Medication Summary
Medications used to treat patients with cystic fibrosis may include pancreatic enzyme supplements, multivitamins (particularly fat-soluble vitamins), mucolytics, antibiotics (including inhaled, oral, or parenteral), bronchodilators, anti-inflammatory agents, and CFTR potentiators (eg, ivacaftor) and correctors (eg, elexacaftor, lumacaftor, tezacaftor).
Enzymes, Pancreatic
Class Summary
These agents aid digestion when the pancreas is malfunctioning. Current pancreatic enzyme preparations are derived from porcine extracts and contain various proportions of lipase, amylase, and protease. Most of the preparations are available in multiple strengths.
A particular dose is prescribed based on clinical symptoms and age and weight and then modified according to the clinical response. Usually, the dose of pancreatic enzymes should not exceed 2000 U/kg/meal of lipase. The novel preparation TheraCLEC-Total, a highly purified microbiologically-derived enzyme preparation, is under investigation in clinical trials.
Pancrelipase (Creon, Pancreaze, Ultresa, Zenpep)
These enteric-coated pancreatic enzyme microspheres contain various amounts of lipase, protease, and amylase. Pancrelipase assists in the digestion of protein, starch, and fat.
Vitamins
Class Summary
Vitamins are organic substances required by the body in small amounts for various metabolic processes. They may be synthesized in small or insufficient amounts in the body or not synthesized at all, thus requiring supplementation. They are classified as fat or water soluble. Vitamins A, D, E, and K are fat soluble while biotin, folic acid, niacin, pantothenic acid, B vitamins (ie, B-1, B-2, B-6, B-12), and vitamin C are generally water soluble.
Vitamin deficiency may result from an inadequate diet, increased requirements (eg, pregnancy, lactation), or secondary to disease or drug use. Vitamins are clinically used for the prevention and treatment of specific vitamin deficiency states. Supplementation of fat-soluble vitamins is routine in cystic fibrosis because of chronic malabsorption.
Vitamin A (Aquasol A)
Vitamin A is a fat-soluble vitamin and is essential for antioxidant effects and as coenzymes for biological pathways, neurodevelopment, bone development, and coagulation. Typical multivitamin preparations formulated especially for patients with CF are referred to as ADEKs. Doses vary by patient age.
Vitamin D (1,25-Dihydroxycholecalciferol, Calciferol, Cholecalciferol)
Vitamin D is a fat-soluble vitamin and is essential for antioxidant effects and as coenzymes for biological pathways, neurodevelopment, bone development, and coagulation. Typical multivitamin preparations formulated especially for patients with CF are referred to as ADEKs. Doses vary by patient age.
Vitamin E (Alpha-tocopherol, Aquasol E, Tocopherol)
Vitamin E is a fat-soluble vitamin and is essential for antioxidant effects and as coenzymes for biological pathways, neurodevelopment, bone development, and coagulation. Typical multivitamin preparations formulated especially for patients with CF are referred to as ADEKs. Doses vary by patient age.
Vitamin K1 (phytonadione) (AquaMephyton, Mephyton)
Vitamin K is a fat-soluble vitamin and is essential for antioxidant effects and as coenzymes for biological pathways, neurodevelopment, bone development, and coagulation. Typical multivitamin preparations formulated especially for patients with CF are referred to as ADEKs. Doses vary by patient age.
Bronchodilators
Class Summary
Albuterol provides selective agonistic action on beta2-adrenoceptors. Stimulation of adenyl cyclase results in smooth muscle relaxation of the bronchi, uterus, and skeletal muscle.
Inhaled beta2-agonists are often administered before chest physical therapy for airway clearance. They also are indicated when clinical evidence of bronchial hyperresponsiveness exists. In children with CF, the use of bronchodilators must be evaluated. Children with bronchiectasis may have a paradoxic bronchodilatation in response to beta-adrenergic agents. Pulmonary function testing before and after bronchodilators is suggested to avoid these counterproductive effects.
Albuterol (AccuNeb, ProAir, Proventil HFA, VoSpire ER, Ventolin HFA)
Albuterol is the most commonly used bronchodilating agent. It is available in multiple dosage forms (eg, solution for nebulization, metered-dose inhaler, PO solution). Typically, 2.5 mg of albuterol nebulizer solution is used either in premixed solution with isotonic sodium chloride solution or 0.5 mL of albuterol solution is mixed with 3 mL of 0.9% NaCl and administered before chest physical therapy.
Mucolytic Agents
Class Summary
Large amounts of neutrophil-derived DNA released from dead neutrophils increase sputum viscosity. Mucolytics, such as dornase alfa, an enzyme that hydrolyses the DNA, are used in patients with CF to improve airway clearance.
The Pulmonary Therapies Committee of Cystic Fibrosis Foundation recommends long-term use of hypertonic saline for patients with cystic fibrosis aged 6 years or older to improve lung function and to reduce the number of exacerbations. [64]
Dornase alfa (Pulmozyme)
Dornase alfa is a recombinant human DNase (rhDNase) that cleaves and depolymerizes extracellular DNA and separates DNA from proteins. This allows endogenous proteolytic enzymes to break down the proteins, thus decreasing viscoelasticity and surface tension of purulent sputum.
CFTR Potentiators and Correctors
Class Summary
Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators are the first available treatment that targets the defective CFTR protein, which is the underlying cause of cystic fibrosis.
CFTR correctors (eg, elexacaftor, lumacaftor, tezacaftor) corrects the processing and trafficking defect of the F508del-CFTR protein to enable it to reach the cell surface where the CFTR potentiator, ivacaftor, can further enhance the ion channel function of the CFTR protein.
A recently published phase 3 extension study reported 42% slower rate of decline in percent predicted FEV1 in patients receiving long term treatment with lumacaftor and ivacaftor than in matched CF registry controls. [81]
Similarly, phase 3 trials with tezacaftor/ivacaftor and ivacaftor measured improvements across multiple disease measures, including lung function and pulmonary exacerbations compared with ivacaftor monotherapy. [59, 60]
Ivacaftor (Kalydeco)
Ivacaftor potentiates the CFTR protein, a chloride channel present at the surface of epithelial cells in multiple organs. This facilitates increased chloride transport by potentiating the channel-open probability (or gating) of certain CFTR gene mutations. It is indicated for cystic fibrosis in adults and children aged 4 months or older who have one mutation in the CFTR gene. It is not effective when used without a CFTR corrector (eg, lumacaftor) if the patient is homozygous for the F508del mutation in the CFTR gene.
Lumacaftor/ivacaftor (Orkambi)
This combination product contains lumacaftor, a CFTR corrector. Lumacaftor corrects the processing and trafficking defect of the F508del-CFTR protein to enable it to reach the cell surface where the CFTR potentiator, ivacaftor, can further enhance the ion channel function of the CFTR protein. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR proteins. The combination is indicated for cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. This combination is well tolerated in young children.
Tezacaftor/ivacaftor (Symdeko)
CFTR corrector and potentiator combination regimen. It is indicated for cystic fibrosis (CF) in patients aged ≥6 yr who are homozygous for the F508del mutation or who have at least 1 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
Elexacaftor/tezacaftor/ivacaftor (Trikafta)
Elexacaftor and tezacaftor bind to different sites on the cystic fibrosis transmembrane conductance regulator (CFTR) protein and have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface.
It is indicated for cystic fibrosis in adults and children aged ≥12 years who have at least 1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90% of the cystic fibrosis population.
Antibiotics
Class Summary
Antibiotic treatment may vary from a short course of one antibiotic agent to a continuous course with multiple antibiotics administered via various routes, including oral, intravenous, or inhalation. Antibiotic therapy has been found to be related to the greater likelihood of recovery after acute decline in FEV1. [82] Because patients with cystic fibrosis have a larger lean body mass, they often have a higher clearance rate for many antibiotics. Achieving effective levels in respiratory secretions is difficult; higher doses of antibiotics and monitoring of aminoglycoside levels are required.
A Cochrane review included four studies (total 328 patients) comparing once-daily dosing of aminoglycosides in the treatment of acute pulmonary exacerbation with thrice-daily dose. There were no significant differences in lung function, weight for height, and body mass index. The creatinine changes significantly favored once-daily treatment in children but not in adults. These findings support the recent trend to use once-daily intravenous aminoglycosides. [83]
Administer aerosolized antibiotics when the airway pathogens are resistant to oral antibiotics or when the infection is difficult to control at home. Aerosolized antibiotics may reduce symptoms by reducing the organism density in the airways. Other advantages include prevention of infection or delay of chronic colonization, treatment of acute infection, and treatment of bacterial colonization in patients following transplantation to prevent infection in the transplanted lungs.
Agents used in the aerosolized form include gentamicin, aztreonam, colistin, and preservative-free high-dose tobramycin especially formulated for inhalation (ie, TOBI). Currently, clinical trials using a powder form of tobramycin and colistin are under way. These preparations use novel delivery devices and shorten the time required for dosage administration. A European study comparing lung function in 380 patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection reported that colistimethate sodium dry powder inhalation was as effective as nebulized tobramycin. [84]
Cephalosporins are effective against staphylococci and Haemophilus influenzae. A small subset of third-generation cephalosporins is effective against Pseudomonas aeruginosa. Generally speaking, moving from first-generation to third-generation cephalosporins gives increasing gram-negative coverage and less gram-positive coverage.
Fluoroquinolones are effective against most gram-positive and gram-negative organisms. They are the only class of oral antibiotics effective against P aeruginosa. The most commonly used medication in this class is ciprofloxacin. No fluoroquinolones are approved for children because of concern regarding their effects on deposition in the cartilage. However, studies from Europe have reported substantial evidence of their safety in patients with CF.
In patients with colonization with P aeruginosa, azithromycin administered orally 3 times per week on a long-term basis has been shown to improve lung function and nutritional status and to reduce acute pulmonary exacerbations. [85] . However, one study reported that azithromycin may interfere with the P aeruginosa, killing the action of inhaled tobramycin in these patients. [86]
Because colonization with P aeruginosa is considered to be an unfavorable event in the clinical course of patients with cystic fibrosis, various regimens have been studied in an attempt to eradicate the organism. A group in Italy compared inhaled tobramycin plus oral ciprofloxacin with inhaled colistin plus oral ciprofloxacin. They reported 62.8% and 65.2% eradication, respectively, thus showing no superiority for either treatment. [87]
Tobramycin inhaled (TOBI, Bethkis, TOBI Podhaler)
Preservative-free high-dose tobramycin especially formulated for oral inhalation (ie, TOBI, Bethkis) has been reported to be safe and effective in patients older than 6 months. The usual dose is 300 mg inhaled via nebulization twice daily administered during alternate months. A dry powder inhaler device is also available (TOBI Podhaler) with a different dosage regimen of 4 capsules (28 mg/cap) inhaled orally BID. Long-term intermittent administration in patients with P aeruginosa infection improves pulmonary function and nutritional status and reduces symptomatic pulmonary exacerbation.
Systemic tobramycin is usually combined with one of the penicillins used to treat pseudomonad infections in patients with CF. It is administered intravenously.
Aztreonam inhalation (Azactam, Cayston)
Aztreonam is a monobactam antibiotic that elicits activity in vitro against gram-negative aerobic pathogens, including P aeruginosa. This agent binds to penicillin-binding proteins of susceptible bacteria, thereby inhibiting bacterial cell wall synthesis, resulting in cell death. Activity is not decreased in the presence of cystic fibrosis lung secretions.
Aztreonam is indicated to improve respiratory symptoms in patients with CF who are infected with P aeruginosa.
Gentamicin
Gentamicin is usually combined with one of the penicillins used to treat pseudomonad infections in patients with CF.
Piperacillin
Piperacillin is effective against most strains of P aeruginosa and H influenzae. It is usually not effective against staphylococci. It is administered intravenously.
Cephalexin (Keflex)
Cephalexin is a first-generation cephalosporin that arrests bacterial growth by inhibiting bacterial cell wall synthesis. It has bactericidal activity against rapidly growing organisms. Its primary activity is against skin flora.
Ceftazidime (Fortaz, Tazicef)
Ceftazidime is a third-generation cephalosporin with broad-spectrum gram-negative activity. It has lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. It arrests bacterial growth by binding to one or more penicillin-binding proteins.
Ciprofloxacin (Cipro XR, Proquin XR)
Ciprofloxacin is a fluoroquinolone with activity against Pseudomonas organisms, streptococci, methicillin-resistant Staphylococcus aureus (MRSA), S epidermidis, and most gram-negative organisms, but with no activity against anaerobes. This agent inhibits bacterial DNA synthesis and, consequently, growth. Oral bioavailability is lower in younger patients with CF (65%) than in those older than 13 years (95%).
Trimethoprim/sulfamethoxazole (Bactrim DS, Septra DS)
The broad spectrum and action of trimethoprim and sulfamethoxazole (TMP-SMZ) against organisms found in patients with CF and the convenience of oral administration make this combination useful for treatment of milder infections on an outpatient basis.
Chloramphenicol
Chloramphenicol is effective against H influenzae and staphylococcal species. It may help treat P aeruginosa infection, for unclear reasons. Oral chloramphenicol is no longer available in the United States.
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Chest radiograph of a patient with advanced cystic fibrosis. Note marked hyperinflation, peribronchial thickening, and bilateral infiltrates with evidence of bronchiectasis especially of the upper lobes.
