Miles Denton. April, 2002. Azithromycin in cystic fibrosis [online]. Leeds University Teaching Hospitals, Leeds, UK. Available from http://www.cysticfibrosismedicine.com

Introduction

Azithromycin is an example of a class of macrolide antibiotics called 'azalides'. One of the features that distinguishes the 15-membered ring azalide azithromycin from the 14-membered ring macrolide erythromycin is its increased stability at acid pH. Other key features are its high oral bioavailability, its long half-life (allowing once a day dosing) and its ability to attain high tissue concentrations, including within macrophages.

Spectrum of activity

Its spectrum of activity is similar to that of other macrolides and, as such, it is active against Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pneumoniae. However, minimum inhibitory concentrations (MICs) are two- to four-fold higher than those of erythromycin versus erythromycin-susceptibile staphylococci and four- to eight-fold higher for Haemophilus influenzae (Lode et al 1996). Cross-resistance between erythromycin and azithromycin is observed; therefore strains resistant to erythromycin are resistant to azithromycin. There is no inherent direct activity of azithromycin against Pseudomonas aeruginosa, Burkholderia cepacia, or other gram-negative non-fermenters such as Stenotrophomonas maltophilia.

Pharmacokinetics

Little data exist regarding the influence of cystic fibrosis (CF) on the pharmacokinetics of azithromycin. The standard adult dose is 500mg once daily. For children over 6 months the dose is 10mg/kg once daily or bodyweight 15-25kg, 200mg once daily; 26-35kg, 300mg once daily; 36-45kg, 400mg once daily. The drug is available as capsules, tablets or oral suspension.

Anti-inflammatory

Azithromycin has recently become a focus of interest because of its potential activity as an anti-inflammatory agent in the treatment of CF, particularly those with chronic infection with P. aeruginosa. This has been stimulated by the reported success of other macrolide antibiotics e.g. erythromycin in the management of diffuse panbronchiolitis in Japan, a condition which shares some similarities with CF. The mode of action is uncertain but there is evidence that macrolides may ameliorate host inflammatory responses by inhibiting neutrophil function and suppressing production of pro-inflammatory mediators. They may also reduce sputum viscosity, the airway adhesion of P. aeruginosa and disrupt the ability of P. aeruginosa to produce alginate (Peckham 2002). Others have postulated that macrolides may upregulate a p-glycoprotein (multidrug-resistant-associated protein or MDR) which is homologous to CFTR (Altschuler, 1998).

Evidence of efficacy of long term azithromycin in this role in CF is lacking at present

1. A three month prospective randomised double-blind placebo-controlled trial of azithromycin 250mg od was conducted in adults (mean age 27.9 years) with CF in Australia (Wolter et al, 2002). Sixty patients were recruited (29 male, 31 female) and 30 received azithromycin and 30 received placebo. Forty-five completed the study (24/30 receiving azithromycin). During the three months of the trial azithromycin significantly improved quality of life scores, reduced CRP, reduced the number of respiratory exacerbations and reduced the rate in decline of lung function. Eight of the 30 patients receiving azithromycin suffered adverse events, although only three actually discontinued the drug as a result. Rashes and drug-associated neutropenia were reported but all events resolved without complication.

2. An open study of children (median age 12.1 years) with CF who took azithromycin for more than 3 months was conducted in the United Kingdom (Jaffe et al, 1998). Seven children (three boys) were studied. Median treatment length was 0.6 years (0.3 to 1.2 years). Significant increases in median %FVC and median %FEV1 were observed but there were no other significant changes. There were no reported adverse events.

3. The effect of combining azithromycin with 'conventional' anti-pseudomonal antibiotics against multi-resistant strains of P. aeruginosa, B. cepacia, S. maltophilia and Acromobacter (Alcaligenes) xylosoxidans has been studied in vitro (Saiman et al, 2002). Although azithromycin has little intrinsic activity of its own against these organisms, it appears synergistic in combination with other antibiotics against some strains. Azithromycin-cotrimoxazole inhibited 40% and 22% of S. maltophilia and A. xylosoxidans respectively. Azithromycin-ceftazidime inhibited 20% and 22% of B. cepacia complex strains and P. aeruginosa strains respectively. However, it is not yet known if these laboratory findings will transcribe into meaningful clinical activity in vivo.

Summary

Azithromycin is a macrolide antibiotic with activity against common respiratory pathogens such as S. pneumoniae and H. influenzae. It has potential anti-inflammatory effects in the management of chronic P. aeruginosa respiratory tract infection in CF patients. There is some evidence that short-term use in both adults and children with CF results in improved clinical and quality of life parameters. The impact of longer-term use is unknown. It may act synergistically with other agents against a range of CF pathogens, enhancing their in-vitro activity. It is not known if this will result in improved clinical efficacy. In general it has been well tolerated by CF patients. The main reported problems have been rashes.

References

Altschuler EL. Azithromycin, the multidrug-resistant protein, and cystic fibrosis. Lancet 1998; 351: 1286.

Jaffe A, Francis J, Rosenthal M, Bush A. Long-term azithromycin may improve lung function in children with cystic fibrosis. Lancet 1998; 351: 420.

Lode H, Borner K, Koeppe P, Schaberg T. Azithromycin - review of key clinical, pharmacokinetic and microbiological features. J Antimicrob Chemother 1996; 37, Suppl C: 1-8.

Peckham DG. Macrolide antibiotics and cystic fibrosis. Thorax 2002; 57: 189-190.

Saiman L, Chen Y, San Gabriel P, Knirsch C. Synergistic activities of macrolide antibiotics against Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans isolated from patients with cystic fibrosis. Antimicrob Agents Chemother 2002; 46: 1105-1107.

Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax 2002; 57: 212-216.

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