Prophylactic antibiotic treatment of bronchiectasis with azithromycin
- Correspondence to:
Dr R Wilson
Host Defence Unit, Royal Brompton Hospital, Sidney Street, London SW3 6NP, UK;
Once a treatable cause of bronchiectasis such as hypogammaglobulinaemia has been excluded, management largely involves physiotherapy and treatment of infective exacerbations with appropriate antibiotics.1 In a proportion of patients this is not adequate to prevent frequent infective exacerbations. Prophylactic antibiotic treatment can be used to try to prolong the exacerbation free period. This may be administered orally, via a nebuliser, or using a cyclical regimen of intravenous antibiotics. Prophylactic treatment may be problematic due to side effects and development of antibiotic resistance.2 Macrolide antibiotics exhibit immunomodulating properties. Long term, low dose erythromycin has been shown in diffuse panbronchiolitis, a disease with some similarities to idiopathic bronchiectasis, to be effective in controlling chronic suppurative airways disease.3 Recently published research has shown benefits of long term azithromycin treatment in patients with cystic fibrosis.4 These results led us to consider using azithromycin as prophylaxis in patients with non-cystic fibrosis bronchiectasis with frequent infective exacerbations.
Patients attending the outpatients department between February 1999 and April 2002 who fulfilled the following criteria were considered for azithromycin prophylaxis:
bronchiectasis defined by CT scan;
any causal condition had been treated if possible;
general management optimised;
>4 documented infective exacerbations requiring oral or intravenous antibiotic treatment during the last 12 months;
Pseudomonas aeruginosa respiratory infection, if present, had not responded to nebulised antibiotic prophylaxis or this had not been tolerated;
failure to control chronic symptoms.
Exclusions included allergy to macrolides and abnormal liver function tests. The dosing schedule was 500 mg once daily for 6 days, 250 mg once daily for 6 days, then 250 mg on Monday/Wednesday/Friday of each week. A safety blood examination was organised 1 month after starting treatment. The patients were fully reviewed at least 4 months after commencement of azithromycin prophylaxis and lung function tests repeated. Sputum culture results before and after starting prophylaxis were noted. Statistical analysis was performed using a paired t test and non-parametric Wilcoxon test.
Thirty nine patients were studied. Fifteen had idiopathic bronchiectasis and the remainder consisted of 13 with post childhood infections, five with primary ciliary dyskinesia, five with common variable immunodeficiency, and one with Young’s syndrome. Their mean (SD) age was 51.9 (16.1) years (range 18–77) with a 2:1 female predominance. All patients had had more than four documented exacerbations during the previous 12 months. Six patients stopped taking the azithromycin prophylaxis because of side effects: abnormal liver function tests (n = 2), diarrhoea (n = 2), rash (n = 1), and tinnitus (n = 1). All occurred during the first month of treatment. Other side effects experienced were mild and mainly gastrointestinal. Five patients were on long term oral corticosteroids with no change in dosage, in two new inhaled corticosteroids were introduced, and one patient was given a short 7 day reducing course of oral corticosteroids. The mean (SD) length of time taking azithromycin, excluding those who stopped because of side effects, was 20 (10.1) months (range 4–38). Twenty six patients are continuing with the prophylaxis at the present time; in the other seven treatment was discontinued because of improvement in their condition.
Sputum culture results (all bacteria isolated) before commencement showed no growth (n = 13), Pseudomonas aeruginosa (n = 8), Staphylococcus aureus (n = 6), Haemophilus influenzae (n = 6), Streptococcus pneumoniae (n = 3), Stenotrophomonas maltophilia (n = 2), Morexella catarrhalis (n = 1), not done (n = 4). After 4 months the results were no growth (n = 18), P aeruginosa (n = 5), S aureus (n = 1), S pneumoniae (n = 1). not done (n = 10). In three patients who had cultured P aeruginosa before starting azithromycin prophylaxis the organism was not recultured at follow up.
In the 33 patients completing at least 4 months treatment there was a statistically significant reduction in infective exacerbations requiring oral antibiotics from a mean of 0.71 per month to 0.13 per month (p<0.001). There was also a reduction in the requirement for intravenous antibiotics from a mean of 0.08 courses per month to 0.003 courses per month (p<0.001). Subgroup analysis of patients with P aeruginosa isolated before starting azithromycin prophylaxis showed no difference compared with all patients included (p = 0.22). Twenty five patients had lung function tests before and after at least 4 months of treatment (range 4–20 months). There was an improvement in all lung function parameters but the improvement in carbon monoxide transfer factor (Tlco) was the only one to reach statistical signficance (p = 0.01).
Symptom data were collected from 32 patients and scored on a 5-point scale (table 1). Statistical analysis using a non-parametric Wilcoxon test showed that there was a significant improvement in all symptoms.
The mechanism by which azithromycin reduces the number of infective exacerbations and chronic symptoms is unknown, but it is likely to be multifactorial. It may be due to downregulation of the host immune response by azithromycin, so decreasing host mediated tissue damage as postulated in the vicious circle hypothesis. It might also benefit patients by reducing bacterial load and therefore the stimulation for neutrophilic inflammation, or by influencing the pathogenic mechanisms of bacteria. Macrolide antibiotics have also been shown to reduce mucus secretion.1,5
Currie et al compared high dosage amoxicillin with placebo over an 8 month period and found a greater reduction in the volume of purulent sputum between exacerbations in the amoxicillin group (to 20% of pretreatment volume) than in the placebo group, but did not demonstrate any reduction in infective exacerbations.6 The superior findings of our study suggest that the anti-inflammatory effects of azithromycin were important in achieving the results obtained. This study was performed with patients who were sufficiently unwell to preclude consideration of a placebo group. The patients therefore acted as their own controls. The results are sufficiently impressive to encourage the design of a randomised study, either enrolling less sick patients and having a placebo comparator or using a comparator antibiotic without immunomodulating properties.