Effect of amoxicillin dose and treatment duration on the need for antibiotic re-treatment in children with community-acquired pneumonia

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, Muller, Jennifer, Marshall, Gail, Nyamugunduru, Godfrey, Furness, John C, Eggington, Dawn, Holt, Susannah J, Gibbs, John, Burchett, Caroline, Lonsdale, Caroline, De-Beger, Sarah, Cheung, Ronny, Sheedy, Alyce B, Ahmad, Mohammad, Stockwell, Zoe, Giwa, Sarah, Murad, Arshid, Jerman, Katherine, Green, Joanna, Bird, Chris, Baron, Tanya K Z, Segal, Shelley, Beer, Sally, Garcia Garcia, Maria Jose, Georgiou, Dom, Beadon, Kirsten, Martinez, Jose, Cantle, Fleur, Eastman, Hannah, Riozzi, Paul, Cotton, Hannah, Mullen, Niall, McCrone, Rhona, Corrigan, Paul, Salt, Gemma, Fairlie, Louise, Smith, Andrew, Starkey, Lizzie, Hayman, Mel, O'Riordan, Sean, Downes, Alice, Allen, Majorie, Turner, Louise, Ellis, Donna, Bandi, Srini, Patel, Rekha, Gough, Chris, McAulay, Megan, Conner, Louise, Gardner, Sharryn, Haslam, Zena, Morrison, Moira, Barrett, Michael J, Niermeyer, Madeleine, Barry, Ellen, Walton, Emily K, Kapur, Akshat, Richmond, Vivien, Foster, Steven J, Bland, RM, Neil, Ashleigh, Milligan, Barry, Bannister, Helen, Bloom, Ben, Parikh, Ami, Skene, Imogen, Power, Helen, Boulton, Olivia, Astin-Chamberlain, Raine, Smith, David, Walters, Jonathon, Martin, Daniel, Noba, Lyrics, Potier, Katherine, Borland, Fiona, Wilson, Jill, Suleman, Zainab, Gilchrist, Judith, West, Noreen, Evans, Jayne, Morecombe, Juliet, Heath, Paul T, Iqbal, Yasser, Kohns Vasconcelos, Malte, Stefanova, Elena, Womack, Claire, Maconochie, Ian K, Laing, Suzanne, Jorgensen, Rikke, Nyirenda, Maggie, Keers, Sophie, Pilgrim, Samia, Gardiner, Emma, Cathie, Katrina, Bayreuther, Jane, Ensom, Ruth, Cornish, Emily K, Herrieven, Elizabeth-Jayne L, Townend, William, Sherris, Leanne and Williams, Paul 2021. Effect of amoxicillin dose and treatment duration on the need for antibiotic re-treatment in children with community-acquired pneumonia. Journal of the American Medical Association 326 (17) , pp. 1713-1724. 10.1001/jama.2021.17843

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Medical Association
ISSN:	0098-7484
Date of Acceptance:	22 September 2021
Last Modified:	06 Jun 2022 14:15
URI:	https://orca.cardiff.ac.uk/id/eprint/150094

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