Macrolides

The use of macrolide antibiotics in cystic fibrosis

Daniel Peckham, April, 2003. The use of macrolide antibiotics in cystic fibrosis [online]. Seacroft and St James's University Hospitals, Leeds, UK. Available from http://www.cysticfibrosismedicine.com

Introduction

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. More recently there has been growing interest in their potential role as anti-inflammatory agents in cystic fibrosis. This follows the success of long-term erythromycin in the treatment of diffuse pan-bronchiolitis (DPB), a condition that exhibits some similarities to cystic fibrosis in that it is associated with chronic sinusitis, mucoid pseudomonas aeuginosa (PA) colonisation and bronchiectasis (Hoiby, 1994; Kayama et al, 1997; Jaffe et al, 2001). The introduction of erythromycin as a treatment for DPB had a dramatic impact on mortality increasing 10-year survival from 12.4-21.9% to over 90% in those colonised with P. aeruginosa (PA) (Hoiby, 1994; Black, 1997). Other macrolides such as clarithromycin and Azithromycin seem to be as equally effective.

There are several theoretical reasons why the macrolides could modulate the disease process in cystic fibrosis. Firstly, several studies have suggested that the macrolides possess important anti-inflammatory activity, which appears to be 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; Kahn et al, 1995; Armonstrong et al, 1995; Black, 1997; Kayama et al, 1997; Bell et al, 2000; Jaffe et al, 2001; Bell et al, 2002). Secondly, they may reducing sputum viscoelasticity and airway adhesion of P. aeruginosa and increase the killing of mucoid P. aeruginosa, a mechanism that may be mediated 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 et al, 2001).

Frederiksen et al carried out the first randomised, double blind, placebo controlled, crossover study of the effect of twice daily clarithromycin in cystic fibrosis (Frederiksen et al, 2001). Various parameters were measured including pulmonary function but, unexpectedly, 20 of 41 patients were excluded from the study so that no conclusions could be drawn. Importantly, failure to complete the study was not related to the active arm. More recently Hansen et al from the same group, reported a retrospective analysis of the effect of long-term azithromycin treatment in 50 patients (30 males) median age 30.1 years (range 18.1-53.8) with cystic fibrosis (Hansen et al, 2002). The median follow up time was 8 months (range 4-12). Azithromycin was associated with a small increase in lung function, weight and a fall in the % of sputum samples containing mucoid PA colonies. Similar results have been reported in children. In a non-randomised open labelled study Pirzada et al compared the effect of 250 mg azithromycin in 18 children with cystic fibrosis and 18 age and sex matched controls over a mean of 0.78 years (Pirzada et al, 1999). The azithromycin treated group showed significant improvement in lung function and weight gain. The drug was well tolerated and no significant side effects were observed. In an earlier study by Jaffe et al, 3 months of 250 mg azithromycin was also associated with a significant increase in lung function, although the study design was open making the results difficult to interpret (Jaffe et al, 1998).

The first published placebo controlled study by Wolter et al investigated the effect of 3 months of 250 mg daily azithromycin versus placebo in 49 adults with cystic fibrosis. (Wolter et al, 2002). In this study treatment with azithromycin was associated with significantly fewer courses of intravenous antibiotics, maintenance of lung function, reduction in median C reactive protein (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 250 mg (<40 kg) or 500 mg (>40 kg) azithromycin or placebo in 41 children with cystic fibrosis (age 8-18 years) (Equi et al, 2002). The study had a randomised double blind, placebo controlled, and crossover design and was carried out over 15 months and included a 6 months treatment period. Importantly 17 out of the 41 patients who completed the study did not culture P aeruginosa from sputum. While the use of azithromycin was associated with a significant but modest (5.4%) group response in FEV1, 5/41 had a clinically important deterioration. Treatment was also associated with the use of fewer oral antibiotic and full benefit appeared to be delayed, occurring after 2-4 months after the commencement of therapy. Interestingly, individuals who were not on concurrent rhDNase showed better response and begs the question as to whether or not azithromycin inhibits rhDNAse in vivo as has been postulated in vitro (Ripoll et al, 1996).

Saiman et al have recently reported their findings of a multicentre, randomised, placebo controlled trial which investigated the effect of azithromycin in patients with cystic fibrosis chroically infected with P.aeruginosa (Saiman et al, 2003). The study included individuals with an age greater than 6 years old and an FEV1 of greater than 30% predicted. The active group received a dose of azithromycin which was titrated to weight (500mg or 250 mg 3 times a week if weight was greater or less than 40 kg respectively). Routine therapies such as Pulmozyme, TOBI and high dose Brufen were continued for the duration of the trial. A total of 185 patients were studied with 87 patients received AZT and 98 Placebo. Treatment with azathioprine resulted in a relative change in % predicted FEV1 and body weight of 6.2% and 0.8kg respectively. The improvement in FEV1 was seen in the 1st 28 days and sustained but declined to baseline levels after discontinuation. AZT also impacted the number of pulmonary exacerbations as indicated by a 40% reduction in the number of courses of i.v. antibiotic courses and a 47% reduction in the number of days in hospital. Trends towards improvement in quality of life were seen in the AZT treated group. There was a mean reduction in PA density from baseline to end of treatment period although there was no significant differences in sputum microbiology at baseline and no difference in acquisition of resistant organisms during the treatment period. While the drug was well tolerated symptoms occurred more frequently in AZT group (nausea, diarrhoea and wheeze).

Conclusion

There is now growing evidence to support the short term use of macrolides in cystic fibrosis. Azithromycin appears to provide a beneficial effect in a proportion of patients with cystic fibrosis. Studies show a modest improvement in lung function, weight gain and a reduction in the number of pulmonary exacerbations. In addition patients seem to experience some improvement in quality of life. Further trials are needed to assess the long-term benefit and safety of this group of drugs in patients with cystic fibrosis.

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