urine less often, and diarrhoea) had good discrimination (bootstrapped area under the receiver operator curve 0.83) and calibration. Parents found it difficult to interpret symptoms and signs, used the sounds of the child's cough to judge the severity of illness, and commonly consulted to receive a clinical examination and reassurance. Parents acknowledged that antibiotics should be used only when 'necessary', and clinicians noted a reduction in parents' expectations for antibiotics. Limitations: The study was underpowered to detect small benefits in key subgroups. Conclusion: Amoxicillin for uncomplicated lower respiratory tract infections in children is unlikely to be clinically effective or to reduce health or societal costs. Parents need better access to information, as well as clear communication about the self-management of their child's illness and safety-netting. Future work: The data can be incorporated in the Cochrane review and individual patient data meta-analysis. Trial registration: This trial is registered as ISRCTN79914298. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 9. See the NIHR Journals Library website for further project information.

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Published date: 26 June 2023
Additional Information: Funding Information: Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in ealth H eT chnology Assessment Vol. 27, No. 9. See the NIHR Journals Library website for further project information. Funding Information: This project is funded by the NIHR Health Technology Assessment (HTA) programme (study reference 13/34/64). Saul N Faust is part-funded by the Southampton NIHR Biomedical Research Centre. We are very grateful to both the Trial Steering Committee [Elaine Hay (chairperson), Robbie Foy, Reuben Ogollah and Kirsty Samuel (PPI representative)] and the DMSC [Sally Kerry (chairperson), Chris Griffiths, Andrew Hayward and Peter Landman (PPI representative)] for their support and advice. Zöe Morrice (student placement) contributed to the qualitative study. This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 9. See the NIHR Journals Library website for further project information. Funding Information: The research reported in this issue of the journal was funded by the HTA programme as project number 13/34/64. The contractual start date was in July 2016. The draft report began editorial review in April 2021 and was accepted for publication in February 2022. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. Funding Information: ?eclared competing interests of authors: Theo Verheij reports grants from the European Union and The Netherlands Organisation for Health Research and ? evelopment during the conduct of the study, and grants from Abbott Laboratories (Chicago, IL, USA), Becton, ?ickinson and Company (Franklin Lakes, NJ, USA), bioMérieux (Marcy-l’C? toile, France) and Janssen Pharmaceuticals (Beerse, Belgium) outside the submitted work. Paul Little was a member of the National Institute for Health and Care Research (NIHR) Journals Library Board (2011–17). Kerenza Hood is a member of the NIHR Health Technology Assessment (HTA) General Committee and the HTA Funding Strategy Group. Saul N Faust is a member of the RECOVERY Trial Steering Committee, the HTA Commissioning Board and other NIHR national groups, and reports funds to his institution but no personal payments for multiple commercial contracts, advisory board participation and presentations [Pfizer (New York, NY, USA), AstraZeneca (Cambridge, UK), MedImmune (Gaithersburg, M? , USA), Sanofi (Paris, France), CSL Seqirus (Maidenhead, UK) and Merck Group (? armstadt, Germany)]. Robert C Read reports that he is NIHR Biomedical Research Centre ?irec-tor and editor-in-chief of Journal of Infection. James Raftery reports membership of the NIHR HTA and Efficacy and Mechanism Evaluation Editorial Board in a paid role. Nick A Francis reports a research grant from Synairgen plc (Southampton, UK) for COVI?-19 research, non-financial support for a NIHR HTA trial on reducing antibiotics for COP? from Abbott Laboratories, a speaker’s fee from Abbott Laboratories, and stock/stock options from Abbott Laboratories and Synairgen plc. Publisher Copyright: © 2023 Little et al.
Keywords: ANTIBACTERIAL AGENTS, ANTIMICROBIAL DRUG RESISTANCE, COUGH, PRIMARY CARE, PUBLIC HEALTH, RESPIRATORY TRACT INFECTIONS

Identifiers

Local EPrints ID: 480358
URI: http://eprints.soton.ac.uk/id/eprint/480358
ISSN: 1366-5278
PURE UUID: bd638367-4de4-4dc3-8c50-8fd641cb0b5e
ORCID for Paul Little: ORCID iD orcid.org/0000-0003-3664-1873
ORCID for Nick A. Francis: ORCID iD orcid.org/0000-0001-8939-7312
ORCID for Beth Stuart: ORCID iD orcid.org/0000-0001-5432-7437
ORCID for Taeko Becque: ORCID iD orcid.org/0000-0002-0362-3794
ORCID for Kim Harman: ORCID iD orcid.org/0000-0002-5173-7753
ORCID for Robert C. Read: ORCID iD orcid.org/0000-0002-4297-6728
ORCID for Saul N. Faust: ORCID iD orcid.org/0000-0003-3410-7642
ORCID for Geraldine Leydon: ORCID iD orcid.org/0000-0001-5986-3300
ORCID for Peter Smith: ORCID iD orcid.org/0000-0003-4423-5410
ORCID for Michael Moore: ORCID iD orcid.org/0000-0002-5127-4509

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Date deposited: 01 Aug 2023 17:50
Last modified: 12 Jul 2024 02:05

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Contributors

Author: Paul Little ORCID iD
Author: Nick A. Francis ORCID iD
Author: Beth Stuart ORCID iD
Author: Gilly O'Reilly
Author: Natalie Thompson
Author: Taeko Becque ORCID iD
Author: Alastair D. Hay
Author: Kay Wang
Author: Michael Sharland
Author: Anthony Harnden
Author: Guiqing Yao
Author: James Raftery
Author: Shihua Zhu
Author: Joseph Little
Author: Charlotte Hookham
Author: Kate Rowley
Author: Joanne Euden
Author: Kim Harman ORCID iD
Author: Samuel Coenen
Author: Robert C. Read ORCID iD
Author: Catherine Woods
Author: Christopher C. Butler
Author: Saul N. Faust ORCID iD
Author: Mandy Wan
Author: Kerenza Hood
Author: Jane Whitehurst
Author: Samantha Richards-Hall
Author: Peter Smith ORCID iD
Author: Michael Thomas
Author: Michael Moore ORCID iD
Author: Theo Verheij

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