Each issue of the CoramClick provides an in-depth focus on timely and practical solutions. In this issue of the Click, we are focusing on Cystic Fibrosis and Lung Transplants. Back issues of the Click are available in the CoramClick archive for easy reference!
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Cystic Fibrosis
Cystic fibrosis (CF) is a disease with multiple system involvement that is ultimately life shortening. In 1938 when first identified, the median predicted life expectancy for a child with CF was less than one year. Today, the predicted life expectancy is 37.4 years. |
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Vancomycin: The Treatment Strategy for MRSA
Vancomycin is indicated for the treatment of serious or severe infections caused by susceptible strains of methicillin-resistant staphylococci, for patients who are allergic to penicillins, and for infections resistant to other antimicrobial drugs. |
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Did You Know?
Trivia, tips, and health-smart to-dos related to MRSA. |
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Tobramycin: IV to Inhalation Therapy
The primary treatment goal for CF is to optimize lung health by controlling bacterial infection and mobilizing viscous secretions. The most successful anti-pseudomonal treatment is tobramycin, primarily administered via IV and/or inhalation therapy. |
Cystic Fibrosis
 While relatively rare, cystic fibrosis (CF) is a disease with multiple system involvement that is ultimately life shortening. In 1938 when first identified, the median predicted life expectancy for a child with CF was less than one year. With a greater understanding of the disease process, improved therapies, and very importantly, the recognized need to focus on preventative care, the predicted life expectancy has consistently gone up and today reaches 37.4 years.1 CF primarily impacts the respiratory, GI, and pancreatic systems, with the most significant impact (and most frequent cause of death) related to pulmonary complications. Patients are faced with exacerbations of complications throughout their lives, requiring aggressive prophylactic and treatment measures.
Cystic fibrosis is an autosomal recessive genetic disorder that results in altered sodium and water distribution. The secretions and mucous that are normally produced by cells throughout the body become thick and salty. Patients with CF have either an absent or abnormal CFTR protein, the job of which is to manage the efflux of chloride ions across membranes. When chloride is not effectively transported into the cell, sodium cannot follow. If sodium cannot enter the cell, neither can water. Without water, the secretions and mucous throughout the body become too thick and salty.
CF is the most common fatal autosomal recessive disorder in Caucasians. Nearly 95 percent of patients with CF are Caucasians, 6.8 percent are Hispanic, and 4.2 percent are African-American. About 1,000 new CF cases are diagnosed each year.
Inheritance Pattern
With an autosomal recessive disorder, a person must inherit two copies of the faulty gene, one from each parent, to get the disorder. If the person inherits one copy of the faulty gene but the gene from the other parent is normal, the person is a carrier but does not clinically present with the disease. A carrier can pass the gene on to his or her children if he/she pairs with another carrier. In this diagram, the first child (farthest left) inherited the normal gene from both parents and therefore does not have CF and is not a carrier. There is a 25 percent chance that this will happen. The next two children inherited the defective gene from one or the other parent. They do not have CF, but are carriers. The youngest child inherited the defective gene from both parents, so is afflicted with CF.
The average time from birth to diagnosis is six months. Greater than 70 percent of CF diagnoses are made prior to a child turning two. CF should be suspected in infants who present with such symptoms as meconium ileus, jaundice, a swollen abdomen and lack of feces production in the first few days after birth, or later in infancy as failing to gain weight or grow at a normal rate; pale, greasy feces that float, and/or recurrent respiratory infections.
Diagnosis
The most common diagnostic tool is the sweat chloride test which measures the levels of salt in a patient’s sweat. Pilocarpine is applied to a small area on an arm or a leg to induce sweating. An electrode is attached to stimulate sweat production which a pad collects for analysis. CF patients typically have sweat chloride levels of greater than 60 mEq/l (normal is 10-35 mEq/L).
Pancreatic/Gastrointestinal Symptoms
The basic defect in the GI tract causes both pancreatic enzyme deficiency and increased thickness of mucosal secretions. Eventually the pancreatic ducts become obstructed with mucous resulting in decreased concentration and secretion of pancreatic enzymes. Pancreatic enzymes are essential for digestion. Patients develop steattorrhea because they are not absorbing fat, and they experience diarrhea. As a result, digestive malabsorption and malnutrition occur. Malnutrition is the most significant contributor to the typically low height and weight of children with CF and must be addressed early and aggressively. Nearly 20 percent of patients have a height and/or weight less than the fifth percentile. Patients typically achieve their highest weight potential at about 4 years of age, declining as they grow older.
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Source: CDC. Retrieved 01-06-09
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There is a proven positive correlation between nutrition and lung function (FEV1), underscoring the importance of adequate nutrition. The graph to the right illustrates the strong association between a higher BMI percentile and better lung function in children from 2 to 20 years of age. The fiftieth percentile is the average BMI percentile for children in the United States who do not have CF and is the goal for children with CF.
Nutrition instruction and counseling, pancreatic enzyme replacement therapy (PERT) and vitamin supplementation become essential components of care for patients with CF.
Because of malabsorption, caloric needs are 20–50 percent higher in patients with CF. If dietary intake is not sufficient, supplemental feedings, either elemental or parenteral, may be needed to help ensure adequate calories. Similarly, patients can become vitamin deficient, especially with fat-soluble vitamins and will require vitamin supplementation.
Pancreatic Enzyme Replacement Therapy (PERT) is necessary for the 85 to 90 percent of patients whose pancreas is affected by CF. The goals of PERT are to decrease the steattorrhea, diarrhea and abdominal pain, and thus improve absorption and nutritional status. Enzyme replacement must be part of every snack or meal, with dosing typically determined by patient size and the amount of fat intake.
Even with PERT, 10–20 percent of intake is not absorbed. For nearly 40 percent of patients, dietary intake is not enough and supplements are needed. Oral supplements include commercial products that are specifically higher in fat and lower in carbohydrates and homemade supplements made by adding, for example, canola oil or MCT oils to shakes or adding butter to foods. Oral supplements must be accompanied by PERT.
It is essential to monitor how well the nutritional strategies are working, assessing:
- Growth and development – How children are following the height and weight growth curves.
- Bone health – Just over 26 percent of patients with CF over 18 years have signs of osteoporosis or osteopenia, the risk increasing as patients age.
- Micronutrient deficiencies, especially the fat-soluble vitamins A, D, and K – Standard multivitamins are recommended for children over 8 years of age and adults, often supplemented by additional fat-soluble vitamins and vitamin E.
- Insulin production and glucose tolerance – The risk of cystic fibrosis related diabetes increases with age, ultimately affecting nearly a quarter of patients by age 45. Nearly 10 percent of patients, even with oral supplements, cannot take in enough calories and require the additional supplement of enteral nutrition. Enteral feedings are typically given at night, via a g-tube and also require PERT.
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A small group of patients, for example those who cannot tolerate or refuse enteral feedings, or are not absorbing nutrients due to such diagnoses as Short Bowel Syndrome, pancreatitis, etc., may require typically short-term TPN.
Pulmonary Symptoms
Lung involvement accounts for much of the morbidity associated with CF and nearly all of the mortality. The degree of lung dysfunction increases with age, although aggressive prevention, recognition, and treatment will make a difference. In the lungs, the cells initially affected are those lining the bronchial airways where thick secretions inhibit air exchange — causing airway obstruction.
- The thick, stagnant mucus provides a medium for bacteria and other pathogens that are either
inhaled or colonized in the airway. Repeated and chronic bronchopulmonary infections are central
to the pathogenesis of CF
- Infections leads to inflammation
- Inflammation leads to endobronchial damage - which leads to additional rounds of infection
and tissue scarring
- Eventually, the patient has progressive, obstructive lung disease with respiratory insufficiency
The CF patient’s lungs appear histologically normal at birth. Soon, however, many species of bacteria can be cultured from the infant’s lungs. Eventually, three organisms predominate:
- Haemophilus influenzae
- Staphylococcus aureus
- Pseudomonas aeruginosa
Staph aureus is often the first bacterial pathogen to colonize the respiratory tract and has been thought to play a key role in the early stages of lung injury. The cascade of immunologic, microbiologic, and inflammatory events that follow S. aureus infection leads to the formation of thick, viscous mucoid secretions that are associated with the cycle of progressive airway obstruction, scarring, and tissue destruction. The stage is set for methicillin-resistant staph aureus (MRSA) and often multiple and resistant strains of Pseudomonas. Pseudomonas is particularly important because once established it is not eradicated, even with prolonged and intensive antibiotic therapy.
IV antibiotics remain the mainstay of treatment of pulmonary infections. For Pseudomonas, combination therapy with two antibiotics with different mechanisms of action is used for synergistic activity and to reduce the potential for resistance. A combination of an antipseudomonal betalactam (e.g. piperacillin, ceftazidime, cefepime, imipenem) plus an aminoglycoside (e.g. gentamicin or tobramycin) or a fluroquinolone (e.g. ciprofloxacin) is typically prescribed for exacerbations involving Pseudomonas aeruginosa.
A highly resistant organism, Burkholderia cepacia, eventually emerges in some patients with CF. Patients with B. cepacia generally have a faster rate of pulmonary decline and a shorter life span. Also, most lung transplant programs will not consider a patient with B. cepacia to be a candidate for transplant as less than 30 percent of patients infected with B. cepacia live beyond five years post transplant, compared to a 70 percent, five-year survival rate for those not infected.2
Aerosolized antibiotics, designed to deliver large quantities of medications to the lungs while decreasing the risk of toxicities from systemic absorption, have become a very important part of infectious therapy. Aerosolized antibiotics are often used as:
- Adjunctive treatment with IV antibiotics for an acute pulmonary exacerbation
- Chronic therapy for patients colonized with Pseudomonas
- Early treatment to prevent colonization
Tobramycin solution for inhalation — TSI or TOBI — is the most commonly used inhaled antibiotic and has been a standard of therapy since 1998. Patients receiving TOBI spend significantly fewer days in the hospital, have a low incidence of systemic toxicities and experience significantly increased lung function. TOBI can also be effective for long-term treatment of Pseudomonas colonization and infection. Ceftazidime is another example of an effective aerosolized treatment for CF. It has an approximate 80 percent susceptibility to Pseudomonas.
Resistance does develop following cyclic inhalation regimens but is rarely significant in the face of the very high concentration of antibiotic achieved by inhalation.
Aerosolized antibiotics are administered via either a jet or ultrasound nebulizer. Jet nebulizers are attached to a compressor while ultrasound nebulizers use an electric current to aerosolize medication.
Airway Clearance
The goals of airway clearance are to loosen mucous and help expectoration — thus lessen the risk of infection. Chest Physical Therapy (PT) is the oldest and most rigorous method of therapy, considered by many to be the gold standard of therapy because of its effectiveness.
The flutter device is a handheld inhaler-like device that works by:
- Positive expiratory pressure (PEP), which helps hold airways open
- Airway oscillation, which helps vibrate mucus away from airway walls
- Intermittent flow acceleration, which helps push mucus upward
for expectoration
High-frequency chest wall oscillation uses an inflatable vest that is connected to a generator, rapidly but gently compressing and releasing the chest wall. The process helps dislodge mucus from the bronchial walls, increase mobilization, and move it along toward central airways. Oscillation also works to thin thick secretions, making them easier to clear. Once the mucus has moved from the smaller to larger airways, it can be removed by coughing or suctioning.
Lung Transplantation
Lung transplantation is an option for many patients with CF. In fact, CF is the second most common diagnosis for lung transplantation representing 15 percent of the 1,900 patients on the lung transplant waiting list.3 Survival rates are generally comparable to those of other lung transplant patient populations. Patients are typically referred for transplant only when they:
- Have severely limited pulmonary function
- Increasingly require hospitalizations and IV antibiotics
- Present with pulmonary hypertension and/or
- Have an unacceptable poor quality of life
Following a referral and evaluation for lung transplantation, a patient is given a lung allocation score (LAS) based on their clinical and laboratory findings. This score determines their priority status on the lung transplant waiting list. Detailed information regarding the LAS as well as general information regarding lung transplantation is available at www.unos.org.
Future Opportunities
There are numerous potential new drugs in the CF drug pipeline. These include:
- Antibiotics
- Drugs designed to restore the function of that missing or ineffective CFTR gene
- Drugs to help hydrate and clear mucous, thus help prevent infections
- Pharmacologic agents designed to modulate the defective gene and thus prevent the cascade of symptoms
- Agents that enhance chloride transport
Gene replacement therapy is also being studied. The goal is to add enough normal genes to CF airways to correct the defective cells.
Conclusion
Cystic fibrosis is a life-shortening disease that manifests with multi-systemic complications. Pulmonary manifestations are the hallmark of the disease, but pancreatic and GI symptoms make nutrition a critically important part of care. Infectious exacerbations are common, but most often treatable. Preventative care measures are essential.
It is well supported that early and aggressive treatment improves outcomes. Comprehensive treatments that include preventative measures as well as aggressive antibiotic therapy at the time of acute exacerbations make a difference.
It is also important, especially in this day of high costs and an ever increasing risk of often resistant nosocomial infections, that site of care be analyzed. Options for outpatient/home care should be considered for appropriate patients.
References: www.unos.org, www.ustransplant.org, www.cff.org
Tobramycin: IV to Inhalation Therapy
The primary treatment goal for CF is to optimize lung health by controlling bacterial infection (Pseudomonas aeruginosa) and mobilizing viscous secretions. The most successful anti-pseudomonal treatment is tobramycin, primarily administered via IV and/or inhalation therapy. With IV tobramycin, like any aminoglycoside, there is significant risk of nephrotoxicity and/or ototoxicity. IV administration requires routine monitoring of serum levels and signs and symptoms of toxicity. Inhalation therapy has proven to be promising for the treatment of P. aeruginosa infections in more stable patients.
Tobramycin is typically administered two to three times a day at 10mg/kg/day. Due to altered tobramycin pharmacodynamics in patients with CF, this is a significantly higher dose than for patients who do not have CF and are typically dosed at 3 to 5 mg/kg/day. Treatment is cycled with 28 days on therapy and 28 days off for a total of 24 weeks up to 96 weeks. Once-daily dosing may be prescribed as well. Once-daily administration is considered equally efficacious and potentially less nephrotoxic than multiple dosing. There is however, a risk that long dosing intervals may increase resistance of Pseudomonas.
Tobramycin solution for inhalation — TSI or TOBI — is the most commonly used inhaled antibiotic and has been a standard of therapy since 1998. Inhaled tobramycin is designed to deliver large quantities of medications to the lungs while decreasing the risk of toxicities from systemic absorption. They may be used:
- As adjunctive treatment with IV antibiotics for an acute pulmonary exacerbation
- As chronic therapy for patients colonized with Pseudomonas
- As early treatment to prevent colonization
It takes approximately 15 to 20 minutes to administer nebulized tobramycin (plus time for cleaning and sterilization). Recently announced, however, is a new pocket-sized drug device using a tobramycin inhalation powder (TIP). Phase 3 studies have shown that the powder inhalation offers not only a shorter administration time (four to six minutes twice daily) but also demonstrates improved lung function and decreased Pseudomonas density.
Peak and trough serum levels should be measured periodically during therapy. Rising trough levels (above 2 mcg/mL) may indicate tissue accumulation. Such accumulation, advanced age, and cumulative dosage may contribute to ototoxicity and nephrotoxicity. It is particularly important to monitor serum levels closely in patients with known renal impairment.
Contraindications
Because of the known cross-sensitivity of patients to drugs in this class, a hypersensitivity to any aminoglycoside is a contraindication to the use of tobramycin. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy instituted.
Common ICD-9 Codes
Listed here are ICD-9 codes and V-codes relevant to cystic fibrosis and lung transplants. Please note, this list is not all-inclusive and ICD-9 codes are updated on a regular basis. To double check that you are using the current and correct code, visit www.coramhc.com/icdcodes.
277.0 |
Cystic Fibrosis |
996.84 |
Complications of Lung Transplant |
V42.6
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Lung Transplant |
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Resource Center
Additional sources of information on CF and lung transplants:
Bibliography
- 1 ATS 2009: American Thoracic Society International Conference. Poster 804. Presented May 17, 2009.
- 2 Dasenbrook, ES, Merlo, CA, Diener-West, M, Lechtzin, N, Boyle, MP. Persistent Methiciliin-resistant staphylococcus aureus and rate of FEV-1 decline in Cystic Fibrosis. AmJl Resp Crit Care Med:2008:174:814-821.
- 3 Smith, A, Elborn, JS. Review series. Exacerbation in cystic fibrosis- 3 Management. Thorax 2008:63:180-184.
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