Cystic fibrosis (CF) is the most common inherited life-shortening disease in whites, occurring in approximately 1 per 2,500 infants. Approximately 3 new patients are diagnosed as having CF each day, and the disease affects approximately 22,000 individuals in the United States.1 CF is caused by an absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) protein. As a result of improving therapies, more than one-third of patients are older than 18 years.1 However, the median survival time has plateaued in recent years and is now approximately 29 years. The burden of the disease remains substantial; 20% of patients require intravenous antibiotics at least once per year, and more than 100 lung transplants are performed each year for patients with CF. Most of the approximately 400 patients who die of the disease each year succumb to respiratory failure.1
More than a decade after the discovery of the generic defect, the etiology of chronic bacterial colonization in patients with CF from a young age remains a mystery. It is believed that lack of the CMK protein causes a breach in the host defense systems of the airways, but the mechanism by which infections occur remains unclear. The defect is not a systemic immune deficiency; indeed, patients with CF rarely have bacteremia despite chronic and severe airway infections.
One hypothesis (the "low volume" hypothesis) suggests that the airways of patients with CF are dehydrated, resulting in mechanical impairment of ciliary function.2 This hypothesis is supported by evidence that CFTR inhibits the epithelial sodium channel, and absence of CFTR results in sodium hyperabsorption. Water is passively absorbed with sodium, and the surface fluid remains isotonic. An alternative hypothesis (the "low salt" hypothesis) suggests that normal airway liquid is relatively hypotonie, whereas the airway liquid in patients with CF has higher concentrations of salt. Additionally, there is a high concentration of polyvalent aruons such as actin and DNA. This environment results in inactivation of host defense antimicrobial proteins, such as defensins.3"5 Difficulties in measuring concentrations of ions in airway liquid and differences in culture techniques among laboratories have hampered evaluation of these hypotheses. Other hypotheses include increased binding of bacteria due to increased asialoganglioside receptors6 or decreased binding of bacteria by CFTR.7
Regardless of the mechanism by which the infection is initiated, there is an exuberant and persistent neutrophilic infiltration of the airways. This, in addition to toxins produced by the bacteria, results in damage to the airway epithelium and submucosa and, eventually, peribronchial fibrosis and bronchiectasis. The airway damage itself further promotes bacterial adherence and inflammation; this has been termed the "vicious circle" of lung disease in CF.
Most older patients with CF are able to expectorate sputum for culture, especially after chest physiotherapy. Younger patients frequently swallow sputum. For these patients, oropharyngeal (throat) swabs are commonly obtained. However, the latter may result in a culture contaminated by upper airway flora rather than reflecting lower airway pathogens. Somewhat surprisingly, for children younger than 5 years, oropharyngeal cultures have been found to have a high specificity and a negative predictive value but a poor sensitivity and a positive predictive value for the presence of Pseudomonas. & In this study, negative results on oropharyngeal cultures correlated strongly with negative results on bronchoalveolar lavage cultures, but positive results on oropharyngeal cultures predicted positive results on bronchoalveolar lavage cultures only 44% of the time. Bronchoalveolar lavage has been used for patients who are unable to produce an informative culture and who have failed to improve with empiric therapy. In many cases, this results in a change in therapy or the isolation of previously unidentified organisms.9
Proper identification of pathogens and accurate antimicrobial sensitivity testing are crucial to the successful treatment of infections. This requires excellent communication between the physician and an experienced microbiology laboratory. The Cystic Fibrosis Foundation Clinical Practice Guidelines recommend that cultures be obtained at least annually,10 It is common practice to obtain additional cultures during pulmonary exacerbations. For example, identification of colonization with Pseudomonas has increased with more frequent cultures.
Figure. Age-specific prevalence of infections in patients with cystic fibrosis. (Reproduced with permission from the Cystic Fibrosis Foundation. Patient Registry 1999 Annual Report. Bethesda, MD: Cystic Fibrosis Foundation; September 2000.)
The Usual Suspects
In infancy and childhood, most patients with CF are colonized with Staphylococcus aureus, Haemophilus influenzae, or both (Figure), Although there is some controversy as to whether H. influenzae is a true pathogen in CF, staphylococci have been known to cause lung disease since Dr. Dorothy Anderson's original description of CF.11 Treatment of staphylococcal colonization with long-term oral antibiotics has not been shown to decrease the number of pulmonary exacerbations, but may facilitate colonization with Pseudomonas}2 Perhaps due to increased use of anti-staphylococcal antibiotics, there is increasing recognition and detection of methicillin-resistant S. aureus (MRSA). In the most recent report from the Cystic Fibrosis Foundation, 4.2% of patients nationwide were colonized with MRSA.1 In some studies, colonization with MRSA did not appear to adversely affect lung function.13'14 Nonetheless, when patients colonized with MRSA fail to improve with antibiotics directed against other colonizing organisms, many physicians attempt to broaden coverage. Unfortunately, the repertoire of antibiotics to treat MRSA is limited, but includes vancomyän, which has also been given by aerosol.15
By adolescence, most patients with CF are colonized with Pseudomonas aeruginosa, a ubiquitous water-borne, gram-negative organism. These infections usually are confined to the airways, but during acute exacerbations may involve the airspaces (pneumonia). Pseudomonas species may be particularly difficult to treat because of their production of a variety of virulence factors, production of a mucoid exopolysaccharide coat, and rapid development of resistance to antimicrobial agents. In vivo, Pseudomonas may exist in biofilms, which poses additional physical and chemical barriers to antimicrobial killing. The recent sequencing of the Pseudomonas genome16 will likely provide new targets for treatment.
Burkholderia cepacia (previously classified as Pseudomonas cepacia) is usually highly resistant to many antibiotics and notoriously difficult to treat. As such, identification of B. cepacia in CF is worrisome to the patient, his or her parents, and the physician. The problem is compounded by the difficulty in properly identifying the organism.17 Approximately 3.3% of patients nationwide are colonized with B. cepacia.1
It was once believed that B. cepacia universally resulted in a rapid decline in clinical status. However, more recent evidence challenges this.18 It appears that approximately 20% of patients have a rapid decline, some of whom have B. cepacia bacteremia, high fevers, and pneumonia ("cepacia syndrome"}.19 Another 20% have a decline in pulmonary function that is more rapid than that prior to colonization. However, most have no obvious change in clinical status or pulmonary function for at least the first year after colonization.18
Because of the rapid decline in some patients, evidence mat the infection may be transmitted from patient to patient, and evidence that overall survival is worse for colonized patients, most CF centers segregate, to some degree, patients colonized with B. cepacia. In addition, social interaction in group settings (eg, camps) is discouraged. The author's CF center has resorted to "universal precautions/' requiring the wearing of masks whenever hospitalized patients are outside of their rooms and when outpatients are in the offices. This approach acknowledges the difficulty in identifying patients colonized with B. cepacia because cultures are routinely obtained approximately 3 to 4 times per year. Additionally, many lung transplantation centers consider colonization with B. cepacia to be a contraindication to transplant.20
Stenotrophomonas maltophilia (previously classified as Pseudomonas maltophilia and subsequently Xanthomonas maltophilia) is another gram-negative bacterium that opportunistically infects hospitalized patients and patients with CF. It is not yet clear whether this organism has special significance in the course of lung disease in CF, but it has been increasingly identified in culture results reported to the Cystic Fibrosis Foundation's national registry (6.4% of patients1). In one study, long-term antibiotics and long courses of intravenous antibiotics were risk factors for acquisition of S. maltophilia and colonized patients had worse growth parameters, clinical scores, and lung function than did age-matched control subjects with CF.21
The Unusual Suspects
There are increasing reports of airway colonization in CF with a variety of atypical, nontuberculous mycobacteria, including Mycobacterium avtum, Mycobacterium chelonae, and Mycobacterium abscessus, The role of these organisms in causing pulmonary disease in CF is not well understood, and, consequently, the need for treatment (frequently requiring multiple drugs) is debated.22'24 Although these organisms are commonly believed to represent colonization, there are some cases of true infection and invasive disease.25 Yeast such as Candida aïbicans are commonly isolated from the sputum of patients with CF, probably as a consequence of alteration of flora from antibiotics, but are generally not thought to play a role in pulmonary disease.
Molds such as Aspergillus fumigatus are also commonly recovered. A well-recognized hypersensitivity reaction to Aspergillus (allergic bronchopulmonary aspergillosis) was originally described in adults with poorly controlled asthma. This reaction, characterized by decreased pulmonary function, wheezing, immediate hypersensitivity to intradermal challenge, and serum markers (elevated total IgE, Aspergillusspecific IgE, and eosinophilia), is treated with systemic corticosteroids and sometimes with adjunctive antifungal therapy such as itraconazole.26-27
The definition of a pulmonary exacerbation varies widely among physicians,28 but commonly includes increases in cough or sputum production, decreases in pulmonary function, or other symptoms (eg, fever or malaise) or signs (eg, crackles or wheezing). These exacerbations are usually treated with antibiotics directed at organisms in the patient's sputum culture. Commonly used oral antibiotics directed against Staphylococcus and Haemophilus include trimethoprimsulfamethoxazole and amoxicillin-clavulanate. The quinolones eg, ciprofloxacin) are the only class of oral antibiotics suitable for treating Pseudomonas. Concerns regarding quinolone impairment of cartilage growth in beagle puppies have not been borne out in humans.29 Antibiotics are usually prescribed for at least 2 weeks, but longer courses may be required depending on the clinical response.
Patients with CF have increased clearance of many antibiotics,30 especially penicillins, related to a larger volume of distribution and increased tubular secretion compared with control subjects. For this reason, patients with CF are commonly given antibiotics at more frequent dosing schedules (eg, every 4 to 6 hours instead of every 6 to 8 hours). For more severe exacerbations or if outpatient treatment has failed, patients are treated with intravenous antibiotics.
Culture results and antimicrobial sensitivity testing guide the choice of antibiotics. Antibiotics commonly used to treat Pseudomonas include aminoglycosides (usually tobramycin) and extended-spectrum penicillins or cephalosporins with anti-pseudomonal activity (eg, ticarcillin or ceftazidime). For aminoglycosides (eg, gentamicin or tobramycin), many clinicians aim to achieve peak serum concentrations between 8 and 12 µg /mL, with the goal of having the serum level 6 to 8 times the minimum inhibitory concentration. Newer agents such as the carbapenems (eg, imipenem or meropenem) are increasingly used and are under investigation by the Cystic Fibrosis Foundation's Therapeutic Development Network. Combination therapy is generally used and has been shown to prolong the clinical response.31 It is also believed to decrease antimicrobial resistance through enhanced killing by separate mechanisms. However, there are data indicating that monotherapy may actually result in less resistance.31,32 Agents such as nafcillin or oxaallin may be added when Staphylococcus is present.
The delivery of antibiotics directly to the airways is attractive for several reasons. It should allow high local concentrations of the drug with lower risk of systemic (eg, renal or acoustic) toxicities. The most common side effect is bronchospasm, which is usually prevented by aerosolized bronchodilators. Administration via nebulizer is more convenient and less expensive than intravenous administration. For these reasons, several antibiotics have been aerosolized to the CF airways, including aminoglycosides,33"35 beta-lactams,36 and the peptide antibiotic colistin.37 However, deposition into the lungs is not efficient and varies by nebulizer, drug, and lung function.
A large, multicenter, randomized trial with inhaled tobramycin demonstrated that 300 mg twice a day for 28-day cycles improved lung function and decreased the need for hospitalization and intravenous antibiotics.38 Development of resistance to tobramycin remains a concern, although in this study the observed rise in minimum inhibitory concentration did not seem to impair the clinical response. The use of inhaled antibiotics for the treatment of acute exacerbations of CF is less well studied, and further data are required before this treatment can be used with confidence.
Synergy Testing and Multiple Combination Bactericidal Testing
In 1991, the Cystic Fibrosis Referral Center was started in the laboratory of Dr. Lisa Saiman at Columbia University (www.cpmcnet.columbia. edu/dept/synergy). This center performs testing of combinations of antibiotics against multiply resistant strains of bacteria. After determination of the fractional inhibitory concentration of each of pairs of antibiotics, it is possible to determine whether the combination is synergistic, additive, indifferent, or antagonistic. The testing is funded by the Cystic Fibrosis Foundation. The author's CF center has used this information routinely in choosing antibiotics to treat resistant organisms. The University of Ottawa has been performing susceptibility testing with single, double, and triple combinations of antibiotics using a large panel of combinations.39 This testing has also been helpful in treating infections due to multiply resistant organisms.
Two caveats should be noted regarding these specialized susceptibility methods. First, there are as yet no data demonstrating in vivo efficacy of therapy based on in vitro assays. Indeed, a discrepancy is often observed. Second, the concentrations of antibiotics used in the testing may not be achievable at the site of infection, at least when administered intravenously. For example, the multiple combination bactericidal testing protocol uses 200 ^g /mL of tobramycin, which can be achieved only via aerosol administration.
CONTROVERSIES IN THE TREATMENT OF INFECTIONS
Antibiotics: Aie More Better?
The optimal strategy to treat pulmonary infections in CF with the long-term goal of preserving lung function continues to be debated. Some physicians advocate suppressive treatment of infection with continuous oral antibiotics. This has largely been proposed for the treatment of staphylococcal infections with beta-lactam antibiotics.
In one small study, newborns diagnosed as having CF by screening were randomized to receive daily oral flucloxacillin or episodic antibiotics for clinical exacerbations. The continuously treated group had fewer hospitalizations and hospital days in the first 2 years of life.40 However, other data show that antibiotic treatment directed at staphylococci may increase the growth of Pseudomonas, if present.41'42 A study of young children in the United States demonstrated no clinical benefit to 5 years of continuous treatment with cephalexin, but a higher incidence of colonization with Pseudomonas (E. Nussbaum, MD, unpublished data, 2001). A meta-analysis of 13 clinical trials of anti-staphylococcal therapy demonstrated that it results in clearance of the organism from sputum, but this did not correlate with improvements in pulmonary function or chest radiographs.43 The author reserves longterm suppressive antibiotics for patients whose exacerbations are so frequent that "elective" courses of antibiotics are nearly contiguous.
During the late 1970s, Danish CF centers began using courses of intravenous antibiotics on a scheduled, quarterly basis, regardless of patient symptoms or lung function. When compared with the 5 years prior to this change, patient mortality decreased and lung function and die 5-year survival rate increased.44 However, many other changes in care (eg, change to a high-fat diet) were instituted at the same time, and this study was not randomized or prospective. In a more recent, prospective study in the United Kingdom, 60 adults with CF were randomized to receive elective (quarterly) courses of antibiotics or courses when symptomatic. The latter group had fewer courses of antibiotics and no difference in forced expiratory volume in 1 second at the end of a 3-year follow-up period.45
Early Eradication of Pseudomonas
Evidence exists that there is an accentuated inflammatory response following initial colonization with Pseudomonas that results in a decline in pulmonary function.46 For almost 900 patients in a comparative study in Cleveland,47 no significant differences in pulmonary function or rates of hospitalization were observed during the 2 years following colonization with Pseudomonas compared with the year prior to colonization. Furthermore, there was no difference in the 10year survival rate between patients colonized as infants and those colonized after the age of 7 years.
Nonetheless, it is believed by many that Pseudomonas colonization is a risk factor for more severe pulmonary disease. Colonization with Pseudomonas may be intermittent initially, and attempts have been made to treat aggressively to "eradicate" the organism from the airways when first identified, before chronic infection is established. This approach, developed in Denmark, uses oral quinolones and inhaled colistin for 3 weeks, with increasing doses if the organism continues to be cultured.
In one study, only 16% of patients treated with this regimen had chronic Pseudomonas infection after 3.5 years, and pulmonary function was better maintained after 2 years in the treated group (forced expiratory volume in 1 second increased 3% in the treated group vs a 6% decline in the control group).48 Several important caveats must be noted. First, the treated group was compared with historical control subjects and not a contemporary, randomized group. Second, there are substantial differences in treatment between the Danish CF center and most U.S. centers. Patients in Denmark are routinely treated with intravenous antibiotics on a quarterly basis. Additionally, patients are evaluated on a monthly basis with respiratory cultures obtained and serum arui-Pseudomonas antibodies measured at each visit, compared with patients usually seen 3 to 4 times per year in the United States. Finally, there are probably substantial differences between Danish and U.S. patients with CF in terms of ethnic heterogeneity and social factors such as access to care.
A subsequent study from Germany randomized 22 patients to receive placebo or aerosolized tobramycin twice daily for 12 months after new colonization with Pseudomonas. The patients treated with tobramycin had negative results on cultures for Pseudomonas in 1 to 3 months, whereas the patients treated with placebo generally continued to have positive results on cultures.49 However, almost one-third of the patients did not complete the study and no differences were found in pulmonary function between the groups.
Some U.S. physicians have chosen to treat newly detected colonization with Pseudomonas aggressively with either oral, inhaled, or intravenous antibiotics. Concerns that have been raised include the risks of toxicity and antimicrobial resistance in patients who may be colonized but otherwise asymptomatic. A multicenter, randomized, placebo-controlled study will be required to evaluate the efficacy of this approach.
Home Versus Hospital Care
Many patients prefer to receive intravenous antibiotic therapy at home. Peripherally inserted central catheters and portable pumps have made this therapy convenient and common. In the author's experience, some patients emphasize USe intravenous antibiotic therapy to the exclusion of all other components of their care, which should include aggressive airway clearance and nutrition.
Bosworth and Nielson compared patients treated for a pulmonary exacerbation at home with a group treated in the hospital.50 Patients treated in the hospital had greater improvements in pulmonary function, fewer total days of intravenous therapy, and lower costs. Patients in the home care group were not closely supervised and used chest physiotherapy less frequently. This may account for part of the observed differences. These differences were not evident in other studies,51 and patients commonly report that their quality of life is better while receiving therapy at home.52 The optimal location for treatment of pulmonary exacerbations may depend on several patient factors, including adherence, family support, and disease severity.
Respiratory tract infections in patients with CF can be treated using newer antibiotics and a variety of strategies. The optimal choice of treatment for each patient needs to be individualized, based on the severity of disease and other factors. Physicians treating patients with CF must use these available tools to aggressively treat the infectious complications of CF. By doing so, we hope to slow progression of the disease until a therapy directed at the underlying defect that causes CF becomes available.
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