Kimberly J. Novak
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Explain the pathophysiology of cystic fibrosis (CF) and its multiorgan system involvement.
2. Describe the common clinical presentation and diagnosis of CF.
3. Consider long-term treatment goals with respect to clinical course and prognosis of CF.
4. Identify nonpharmacologic therapies for CF management.
5. Recommend appropriate pharmacologic therapies for chronic CF management.
6. Design appropriate antibiotic regimens for acute pulmonary exacerbations of CF.
7. Employ pharmacokinetic principles when calculating drug doses in CF patients.
8. Formulate monitoring plans for acute and chronic CF pharmacotherapy.
KEY CONCEPTS
In cystic fibrosis (CF), the CF transmembrane regulator (CFTR) chloride channel is dysfunctional and usually results in decreased chloride secretion and increased sodium absorption, leading to altered viscosity of fluid excreted by the exocrine glands and mucosal obstruction.
Pulmonary disease is characterized by thick mucus secretions, impaired mucus clearance, chronic airway infection and colonization, obstruction, and an exaggerated neutrophil-dominated inflammatory response.
Maximizing nutritional status through pancreatic enzyme replacement and vitamin and nutritional supplements is necessary for normal growth and development and for maintaining long-term lung function.
Airway clearance therapy is a necessary routine for all CF patients to clear secretions and control infection.
Antibiotic therapy is indicated in three distinct situations over the course of CF: (a) early eradication and delay of colonization; (b) suppression of bacterial growth once colonization occurs; and (c) reduction of bacterial load in acute overgrowth.
Antibiotic selection is based on periodic culture and sensitivity data, typically covering all organisms identified during the preceding year. If no culture data are available, empiric antibiotics should cover the most likely organisms for the patient’s age group.
Antibiotic regimens in severe CF exacerbations usually include an IV antipseudomonal β-lactam plus an aminoglycoside.
CF patients have larger volumes of distribution for many antibiotics due to an increased ratio of lean body mass to total body mass and lower fat stores. CF patients also have an enhanced total body clearance, although the exact mechanism has not been determined.
Titration of pancreatic enzyme doses is based on control of steatorrhea, stool output, and abdominal symptoms.
Because CF-related diabetes results from insulin insufficiency, exogenous insulin replacement is usually required.
INTRODUCTION
Cystic fibrosis (CF) is an inherited multiorgan system disorder affecting children and an ever-growing adult population. It is the most common life-threatening genetic disease among Caucasians and the major cause of severe chronic lung disease and pancreatic insufficiency in children. The disease generally manifests as mucosal obstruction of exocrine glands caused by defective ion transport within epithelial cells. Due to the array of affected organ systems and complicated medical therapies, appropriate CF treatment necessitates multidisciplinary team collaboration.
EPIDEMIOLOGY AND ETIOLOGY
In the United States, CF most commonly occurs in the Caucasian population, ranging from 1 in 1,900 to 3,700 individuals. CF is less common in Hispanics (1 in 9,000), African Americans (1 in 15,000), and Asian Americans (1 in 32,000).1 CF is inherited as an autosomal recessive trait, and approximately 1 in 25 Caucasians are heterozygous carriers. Offspring of a carrier couple (each parent being heterozygous) have a 1 in 4 chance of having the disease (homozygous), a 1 in 2 chance of being a carrier (heterozygous), and a 1 in 4 chance of receiving no trait. The gene mutation is found on the long arm of chromosome 7 and encodes for the CF transmembrane regulator (CFTR) protein, which functions as a chloride channel to transport water and electrolytes. Over 1,000 mutations have been described in the CF gene; however, the ΔF508 mutation is the most common and is present in 70% to 90% of CF patients in the United States.2
PATHOPHYSIOLOGY
CF is a disease of exocrine gland epithelial cells where CFTR expression is prevalent. Normally, these cells transport chloride through CFTR chloride channels with sodium and water accompanying this flux across the cell membrane (Fig. 16–1). CFTR is regulated by protein kinases in response to varying levels of the intracellular second messenger cyclic-3’,5’-adenosine monophosphate (cAMP). CFTR also downregulates the epithelial sodium channel, regulates calcium-activated chloride and potassium channels, and may function in exocytosis and formation of plasma membrane molecular complexes and proteins important in inflammatory responses.2 In CF, the CFTR chloride channel is dysfunctional and usually results in decreased chloride secretion and increased sodium absorption, leading to altered viscosity of fluid excreted by the exocrine glands and mucosal obstruction.
Pulmonary System
Chronic lung disease is a hallmark of CF, leading to death in 90% of patients.3 Pulmonary disease is characterized by thick mucus secretions, impaired mucus clearance, chronic airway infection and colonization, obstruction, and an exaggerated neutrophil-dominated inflammatory response.4 Over time, chronic obstruction and inflammations lead to air trapping, atelectasis, mucus plugging, bronchiectasis,cystic lesions, pulmonary hypertension, and eventual respiratory failure. In the U.S.-CF population, pulmonary function declines at an average yearly rate of 2%, as measured by forced expiratory volume in 1 second (FEV1). The rate in an individual patient may be higher or lower depending on severity of CFTR dysfunction and comorbidities. Patients may show a slow steady decline over time, or they may have stable lung function with intermittent periods of sharp decline.1 In the upper airways, sinusitis and nasal polyps are also common, and microbial colonization is similar to that of the lungs.
FIGURE 16–1. Electrolyte transport in the airway epithelial cell. (Ca, calcium; cAMP, cyclic-3’, 5’-adenosine monophosphate; CI, chloride; Na, sodium; K potassium.) (From Milavetz G, Smith JJ. Cystic fibrosis. In: DiPiro JT, Talbert RL, Yee GC, et al. (eds.) Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill, 2008: 536.)
Bacterial pathogens are often acquired in an age-dependent sequence, and prevalence is tracked in the Cystic Fibrosis Foundation Patient Registry. Early infection is most often caused by Staphylococcus aureus and nontypeable Haemophilus influenzae (and thus is not prevented by childhood H. influenzae type b immunization). Pseudomonas aeruginosa infection also occurs early in life and is the most significant CF pathogen among all age groups. P. aeruginosa expresses extracellular toxins that perpetuate lung inflammation. Mucoid strains of P. aeruginosa produce an alginate biofilm layer that interferes with antibiotic penetration. Other organisms identified later in the disease course include Stenotrophomonas maltophilia, Achromobacter (Alcaligenes) xylosoxidans, Burkholderia cepacia, fungi including Candida and Aspergillus species, and nontuberculous mycobacteria.1 Other organisms may also present chronically or intermittently. Similarly, cultured organisms may represent an initial infection, chronic colonization, or microbial overgrowth in an acute exacerbation.
Gastrointestinal System
GI involvement may present initially as small bowel obstruction shortly after birth due to abnormally thick meconium that cannot be passed (meconium ileus). Older CF patients may develop distal intestinal obstruction syndrome (DIOS), formerly called meconium ileus equivalent, which occurs due to fecal impaction in the terminal ileum and cecum.
Maldigestion due to pancreatic enzyme insufficiency is present in about 85% to 90% of CF patients.5 Thick pancreatic secretions and cellular debris obstruct the pancreatic ducts and lead to fibrosis. Volume and concentration of pancreatic enzymes and bicarbonate are reduced, leading to maldigestion of fat and protein and subsequent malabsorption of fat-soluble vitamins (A, D, E, and K). Maldigestion is characterized by abdominal distention, steatorrhea,flatulence, and malnourishment despite voracious intake. Maldigestion is progressive and may develop later in a previously pancreatic sufficient patient. Other complications may include gastroesophageal reflux, dysmotility, salivary dysfunction, intussusception, volvulus, atresia, rectal prolapse, and complications related to corrective surgery for meconium ileus.6
Hepatobiliary disease occurs due to bile duct obstruction from abnormal bile composition and flow. Hepatomegaly, splenomegaly, and cholecystitis may be present. Hepatic steatosis may also be present due to effects of malnutrition. The progression from cholestasis (impaired bile flow) to portal fibrosis and to focal and multilobar cirrhosis, esophageal varices, and portal hypertension takes several years. Many patients are compensated and asymptomatic but may be susceptible to acute decompensation in the event of extrinsic hepatic insult from viruses, medications, or other factors.7
Endocrine System
CF-related diabetes (CFRD) shares characteristics of both type 1 and type 2 diabetes mellitus, but CFRD is categorized separately. Reduced functional pancreatic islet cells and increased islet amyloiddeposition results in insulin deficiency, the primary cause of CFRD. Insulin secretion is delayed in response to glucose challenge, and absolute insulin secretion over time is reduced. Some insulin resistance may also be present in CFRD; however, sensitivity maybe increased in CF patients without diabetes.8
Postprandial hyperglycemia is common, but because some basal insulin secretion is maintained, fasting hyperglycemia is less severe and ketosis is rare.5 Diet, acute and chronic infection, and corticosteroid use lead to fluctuations in glucose tolerance over time.8 CFRD is associated with greater nutritional failure, increased pulmonary disease, and earlier death. The average age of onset is 18 to 21 years; but underdiagnosis is thought to be common.
Reproductive System
CF patients often experience delayed puberty. In females, menarche occurs 18 months later than average, and menstrual irregularity is common. Females also have reduced fertility due to increased viscosity of cervical mucus. Due to increasing life expectancy, pregnancy is becoming more common; however, outcomes depend on prepartum nutritional and pulmonary status. Almost all males with CF are azoospermicdue to congenital absence of the vas deferens with resultant obstruction; however, conception still occurs occasionally. Conception can also occur through application of assisted reproductive technologies.9
Musculoskeletal System
Several factors contribute to development of bone disease in CF: (a) malabsorption of vitamins D and K and calcium; (b) poor nutrition and decreased body mass; (c) physical inactivity; (d) corticosteroid therapy; and (e) delayed puberty. Chronic pulmonary infection, through release of inflammatory cytokines, can cause increased bone resorption and decreased formation. Osteopenia, osteoporosis, pathological fractures, and kyphosis can then occur.10Episodic or chronic arthritis and hypertrophic pulmonary osteoarthropathy may also occur due to immune complex formation in response to chronic inflammation.11Digital clubbing is commonly observed and is a marker for hypoxia.
Hematologie System
Anemia may be present in some patients due to impaired erythropoietin regulation, nutritional factors (vitamin E and iron malabsorption), or chronic inflammation. With chronic pulmonary disease, increased cytokine production can lead to shortened red blood cell survival, reduced erythropoietin response, and impaired mobilization of iron stores. Additionally, with chronic hypoxia, normal hemoglobin and hematocrit values may represent relative anemia.12Increased red blood cell production is a physiological response to hypoxia; however, this response may be blunted in CF and may result in symptoms of anemia despite normal lab values.
Abnormal bleeding may also be observed as a result of vitamin K malabsorption or antibiotic-associated depletion of GI flora and vitamin K synthesis.
Integumentary System
Abnormally high concentrations of sodium and chloride are found in sweat due to impaired reabsorption within the sweat duct from loss of CFTR channels. Patients are usually asymptomatic (other than a characteristic salty taste to the skin).2 In rare instances such as hot weather or excessive sweating during physical activity, patients may become dehydrated and experience symptoms of hyponatremia (nausea, headache, lethargy, and confusion).
CLINICAL PRESENTATION AND DIAGNOSIS
Diagnosis
Diagnosis of CF is based on two separate elevated sweat chloride concentrations of 60 mEq/L (60 mmol/L) or greater obtained through pilocarpine iontophoresis (referred to as the “sweat test”). Genetic testing (CFTR mutation analysis) may be performed to confirm the diagnosis, screen in utero, or detect carrier status. More than 70% of diagnoses are made by 12 months of age and almost all are made by age 12. Many states have added CF to their routine newborn screening panels in an effort to identify patients prior to symptom development. This allows for early intervention with CF therapies and improvement in long-term outcomes. A positive newborn screen for CF is not diagnostic (due to false-positive results among CF carriers), nor does a negative screen universally exclude the diagnosis. All “positive screens” are referred to a CF care center for sweat chloride test and genetic evaluation.
Clinical Presentation of CF
General
• CF is usually diagnosed in neonates (due to meconium ileus at birth or newborn screening programs) or during early childhood. Some patients may present much later in life due to less severe symptoms or misdiagnosis
Symptoms
• Pulmonary: chronic cough, sputum production, decreased exercise tolerance, and recurrent respiratory tract infections (pneumonia and sinusitis). Acute infection may be marked by increased cough, changes in sputum (darker and thicker), dyspnea, and fever
• Gl: numerous large, foul-smelling loose stools (steatorrhea), flatulence, and abdominal pain. Intestinal obstruction may present as abdominal pain and distention and/or decreased bowel movements
• Nutritional: poor weight gain, voracious appetite, and hunger. Dry skin, skin rash, and visual disturbances may be noted in vitamin deficiency
• CFRD: weight loss, increased thirst, and more frequent urination
Signs
• Obstructive airway disease: tachypnea, dyspnea, cyanosis, wheezes, crackles, sternal retractions, digital clubbing, and barrel chest
• Failure to thrive: despite apparent adequate caloric intake, children may be below age-based normal in both height and weight, and adults may be near/below ideal body weight or have a low BMI
• Salty taste to the skin
• Hepatobiliary disease: asymptomatic or evidenced by hepatomegaly, splenomegaly, or prolonged bleeding
• Recurrent pancreatitis (usually in pancreatic-sufficient patients): episodic epigastric abdominal pain, persistent vomiting, and fever
Laboratory Tests
• WBC with an associated increase in polymorphonuclear (PMN) leukocytes and bands may occur in acute
pulmonary infection; however, infection may occur without these laboratory abnormalities
• Maldigestion: decreased serum levels of fat-soluble vitamins (A, D, E, and K). Decreased vitamin K levels may result in elevated prothrombin time (PT) and international normalized ratio (INR)
• Glucose intolerance: blood glucose between 140 and 199 mg/dL (7.77–11.04 mmol/L) 2 hours after an oral glucose-tolerance test
• CFRD: blood glucose 200 mg/dL (11.1 mmol/L) or higher 2 hours after an oral glucose-tolerance test or fasting hyperglycemia (fasting blood glucose 126 mg/dL (6.99 mmol/L) or more regardless of the postglucose challenge level)
• Hepatobiliary disease: serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, γ-glutamyltransferase, and bilirubin may be elevated
Other Tests
• Microbial cultures (sputum, throat, bronchoalveolar lavage, or sinus): isolation of P. aeruginosa, S. aureus, 5. maltophilia, and other CF-related organisms
• PFTs: decreased FEV1, decreased forced vital capacity (FVC), and increased residual volume. Values are typically lower during acute pulmonary exacerbations
• Chest x-ray or chest CT scan: infiltrates, atelectasis, bronchiectasis, and mucus plugging
• Abdominal x-ray or CT scan: if present, intestinal obstruction may be manifested as meconium ileus, DIOS, or intussusception. Rectal prolapse may be noted on physical exam
• Maldigestion: elevated fecal fat content, reduced fecal pancreatic elastase-1 (less than or equal to 200 mcg/g of feces)
Clinical Course and Prognosis
Life expectancy has greatly increased from a predicted survival of 16 years in 1970 to more than 40 years for patients born in the 1990s.5 The average age of patients in the Cystic Fibrosis Foundation Registry is now more than 16 years, and almost 45% of CF patients in the 2006 Registry annual report are over 18 years old with the oldest being age 78.13
The clinical course varies greatly among patients because of the multiple genetic mutations and heterogeneous profile of the ΔF508 mutation. Some patients develop severe lung disease early in childhood and reach end-stage lung disease by their teens, whereas others maintain near-normal lung function into adulthood. Newly diagnosed adults tend to present with chronic respiratory symptoms but usually have milder lung disease, less frequent Pseudomonasinfection, and less severe pancreatic insufficiency.5
Patient Encounter, Part 1
Jessica is an 18-month-old female who is brought to her pediatrician because of difficulty gaining weight. Her mother states that Jessica has had four to five loose stools daily “ever since I can remember.” She was previously diagnosed with reflux and milk allergy. Oral ranitidine and elimination of cow’s milk-based dairy products have not helped. Jessica is plotted on the growth chart at less than the third percentile for both height and weight. Mom also reports that she has been treated in the emergency department for pneumonia twice since birth. Mom is concerned because her mother’s older sister died from some strange “wasting illness” when she was a young child.
What information is consistent with a diagnosis ofCF?
What other information would you like to gather?
How would you pursue making the diagnosis ofCF?
TREATMENT
Desired Outcomes
Therapeutic outcomes in CF care relate to both chronic and acute treatment goals. With chronic management, the primary goals are to delay disease progression and optimize quality of life. Maximizing nutritional status through pancreatic enzyme replacement and vitamin and nutritional supplements is necessary for normal growth and development and for maintaining long-term lung function. Reduction of airway inflammation and infection and aggressive preventive therapies minimize acute pulmonary exacerbations and delay pulmonary decline. In pulmonary exacerbations, therapy is directed toward reducing acute airway inflammation and obstruction. This is accomplished through more aggressive airway clearance regimens and antibiotic therapy with a goal of returning lung function to pre-exacerbation levels or greater.
Nonpharmacologic Therapy
Airway Clearance Therapy
Airway clearance therapy is a necessary routine for all CF patients to clear secretions and control infection, even at diagnosis prior to becoming symptomatic. Waiting until development of a first pneumonia or until daily symptoms are present delays benefits and may contribute to a faster pulmonary decline. The traditional form of chest physiotherapy (CPT) is known as percussion and postural drainage. Areas of the patient’s chest, sides, and back are rapidly “clapped” by hand in different patient positions, followed by cough or forced expiration to mobilize secretions. Patients may also be taught autogenic drainage, which consists of deep breathing exercises followed by forced cough.
Several devices are also available to promote airway clearance. Flutter valve devices employ oscillating positive expiratory pressure (OPEP) to cause vibratory airflow obstruction and an internal percussive effect to mobilize secretions. Intrapulmonary percussive ventilation (IPV) provides continuous oscillating pressures during inhalation and exhalation. Finally, the most commonly used technique is high-frequency chest compression (HFCC) with an inflatable vest that provides external oscillation. Vest therapy is often preferred by patients because they can independently perform the therapy even from an early age.5,14
If performed appropriately, airway clearance techniques provide similar clearance results, so choice should be based on patient preference and compliance. Airway clearance therapy is typically performed once or twice daily for maintenance care and is increased to three or four times per day for acute exacerbations. Inhaled medications are usually given with the therapies and will be discussed in a later section.
Nutrition
Most CF patients have an increased caloric need due to increased energy expenditure through increased work of breathing, increased basal metabolism, and maldigestion. Prevention of malnutrition requires early patient-specific nutritional intervention. Caloric requirements to promote age-appropriate weight gain or maintenance are typically 110% to 200% of the recommended daily allowance (RDA) for age, gender, and size and increase as disease progresses.15
Nutrition in malnourished patients consists of baseline required calories plus additional calories for weight gain. Even with aggressive diet and oral supplements, the caloric requirement may not be achieved, and placement of a gastrostomy or jejunostomy tube to allow for nighttime supplemental feeds may be necessary.5 Patients with refractory malabsorption, CFRD, and/or tube feedings are especially challenging due to their unique caloric needs. Collaboration with a dietician specially trained in CF nutrition is essential.
Pharmacologic Therapy
Pulmonary System
Treating Obstruction and Inflammation (Table 16–1)
Airway clearance therapy is usually accompanied by bronchodilator treatment (albuterol [also known as salbut-amol outside the United States] by nebulizer or metered-dose inhaler) to stimulate mucociliary clearance and prevent bronchospasm associated with other inhaled agents.
A mucolytic agent may be administered subsequently to reduce sputum viscosity and enhance clearance. Dornase alfa (Pulmozyme) is a recombinant human (rh) DNase that selectively cleaves extracellular DNA. This DNA is released during neutrophil degradation and contributes to the high viscosity of CF sputum. Nebulization of dornase alfa 2.5 mg once or twice daily improves daily pulmonary symptoms and function, reduces pulmonary exacerbations, and improves quality of life.16
Table 16–1 Common Pulmonary Medications in CF
Hypertonie saline for inhalation (Hyper-Sal) 7% or 3.5% is sometimes used as an add-on mucolytic agent or for sputum induction. It must be preceded by a bronchodilator due to a greater incidence of bronchospasm and may not be tolerated by some patients.17 N-acetylcysteine is another mucolytic agent, but its unpleasant odor and taste limit patient acceptance.5
Many patients with CF also have reactive airways or concurrent asthma and benefit from long-acting β2-agonists.5 Patients with recurrent wheezing or dyspnea who have demonstrated improvement with albuterol (known as salbutamol outside the United States) should be considered for maintenance therapy, as should patients with bronchodilator-responsive pulmonary function tests (PFTs). Inhaled corticosteroids may also attenuate reactive airways and reduce airway inflammation in some patients; however, clear benefit in CF has not been established.1,18 Drug delivery to the site of inflammation is limited by the severity of lung disease, which may limit efficacy. Patients on inhaled corticosteroids and/or long-acting β2-agonists should administer these medications after airway clearance therapies to optimize drug delivery. Montelukast, antihistamines, and/or intranasal steroids are sometimes used for CF patients with reactive airways or allergic rhinitis symptoms.
Long-term systemic corticosteroids have been shown to reduce airway inflammation and improve lung function. However, beneficial effects diminish upon discontinuation, and concern for long-term adverse effects limits their use as maintenance therapy.18 In clinical practice, systemic corticosteroids may be added for short courses in acute exacerbations or for treatment of allergic response to Aspergilluscolonization (allergic bronchopulmonary aspergillosis or ABPA); however, dose and duration of therapy should be minimized.1,19
High-dose ibuprofen to achieve peak concentrations of 50 to 100 mcg/mL (243–485 μmol/L) has been shown to slow progression of disease, particularly in children 5 to 13 years of age with mild lung disease (FEV1 greater than 60%). At high doses, ibuprofen inhibits the lipoxygenase pathway, reducing neutrophil migration and function as well as release of lysosomal enzymes. At the lower concentrations achieved with analgesic dosing, neutrophil migration increases, potentially increasing inflammation.20,21 A dose of 20 to 30 mg/kg given twice daily is usually needed to attain target levels, but interpatient variability necessitates serum concentration monitoring.20 Due to the need for pharmacokinetic monitoring and concerns regarding long-term safety and tolerability, only a few CF centers currently prescribe high-dose ibuprofen.1,18
Azithromycin is a macrolide antibiotic commonly used in CF as an anti-inflammatory agent. The exact mechanism for this activity is unclear, but azithromycin has been shown to improve overall lung function. Proposed mechanisms include interference with Pseudomonas alginate biofilm production, bactericidal activity during stationary Pseudomonas growth, neutrophil inhibition, interleukin-8 reduction, and reduction in sputum viscosity.22,23 Due to its long tissue half-life, azithromycin is typically dosed 3 days per week (Monday, Wednesday, and Friday), with a dose of 500 mg for patients weighing at least 40 kg and 250 mg for patients weighing 25 to 39 kg. Alternatively, patients may take 500 mg or 250 mg either every day or only Monday through Friday, based on the same weight parameters. To minimize the risk of selecting for macrolide-resistant nontuberculous mycobacteria (a contraindication to chronic azithromycin therapy), patients should have a screening acid-fast bacillus sputum culture obtained prior to initiation and then every 6 months.18
Antibiotic Therapy
Antibiotic therapy is used in three distinct clinical settings within the course ofCF: (a) eradication and delay of colonization in early lung disease; (b) suppression of bacterial growth once colonization is present; and (c) reduction of bacterial load in acute exacerbations in an attempt to return lung function to pre-exacerbation levels or greater.1 Antibiotic selection is based on periodic culture and sensitivity data, typically covering all organisms identified during the preceding year. If no culture data are available, empiric antibiotics should cover the most likely organisms for the patient’s age group.Due to altered pharmacokinetics and microorganism resistance, care must be taken to ensure that optimal doses are prescribed (Table 16–2).
Severity of pulmonary symptoms also guides selection of antibiotic regimens for treatment of acute exacerbations. For recent-onset or mild symptoms, patients may be treated with outpatient oral and inhaled antibiotics for 14 to 21 days. Oral fluoroquinolones are a mainstay among CF patients infected with P. aeruginosa, even in children. Despite concerns regarding cartilage and tendon toxicity in young animals, clinical practice has not shown an increased risk in human children.24 To prevent development of resistance and promote synergy, inhaled tobramycin or colistin is usually added for double coverage.1,3Methicillin-sensitive S. aureus (MSSA) may be treated with oral amoxicillin-clavulanic acid, dicloxacillin, first-or second-generation cephalosporins, trimethoprim-sulfamethoxazole, or clindamycin, depending on sensitivity. Likewise, methicillin-resistant S. aureus (MRSA) may be treated with oral trimethoprim-sulfamethoxazole, clindamycin, minocycline, or linezolid. H. influenzae often produces β-lactamases but can usually be treated with amoxicillin-clavulanic acid, a cephalosporin, or trimethoprim-sulfamethoxazole. Oral trimethoprim-sulfamethoxazole or minocycline may be used to treat S. maltophilia.
Table 16–2 Antibiotic Dosing in CFa
For more severe infections or patients failing outpatient therapy, IV antibiotic therapy is prescribed for 2 to 3 weeks as inpatient therapy. However, depending on the availability of home health services, some patients may be discharged to finish their course or even receive their entire course at home. Typical regimens for severe infections include an antipseudomonal β-lactam plus an aminoglycoside for added synergy and delay of resistance development.1,1 Cephalosporins tend to be better tolerated and offer the benefit of administration every 8 hours. Extended-spectrum penicillins have been associated with a higher incidence of allergy. Aztreonam offers the added benefit of little cross-reactivity in penicillin-or cephalosporin-allergic patients; however, it has no gram-positive coverage. Meropenem should be reserved for organisms resistant to all other antibiotics to minimize development of resistance in the carbapenem drug class, as it is the last line of defense against extended-spectrum β-lactamase (ESBL)-producing organisms.
Tobramycin IV is generally the first-line aminoglycoside. Isolates are usually resistant to gentamicin, and amikacin is reserved for tobramycin-resistant strains. Pharmacokinetic goals are listed in Table 16–3. In general, higher peak serum concentrations are targeted to maximize efficacy, whereas lower serum trough levels are targeted to reduce the risk of toxicity. Some centers use once-daily aminoglycoside dosing (tobramycin 10–15 mg/kg/day or amikacin 35 mg/kg/day) to achieve higher peaks and lower troughs. Because aminoglycosides exhibit concentration-dependent killing, once-daily dosing may optimize this effect. However, time below the minimum inhibitory concentration (MIC) is prolonged with once-daily administration in children, possibly leading to loss of synergy for a substantial portion of the dosing interval. Due to a shorter half-life, once-daily aminoglycoside dosing is not optimal for younger children. However, it may be a reasonable option in adults and older teens, in whom the time below the MIC can be minimized. Long-term studies are needed to examine the efficacy and resistance patterns associated with once-daily aminoglycosides in the CF population.1,3
Most other serious gram-negative infections are also treated with combination therapy. S. maltophilia is highly resistant and is most often treated with trimethoprim-sulfamethoxazole or ticarcillin-clavulanate. A. xylosoxidans and B. cepacia are also highly resistant and may have minimal therapeutic options. In some cases, fluoroquinolones maybe substituted for aminoglycosides based on sensitivity data or if renal dysfunction and/or ototoxicity are present. Due to excellent bioavailability, oral fluoroquinolones, trimethoprim-sulfamethoxazole, minocycline, and linezolid should be used whenever possible. Due to toxicity risk, colistin and chloramphenicol are reserved for life-threatening, highly resistant infections. Additional combinations of two or three drugs may be used for highly resistant organisms based on synergy studies that test susceptibility of different antibiotic combinations.
Inpatient treatment of MRSA can consist of IV vancomycin or oral agents as described above, depending on the severity of infection and concomitant organisms. Vancomycin IV may also be converted to oral step-down therapy upon discharge.
Chronic maintenance antibiotic therapy may be used in patients with Pseudomonas colonization in an attempt to prevent bacterial overgrowth. However, long-term systemic antibiotics are not recommended due to emergence of resistance.1 Chronic or rotating inhaled-antibiotic maintenance therapy is used for suppressing P. aeruginosa colonization. Inhaled tobramycin (TOBI) is typically administered to patients 6 years of age and older in alternating 28-day cycles of 300 mg nebulized twice daily, followed by a 28-day washout period to minimize development of resistance. Long-term intermittent administration improves pulmonary function, decreases microbial burden, and reduces the need for hospitalization for IV therapy.25,26 Due to minimal systemic absorption, pharmacokinetic monitoring is not necessary with normal renal function. Lower doses of nebulized tobramycin solution for injection have been used in younger children, and studies are underway using 300 mg twice daily in children under age 6 years. Nebulized colistin using the IV formulation may be an option in patients with tobramycin-resistant strains or intolerance to inhaled tobramycin, but pretreatment with albuterol is necessary due to increased riskofbronchoconstriction.1,5 Inhaled antibiotics are typically stopped during an acute exacerbation requiring IV therapy. Drug delivery is reduced with increased sputum production, and concomitant use of IV aminoglycosides may increase risk of toxicity.
Pharmacokinetic Considerations
CF patients have larger volumes of distribution for many antibiotics due to an increased ratio of lean body mass to total body mass and lower fat stores. CF patients also have an enhanced total body clearance, although the exact mechanism has not been determined. Increased renal clearance, increased glomerular filtration rate, decreased protein binding, increased tubular secretion, decreased tubular reabsorption, extrarenal elimination, and increased metabolism have all been proposed as possible reasons for the increased clearance.
Table 16–3 Pharmacokinetic Goals in Cystic Fibrosis
Because of these pharmacokinetic changes, higher doses of aminoglycosides are needed to achieve target serum levels and promote adequate tissue penetration. Higher doses of β-lactam antibiotics are also needed to achieve and sustain levels above the MIC. Trimethoprim-sulfamethoxazole displays enhanced renal clearance and hepatic metabolism in the CF population. Fluoroquinolones and vancomycin have fewer pharmacokinetic deviations in the CF population; however, higher doses are typically needed to attain inhibitory serum and tissue concentrations against CF pathogens.27
Although most CF patients have shorter half-lives and larger volumes of distribution than non-CF patients, some patients exhibit decreased renal clearance. Reasons may include concomitant use of nephrotoxic medications, presence of diabetic nephropathy, history of transplantation (immunosuppressant use and/or procedural hypoxic injury), age-related decline in renal function in adult patients, and multiple lifetime exposures to aminoglycosides. Evaluation of previous pharmacokinetic parameters and trends, along with incorporation of new health information, is key to appropriate dosing.
Gastrointestinal System
Pancreatic enzyme replacement is the mainstay of GI therapy. Most enzyme products are formulated as capsules containing enteric-coated microspheres or microtablets to avoid inactivation of enzymes by gastric acid; instead, they dissolve in the more alkaline environment of the duodenum. Capsules may be opened and the microbeads swallowed with food (for infants and young children), as long as they are not chewed or mixed with alkaline or hot foods, as enzymes may be denatured. A powder form is available for patients unable to swallow the capsules or microbeads, but bioavailability is poor. While products may contain similar enzyme ratios, they are not bioequivalent and cannot be substituted. Generic enzyme products generally display poor dissolution and should not be used.5,28 Table 16–4 lists commonly used enzyme replacement products. Note that enzyme formulations are frequently changing due to a newly mandated FDA approval process. Consult a specialized drug reference for updated product availability.
Pancreatic enzymes are initiated at 500 to 1,000 units/kg/meal of lipase component (because fats are the most difficult food components to digest) with half-doses given for snacks. Enzymes should be taken at the beginning or divided throughout the meal and must be given with any fat-containing snack. Infants are typically started at 1,500 to 2,500 units of lipase per 120 mL of formula or breast milk and may require division of capsule contents via visual estimation to obtain appropriate doses. Pancreatic enzymes cannot be placed in formula bottles due to inability to consistently pass through the nipple slit. Instead, enzyme microbeads are placed on a small dot of infant applesauce (or moistened infant rice cereal) and administered via infant spoon with subsequent nursing or bottle-feeding to facilitate swallowing. The oral mucosa must be examined afterward to ensure that all enzymes are swallowed, because remnant microbeads can cause oral erosions (ulcers).
Table 16–4 Common Pancreatic Enzyme Replacement Products
Titration of pancreatic enzyme doses is based on control of steatorrhea, stool output, and abdominal symptoms. Infants should have no more than three to four stools per day, whereas older patients should have no more than two to three (children) or one to two (adolescents/adults) well-formed stools per day. Pancreatic enzymes are titrated at 2- to 3-week intervals in increments of 150 to 250 units of lipase/kg/meal (or the next easily administered capsule or half-capsule). Doses up to 2,500 units/kg/meal may be needed, but higher doses should be used with caution due to the risk of fibrosing colonopathy.5,6,28 Patients who respond poorly to maximal doses of one product may benefit from changing to another product6 and/or addition of a histamine H2-receptor antagonist or proton pump inhibitor. Acid suppression may boost effective enzyme dose if duodenal pH is not alkaline enough to neutralize residual gastric acid and dissolve enteric coating as well as treat concomitant gastroesophageal reflux.5,6,28
Fat-soluble vitamin supplementation is usually required in pancreatic insufficiency. Specially-formulated products for CF patients (e.g., ADEKs, AquADEKs, SourceCF, and Vitamax) are usually sufficient to attain normal serum vitamin levels at a dose of one tablet daily for younger children and one tablet twice daily for teenagers and adults. Additional supplementation may be needed in uncontrolled malabsorption or for replacement of severe vitamin deficiency.5,28 Appetite stimulants such as cyproheptadine may be an option for promoting nutrition and weight gain, but efficacy has not been established.
Patient Encounter, Part 2
Laboratory testing confirms the diagnosis of CF, and Jessica has been referred to her regional CF center for treatment. Additional stool studies indicate the presence of severe fat maldigestion. The pulmonologist indicates that she would like to start Jessica (weight 8.2 kg) on pancreatic enzyme replacement therapy.
What formulation and dose would you recommend?
How would you administer the enzymes?
How would you titrate the dose?
Ursodiol at 15 to 20 mg/kg/day in two divided doses may slow progression of liver disease. It improves bile flow and may displace toxic bile acids that accumulate in a cholestatic liver, stimulate bicarbonate secretion into the bile, offer a cytoprotective effect, and reduce elevated liver tests.5,7
Treatment of DIOS consists of oral or nasogastric administration of polyethylene glycol (PEG) electrolyte solutions. Enemas may also be used to facilitate stool clearance, and severe presentations may require surgical resection. IV fluids are often required to correct dehydration due to vomiting or decreased oral intake. Reevaluation of enzyme compliance and dosing is essential to prevent further episodes, and some patients with recurrent symptoms may require daily PEG administration (Miralax).5
Endocrine System
Patients with mild CFRD may be managed with carbohydrate modification if their nutritional status is optimal. However, most patients present with poor nutrition and weight loss and require more aggressive treatment. Because CFRD results from insulin insufficiency, exogenous insulin replacement is usually required. Many patients can be successfully managed by meal coverage with short- or rapid-acting insulin (regular, lispro, or aspart) dosed per carbohydrate counting. Patients with fasting hyperglycemia or patients receiving nighttime tube feedings typically also require longer-acting basal insulin. Regular home glucose monitoring is essential to appropriate therapy. Little information is available regarding use of oral antidiabetic agents in CFRD, and routine use is not recommended.5,8
Musculoskeletal System
CF patients with low bone mineral density and low serum vitamin D levels may improve bone health through supplemental vitamin D analogs beyond those found in standard CF vitamins. For ergocalciferol, a minimum of 400 IU and 800 IU should be taken daily by infants and patients over 1 year of age, respectively.28 Total weekly doses of 12,000 IU for children less than 5 years of age and 50,000 IU for patients 5 years of age and older may be required to achieve target vitamin D concentrations. Supplemental calcium should be provided if 1,300 to 1,500 mg of elemental calcium intake cannot be achieved through diet.27
Patient Encounter, Part 3
At Jessica’s follow-up appointment 1 month later, her weight is up to 8.8 kg. Her mother reports that she seems to have caught a cold and has been coughing quite a bit of late and has not been eating as well as usual. In clinic, the following vitals are noted: respiratory rate 40/min, temperature 38.3°C (100.9°F), and oxygen saturation 92%. The throat culture from her previous visit was positive for S. aureus (sensitive to cefazolin, nafcillin, trimethoprim-sulfamethoxazole, clindamycin, vancomycin, doxycycline, and linezolid; resistant to erythromycin) and P. aeruginosa (sensitive to ceftazidime, cefepime, piperacillin, aztreonam, meropenem, ciprofloxacin, tobramycin, and amikacin; resistant to gentamicin). She has no drug allergies.
What antibiotic(s) and dose(s) would you recommend for outpatient therapy?
What antibiotic(s) and dose(s) would you recommend for inpatient therapy?
Develop a monitoring plan to assess antibiotic response.
Antiresorptive agents (oral or IV bisphosphonates) may be used to treat adult CF patients with osteoporosis. Remaining upright each day for 30 minutes after dosing may be difficult for patients needing to perform airway clearance therapy, so products offering less frequent dosing should be considered. Gastroesophageal reflux or cirrhosis-associated esophageal varices may also complicate therapy and increase the risk of erosive esophagitis. Pamidronate 30 mg IV every 3 months has increased bone mineral density in adult CF patients, and studies using IV bisphosphonates in children with CF are underway.29Androgen replacement in male CF patients with documented hypogonadism may also benefit bone health but should be decided on an individual basis.10,29
Short courses of nonsteroidal anti-inflammatory drugs (NSAIDs) can be used to treat CF-related arthritis and hypertrophic pulmonary osteoarthropathy.5 The impact on neutrophil recruitment in the lung with long-term NSAID therapy at lower analgesic doses is unknown.
Future Therapeutic Directions
Development of new therapies has extended the CF lifespan over the past several decades. Since the discovery of the CF gene and the CFTR protein defect, research has focused on gene therapy to restore normal CFTR function through DNA transfer. Pharmacologic approaches are being investigated to correct dysfunctional CFTR by suppressing premature stop codons in the CFTR gene and to activate alternative chloride channels, effectively bypassing dysfunctional CFTR. Additional research is being conducted with anti-inflammatory therapies, antipseudomonal vaccines, and development of exogenous cationic antimicrobial peptides to mimic those found naturally in the lung.1Development of more effective systemic and inhaled antibiotic agents (such as tobramycin powder for inhalation, aztreonam lysine, and amikacin) continues to be a major focus as well.
Patient Care and Monitoring
1. Perform a thorough history of prescription, nonprescription, and alternative medications. Assess adherence to the prescribed regimen, including timing of inhaled medications with respect to airway clearance therapies and timing of enzymes and insulin with regard to meals. Is the patient taking any medications not prescribed by the CF center team?
2. Is the patient on all appropriate maintenance medications? Are medications at the appropriate doses for weight and/or age? If the patient is admitted, are maintenance medications ordered?
3. Evaluate the medication regimen for drug interactions, adverse reactions, and allergies.
4. Assess pulmonary symptoms. Review the incidence and quality of cough, dyspnea, respiratory rate, sputum production, and fever. Are the patient’s PFTs decreased? Is there an oxygen requirement?
5. Review culture and sensitivity history over the last 1 to 2 years. What antibiotics were used in the past, and did the patient appear to respond better to a particular regimen? Is the patient currently on antibiotics, and if so, are the symptoms improving? Recommend an appropriate antibiotic regimen based on culture and sensitivity data.
6. Review the pharmacokinetic history. Are there any possible changes in clearance since the last antibiotic course? Will the patient be discharged home on IV antibiotics? Can the IV regimen be simplified or made more convenient for home administration? Recommend appropriate doses based on the patient’s clearance and an appropriate but convenient schedule.
7. Perform pharmacokinetic adjustments as necessary. Recommend a monitoring plan for the antibiotic course. Are any other laboratory tests necessary? Are signs of toxicity present?
8. Assess nutritional status. Is the patient gaining or maintaining weight according to age? Are any oral supplements or tube feedings being used?
9. Assess Gl symptoms. What is the quantity and quality of bowel movements? Does the patient have bloating, flatulence, or abdominal pain?
10. Assess quality-of-life measures such as physical, psychological, and social well-being.
11. Understand that CF therapy is complicated, and recommend regimens to ease the care burden if possible.
12. Educate the patient and family, stressing the importance of adherence to the regimen.
OUTCOME EVALUATION
Pulmonary System
• Monitor for changes in pulmonary symptoms such as cough, sputum production, respiratory rate, and oxygen saturation. Symptoms should improve with antibiotics and aggressive airway clearance therapy. PFTs should be markedly increased after 1 week and trend back to pre-exacerbation levels after 2 weeks of therapy. If improvement lags, 3 weeks of therapy maybe needed.
• For IV antimicrobial therapy, obtain serum drug levels for aminoglycosides and/or vancomycin and perform pharmacokinetic analysis. Adjust the dose, if needed, according to the parameters in Table 16–3. Obtain follow-up trough levels at weekly intervals or sooner if renal function is unstable. Follow serum creatinine levels if renal function is unstable. Hearing tests maybe scheduled yearly or per patient preference.
Gastrointestinal System
• Monitor short- and long-term nutritional status through evaluation of height, weight, and body mass index (BMI). Ideally, parameters should be near the normals for non-CF patients.
• Evaluate the patient’s stool patterns. Steatorrhea indicates suboptimal enzyme replacement or noncompliance. Infants should have two to three well-formed stools daily, whereas older children and adults may have one or two stools daily.
• Monitor efficacy of vitamin supplementation through yearly serum vitamin levels. Obtain levels more frequently if an identified deficiency is being treated.
Endocrine System
• Monitor blood glucose several times daily in patients with CFRD or those taking systemic corticosteroids. Follow glycosylated hemoglobin levels on an outpatient basis to assess long-term glucose control. Levels may be falsely low in CF due to a shorter red blood cell half-life.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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