Title: Efficacy, safety and impact on antimicrobial resistance of duration and dose of amoxicillin treatment for young children with Community-Acquired Pneumonia (CAP): a randomised controlled trial
Funder: Department of Health and Social Care

Abstract: DESIGN: Randomised placebo-controlled factorial non-inferiority trial of amoxicillin dose and duration in paediatric CAP. PRIOR LITERATURE: Cochrane/Medline identifies no placebo-controlled randomised trials of amoxicillin dose and duration for childhood CAP and development of antimicrobial resistance in the well-resourced setting. SETTING: Paediatric Emergency Departments (PEDs) and paediatric wards at UK NHS hospitals and one hospital in the Republic of Ireland. TARGET POPULATION: Previously healthy children aged greater than 6 months and weighing less than 24kg with uncomplicated CAP (cough+fever+ signs of breathing difficulty) in whom the decision has been made to treat with antibiotics. Exclusion: Documented penicillin allergy, patient already on antibiotics, bilateral wheezing without focal chest signs, complicated CAP: requirement for invasive ventilation/ non-invasive positive pressure ventilation, accompanying shock (>20ml/kg fluid resuscitation), hypotension, GCS<15, complications involving pleural space, pulmonary abscess. HEALTH TECHNOLOGY: Concurrent randomisation to: (1) 3 days of amoxicillin followed by placebo for 4 days or 7 days of amoxicillin; AND to (2) amoxicillin 35-50mg/kg/d or 70-90mg/kg/d in 2 doses (blinded). Randomisation will be in PEDs for children managed there (PED group) and at the time of switch to oral treatment following no more than 48 hours of oral or intravenous beta-lactam in-hospital treatment (WARD group). BASELINE MEASURES: Structured history/examination including X-ray and blood tests as indicated clinically, nasopharyngeal (NP) swab, stool sample in a subset of children. OUTCOME MEASUREMENTS: Treatment failure rate by day 29 (any clinically indicated systemic antibacterial treatment prescribed for respiratory tract infection (including CAP) other than trial medication up to and at week 4 final follow-up). Main secondary outcome: phenotypic resistance to penicillin at week 4 measured in S. pneumoniae isolates colonising the nasopharynx. Other secondary outcomes: 1)severity and duration of parent/guardian-reported CAP symptoms, 2)specified clinical adverse events, including thrush, skin rashes and diarrhoea, , 3)adherence to trial drug. MICROBIOLOGY: Detection of S. pneumoniae in nasopharyngeal swabs will primarily use culture-based techniques; identification of changes in antibiotic resistance will use traditional techniques. . SAMPLE SIZE: To demonstrate non-inferiority for the primary outcome for both interventions, a minimum of 800 children will be recruited. Assumptions: 1)15% failure rate, 2)non-inferiority margin 8%, 3)1- sided 95% CI, 4)power = 90%, 5)15% loss to follow-up. DATA ANALYSIS: Analyses will be intention to treat and follow CONSORT. PED and WARD strata will be analysed jointly. Estimates of main primary and secondary effects (efficacy, resistance and toxicity) will be undertaken using multivariate logistic analyses. TIMETABLE: Recruitment started in February 2017, and is planned to finish in April 2019. EXPERTISE: The study team is a multidisciplinary research group bringing together expertise in clinical trials and epidemiology of paediatric bacterial infections and with the microbiology of antimicrobial resistance.

Lay abstract: Pneumonia (an infection of the lungs) is one of most common infections in young children worldwide. Because there are no good tests to clearly identify whether pneumonia is caused by bacteria in children, the decision to prescribe antibiotics has to be made based on clinical assessment. Therefore antibiotics are very commonly prescribed to children for possible pneumonia. We know that treatment with antibiotics can lead to changes in the bacteria carried by the person taking them, making the bacteria become more resistant to the effect of the antibiotics. These resistant bacteria can subsequently cause an infection in the treated children or spread to other persons in close contact. Infections caused by resistant bacteria are more difficult to treat. The amount of antibiotic (dose) and the number of days of treatment (duration) is likely to have an effect on the development of resistant bacteria in individual patients. Currently we do not know which antibiotic treatment duration and dose are optimal for treating childhood pneumonia. Also the relationship between dose, duration and the development of resistant bacteria in the nose and gut (two preferred places where bacteria live) is not understood. The CAP-IT trial will look at whether lower doses and shorter duration of antibiotic treatment with amoxicillin, the antibiotic most commonly used for pneumonia in children, are as good at treating pneumonia as higher doses and longer duration of treatment. Parents or carers of children will be asked to join the study if the child has pneumonia and will be treated in hospital or at home, as long as there are no signs of very severe pneumonia or other complications. Children seen in the emergency department who can go home can join the study immediately. Children in hospital often need a short period of intravenous treatment or observation; their carers would be invited to join the trial after up to 48 hours of inpatient therapy. The trial will be investigating: (1) whether 3 days is as good as 7 days and low dose is as good as high dose for treating pneumonia and (2) how do these different doses and duration affect the appearance of resistant bacteria. Lower dose and shorter treatment could reduce side effects and cause less resistance for the child. In order to treat the groups of children in the same way in the study, neither the doctors nor the families will know whether their child is receiving high or low dose amoxicillin. Similarly, while children receiving 7 days will have amoxicillin every day, those receiving 3 days will have 3 days of amoxicillin followed by 4 days of placebo (medicine with no active ingredients). Overall, 800 children will be included, randomised (by chance like tossing a coin) to either high or low dose and to either 3 or 7 days amoxicillin. Children in the trial will be closely followed for one month. The trial will compare how frequently children fail to get better or have to be treated again for pneumonia in the different groups of the trial. To look at the development of resistant bacteria, a nose swab will be collected before or shortly after starting treatment and again after treatment. Therefore the trial will be able to address whether shorter treatments and/or those using a specific dose lead to less resistant bacteria in the nose at the end of treatment. The results of the trial will inform how children in the UK and also in other countries should best be treated for pneumonia.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION