Inhaled antibiotics can expand the role and importance of RCPs.
Endobronchial infection due to Pseudomonas aeruginosa contributes to progressive lung deterioration and obstructive pulmonary disease, known to be the major cause of morbidity and mortality in patients with cystic fibrosis (CF).1 A recent breakthrough in aerosolized antibiotic therapy has improved the CF caregiver’s armamentarium to thwart progressive damage and to decrease the frequency and severity of chronic infectious exacerbations due to this pathogen. A new formulation of inhaled tobramycin has been shown to be safe and effective in the management of CF patients with P aeruginosa2 (although there are insufficient data to support its use for patients under the age of 6 years, patients with forced expiratory volumes in 1 second of less than 25 percent or more than 75 percent of predicted values, and patients colonized by Burkholderia cepacia).
When to initiate therapy using this new antibiotic inhalation solution remains somewhat controversial. Its use in conjunction with standard CF therapies, however, has been clinically demonstrated3 to provide significant improvements in pulmonary function, to decrease P aeruginosa density in expectorated sputum, to decrease the use of parenteral antipseudomonal antibiotics, and to reduce the need for hospitalization.
CF Overview
CF is a multisystem genetic disorder most commonly found in Caucasian populations of European origin. It affects about 70,000 people worldwide, of whom 30,000 reside in the United States.4 CF has an autosomal recessive inheritance pattern and results from a mutation in the gene encoding a chloride channel protein, the CF transmembrane conductance regulator. The defect causes a reduction in the water content of exocrine-gland secretions due to abnormal transport of ions across the epithelial membranes.1
The Clinical Picture
Nearly all CF patients develop chronic, progressive lung disease, which causes the majority (approximately 90 percent) of deaths. When CF was initially described in 1938, the mean age of survival was less than 1 year. Over time, median survival has increased.5,6 Today, with improved therapeutics and more aggressive patient management, the prognosis for CF has improved greatly, with the average life span of a patient now exceeding 31 years of age.7 Despite these gains, however, more than 50 percent of patients are hospitalized at least once a year for a median duration of 10 days per admission.7
Progressive obstruction of the airways results in an average loss of lung function of about 2 percent, or 100 to 115 mL in tidal volume, per year.4,8 Sinusitis, malabsorption due to pancreatic insufficiency, increased salt loss in sweat, obstructive hepatobiliary disease, and reduced fertility also are common.9 In the early stages of CF, pulmonary effects are primarily inflammatory; however, thick mucus (collected in the airways) acts as an excellent medium for bacterial colonization. This produces the vicious cycle of infection, inflammation, and tissue destruction (which encourages reinfection) commonly observed in CF.1
CF Bacterial Pathogens
A number of bacteria and other microorganisms, including viruses, fungi, and mycoplasmas, may be present in patients with CF; however, three chronic bacterial pathogens predominate. In early childhood, patients may have Staphylococcus aureus and Haemophilus influenzae, and by the age of 17 years, nearly 70 percent of CF patients are colonized by P aeruginosa. Early in CF, lung infection occurs intermittently, although it eventually becomes chronic in most patients.1 The prevalence of P aeruginosa in CF is so great that it is found in the vast majority of CF patients (approximately 90 percent) at some time during their lives.7 Once a CF patient’s lungs become colonized by P aeruginosa, lung function declines more rapidly.
Rationale for Aerosolized Antibiotics
Treatment of CF is aimed at managing the bacterial load, minimizing airway obstruction, and reducing inflammation. In addition to standard airway clearance techniques that improve mucociliary clearance and are an important part of the daily treatment regimen, treatment of CF lung disease includes antibiotic therapy to reduce P aeruginosa colonization.10,11 Bronchodilators,12 as well as mucolytics such as rhDNase (dornase alfa),13 are employed to reduce airway obstruction, and ibuprofen is used to decrease airway inflammation.14 Antibiotic therapy in CF improves lung function and decreases the density of P aeruginosa in sputum. Some CF centers have experimented with chronic oral administration of antibiotics to suppress bacterial growth, but there is little convincing evidence for its long-term efficacy in the CF population.15 Parenterally administered aminoglycosides (such as tobramycin, gentamicin, and amikacin) have demonstrated effectiveness against most strains of Pseudomonas and are commonly used to treat P aeruginosa infection in CF patients.
Acute CF lung exacerbations commonly require hospitalization, and administration of intravenous (IV) antibiotic therapy is the accepted treatment approach. Parenteral aminoglycosides, in combination with b-lactam antibiotics, are frequently the agents of choice;15 however, effective implementation of this treatment regimen is tempered by several factors.
Use of Aminoglycosides
The penetration of aminoglycosides into sputum is low following IV administration, and high doses can be required to achieve concentrations inhibitory to P aeruginosa growth in the lung. The increased risk of systemic toxicity associated with high-dose IV aminoglycosides complicates this strategy because achieving therapeutic concentrations at the site of infection in the lumen of the airway–without concurrent iatrogenic ototoxicity or nephrotoxicity–can be difficult and, in some patients, impossible. Despite 20 years of experience with concomitant parenteral antibiotic use, a 2 percent decline in lung function persists in the CF population.8 Further, hospitalization is costly and disruptive to the patient’s life, and can increase the potential for nosocomial infections.15
Prior to the recent development and commercial availability of a specially formulated tobramycin solution for inhalation, inhaled antibiotic preparations were derived from IV medications that contained preservatives; these caused patients to experience airway irritation, bronchospasm, and bronchoconstriction.16 For example, preservatives like phenol and bisulfites (found in IV tobramycin) have been observed to produce airway irritation and bronchospasm when inhaled.16,17 In addition, phenol, which has a very unpleasant taste and odor, also increases the time required to nebulize the solution (B. Montgomery, oral communication, April 1997).
Another IV agent, gentamicin, contains methyl and propyl parabens, as well as sodium bisulfite and ethylenediaminetetraacetic acid (EDTA). The latter two agents are known bronchoconstrictors.17 It quickly became apparent to clinicians that these antibiotic agents, not indicated (or intended) for administration by inhalation, were inappropriate for introduction into the airways.
Resistant Pathogens
In CF, antibiotic treatment of P aeruginosa colonization rarely leads to bacterial eradication. To complicate therapy further, resistant strains may develop that become increasingly less susceptible to short-term parenteral antibiotic therapy. For example, resistant isolates were found in 15 percent of patients after 10 days of combination treatment with IV tobramycin plus IV ticarcillin, and in 100 percent of patients after 21 days of IV ciprofloxacin monotherapy.18,19 No long-term resistance studies have been conducted in CF patients, so the changes in minimum inhibitory concentration values that might occur with extended antimicrobial treatment are unknown. In addition, whether a single strain mutates to drug resistance or a different strain replaces it is unknown.
It is known, however, that parenteral antibiotic therapy can adversely affect the balance of respiratory flora, and antibiotic treatment of S aureus is thought to be at least partly responsible for the current prevalence of P aeruginosa infections.15 Stutman and Marks20 reported that the overall incidence of P aeruginosa approximately doubled after cephalexin prophylaxis for S aureus infection. Hypothetically, suppression of P aeruginosa could lead to an increase in other pathogens, such as B cepacia, associated with chronic infection (and implicated in declining lung function and death from severe fulminant lung infection) and resistance to b-lactam antibiotics, aminoglycosides, chloramphenicol, and colistin.1,21,22
Inhaled Antibiotic Therapy
As physicians and researchers observed the challenges of treating respiratory exacerbations in CF, the rationale for the delivery of antibiotics directly to the site of infection–the lumen of the airway–became more and more evident. Inhalation therapy with various IV antibiotics has been used in CF for about 50 years,1,15,23 but a number of problems have complicated the search for, and evaluation of, safe and effective aerosol antibiotics for CF patients.
Clinical trial results of inhaled antibiotic studies have been conflicting. Variations in study designs and patient characteristics have made interpretation and comparison difficult.1,15 Review of the literature up to 1995 suggested that inhaled antibiotic therapy could produce a reduction in loss of pulmonary function, a decrease in sputum bacterial density, and a decrease in hospitalization, with no nephrotoxicity or ototoxicity, during short-term therapy for exacerbations of CF.1 Well-controlled multicenter studies of the long-term toxicities of aminoglycoside therapy relating to dose and duration of therapy1,15,24,25 and clinical efficacy outcome measures, however, had not yet been conducted.
Another critical clinical challenge for effective antibiotic inhalation therapy requires that inhaled particles reach the site of infection, usually beginning in the smaller bronchioles and extending toward the bronchi. Deposition patterns of inhaled particles in the normal lung are dependent on the rate of nebulized flow and the size and rate of branching of the airways.1,15 Particles with a mass median aerodynamic diameter (MMAD) of less than 5 mm are deposited in the central airways and the oropharynx, while particles with an MMAD of 1 to 2 mm are deposited in the alveoli. The optimal particle size for lower-airway deposition is 3 to 4 mm.
The site of particle deposition affects systemic absorption, influencing both therapeutic effects and the occurrence of adverse events. Thus, to minimize toxicities and maximize therapeutic effectiveness, the deposition of antibiotic particles of 3 to 4 mm into the lower airways is required. Despite technology that renders most commercially available nebulizers effective in producing particles that are within the correct therapeutic size range, antibiotics intended for IV administration were not designed for nebulization. When nebulized, these IV solutions may absorb water in the respiratory tract, resulting in increases in particle size, and thus, a decreased likelihood of antibiotic deposition at the site of infection.
Incrementally, the osmolarity, pH, and excipients present in the antibiotic solution must be considered. Bronchial secretions are iso-osmolar in normal adults. This means that the total osmotic pressure, or osmolality, of these bronchial secretions matches that of the intracellular fluids.1 The addition of large amounts of hypotonic or hypertonic solution, or of solutions with an altered pH, can cause mucosal irritation.1,26 Studies27 suggest that the airway mucus of CF patients is hypotonic, so that adding hypertonic, or even isotonic, solutions can cause mucosal irritation. In addition to the problems of osmolarity and pH, the presence of preservatives and other excipients known to be associated with bronchoconstriction and bronchospasm further complicates the challenge.
Delivery of medications via aerosol is inefficient, with only about 10 percent of the agent actually reaching the lung for deposition. The remaining 90 percent is deposited in the oropharynx, swallowed, or exhaled.1,15,28 In addition, physiologic deposition of antibiotic particles in the CF lung is substantially more variable than deposition in the normal lung, so the efficacy of aerosol therapy, particularly in the more severely affected CF patient, could be impaired. Thus, to produce a therapeutic effect, high antibiotic doses–at a high cost, and with considerable waste–would be required. To be cost-effective, inhaled antibiotics must be unequivocally demonstrated to produce clinical improvements and a reduction in inpatient days per year.15
Meeting the Challenges
There has been wide variation in doses delivered, patterns of particle deposition, and side effects observed for inhaled antibiotic therapy; in addition, it has yielded inconsistent, unreliable treatment outcomes. Such findings have proven to be quite challenging to researchers and clinicians alike, necessitating that each agent (and the chosen nebulizer) be individually studied and evaluated–a time-consuming, expensive, and difficult process. A great deal of research1,3,6,15-19,23-25,29-33 has been devoted to the evaluation of various antibiotics, dosing regimens, durations of therapy, safety, outcome measures, and long-term outcomes. Recently, a well-controlled, multicenter 6-month study was completed. It was designed to evaluate chronic intermittent administration of inhaled tobramycin, and it assessed safety, effectiveness, treatment outcomes, and potential development of multiresistant pathogens. These data are scheduled to appear in the New England Journal of Medicine.
Conclusion
CF affects approximately 70,000 people worldwide. It is characterized by lung disease resulting from endobronchial infection by P aeruginosa. The prevalence of P aeruginosa in CF is so great that it is found in the vast majority of CF patients (90 percent) at some time during their lives.7 Antibiotic treatment of P aeruginosa colonization and infection rarely leads to bacterial eradication. To complicate therapy further, resistant strains may develop that become decreasingly susceptible to short-term parenteral antibiotic therapy. Once a CF patient’s lungs become colonized by P aeruginosa, lung function declines more rapidly. Loss of lung function correlates with progressive disability. As CF progresses, the frequency of pulmonary exacerbations increases. These exacerbations require increases in the use of IV antipseudomonal antibiotics and in annual days of hospitalization. The CF patient’s quality of life is greatly diminished when CF becomes severe.
The use of inhaled antibiotics has permitted clinicians to target therapy directly to the site of infection–the lower airways. Inhalation of antibiotics, versus parenteral administration, reduces systemic exposure and the potential for serious toxicities.
Until recently, the appropriate use of aerosol antibiotics for CF has been unclear because of inconsistencies in clinical trials. Although fraught with many challenges and disparities, clinical studies and trials have suggested therapeutic benefits for a number of inhaled antibiotics (including colistin, b-lactams, polymyxins, and aminoglycosides). In late 1997, an inhalation solution of tobramycin, specifically formulated for aerosolized delivery to the lower airways, was granted FDA approval and became commercially available for the treatment of CF patients. Results of a 6-month23 multicenter trial using tobramycin solution for inhalation administered in an intermittent regimen (28 days on and 28 days off) will soon be published. The investigators demonstrated product safety, improved lung function, decreased sputum bacterial density, decreased durations of hospitalization, and decreased days of use for IV antipseudomonal antibiotics.
Despite these advances, a number of other questions about inhalation therapy remain unanswered. For example, can early intervention using inhaled antipseudomonal antibiotics prevent or delay chronic infection? As experience with antibiotics that are indicated for inhalation therapy expands, which products will be found to be most effective in patient populations of varying ages and disease severities? What long-term effects will be found to occur in association with future inhalation antibiotics? What combinations of CF therapies will be most cost effective and yield the best long-term outcomes for these patients?
Therapeutic regimens for CF have evolved slowly over the past four decades, resulting in an increase in median survival age. By the early 21st century, nearly half of CF patients will be adults. Aggressive monitoring and treatment of CF exacerbations during the early stages of pulmonary disease can slow disease progression. There is much hope that today’s research efforts will produce a biological or pharmacologic therapy that will treat the underlying defect in CF.
It is likely that inhaled antibiotics–and new investigational agents–will address other lung diseases (such as chronic obstructive pulmonary disease, chronic bronchitis, and tuberculosis) in addition to CF. Continued advances in this category of inhaled therapeutic agents targeted to the site of infection can expand the role and importance of the RCP. Keeping abreast of these and other developments will be a key to providing optimal care of patients in the future.
Stanley B. Fiel, MD, is professor and chief, Division of Pulmonary/Critical Care Medicine, Allegheny University of the Health Sciences, MCPlHahnemann School of Medicine, Philadelphia.
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