Since the description of the pathological features of cystic fibrosis (CF) in the pancreas of babies born with malabsorption by Dorothy Anderson in the Columbia Medical Centre, New York, in the 1930s, the cornerstones of therapy in patients with CF have been maintenance of nutrition with pancreatic enzyme replacement and the treatment and prevention of pulmonary infections. 

Since the 1930s CF care has resulted in most patients living well into adulthood with a continually rising median life expectancy. Improvements in CF care have resulted from the development of new therapies and the delivery of comprehensive multidisciplinary care from childhood into adulthood. 

Today the primary goals of CF treatment involve: 

• Maintaining lung function
• Maintaining adequate nutrition
• Managing complications.

This article will concentrate on therapies that are aimed at maintaining lung function. 

Antibiotic therapy

Lung function declines in patients with CF as they age but declines at an accelerated rate if they suffer repeated pulmonary infections. Therefore, treatment and prevention of infective exacerbations is a key focus of therapy in CF. The microbiology of CF generally is characterised by the early acquisition of Staphylococcus aureus and this is followed by Pseudomonas aeruginosa infection in the mid-teens. 

Treatment of exacerbations is directed primarily at these two organisms. As patients get older and have more frequent hospital admissions other micro-organisms such as MRSA and Stenotrophomonas may also play a role. Generally, for exacerbations involving Pseudomonas, oral treatment is ciprofloxacin; exacerbations not fully responsive to oral therapy may require treatment with intravenous (IV) antibiotics. 

Standard antibiotic regimens include the combination of an extended spectrum beta-lactam with an aminoglycoside such as tobramycin or colistin, which is a polymyxin. 

Combination antibiotic therapy is employed for synergy and to reduce the risk of the emergence of resistant strains of Pseudomonas, although there is scant evidence for this.  Treatment is usually for up to 14 days and response is judged by the return of symptoms to baseline, by improvement in FEV1 and by a fall in their inflammatory markers. 

Because patients with CF have a larger lean body mass, they often have a higher clearance rate for many antibiotics. Achieving effective levels in respiratory secretions can be difficult; higher doses of antibiotics are often required and aminoglycoside levels need to be monitored carefully to avoid toxicity. 

Apart from IV and oral therapy for acute exacerbations, inhaled antibiotic therapy has become one of the mainstays of chronic therapy for CF. The most common airway pathogen in patients with CF is Pseudomonas aeruginosa. Because chronic colonisation of the airways with this bacterium is associated with a more rapid decline in lung function, aerosolised antibiotics are used for both eradication of the initial infection and for the suppression of chronic infection. 

Aerosolised tobramycin (TOBI) has been the most thoroughly studied chronic suppressive therapy. In trials, treatment with TOBI was found to produce significant improvement in pulmonary function, to decrease the density of P. aeruginosa in the sputum, and to decrease the number of days that patients were hospitalised. These studies included patients with moderate-to-severe pulmonary disease, defined as having an FEV1 between 25% and 75% of predicted. TOBI is also effective in milder disease with significant reduction in exacerbations. TOBI supplanted traditional inhaled colistin. 

Inhaled colistin, though, is still used frequently for treatment of patients with CF and who are infected with P. aeruginosa, particularly in the off-month. However, there is very little evidence in the literature to favour colistin; in one trial when compared with placebo, no advantage was seen in the colistin group. Also in a head-to-head study with tobramycin in 115 patients over four weeks, the patients treated with inhaled colistin did not show any measured improvement in lung function, whereas patients receiving tobramycin inhaled solution experienced an increase in FEV1 of 6.7%. 

A dry powder inhaled version of colistin is now available, an initial phase III study showed non-inferiority in the change of FEV1 compared to tobramycin solution, but both groups did not have a significant increase in FEV1 from baseline over the 24-week study. 

A new aerosolised antibiotic approved for use in CF is inhaled aztreonam. Aztreonam is a monobactam antibiotic and can be used in penicillin-allergic patients. A number of studies have looked at inhaled aztreonam in individuals with moderate-to-severe airway obstruction. Two trials found a statistically significant absolute improvement in FEV1 after aztreonam treatment for 28 days compared with placebo (6.3-10.3%). An 18-month open-label study demonstrated that long-term use of inhaled aztreonam every other month is safe and effective and not associated with increased resistance. In addition, another study of 273 individuals with CF aged six years or older demonstrated improved lung function and fewer exacerbations over three 28-day cycles of inhaled aztreonam compared with inhaled tobramycin. 

Mucolytics

Airway obstruction by thickened secretions and cellular debris is the hallmark of CF lung disease. Recombinant human DNase (dornase alfa) was developed to degrade the large amount of free DNA that accumulates within CF mucus, thereby improving the viscoelastic properties of airway secretions and promoting airway clearance. Most short-term studies of dornase alfa in patients with moderate-to-severe disease showed a significant improvement in lung function as measured by FEV1 by 11.2-15.4% when compared with placebo. 

Long-term studies also uniformly demonstrate improvement in lung function with dornase alfa of 5.8-7.3% FEV1. A number of trials have looked at quality-of-life measures, all reporting higher overall well-being scores for those patients receiving dornase alfa compared with placebo. Dornase alfa is generally well tolerated, with few adverse events compared with placebo and the most common of these being voice alteration.

Hypertonic saline

Hypertonic saline (HS) inhalation is used as a therapy to increase hydration of airway surface liquid in patients with CF, thereby improving mucociliary clearance. Randomised controlled trials have shown benefits in FEV1 but not as great as that with dornase alpha. Elkins et al in a large multicentre study in Australia showed a reduction in exacerbations of almost 56% in those receiving twice-daily 7% hypertonic saline compared to placebo. The benefits of hypertonic saline are that it is generally well tolerated, with bronchospasm being the only major side-effect, which can be ameliorated by pre-treatment with bronchodilators. Hypertonic saline is also cheap with minimal side-effects and no other drug interactions. 

Macrolide antibiotics

Macrolide antibiotic therapy was originally used in diffuse pan-bronchiolitis, a rare obstructive lung disease affecting Japanese individuals, with good effect. The mechanism of action may be related to either the antimicrobial or anti-inflammatory properties of the drugs. There is strong evidence in studies in CF patients with and without Pseudomonas infection that azithromycin has benefit. Some studies used 500mg three times per week and some used 250mg once daily. Most studies showed benefits in terms of a significant reduction in exacerbations. Some showed benefit in reduced antibiotic usage. 

Adverse events reported with the use of macrolide antibiotics included nausea and diarrhoea, but in clinical practice macrolide therapy is generally well tolerated. It is important not to treat individuals infected with non-tuberculous mycobacteria (NTM) in their sputum cultures. Patients should be screened for NTM before initiating azithromycin therapy, and reassessed periodically at six-to-12-month intervals. Macrolides as monotherapy should be withheld in those infected with NTM due to the risk of development of resistant organisms.

Ivacaftor

A significant development in CF care has been the recent development of personalised therapy for CF patients with particular genotypes. Ivacaftor is a potentiator drug that activates defective CF transmembrane conductance regulator (CFTR) at the cell surface. The primary target for this therapy is mutated CFTR in which glycine has been replaced by aspartic acid at position 551 (the G551D mutation), interfering with the opening of this chloride channel. 

In a landmark study, Ramsey et al studied the effect of 48 weeks of ivacaftor 150mg twice daily compared with placebo in 161 subjects aged 12 years or older with at least one G551D mutation. The FEV1 increased 10.4% from baseline in the treated patients compared with -0.2% for those receiving placebo at 24 weeks (p < 0.001). Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than those receiving placebo (p < 0.001). There were significant improvements in quality of life, as well as nutritional status. The patients on the drug had a 48.1mmol/L decrease in their sweat chloride concentration compared with placebo (p < 0.001), reflecting the significant impact of the drug on the basic defect in CF. 

This therapy has transformed the lives of many of the patients who have started it. The proportion of CF patients with this mutation in Ireland is approximately 10%, which is twice the frequency in North America and other parts of the world. Unfortunately ivacaftor is not effective on its own in patients with the more common homozygous F508del CFTR mutation, but the efforts that have gone into developing this compound and the potential for the development of future therapies is exciting. 

Further reading

1. Flume PA, O’Sullivan BP, Robinson KA et al. Cystic fibrosis pulmonary guidelines: Chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2007; 176: 957-969
2. Yankaskas JR, Marshall BC, Sufian B et al. Cystic fibrosis adult care: Consensus conference report. Chest 2004 Jan; 125(1 Suppl):1S-39S
3. Flume PA, Robinson KA, O’Sullivan BP et al. Clinical Practice Guidelines for Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: Airway clearance therapies. Respir Care 2009 Apr; 54(4): 522-37