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Three Part Question

Do [children with chronic lung disease (not bronchopulmonary dysplasia) and/or bronchiectasis] who are [prescribed long-term azithromycin as prophylaxis] have a [reduction in frequency of respiratory exacerbations without a change in the bacterial flora found on sputum culture]?

Clinical Scenario

Fraser is an 8-year-old boy well known to everyone in A&E and the hospital. He has severe dystonic cerebral palsy as a result of his premature birth at 26 weeks' gestation. Although he was ventilated for 5 weeks he did not develop chronic lung disease. He is gastrostomy fed and had a Nissen's fundoplication 5 years ago. He has copious secretions and a poor cough reflex. These are made worse by nitrazepam which he requires for his dystonia. Evidence from previous barium studies and swallow assessments show that he chronically aspirates his secretions. He has no symptoms of upper airway obstruction.
Over the last year, he has had increasingly frequent lower respiratory tract infections, requiring admission and intra-venous antibiotics. His weight and height have fallen from the 10th to the 3rd percentile. A chest x ray shows chronic changes suggestive of underlying bronchiectasis and he is now colonised with Pseudomonas aeruginosa. Immune function and a sweat test are normal. He has not had a recent pH study or barium swallow. He awaits a CT scan of his chest.
He has daily physiotherapy and regular suction and usually produces copious muco-purulent secretions. He is on maximal anti-reflux medication already. Would prophylactic azithromycin reduce his risk of further lower respiratory tract infections? Or might it increase growth of multi-resistant organisms within his sputum?

Search Strategy

Medline, EMBASE and Ovid search: (1) "exp Bronchiectasis/ and exp Azithromycin/" retrieved six articles of which only two were relevant; (2) "exp Cystic Fibrosis/ and exp Azithromycin/ then limited to randomized controlled trial" retrieved eight articles of which four were relevant. Three were included in the Cochrane systematic review.
Cochrane Collaboration: "respiratory" and "prophylactic antibiotics" terms used. Five hits found, only one of which was relevant; however, this was a systematic review of prophylactic use of antibiotics in cystic fibrosis.

Search Outcome

4 articles were relevant

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Clement et al, 2006	2 patients with cystic fibrosis aged 6–21 years randomised to placebo group or azithromycin x3/week for 12 months. Excluded from study if there had been a change in their treatment 3 months prior to starting study	Multicentre, randomised, double-blind, placebo controlled trial (level 1+)	Change in % predicted FEV1 over 12 months	No significant change in % predicted FEV1 at 12 months: azithromycin: –4.3, placebo: –1.5	A subgroup of patients with pseudomonal colonisation was delineated in each trial group. There was no difference in the results from this subgroup in either placebo or treatment subjects. Small study and only recruited two-thirds of population required by power calculation. Not clear if other changes made to medication during study
			Use of antibiotics and number of pulmonary exacerbations	Significant reduction in number of oral antibiotic courses in azithromycin group: 2.1 (0.4) vs 3.8 (0.5) course/person/year (p<0.01)
			Modification of sputum cultures	Reduction in number of exacerbations: average time to remain free of exacerbation: azithromycin – 8.7 months vs placebo 2.9 months (p<0.001)
			Nutritional status and quality of life	No change in frequency of positive cultures between groups (24 vs 29)
Southern et al, 2004	Systematic review which identified 19 RCTs of prophylactic azithromycin use in cystic fibrosis. Four of these were felt to be relevant and of sufficient quality to be included. Total of 296 patients, both adults and children. Prophylactic azithromycin vs placebo for 4–6 months. Majority colonised with Pseudomonas aeruginosa	Systematic review (level 1+)	Lung function (FEV1 and FVC)	nly possible to perform meta-analysis for changes in FEV1 at 1 and 6 months. Significant weighted mean difference in favour of azithromycin at 1 month: 3.99% (1.47 to 6.38) and 6 months: 5.82% (2.45 to 9.2)	Well conducted meta-analysis in which all individual studies suggest a small but significant improvement in respiratory function. Varied outcomes studied made meta-analysis of data difficult. No serious side effects noted, however nausea, wheezing and diarrhoea occurred more frequently in the azithromycin group.
			Number of courses of antibiotics	Individual studies reported a significant reduction in courses of oral and iv antibiotics
			Hospital inpatient days	Few adverse effects noted
			Acquisition of other common pathogens	No difference between groups in acquisition of common pathogens
Cymbala et al, 2005	30 Adult patients with CT confirmed bronchiectasis recruited. Randomised to receive prophylactic azithromycin or placebo for 6 months	Randomised, cross over, controlled trial with poor randomisation and only 11 patients accounted for at end of study (level 2)	Pulmonary function tests	Pulmonary function tests did not significantly change between groups.	Small number of patients and clumsy trial design make analysis of results difficult
			Need for medical intervention	Significant reduction in amount of exacerbations
Davies et al, 2004	39 adult patients with CT confirmed bronchiectasis received a reducing course of azithromycin for 4–20 months	Cohort study (level 2)	Frequency of exacerbations	33/39 completed at least 4 months follow-up. Six patients stopped azithromycin because of side effects	No significant improvement in lung function parameters. Small number of patients and those lost to follow-up not accounted for or included in analysis
			Change in lung function tests	Decrease in exacerbations per month from 0.71 (previous 12 months) to 0.13 (p<0.001)
			Change in sputum culture	No change in sputum cultureNo difference in pseudomonal subgroup

Comment(s)

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. Among the mechanisms responsible for respiratory disease in these children are poor cough (and hence difficulty clearing secretions), recurrent lower respiratory tract infections and colonisation with commensal bacteria. They often suffer from chronic aspiration of secretions and subsequent lower airway inflammation that if unrecognised may cause bronchiectasis and lung parenchymal damages (Seddon). Children with cystic fibrosis, for different reasons, also have difficulty clearing secretions, recurrent infection and colonisation with commensal bacteria. They, in contrast, have been extensively studied in well conducted trials as regards treatment and prophylaxis. As there are similar mechanisms involved in the lung disease in both groups and it is so difficult to conduct trials in children with severe neurological impairment, it is not unreasonable to extrapolate evidence from data for children with cystic fibrosis. Macrolide antibiotics are known from studies conducted in Japan in adults with diffuse panbronchiolitis 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. Azithromycin has particular pharmacokinetic and bioavailability properties that make it useful for prophylaxis treatment and therefore it has been the most widely studied marcolide in this respect. An initial literature search for antibiotic prophylaxis in children with respiratory problems and neurological impairment revealed no results. A further search for the use of prophylactic antibiotics in bronchiectasis also yielded few relevant results and papers of poor methodological quality. The two studies identified in adults were both very poorly designed and therefore analysis of results was difficult. However, both claimed a significant reduction in the number of pulmonary exacerbations and neither reported any change in sputum cultures or serious side effects in the prophylaxis group. Nevertheless, several papers (including a meta-analysis) on use of azithromycin prophylaxis in cystic fibrosis were identified. All studies showed a reduction in pulmonary exacerbations in those treated. Although the Clement paper, a multi-centre, double-blind, randomised controlled trial in children with cystic fibrosis, did not show a significant change in % predicted FEV1 at 12 months, it did show a significant reduction in the number of courses of antibiotics and frequency of pulmonary exacerbations in the prophylaxis group. The average time patients remained free of an exacerbation was 8.7 months in the azithromycin group and 2.9 months in the placebo group (p<0.001). Individual studies in the Cochrane meta-analysis, also in patients with cystic fibrosis, all showed a significant reduction in the number of pulmonary exacerbations and no difference between groups in sputum cultures. The studies were, however, conducted over a relatively short time period, up to 20 months, although most were 12 months or less. Most importantly, they all showed few adverse effects in the treatment group when compared to the placebo and no serious or life-threatening adverse events in the treatment group. The consequences of lower respiratory tract infection in a child with severe neurological impairment and chronic lung disease are serious. Prolonged recovery in this population impacts significantly on the child's quality of life and puts them at risk of further acquired infections in hospital. 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.

Clinical Bottom Line

Prophylactic azithromycin may decrease the frequency of respiratory exacerbations in children with severe neurological impairment and chronic lung disease. (Grade B) Prophylactic azithromycin should not produce serious or life-threatening side effects in this population. (Grade B)

References

1. Clement A, Tamalet A, et al. Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial. Thorax 2006; 61: (10): 895–902.
2. Southern KW, Barker PM, Solis A. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2004; (2): CD002203.
3. Cymbala AA, Edmonds LC, et al. The disease-modifying effects of twice-weekly oral azithromycin in patients with bronchiectasis. Treat Respir Med 2005; 4: (2): 117–22.
4. Davies G, Wilson R. Prophylactic antibiotic treatment of bronchiectasis with azithromycin. Thorax 2004; 59: (6): 540–1.
5. Seddon PC, Khan Y. Respiratory problems in children with neurological impairment. Arch Dis Child 2003; 88: 75–8.