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

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.

Figure 1.. Patient Recruitment, Randomization, and Follow-up in the CAP-IT Trial

^aWard criteria indicates children recruited from inhospital pediatric wards or units with an inpatient stay longer than 48 hours and treated with non–β-lactam antibiotics as inpatients. ^bFollow-up included time up to withdrawal.

Figure 2.. Kaplan-Meier Curves Indicating Time to Experiencing the Primary End Point

The primary end point is clinically indicated treatment with systemic antibiotics (other than trial medication) for a respiratory tract infection within 4 weeks of randomization. Median observation time was not reported since more than 75% of participants were observed for the entire 28-day period. Lower dose indicates 35 to 50 mg/kg/d; higher dose, 70 to 90 mg/kg/d; shorter duration, 3-day course; longer duration, 7-day course. A, No. (%) with primary end point by day 28: lower + shorter, 25 (12.1 [90% CI, 8.9-16.4]); lower + longer, 26 (13.1 [90% CI, 9.7-17.7]); higher + shorter, 26 (13.1 [90% CI, 9.6-17.6]); and higher + longer, 23 (11.8 [90% CI, 8.5-16.2]). B, No. (%) with primary end point by day 28: lower, 51 (12.6 [90% CI, 10.1-15.6]); higher, 49 (12.4 [90% CI, 10.0-15.5]). Difference, 0.2% (upper bound of 1-sided 95% CI, 4.0%). C, No. (%) with primary end point by day 28: shorter, 51 (12.5 [90% CI, 10.1-15.5]); longer, 49 (12.5 [90% CI, 10.0-15.5]). Difference, 0.1% (upper bound of 1-sided 95% CI, 3.9%).

Figure 3.. Noninferiority Sensitivity and Subgroup Analyses for the Primary End Point for the Amoxicillin Dose and Dose Duration Randomizations

The primary analysis and 3 prespecified analyses are shown for both randomizations including all systemic antibacterial re-treatments, only re-treatments for community-acquired pneumonia (CAP) or chest infection, and by severe CAP subgroups. In addition, a post hoc subgroup analysis by prior inpatient antibiotic exposure is shown. A sensitivity analysis including only re-treatments after day 3 is shown for the duration randomization. One-sided 95% CIs are shown with the lower bound extending to −100%. The blue dashed vertical line at 8% indicates the noninferiority margin.