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

Bielicki, Julia A.; Stöhr, Wolfgang; Barratt, Sam; Dunn, David; Naufal, Nishdha; Roland, Damian; Sturgeon, Kate; Finn, Adam; Rodriguez-Ruiz, Juan Pablo; Malhotra-Kumar, Surbhi; Powell, Colin; Faust, Saul N.; Alcock, Anastasia E.; Hall, Dani; Robinson, Gisela; Hawcutt, Daniel B.; Lyttle, Mark D.; Gibb, Diana M.; Sharland, Mike; Molyneux, Elizabeth; Butler, Chris C; Smyth, Alan; Prichard, Catherine; Peto, Tim E.A; Cousens, Simon; Logan, Stuart; Bamford, Alasdair; Turkova, Anna; Goodman, Anna L; Fitzgerald, Felicity; Little, Paul S; Robotham, Julie; Wan, Mandy; Klein, Nigel; Rogers, Louise; Vitale, Elia; Rotheram, Matthew; Wright, Rachel; Lee, Elizabeth; Ohia, Udeme; Hartshorn, Stuart; Jyothish, Deepthi; Hopkins, Juliet; Ross, James G; Patel, Poonam; Fletcher, Hannah; Nundlall, Kribashnie; Carungcong, Jamie; Bull, Rhian; Burney, Nabila; Correia Da Costa, Patricia; Vergnano, Stefania; Walton, Beth; Smith, Alice; Ross, Michelle; Aplin, Lucie; Sheedy, Sarah; Kaur, Gurnie; Morgan, Jeff; Mulle...

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.

• Journal Article Type: Article
• Acceptance Date: Oct 18, 2021
• Online Publication Date: Nov 2, 2021
• Publication Date: Nov 2, 2021
• Deposit Date: Dec 31, 2021
• Publicly Available Date: May 3, 2022
• Journal: JAMA - Journal of the American Medical Association
• Print ISSN: 0098-7484
• Electronic ISSN: 1538-3598
• Publisher: American Medical Association (AMA)
• Peer Reviewed: Peer Reviewed
• Volume: 326
• Issue: 17
• Pages: 1713-1724
• DOI: https://doi.org/10.1001/jama.2021.17843
• Keywords: General Medicine
• Public URL: https://uwe-repository.worktribe.com/output/8509342