Amoxicillin duration and dose for community-acquired pneumonia in children: the CAP-IT factorial non-inferiority RCT

Barratt, Sam; Bielicki, Julia A.; Dunn, David; Faust, Saul N.; Finn, Adam; Harper, Lynda; Jackson, Pauline; Lyttle, Mark D.; Powell, Colin Ve; Rogers, Louise; Roland, Damian; Stöhr, Wolfgang; Sturgeon, Kate; Vitale, Elia; Wan, Mandy; Gibb, Diana M.; Sharland, Mike

Abstract

Background: Data are limited regarding the optimal dose and duration of amoxicillin treatment for community-acquired pneumonia in children. Objectives: To determine the efficacy, safety and impact on antimicrobial resistance of shorter (3-day) and longer (7-day) treatment with amoxicillin at both a lower and a higher dose at hospital discharge in children with uncomplicated community-acquired pneumonia. Design: A multicentre randomised double-blind 2 × 2 factorial non-inferiority trial in secondary care in the UK and Ireland. Setting: Paediatric emergency departments, paediatric assessment/observation units and inpatient wards. Participants: Children aged > 6 months, weighing 6-24 kg, with a clinical diagnosis of community-acquired pneumonia, in whom treatment with amoxicillin as the sole antibiotic was planned on discharge. Interventions: Oral amoxicillin syrup at a dose of 35-50 mg/kg/day compared with a dose of 70-90 mg/kg/day, and 3 compared with 7 days’ duration. Children were randomised simultaneously to each of the two factorial arms in a 1: 1 ratio. Main outcome measures: The primary outcome was clinically indicated systemic antibacterial treatment prescribed for respiratory tract infection (including community-acquired pneumonia), other than trial medication, up to 28 days after randomisation. Secondary outcomes included severity and duration of parent/guardian-reported community-acquired pneumonia symptoms, drug-related adverse events (including thrush, skin rashes and diarrhoea), antimicrobial resistance and adherence to trial medication. Results: A total of 824 children were recruited from 29 hospitals. Ten participants received no trial medication and were excluded. Participants [median age 2.5 (interquartile range 1.6-2.7) years; 52% male] were randomised to either 3 (n = 413) or 7 days (n = 401) of trial medication at either lower (n = 410) or higher (n = 404) doses. There were 51 (12.5%) and 49 (12.5%) primary end points in the 3- and 7-day arms, respectively (difference 0.1%, 90% confidence interval -3.8% to 3.9%) and 51 (12.6%) and 49 (12.4%) primary end points in the low- and high-dose arms, respectively (difference 0.2%, 90% confidence interval -3.7% to 4.0%), both demonstrating non-inferiority. Resolution of cough was faster in the 7-day arm than in the 3-day arm for cough (10 days vs. 12 days) (p = 0.040), with no difference in time to resolution of other symptoms. The type and frequency of adverse events and rate of colonisation by penicillin-non-susceptible pneumococci were comparable between arms. Limitations: End-of-treatment swabs were not taken, and 28-day swabs were collected in only 53% of children. We focused on phenotypic penicillin resistance testing in pneumococci in the nasopharynx, which does not describe the global impact on the microflora. Although 21% of children did not attend the final 28-day visit, we obtained data from general practitioners for the primary end point on all but 3% of children. Conclusions: Antibiotic retreatment, adverse events and nasopharyngeal colonisation by penicillin-nonsusceptible pneumococci were similar with the higher and lower amoxicillin doses and the 3- and 7-day treatments. Time to resolution of cough and sleep disturbance was slightly longer in children taking 3 days’ amoxicillin, but time to resolution of all other symptoms was similar in both arms. Future work: Antimicrobial resistance genotypic studies are ongoing, including whole-genome sequencing and shotgun metagenomics, to fully characterise the effect of amoxicillin dose and duration on antimicrobial resistance. The analysis of a randomised substudy comparing parental electronic and paper diary entry is also ongoing. Trial registration: Current Controlled Trials ISRCTN76888927, EudraCT 2016-000809-36 and CTA 00316/0246/001-0006.

• Journal Article Type: Article
• Acceptance Date: Nov 1, 2021
• Publication Date: 2021-11
• Deposit Date: Jan 6, 2022
• Publicly Available Date: Jan 12, 2022
• Journal: Health Technology Assessment
• Print ISSN: 1366-5278
• Electronic ISSN: 2046-4924
• Publisher: NIHR Journals Library
• Peer Reviewed: Peer Reviewed
• Volume: 25
• Issue: 60
• Pages: 1-72
• DOI: https://doi.org/10.3310/hta25600
• Keywords: Health Policy
• Public URL: https://uwe-repository.worktribe.com/output/8509504
• Additional Information: Free to read: This content has been made freely available to all.; Contractual start date: 3-2016; Editorial review begun: 10-2020; Accepted for publication: 6-2021