Title: Prophylactic antibiotics to prevent recurrent respiratory infections in high risk children
Funder: Department of Health (England)

Abstract: Proposed commissioning brief for advertisementResearch Question: What is the clinical effectiveness and current practice of prescribing prophylactic antibiotics for the prevention of recurrent lower respiratory infections in high risk children?1. Intervention: The use of prophylactic antibiotics to prevent recurrent lower respiratory infections.2. Patient group: Children and adolescents (2-16 years) with a neurological disorder causing a physical disability that puts them at high risk of recurrent lower respiratory infections (e.g. those with severe cerebral palsy or neuromuscular disease but not cystic fibrosis). To be defined by applicants.3. Setting: Primary care and out-patient secondary care.4. Control: Placebo or standard care.5. Study design: A systematic review of all the evidence (not just limited to RCT evidence) for antibiotic prophylaxis used for children with recurrent lower respiratory infections and a survey/database analysis of current practice. Results to be stratified by underlying condition causing high risk of respiratory infections.6. Important outcomes: 1) Systematic review: efficacy of prophylactic antibiotics; incidence of further respiratory infections; types of antibiotics prescribed; development of antibiotic resistance. 2) Survey and/or database analysis of current practice; patient groups most commonly prescribed to; types of antibiotics prescribed; doses.NHS decision problem to be addressed by this research:Recurrent chest infections are a common reason for children to be seen by their GP or a paediatrician. While most lower respiratory infections are mild and self-limiting some children such as those with cystic fibrosis immune deficiency disorders and neurological impairment suffer repeated chest infections with a significant impact on their quality of life. While antibiotics are often prescribed to treat such infections they are sometimes also given prophylactically to try to prevent further infections especially during the winter when the incidence of these infections increases.There has been much research done on the prophylactic use of antibiotics in children with cystic fibrosis however for children in the other high risk groups such as those with neurological disorders very little is known and there appears to be wide variation in clinical practice. Understanding the evidence base for the use of prophylactic antibiotics for recurrent chest infection and what current practice regimes are will help us determine if and where the need for further research may lie.Patient group• Acute respiratory infections are the commonest illnesses of childhood. The estimated incidence of lower respiratory tract infection is 30 per 1000 children per year in the UK (patient.co.uk).• Respiratory problems in children account for 20-35% of acute paediatric admissions and are the fifth most common cause of death in children between the age of 1 and 14 in the UK (patient.couk).• Most respiratory infections are mild self-limiting and caused by viruses. However some children are prone to recurrent respiratory infections that can severely impact their quality of life [1].• Children with neurological disorders causing a physical disability for example in children with cerebral palsy and neuromuscular disease are at greater risk of recurrent lower respiratory infections and respiratory problems play a major role in the quality of life and life expectancy of these children [2].• A number of factors contribute to respiratory difficulties and in many severely handicapped children several of these factors coexist and may interact with each other. These factors include [2]:o Recurrent aspiration: as a result of poor swallowing due to muscle weakness and gastro-oesophageal reflux. Recurrent aspiration results in acute lower respiratory infections and in chronic lower airway inflammation and damage. The latter may go unnoticed for some time but ultimately may cause both bronchiectasis and lung damage.o Poor cough and airway clearance: again due to poor muscle coordination and strength of expiratory abdominal and intercostal muscles as well as a diminished sensitivity to cough perhaps as a result of desensitisation of airway irritant receptors from chronic aspiration.o Respiratory muscle weakness.o Kyphoscoliosis: this restricts lung function which increases the work of breathing and predisposes to respiratory failure.o Sleep apnoea.o Asthma and bronchial hyperreactivity.o Poor nutrition.NICE and other guidanceThere is no NICE guidance on the use of prophylactic antibiotics for recurrent respiratory tract infections in children.CG 69 (2008) Respiratory tract infection – antibiotic prescribing does not include reference to prophylactic antibiotic use.For children with recurrent urinary tract infections ‘antibiotic prophylaxis may be considered’ (NICE CG54 2007).Proposed intervention and current practiceIt is proposed to explore if there is any evidence on the use of prophylactic antibiotics for children that are prone to recurrent chest infections due to a neurological disorder and to determine what current practice in the UK is.A quick survey among 5 neuro-disability and 3 community paediatricians conducted by the British Academy of Childhood Disability on behalf of the HTA revealed that there are differences in practice. Practices include:• Azithromycin 3 times a week over the winter months• Septrin• 3 month rotating scheme of augmentin azithromycin and flucloxacillin• Azithromycin combined with Cefixime• Do not use prophylactic antibioticsAzithromycin (part of the Macrolide group of antibiotics) is used as a prophylactic antibiotic in children with cystic fibrosis. Macrolides are known to have both direct antibacterial properties and additional anti-inflammatory properties. They are also thought to reduce so-called virulence factors such as the production of a mucoid biofilm which protects P. aeruginosa from host defences and hence theoretically have an additional beneficial outcome for those with cystic fibrosis who are colonised with pseudomonas [3].Currently azithromycin is prescribed by some practitioners to neurologically impaired children with recurrent chest infections based on evidence that the antibiotic reduces respiratory exacerbations in children with cystic fibrosis who experience problems with clearing secretions and recurrent lung infections due to the nature of the disease. Neurologically impaired children such as those with severe cerebral palsy also have difficulty in coughing and clearing secretions as a result of poor muscle function and posture which can lead to recurrent lower respiratory tract infections and colonisation with bacteria and hence treatment with Azithromycin. However there is very limited evidence in the literature for its use in these children.Cost and implications for NHS spendNot known.Summary of previous and completed researchEvidence Synthesis:In their review of the literature of Assessing and managing lung disease and sleep disordered breathing in children with cerebral palsy Fitzgerald (2009) highlights that the major morbidity and mortality associated with cerebral palsy (CP) relates to respiratory compromise which manifests through repeated pulmonary aspiration airway colonization with pathogenic bacteria the evolution of bronchiectasis and sleep disordered breathing. The review states that there should be a low threshold for antibiotic use for intercurrent respiratory infections in children with CP particularly in those with evidence of suppurative lung disease. Ideally antibiotic choice should be based on sputum culture results and prolonged courses (3–4 weeks) are usually required in these patients [4].An article by Kirk (2008) [3] in the BMJ Archimedes series set out to answer the question “is the frequency of recurrent chest infections in children with chronic neurological problems reduced by prophylactic azithromycin?” Kirk raises the following points:• Children with severe neurological impairment and chronic lung disease are a disparate patient group with many causes for their respiratory problems which makes it difficult to conduct well designed randomised controlled trials.• These patients are however a population who frequently present to hospital and in whom there is increasingly a high expectation of intervention.• A literature search for antibiotic prophylaxis in children with respiratory problems and neurological impairment revealed no results. Nevertheless several papers (including a meta-analysis) on use of azithromycin prophylaxis in cystic fibrosis were identified.• Azithromycin has few side effects is not costly and extrapolating evidence from children with cystic fibrosis may reduce the frequency of respiratory exacerbations in these children.Del-Rio-Navarro (2006) Immunostimulants for preventing respiratory tract infection in children searched to January 2006 and found 34 placebo-controlled trials (n=3877). When compared with placebo the use of immunostimulants (IS) was shown to reduce acute respiratory tract infections (ARTIs) measured as the total numbers of ARTIs (mean difference -1.27; 95% CI -1.58 to -0.97) and the difference in ARTIs rates (mean difference -39.68%; 95% CI -47.27% to -32.09%). The trial quality was generally poor and a high level of statistical heterogeneity was evident. The subgroup analysis of bacterial IS studies produced similar results with lower heterogeneity. No difference in adverse events was evident between the placebo and IS groups. The review authors conclude that IS reduces the incidence of ARTIs in children by 40% on average. However due to significant heterogeneity and the poor quality of the trials this positive result should be interpreted with caution [5].


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: RESPIRATORY