The macrolides are a group of antibiotics which have been widely used for their antibacterial effect against diseases such as Mycoplasma pneumonia, Chlamydia pneumonia and Legionella species. Their value in CF depends on their anti-inflammatory properties and their ability to interfere with pseudomonas adherence to epithelial cells and biofilm mode of growth. Macrolide use in CF was stimulated by the success of long-term erythromycin in the treatment of diffuse pan-bronchiolitis (DPB), a condition that shows some similarities to CF in that it is associated with chronic sinusitis, mucoid P. aeruginosa colonisation and bronchiectasis (Hoiby, 1994; Koyama & Geddes, 1997; Jaffe & Bush, 2001). The introduction of erythromycin as a treatment for DPB had a dramatic impact on mortality increasing 10-year survival from between 12% to 22% to over 90% in those colonised with P. aeruginosa (Hoiby, 1994; Black, 1997). The effectiveness of these drugs appears to be limited to the 14-membered and 15-membered macrolides, such as erythromycin, clarithromycin and azithromycin.
Macrolide modulation of airway inflammation
There are several theoretical reasons why macrolides modulate the disease process in CF. Important anti-inflammatory activity is mediated by an inhibition of neutrophil chemotaxis, reduction of neutrophil elastase and modification of pro-inflammatory cytokines with suppression of interleukin IL-1ß, IL-6, IL-8 and tumour necrosis factor (TNF) production (Konstan et al, 1994; Khan et al, 1995; Armstrong et al, 1995; Black, 1997; Koyama & Geddes, 1997; Bell et al, 2000; Jaffe & Bush, 2001; Bell et al, 2002; Hodge et al, 2006). Secondly, macrolides may reduce sputum viscoelasticity, airway adhesion of P. aeruginosa, and increase the killing of mucoid P. aeruginosa, by their ability to disrupt the integrity of the protective biofilm and impair the transformation of non-mucoid P. aeruginosa to the more virulent mucoid phenotype (Yasuda et al, 1993; Kobayashi, 1995; Tai et al, 1999; Fisher et al, 1999; Jaffe & Bush, 2001; Carfartan et al, 2004; Wozniak & Keyser, 2004). Finally, low dose azithromycin has been shown to improve macrophage function, reduce neutrophil counts in the bronchial lavage fluid and reduce pulmonary tissue damage by impairing superoxide generation by activated neutrophils (Tamaoki, 2004; Hodge et al, 2006).
Evidence for the use of macrolides in CF
Hansen et al reported a retrospective analysis of the effect of long-term azithromycin treatment in 50 adult patients (Hansen et al, 2005). The median follow up time was eight months (range 4-12 months). Azithromycin was associated with a small increase in lung function and weight and a fall in the percentage of sputum samples containing mucoid P. aeruginosa colonies. Similar results have been reported in children (Jaffe et al, 1998; Pirzada & Taylor, 1999).
The first published placebo-controlled study investigated the effect of three months of 250mg daily azithromycin versus placebo in 49 adults with CF (Wolter et al, 2002). Treatment with azithromycin was associated with significantly fewer courses of intravenous antibiotics, maintenance of lung function, reduction in median CRP levels and improvement in quality of life scores. These results were supported by the findings from a study by Equi et al who investigated the effect of 250mg (<40 kg) or 500mg (>40 kg) azithromycin versus placebo in 41 children with CF (age 8-18 years), (Equi et al, 2002). The study had a randomised, double-blind, placebo controlled, crossover design and included a six month treatment period. Importantly, 17 out of the 41 patients who completed the study did not culture P. aeruginosa from sputum. The use of azithromycin was associated with a significant but modest (5.4%) group response in FEV1 and less use of oral antibiotics. Five of 41 patients had a clinically important deterioration. The full benefit of treatment was seen two to four months after the commencement of therapy.
A multicentre, randomised, placebo-controlled trial which investigated the effect of azithromycin (500 mg or 250 mg three times a week if weight was greater or less than 40 kg respectively) in patients chronically infected with P. aeruginosa included individuals with an age greater than six years old and an FEV1 greater than 30% predicted (Saiman et al, 2003). Routine therapies such as Pulmozyme®, TOBI® and high dose ibuprofen were continued. Eighty-seven patients received azithromycin and 98 placebo. Treatment with azithromycin resulted in a relative change in % predicted FEV1 and body weight of 6.2% and 0.8 kg respectively. The improvement in FEV1 was seen in the first 28 days and was sustained with treatment but declined to baseline levels after discontinuation of azithromycin. Patients on active treatment had less risk of developing a pulmonary exacerbation when compared to placebo (p=0.03). Azithromycin reduced the number of participants hospitalised and the mean number of days of non quinolone oral antibiotics use. Although not statistically significant, there was a 40% reduction in the number of intravenous antibiotic courses, a 47% reduction in the number of days in hospital and a trend to improvement in quality of life. There was a mean reduction in P. aeruginosa density from baseline to the end of the treatment period. There was no difference in acquisition of resistant organisms during the treatment period. Azithromycin was well tolerated but symptoms were reported more frequently in the active study arm (nausea, diarrhoea and wheeze).
Clement et al have recently published their results of a multicentre, randomised, double-blind, placebo controlled trial in young patients with CF (Clement et al, 2006). The criteria for enrolment were age older than six years and FEV1 40% predicted or more. The active group received either 250 mg or 500 mg (body weight < or > 40 kg) oral azithromycin three times a week for 12 months. The primary end point was change in FEV1. A total of 82 patients (mean age 11.0 years, mean FEV1 85% predicted) were randomised; 40 in the azithromycin group and 42 in the placebo group. Nineteen patients were infected with P. aeruginosa. The relative change in FEV1 at month 12 did not differ significantly between the two groups. The number of pulmonary exacerbations (p<0.005), and the number of additional courses of oral antibiotics were significantly reduced, and the time to the first pulmonary exacerbation significantly increased in the azithromycin group, regardless of the patient’s infection status (p<0.0001). No severe adverse events were reported. Low dose azithromycin appears to have beneficial effects in both patients with milder disease and those free from chronic P. aeruginosa colonisation (Kastelik et al, 2005; Clement et al, 2006) .
Patients receiving long term azithromycin show an increased prevalence of macrolide resistant strains of S. aureus and H. influenzae (Prunier et al, 2003; Phaff et al, 2006). In the Leeds CF Unit, staphylococcal macrolide resistance has increased since the greater use of azithromycin therapy (unpublished data). There is also a theoretical risk of inducing resistance in atypical mycobacteria and encouraging the emergence of bacteria intrinsically resistant to macrolides. Units prescribing macrolides should monitor the emergence of resistance very carefully.
There have been no reports of any serious adverse outcomes in any studies of azithromycin use in CF. Nausea and diarrhoea were significantly more common but did not lead to an increased withdrawal rate in any of the clinical trials. Although a rise in liver enzymes was seen in three patients these returned to normal levels. Hearing loss and tinnitus are potential side effects in patients receiving concurrent ototoxic medication but Saiman et al found no ototoxicity in a subpopulation of 94 patients (Saiman et al, 2003).
Precautions before starting treatment
Patients attending the Leeds CF Unit have an ECG prior to starting long term, low dose macrolide therapy. This is because macrolides have been associated with prolongation of cardiac repolarisation. The overall risk of ventricular arrhythmias is very small but treatment should be avoided in patients with an abnormal ECG and a prolonged QT interval (Owens, 2004).
• There is an increasing body of evidence to support the use of macrolides in CF
• Studies of macrolide use show a modest improvement in lung function, weight gain and a reduction in the number of pulmonary exacerbations
• Clinical response varies between individuals
• Greater macrolide use has been associated with increased staphylococcal macrolide resistance
• Units should perform microbial surveillance for emerging bacterial resistance in patients receiving long term macrolide therapy
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