Bielicki JA, Stöhr W, Barratt S, et al. 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. JAMA. 2021;326(17):1713–1724. doi:10.1001/jama.2021.17843
Why is this study needed?
Children under five commonly receive antibiotics for respiratory tract infections, yet our main diagnostic tools (the findings on chest x-rays and inflammatory markers) are poor at discriminating between bacterial and viral infection. Striking an appropriate balance between minimising drug exposure whilst maintaining effective treatment is key for antimicrobial stewardship.
Who were the patients?
Over a 26 month period, from February 2017 to April 2019, children were assessed for trial eligibility across 28 hospitals in the UK and one in Ireland. All patients were discharged from Emergency Departments, Observation Units or inpatient wards within 48 hours of admission.
Children were included if they were aged >6 months, weighed 6-24kg and were clinically diagnosed with community-acquired pneumonia on discharge.
- Parent/guardian reported cough within 96 hours
- Measured temperature >38ºC or parent/guardian reported fever within 48 hours
- Signs of laboured/difficult breathing or focal chest signs (dullness to percussion, bronchial breathing, reduced breath sounds, crackles/crepitations)
There was no requirement for radiological or other diagnostics tests for inclusion in the study.
Children were excluded if they had recent antibiotic treatment (beta-lactam antibiotics for more than 48 hours or any non-beta lactam treatment), severe underlying chronic disease, contraindications to amoxicillin, complicated pneumonia or bacterial wheeze without focal signs. 2642 patients were assessed for eligibility during the trial period and 824 were enrolled. 1818 were excluded due to being discharged on a different antibiotic, failure of ward criteria (admitted >48h or treated with non-beta lactam antibiotics as inpatients), language barrier or parent preference. Ten children included did not take the trial medicine, so the total number involved in the study analysis was 814; 52% were male and 48% female. The mean age was 2.5 years at presentation.
What was the intervention?
There were two interventions in this study: dose of amoxicillin (35-50mg/kg/day or 70-90mg/kg/day) and duration of treatment from discharge (3 or 7 days). In both treatment groups, the amoxicillin was divided into BD doses, (which has been approved by international guidance), rather than three times daily dosing that is commonly used in UK practice.
What were the outcomes measured?
The primary outcome of this study was whether treatment with a further course of antibiotics was required within 28 days of randomisation. The secondary outcomes were severity and duration of symptoms, side-effects, antibiotic resistance in colonising S. pneumoniae and adherence to treatment.
What were the results?
First, let’s compare the results for the primary outcome:
Of the patients randomised to the lower dose and shorter duration 25/208 (12.1%) required re-treatment with antibiotics for chest infection within 28 days. For the group randomised to lower dose and longer course, 26/202 (13.1%) met the primary outcome.
Of the patients randomised to the higher dose and shorter course 26/205 (13.1%) required re-treatment, For the patients randomised to the higher dose and longer duration 23/199 (11.8%).
These results were not statistically significant (p= 0.63), and demonstrated non-inferiority of the reduced dose and reduced duration of therapy.
Post-hoc analysis of children with severe CAP showed no statistically significant difference in outcome with reduced dose or duration of therapy.
Now, let’s consider the secondary outcomes:
Duration of cough was longer for the patients randomised to shorter treatment (12 days, compared to 10 for the longer treatment regime). Other clinical symptoms showed no difference between the treatment groups.
Adverse events reported included diarrhoea (44% of patients), skin rash (24%) and oral thrush (7%). Of these side effects, skin rash showed a statistically significant relationship to duration of use – it occurred in 22% of patients treated for 3 days, and 27% of patients treated for 7 days.
There was no statistically significant difference in colonisation with S. pneumoniae (42% of patients were colonised at baseline, and 30% on their final visit). No penicillin-resistant pneumococci were identified however, pneumococci that were non-susceptible to penicillin (reduced MIC) were detected in 46 children on baseline swabs and 21 children at the final visit (again this was not statistically significant). Children randomised to the 3-day treatment course were more likely (98%) to complete their full course of treatment than those randomised to the 7-day course (91%). This was statistically significant.
How good was the paper – CASP checklist?
Does the study address a clearly focussed issue?
Was the cohort recruited in an acceptable way?
Yes. Suitable patients were identified during their ED/hospital stay and recruited prospectively at the point of discharge.
Was the exposure accurately measured to minimise bias?
Participants were randomised into one of four study groups (low dose/short duration; low dose/long duration; high dose/short duration; high dose/long duration) at a 1:1 ratio.
Blinding was achieved by rebottling and repackaging two brands of amoxicillin suspension, available in 125mg/5ml and 250mg/5ml concentrations. The first brand was given for days 1-3 of treatment and the second (or an identical placebo) was given for days 4-7.
Was the outcome accurately measured to minimise bias?
Symptoms relating to primary and secondary outcomes were recorded using a diary (given to parents at the time of discharge) and communicated to the research team via scheduled telephone follow up. Contemporaneous recording improves accuracy and limits bias.
Have the authors identified all important confounding factors?
The authors identified several limitations to this study, which should be considered for practice.
Clinical criteria as outlined by the British Thoracic Society were used to define a diagnosis of CAP in this study (i.e. without specific biochemical or radiological tests). This is just the same as we do in our clinical practice, but realistically it means that a (possibly large) proportion of these children are likely to have been ill with a viral respiratory tract infection.
Re-treatment rates were relatively high in both the lower and higher dose groups (9.1% and 9.8%) despite antibiotic treatment, which raises a question about whether we should be re-thinking our diagnostic criteria and treatment options for lower respiratory tract infections.
The results do not take into consideration the total duration of antibiotic treatment for patients discharged from inpatient wards, and the study was not powered to assess non-inferiority of shorter course, lower dose antibiotics in this group.
Was the follow up of the subjects complete and accurate?
59% of subjects had face to face follow up at 28 days, with a further 19% receiving telephone follow up. GP records of subsequent prescriptions for antibiotics enabled 97% of participants to be followed up at 28 days.
What were the results?
Treatment with 3 days of amoxicillin at 30-50mg/kg/day is non-inferior to 7 days of higher dose treatment for children over 6 months discharged from ED or short inpatient stay (48 hours).
Do you believe the results?
Can the results be applied to a local population?
Yes, on the basis that there is a relatively low prevalence of resistant S. pneumoniae among the UK population.
Do the results fit with the other evidence available?
Trials comparing the duration of antibiotic prescribing in children with CAP are relatively sparse, but the results of this trial echo those found in the Canadian SAFER trial (comparing 5 days with 10 days of amoxicillin for CAP). The authors of this trial cite CAP-IT as the first trial comparing both antibiotic dose and duration for childhood CAP.
What did the authors conclude, and what can we take away from this study?
For children diagnosed with CAP that are discharged from ED, observation units or after a short (<48h) inpatient stay treatment with a three-day course of amoxicillin at a dose of 30-50mg/kg/day is non-inferior to treatment for seven days with higher doses.
Author’s Comment – Dr Julia Bielicki, MPH PhD on behalf of the CAP-IT study
Thanks to Natalie Clarke and Tessa Davis for their excellent summary.
CAP-IT is the largest hospital-based trial of oral antibiotic dose and duration for childhood community acquired pneumonia (CAP) to date. It provides randomised controlled trial evidence in the hospital setting, and the results suggests we should consider changing how we manage children with a clinical diagnosis of CAP.
Most importantly, a shorter course (three days) of amoxicillin treatment is as good as longer treatment courses, for the majority of children being discharged from hospital with CAP. This is considerably shorter than the 5-7 day treatment courses currently advised in most guidelines, with 3 days recommended by WHO only for fast-breathing pneumonia. By randomising children to receive doses from the lower or higher end of internationally recommended ranges, findings from the CAP-IT trial also challenge practice in regards to amoxicillin doses. In contrast to the accepted paradigm that higher doses are better for the treatment of severe infections, we did not find lower doses to be disadvantageous for children in CAP-IT in terms of clinical outcome, side effects or emergence of resistance. In all participant groups enrolled in the CAP-IT trial, children received treatment twice a day, as opposed to three times a day. Retreatment rate in all groups was the same as seen in other sources within the UK, suggesting that a negative impact of twice daily dosing as opposed to thrice daily is highly unlikely (this was not formally investigated).
It is unclear how important it is to families that children experience cough for a couple more days with a three day course of amoxicillin. Pragmatically, this is likely to be weighed against compliance (recognising the challenges of giving medicine to children for more days), and the immediate and potential longer-term effects of unnecessary antibiotic exposure, including impact on the microbiome.
In summary, in settings with low pneumococcal resistance, findings from the CAP-IT trial support simplified dosing of amoxicillin as either liquid or dispersible solid formulations, resulting in six doses per treatment course, provided daily doses are within the range used in the CAP-IT trial.