Impact of oral step-down to amoxicillin or co-amoxiclav and of duration of antibiotic therapy on effectiveness, safety and selection of antibiotic resistance in severe childhood community-acquired pneumonia (CAP): a randomised controlled trial
Paediatric community-acquired pneumonia
Open-label parallel-group 2 x 5 factorial randomised trial assessing 2 different oral step-down antibiotics (amoxicillin and co-amoxiclav (amoxicillin:clavulanate 7:1)) given after intravenous antibiotics for a total of 5 different durations (factorial design) with an additional continued intravenous control group, using a novel design to optimise duration of treatment (main trial, PediCAP-A) Plus a parallel Phase II pharmacokinetic (PK) trial comparing two additional different ratios for one of the oral step-down options, co-amoxiclav (14:1 and 4:1) (PediCAP-B), to enable the PK of all three ratios to be compared across the main trial (PediCAP-A) and the PK trial (PediCAP-B) All children will initiate or have already initiated treatment with WHO-recommended intravenous antibiotics. In the main trial (PediCAP-A), children who have received at most 24 hours of intravenous antibiotics will be randomised to step-down from intravenous antibiotics when they are clinically stable and able to take oral medication to either oral amoxicillin or oral co-amoxiclav (7:1 amoxicillin:clavulanate) (1:1), both as dispersible tablets for a total duration of 4, 5, 6, 7 or 8 days antibiotics (1:1:1:1:1) (from start of intravenous antibiotics) (total 10 groups), or to remain on intravenous antibiotics for a total of 5 days following current WHO recommendation (additional eleventh group of the same size as each duration/drug group). In the parallel Phase II PK trial (PediCAP-B), children who have received at most 24 hours of intravenous antibiotics will be randomised to step-down from intravenous antibiotics when they are clinically stable and able to take oral medication to either oral co-amoxiclav 4:1 or 14:1 (1:1) for a total duration of 6 days antibiotics (from start of intravenous antibiotics) (two groups). All children will receive at least 24 hours of intravenous antibiotics before stepping down to oral medication.
1. Aged 2 months to 6 years inclusive 2. Weighing >= 3 kg and <30 kg 3. Admitted to hospital with severe pneumonia judged to require at least 24h of intravenous antibiotics by the treating physician 4. Difficulty breathing (with or without cough reported by parent/carer) PLUS one or more of 4.1. Central cyanosis or hypoxaemia (room air pulse oximetry <90%) 4.2. Any sign of severe respiratory distress (e.g. severe chest indrawing, grunting, nasal flaring, head nodding) 4.3. Signs of pneumonia (fast breathing (defined as respiratory rate ≥50 breaths per minute at age 2-11 months and ≥40 breaths per minute at age 1 years or older) or chest indrawing) PLUS a general danger sign (inability to breastfeed or drink, lethargy or reduced level of consciousness, convulsions) occurring at any time from admission up to randomisation. 5. About to initiate or already initiated intravenous benzylpenicillin plus gentamicin, ampicillin plus gentamicin, benzylpenicillin or ampicillin alone, ceftriaxone alone or cefotaxime alone 6. Received at most 24h of these intravenous antibiotics at the point of randomisation (that is, first dose of any intravenous antibiotics must have been administered no more than 24h previously at randomisation) 7. Parent/carer willing to accept and adhere to all possible randomised allocations for their child, including 5 days of intravenous antibiotics, and signed written informed consent available from parent/carer 8. Available for follow-up for the entire study period; specifically, parent/carer willing to return with their child to clinic at 4 weeks, and be contacted at minimum by telephone at weeks 1, 2 and 3 For children enrolled in PK (Section 10.1) or microbiology (Section 10.2) substudies, additional inclusion criteria are: 9. If undergoing additional PK sampling: willing to provide samples and potentially to stay in hospital for up to an additional 12h (separate consent will be obtained for PK sampling which may be refused and the child still joi
1. Point-of-care semi-quantitative C-reactive protein (CRP) test < 10 mg/l at screening (very unlikely to represent severe pneumonia requiring antibiotics) 2. Likely nosocomial pneumonia (onset >48h post-admission) 3. Admitted to hospital overnight in the last 28 days (possibility of nosocomially-acquired pneumonia) 4. Known or anticipated need for invasive ventilation or admission to intensive care 5. Clinician considers this episode to be predominantly due to reactive airways disease (e.g. asthma) (wheeze responsive to bronchodilators, see Manual of Operations (MOP) for more details) 6. Clinician considers this episode to be due to viral bronchiolitis alone in a child under 1 year 7. Documented penicillin allergy or contra-indications to penicillin/amoxicillin/co-amoxiclav 8. Anticipated need for systemic treatment with an antibiotic other than trial regimens during hospital admission or in the following 28 days (e.g. for Pneumocystis jiroveci) 9. On long-term antibiotics for prophylaxis or treatment (e.g. for tuberculosis treatment or cotrimoxazole prophylaxis for HIV infection) 10. Previously enrolled in PediCAP