Amoxicillin duration and dose for community-acquired pneumonia in children: the CAP-IT factorial non-inferiority RCT
Sam Barratt1, Julia A Bielicki2, David Dunn1
1MRC Clinical Trials Unit, University College London, London, UK.
Insights
This study found that 3-day and 7-day amoxicillin treatments, at both lower and higher doses, are equally effective for childhood community-acquired pneumonia. Shorter treatment courses showed slightly longer cough and sleep disturbance resolution times but were otherwise comparable.
Area of Science:
- Pediatric infectious diseases
- Antibiotic stewardship
- Clinical pharmacology
Background:
- Limited data exists on optimal amoxicillin dosing and duration for pediatric community-acquired pneumonia (CAP).
- Determining effective treatment regimens is crucial for managing CAP and preventing antimicrobial resistance.
Purpose of the Study:
- To compare the efficacy and safety of 3-day versus 7-day amoxicillin treatment for pediatric CAP.
- To evaluate the impact of lower (35-50 mg/kg/day) versus higher (70-90 mg/kg/day) amoxicillin doses on treatment outcomes and antimicrobial resistance.
- To assess the non-inferiority of shorter/lower-dose regimens compared to longer/higher-dose regimens.
Main Methods:
- A multicenter, randomized, double-blind, 2x2 factorial non-inferiority trial was conducted in UK and Ireland secondary care settings.
- 824 children aged >6 months with uncomplicated CAP were randomized to receive amoxicillin for 3 or 7 days at either a lower or higher dose.
- The primary outcome was the need for additional systemic antibacterial treatment within 28 days; secondary outcomes included symptom resolution, adverse events, and antimicrobial resistance.
Main Results:
- Both 3-day and 7-day amoxicillin treatments were non-inferior to each other, as were the lower and higher doses, regarding the need for additional antibiotic treatment (12.5% vs. 12.5% and 12.6% vs. 12.4%, respectively).
- Resolution of cough was slightly faster with 7-day treatment (10 days) compared to 3-day treatment (12 days) (p=0.040), but other symptoms resolved similarly.
- Adverse events, including rash and diarrhea, and nasopharyngeal colonization by penicillin-non-susceptible pneumococci were comparable across all treatment arms.
Conclusions:
- Amoxicillin treatment for pediatric CAP is effective and safe for both 3-day and 7-day durations, and for both lower and higher doses.
- While 7-day treatment showed a marginal benefit in faster cough resolution, the overall clinical outcomes and safety profiles were similar, supporting shorter treatment durations.
- Further genotypic studies are underway to fully elucidate the impact on antimicrobial resistance.
Background:
Data are limited regarding the optimal dose and duration of amoxicillin treatment for community-acquired pneumonia in children.
Objectives:
To determine the efficacy, safety and impact on antimicrobial resistance of shorter (3-day) and longer (7-day) treatment with amoxicillin at both a lower and a higher dose at hospital discharge in children with uncomplicated community-acquired pneumonia.
Design:
A multicentre randomised double-blind 2 × 2 factorial non-inferiority trial in secondary care in the UK and Ireland.
Setting:
Paediatric emergency departments, paediatric assessment/observation units and inpatient wards.
Participants:
Children aged > 6 months, weighing 6-24 kg, with a clinical diagnosis of community-acquired pneumonia, in whom treatment with amoxicillin as the sole antibiotic was planned on discharge.
Interventions:
Oral amoxicillin syrup at a dose of 35-50 mg/kg/day compared with a dose of 70-90 mg/kg/day, and 3 compared with 7 days' duration. Children were randomised simultaneously to each of the two factorial arms in a 1 : 1 ratio.
Main Outcome Measures:
The primary outcome was clinically indicated systemic antibacterial treatment prescribed for respiratory tract infection (including community-acquired pneumonia), other than trial medication, up to 28 days after randomisation. Secondary outcomes included severity and duration of parent/guardian-reported community-acquired pneumonia symptoms, drug-related adverse events (including thrush, skin rashes and diarrhoea), antimicrobial resistance and adherence to trial medication.
Results:
A total of 824 children were recruited from 29 hospitals. Ten participants received no trial medication and were excluded. Participants [median age 2.5 (interquartile range 1.6-2.7) years; 52% male] were randomised to either 3 (n = 413) or 7 days (n = 401) of trial medication at either lower (n = 410) or higher (n = 404) doses. There were 51 (12.5%) and 49 (12.5%) primary end points in the 3- and 7-day arms, respectively (difference 0.1%, 90% confidence interval -3.8% to 3.9%) and 51 (12.6%) and 49 (12.4%) primary end points in the low- and high-dose arms, respectively (difference 0.2%, 90% confidence interval -3.7% to 4.0%), both demonstrating non-inferiority. Resolution of cough was faster in the 7-day arm than in the 3-day arm for cough (10 days vs. 12 days) (p = 0.040), with no difference in time to resolution of other symptoms. The type and frequency of adverse events and rate of colonisation by penicillin-non-susceptible pneumococci were comparable between arms.
Limitations:
End-of-treatment swabs were not taken, and 28-day swabs were collected in only 53% of children. We focused on phenotypic penicillin resistance testing in pneumococci in the nasopharynx, which does not describe the global impact on the microflora. Although 21% of children did not attend the final 28-day visit, we obtained data from general practitioners for the primary end point on all but 3% of children.
Conclusions:
Antibiotic retreatment, adverse events and nasopharyngeal colonisation by penicillin-non-susceptible pneumococci were similar with the higher and lower amoxicillin doses and the 3- and 7-day treatments. Time to resolution of cough and sleep disturbance was slightly longer in children taking 3 days' amoxicillin, but time to resolution of all other symptoms was similar in both arms.
Future Work:
Antimicrobial resistance genotypic studies are ongoing, including whole-genome sequencing and shotgun metagenomics, to fully characterise the effect of amoxicillin dose and duration on antimicrobial resistance. The analysis of a randomised substudy comparing parental electronic and paper diary entry is also ongoing.
Trial Registration:
Current Controlled Trials ISRCTN76888927, EudraCT 2016-000809-36 and CTA 00316/0246/001-0006.
Funding:
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 60. See the NIHR Journals Library website for further project information.
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