Community Acquired Pneumonia in Children: RCT for dose & duration of Amoxycillin

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 JAMA 2021 Nov 2;326(17):1713-1724. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564579/

Children receive antibiotics for upper and lower respiratory tract infections. Bacteria has been causally implicated in about a third of community acquired pneumonia (CAP) in children admitted to hospitals. Neither chest radiographs nor inflammatory biomarkers differentiate which children with CAP require antibiotics. Due to these reasons children continue to be prescribed antibiotics.

Optimising antibiotic treatment to minimise drug exposure while achieving high rates of clinical cure would inform essential antibiotic stewardship interventions.

Amoxicillin is widely recommended as the first-line antibiotic for CAP in young children. Randomised clinical trial evidence from low and middle income countries supports treatment duration of 3 to 5 days in mild or moderate disease. However, the most appropriate total daily dose of oral amoxicillin treatment has not been investigated in any trial, and it is unclear whether evidence supporting 3-day treatment can be generalised from low-and middle-income countries to high-income secondary care settings with differing diagnostic criteria.

In the current Sri Lankan situation where even essential medicines are in short supply it will be important to give antibiotics using appropriate duration without compromising the quality of care

The clinical question is – what is the optimum dose of amoxycillin for managing community acquired pneumonia in children?


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, randomised, 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 randomised 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 randomisation. 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 colonising Streptococcus pneumoniae isolates.

RESULTS Of 824 participants randomised 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.


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.

What is a noninferiority trial?

A study that tests whether a new treatment is not worse than an active treatment it is being compared to. Non-inferiority trials are sometimes done when a placebo (an inactive treatment) cannot be used. These trials may show that a new treatment (such as a drug) is not worse than the active treatment being compared, and it may be safer and easier to take or cause fewer side effects.


If you need more information about ‘Noninferiority Trials’

  1. Non-Inferiority Trials: Understanding the ConceptsRead More

2. Watch Video



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