Lower dose and shorter duration of amoxicillin treatment noninferior to higher dose and longer treatment in children with community-acquired pneumonia

1. Low-dose outpatient oral amoxicillin was noninferior to high-dose, and 3-day duration was noninferior to 7 days in children with community-acquired pneumonia, with regards to the need for later antibiotic retreatment.

2. However, disease severity, treatment setting, prior antibiotics, and acceptability of the noninferiority margin require further consideration when interpreting these findings.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Bacterial infections are implicated in approximately one-third of community-acquired pneumonia (CAP) cases among children younger than 5 years admitted to hospital. The lack of predictive diagnostic tests and criteria to rule out or confirm the need for antibiotics means that most children with clinical findings of CAP are prescribed antibiotics, where the optimal dose and duration of antibiotics are unclear. The CAP-IT trial evaluated whether lower dose and shorter duration of amoxicillin treatment were noninferior to higher dose and longer treatment course. The primary endpoint was the need for clinically indicated antibiotic re-initiation treatment for respiratory infection within 28 days after randomization, where the noninferiority margin was 8%. Secondary endpoints included severity and duration of 9 parent-reported CAP symptoms, 3 antibiotic-related adverse events, and phenotypic resistance in colonizing Streptococcus pneumoniae isolates. Among 814 children requiring oral amoxicillin for CAP at hospital discharge, antibiotic re-treatment within 28 days occurred in 12.6% vs 12.4% of those randomized to lower vs higher doses respectively, and in 12.5% vs 12.5% of those randomized to 3-day vs 7-day course, respectively, with both comparisons well below the prespecified 8% noninferiority margin. These results suggest that low-dose outpatient oral amoxicillin was noninferior to high dose, and 3-day duration was noninferior to 7 days in children with CAP on hospital discharge, with regards to the need for later antibiotic retreatment. However, disease severity, treatment setting, prior antibiotics, and acceptability of the noninferiority margin require further consideration when interpreting the findings. A limitation of this study was the exclusion of children with severe CAP, including those with underlying comorbidities who may benefit from higher dose and/or longer treatment duration, limiting the generalizability of the study findings in this patient population.

Click to read the study in JAMA

Relevant Reading: Community-acquired pneumonia requiring hospitalization among US children

In-Depth [randomized clinical trial]: This multicenter, randomized, 2 x 2 factorial noninferiority trial enrolled 814 children (median [IQR] age, 2.5 years [1.6-2.7]; 421 [52%] males) from 28 hospitals in the UK and 1 in Ireland between February 2017 and April 2019. Children were 6 months and older with CAP, treated with oral amoxicillin on hospital discharge. Participants were randomized to 4 treatment groups including lower dose (35-50mg/kg/d; n = 410) or higher dose (70-90mg/kg/d; n = 404) and shorter duration (3 days; n = 413) or a longer duration (7 days; n = 401). Overall, the primary outcome was available for 789 (97%) individuals, where the primary outcome occurred in 12.6% of lower-dose recipients vs 12.4% of higher-dose recipients (difference, 0.2% [1-sided 95%CI –∞ to 4.0%]), and in 12.5% with 3-day course vs 12.5% with 7-day course (difference, 0.1% [1-sided 95%CI –∞ to 3.9]). Both groups demonstrated noninferiority with no significant interaction between dose and duration (P = .63). For secondary outcomes, the only significant differences were observed in the 3-day vs 7-day treatment groups for cough duration (median 12 days vs 10 days; HR, 1.2 [95%CI, 1.0 to 1.4]; P = .04) and cough-disturbed sleep (median, 4 days vs 4 days; HR, 1.2 [95%CI, 1.0 to 1.4]; P = .03). In a subset of patients with severe CAP, the primary outcome occurred in 17.3% with lower dose vs 13.5% with higher dose (difference, 3.8% [1-sided 95%CI, –∞ to 10%]; P value for interaction = .18) and in 16.0% with 3-day course vs 14.8% with 7-day course (difference, 1.2% [1-sided 95%CI, –∞ to 7.4%]; P value for interaction = .73).

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