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Effect of Amoxicillin Dose and Treatment Duration on the Need for Antibiotic Re-treatment in Children With Community-Acquired Pneumonia

Julia BielickiPediatric Infectious Diseases Research Group, Medical Research Council Clinical Trial Unit at University College London, Institute for Infection and Immunity, St George’s University of London, London, United KingdomWolfgang StöhrMedical Research Council Clinical Trials Unit at University College London, London, United KingdomSam BarrattMedical Research Council Clinical Trials Unit at University College London, London, United KingdomDavid DunnMedical Research Council Clinical Trials Unit at University College London, London, United KingdomNishdha NaufalMedical Research Council Clinical Trials Unit at University College London, London, United KingdomDamian RolandPediatric Emergency Medicine Leicester Academic (PEMLA) Group, Emergency Department, Leicester, United KingdomKate SturgeonMedical Research Council Clinical Trials Unit at University College London, London, United KingdomAdam FinnBristol Children’s Vaccine Centre, Schools of Population Sciences and Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomJuan Pablo Rodríguez-RuizLaboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, BelgiumSurbhi Malhotra‐KumarLaboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, BelgiumColin PowellDivision of Population Medicine, Cardiff University School of Medicine, Cardiff, United KingdomSaul N. FaustFaculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, United KingdomAnastasia AlcockPediatric Emergency Medicine, Evelina Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, United KingdomDani HallPediatric Emergency Medicine, Children’s Health Ireland at Crumlin, IrelandGisela RobinsonPediatric Emergency Medicine, University Hospitals of Derby and Burton NHS Foundation Trust, Derby, United KingdomDaniel B. HawcuttInstitute of Translational Medicine, University of Liverpool, Liverpool, United KingdomMark D LyttleEmergency Department, Bristol Royal Hospital for Children, Bristol, United KingdomDiana M. GibbMedical Research Council Clinical Trials Unit at University College London, London, United KingdomMike SharlandPediatric Infectious Diseases Research Group, Medical Research Council Clinical Trial Unit at University College London, Institute for Infection and Immunity, St George’s University of London, London, United KingdomPERUKI, GAPRUKI, and the CAP-IT Trial GroupElizabeth MolyneuxChristopher ButlerAlan R SmythCatherine PrichardTim PetoSimon CousensStuart LoganAlasdair BamfordAnna TurkovaAnna L. GoodmanFelicity FitzgeraldPaul LittleJulie V. RobothamMandy WanNigel KleinLouise RogersElia VitaleMatthew RotheramRachel WrightElizabeth LeeUdeme OhiaStuart HartshornDeepthi JyothishJuliet HopkinsJames G. RossPoonam PatelHannah FletcherKribashnie NundlallJamie CarungcongRhian BullNabila BurneyPatricia CostaStefania VergnanoBeth WaltonAlice C. SmithMichelle RossLucie AplinSarah SheedyGurnie KaurJeffrey R. MorganJennifer MullerGail MarshallG NyamugunduruJohn FurnessDawn EggingtonSusannah J. HoltJohn GibbsCaroline BurchettCaroline LonsdaleSarah De-BegerRonny CheungAlyce B SheedyMohammad AhmadZoe StockwellSarah GiwaArshid MuradKatherine JermanJoanna GreenChris BirdTanya BaronShelley SegalSally BeerMaría José GarcíaDom GeorgiouKirsten BeadonJosé Luis MartínezFleur CantleHannah EastmanPaul RiozziHannah CottonNiall MullenRhona McCronePaul CorriganGemma SaltLouise FairlieAndrew M. SmithLizzie StarkeyMelanie HaymanSéan O’RiordanAlice Downes

2021en

ABI

Annotatsiya

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.

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DOI: 10.1001/jama.2021.17843

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