Treatment outcomes for CF are divided into short-term and long-term outcomes. The short-term goals for the intestinal disease are normal bowel habits, weight gain, and normal vitamin levels. The long-term goal for the intestinal disease is optimal nutrition. The short-term goals for the pulmonary treatment are to reduce the airway infection, inflammation, and obstruction. The goal of an acute exacerbation is to return pulmonary function to the preexacerbation status. The long-term goal of pulmonary treatment is to arrest the persistent decline in forced vital capacity (FVC), forced expiratory volume at 1 s (FEV1), and increase in residual volume (RV).
Pancreatic Enzyme Replacement Therapy
Gastrointestinal treatment is primarily accomplished with pancreatic enzyme replacement therapy. The preferred products are the microencapsulated pancreatic enzymes (Table 44-3). The enteric-coated spheres inside these capsules are protected from destruction by gastric acid and therefore can be given in much lower doses than the older noncoated products. These products are dosed based on the lipase component at an initial dose of 1000 lipase units/kg/meal; one-half of this amount is administered with snacks.3 For patients unable to swallow capsules, the contents may be opened and sprinkled over applesauce, jelly, or some nonalkaline soft food. Side effects are associated with high doses of the enzyme products. Hyperuricosuria has been reported due to the high purine content of the products. Proximal colonic stricture is associated with doses in excess of 24,000 units/kg/d. Histamine H2-receptor antagonists and proton pump inhibitors have been used to decrease the enzyme dose in patients who are hypersecretors of acid. Constant acid in the colon prevents the enteric coating from dissolving.
TABLE 44-3 Enteric Coated Pancreatic Enzyme Products ||Download (.pdf)
TABLE 44-3 Enteric Coated Pancreatic Enzyme Products
|Pancrease MT 4||4,000||12,000||12,000|
|Pancrease MT 10||10,000||30,000||30,000|
|Pancrease MT 16||16,000||48,000||48,000|
|Ultrase MT 12||12,000||39,000||39,000|
|Ultrase MT 20||20,000||65,000||65,000|
|Ultrase MT 18||24,000||78,000||78,000|
Vitamin Replacement Therapy
Vitamins are required in CF patients who pass fat in their stools; especially the fat-soluble vitamins. These deficiencies become clinically evident as neurologic dysfunction (vitamin E); demineralization of the bone (vitamin D); bleeding problems (vitamin K); and dermatitis, vision difficulties (vitamin A). Vitamin K, at a dose of 5 mg twice weekly, should be given to patients with a prolonged international ratio (INR).3 Recommended daily allowance (RDA) of the fat-soluble vitamins are administered in water-miscible products, such as ADEK, that are better absorbed in the CF patient but more expensive. Higher doses of the older fat-soluble vitamin products overcome this poor bioavailability and are much less expensive. These products can be administered starting at twice the RDA and adjusted as needed.
The older CF patient can benefit from ursodeoxycholic acid (UDCA), a bile acid with choleretic properties. This medication has been shown to produce morphologic and functional improvement in patients with liver disease. Doses range from 15 to 20 mg/kg/d in combination with taurine supplementation.3 This agent is recommended to be given prophylactically to prevent end-stage liver failure.
Pulmonary treatment is focused on three areas: anti-obstruction, anti-inflammation, and anti-infective therapy.
The main treatment for removal of mucous and secretions from the airways is percussion and postural drainage. Vibrations loosen mucous and secretions (eg, percussion) and placing the head lower than the body (eg, postural drainage) facilitates removal of the mucous and secretions. Nebulized mucolytics, such as sterile sodium chloride or N-acetylcysteine (eg, Mucomyst), can increase the results of the percussion; and nebulized bronchodilators, such as albuterol, can increase the results of postural drainage. Two new nebulized products have been studied for long-term chronic use to prevent the accumulation of mucous and secretions in the lungs of CF patients. The first is recombinant human DNAse to be given by inhalation (2.5 mg once or twice daily) to reduce the viscosity of pulmonary secretions. This medication has been shown to increase the time between pulmonary exacerbations in CF patients. The second nebulized product for chronic use is hypertonic saline in a 7% sterile solution. It is thought that this product will slow the progression of lung damage in CF patients.4,5
Anti-inflammatory treatments for CF patients can be accomplished with three groups of medications: oral corticosteroids, inhaled corticosteroids, and ibuprofen. Oral corticosteroids have shown improvements in pulmonary function tests but detrimental effects on linear growth and glucose metabolism.6 Inhaled corticosteroids have not been studied sufficiently in this population. High-dose ibuprofen slowed the rate of progression of pulmonary disease but serum concentration monitoring is needed and is very costly. Low-dose ibuprofen has been shown to increase inflammation.7
Antibiotic therapy for CF results in clinical improvement without eradicating all bacteria from the sputum (ie, suppressive therapy). The primary bacteria in the lungs of the CF patient is P. aeruginosa which secretes an extracellular matrix known as a biofilm that protects it from local host defenses and most antibiotics. Also, the bacteria is colonizing the airway surface, rather than penetrating the tissue as a pathogen and this is another way the bacteria is protected from host defenses and antibiotics (ie, endobronchial infection). Suppressive antibiotic therapy is aimed at P. aeruginosa and S. aureus and is accomplished with an aminoglycoside plus an extended-spectrum penicillin. Double antibiotic therapy is recommended to take advantage of synergy with the antibiotic combination and to prevent the emergence of resistance.8 Since most of the S. aureus encountered are β-lactamase producers, the use of an extended-spectrum penicillin plus a β-lactamase inhibitor combination (eg, ticarcillin-clavulanate) will avoid triple antibiotic therapy. Double-drug therapy has shown superiority over treatment with single drugs9-12 and decreases the development of resistance.12 Unlike other lower respiratory tract infections, CF sputum cultures correlate well with lower tract organisms and should guide therapy. Older CF patients will usually have resistant organisms such as MRSA (ie, methicillin-resistant S. aureus), B. cepacia, and S. maltophilia. These organisms are generally resistant to most antibiotics and treatment should be guided by the culture and sensitivity report. Older antibiotics with unique mechanisms of action (eg, colistin, polymyxin B) may exhibit susceptibility in patients with resistant organisms. Patients with resistant organisms should wear a respirator mask when with other CF patients as they have been shown to pass these organisms to other CF patients. Because of this observation, CF camps have been discontinued.
Oral antibiotics have been prescribed in symptomatic outpatients with susceptible organisms. This "prophylactic practice" is discouraged because the beneficial effect does not outweigh the risk of the development of resistant organisms.13 The fluoroquinolone antibiotic ciprofloxacin has activity against all the CF pathogens and has been evaluated in adults undergoing CF exacerbation. Studies are inconclusive due to flaws in design but suggest this oral therapy is as effective as IV therapy.14 This agent appears to be safe but should be used with caution in those younger than 18 years due to the possibility of joint or cartilage toxicity.15
Once-daily dosing of aminoglycosides has been attempted in this population to achieve higher pulmonary concentrations of antibiotic. More studies are needed to determine the efficacy and safety of this method of administration.16
The inhaled route of antibiotic delivery has also been tried in the CF population. Topical delivery via inhalation ensures delivery of the drug in high concentrations to the site of infection while avoiding systemic toxicity. Original studies with small doses reported a high incidence of resistant organisms during inhalation treatment. A more recent placebo-controlled, multicenter trial of tobramycin 600 mg administered by aerosol three times daily produced a statistically significant improvement in FEV1, FVC, FEV 25% to 75%, P. aeruginosa density in the sputum, and peripheral WBC count.17 Appropriate clinical use of this therapy (prophylaxis, treatment, length of therapy, frequency of therapy) remains to be determined. More studies are needed and preservative-free antibiotic preparations should be used with these larger doses.
CF patients have increased clearance of many antibiotics including aminoglycosides, some β-lactams, and trimethoprim-sulfamethoxazole. Increased clearance means higher doses in most patients. A CF dosing chart such as Table 44-4 should be consulted for dosing in this population and subsequent pharmacokinetic calculations performed to further individualize the dose.
TABLE 44-4 Antibiotic Doses in Cystic Fibrosis ||Download (.pdf)
TABLE 44-4 Antibiotic Doses in Cystic Fibrosis
|Antibiotic||Dosea||Max Doseb||Regimen||Serum Levelc|
|Tobra/Gent||6-9||NA||Every 8 h||Peak >8, trough <2|
|Amikacin||20-30||NA||Every 8 h||Peak >24, trough <9|
|Aztreonam||200||8||Every 6 h||NA|
|Ceftazidime||150||6||Every 8 h||NA|
|Colistin||2.5-6||NA||Every 6-8 h||NA|
|Imipenem||45-100||4||Every 6 h||NA|
|Nafcillin||100||6||Every 4-6 h||NA|
|Ticarcillin||400||18||Every 4-6 h||NA|
|Ticarcillin + clavulanate||400||18||Every 4-6 h||NA|
|Piperacillin||400||18||Every 4-6 h||NA|
|Amoxicillin||20||NA||Every 8 h||NA|
|Amoxicillin + clavulanate||20||NA||Every 6 h||NA|
|Ciprofloxacin||1.5 g/d||1.5||Every 12 h||NA|
|Cephalexin||50-100||6||Every 6-8 h||NA|
|Dicloxacillin||80-100||6||Every 6 h||NA|
|Trim/Sulfa||10-15||0.64||Every 12 h||NA|
|Tobra/Gent||0.6-1.8 g/d||NA||Every 12 h||NA|
|Colistin||150 mg/d||NA||Every 6-12 h||NA|
|Polymyxin B||250 mg/d||NA||Every 6-12 h||NA|