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

TY - JOUR

T1 - Effect of Amoxicillin Dose and Treatment Duration on the Need for Antibiotic Re-treatment in Children With Community-Acquired Pneumonia

T2 - The CAP-IT Randomized Clinical Trial

AU - Bielicki, Julia A

AU - Stöhr, Wolfgang

AU - Barratt, Sam

AU - Dunn, David

AU - Naufal, Nishdha

AU - Roland, Damian

AU - Sturgeon, Kate

AU - Finn, Adam

AU - Rodriguez-Ruiz, Juan Pablo

AU - Malhotra-Kumar, Surbhi

AU - Powell, Colin

AU - Faust, Saul N

AU - Alcock, Anastasia E

AU - Hall, Dani

AU - Robinson, Gisela

AU - Hawcutt, Daniel B

AU - Lyttle, Mark D

AU - Gibb, Diana M

AU - Sharland, Mike

AU - PERUKI

AU - GAPRUKI

AU - CAP-IT Trial Group

AU - Kohns Vasconcelos, Malte

PY - 2021/11/2

Y1 - 2021/11/2

N2 - 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.

AB - 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.

KW - Administration, Oral

KW - Amoxicillin/administration & dosage

KW - Anti-Bacterial Agents/administration & dosage

KW - Child, Preschool

KW - Community-Acquired Infections/drug therapy

KW - Drug Administration Schedule

KW - Duration of Therapy

KW - Female

KW - Humans

KW - Infant

KW - Male

KW - Patient Discharge

KW - Pneumonia/drug therapy

KW - Retreatment/statistics & numerical data

KW - Severity of Illness Index

U2 - 10.1001/jama.2021.17843

DO - 10.1001/jama.2021.17843

M3 - SCORING: Journal article

C2 - 34726708

VL - 326

SP - 1713

EP - 1724

JO - JAMA-J AM MED ASSOC

JF - JAMA-J AM MED ASSOC

SN - 0098-7484

IS - 17

ER -