Effect of Amoxicillin Dose and Treatment Duration on the Need for Antibiotic Re-treatment in Children With Community-Acquired Pneumonia
Authors: Julia A. Bielicki, Wolfgang Stöhr, Sam Barratt, David Dunn, Nishdha Naufal, Damian Roland, Kate Sturgeon, Adam Finn, Juan Pablo Rodriguez-Ruiz, Surbhi Malhotra-Kumar, Colin Powell, Saul N. Faust, Anastasia E. Alcock, Dani Hall, Gisela Robinson, Daniel B. Hawcutt, Mark D. Lyttle, Diana M. Gibb, Mike Sharland, Elizabeth Molyneux, Chris C Butler, Alan Smyth, Catherine Prichard, Tim E.A Peto, Simon Cousens, Stuart Logan, Alasdair Bamford, Anna Turkova, Anna L Goodman, Felicity Fitzgerald, Paul S Little, Julie Robotham, Mandy Wan, Nigel Klein, Louise Rogers, Elia Vitale, Matthew Rotheram, Rachel Wright, Elizabeth Lee, Udeme Ohia, Stuart Hartshorn, Deepthi Jyothish, Juliet Hopkins, James G Ross, Poonam Patel, Hannah Fletcher, Kribashnie Nundlall, Jamie Carungcong, Rhian Bull, Nabila Burney, Patricia Correia Da Costa, Stefania Vergnano, Beth Walton, Alice Smith, Michelle Ross, Lucie Aplin, Sarah Sheedy, Gurnie Kaur, Jeff Morgan, Jennifer Muller, Gail Marshall, Godfrey Nyamugunduru, John C Furness, Dawn Eggington, Susannah J Holt, John Gibbs, Caroline Burchett, Caroline Lonsdale, Sarah De-Beger, Ronny Cheung, Alyce B Sheedy, Mohammad Ahmad, Zoe Stockwell, Sarah Giwa, Arshid Murad, Katherine Jerman, Joanna Green, Chris Bird, Tanya K Z Baron, Shelley Segal, Sally Beer, Maria Jose Garcia Garcia, Dom Georgiou, Kirsten Beadon, Jose Martinez, Fleur Cantle, Hannah Eastman, Paul Riozzi, Hannah Cotton, Niall Mullen, Rhona McCrone, Paul Corrigan, Gemma Salt, Louise Fairlie, Andrew Smith, Lizzie Starkey, Mel Hayman, Sean O'Riordan, Alice Downes, Majorie Allen, Louise Turner, Donna Ellis, Srini Bandi, Rekha Patel, Chris Gough, Megan McAulay, Louise Conner, Sharryn Gardner, Zena Haslam, Moira Morrison, Michael J Barrett, Madeleine Niermeyer, Ellen Barry, Emily K Walton, Akshat Kapur, Vivien Richmond, Steven J Foster, RM Bland, Ashleigh Neil, Barry Milligan, Helen Bannister, Ben Bloom, Ami Parikh, Imogen Skene, Helen Power, Olivia Boulton, Raine Astin-Chamberlain, David Smith, Jonathon Walters, Daniel Martin, Lyrics Noba, Katherine Potier, Fiona Borland, Jill Wilson, Zainab Suleman, Judith Gilchrist, Noreen West, Jayne Evans, Juliet Morecombe, Paul T Heath, Yasser Iqbal, Malte Kohns Vasconcelos, Elena Stefanova, Claire Womack, Ian K Maconochie, Suzanne Laing, Rikke Jorgensen, Maggie Nyirenda, Sophie Keers, Samia Pilgrim, Emma Gardiner, Katrina Cathie, Jane Bayreuther, Ruth Ensom, Emily K Cornish, Elizabeth-Jayne L Herrieven, William Townend, Leanne Sherris, Paul Williams
Journal: JAMA (2021)

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.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).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).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.