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Original Investigation
November 2, 2021

Effect of Amoxicillin Dose and Treatment Duration on the Need for Antibiotic Re-treatment in Children With Community-Acquired Pneumonia: The CAP-IT Randomized Clinical Trial

Author Affiliations
  • 1Pediatric Infectious Diseases Research Group, Medical Research Council Clinical Trial Unit at University College London, Institute for Infection and Immunity, St George’s University of London, London, United Kingdom
  • 2Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom
  • 3Pediatric Emergency Medicine Leicester Academic (PEMLA) Group, Emergency Department, Leicester, United Kingdom
  • 4SAPPHIRE Group, University of Leicester, Department of Health Sciences, Leicester, United Kingdom
  • 5Bristol Children’s Vaccine Centre, Schools of Population Sciences and Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
  • 6Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
  • 7Emergency Medicine, Sidra Medical and Research Center, Doha, Qatar
  • 8Division of Population Medicine, Cardiff University School of Medicine, Cardiff, United Kingdom
  • 9National Institute for Health Research Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
  • 10Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
  • 11Pediatric Emergency Medicine, Evelina Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom
  • 12Pediatric Emergency Medicine, Children’s Health Ireland at Crumlin, Ireland
  • 13Pediatric Emergency Medicine, University Hospitals of Derby and Burton NHS Foundation Trust, Derby, United Kingdom
  • 14Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
  • 15Pediatric Medicines Research Unit, Alder Hey Children’s NHS Foundation Trust, Liverpool, United Kingdom
  • 16Emergency Department, Bristol Royal Hospital for Children, Bristol, United Kingdom
  • 17Faculty of Health and Applied Science, University of the West of England, Bristol, United Kingdom
JAMA. 2021;326(17):1713-1724. doi:10.1001/jama.2021.17843
Key Points

Question  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?

Findings  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.

Meaning  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.

Abstract

Importance  The optimal dose and duration of oral amoxicillin for children with community-acquired pneumonia (CAP) are unclear.

Objective  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.

Interventions  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.

Results  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.

Trial Registration  ISRCTN Identifier: ISRCTN76888927

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