Pulmonary pharmacotherapy options changing for cystic fibrosis patients

October 2006

Cystic fibrosis is the most common fatal genetic disorder among white children in the United States, affecting approximately 30,000 individuals. Specialized centers that provide care for children and adults with CF are available in the United States, and can be valuable sources of information for primary care clinicians. Infants and children with clinical symptoms consistent with CF should be referred to one of these centers for accurate diagnosis and optimal care.

Some states have instituted newborn screening for CF. In these states, newborn blood samples are tested for immunoreactive trypsinogen (elevated in CF). Newborns with positive screens are referred for more definitive diagnostic testing, which includes sweat testing or genetic analysis. Currently, 32 states and Washington D.C. require CF newborn screening. Clinicians that provide primary care for infants or children with CF should be familiar with this multi-organ system disorder. This month’s Pharmacology Consult column will review the pulmonary pharmacotherapy of CF.

Concerns in CF patients

The CF transmembrane conductance regulator (CFTR), the abnormal gene responsible for CF, codes for a protein that primarily functions as a chloride channel. It is located on the apical membrane of epithelial cells in exocrine glands (lung, pancreas, intestine, renal tubules, sweat glands, and male genital tract). Abnormalities of the CFTR result in reduced chloride transport and enhanced sodium transport, which affects passive water movement. These abnormalities result in thickened mucus layers of the affected organ systems (pulmonary, gastrointestinal), and cause obstruction. In the lungs, mucociliary clearance is reduced, which results in mucus plugging and airway obstruction. Pancreatic and hepatic bile ducts also develop mucus plugs due to thickened secretions, which leads to functional pancreatic enzyme (lipase, amylase, protease) deficiency and the potential for portal fibrosis. These changes in the pulmonary environment also allow for bacterial pathogen invasion. An intense inflammatory response develops following bacterial invasion and causes airway destruction. Most CF mortality results from pulmonary disease.

Changes in the airways of infants and children with CF result in a more suitable environment for microbial infection and establishment of an inflammatory response. Bacterial pathogens that primarily affect infants and young children include Staphylococcus aureus and Haemophilus influenzae. Pulmonary infection with Pseudomonas aeruginosa is important to review, since this pathogen is responsible for significant morbidity. P. aeruginosa may be isolated in young children as well. Appropriate antibiotic therapy may result in eradication. However, repeat acquisition and infection often occurs, resulting in chronic colonization.

P. aeruginosa adapts to the altered pulmonary environment by producing alginate (exopolysacharide) and converting to a mucoid phenotype. Conversion to this mucoid phenotype occurs over several years; the median age for acquisition of mucoid P. aeruginosa is 13 years. Colonization with mucoid P. aeruginosa is associated with increased pulmonary morbidity (2.6-fold increase in death) and loss of lung function. Thus, preventing or delaying the acquisition of nonmucoid P. aeruginosa becomes an important therapeutic goal. Once acquisition of mucoid P. aeruginosa occurs, eradication is not possible.

Because of its relationship with decreased lung function, prevention or delay of colonization and chronic infection with P. aeruginosa is desirable. Several studies have evaluated this premise, using various antibiotics (aerosol tobramycin, colistin, ciprofloxacin). Authors of a recent literature review of these studies concluded that early antibiotic treatment could reduce the number of positive P. aeruginosa sputum cultures and anti- P. aeruginosa antibody titer, and thus delay chronic colonization and infection. Because differing antibiotic regimens were used in these studies, the most effective antibiotic regimen is not known.

There is great variability in the age of first onset of a pulmonary exacerbation in patients with cystic fibrosis. As pulmonary disease worsens, the frequency of pulmonary exacerbations increases. A pulmonary exacerbation is defined as a change in respiratory signs and symptoms from baseline, including: increased cough and/or sputum production, decreased exercise tolerance, loss of weight and/or appetite, decreased lung function (forced vital capacity or forced expiratory volume in one second) by greater than 10%, or onset of new or increased crackles. Patients with mild pulmonary exacerbations may be treated as an outpatient, but patients with more severe symptoms should be hospitalized.

Antibiotic choice is guided by sputum culture and sensitivity reports. Pathogens isolated from sputum cultures are usually the same as those isolated during asymptomatic periods. Typically, two antibiotics with differing mechanisms of action are used when P. aeruginosa is suspected or isolated upon culture (eg, antipseudomonal -lactam {ceftazidime} plus an aminoglycoside or fluoroquinolone). The use of ciprofloxacin is appropriate for this indication as discussed in the 2006 Report of the Committee on Infectious Diseases (Red Book). Ciprofloxacin is available as an oral suspension (50, 100 mg/ml) for use in younger children. The pharmacokinetics of some antibiotics has been found to differ when used in patients with CF. Higher doses or more frequent dosing may be necessary. Appropriate oral dosing of ciprofloxacin for treatment of a pulmonary exacerbation is 20 mg/kg per dose given twice daily.

Airway clearance is an important component of care for patients with CF. Viscous pulmonary secretions should be mobilized to prevent mucus plugging and airway obstruction. Chest physiotherapy and percussion or more technologically advanced devices (e.g., high-frequency chest oscillation) are all effective therapies.

Pulmonary drugs

Dornase alpha (Pulmozyme, Genentech) is a unique drug labeled only for the treatment of CF to improve pulmonary function. Pulmozyme solution is administered orally by inhalation of an aerosol mist once or twice daily. Pulmozyme is recombinant human deoxyribonuclease I (rhDNase), an enzyme which cleaves DNA. Mucus of patients with CF contains high amounts of extracellular DNA released from degenerating leukocytes, present because of bacterial invasion and infection. This extracellular DNA increases mucus viscosity. Benefits of using Pulmozyme include a modest improvement in pulmonary function (6% relative change in forced expiratory volume in one second) and reduced risk of pulmonary exacerbation and hospitalization. Limitations of use include high cost – $1,500 for 30-day supply. In 2004, 72.4% of eligible patients with CF were prescribed Pulmozyme. Some CF physicians may harbor concerns about the relatively modest benefits of Pulmozyme and its high cost.

Another solution administered by oral inhalation of an aerosol mist is tobramycin (TOBI, Chiron), an aminoglycoside antibiotic. It is labeled for patients chronically colonized with P. aeruginosa to suppress bacterial growth and infection and to preserve pulmonary function. TOBI is given in alternating 28-day periods and is dosed at 300 mg twice daily. Most of the administered drug remains in the lungs, but a small amount may appear in plasma (approximately one µg/ml, one hour after administration). TOBI is generally well tolerated, however, tinnitus and hearing loss have been reported. TOBI is expensive – $3,500 for a 56 day treatment supply.

A controlled trial that evaluated the use of nebulized hypertonic saline (7%) in patients with CF recently demonstrated a beneficial effect on lung function and a reduced risk of pulmonary exacerbations. Hypertonic saline likely increases water transport into the mucus layer, reducing mucus viscosity and improving mucus flow. Hypertonic saline is not commercially available as a 7% solution. The patient can mix it prior to use by using the commercially available 3% and 10% solutions, or multiple doses can be compounded by a pharmacy.

Ibuprofen is likely the least used preventive pulmonary agent for the pharmacotherapy of CF. Ibuprofen possesses anti-inflammatory effects, and when used in high doses (20-30 mg/kg per dose, given twice daily) it reduces neutrophil migration and lysosomal enzyme release. In clinical trials, ibuprofen slowed the rate of decline of pulmonary function. Benefits of ibuprofen therapy are apparent mostly in children aged 5 to 13 years. Ibuprofen must be dosed pharmacokinetically, to achieve plasma levels of 50-100 µg/ml. In 2004, ibuprofen was prescribed to less than 5% of patients with CF who were eligible to receive it. Clinicians have raised concerns about adverse effects (gastrointestinal bleeding, reduced renal function) with the use of high doses of ibuprofen. Although these adverse effects occur less commonly in children than adults, they have been reported.

In a recent controlled-trial, azithromycin (Zithromax, Pfizer), an azalide antibiotic (subclass of macrolides), was shown to improve lung function and reduce the risk of a pulmonary exacerbation in patients with CF who were chronically colonized with P. aeruginosa. Azithromycin is dosed 3 days per week (Monday, Wednesday, Friday) when used for CF. The exact mechanism of action of azithromycin has not been clearly elucidated. Speculations on its action include antiinflammatory effects or the ability to reduce alginate production by P. aeruginosa.

Conclusion

Tremendous advances have occurred in recent years in the treatment of cystic fibrosis, with new drugs and new uses for older drugs contributing to these advancements. The median age of survival is now approaching 37 years. More than 115 specialized CF care centers are located throughout the United States, and patients with CF should be referred to one of these centers when a diagnosis of CF is suspected. Clinicians at these centers can be helpful to physicians who provide primary care for their patients with cystic fibrosis.

For more information:

• For CF specialized center locations, visit www.cff.org/chapters_and_care_centers/
• Marchetti F. Early antibiotic treatment of pseudomonas aeruginosa colonization in cystic fibrosis: a critical review of the literature. European Journal of Clinical Pharmacology 2004;60:67-74.
• Elkins MR. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. New Engl J Med. 2006;354:229-240.
• Saiman L. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa. JAMA. 2003;290:1749-1756.
• Gibson RL. Pathophysiology and management of pulmonary infections in cystic fibrosis. Amer J Crit Care Med. 2003;168:918-951.