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For children with community-acquired pneumonia discharged from an emergency department, observational unit, or inpatient ward (within 48 hours), is subsequent outpatient treatment with oral amoxicillin at a dose of 35 to 50 mg/kg per day noninferior to 70 to 90 mg/kg per day, and is a 3-day course noninferior to 7 days, with regard to the need for antibiotic re-treatment?
In this 2 × 2 factorial randomized clinical trial of 814 children requiring amoxicillin for community-acquired pneumonia at hospital discharge, antibiotic re-treatment within 28 days occurred in 12.6% vs 12.4% of those randomized to lower vs higher doses, and in 12.5% vs 12.5% of those randomized to 3-day vs 7-day amoxicillin duration. Both comparisons met the prespecified 8% noninferiority margin.
Among children with community-acquired pneumonia discharged from an emergency department, observational unit, or inpatient ward, further outpatient treatment with oral amoxicillin at a dose of 35 to 50 mg/kg per day was noninferior to a dose of 70 to 90 mg/kg per day and 3 days was noninferior to 7 days with regard to the need for later antibiotic re-treatment.
The optimal dose and duration of oral amoxicillin for children with community-acquired pneumonia (CAP) are unclear.
To determine whether lower-dose amoxicillin is noninferior to higher dose and whether 3-day treatment is noninferior to 7 days.
Design, Setting, and Participants
Multicenter, randomized, 2 × 2 factorial noninferiority trial enrolling 824 children, aged 6 months and older, with clinically diagnosed CAP, treated with amoxicillin on discharge from emergency departments and inpatient wards of 28 hospitals in the UK and 1 in Ireland between February 2017 and April 2019, with last trial visit on May 21, 2019.
Children were randomized 1:1 to receive oral amoxicillin at a lower dose (35-50 mg/kg/d; n = 410) or higher dose (70-90 mg/kg/d; n = 404), for a shorter duration (3 days; n = 413) or a longer duration (7 days; n = 401).
Main Outcomes and Measures
The primary outcome was clinically indicated antibiotic re-treatment for respiratory infection within 28 days after randomization. The noninferiority margin was 8%. Secondary outcomes included severity/duration of 9 parent-reported CAP symptoms, 3 antibiotic-related adverse events, and phenotypic resistance in colonizing Streptococcus pneumoniae isolates.
Of 824 participants randomized into 1 of the 4 groups, 814 received at least 1 dose of trial medication (median [IQR] age, 2.5 years [1.6-2.7]; 421 [52%] males and 393 [48%] females), and the primary outcome was available for 789 (97%). For lower vs higher dose, the primary outcome occurred in 12.6% with lower dose vs 12.4% with higher dose (difference, 0.2% [1-sided 95% CI –∞ to 4.0%]), and in 12.5% with 3-day treatment vs 12.5% with 7-day treatment (difference, 0.1% [1-sided 95% CI –∞ to 3.9]). Both groups demonstrated noninferiority with no significant interaction between dose and duration (P = .63). Of the 14 prespecified secondary end points, the only significant differences were 3-day vs 7-day treatment for cough duration (median 12 days vs 10 days; hazard ratio [HR], 1.2 [95% CI, 1.0 to 1.4]; P = .04) and sleep disturbed by cough (median, 4 days vs 4 days; HR, 1.2 [95% CI, 1.0 to 1.4]; P = .03). Among the subgroup of children with severe CAP, the primary end point occurred in 17.3% of lower-dose recipients vs 13.5% of higher-dose recipients (difference, 3.8% [1-sided 95% CI, –∞ to10%]; P value for interaction = .18) and in 16.0% with 3-day treatment vs 14.8% with 7-day treatment (difference, 1.2% [1-sided 95% CI, –∞ to 7.4%]; P value for interaction = .73).
Conclusions and Relevance
Among children with CAP discharged from an emergency department or hospital ward (within 48 hours), lower-dose outpatient oral amoxicillin was noninferior to higher dose, and 3-day duration was noninferior to 7 days, with regard to need for antibiotic re-treatment. However, disease severity, treatment setting, prior antibiotics received, and acceptability of the noninferiority margin require consideration when interpreting the findings.
ISRCTN Identifier: ISRCTN76888927
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Corresponding Author: Julia A. Bielicki, PhD, Paediatric Infectious Diseases Research Group, St George's University of London, Jenner Wing, Level 2, Room 2.215E, Cranmer Terrace, London, UK SW17 0RE (email@example.com).
Accepted for Publication: September 22, 2021.
Correction: This article was corrected on December 7, 2021, to correct a misspelling in the surname of a member of the trial steering committee.
Author Contributions: Drs Bielicki and Stöhr had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Joint first authors: Drs Bielicki and Stöhr. Drs Lyttle, Gibb, and Sharland contributed equally.
Concept and design: Bielicki, Stöhr, Barratt, Dunn, Roland, Sturgeon, Finn, Powell, Faust, Lyttle, Gibb, Sharland.
Acquisition, analysis, or interpretation of data: Bielicki, Stöhr, Barratt, Dunn, Naufal, Roland, Finn, Rodriguez Ruiz, Malhotra-Kumar, Powell, Faust, Alcock, Hall, Robinson, Hawcutt, Lyttle, Gibb, Sharland.
Drafting of the manuscript: Bielicki, Stöhr, Dunn, Sturgeon, Lyttle, Gibb.
Critical revision of the manuscript for important intellectual content: Bielicki, Stöhr, Barratt, Dunn, Naufal, Roland, Finn, Rodriguez Ruiz, Malhotra-Kumar, Powell, Faust, Alcock, Hall, Robinson, Hawcutt, Lyttle, Sharland.
Statistical analysis: Stöhr, Dunn.
Obtained funding: Bielicki, Faust, Lyttle, Gibb, Sharland.
Administrative, technical, or material support: Barratt, Naufal, Roland, Sturgeon, Finn, Powell, Faust, Robinson, Lyttle, Gibb.
Supervision: Dunn, Finn, Malhotra-Kumar, Powell, Faust, Lyttle, Gibb, Sharland.
Other - Data generation: Malhotra-Kumar.
Conflict of Interest Disclosures: Dr Bielicki reported grants from the National Institute of Health Research (NIHR; grant No. 13/88/11) during the conduct of the study; her spouse was senior corporate counsel at Novartis International AG, Basel, Switzerland until June 2020 and owns stock and stock options. Dr Barratt reported grants from (NIHR) Health Technology Assessment (HTA) (grant No. 13/88/11) during the conduct of the study. Dr Roland reported being chair of Paediatric Emergency Research United Kingdom and Ireland (PERUKI). Dr Sturgeon reported grants from NIHR HTA (HTA project ID, 13/88/11) during the conduct of the study. Dr Finn reported grants from UK Research and Innovation-NIHR/HTA funding for laboratory work during the conduct of the study, and grants from Pfizer collaborative outside the submitted work. Dr Faust reported grants from NIHR during the conduct of the study; other (fees paid to the institution for advisory board participation) from Medimmune, Sanofi, Pfizer, Seqrius, Sandoz, and Merck; grants for serving as clinical trial investigator on behalf of the institution (no personal payments of any kind) from Pfizer, Sanofi, GlaxoSmithKline, Johnson & Johnson, Merck, AstraZeneca, and Valneva outside the submitted work. Dr Sharland reported grants from NIHR HTA (grant No. 13/88/11) during the conduct of the study. No other disclosures were reported.
Group Information: PERUKI, GAPRUKI, and the CAP-IT trial group members are listed in Supplement 4.
Funding/Support: The CAP-IT trial (Community-Acquired Pneumonia: a randomized controlled trial) was funded by the NIHR Health Technology Assessment Program, Antimicrobial Resistance Themed Call (grant No. 13/88/11).
Role of the Funder/Sponsor: The NIHR had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 5.
Additional Contributions: We thank all members of the trial committees, all families and children who have taken part, and all participating sites for their invaluable contributions to the CAP-IT trial. Trial steering committee independent members: Elizabeth Molyneux (chair), MD, College of Medicine, Blantyre, Malawi; Chris Butler, MD, University of Oxford, Oxford, UK; Alan Smyth, MD, University of Nottingham, Nottingham, UK; and Catherine Prichard, BSc, patient representative. Independent data monitoring committee: Tim Peto (chair), MD, University of Oxford, Oxford, UK; Simon Cousens, DipMathStat, London School of Hygiene and Tropical Medicine, London, UK; and Stuart Logan, MSc, University of Exeter Medical School, Exeter, UK. Independent end point review committee members: Alasdair Bamford (chair), PhD, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; Anna Turkova, MD, MRC CTU, at University College London, London, UK; Anna Goodman, DPhil, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; and Felicity Fitzgerald, PhD, University College London Great Ormond Street Institute of Child Health, London, UK. Trial management group: Paul Little, MD, University of Southampton, Southampton, UK; Julie Robotham, PhD, Imperial College London, London, UK; Mandy Wan, MSc, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; Nigel Klein, PhD, University College London Great Ormond Street Institute of Child Health, London, UK; Louise Rogers, BSc, Birmingham’s Children’s Hospital, Birmingham, UK; and Elia Vitale, BSc, St George’s University, London, UK. Members of the trial steering committee, independent data monitoring committee, the end point review committee, and the trial management group did not receive specific compensation for their contribution to the study, but were reimbursed for study-related expenses (travel, accommodation).
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