Cystic fibrosis: Overview of the treatment of lung disease

INTRODUCTION  — Cystic fibrosis (CF) is a multisystem disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on chromosome 7 [ 1 ]. Pulmonary disease remains the leading cause of morbidity and mortality in patients with CF. (See "Cystic fibrosis: Genetics and pathogenesis" .)

The treatment of CF lung disease is experiencing a period of rapid evolution, supported by well-designed clinical trials and improved understanding of the genetics and pathophysiology of the disease [ 2-4 ]. Undoubtedly, these advancements are responsible for a substantial portion of the improvement that has occurred in patient survival ( figure 1 ) [ 2,5 ].  

While the focus of this discussion is on pulmonary therapies, it must be kept in mind that management is often suboptimal unless the multisystem nature of the disease is considered. Sinus infection, nutritional status, glucose control, and psychosocial issues must all be assessed at regular intervals [ 6 ]. This requires a multidisciplinary approach to care that, in the United States, is best provided at one of the approximately 115 CF Care Centers (most with dedicated adult care programs) that are supported and accredited by the Cystic Fibrosis Foundation. Patients treated at these centers are seen on a regular basis by physicians, nurses, dietitians, respiratory therapists, physical therapists, and social workers with special competence in CF care. A listing of these centers can be obtained at the Cystic Fibrosis Foundation Web site ( www.cff.org ). In the United Kingdom, CF patients receiving their medical care at specialized CF centers have better clinical outcomes compared to patients followed in the general community [ 7 ]. In the United States, more frequent caregiver-patient interaction (visit frequency, monitoring, and interventions for pulmonary exacerbations) is associated with improved outcomes [ 8 ].

An overview of the treatment of CF lung disease will be reviewed here. Details of treatment with antibiotics are discussed separately. The diagnosis, clinical manifestations, and investigational treatments for CF are discussed separately. (See "Cystic fibrosis: Antibiotic therapy for lung disease" and "Cystic fibrosis: Clinical manifestations and diagnosis" and "Cystic fibrosis: Clinical manifestations of pulmonary disease" and "Cystic fibrosis: Investigational therapies" .)

CFTR MODULATORS  —  Ivacaftor (VX-770) is a small molecular weight oral drug that is specifically designed to treat patients who have a G551D mutation in at least one of their CFTR genes. As of January, 2012, ivacaftor is available and approved in the United States for patients with this mutation [ 9 ]. Of considerable importance, ivacaftor is the first approved CF therapy that restores the functioning of a mutant CF protein rather than trying to target one or more of its downstream consequences. The magnitude and breadth of its beneficial effects significantly exceed any other treatment currently available for cystic fibrosis [ 10 ].  

The G551D mutation, which occurs in approximately 5 percent of CF patients, impairs the regulated activation of the ion channel that is formed by the CFTR protein. (see "Cystic fibrosis: Genetics and pathogenesis", section on 'Class III mutations: Defective regulation' ). Ivacaftor was developed using high-throughput screening of large chemical

libraries, by which candidate molecules (called “potentiators”) were identified that increased chloride ion flux in cultured cells expressing G551D CFTR [ 11 ]. From these candidate molecules, ivacaftor was developed.

Clinical trials of ivacaftor have demonstrated important benefits. In a phase 3 multicenter randomized trial of 161 subjects 12 years of age or older with a G551D mutation, ivacaftor for 24 weeks improved mean FEV1 percent predicted by 10.4 percent compared to a decline by 0.2 percent in subjects receiving a placebo (primary endpoint, p <0.001) [ 12 ]. The beneficial effect was maintained through 48 weeks of ivacaftor treatment. Ivacaftor also decreased sweat chloride values by 48.1 mmol/L compared with that in the placebo group (p <0.001), bringing the mean value in the ivacaftor group to 51.7 mmol/L, which is below the cutoff point of 60mmol/L that is used for diagnosing cystic fibrosis. Finally, treatment with ivacaftor reduced the frequency of pulmonary exacerbations (55 percent reduction in risk), improved pulmonary symptoms, and resulted in a significant weight gain of 2.7 kg after 48 weeks of treatment. The frequency of serious adverse events was lower in the ivacaftor group than in the placebo-treated patients. Another randomized, blinded, placebo controlled trial of 52 subjects age 6 to 11 years and at least one G551D CFTR mutation found similar improvements in lung function ( NCT00909727 ) [ 13 ].

All CF patients should undergo CFTR genotyping to determine if they carry a G551D mutation in their CFTR genes. Because this mutation was identified in 1990, it is highly likely that most CF patients who were genotyped after the early 1990s would have G551D identified if it was present.

We recommend ivacaftor for all CF patients 6 years of age and older who carry at least one copy of the G551D CFTR mutation. Ivacaftor, 150 mg PO every 12 hours, should be taken with fat-containing foods. Dose reductions are needed for patients with hepatic impairment or who are taking drugs that are inhibitors of cytochrome P4503A such as ketoconazole or fluconazole (see manufacturer’s prescribing information ). Because elevations in serum hepatic enzyme levels were noted in a small number of subjects during clinical trials, liver function tests are recommended prior to ivacaftor treatment, every three months for the first year, and then annually thereafter.  

The pharmaceutical company that developed ivacaftor plans to test its efficacy in CF subjects who have other mutations that affect CFTR channel activation [ 14 ]. Unfortunately, when used alone, ivacaftor does not help patients who are homozygous for delta F508 (F508del), the most common CFTR mutation and one that causes abnormal CFTR protein folding that prevents its translocation to the apical cell membrane [ 15 ]. Studies are underway to determine if ivacaftor may have a potentiating effect when combined with investigational drugs designed to correct delta F508 folding. (See "Cystic fibrosis: Investigational therapies", section on 'Combination strategy for the F508del mutation' .)

ANTIBIOTICS  — The course of pulmonary disease in cystic fibrosis is characterized by chronic infections with multiple organisms, causing a gradual decline in pulmonary function, with periodic acute exacerbations heralded by symptoms such as increased sputum production and cough.

At birth, the lungs of patients with CF are free of infection. Whether beginning in infancy or later in life, virtually all patients eventually develop repeated acute, viral, and bacterial infections that upregulate inflammation and lead to airway injury. Ineffective innate and acquired immunity ultimately results in a state of chronic bacterial infection.

The onset and rate of chronic airway infection varies widely among patients due to differences in environmental influences (eg, primary or passive exposure to tobacco smoke, socioeconomic status), genetic effects (CFTR mutations and non-CFTR genetic modifiers), and medical interventions. Nonetheless, some patterns of infection can be observed: (See "Cystic fibrosis: Antibiotic therapy for lung disease", section on 'Pathogens' .)  

Clinical microbiology laboratories identify Staphylococcus aureus as the most prevalent infecting bacteria in childhood; it continues to be a frequent pathogen throughout adulthood ( figure 2 ). The portion of S. aureus that is methicillin resistant has been increasing.  

Haemophilus influenza is present in 20 to 30 percent of patients in childhood, but it becomes less prevalent in adults.

Pseudomonas aeruginosa, which can be isolated in about 25 percent of infants, becomes the most frequently isolated bacteria in adults, reaching a prevalence rate of up to 80 percent.

Antibiotics are essential tools for the treatment of both chronic infections and acute exacerbations of CF lung disease. Based on a few randomized trials, it appears that there is no advantage to scheduling elective periodic hospitalization and intravenous antibiotics for pulmonary toilet ("clean-out"), so this practice is now used infrequently in the United States, although it is variably embraced in Europe [ 16,17 ].

Chronic treatment with oral antibiotics to control infection is not encouraged because the benefits have not outweighed the problems associated with antibiotic resistance [ 18 ] with two exceptions:  

Azithromycin is recommended for many patients with CF; its benefits may be due to its antiinflammatoryand/or antibacterial properties. (See 'Macrolide antibiotics' below.)

Chronic treatment with nebulized antibiotics directed against Pseudomonas aeruginosa (eg, tobramycin andaztreonam ) appears to improve lung function and is recommended for many patients. These approaches are discussed in detail separately. (See "Cystic fibrosis: Antibiotic therapy for lung disease", section on 'Aerosolized antibiotics' .)

BRONCHODILATORS  — Airflow obstruction is a central feature of CF lung disease, and is caused by several mechanisms. Impairment to flow is due to bronchial plugging by purulent secretions, bronchial wall thickening due to inflammation, and airway destruction. A subgroup of CF patients also have airflow obstruction from bronchial hyperreactivity; many, but not all, of these patients show typical signs and symptoms of asthma, such as chest tightness, wheezing, and cough following exercise or exposure to allergens or cold air [ 19 ]. Some of these patients are colonized with Aspergillus species and fulfill diagnostic criteria for allergic bronchopulmonary aspergillosis [ 20 ]. (See "Allergic bronchopulmonary aspergillosis" .)

Many patients with CF demonstrate acute improvement in FEV1 following the administration of beta-adrenergic agonists, anticholinergic drugs, and/or theophylline , regardless of the presence of typical asthmatic symptoms; the greatest improvements occur in those who have airway hyperreactivity and milder overall lung disease [ 19 ]. In general, patients with severe airflow obstruction are less likely to show improvement, and a small number of patients show paradoxical reductions in airflow following inhalation of beta-adrenergic agonists.

Despite the widespread use of bronchodilators in CF, few long-term studies have been performed to evaluate the chronic effects of bronchodilator treatment. One placebo-controlled crossover study of 27 patients found that one month of albuterol treatment improved peak flow measurements only in patients with a positive pretreatment bronchoprovocation study [ 21 ]. (See "Bronchoprovocation testing" .) A comprehensive review of the literature concluded that beta-2 agonists have demonstrable efficacy only in this group [ 22 ].

A separate nonrandomized observational study found that FEV1 improved during a year of albuterol treatment, compared to a decline in FEV1 in a parallel population not taking the drug [ 23 ]. However, a subsequent placebo-controlled, double blind study in 21 patients failed to show that albuterol was superior to placebo, although the power to detect such a difference was low [ 24 ]. A randomized placebo controlled trial comparing albuterol with high-dose salmeterol (100 mcg twice daily) showed better FEV1 percent predicted levels during treatment with salmeterol [ 25 ].

Inhaled beta-2-adrenergic receptor agonists  — In general, we support the recommendations of a guidelines committee of the Cystic Fibrosis Foundation [ 26 ] who advise the regular use of inhaled beta-2-adrenergic receptor agonists in virtually all patients with CF. In practice, we recommend these agents ( albuterol or a similar beta-2 adrenergic receptor agonist with rapid onset of action) for virtually all patients with CF, in the following situations:

Immediately prior to sessions of chest physiotherapy and exercise to facilitate clearance of airway secretions. (See 'Chest physiotherapy' below.)

Immediately prior to inhalation of nebulized hypertonic saline, antibiotics, and/or DNase to limit nonspecific bronchial constriction induced by these agents and to potentially improve penetration and distribution of the drugs within the airways. (See 'Inhaled DNase I (dornase alfa)' below.)

There is clinical evidence that chronic use of beta-2-adrenergic receptor agonist therapy increases expiratory flow rates in patients with CF [ 21,25 ]. This has led to the recommendation that clinicians prescribe albuterol every four to six hours, or a long-acting beta-agonist ( salmeterol or formoterol ) every 12 hours [ 26 ].

Other bronchodilators  — The anti-cholinergic agent ipratropium bromide can induce bronchodilation following acute administration in patients with CF. Trials of the longer-acting tiotropium are underway to determine its role in the chronic management of CF lung disease.

Theophylline is infrequently prescribed in cystic fibrosis due both to the lack of proven efficacy and to its narrow therapeutic index and propensity to cause adverse gastrointestinal symptoms, tachycardia, and rarely seizures.

AGENTS TO PROMOTE AIRWAY SECRETION CLEARANCE  — Difficulty clearing purulent secretions from the airways is a universal complaint from CF patients who have moderate to severe lung disease. Chemical analysis of CF sputum has shown that its high viscosity is caused by the interaction of several macromolecules, including mucus glycoproteins, denatured DNA, and protein polymers such as actin filaments [ 27,28 ].

Inhaled DNase I (dornase alfa)  — The endonuclease DNase I can decrease the viscosity of purulent CF sputum by cleaving long strands of denatured DNA that are released by degenerating neutrophils. The human DNase I gene has been cloned, and the protein that it encodes can help liquefy CF sputum. A randomized, blinded, placebo-controlled trial of 968 stable patients with an FVC >40 percent of predicted values showed that the daily inhalation of 2.5 mg of nebulized DNase ( dornase alfa ) for six months resulted in a statistically significant improvement in FEV1 of approximately 6 percent [ 29 ]. A small but statistically significant reduction in the number of hospital days for exacerbations of respiratory disease was also seen in patients receiving the drug. Subsequent clinical trials have confirmed these findings and demonstrated benefit in children older than 6 years of age and with mild CF lung disease [ 26 ]. A metaanalysis of randomized trials concluded that DNase treatment improves lung function and is well tolerated [ 30 ].

Patients are generally treated daily; however, results from a 12-week cross-over trial of 48 patients found alternate day dosing of nebulized DNase resulted in equivalent clinical outcomes, and substantially lower drug costs [ 31,32 ]. There is some variability among US CF centers in prescribing practices for DNase, probably influenced by the high cost of the drug [ 33 ]. A guideline committee of the CF Foundation recommends the chronic use of DNase for all children with CF older than 6 years of age, regardless of symptoms or pulmonary function tests [ 26 ]. Nebulized DNase is also suggested for infants and young children with CF with pulmonary symptoms, although this suggestion is based on inference from results in older age groups [ 34 ] and results of a small pilot study [ 35 ]. Our practice has been to offer it to all patients who have daily cough and to those with FEV1 below the normal range. We also begin chronic DNase if a patient's FEV1 drops below his or her baseline, even if it remains in the normal range, but fails to improve with treatment for an acute exacerbation.

Inhaled hypertonic saline  — Hypertonic saline has been administered by inhalation to hydrate inspissated mucus that is present in the airways of patients with CF. It is presumed that the high osmolality of the solution draws water from the airway to re-establish the aqueous surface layer that is deficient in CF [ 36 ]. The effectiveness of this strategy was shown by a study of 24 patients (≥14 years of age) with stable CF who were treated with 5 mL of 7 percent saline four times per day for 14 days [ 36 ]. The mucus clearance rate was improved after 1 and 14 days of hypertonic saline treatment, and there were modest improvements in lung function and symptom scores. Parallel in vitro studies using cultured monolayers of airway epithelial cells showed that hypertonic saline caused sustained hydration of airway surfaces.

The medium-term benefit of hypertonic saline was demonstrated by an Australian clinical trial in which 164 patients (≥6 years of age) with stable CF were randomly assigned to inhalation therapy with 4 mL of 7 percent saline or 0.9 percent saline following administration of a bronchodilator twice daily for 48 weeks [ 37 ]. The study failed to show a statistically significant difference in its primary outcome, namely the rate of change in lung function during the 48 week trial. However, when averaged over the full duration of the study, lung function showed a small, statistically significant improvement in the hypertonic saline group. Patients treated with hypertonic saline had considerably fewer pulmonary exacerbations requiring antibiotic therapy (mean number of exacerbations per participant 0.39 versus 0.89) and fewer days absent from school or work or unable to participate in usual activities (7 versus 24 days). Treatment with hypertonic saline was not associated with worsening bacterial infection or inflammation. The treatment was well tolerated. A systematic review that included this study concluded that hypertonic saline has beneficial effects in patients ≥six years of age with CF [38 ].

By contrast, hypertonic saline cannot be considered to be part of the routine care of CF children under the age of six years. This was shown in a randomized clinical trial involving 344 subjects between 4 and 60 months of age (the ISIS trial), which failed to show clinical benefit of inhaling hypertonic saline (7 percent) compared to a control group receiving 0.9 percent saline [ 39 ]. There was no benefit in the rate of pulmonary exacerbations (primary endpoint) or any of the secondary endpoints including a respiratory symptom score. As “exploratory” investigations in the ISIS study, infant pulmonary function tests including spirometry using the raised volume technique and lung volumes were performed on a subgroup of the subjects. Of these, only FEV0.5 showed a statistically significant improvement (38 mL) in the hypertonic saline group compared to controls. Given the exploratory nature of these tests, the FEV0.5 result can only be considered hypothesis-generating and not evidence of benefit [ 40 ]. It has been suggested that the endpoints used in the ISIS trial may not have been adequately sensitive to detect clinically meaningful benefit in young patients with very mild pulmonary disease. Chest computed tomography, magnetic resonance imaging, and lung clearance index measurements are undergoing clinical investigations to determine if these are better modalities to detect early changes.    

Additional studies are needed to refine the criteria for use of hypertonic saline in older patients with CF and optimal timing of treatments [ 41 ]. In a study of patient preference, the majority of patients favored inhaling hypertonic saline before or during their chest physiotherapy rather than after [ 42 ]. Prescribing patterns vary greatly across CF centers [ 33 ]. Our practice is to offer it to all patients six years of age and older who have chronic cough and/or a mild reduction pulmonary function test results (eg, in FEV1) despite good compliance with the medical regimen. A convenient means to dispense hypertonic saline is now available through the CF Services Pharmacy ( www.cff.org/cf_services_pharmacy ). Albuterol should be inhaled from a metered dose inhaler immediately prior to hypertonic saline administration to limit bronchospasm [ 37 ].

Comparing the use of DNase and hypertonic saline  — An open, crossover-design trial of 48 children receiving DNase or hypertonic saline in 12-week blocks reported a significantly greater increase in FEV1 with DNase compared to hypertonic saline [ 31 ]. In the previously mentioned large 48-week study of hypertonic saline, 38 percent of the

subjects were also receiving DNase throughout the trial [ 37 ]. Subgroup analysis revealed no difference in the beneficial effects of hypertonic saline between those receiving or not receiving DNase. However, the power of the study to detect clinically significant differences was not presented and probably was low.

In the absence of well-designed comparison studies, the decision of when to prescribe DNase and hypertonic saline remains a conundrum. Because the mechanisms of action of DNase and hypertonic saline are different, their benefits may well be complementary. The guidelines committee of the CF Foundation addressed each treatment separately and recommended both for the majority of patients with CF without assigning priority of one over the other [ 26 ]. We follow this recommendation but are frequently confronted with situations where a patient will not use both because of cost (DNase costs approximately 30-fold more than hypertonic saline), time required for administration (hypertonic saline is administered twice daily, and DNase once daily), tolerability (DNase typically is better tolerated than hypertonic saline in our experience), or general non-compliance.

For patients willing and able to use both treatments, the following order of administration is recommended [ 26]: (1) albuterol by metered dose inhaler, (2) hypertonic saline, (3) chest physiotherapy/exercise and DNase in either order, and (4) other inhaled treatments such as aerosolized antibiotics. Inhaled medications should not be mixed together in the same nebulizer because the consequences of doing so are unknown. Of special note is DNase, which is inactivated when mixed with 7 percent saline. (See 'Chest physiotherapy' below and "Cystic fibrosis: Antibiotic therapy for lung disease" .)

Inhaled N-acetylcysteine  — N-acetylcysteine, a free sulfhydryl reagent that cleaves disulfide bonds within mucus glycoproteins, can liquefy CF sputum in vitro. Although originally developed as an inhaled mucolytic agent, there are no well-designed studies that demonstrate its clinical utility [ 26,43 ]. Furthermore, its potential to induce airway inflammation and/or bronchospasm in a subgroup of patients and to inhibit ciliary function has led to reduction in its use. These deficiencies, in conjunction with its disagreeable odor, relatively high cost, and time required for administration cause us not to prescribe it.

CHEST PHYSIOTHERAPY  — Retained purulent secretions are an important cause of airflow obstruction and airway injury in CF. In 1950, chest physiotherapy in the form of postural drainage and percussion was introduced to CF care and became the standard method to promote secretion clearance [ 44 ]. Increasingly, methods that can be performed without the aid of another person are replacing the traditional technique in older children and adults. These alternatives include a variety of breathing and coughing techniques such as "autogenic drainage", "active cycle of breathing", and "huffing" [ 45 ]. Medical devices of varying cost and complexity have been developed to assist with airway clearance. These include airway oscillating devices, external percussion vests, and intrapulmonary percussive ventilation.

Though practiced widely, there are relatively few high-quality clinical trials that evaluate the benefits of chest physiotherapy over extended periods of time. A year-long randomized trial studied the use of a "PEP mask", which contains a valve to generate positive expiratory pressure, and found that use of the device was associated with significant improvements in

pulmonary function compared to postural drainage and percussion [ 44 ]. However, an examination of five Cochrane systematic reviews performed between 2000 and 2006 concluded there were insufficient data to assess the long-term effects of airway clearance therapy [ 46 ]. Short-term trials suggested some benefit. No long-term studies show that one method of secretion clearance is superior to another [ 47 ]. An attempt to perform such a trial failed due to subject recruitment problems and high withdrawal rates [ 48 ].  

Based upon available information, we recommend that all patients who produce sputum should be instructed in chest physiotherapy for secretion clearance. Adherence to chest physiotherapy is often poor, particularly among patients with mild disease [ 49,50 ]. Because patients vary in their acceptance and preference for different modes, several techniques should be introduced to each patient. Methods that can be performed without assistance from another person should be included to allow patients to have more control over their regimen. The cost of equipment should be considered, with less expensive modalities prescribed first. More expensive apparatus such as percussive vests may be appropriate for those patients who fail to clear secretions with less expensive methods, who report that the more expensive modalities are effective for them, and who remain compliant with their use.

Exercise  — Many patients with CF report that they mobilize secretions during aerobic exercise. One randomized, controlled trial of a three-year home exercise program was performed in children with CF [ 51 ]. Those assigned to the exercise arm of the study lost less forced vital capacity compared to the control group. The comparison of change in FEV1 showed the same trend (p <0.07). In addition, one meta-analysis concluded that exercise with physiotherapy was superior to physiotherapy alone, but there is no evidence that exercise can substitute for airway clearance treatment [ 46 ]. Those with moderate or advanced disease should participate in organized pulmonary rehabilitation programs. (See "Pulmonary rehabilitation in COPD" .)

ANTI-INFLAMMATORY THERAPY  — Intense neutrophilic inflammation is a dominant pathological feature of the airways of patients with CF. Although the inflammatory response was formerly viewed as being necessary to prevent the spread of infection, increasing information indicates that the amount of inflammation developed is probably excessive and harmful [ 52 ].

Macrolide antibiotics  — Macrolide therapy was found to be beneficial for patients with panbronchiolitis, a non-CF lung disease that is seen predominantly in Japan and is manifested by bronchiectasis and chronic pseudomonas infection (see "Diffuse panbronchiolitis" ). Clinicians caring for patients with CF began using macrolides empirically and their favorable observations prompted several well-constructed clinical trials of macrolides in CF.

The largest clinical trial to date of macrolide therapy in CF studied 185 patients who were chronically infected with Pseudomonas aeruginosa and who had an FEV1 >30 percent [ 53 ]. Subjects were randomly assigned to receive azithromycin 500 mg PO or placebo three days a week for 24 weeks. By the end of the trial, subjects taking azithromycin had a 4.4 percent improvement in percent predicted FEV1, although those receiving placebo had a 1.8 percent reduction; the difference was statistically significant. In addition, there were 40 percent fewer respiratory exacerbations in the azithromycin-treated group than in the control group.

A subsequent report, which included patients with and without P. aeruginosa, concluded that even patients who did not demonstrate an improvement in lung function still derived benefit because of a decreased incidence of acute pulmonary exacerbations [ 54 ]. These results are in close agreement with three smaller studies that showed similar benefits from macrolides in patients with CF [ 55-57 ], and a one-year randomized trial in children with CF that revealed reductions in the frequency of pulmonary exacerbations and the need for additional antibiotics, although no change in FEV1 [ 58 ].

One placebo-controlled trial focused only on patients uninfected with P. aeruginosa, who were treated withazithromycin or placebo for 24 weeks [ 59 ]. In this population of relatively healthy patients (mean FEV1 97 percent predicted), azithromycin did not improve lung function, as measured by FEV1. However, use of azithromycin was associated with clinically important improvements in several exploratory end points, including a 50 percent reduction in pulmonary exacerbations, 27 percent reduction in the initiation of new oral antibiotics (other than azithromycin), 0.58 kg weight gain, and 0.34 unit increase in BMI. There were no differences in treatment groups in use of intravenous or inhaled antibiotics or hospitalizations.

A systematic review that included all of the above studies concluded that six months of treatment withazithromycin improves respiratory function in patients with CF and reduces the frequency of pulmonary exacerbations [ 60 ].

The mechanisms by which macrolides improve CF lung disease are uncertain and may involve direct effects on infecting bacteria and/or suppression of the excessive inflammatory response seen in the CF lung. Macrolides are unable to kill pseudomonas bacteria that are grown under conditions routinely used in clinical microbiology laboratories. However, macrolides have microbicidal activity against pseudomonas bacteria that are grown under conditions that induce biofilm formation [ 61 ]. Furthermore, macrolides can block quorum sensing and reduce the ability of pseudomonas to produce biofilms, which is considered one of the mechanisms by which the bacteria avoid being killed by traditional antipseudomonal antibiotics [ 62 ]. Independent of their effect on bacteria, there is mounting evidence that macrolides may be beneficial in CF lung disease by suppressing the excessive inflammatory response [ 63,64 ].

In our practice, we recommend using azithromycin for all patients with CF older than six years of age regardless of P. aeruginosa infection status who have clinical evidence of airway inflammation such as chronic cough, or who have any reduction in FEV1. The guidelines published by the CF Foundation do not restrict the use of azithromycin to those with evidence of airway inflammation or reduction in FEV1 as we suggest here [ 26 ]. However, because of limited data on the safety of prolonged use of azithromycin, we recommend delaying its routine use in patients who have negligible evidence of airway disease and whose expected benefit may be minimal. We usually prescribe the medication three times a week, using 250 mg for patients with body weight less than 40 kg, and 500 mg for those over 40 kg. A study in adults shows that 250 mg daily is similarly efficacious, so daily dosing could be used for those patients who find it easier to adhere to a daily treatment schedule [ 57 ]. For the small number of patients who develop gastrointestinal side effects on full dose, a lower dose may be used (eg, 250 mg three times a week for

adult-sized patients); this dose reduction was employed in one study and was thought to be of benefit [ 53 ].

Prior to initiating treatment with azithromycin , we recommend that a sputum specimen be examined for nontuberculous mycobacteria; macrolide therapy should NOT be initiated if nontuberculous mycobacteria are present. This is because macrolides are an important component of treatment regimens for M. avium complex infection and should be used only as part of a multi-drug regimen, to avoid development of macrolide resistant mycobacterial species. If smear-negative patients are subsequently positive by culture, the macrolide should be stopped to avoid induction of macrolide resistance. The decision to treat nontuberculous mycobacteria with multiple antibiotics should be based on an assessment of the likelihood that the mycobacteria are causing tissue injury and clinical deterioration, and is discussed elsewhere. (See "Treatment of nontuberculous mycobacterial infections of the lung in HIV-negative patients" .)  

Ibuprofen  — Based on the recognition that anti-inflammatory glucocorticoids reduce the rate of FEV1 decline in CF, ibuprofen was studied to determine if similar benefits could be obtained without the prohibitive side effects of glucocorticoids. The clinical value of high-dose ibuprofen was demonstrated in two long-term studies in patients with mild CF lung disease.

A randomized trial of high-dose ibuprofen was conducted in 85 individuals 5 to 39 years old with mild disease. Repeated pharmacokinetic studies were performed on study subjects to ensure that high-peak blood levels of ibuprofen (50 to 100 mcg/mL) were obtained [ 65 ]. After four years, patients in the ibuprofen group who completed the study lost only 1.5 percent of their predicted FEV1 per year, compared to a loss of 3.6 percent of predicted FEV1 per year for the control group. However, the beneficial effects of ibuprofen were seen only in the subgroup of patients who were younger than 13 years of age at the start of the study. Gastrointestinal bleeding and renal impairment, known adverse effects of ibuprofen, were not observed in either group.

In a multicenter randomized trial, a similar protocol was tested in 142 patients 6 to 18 years old [ 66 ]. The primary outcome of this study, rate of decline in FEV1 percent predicted, was not statistically reduced byibuprofen as compared to placebo. However, the study did not meet its recruitment targets, causing it to be underpowered to detect a difference of 2 percent. The group treated with ibuprofen did show a statistically significant reduction in the rate of decline of FVC percent predicted (0.07 ± 0.51 versus -1.62 ± 0.52), which was a secondary endpoint of the study.

The guidelines committee of the CF Foundation suggests the use of high-dose ibuprofen in children older than 6 years of age who have good lung function (FEV1 >60 percent predicted) [ 26 ]. However, the evidence supporting this treatment is still limited, and concerns remain about the potential long-term effects on renal function. We do not recommend initiation of ibuprofen after the age of 13 years because of lack of any proof of efficacy in this population. If high-dose ibuprofen is prescribed, pharmacokinetic studies should be performed periodically to ensure correct dosing, and patients should be monitored closely for the development of adverse effects [ 67 ]. (See "Nonselective NSAIDs: Overview of adverse effects" .)

In practice, high-dose ibuprofen is being prescribed for only a small minority of pediatric-aged patients in the United States [ 33 ]. The requirement for periodic pharmacokinetic adjustment of the dose and concern for side effects appear to be restricting its acceptance.

Systemic glucocorticoids  — Based on the theory that excessive inflammation may be a contributor to lung damage in CF, systemic glucocorticoids have been investigated for their anti-inflammatory effects.

Chronic administration  — In 1985, the results of a randomized, placebo-controlled study of glucocorticoids in children with CF were reported [ 68 ]. After 40 months of treatment, the group receiving 2 mg/kg ofprednisone every other day had higher values of FEV1 and fewer hospitalizations for pulmonary disease compared to the placebo group. Adverse effects from the prednisone were minimal. These observations spawned a larger multi-center study testing every other day prednisone (either 1 mg/kg or 2 mg/kg) against placebo [ 69]. The high-dose arm of the study was halted early because of an unacceptably high incidence of abnormal glucose metabolism, cataracts, and growth failure. Long-term follow up of this trial revealed that boys treated with prednisone had significant reductions in adult height as compared with those treated with placebo [ 70 ]. Among girls, the long-term effects of prednisone on height were not statistically significant. Similar but milder changes were seen in the lower-dose prednisone group when data were analyzed at the planned conclusion of the trial.

We agree with the guidelines committee of the CF Foundation, which recommends against the routine chronic use of oral corticosteroids for children with CF aged 6 to 18 years, in the absence of asthma or allergic bronchopulmonary aspergillosis, because of the associated adverse effects. The committee found insufficient data on which to judge the value of chronic glucocorticoids in adults. Because of concerns about the increased susceptibility of CF patients to glucocorticoid-induced hyperglycemia and osteoporosis in addition to the other complications of long-term treatment with corticosteroids, we also do not recommend chronic oral corticosteroids to patients in the adult age group, unless needed for concomitant asthma or allergic bronchopulmonary aspergillosis.

Short-term treatment for acute pulmonary exacerbations  — Systemic glucocorticoids have established benefits in acute exacerbations of non-CF COPD, prompting some clinicians to use them for acute exacerbations in patients with CF [ 71 ]. (See "Role of systemic glucocorticoid therapy in COPD" .) A pilot study evaluated this practice in a randomized, double blind, placebo controlled trial [ 72 ]. Twenty-four patients with CF and an acute pulmonary exacerbation were treated with either prednisone at 2 mg/kg/d (maximum 60 mg) or placebo for five days. The primary endpoint, the rate of improvement in FEV1 from days one to six, did not differ significantly between groups, although the power of the study to detect differences was small. None of the secondary endpoints showed a statistically significant difference. Using the data from this pilot study, the investigators concluded that more than 250 patients would need to be entered to detect a 4 percent improvement in FEV1 percent predicted.

In practice, we use systemic glucocorticoids during acute pulmonary exacerbations only for those patients with predominant asthma-like symptoms, eg, those with prominent sensation of chest tightness, minimal expectoration of sputum despite mucus plugging on chest x-ray,

documented response to bronchodilator in the pulmonary function laboratory, and high-pitched wheezes and/or poor air movement by auscultation. For these patients, we use 0.5 to 1.0 mg/kg per day prednisone (maximum of 40 to 60 mg/day) and restrict the duration to approximately five days.

Inhaled glucocorticoids  — Inhaled glucocorticoids have been prescribed in an effort to obtain the benefits that were demonstrated in the oral glucocorticoid trials while reducing the adverse effects of oral therapy. However, only a few studies have evaluated their effect:

One trial randomly assigned 55 patients with CF but without clinically evident asthma to receivebudesonide (800 mcg) or placebo twice daily for three months [ 73 ]. Deterioration of lung function (measured by the FEV1) was less in the budesonide group, suggesting that inhaled glucocorticoids are beneficial in this subset of CF patients.

In contrast, two randomized, controlled trials of 49 patients [ 74 ] and 12 patients [ 75 ] failed to demonstrate any benefit of inhaled glucocorticoids on the FEV1 in unselected CF patients.

In a larger placebo-controlled trial, 171 patients who were receiving inhaled glucocorticoids at study entry were randomly assigned to either continue or stop treatment for six months [ 76 ]. An additional 31 subjects who were otherwise eligible for the study were excluded by their clinicians, usually because they had signs and symptoms suggesting a significant asthmatic component to their CF lung disease. Cessation of glucocorticoids had no impact on the duration until the first exacerbation, lung function, antibiotic use, or bronchodilator use.

Although it seems reasonable to continue prescribing aerosolized glucocorticoids to CF patients who have definite signs and symptoms of asthma or allergic bronchopulmonary aspergillosis, there is insufficient evidence to warrant broader use [ 77 ]. We agree with the guidelines committee of the CF Foundation, which recommends against their routine use [ 34 ]. One of the reasons for caution is that inhaled glucocorticoids may modestly impair linear growth in children with CF or asthma [ 78,79 ]. These effects are dose-related and less severe than those seen in children treated with systemic glucocorticoids.

Cromolyn  — Sodium cromoglycate and nedocromil are anti-inflammatory drugs that have been used for the treatment of asthma; nedocromil is no longer available in the United States. Neither has been studied adequately in patients with CF. The few small studies that have been performed detected no benefit or adverse effects. As an example, one double-blind, placebo-controlled, crossover study was performed on 14 patients with cystic fibrosis and bronchial hyperreactivity; no improvement in clinical status or pulmonary function tests was seen among patients receiving sodium cromoglycate [ 80 ].

Given the lack of adequate studies of cromolyn in patients with CF, the relatively high expense, and the evidence of inferiority relative to inhaled glucocorticoids in patients with asthma [ 81 ], we do not prescribe cromoglycate or nedocromil for our patients.

VACCINATIONS AND PALIVIZUMAB

Influenza vaccine  — Viral respiratory infections have been implicated as a frequent cause of exacerbations of CF lung disease (reviewed in [ 34,82,83 ]). Based on efficacy in other populations, annual vaccination against viral influenza is recommended for all patients with

CF older than 6 months of age, using an inactivated vaccine delivered by injection, but not the live attenuated vaccine delivered by intranasal spray. (See "Seasonal influenza vaccination in adults" and "Seasonal influenza vaccination in children", section on 'Indications' .)

Pneumococcal vaccine  — The pneumococcal vaccine is recommended for all patients with CF because of a favorable risk-benefit profile, although Streptococcus pneumoniae is not a major cause of pulmonary exacerbations in CF. (See "Pneumococcal vaccination in adults" and "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Indications' .)

Palivizumab  — Retrospective studies of palivizumab , a humanized monoclonal antibody against respiratory syncytial virus for children younger than 24 months of age, have suggested possible efficacy in CF, but definitive studies have not been performed, preventing firm recommendations [ 84 ]. (See "Respiratory syncytial virus infection: Treatment" .)

SUPPLEMENTAL OXYGEN  — Progressive cystic fibrosis is routinely accompanied by worsening hypoxemia. However, there is little information about the effect of supplemental oxygen on the course of the disease. The use of short-term oxygen therapy during sleep and exercise was evaluated in a systematic review of nine small, randomized, controlled trials of patients with CF [ 85 ]. Supplemental oxygen during exercise was associated with improved exercise duration and peak performance. Use of nocturnal oxygen did not improve qualitative sleep parameters.

Only one of the studies in the systematic review examined long-term oxygen therapy [ 86 ]. No statistically significant improvement in survival, lung function, or cardiac health was detected. In addition, improvement of oxygenation was accompanied by modest but probably clinically inconsequential hypercapnia.

Until larger, controlled trials exist, we recommend supplemental oxygen for patients with CF to treat intermittent or chronic hypoxemia. We believe it is appropriate to assume that supplemental oxygen will delay or ameliorate the complications of chronic hypoxemia in CF, as it does in chronic obstructive pulmonary disease [ 6 ]. In the absence of studies examining oxygen use in patients with CF, we follow the same recommendations for use as in patients with COPD. (See "Long-term supplemental oxygen therapy" .)

NONINVASIVE POSITIVE PRESSURE VENTILATION  — Noninvasive positive pressure ventilation (BiPAP) has been used for patients with advanced cystic fibrosis lung disease and hypercapnia [ 87,88 ]. In a randomized trial in adults with daytime hypercapnia, nocturnal use of BiPAP was compared to supplemental oxygen or placebo (air). Six weeks of BiPAP improved chest symptoms, exertional dyspnea, nocturnal hypoventilation, and peak exercise capacity, without measurable improvement in lung function. Based on these studies, it would be appropriate to offer nocturnal noninvasive BiPAP to patients whose arterial carbon dioxide level remains elevated (eg, ≥50 mmHg) despite maximizing other treatments.

INTENSIVE CARE UNIT TREATMENT  — Outcomes for CF patients requiring treatment in an intensive care unit was previously reported to be uniformly poor [ 89 ], but has

fortunately improved. In modern series, survival was dependent upon the severity of respiratory failure, with the best outcomes for those who could be managed by noninvasive ventilation and the worst for those requiring endotracheal intubation/ventilation [ 90-95 ]. Most of these studies were of adult CF patients, but one included five children who were less than two years old, all of whom survived [ 94 ]. There are probably multiple reasons for the improved outcomes, including the use of non-invasive ventilation to sustain the patient until other measures to reverse the respiratory failure take effect [95,96 ].

Although the long-term prognosis following an episode of respiratory failure is still poor in older children and adults, intensive care unit support appears to be particularly useful for those patients who are candidates for lung transplantation. In addition, intubation and positive pressure ventilation are indicated for infants and young children with acute bronchiolitis but without extensive bronchiectasis, especially in the context of a documented acute viral infection.

An episode of respiratory failure, regardless of age (except for infants and young children with pure bronchiolitis), should prompt discussion of end-of-life care, quality of life, and the possible indications for lung transplantation, if and when extubation occurs.

LUNG TRANSPLANTATION  — Advancements in the treatment of CF lung disease have delayed but not arrested disease progression; premature death from respiratory failure still occurs in the majority of patients. As in other progressive lung diseases, lung transplantation provides an additional, albeit imperfect, management option [ 97-100 ].

Virtually all lung transplants for patients with CF require replacing both lungs, because leaving a native lung in place would present a huge source of infected secretions that would threaten the transplanted lung. A registry compiled by the International Society for Heart and Lung Transplantation reports that 758 lung transplants were performed in children with CF from January 2000 to June 2009 [ 101 ], and 4161 transplants were performed in adults with CF from January 1995 to June 2009 [ 102 ].

Timing of transplantation  — The indications for referral to a lung transplant center are driven by estimates of a patient's predicted survival and quality of life with and without lung transplant. A retrospective study using data from the CF Foundation Registry concluded that transplantation extends life if performed when the patient has a five-year predicted survival without transplant of less than 30 percent, and possibly when the predicted survival is less than 50 percent [ 103 ]. A means to calculate the survival likelihood was provided. (See'Outcomes' below.)

Based on a consensus report from the International Society for Heart and Lung Transplantation [ 104 ], we recommend that a patient should be referred to a transplant center when any of the following indications are present:  

FEV1 below 30 percent predicted or a rapid decline in FEV1, particularly in young female patients

Increasing frequency of exacerbations requiring antibiotic therapy Refractory and/or recurrent pneumothorax Recurrent hemoptysis not controlled by embolization

Since 2005, in the United States, the position of each individual lung transplant candidate on the priority list for transplant is determined by a lung allocation score formulated by UNOS (United Network for Organ Sharing). The score is based on lung diagnosis, age, body mass index, diabetes, supplemental oxygen use, six-minute walk distance, pulmonary artery systolic pressure, pulmonary capillary wedge pressure, serum creatinine functional status, and need for assisted ventilation. Details about the scoring system are available from the Organ Procurement and Transplantation Network [ 105 ]. Because the number of lungs available for transplantation is insufficient for the number of patients needing them, the timing of when a patient receives lungs is determined more by when they become sick enough to reach the top of the priority list rather than when they are referred for transplant evaluation. There are wide variations in the length of waiting lists among transplant centers and individual patients may be served by exploring a number of different lung transplant centers.

Contraindications  — Each transplant center has its own list of relative and absolute contraindications for lung transplantation. In addition to the general contraindications for lung transplantation applicable for all disease indications, there are several CF-specific considerations. Chronic infection with Burkholderia cenocepacia connotes a worse prognosis following transplantation [ 106-109 ]. Most, but not all, transplant centers consider infection with this organism to be a contraindication to the procedure. Other species of Burkholderia do not appear to have the same adverse effects, with the possible exception of B. gladioli [ 106-109 ]. Patients infected with multidrug-resistant Pseudomonas aeruginosa have slightly worse survival following lung transplant compared to those infected with drug-sensitive P. aeruginosa, but the decrement is minor; their survival is similar to that of patients undergoing lung transplantation for non-CF diagnoses [ 110 ]. (See 'Outcomes' below and "Lung transplantation: General guidelines for recipient selection" and "Lung transplantation: Disease-based choice of procedure" .)

Most lung transplant centers in the United States will not accept the referral of intubated patients in acute respiratory failure for lung transplant evaluation. The survival of these patients without transplantation is poor, and prolonged ICU stays are associated with progressive deconditioning of affected individuals, another strong contraindication to transplantation in many centers. In addition, their poor clinical status prohibits education and informed consent of the patient, who is expected to adhere to a post-transplant regimen that is complex and can be onerous.

Symptomatic osteoporosis is a relative contraindication for lung transplantation in general, but it takes on special significance for patients with CF. The frequency of osteoporosis in CF increases with age and affects about 20 percent of individuals in the 18- to 25-year age group [ 33 ]. Thus, pre-symptomatic diagnosis and treatment ofosteopenia/osteoporosis is important to avoid exclusion of a patient from consideration for transplantation [ 111].

Outcomes  — Patients with CF who undergo lung transplantation have better survival rates compared with those of patients who are transplanted for other disease indications ( figure 3 ) [ 102 ]. (See "Lung transplantation: An overview" .)  

The benefits of lung transplantation in CF have been assessed using retrospective data from the CF Foundation Registry. Outcomes for 458 patients who underwent lung transplantation

for CF between 1992 and 1998 were compared to those of 11,630 patients who did not undergo transplantation [ 103 ]. The following observations regarding transplantation and survival were noted:

For patients with predicted five-year survival of less than 30 percent, lung transplantation is associated with a clear improvement in survival.

Survival benefit was equivocal for patients with a predicted five-year survival of 30 to 50 percent.

Patients with predicted five-year survival of greater than 50 percent and who underwent transplantation (though few in number) had a lower rate of survival than their nontransplanted counterparts.

The benefit of transplantation also varied with time. Overall survival was superior in nontransplanted controls during the first 2.5 years of follow-up; however, after four years transplanted patients demonstrated increased survival.

An analysis of 514 pediatric aged patients who were listed for lung transplantation between 1992 and 2002 was performed by the same research group using merged data from the CF Foundation Registry and the Organ Procurement and Transplantation Network [ 112 ]. This study failed to show a definite survival advantage, except for a small minority of transplanted patients who were younger than 18 years of age at the time of listing [ 112]. This contradicts a previous report from the United Kingdom that found a survival advantage for transplanted children [ 113 ]. After correcting for multiple potential risk factors, the older study reported that the hazard ratio for death in the transplanted group was 0.31 (95% Cl 0.13-0.72, p = 0.007).

Reasons for the discrepancy described above are the subject of active debate [ 114 ]. It is possible that the worse survival for transplanted pediatric CF patients compared to those on the wait list in the US study [ 112 ] may be an artifact of the method by which patients were prioritized for transplantation. Specifically, the data in the US study were collected at a time when transplant priority was based upon time spent on the waiting list. This induced clinicians to list patients early so that they had a very good chance of surviving long enough to accrue the two or more years that were sometimes necessary to reach the top of the list. The current lung allocation system places no premium on how long the patient is on the list for all individuals 12 years and older. Instead, it distributes donor lungs to those with the greatest predicted increase in one-year survival after transplantation.

Subsequent studies from experienced centers have reported five-year survival rates around 65 percent [ 99,115]. These investigators argue that transplantation does indeed improve survival as compared with estimated five-year survival in non-transplanted patients. Because of limited numbers of patients in the pediatric age group, these studies were unable to draw definitive conclusions regarding this subgroup. However, Cox regression analysis detected no adverse effect of age <18 years on survival [ 115 ].

Limitations of transplantation  — Many problems remain after lung transplantation for CF. The procedure does not address the non-pulmonary problems associated with CF. Chronic sinusitis, cirrhosis, cholelithiasis, pancreatic insufficiency, CF-associated diabetes mellitus, osteoporosis, and distal intestinal obstruction syndrome remain causes of morbidity and occasionally of mortality. Pancreatic insufficiency and abnormalities in bowel motility can make cyclosporine absorption and dosing difficult; glucocorticoid treatment to suppress

graft rejection complicates diabetic management and accelerates osteoporosis. Studies examining quality of life after lung transplantation for CF generally show improvement [ 116-118 ]. Most children return to school and many adults return to work.

PREGNANCY  — In 2009, there were 226 pregnancies reported in the CF Foundation Registry, which is a rate of 1.6 live births per 100 women in a reproductive age range. Small case series and larger cohort studies have not documented adverse maternal outcomes for women with mild to moderate pulmonary disease (ie, FEV1 >60 percent predicted) who become pregnant [ 119-124 ]. Severe lung disease, especially when pulmonary hypertension is present, is a bad prognostic indicator [ 124 ], although successful outcomes have been reported in a few women who had severe impairment of lung function prior to conception [ 122 ].

Most studies report an increased rate of premature delivery for pregnancies in women with cystic fibrosis (around 25 percent, range 5 to 45 percent [ 124-127 ]), but the rate of spontaneous abortion is not increased [ 128 ]. Breastfeeding is not contraindicated, although there has been one report of hypernatremic colostrum [ 129 ].

The general principles of pregnancy management for women with cystic fibrosis include the following [ 130 ]:

Achieving optimal, stable pulmonary function prior to conception and carefully monitoring during pregnancy

Providing genetic counseling regarding the risk of disease in offspring, carrier testing of the father, and options for prenatal diagnosis (see "Cystic fibrosis: Prenatal genetic screening" )

Close monitoring maternal nutrition and weight gain Screening for gestational diabetes early in pregnancy because of the increased risk

for secondary insulin deficiency

NONINFECTIOUS PULMONARY COMPLICATIONS  — Spontaneous pneumothorax and hemoptysis are well-recognized complications of CF, particularly among adults. These complications have become increasingly common as overall survival continues to improve [ 131,132 ].

Spontaneous pneumothorax  — Spontaneous pneumothorax occurs in 3 to 4 percent of patients with cystic fibrosis during their lifetime [ 131 ]. Major risk factors are older age and more severe obstructive lung disease. Treatment of pneumothorax in CF patients does not differ from that of patients with other types of lung disease (see "Secondary spontaneous pneumothorax in adults" and "Spontaneous pneumothorax in children" ).

Guidelines have been published for the management of pneumothorax in patients with CF [ 133 ]. Pleurodesis when needed to address persistent air leaks or other pleural space problems should not preclude subsequent lung transplantation [ 134,135 ]. However, avoidance of more aggressive pleural stripping procedures or the use of talc may be advisable to reduce subsequent bleeding complications if and when the native lungs are removed at transplantation [ 136 ]. Collaboration between the consulting CF Center surgeon and a lung transplant surgeon is recommended.

Hemoptysis  — Minor hemoptysis is a common occurrence in patients with cystic fibrosis, particularly during pulmonary exacerbations. Other than assuring that vitamin K deficiency is not a contributing factor, it requires no special treatment beyond the usual approach for the exacerbation. However, even minor hemoptysis can be alarming to patients and reassurance as to its usually benign nature is needed.

Massive hemoptysis is defined as acute bleeding of more than 240 mL within 24 hours, or recurrent bleeding of more than 100 mL daily for several days. This occurs in approximately 1 percent of patients each year with the major risk factors being age and worse pulmonary function [ 132 ]. Management guidelines generated by a panel of experts have been published [ 133 ]. The guidelines recommend suspension of all chest physiotherapy in the event of massive hemoptysis. Consensus could not be reached for use of aerosolized medications for massive hemoptysis. Other than maximizing treatment as one would for a severe pulmonary exacerbation, the management of massive hemoptysis in CF does not otherwise differ from that of hemoptysis in other patients with bronchiectasis. Tranexamic acid has been used successfully in several case reports. (See "Hemoptysis in children", section on 'Hemostasis' and "Massive hemoptysis: Initial management" .)

FUTURE DIRECTIONS  — Analysis of registry data collected by the CF Foundation shows moderate variability in the clinical outcomes and treatment approaches across the 115 CF Centers within the United States [ 137 ]. After correcting for adverse risk factors that differ between centers such as patient age and socioeconomic status, a conservative estimate is that median survival in CF could be improved by at least several years if best practices could be identified and implemented across all CF Centers. On the other hand, there is no question that individually tailored therapies by experienced clinicians will remain equally important in the management of these complex patients. In response to knowledge and a strong endorsement from the CF Foundation, an intensive quality assessment/quality improvement program is ongoing in all CF Centers [ 137 ].

A wide variety of new treatment strategies are being investigated for CF (see www.cff.org/treatments/Pipeline/ ). They span a wide range of approaches that include (See "Cystic fibrosis: Investigational therapies" .):

Gene therapy Correction of abnormal protein folding that is induced by many of the more prevalent

CFTR mutations Improvement in ion channel function of various mutant CFTR proteins Drugs to induce ribosomes to selectively read through premature CFTR stop codons Induction of alternative ion channels Suppression of excessive inflammatory responses Development of alternative delivery methods for antibiotics

Some of the promising investigational therapies that have reached the stage of clinical trials are discussed in a separate topic review. Successful completion of even a subset of these investigations should serve to continue the trend of improved survival in CF. (See "Cystic fibrosis: Investigational therapies" .)

INFORMATION FOR PATIENTS  — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are

written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient information: Cystic fibrosis (The Basics)" and "Patient information: Bronchiectasis in children (The Basics)" )

SUMMARY AND RECOMMENDATIONS  — The following treatment recommendations apply to children 6 years of age and older unless otherwise specified.

Cystic fibrosis lung disease typically has a course of intermittent acute exacerbations, superimposed on a gradual decline in pulmonary function. Exacerbations are treated with antibiotics, given either orally, via inhalation, or intravenously, depending on the infecting organisms and the severity of the exacerbation. The role of antibiotics in the treatment of cystic fibrosis lung disease is discussed in detail separately. (See"Cystic fibrosis: Antibiotic therapy for lung disease" .)

All patients with cystic fibrosis should undergo CFTR genotyping to determine if they carry a G551D mutation in their CFTR genes. Because this mutation was identified in 1990, it is highly likely that most CF patients who were genotyped after the early 1990s would have G551D identified if it was present. (See'CFTR modulators' above.)

For all patients with cystic fibrosis who carry at least one copy of the G551D mutation and are six years of age or older, we recommend treatment with ivacaftor ( Grade 1A ). Ivacaftor is given at a dose of 150 mg by mouth every 12 hours with fat-containing foods. (See 'CFTR modulators' above.)

We suggest using short-acting inhaled beta-2-adrenergic receptor agonists for patients with CF prior to inhalation of hypertonic saline, antibiotics, or initiating chest physiotherapy ( Grade 2C ). We also suggest chronic use of these agents if there is evidence that they improve expiratory flow rates in those with baseline airflow obstruction ( Grade 2B ). (See 'Bronchodilators' above.)

We recommend chronic treatment with DNase I ( dornase alfa ) for children with moderate to severe cystic fibrosis lung disease ( Grade 1A ). We also suggest treatment for patients with mild or asymptomatic lung disease, but the quality of evidence and likely clinical benefit are lower for this group ( Grade 2B ). (See'Inhaled DNase I (dornase alfa)' above.)

We recommend chronic treatment with hypertonic saline via nebulizer for patients six years and older who have a chronic cough and any reduction in FEV1 ( Grade 1B ). We also suggest it may be of benefit for patients in this age group with milder disease manifestations ( Grade 2B ). A typical treatment regimen is 4 mL of 7 percent saline following administration of a bronchodilator twice daily. (See 'Inhaled hypertonic saline' above.)

We suggest that all patients who produce sputum be treated with a form of physiotherapy for mucus clearance ( Grade 2C ). This suggestion is based on demonstrated benefits to secretion clearance with the use of a variety of methods of physiotherapy, including aerobic exercise. However, it should be recognized that

long-term improvement in clinical outcome has not been shown, and any clinical benefits must be weighed against the potential treatment burden for the patient. Because patients vary in their responses to different modes, several techniques should be introduced to each patient. (See 'Chest physiotherapy'above.)

We recommend the chronic use of azithromycin for patients six years and older who have clinical evidence of airway inflammation such as chronic cough, or any reduction in FEV1, regardless of the patient’s P. aeruginosa infection status ( Grade 1B ). To avoid induction of antibiotic resistance, azithromycin should not be given to patients infected with nontuberculous mycobacteria. This drug slows decline of lung function, likely through antiinflammatory and/or antibacterial effects. (See 'Macrolide antibiotics' above.)

We suggest treatment with high-dose ibuprofen in children and young adolescents with good lung function (>60 percent predicted) in whom there is no contraindication to this therapy ( Grade 2C ). The evidence base for this practice is limited to a few studies, and there is inadequate evidence to support this suggestion for adult patients or for patients with poor lung function. (See 'Ibuprofen' above.)

For patients with CF but without asthma or allergic bronchopulmonary aspergillosis, we recommend AGAINST treating with inhaled corticosteroids ( Grade 1C ). For this group, there are no clear benefits, and the treatment may impair linear growth. For patients with CF and asthma, inhaled corticosteroids have greater clinical benefit, and the treatment may be considered along with other anti-asthmatic treatments. (See 'Inhaled glucocorticoids' above.)

For children and adolescents with CF, we recommend AGAINST chronic treatment with systemic glucocorticoids ( Grade 1B ). Although there is a slight benefit to lung function, these do not outweigh the adverse effects on growth, glucose metabolism, and cataract risk for most patients. In adults, we also suggest AGAINST chronic treatment with systemic glucocorticoids ( Grade 2C ). (See 'Systemic glucocorticoids' above.)

The use of supplemental oxygen to treat chronic hypoxemia has not been studied in patients with cystic fibrosis. In the absence of such evidence, it is reasonable to extrapolate from the benefits demonstrated for this treatment for patients with COPD and to apply the same indications for its chronic use. (See'Supplemental oxygen' above.)

Severe cystic fibrosis lung disease is a common indication for lung transplantation, and outcomes are better than those of patients undergoing lung transplantation for other indications. Chronic infection with Burkholderia cenocepacia connotes a worse prognosis following transplantation and is often considered a contraindication to the procedure. (See 'Lung transplantation' above.)

Cystic fibrosis: Antibiotic therapy for lung diseaseINTRODUCTION  — Cystic fibrosis (CF) is a multisystem disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on chromosome 7 [ 1 ]. (See "Cystic fibrosis: Genetics and pathogenesis" .)

Pulmonary disease remains the leading cause of morbidity and mortality in patients with CF [ 2-5 ]. One of the major drivers of CF lung disease is infection [6,7 ]. The approach to treating infection in CF is multifaceted, involving antibiotics, chest physiotherapy, inhaled medications to promote secretion clearance, and anti-inflammatory agents. Undoubtedly, improved use of antibiotics is responsible for a substantial portion of the increased survival that has occurred in patients with CF ( figure 1 ) [ 4,6 ].

The use of antibiotics to treat CF lung disease will be reviewed here. Treatments other than antibiotics for CF lung disease and the diagnosis, clinical manifestations, and investigational therapies for CF are discussed separately. (See "Cystic fibrosis: Overview of the treatment of lung disease" and "Cystic fibrosis: Clinical manifestations and diagnosis" and "Cystic fibrosis: Clinical manifestations of pulmonary disease" and "Cystic fibrosis: Investigational therapies".)

PATHOGENS  — Chronic bacterial infection within the airways occurs in most patients with cystic fibrosis (CF) ( table 1 ); the prevalence of each bacterial type varies with the age of the patient ( figure 2 ).

Pseudomonas aeruginosa  — For reasons that are poorly understood, the CF airway is particularly susceptible to Pseudomonas aeruginosa (P. aeruginosa), with infection occurring as early as the first year of life. The prevalence of P. aeruginosa increases as patients’ age, such that more than 73 percent of adults are chronically infected [ 8 ]. With prolonged infection, P. aeruginosa converts to a mucoid phenotype by the production of alginate. This mucoid phenotype is seen infrequently in populations without CF but is manifested by over 66 percent of the P. aeruginosa isolated from patients with CF. (See "Epidemiology and pathogenesis of Pseudomonas aeruginosa infection" .)  

Chronic infection with P. aeruginosa is an independent risk factor for accelerated loss of pulmonary function and decreased survival [ 9,10 ]. Conversion of P. aeruginosa to the mucoid phenotype worsens prognosis. Transmissible strains of P. aeruginosa have been detected in CF populations in Europe, Australia, and Canada, and some of these strains are associated with a worse prognosis compared with non-transmissible strains [ 11 ].

Staphylococcus aureus  — Staphylococcus aureus (S. aureus) is the bacterial pathogen most frequently identified in respiratory secretions of CF infants and children. It remains a significant pathogen throughout adulthood. In children under 6 years of age infected with P. aeruginosa, co-infection with S. aureus has an independent and additive effect on airway inflammation [ 7 ].

Methicillin-resistant Staphylococcus aureus  — Methicillin-resistant Staphylococcus aureus (MRSA) has become more prevalent in the CF population, increasing from 2.1 percent in 1996 to 26 percent in 2009 [ 8 ]. Regarding the role of MRSA in patients with CF:

One study reported that acquisition of MRSA was associated with a slightly greater rate of decline in pulmonary function (as measured by forced expiratory volume at one minute [FEV1]) in children, but not in adults [ 12 ], while another study reported that MRSA had no effect on the rate of FEV1 decline [ 13 ].

A study of nearly 20,000 CF patients in the United States found that MRSA was associated with 1.3 times the risk of death compared with individuals never infected with MRSA [ 14 ]. Multivariate analysis showed that MRSA was an independent risk factor whose effect could not be explained by its association with other known risk factors including age, sex, diabetes, pancreatic status, FEV1 at baseline, and socioeconomic status, or co-infection with Burkholderia cepacia (B. cepacia) complex or P. aeruginosa.

Burkholderia cepacia complex  — Advances in bacterial genetics have revealed that Burkholderia cepacia, which was originally thought to be a single species, is now known to

constitute multiple separate species, each of which is a member of the Burkholderia cepacia complex [ 15 ]. The species most commonly isolated from the sputum of CF patients are Burkholderia multivorans (B. multivorans) and Burkholderia cenocepacia (B. cenocepacia) [ 16-18 ].

Chronic infection with B. cepacia complex bacteria is associated with an accelerated decline in pulmonary function and shortened survival in CF [ 19-21 ]. Lung transplantation in patients infected with B. cepacia complex is associated with recurrent and often severe infection, with poor outcomes, particularly for those carrying B. cenocepacia [ 22-24 ]. Infection with B. cenocepacia is considered to be a contraindication to transplantation in many centers. (See"Bacterial infections following lung transplantation", section on 'Burkholderia cepacia' .)

Other pathogens  — Other pathogens have been identified in respiratory secretions of CF patients, with varying prevalence ( table 1 and figure 2 ) [ 25 ]. These include:

Non-typeable Haemophilus influenzae Stenotrophomonas maltophilia Achromobacter (formerly Alcaligenes) xylosoxidans Nontuberculous mycobacteria, including Mycobacterium avium (M. avium) complex,

Mycobacterium abscessus (M. abscessus), and other less common mycobacterial species

Aspergillus species

Other species identified in the respiratory secretions of occasional CF patients include non-cepacia complex Burkholderia species (gladioli and pseudomallei), Ralstonia species, and Pandoraea species. Although these organisms are identified more frequently than in the past, this may be due to refinements in microbial culture techniques and the use of molecular genetic methods that separate these organisms into an ever expanding taxonomy of bacterial pathogens, rather than increasing prevalence [ 26 ]. Furthermore, non-culture-based molecular genetic techniques have identified microorganisms in respiratory secretions of patients with CF that were previously unrecognized as being present [ 27 ]. Both culture-based and genetic methods have revealed high densities of anaerobic bacteria in respiratory secretions from CF patients [ 27,28 ]. Investigations are ongoing to determine which members of this complex microbiome are important for driving pulmonary exacerbations and disease progression.

CONSEQUENCES OF CF LUNG INFECTION  — Once established in the cystic fibrosis (CF) airway, many of the above organisms are difficult to eliminate. However, definitive studies have demonstrated that P. aeruginosa infection can be eradicated if detected early and treated aggressively. (See 'Early eradication of P. aeruginosa' below.) The same may be true for methicillin-resistant Staphylococcus aureus (MRSA), but this will require further study [ 29 ].

Although chronic infection of the CF airway is sometimes referred to as "airway colonization", the presence of many of these bacteria is not benign:

Chronic infection with P. aeruginosa is an independent risk factor for accelerated loss of pulmonary function and decreased survival, and conversion of P. aeruginosa to the mucoid phenotype worsens prognosis. (See 'Pseudomonas aeruginosa' above.)

Infection with Burkholderia cepacia complex connotes an even worse prognosis that may be due in part to the behavior of a few particularly virulent species within the complex. (See 'Burkholderia cepacia complex' above.)  

Infection with MRSA is also associated with worse survival. (See 'Methicillin-resistant Staphylococcus aureus' above.)  

The persistence of bacteria despite aggressive treatment is thought to be due to one or more of the following factors:

Poor penetration of antibiotics into purulent airway secretions Native or acquired antibiotic resistance CF-related defects in mucosal defenses Biofilms produced by the bacteria that may render antibiotics ineffective or interfere

with host defenses  

TREATMENT OF ACUTE PULMONARY EXACERBATIONS  — The clinical course of most patients with cystic fibrosis (CF) is punctuated by episodes of acute worsening of respiratory status. These pulmonary exacerbations appear to drive long-term deterioration in lung function [ 30 ]. Although practicing physicians have been recognizing and treating pulmonary exacerbations for many years, it has been difficult to arrive at a precise definition for these events. To determine what information clinicians appeared to be using to decide when to initiate treatment for pulmonary exacerbations, data from the placebo arm of an inhaled tobramycin trial were retrospectively analyzed [ 31 ]. The following characteristics were associated with initiation of antibiotic treatment for pulmonary exacerbations:

Increased cough Increased sputum production or chest congestion Decreased exercise tolerance or increased dyspnea with exertion Increased fatigue Decreased appetite Increased respiratory rate or dyspnea at rest Change in sputum appearance Fever (present in a minority of patients) Absenteeism from school or work Increased nasal congestion or drainage

Reductions in pulmonary function are often present during pulmonary exacerbations, but chest radiographs may not show significant changes over baseline.

Surprisingly, the evidence that antibiotics are beneficial in treating pulmonary exacerbations is derived from only a few studies. A small randomized study of patients experiencing acute pulmonary exacerbations showed that the rate of clinical improvement was accelerated in patients treated with antipseudomonal antibiotics as compared with those receiving only bronchodilators and chest physiotherapy [ 32 ]. After 14 days of treatment, patients initially receiving antibiotics had greater improvements in several pulmonary function measurements than those initially treated with placebo. A similar randomized study showed

that addition of antipseudomonal antibiotics to oxacillin improved outcomes as measured by forced expiratory volume at one minute (FEV1) [ 33 ].

ANTIBIOTIC SELECTION  — Management of patients with cystic fibrosis (CF) includes routine cultures of respiratory secretions to identify infecting organisms and guide antibiotic selection. Because CF patients frequently carry the same bacteria for prolonged periods of time, past culture results can be used to guide antibiotic choices when a patient’s condition warrants intensifying treatment. The current recommendation is to perform cultures every three months so that relatively current information is available to guide treatment when a pulmonary exacerbation occurs [ 34,35 ].

General considerations  — It is not unusual for CF patients to have several bacterial species identified in their respiratory secretions. Selecting an antibiotic combination that covers all the isolates is occasionally difficult without resorting to an impractically large number of antibiotics. Unfortunately, too little information is available to rank the relative importance of the different pathogens if only a subgroup can be reasonably covered.

Our practice is to select antibiotics based on the culture results and the following considerations:  

We target at a minimum any mucoid P. aeruginosa and S. aureus. Attempts are made to cover non-mucoid P. aeruginosa isolates whenever possible without sacrificing coverage of the mucoid strains.

We also treat Achromobacter xylosoxidans if present because limited evidence suggests that some of these isolates can be particularly inflammatory in nature and are associated with rates of forced expiratory volume at one minute (FEV1) deterioration, similar to that induced by P. aeruginosa [ 36 ].

There is more uncertainty regarding the importance of treating Stenotrophomonas maltophilia (S. maltophilia). Some studies have shown that identification of S. maltophilia in CF sputum is not an independent risk factor for accelerated deterioration in pulmonary function [ 37 ]. However, another study reported chronic infection with S. maltophilia was associated with a higher frequency of pulmonary exacerbations [ 38 ]. It remains uncertain whether S. maltophilia is merely a marker of more severe lung disease or is a cause of it. Of relevance, we have occasionally seen patients with a deteriorating clinical course in whom S. maltophilia appears to be the only delectable pathogen and which therefore warrants targeted treatment. Until its true nature is resolved, we attempt to treat S. maltophilia but place less emphasis on it if doing so would sacrifice optimal coverage of any of the above organisms.

Aspergillus species that are identified in respiratory secretions are generally not treated because they appear to be an unlikely cause of pulmonary exacerbations. (See 'Aspergillus species' below.)

When in vitro testing can identify no antibiotic to which a bacterium is susceptible, our practice is to select a combination of antibiotics that would otherwise be chosen empirically for that pathogen.

We generally avoid using two beta lactam antibiotics simultaneously, but some CF physicians are not as reluctant, particularly when other regimens have failed. Our decision is based upon in vitro studies showing the antimicrobial effect of adding the second beta lactam is unpredictable and can sometimes be antagonistic to the first [ 39,40 ].

We continue administering oral azithromycin during the acute exacerbation if it is a component of the chronic pulmonary regimen. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Macrolide antibiotics' .)

Susceptibility testing strategies  — As discussed below, the value of antibiotic susceptibility testing based on conventional in vitro cultures has been questioned because the correlation between test results and clinical response is poor. Therefore, alternate susceptibility strategies including biofilm culture and antibiotic synergy testing are under investigation. Nonetheless, currently available information is not sufficient to recommend a change in the current practice of most physicians who typically select antibiotics based on conventional in vitro testing results, rather than performing in vitro synergy testing [ 41]. These perspectives are in agreement with guidelines published by the CF Foundation [ 42 ].  

In vitro antibiotic susceptibility testing  — In practice, most clinicians select antibiotics based on in vitro antibiotic susceptibility testing. Of note, special laboratory procedures are required to adequately test many of the gram negative bacilli isolated from CF patients because these tend to grow poorly on standard media [ 6 ]. Many laboratories test multiple morphotypes of the same species. (See "Sputum cultures for the evaluation of bacterial pneumonia" .)

However, the value of in vitro susceptibility testing for CF patients is being questioned based on several pieces of information. In particular, a retrospective study evaluated whether clinical outcome was dependent upon whether patients received antibiotics to which their isolated bacteria were susceptible [ 43 ]. Among 77 patients who were chronically infected with P. aeruginosa and treated with parenteral ceftazidime and tobramycin for a pulmonary exacerbation, improvement in FEV1 did not correlate with whether the isolated pseudomonas was sensitive to the antibiotics. Furthermore, there is concern about the reproducibility of antibiotic susceptibility testing of pseudomonas isolated from CF patients; considerable variation was found when the same morphotype was tested multiple times and when a single isolate was tested by multiple laboratories [ 44 ].

Testing bacteria grown as biofilms  — One possible explanation for why in vitro testing may not closely predict clinical response is that bacteria in the airways of patients with CF have diverse phenotypes, with a portion growing in self-generated biofilms. Some investigators have cultured bacteria isolated from CF sputum samples under conditions that induce them to form biofilms in vitro. In general, bacteria grown as biofilms are less susceptible to antibiotics compared with the same isolates grown under standard clinical laboratory conditions [ 45 ]. In a pilot study, 39 patients were randomized to treatment with an antibiotic regimen based upon the susceptibilities of their organisms as measured under biofilm or conventional conditions [ 46 ]. No differences in outcomes were noted whether antibiotics were chosen based on susceptibility results from biofilm versus conventional cultures, although the power of the study to detect clinically important differences was not very high.

Antibiotic synergy testing  — Multidrug-resistant bacteria are frequently encountered in patients with CF, particularly in those who have advanced disease and have received multiple courses of antibiotics. When such bacteria are isolated, combinations of antibiotics can be administered in the hope of achieving activity via synergy, despite apparent resistance to each individual antibiotic. To guide selection, studies have described in vitro synergistic effects of various combinations of antibiotics for many isolates of multidrug-resistant P. aeruginosa [ 39 ] and B. cepacia complex [ 47 ].

However, the only large clinical trial that studied the effect of combination antibiotic susceptibility testing in the management of pulmonary exacerbations failed to demonstrate any benefit associated with this approach [ 41,48 ]. In this trial, 132 patients with chronic multidrug resistant Gram negative infection and pulmonary exacerbations were randomly assigned to have their bacterial isolates tested by standard clinical laboratory techniques or by methods that evaluate combinations of antibiotics for synergistic effects. Subsequent antibiotic management was guided by the results of these studies. Combination antibiotic susceptibility testing did not improve clinical or bacteriologic outcomes, nor did this approach prolong the period until the next acute exacerbation [41 ].

Number and choice of antibiotics  — Typical antibiotic regimens based on the species of bacterial isolated from a given patient are outlined in the table (table 2 ). The selection is then modified based on the results of susceptibility testing, renal function, and clinical response.

The standard of practice has been to treat pulmonary exacerbations in patients with P. aeruginosa with two antipseudomonal antibiotics [ 42 ]. The rationale for choosing two rather than one is to take advantage of possible synergistic effects and potentially decrease the risk of developing treatment emergent antibiotic resistance. A small double blind trial provided some support for this practice. In this study, 76 patients with pulmonary exacerbations of CF were randomly assigned to receive azlocillin and either tobramycin or placebo [ 49 ]. The time to readmission for a new pulmonary exacerbation was significantly longer among patients who received azlocillin plus tobramycin; other clinical parameters were similar between groups. Unfortunately, larger clinical trials are lacking [ 50 ]. We agree with the conclusions of the CF Guidelines Committee that in the absence of more definitive information, there is insufficient justification to change the current practice of using two antipseudomonal antibiotics [ 42 ].

The most commonly selected intravenous regimens for P. aeruginosa combine tobramycin with an antipseudomonal semisynthetic penicillin (eg, piperacillin-tazobactam ), an extended third generation cephalosporin (eg, ceftazidime , cefepime ), a carbapenem (eg, imipenem-cilastatin or meropenem , but notertapenem , which has less activity against P. aeruginosa), or less frequently a monobactam aztreonam ( table 2 ). Tobramycin, rather than gentamicin , is selected because it usually has greater activity against P. aeruginosa. Oral or intravenous ciprofloxacin may replace the aminoglycoside if the pseudomonas is sensitive to it. If an organism is resistant to tobramycin, amikacin occasionally is efficacious and is used (see "Epidemiology and pathogenesis of Pseudomonas aeruginosa infection" ). When the P. aeruginosa demonstrates in vitro resistance to all aminoglycosides or the patient fails to improve on an aminoglycoside containing regimen, we use intravenous colistin (colistimethate sodium) in combination with either a fluoroquinolone or beta-lactam antibiotic [ 51,52 ]. Intravenous colistimethate should not be used in combination with intravenous aminoglycosides due to potential for additive renal toxicity. (See'Colistimethate sodium' below.)

Although we routinely use in vitro susceptibility testing to guide antibiotic selection, we recognize that the correlation between laboratory test results and clinical response is not high for Gram negative pathogens in patients with CF (see 'In vitro antibiotic susceptibility

testing' above). We therefore are willing to modify an antibiotic regimen when a patient fails to show anticipated improvement. This may include selecting antibiotics to which the organisms demonstrate in vitro resistance when no other options are available. Antibiotics that were found to be effective during a patient’s prior exacerbations may be selected in preference for those favored by in vitro testing.

When methicillin-sensitive S. aureus accompanies the P. aeruginosa, treatment options are piperacillin-tazobactam , ticarcillin-clavulanate , cefepime ,imipenem-cilastatin , or meropenem PLUS one of the following: tobramycin or amikacin . In contrast, we treat methicillin-resistant Staphylococcus aureus (MRSA) and P. aeruginosa with vancomycin or linezolid PLUS the same antibiotic combination as for P. aeruginosa alone (three antibiotics total) ( table 2 ). (See "Treatment of invasive methicillin-resistant Staphylococcus aureus infection in children", section on 'Pneumonia' and "Treatment of invasive methicillin-resistant Staphylococcus aureus infections in adults", section on 'Pneumonia' .)

The Burkholderia cepacia complex bacteria (which include B. multivorans and B. cenocepacia) are often highly resistant to multiple antibiotics. Antibiotic selection should be guided by in vitro susceptibility testing when possible. Treatment options are often limited, but some isolates show susceptibility totrimethoprim-sulfamethoxazole , doxycycline , ceftazidime , and/or meropenem . When no single antibiotic is effective, combinations of two or more antibiotics sometimes show in vitro susceptibility [ 47 ]. (See 'Burkholderia cepacia complex' above.)

Route of antibiotic administration

Oral  — Oral antibiotics are appropriate under some circumstances. As examples:

Mild exacerbations due to methicillin-sensitive Staphylococcus aureus can be treated with dicloxacillin , amoxicillin-clavulanate , cephalexin , a macrolide, trimethoprim-sulfamethoxazole , or doxycycline when in vitro testing shows susceptibility.

MRSA can be treated with trimethoprim-sulfamethoxazole or doxycycline when in vitro testing shows susceptibility.

For more serious exacerbations, oral linezolid , which has good activity against MRSA, can be used.

Oral ciprofloxacin is appropriate for P. aeruginosa when in vitro testing shows susceptibility.

Of note, in patients treated chronically with azithromycin , S. aureus resistance to macrolides is increasing, causing macrolides to be less reliable for the treatment of S. aureus infections [ 53 ]. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Macrolide antibiotics' .)

Inhaled  — Practice varies among clinicians regarding use of inhaled antibiotics in conjunction with oral and/or IV antibiotics for treatment of pulmonary exacerbations. In general, we do not consider an inhaled antibiotic to be an equivalent substitute when systemic antibiotics would otherwise be used as recommended, as shown in the table ( table 2 ) [ 54 ]. This is based in part on our concern that the distribution of inhaled medications to the lungs of CF patients can be very inhomogeneous [ 55 ]. When a beta

lactam and/or either an aminoglycoside or colistimethate are indicated, we deliver them parenterally and do not rely on their inhaled versions. An exception might be for a relatively mild pulmonary exacerbation when an inhaled antibiotic can be added to an oral medication, eg, a fluoroquinolone. Furthermore, we might add an inhaled antibiotic when the best systemic regimen still leaves a bacterial isolate uncovered.  

There is insufficient information to recommend whether to continue an inhaled antibiotic during an acute exacerbation when it is part of a patient’s chronic pulmonary regimen. Our local practice is to suspend the inhaled medication. Others would continue the inhaled medication during an acute exacerbation, but generally not use the inhaled medication as a substitute for one of the two-drug intravenous regimens for P. aeruginosa outlined in the table ( table 2 ). Similarly, a guidelines committee of the CF Foundation could not reach a conclusion regarding the risks and benefits of administering the same antibiotic by both intravenous and inhaled routes [ 42 ]. If both inhaled and intravenous tobramycin are used, one needs to be aware that the inhaled drug can cause a modest increase in serum levels, possibly interfering with pharmacokinetic analyses and causing errors in IV dosing [ 42 ].

Intravenous  — Intravenous antibiotics are indicated in any of the following situations:

Severe exacerbations Bacterial resistance to all orally administered antibiotics Failure of oral antibiotic therapy to resolve the exacerbation

Dosing  — Care must be taken to dose and adjust antimicrobials to achieve lung penetration and maximize the bactericidal efficacy of each agent. As an example, with beta-lactam antibiotics, efficient bacterial clearance requires prolonged tissue concentrations above the minimum inhibitory concentration (MIC) through much of the dosing interval. By contrast, for aminoglycosides, bactericidal effect is proportional to the peak antimicrobial tissue concentrations.

The pharmacokinetics of many antibiotics differs in patients with CF as compared with normal individuals [ 56 ]. In general, the volume of distribution and total body clearance is increased for hydrophilic drugs (such as aminoglycosides, penicillins, and cephalosporins), in part because CF patients are generally undernourished and have decreased adipose tissue [ 57,58 ]. Thus, higher and/or more frequent dosing is required for many CF patients [ 59,60 ]. There has been some interest in prolonging the duration of dose infusion of some beta-lactam antibiotics to better maintain drug concentrations above minimal inhibitory concentrations, although the clinical advantage of this approach has not yet been proven [ 61-63 ].

Aminoglycosides  — In patients with CF receiving aminoglycosides, the volume of distribution is increased and renal clearance rate is considerably accelerated as compared to patients without CF. Therefore, starting doses of aminoglycosides for CF patients should be approximately 30 to 35 percent larger than those recommended for individuals without CF [ 59 ]. The dose and frequency from a previous course of treatment may be used initially if serum concentrations were in the target range and creatinine clearance is not substantially changed, but drug levels should still be monitored.  

Once daily  — For patients without CF who require intravenous aminoglycosides, once daily administration appears to be as effective as conventional dosing (in which the daily dose is divided into three separate administrations) [ 64 ]. To assess the safety and efficacy of this approach in patients with CF, a multicenter trial randomly assigned 244 patients greater than 5 years of age with acute CF exacerbations to 14 days of treatment with daily or three times a day intravenous tobramycin [ 65 ]. The treatments were equally effective in improving pulmonary function (for change in FEV1, adjusted mean difference 0.4 percent [95% CI -3.3-4.1]). Once daily therapy was associated with a decreased incidence of nephrotoxicity (mean percent change in creatinine -4.5 [once daily] versus +3.7 [thrice daily]).

Based on these results, we routinely dose aminoglycosides once daily (known as “consolidated dosing”) in CF patients with normal renal function. This approach is consistent with the guidelines endorsed by the CF Foundation [ 42 ] and is supported by a Cochrane systematic review [ 64 ]. This practice has been adopted by the majority of CF Centers including pediatric programs [ 66 ]. Of note, most of the data assessing efficacy and safety of once dailytobramycin dosing are derived from studies of patients greater than 5 years of age. The starting dose for tobramycin is 10 mg/kg/24 hours for children and adults without renal insufficiency ( table 2 ).

We do not use published tables or nomograms for selecting and adjusting aminoglycoside doses and intervals in patients with CF, because the pharmacokinetics differ from those in non-CF patients and may result in suboptimal aminoglycoside concentrations [ 67,68 ]. Instead, serum levels are measured twice following the first dose (eg, at 2 and 10 hours after the dose) and pharmacokinetic analysis is used to calculate the peak serum level, with the target being between 20 and 30 mcg/mL [ 65 ]. We also use pharmacokinetic calculation to extrapolate forward to be certain that there is at least a six-hour period prior to the next dose during which the patient will have low serum levels, (eg, less than or equal to 0.5 mcg/mL at 18 hours), to minimize toxicity. Slightly higher 18-hour levels (eg, <1.0 mcg/mL) are also acceptable provided the patient’s renal function and clinical status are stable and the 18-hour level will be rechecked within 3 to 4 days. If a dose that achieves the target peak level leads to too high a serum level at 18 hours, the dosing strategy is changed to the “conventional” approach (which is described in the next paragraph), to reduce the risk of toxicity. Directly measured peak and trough concentrations are not accurate for assessing whether the consolidated dosing regimen meets targeted levels in CF patients. Because of higher doses used for these patients, prolonged drug distribution time and rapid clearance rates, the time of the peak serum level is unpredictable. In CF patients with normal renal function, trough levels are often below the lower limit of detection of the assays, thus precluding accurate pharmacokinetic analysis. Consultation with a clinical pharmacist skilled in pharmacokinetic-based drug management may be helpful and is suggested.  

Conventional  — For patients with delayed aminoglycoside clearance due to renal insufficiency, we do not use once daily dosing for aminoglycosides. Instead, we adjust the dose and interval to achieve a peak serum concentration of 8 to 12 mcg/mL and a trough of less than 2 mcg/mL. In this situation, the dose and frequency from a previous course of treatment may be used initially if the creatinine clearance is not substantially changed and

serum concentrations were within the target range [ 69 ]. If there is no reliable historical information, we consult our pharmacist to guide dosing with a pharmacokinetic analysis. If pharmacist consultation is not available, it is reasonable to use an empiric loading dose of 3.3 mg/kg (if patient is overweight, use ideal body weight or dosing weight) [ 42,65 ] and select an initial maintenance dose and dosing interval based upon the patient’s creatinine clearance ( table 3 ). Serum concentrations should be monitored and the dose and interval adjusted to achieve the above target peak and trough concentrations. These steps are detailed in a separate topic review. (See "Aminoglycosides", section on 'Monitoring serum aminoglycoside concentrations' .)      

Monitoring  — Careful monitoring is necessary to limit the risks of aminoglycoside-induced renal injury and ototoxicity [ 70-74 ]. The renal damage can be manifested by elevation in creatinine; patients receiving multiple courses of aminoglycosides may develop a syndrome of magnesium-wasting without azotemia [ 75 ]. These adverse effects can be limited but not prevented by adjusting antibiotic dose and interval to avoid exceeding target serum levels. When clinically significant renal damage or ototoxicity is noted, efforts should be made to minimize subsequent aminoglycoside use. However, the antibiotic susceptibility pattern of many CF-prevalent bacteria may provide limited options for non-aminoglycoside regimens and require further use of these antibiotics.

If a once daily regimen is used, we monitor the treatment course by measuring an aminoglycoside level several hours prior to the next dose (ie, at 18 hours following the previous dose). The goal is to ensure that the aminoglycoside level remains relatively low for several hours prior to the next dose (eg, below 0.5 or 1 mcg/mL for tobramycin at 18 hours (see 'Once daily' above)). An increasing 18 hour level may be the first indication of renal injury that requires dose adjustment. We believe that the 18 hour time point is preferable to a true trough at 24 hours because in CF patients with normal renal function, the drug concentration is frequently below the level of detection at 24 hours, which would prevent early detection of renal impairment as manifested by increasing drug levels. Interpreting these low serum levels can be confounded if the patient is also receiving inhaled tobramycin. As an example, serum levels one hour after inhaling 300 mg tobramycin are 1.05 ± 0.67 mcg/mL (mean ± SD) [ 76 ]. 

During treatment, serum levels are measured once or twice a week. The appropriate frequency of monitoring depends on baseline renal function, the concomitant use of potentially renal toxic drugs, and whether the patient has a history of prior aminoglycoside toxicity. In addition, we suggest measuring two levels (eg, at 2 and 10 hours after the dose) following any substantial change in dose, to allow pharmacokinetic calculations and assure that targeted levels are achieved. Two time point measurements are also recommended if large changes in volume of distribution are likely to have occurred during the course of treatment, eg, sepsis with capillary leak or right-sided heart failure, although these scenarios are uncommon in CF patients having a typical pulmonary exacerbation. (See 'Once daily' above.) [ 67 ].  

If a conventional dosing regimen is used, we measure peak and trough levels once or twice a week to ensure that the target levels are achieved (see'Conventional' above).  

To monitor for renal toxicity, blood urea nitrogen (BUN) and creatinine levels are also measured whenever aminoglycoside serum levels are assessed. We also monitor serum

magnesium levels in patients who have received multiple aminoglycoside courses within the past year and are therefore at increased risk for isolated tubular damage manifested by magnesium wasting.

Colistimethate sodium  — Intravenous colistin (colistimethate sodium) is a useful option for P. aeruginosa strains that demonstrate in vitro resistance to aminoglycosides. It is used in combination with either fluoroquinolones or beta lactam antibiotics. It should not be used in combination with intravenous aminoglycosides due to their additive renal toxicities. There is potential for confusion when choosing drug dosage due to variability in how the antibiotic is labeled [ 77,78 ]. In the United States, each vial of colistimethate sodium is labeled as containing 150 mg of colistin base activity. Using this designation, we administer 2.5 to 5 mg/kg per day divided into three doses to a maximum of 100 mg per dose. Obese patients should be dosed by ideal body weight. In other countries, the drug is labeled using international units, milligrams of colistimethate sodium, or milligrams of colistin base [ 52 ]. Careful attention to the details of the licensed prescribing information is advised. We suggest monitoring of drug levels during treatment for patients with CF. (See "Colistin: An overview" .)

Vancomycin  — The pharmacokinetics of vancomycin does not appear to be altered in patients with CF as compared with other patients [ 79 ]. When vancomycin is given for a pulmonary exacerbation in a patient with CF, we use the same dose that is used for treating a serious pulmonary infection in a patient without CF. We start with a weight-based dose of vancomycin of 15 mg/kg (up to 1 gram per dose) every six or eight hours, measure trough serum concentration before the fourth dose, and adjust the dose and interval to achieve a trough of approximately 15 to 20 mcg/mL. Drug levels should be measured earlier in patients with impaired renal function. (See "Vancomycin dosing and serum concentration monitoring in adults" and "Treatment of invasive methicillin-resistant Staphylococcus aureus infection in children", section on 'Vancomycin' .)

Ciprofloxacin  — The pharmacokinetics of ciprofloxacin in patients with CF are more variable than in patients without CF and may be altered by disease severity, concurrent drug therapy, and patient age [ 80-82 ].

Children with CF generally require higher doses of ciprofloxacin than other children. As an example, in a group of children with CF treated for severe pulmonary infection, clearance of ciprofloxacin was two times higher than in children without CF [ 80 ]. We use oral ciprofloxacin at a dose of 40 mg/kg/day (up to 1.5 grams daily) divided every 12 hours, instead of standard doses of ciprofloxacin [ 82,83 ].  

By contrast, the pharmacokinetics of ciprofloxacin in adults with CF appears to be similar to that of adults without CF [ 84,85 ]. Therefore, for adults with CF, we use the manufacturer's recommended dosing (750 mg by mouth twice daily) for severe respiratory tract infection, although higher dosing levels (eg, 1 gram twice daily) may also be appropriate based on theoretical considerations of pharmacokinetics and the level of susceptibility of the bacteria [ 81 ].

Sulfonamides  — Hepatic clearance of sulfamethoxazole is increased in CF due to accelerated acetylation, and renal clearance of trimethoprim is accelerated by unknown

mechanisms [ 86 ]. For these reasons, the dose of oral trimethoprim-sulfamethoxazole should be increased by approximately 50 percent relative to that used for patients without CF. For example, trimethoprim-sulfamethoxazole (160 mg TMP-800 mg SMX) should be taken three times daily for an adult with CF rather than twice a day.

Duration of treatment  — Antibiotic treatment is typically continued until the signs and symptoms that defined the pulmonary exacerbation are largely resolved. In practice, this usually entails treatment for a minimum of 10 days to as long as three weeks, and occasionally more.

To provide a more objective assessment of response rates, studies have monitored improvement in FEV1. In a study of 95 subjects, peak FEV1 was achieved in an average of 8.7 days although treatment continued longer for an average of 13.5 days [ 87 ]. Another retrospective analysis of 492 patients receiving treatment for 1331 exacerbations showed that most of the improvement in FEV1 occurred by 8 to 10 days [ 88 ]. These data have been used to suggest that the current practice of treating for two to three weeks may be longer than required. However, in our experience only a minority of patients with moderate to severe CF lung disease report that their symptoms of cough, sputum production, anorexia, and fatigue have returned to their baseline by 8 to 10 days. This observation leads us to be hesitant to reduce the duration of treatment for these more severely ill patients until a well constructed clinical trial indicates otherwise.

Home management of acute exacerbations  — Concern over medical costs as well as the preference of many patients have encouraged home treatment for pulmonary exacerbations in CF. Some [ 88-91 ], but not all [ 92-94 ], of the currently available studies support the use of home treatment. The largest study to date retrospectively analyzed data on 1535 subjects treated for a pulmonary exacerbation [ 88 ]. No difference was detected in long-term FEV1 change or time to next antibiotic treatment for pulmonary exacerbation between subjects receiving home therapy as compared with hospital therapy.

When considering home therapy for a pulmonary exacerbation, resources must be available at home to replicate the hospital program including provisions for rest, meals, medications, and physiotherapy [ 42 ]. Children require greater assistance than adults to accomplish these goals, and adult supervision is needed even for teenagers. In considering home treatment for children, one must consider the impact of lost work hours, the number of other children in the household, the number and competence of available adult care-givers, and family stress before deciding whether home treatment is preferable to hospitalization.

TREATMENT OF CHRONIC PULMONARY INFECTION  — Once P. aeruginosa or B. cepacia complex becomes established in the airways of a patient with cystic fibrosis (CF) for more than a few months, the organisms usually persist for years despite aggressive attempts at eradication. Although it has not been possible to eradicate these bacteria, antibiotics are frequently used as chronic suppressive therapy to reduce the bacterial burden and thus lessen their impact.

Chronic oral antibiotics  — In recognition of the central role that bacterial infection plays in the progression of CF lung disease, a variety of chronic antibiotic regimens have been tested in an attempt to suppress bacterial numbers, reduce airway damage, and decrease

the frequency of acute exacerbations. Despite the lack of experimental evidence, it is the practice of some physicians to administer oral antibiotics chronically, particularly when sputum cultures demonstrate bacteria that are sensitive to such drugs. However, chronic use of antibiotics frequently induces antibiotic resistance, which does not necessarily abate when antibiotic treatment is stopped [ 95 ]. This is particularly true for fluoroquinolones, which have a high propensity to induce both reversible and permanent resistance in P. aeruginosa. We believe that the potential benefits of chronic oral antibiotics in general do not outweigh the problems caused by induction of antibiotic resistance and side effects; we therefore do not recommend their use.

An important exception is azithromycin , a macrolide antibiotic that has been shown in randomized trials to have clinical benefit, despite the fact that P. aeruginosa is routinely resistant to it when tested by standard methodology in clinical microbiology laboratories. Possible explanations for its beneficial effects are that it alters pseudomonas phenotype without inhibiting bacterial growth, or that it has direct immunomodulatory activities. Because the benefits of azithromycin do not appear to be due to direct antimicrobial effects, its use is discussed separately. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Macrolide antibiotics' .)  

Intermittent courses of prophylactic antibiotics have been advocated as a means of conferring benefit with less risk of subsequent resistance. However, there is little clinical data documenting the effectiveness of such an approach. One study of oral ciprofloxacin administered for 10 days every three months for one year in a small number of patients failed to show benefits in terms of forced expiratory volume at one minute (FEV1), the number of hospitalizations, or the requirement for intravenous antibiotics [ 96 ].

Periodic hospitalization  — Periodic hospitalizations for preventive therapy, including intravenous antibiotics (referred to as "clean outs"), were utilized more in the past than at the present in the United States. To date, only a few randomized trials have examined the practice, and these have failed to show benefit from periodic elective hospitalization as compared with patients who are hospitalized and treated only when symptomatic [ 97-99 ].

Among the strongest advocates for the continued use of periodic hospitalization for "clean out" are physicians in the Danish Cystic Fibrosis Center in Copenhagen [ 100 ]. At that site, all patients who are chronically infected with P. aeruginosa spend two weeks in the hospital every three to four months, receiving intravenous beta-lactam and aminoglycoside antibiotics and aerosolized colistin . After this practice was initiated, there was an improvement in survival compared with a historical control population from the same institution. However, the lack of a concurrent, randomized control population makes it difficult to determine whether the periodic hospitalizations are responsible for the improvement.  

Contrasting results were found in a prospective trial in the United Kingdom, in which 60 patients were randomly assigned to receive either regular antipseudomonal antibiotics every three months (“clean out”), or antibiotics only when indicated by clinical deterioration (symptomatically treated) [ 98 ]. After three years of follow-up, no significant differences in spirometry or survival were noted between the two groups.

It is possible that the discrepancy in findings between the studies described above is explained by differences in the total dose of antibiotics administered in the symptomatically treated control groups. In the Danish study, patients treated with periodic hospitalization for “clean out” received approximately 1.9 times the amount of intravenous antibiotics as compared with symptomatically treated historical controls [ 100 ]. By contrast, in the UK study, the patients treated with periodic hospitalizations received about 1.2 to 1.5 times more intravenous antibiotics than the symptomatically treated control group. Some authors have suggested that the UK study did not adequately test the role of scheduled therapy because the intensity of antibiotic therapy in the symptomatically treated group was relatively high [ 101 ].  

In North America, the practice of admitting patients routinely for "clean outs" has been largely abandoned. Lack of proof of benefit, the high cost of such treatment, and the disruption to patients' daily lives have decreased the enthusiasm for the practice. Furthermore, there is the continuing concern that frequent use of intravenous antibiotics will prematurely select multidrug-resistant organisms, making treatment of inevitable acute exacerbations more difficult.

Aerosolized antibiotics  — Most classes of antibiotics that show in vitro activity against P. aeruginosa are ineffective when administered orally. Inhalation of nebulized preparations has been studied as an alternate route of delivery that is less cumbersome and toxic than the intravenous route [ 102 ]. The evidence and other considerations for different types of aerosolized antibiotics is described below, followed by a description of our approach, based on this information. (See 'Our approach' below.)  

Inhaled tobramycin  — Treatment with nebulized tobramycin in patients chronically infected with P. aeruginosa improves lung function and reduces acute pulmonary exacerbations [ 103-106 ]. The preparation does not have preservatives and is adjusted to pH 6.0. Prospective studies following patients for up to 2.5 years on aerosolized tobramycin show continuing benefit, although at the price of slightly increased bacterial resistance.    

The pivotal study of inhaled tobramycin was a 24-week randomized, double blind, multicenter trial in 520 patients with stable CF [ 103 ]. Twice daily treatment with 300 mg of inhalational tobramycin solution (TOBI ® ) was administered via jet nebulizer in cycles of 28 days on the medication followed by 28 days off. Compared with a control group, subjects receiving tobramycin had a 10 percent higher FEV1 at 20 weeks, a decrease in the sputum density of P. aeruginosa, and a 26 percent decrease in the likelihood of hospitalization during the trial. There were higher rates of slight voice alteration and tinnitus in the treatment arm. The tinnitus was mild and transient, and there was no associated hearing loss.

In a two-year, open-label follow-up of patients participating in the above study, ongoing use of inhaled tobramycin was associated with greater improvement in FEV1 and with an increase in body mass index [ 104 ]. Importantly, patients receiving placebo during the randomized portion of the study improved their FEV1 when starting tobramycin in the open label phase, but their FEV1 levels did not catch up with those attained by subjects that began tobramycin during the randomized portion of the trial [ 106 ]. A trend toward increased aminoglycoside resistance among sputum flora was observed among patients treated with tobramycin during the randomized portion of the trial, although the clinical relevance of this finding is unclear, since the need for hospitalization or

intravenous antibiotic therapy was similar for both groups and did not increase over the course of the study [104,105 ]. Peak serum tobramycin concentrations averaged <1 mcg/mL, and no nephrotoxicity or ototoxicity was detected.

Inhaled aztreonam lysine  — Following the success of inhaled tobramycin , investigators have considered a number of other antibiotics for administration by inhalation to treat CF lung disease. Aztreonam , a monobactam antibiotic with antipseudomonal activity that was approved for intravenous use in 1986, became a likely candidate. Because inhalation of the IV preparation of aztreonam induces airway inflammation, a lysine salt formulation was developed that circumvents this problem. This preparation has undergone large scale clinical trials.

In a randomized trial, 211 subjects with chronic pseudomonal lung infection were given either inhaled aztreonam lysine (75 mg) or placebo either two or three times daily for 28 days. All patients were older than 6 years, had had FEV1 between 25 and 75 percent predicted, and had received 28 days of inhaled tobramycin prior to the trial [ 107 ]. The group treated with inhaled aztreonam had a longer time before needing additional antipseudomonal antibiotics (92 days) as compared with those given placebo (71 days). Furthermore, patient-reported respiratory symptom scores, FEV1, and pseudomonas density in sputum samples also improved in the group given aztreonam. There were no differences between two and three times a day aztreonam dosing.

Another randomized trial compared inhaled aztreonam with placebo in 164 subjects using a similar protocol. This study used the same entry criteria as in the study described above, and the drug was administered three times daily for 28 days [ 108 ]. Compared with the placebo group, those receiving inhaled aztreonam had better patient reported respiratory symptom scores (primary endpoint), better FEV1 percent predicated levels, and lower densities of pseudomonas in their sputum.    

An open label study enrolled 271 of the subjects from the two trials described above [ 107,108 ]. Each of these subjects took aztreonam by inhalation either two or three times a day for one month, every other month, for up to nine cycles [ 109 ]. Without a control group, the level of efficacy could not be quantified, but the treatments appeared to be well tolerated, and the frequency of adverse events was in the range expected for the study population. Importantly, those receiving three times a day aztreonam had greater improvements in FEV1 and better patient reported respiratory symptom scores than those receiving twice a day aztreonam.

A randomized, blinded, placebo-controlled study evaluated the efficacy of inhaled aztreonam in 157 subjects ages >6 years who had mild lung disease (FEV1 >75 percent predicted) [ 110 ]. Aztreonam inhalation was associated with a modest improvement in relative percent FEV1 predicted (2.7 percent, p = 0.021). Those with FEV1 <90 percent predicted benefited more than those with higher values.

Based on the results of these and other studies, the US Food and Drug Administration (FDA) approved inhaled aztreonam (Cayston®) in February 2010. A clinical trial comparing inhaled aztreonam and tobramycin is underway. In all of these studies, aztreonam was administered using a high efficiency nebulizer(eFlow/Altera®) that delivers the dose in less than three minutes, which compares favorably with the 15 to 20 minutes required to deliver other inhaled antibiotics using conventional nebulizers. However, the time advantage is somewhat mitigated by the need to administer aztreonam three times a day compared with twice a

day for tobramycin. Also, to maintain the efficiency of the nebulizer, the system must be carefully cleaned after each use, which adds additional time to the treatments. The FDA-approved drug insert stipulates that aztreonam must be administered using this nebulizer, which is provided to the patient together with the first supply of drug.

Inhaled colistin  — The polypeptide antibiotic colistin has antipseudomonal activity, which is preserved against many multidrug-resistant strains. Intravenous use of colistin became infrequent because experience from the 1970s found a relatively high frequency of neurologic and renal side effects. However, some CF centers are reassessing the intravenous use of colistin for patients infected with otherwise pan-resistant organisms [ 111 ]. To achieve benefit without the systemic toxicity, the inhalation route also has been used for colistin. The renal and neurotoxicity of inhaled colistin appears minimal when 150 mg of colistimethate sodium is diluted in 2 mL of sterile water and administered by nebulizer twice per day. However, bronchospasm may be induced, particularly among patients with a history of wheezing, atopy, or asthma [ 112 ].

In a small clinical trial, 40 subjects with CF were randomized to receive twice a day colistin or isotonic saline by inhalation [ 113 ]. A high dropout rate compromised the value of the study; only 11 saline subjects and 18 colistin subjects completed the three-month treatment period. Comparison of the groups showed that those receiving colistin had better clinical symptom scores and preservation of pulmonary function.

In a randomized trial, one month treatment with either colistin or tobramycin resulted in a decrease in bacterial load; however, only tobramycin therapy was associated with improvement in lung function [ 114 ].

An open label five-month extension of the above study showed persistence of the superiority of tobramycin over colistin relative to preservation of FEV1 percent predicted [ 115 ].

Thus, inhaled colistin appears to be potentially effective but may be inferior to inhaled tobramycin . No studies have compared colistin with inhaled aztreonam.

Our approach  — Until high quality comparison trials become available, uncertainty remains regarding when to prescribe the various inhaled antibiotics.

We agree with the recommendations of an expert panel that all patients over 6 years of age who are colonized with P. aeruginosa should be treated chronically with inhaled tobramycin [ 116 ]. It is our first choice of inhaled antibiotic because of the extensive information supporting the efficacy of tobramycin and its good safety record following many years of use. The level of evidence and clinical benefit is greatest for patients with moderate or severe lung disease. Tobramycin is typically given as 300 mg in 5 cc by nebulizer twice daily for one month, on alternate months.

In our practice, we offer inhaled aztreonam instead of tobramycin to patients older than 6 years of age who have chronic pseudomonas infection, under any of the following circumstances:

The patient does not tolerate inhaled tobramycin The patient is deteriorating clinically despite inhaled tobramycin

The patient is considered more likely to be adherent to inhaled aztreonam treatment because it can be delivered more rapidly than tobramycin

The patient is or may soon become pregnant, which makes aminoglycosides relatively contraindicated

Aztreonam is given at a dose of 75 mg by inhalation three times a day for one month, every other month. Alternatively, it can be given for one month alternating with inhaled tobramycin for one month; this approach may be particularly appropriate for patients with deteriorating pulmonary status and/orrecurrent pulmonary exacerbations despite taking just one antibiotic every other month. Data from well-designed comparative effectiveness trials for tobramycin and aztreonam are needed to better inform the decision as to when to use each. There is no reported experience for using more than one of the currently available inhaled antibiotics simultaneously.

Given the less robust data supporting colistin use and the suggestion that it may be inferior to tobramycin , we prescribe colistin only in those patients who are not doing well despite tobramycin and/or aztreonam , or in those who do not tolerate them.

Antibiotic resistance as measured by in vitro susceptibility testing does not preclude a response to inhaled medications. This was illustrated by studies of patients participating in clinical trials of inhaled tobramycin and aztreonam , some of whom were found to be infected with P. aeruginosa strains that would be considered antibiotic-resistant relative to drug levels that are safely attainable by parenteral administration. Subjects with these relatively resistant pseudomonal isolates were just as likely to show clinical responses to inhalational treatment as those with drug sensitive strains [ 117,118 ]. This is probably because antibiotic concentrations that occur in respiratory secretions following inhalation of the FDA-approved formulations far exceed the breakpoints used for determining susceptibility when the drugs are given parenterally.

CONSIDERATIONS FOR SPECIFIC PATHOGENS

Other strategies against pseudomonas aeruginosa  — Several approaches have been investigated to prevent P. aeruginosa from chronically infecting the airways of cystic fibrosis (CF) patients.

Prevention of acquisition  — Because S. aureus was often noted to infect CF patients prior to the appearance of P. aeruginosa, it was hypothesized that damage from S. aureus might cause the CF airway to be more susceptible to P. aeruginosa. If so, chronic prevention or suppression of S. aureus infection might reduce the frequency of P. aeruginosa and preserve airway function [ 119 ].

To test this hypothesis, a randomized trial of oral cephalexin was performed in young children [ 120 ]. Cephalexin or placebo was started at the time of CF diagnosis and administered continuously for seven years. Cephalexin was successful in reducing the prevalence of S. aureus infection, but the incidence of P. aeruginosa infection actually increased, and there was no evidence of overall clinical benefit.

A separate randomized trial evaluated the effects of treating children without P. aeruginosa infection with cycles of oral ciprofloxacin and inhaled colistin [ 121]. Three-week courses of

these medications were administered every three months for three years. At the end of the three-year trial, there was no difference between rates of initial or chronic P. aeruginosa infection among children who had received this intervention as compared with controls.

Early eradication of P. aeruginosa  — The Cystic Fibrosis Center in Copenhagen, Denmark has adopted a policy of performing monthly sputum cultures for all patients with cystic fibrosis (CF) [ 122,123 ]. When P. aeruginosa is first isolated, oral ciprofloxacin and aerosolized colistin are begun. The treatment is repeated and prolonged if P. aeruginosa is not eradicated or if it reappears after treatment. When the clinical status of patients treated with this protocol was compared with historical data from the same center, pulmonary function tests were better, the time to permanent acquisition with P. aeruginosa was delayed, and the overall prevalence of P. aeruginosa infection in their center was reduced.

The results from these and other small studies have led the majority of CF centers including our own to use antibiotic protocols targeting P. aeruginosa when it is first identified in respiratory secretions, regardless of the patient’s clinical signs or symptoms [ 124 ]. Small studies have shown that the permanent acquisition of P. aeruginosa can be delayed, and one reported that eradication was associated with sustained improvement in two biochemical measures of inflammation [ 125 ]. Nonetheless, the long-term outcomes from such efforts to achieve early eradication are unknown.

Although a variety of antibiotic protocols have been used for early eradication, current evidence supports the use of inhaled tobramycin alone to treat patients for newly acquired P. aeruginosa:

In one trial 88 subjects who had recently acquired P. aeruginosa were given inhaled tobramycin , 300 mg twice daily, for either 28 or 56 days [ 126 ]. More than 90 percent of the patients in both arms had negative cultures for P. aeruginosa one month after the end of treatment, and more than half of these continued to have negative cultures when followed for up to 27 months. There was no significant difference in outcomes among patients treated for 28 versus 56 days, suggesting that the shorter course of treatment may be sufficient.

A small, uncontrolled study of 15 patients who had new infection with P. aeruginosa showed that inhaled tobramycin (80 mg twice daily for 12 months) eliminated P. aeruginosa from throat cultures in 14 of the patients [ 127 ]. The authors concluded that this treatment had a beneficial effect based upon persistent negative cultures at one year, absence of serum antibodies to P. aeruginosa, and maintenance of stable pulmonary function tests for two years after therapy was completed.

In a multicenter trial, 304 children with newly acquired P. aeruginosa were treated with inhaled tobramycin for 28 days, with or without concomitant oralciprofloxacin [ 128 ]. After the first cycle of treatment, only 13 percent of children tested positive for P. aeruginosa, and there was no apparent advantage to including ciprofloxacin in the treatment regimen. During the subsequent 18 months, the rate of pulmonary exacerbations was 16 percent and was no different for subjects re-treated with scheduled courses of antibiotics every three months, as compared with those treated only when surveillance cultures again became positive for P. aeruginosa.

Supported by these results, we suggest using a protocol to detect and treat P. aeruginosa when it is first acquired. We perform cultures of expectorated sputum or throat swabs every

three months during routine clinic visits. When P. aeruginosa is first detected, we recommend treatment with inhaledtobramycin alone (300 mg in 5 mL, administered twice daily) for 28 days rather than a regimen including ciprofloxacin or other antibiotics. The therapy is repeated only if surveillance cultures show recurrence of P. aeruginosa.    

Nontuberculous mycobacteria  — Nontuberculous mycobacteria (NTM) can be isolated from the sputum in approximately 13 percent of patients with CF [129,130 ]. Mycobacterium avium complex is identified in up to 59 to 75 percent of these patients; the other frequently identified pathogen is M. abscessus, which grows rapidly in culture and is found in up to 16 to 41 percent of NTM-positive patients with CF [ 130-132 ]. (See "Epidemiology of nontuberculous mycobacterial infections" and "Microbiology of nontuberculous mycobacteria" .)

The clinical implications of detecting NTM in sputum samples of patients with CF are quite variable. However, on average the rate of decline in forced expiratory volume at one minute (FEV1) is greater in patients infected with M. abscessus than a control population [ 132 ]. The impact appears to be less in patients with other NTM [ 130,132,133 ].

Clinically important invasive mycobacterial disease occurs in a subset of patients, causing systemic symptoms, deteriorating pulmonary function, and the appearance of nodular infiltrates and/or parenchymal cavities on chest radiograph or high resolution chest computed tomography (HRCT). For these patients, we recommend the following approach, which was suggested by the NTM CF study group [ 134 ]:

Once NTM is identified in respiratory secretions, serial studies should be obtained to determine if the American Thoracic Society microbiologic criteria for NTM disease are fulfilled [ 133 ]. (See "Overview of nontuberculous mycobacterial infections in HIV-negative patients", section on 'Diagnostic criteria for pulmonary disease' .)

If the microbiologic criteria for NTM are fulfilled, a HRCT of the chest should be obtained to detect nodules or cavities.

If nodules or cavities are present, or if the patient is experiencing deterioration in pulmonary status despite intensified treatment for non-NTM bacteria that commonly infect CF airways, treatment directed at the NTM should be seriously considered.

Unfortunately, eradication of the NTM from airway secretions of CF patients is difficult to achieve, particularly in those infected with M. abscessus [ 131 ]. There is no specific evidence to suggest that NTM in patients with CF should be treated differently from NTM in other patients [ 135 ]. (See "Overview of nontuberculous mycobacterial infections in HIV-negative patients" and "Treatment of nontuberculous mycobacterial infections of the lung in HIV-negative patients" .)

Infection with M. avium complex appears to have no adverse impact on patients with CF who undergo lung transplantation [ 136,137 ]. However, M. abscessus infection can complicate lung transplantation causing soft tissue and mediastinal abscesses that can recur despite treatment with surgical drainage and antibiotics.

Aspergillus species  — Cultures of sputum from patients with CF often yield Aspergillus species. Two studies suggest that for most patients without allergic symptoms, the presence of Aspergillus does not seem to affect the clinical course [ 138,139 ]. However, a third study

found that persistently positive cultures for Aspergillus species is associated with reduced pulmonary function and more pulmonary exacerbations requiring hospitalization [ 140 ]. It is not clear whether this association is causal or whether aspergillus is merely a marker of more severe lung disease. Therefore, we recommend no special treatment except when criteria are met for allergic bronchopulmonary aspergillosis (ABPA) or an aspergilloma [ 141-143 ]. (See "Allergic bronchopulmonary aspergillosis", section on 'ABPA in cystic fibrosis' and "Treatment of chronic pulmonary aspergillosis" .) Also, some transplant centers recommend suppression of aspergillus with itraconazole or voriconazole for infected patients who are on the waiting list for lung transplant.

INFECTION CONTROL  — Burkholderia cepacia complex organisms are occasionally transmitted between cystic fibrosis (CF) patients [ 144-147 ]. Sporadic outbreaks of infection have been linked to contaminated sink drains, nebulized medications, and soil [ 145,148,149 ]. The most appropriate method to prevent acquisition of Burkholderia cepacia complex bacteria is to limit patient-to-patient transmission by minimizing physical contact between CF patients and scrupulously adhering to standard isolation precautions. Highly transmissible strains of P. aeruginosa also have been reported in Europe, Canada, and Australia [ 150 ], and infection with these strains is associated with increased health care needs and antibiotic use as compared with infection with sporadic strains [11,151 ].  

General and specific infection control measures have been proposed to limit the spread of infection within this population ( table 4A-B ) [ 6,34,152 ]. (See"General principles of infection control" .)

PREVENTIVE CARE  — Inflammation induced by viral upper respiratory tract infections appears to initiate exacerbations of cystic fibrosis (CF) lung disease. Thus, all patients with CF should receive annual immunization against influenza beginning at 6 months of age, unless a patient has strong contraindications to use of the vaccine. Administration of the pneumococcal vaccine also is recommended. Although patients with CF become infected with Streptococcus pneumoniae only rarely, the availability and safety of the vaccine make its use advisable in this population. The role of Palivizumab for prevention of respiratory syncytial virus infection in young children with CF has not been established, as discussed separately. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Vaccinations and palivizumab' .)  

INFORMATION FOR PATIENTS  — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topic (see "Patient information: Cystic fibrosis (The Basics)" )

SUMMARY AND RECOMMENDATIONS

Cystic fibrosis (CF) lung disease is characterized by persistent bacterial infection; Staphylococcus aureus and Pseudomonas aeruginosa (P. aeruginosa) are the most prevalent pathogens ( figure 2 ). (See 'Pathogens' above.)

The clinical course is frequently complicated by acute pulmonary exacerbations, superimposed on a gradual decline in pulmonary function. Exacerbations are treated with antibiotics, given either orally or intravenously depending on the severity of the exacerbation, and on the sensitivities of the infecting bacteria ( table 2 ). Current practice is to select at least one antibiotic to cover each bacterial isolate that is cultured from respiratory secretions, and two antibiotics for P. aeruginosa infections, if possible. We typically treat P. aeruginosa with piperacillin-tazobactam , ticarcillin-clavulanate ,ceftazidime , imipenem-cilastin, or meropenem , PLUS one of the following: tobramycin , amikacin , or a fluoroquinolone (eg, ciprofloxacin ), depending on antibiotic susceptibility test results. (See 'Antibiotic selection' above.)      

The pharmacokinetics of many antibiotics differs in patients with CF as compared with normal individuals. Patients with CF generally require larger and/ormore frequent dosing for penicillins, cephalosporins, sulfonamides, and fluoroquinolones. Starting doses of aminoglycosides should also be larger than those recommended for individuals without CF, but dosing must be adjusted based on pharmacokinetic analysis of serum levels because of considerable interindividual variation in clearance rates. (See 'Dosing' above.)

In the absence of an acute pulmonary exacerbation, we generally suggest not administering chronic or intermittent systemic antibiotics to patients with CF ( Grade 2C ), EXCEPT for the following:

We recommend the chronic use of azithromycin for patients 6 years and older who have clinical evidence of airway inflammation such as chronic cough or any reduction in forced expiratory volume at one minute (FEV1), regardless of the patient’s P. aeruginosa infection status ( Grade 1B ).  To avoid induction of antibiotic resistance, azithromycin should not be given to patients infected with nontuberculous mycobacteria. (See 'Chronic oral antibiotics'above and "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Macrolide antibiotics' .)    

For patients older than 6 years with persistent P. aeruginosa infection and moderate or severe lung disease, we recommend chronic treatment with inhaled tobramycin ( Grade 1A ). We also suggest this treatment for patients with mild lung disease and persistent P. aeruginosa infection ( Grade 2B ). Inhaled aztreonam lysine is a reasonable alternative for some patients. Either inhaled tobramycin or aztreonam lysine are given for one month, on alternate months. (See 'Aerosolized antibiotics' above.)

We suggest not scheduling elective hospitalizations for antibiotics and intensified chest physiotherapy ("clean out") ( Grade 2C ). (See 'Periodic hospitalization' above.)

We suggest using a protocol to detect and treat P. aeruginosa when it is first acquired ( Grade 2B ). Cultures of expectorated sputum or throat swabs are performed every three months during routine clinic visits. When P. aeruginosa is first detected, we recommend treatment with inhaled tobramycinalone (300 mg in 5 mL, administered twice daily) for 28 days rather than a regimen including other

antibiotics ( Grade 1B ). The therapy is repeated only if surveillance cultures show recurrence of P. aeruginosa. (See 'Early eradication of P. aeruginosa' above.)

In addition to antibiotics, optimal care for pulmonary disease in cystic fibrosis includes measures to promote airway clearance and to reduce bronchial obstruction and inflammation. Airway clearance therapies should be intensified during an acute pulmonary exacerbation. These approaches are discussed separately. (See "Cystic fibrosis: Overview of the treatment of lung disease" .)

Cystic fibrosis: Assessment and management of pancreatic insufficiencyINTRODUCTION  — Pancreatic insufficiency is the most common gastrointestinal complication of cystic fibrosis (CF), affecting approximately 85 percent of patients at some time in their lives [ 1 ]. The major consequences of pancreatic insufficiency are due to fat malabsorption, which is caused by decreased production of pancreatic enzymes. As a result, patients are at risk for steatorrhea, malnutrition, and fat-soluble vitamin deficiencies.

The pathogenesis, clinical manifestations, diagnosis, and management of pancreatic insufficiency in children with CF will be discussed here. The nutritional consequences of this disorder and other gastrointestinal complications of CF are discussed separately. (See "Cystic fibrosis: Nutritional issues" and "Cystic fibrosis: Overview of gastrointestinal disease" .)

EPIDEMIOLOGY  — Traditionally, patients with CF have been categorized as pancreatic sufficient (10 to 15 percent) and pancreatic insufficient (the remainder) [ 2 ]. It is now clear that pancreatic function in CF varies along a spectrum from normal to severely deficient. Patients with normal or near normal pancreatic function tend to have less severe lung disease, and their nutritional status is better than their counterparts who have more severe pancreatic dysfunction. Pancreatic function also varies with the age of the patient, tending to worsen over time.

Pancreatic function correlates strongly with genotype in patients with cystic fibrosis. Pancreatic insufficiency generally develops within the first few months of life in patients with two class I or II Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations; these classes of mutation are characterized by defective production or processing of the CFTR protein, and include delta F508, N1303K, G542X, G551D and others [ 3 ]. The presence of at least one "mild" mutation (such as R117H, 3171insC, A155P2, 138insL, 296 +IG-A, E92GK, E217G, 2789 +5G-A, or 3849 +10kbC-T and others) is generally associated with pancreatic sufficiency; however, patients with one "mild" mutation may still develop pancreatic insufficiency [ 4,5 ]. (See "Cystic fibrosis: Genetics and pathogenesis" .)

PATHOGENESIS  — Defective functioning of the CFTR leads to impaired transport of chloride and sodium. As a result, water does not diffuse out of the cell into the mucus layer, leading to viscous epithelial secretions. The resultant protein-rich, viscous exocrine fluid becomes inspissated in the proximal pancreatic ducts, leading to their obstruction.

Pancreatic duct obstruction begins as early as the mid-trimester of gestation. The functioning acinar cells are gradually replaced with adipose tissue and, later, with fibrotic tissue. Patients with pancreatic insufficiency have decreased or absent levels of pancreatic

amylase, lipase, colipase, and phospholipases. However, they have increased or normal production of salivary and brush border amylases, brush border peptidases, and lingual lipases, which account for increased monosaccharide absorption, increased amino acid absorption, and some residual lipolysis, respectively [ 1 ]. Because of the CFTR mutation, patients with CF also have decreased amounts of bicarbonate in their pancreatic secretions, which may further contribute to the enzyme deficiency since remaining enzymes may not function optimally in an acidic environment [ 1 ].

In addition, patients with CF may have primary abnormalities in fatty acid metabolism, as have been noted in biopsies of CFTR-expressing tissues [ 6 ]. These changes, which result in increased tissue levels of arachidonic acid, are also present in the mouse model of CF.

CLINICAL MANIFESTATIONS  — Approximately two-thirds of infants with CF have pancreatic insufficiency at birth [ 7 ]. If CF is not diagnosed through newborn screening, it will usually be diagnosed because of failure to thrive, protein-calorie malnutrition, or rectal prolapse, typically presenting before the age of one year [ 8 ]. Even individuals with relatively normal pancreatic function at birth will usually develop pancreatic dysfunction and insufficiency over time, but clinically apparent protein and fat deficiencies do not occur until over 90 percent of pancreatic function is lost.

Patients with pancreatic insufficiency characteristically have frequent, bulky, foul-smelling stools that may be oily. Older children may also report that their stools float (reflecting their high fat content). These features may not be as evident in infants since they have wide variation in stool patterns at baseline [ 7]. Abdominal distention may also be present [ 9 ]. These characteristics, all suggestive of fat malabsorption, are not specific to pancreatic insufficiency due to CF; they can also be seen in patients with small bowel mucosal disease, and other causes of pancreatic insufficiency [ 7 ]. Moreover, these symptoms are subjective and nonspecific, so laboratory testing should usually be performed to determine if fat malabsorption is present. (See 'Diagnosis' below.)

Fat malabsorption can develop at variable time points in the course of CF. As a result, patients with CF may require modification of their therapy as the disease progresses. It is imperative that the clinician inquire about signs and symptoms of pancreatic insufficiency at every visit. Patients who are considered to be pancreatic sufficient should undergo laboratory screening (eg, fecal elastase and serum levels of fat-soluble vitamins) periodically to assess fat absorption [ 8 ].

Individuals with cystic fibrosis involving the pancreas also may develop pancreatic endocrine insufficiency, causing CF related diabetes. Others may develop pancreatitis, which is most common among patients with pancreatic sufficiency at diagnosis. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'CF-related diabetes' and "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatitis' .)

DIAGNOSIS  — Because a variety of factors can contribute to growth failure and abdominal symptoms, we suggest an objective assessment of pancreatic insufficiency (eg, fecal elastase testing) to document the need for pancreatic enzyme replacement therapy (PERT). This approach is particularly appropriate for patients identified by newborn screening

programs [ 10 ]. Approximately 60 percent of infants with CF have pancreatic insufficiency at birth, and 90 percent have developed pancreatic insufficiency by one year of age [ 11 ].

For patients with CF and typical symptoms of pancreatic insufficiency (growth failure and symptoms of steatorrhea), or for those with two CFTR mutations known to be associated with pancreatic insufficiency, it is reasonable to begin PERT therapy prior to formal documentation of pancreatic insufficiency [ 10] (see 'Epidemiology' above). In this case, pancreatic insufficiency should be confirmed after starting PERT therapy. If such patients do not respond to PERT treatment, alternate causes of abdominal symptoms, including the possibility of constipation or small intestine bacterial overgrowth, should be sought and treated.

Individuals with normal fecal elastase or fecal fat testing and no clinical evidence of malabsorption do not require PERT. In particular, patients with one or two CFTR mutations known to be associated with pancreatic sufficiency should not be given PERT unless there is clear evidence of fat malabsorption [ 10 ] (see'Epidemiology' above). Because pancreatic insufficiency may develop over time, these patients should be monitored with periodic measurements of fecal elastase and for clinical symptoms of fat malabsorption [ 12 ].

Fecal elastase  — Measurements of fecal elastase provide a useful index of exocrine pancreatic function [ 2,13,14 ]. We suggest that this test be performed for each patient with CF to help determine the need for pancreatic enzyme replacement therapy (PERT). Because it is not a quantitative test, it is not valuable as a measure to monitor the effectiveness of PERT [ 2 ].

Fecal elastase values less than 200 micrograms/gram indicate pancreatic insufficiency [ 10,12 ]. Fecal elastase testing has high sensitivity and specificity in detecting severe pancreatic insufficiency in children with CF. However, the test performs less well for detecting mild or moderate pancreatic insufficiency, and also displays variability with repeat testing in this type of patient [ 15,16 ]. Thus, results of fecal elastase testing should be combined with clinical observations, including nutritional status and symptoms of steatorrhea, to determine the need for PERT.

Determination of fecal elastase can be performed on a single stool sample that requires no special storage, and does not require discontinuation of pancreatic enzymes. Thus, it is more clinically practical than a 72-hour collection of fecal fat or secretin stimulation tests, which are discussed below.

The results of fecal elastase testing correlate well with the secretin stimulation test [ 17 ]. The sensitivity and specificity of fecal elastase in detecting severe pancreatic insufficiency in children with CF range from 89 to 100 percent and 86 to 100 percent, respectively, depending upon the cut-off values (<100 versus <200 mcg/g stool) and the gold-standard for diagnosis (eg, secretin stimulation, fecal fat collection, clinical evaluation) [ 14,17-20 ].

Other tests  — There are two approaches for the diagnosis of pancreatic insufficiency, which can be categorized as direct and indirect tests. The direct tests are more accurate across the entire range of pancreatic function but are invasive and expensive [ 9,13 ]. The diagnostic accuracy of these tests is discussed in greater detail separately. (See "Pancreatic exocrine function tests" .)

Direct tests involve the collection of duodenal aspirates after stimulation of the pancreas with a secretagogue, such as secretin . The basis for this test is that secretin causes the secretion of bicarbonate-rich fluid from the pancreas. A peak bicarbonate concentration of less than 80 mEq/L is consistent with pancreatic exocrine insufficiency.

Indirect tests are performed on stool samples to measure the concentrations of pancreatic enzymes, such as trypsin, chymotrypsin, and elastase or fat. The most commonly used indirect test is the collection of a 72-hour stool sample with a careful dietary inventory ( table 1 ). Fecal fat excretion is considered abnormal if it is more than 7 percent of the fat intake [ 8,9 ]. For infants under 6 months of age, fecal fat excretion of up to 15 percent of total fat intake can be normal [ 10 ]. (See "Clinical features and diagnosis of malabsorption" .) 

Although measurement of 72-hour fecal fat excretion is the most commonly used indirect test, it is not ideal [ 2 ]. The 72 hour stool collection procedure is onerous for most patients, and PERT must be discontinued during the collection period. Furthermore, the test does not distinguish between hepatobiliary, mucosal, and pancreatic causes of fat malabsorption. 

Because of these considerations, measurement of fecal elastase, chymotrypsin, or lipase are frequently used. These tests can be performed on single samples of stool. Fecal elastase appears to be the most sensitive of these tests [ 21,22 ]. (See 'Fecal elastase' above.)

MANAGEMENT

Pancreatic enzyme replacement therapy  — The mainstay of treatment for pancreatic insufficiency in CF is pancreatic enzyme replacement therapy (PERT). Multiple formulations of pancreatic enzymes exist with different combinations of lipase, protease, and amylase ( table 2 ). Preparations with equivalent doses of enzymes may still differ in their effects. Patients should be reevaluated after any changes in the enzyme preparation or dose. The guidelines endorsed by the CF foundation do not recommend use of generic or non-proprietary preparations [ 10,23 ]. Individual product contents, preparation type, and units of activity vary by country, so local product information should be consulted before using or changing products. (See "Pancrelipase: Pediatric drug information" .)  

Pancreatic enzymes are extracts of porcine pancreas containing varying amounts of lipase, protease, and amylase. Most enzyme preparations are in the form of granules or microspheres that are coated with a pH-sensitive material that protects the enzyme from destruction by acid in the stomach ( table 2 ). The coating dissolves in the alkaline milieu of the duodenum, releasing the enzyme [ 24 ].

PERT clearly improves fecal fat absorption in most patients with pancreatic insufficiency. This was demonstrated by a double-blind placebo-controlled trial in which PERT increased the coefficient of fat absorption (CFA), decreased stool frequency, and improved stool consistency in both adult and pediatric patients with CF [ 25 ]. The effectiveness of PERT in an individual patient may be limited by variations in the pH of the gastrointestinal tract in CF from patient to patient and also varies over time in the same patient.

Dosing considerations  — Most pancreatic enzyme preparations consist of capsules containing microspheres. Older children and adults generally swallow the capsule whole. For

younger children and infants, enzymes are administered by opening the capsule and sprinkling the microspheres on food. The food should be soft so that it does not require chewing, and should be relatively acidic to avoid dissolving the enteric coating (eg, applesauce, gelatins, pureed apricot, bananas, or sweet potatoes).

Dosing of pancreatic enzymes is based upon the units of lipase determined as a function of patient weight or dietary fat intake.

The weight-based method can generally be used at any age. The starting dose for children less than four years of age is 1000 lipase units/kg body weight per meal, and for children older than four years of age is 500 lipase units/kg body weight per meal [ 23,26,27 ]. Smaller doses usually are offered with fat-containing snacks eaten between meals. Dosing is increased based upon symptoms of pancreatic insufficiency to a maximum of 2500 lipaseunits/kg body weight per meal to avoid fibrosing colonopathy.

The fat-based method is useful for infants who take a known amount of formula or in patients who receive tube feedings. The dose starts at approximately 2000 lipase units/120 ml of formula or per breast feeding (about 1600 lipase units/gram of fat ingested per day). The dose can be adjusted up to no more than 2,500 lipase units per kg body weight per feeding, with a maximum daily dose of 10,000 lipase units per kg [ 10 ].

Patients who fail to respond to maximal doses of supplemental pancreatic enzymes may benefit from reduction of gastric acidity by addition of histamine 2 receptor antagonists, such as ranitidine . The reason for this improvement is that some enzyme products require a higher pH for the entire product to be released [ 28 ], but the practice is based on limited evidence [ 29 ].

Adjustment of PERT doses is typically guided by patient-reported symptoms of malabsorption, such as diarrhea (foul smelling, greasy, bulky stools), bloating, gassiness, and abdominal pain. Unfortunately, symptoms do not correlate well with the efficacy of PERT in individual patients [ 30,31 ]. Thus, if PERT dosing appears to be adequate, alternate causes of abdominal symptoms, including the possibility of constipation or small intestine bacterial overgrowth, should be sought and treated. There is no evidence that constipation is caused by higher enzyme doses.

There are no accurate and clinically practical laboratory methods for quantifying fat malabsorption. The 72-hour fecal fat determination is currently the only clinical method of quantifying fat malabsorption ( table 1 ), but this technique is seldom used because it is tedious and unpleasant for caretakers, and results are not particularly accurate.

Adverse effects  — Prolonged contact of the enzyme supplements with oral mucosa may cause ulcers, especially with the powdered form. Thus, the microspheres should preferably be administered with food (eg, applesauce), even in infants. To further prevent this complication, the mouth should be rinsed after administration, particularly in infants [ 28 ].

Excessive doses of PERT can cause fibrosing colonopathy, characterized by inflammation and strictures. The risk can be reduced significantly by limiting the dose of supplemental pancreatic enzymes to less than 2500 lipase units/kg body weight per meal, or less than 10,000 lipase units/kg body weight per day [27,31 ].

COMPLICATIONS

Growth failure  — Pancreatic insufficiency in CF may cause malabsorption of fat and other macronutrients, which is particularly problematic because the disease may also cause increased energy requirements. Thus it is imperative that growth parameters are followed closely. Weight, and length or height are measured every three months in all patients, and weight/length or body mass index (BMI) is calculated; mid-arm circumference and triceps skin-fold thickness is also measured annually in children over one year of age, and head circumference is monitored every three months in those younger than two years of age (table 3 ). (See "Cystic fibrosis: Nutritional issues", section on 'Assessing and monitoring nutrition' .)

Many patients with CF require dietary supplementation either by mouth or by tube feeds to maintain adequate nutrition [ 28 ]. (See "Cystic fibrosis: Nutritional issues", section on 'Nutrition support' .)

Fat-soluble vitamin deficiencies  — Pancreatic insufficiency and CF-related liver disease lead to fat malabsorption that predisposes patients to deficiencies of the fat-soluble vitamins: vitamins A, D, E, and K. Requirements for these nutrients and monitoring recommendations for patients with CF are discussed in detail separately. (See "Cystic fibrosis: Nutritional issues", section on 'Fat soluble vitamins' .)

Bone disease  — Bone disease, characterized by decreased mineral density, increased fracture rates, and kyphosis is common in patients with cystic fibrosis, even among those with pancreatic sufficiency. Important contributors to the problem include malabsorption of calcium, magnesium, and fat-soluble vitamins (vitamin D and possibly vitamin K). (See "Cystic fibrosis: Nutritional issues", section on 'Bone disease' .)

INFORMATION FOR PATIENTS  — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topic (see "Patient information: Cystic fibrosis (The Basics)" )

SUMMARY AND RECOMMENDATIONS

Most patients with CF have some degree of pancreatic exocrine dysfunction. This problem tends to worsen over time, and at least 85 percent develop clinically important pancreatic insufficiency. (See 'Epidemiology' above.)

All patients with CF should be screened for pancreatic insufficiency; this is generally done with fecal elastase testing. Those with normal results should be retested periodically to monitor for development of pancreatic insufficiency. (See 'Diagnosis' above.)

Patients with pancreatic insufficiency (as determined by fecal elastase testing or other measure) should be treated with pancreatic enzyme replacement therapy (PERT) ( table 2 ). Dosing is generally estimated by the patient's weight and adjusted depending on the patient's response and symptoms. (See'Dosing considerations' above.)

Prolonged contact of the enzyme supplements with oral mucosa may cause ulcers and should be avoided. PERT doses should be limited to 2500 lipaseunits/kg body weight per meal to avoid fibrosing colonopathy. (See 'Adverse effects' above.)

Even with optimal management, patients with pancreatic insufficiency are at risk for growth failure, deficiencies of fat-soluble vitamins and other micronutrients, and bone disease. Prevention and monitoring for these complications is discussed separately. (See 'Complications' above and "Cystic fibrosis: Nutritional issues" .)

Cystic fibrosis: Nutritional issuesINTRODUCTION  — Children and adolescents with cystic fibrosis (CF) frequently have growth failure, caused by the combination of malabsorption, increased energy needs, and reduced appetite. Nutrient delivery and correction of maldigestion and malabsorption are essential to achieve normal growth to support optimal pulmonary function and to prolong life.

The CF Foundation (CFF) patient registry has documented substantial improvement in life expectancy of patients with CF ( figure 1 ) [ 1 ]. To a large degree, the longer life achieved by patients with CF can be ascribed to improved treatment of lung disease, pulmonary toilet, potent and tailored antibiotics, DNAse, and lung transplantation. However, greater emphasis on CF nutrition is considered important to improve longevity and quality of life. As a result, the CFF created a consensus report on nutrition in pediatric CF [ 2 ], and a more theoretic report on gastrointestinal outcomes and confounders in CF [ 3 ].

The evaluation, monitoring, and treatment of nutritional problems will be addressed here. The diagnosis and management of CF-related pancreatic insufficiency, and screening for CF related comorbidities that affect nutritional status will also be discussed briefly here and in detail separately. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency" and "Cystic fibrosis: Overview of gastrointestinal disease" .)

PATHOPHYSIOLOGY  — CF is caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR), a cell membrane protein that forms a chloride channel and that regulates chloride and water flux [ 4 ]. The spectrum of CF disease varies according to the genotype and with individual and environmental factors. The nutritional risks and requirements for a patient with CF also vary along this disease spectrum but do not precisely coincide with the severity of pulmonary disease.

Insufficient production of pancreatic enzymes (pancreatic insufficiency) causes malabsorption of fat, protein, and several micronutrients including the vitamins A, D, E, and K. Malabsorption of fat is exacerbated by bile salt abnormalities if there is concurrent liver disease. Pancreatic function tends to worsen with age. Across all age groups, about 90

percent of patients with CF have marked pancreatic insufficiency. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency" .)

Although pancreatic dysfunction is the major gastrointestinal contributor to malnutrition in CF, several other factors may contribute to the problem. These include CF-related liver disease, bile salt abnormalities, CF-related diabetes mellitus, altered gastrointestinal motility, and small bowel bacterial overgrowth. Gastroesophageal reflux, distal intestinal obstructive syndrome, and constipation can also negatively affect nutrition. (See "Cystic fibrosis: Overview of gastrointestinal disease" .)

In addition to malabsorption and gastrointestinal dysfunction, two other mechanisms contribute to nutritional deficiencies and growth failure in patients with CF: chronic, progressive pulmonary infection with bronchiectasis leads to increased work of breathing and higher than expected nutrient needs [ 5 ], and chronic infection may reduce appetite and cause cytokine-induced catabolism [ 6 ].

PANCREATIC INSUFFICIENCY  — Pancreatic insufficiency is a major contributor to nutritional problems in patients with CF. The diagnosis and management of pancreatic insufficiency in this population, including strategies for pancreatic enzyme replacement, are discussed separately. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency" .)

The nutritional problems that may be caused by pancreatic insufficiency, including growth failure, fat-soluble vitamin deficiencies, and bone disease, are addressed below.

ASSESSING AND MONITORING NUTRITION  — The most effective way to maintain good nutrition status in CF, as in other chronic diseases, is to prevent suboptimal nutrition from occurring.

Growth  — The nutritional status of individuals with CF tends to decline during childhood. Data from the Cystic fibrosis Foundation (CFF) shows that the body mass index (BMI) percentile typically begins to decline at about five years of age but does not cross the 50th percentile (defined as "below BMI goal") until about nine years of age ( figure 2 ) [ 1,2 ].

Careful and repeated nutritional assessments allow for early detection of nutritional deterioration. The CFF recommends that children with CF be seen at three monthly intervals. A thorough dietary history and measurements of height and weight should be performed at each visit. Additional measures are tracked according to a schedule for nutrition assessment ( table 1 ).

Each patient's height, weight, and BMI should be tracked against standard curves provided by the Center for Disease Control and Prevention (file://www.cdc.gov/growthcharts ). For children under two years of age, recumbent length is tracked rather than height, and weight/length is used instead of BMI. (See "Measurement of growth in children", section on 'CDC growth reference' .)

For children with CF, the BMI target range is above the 50th percentile [ 1,7 ]. Children with BMIs between the 10th and 50th percentiles are generally considered at nutritional risk, and those with BMIs below the 10th percentile are in need of nutritional rehabilitation, although we would not intervene for children in the upper end of this range. Children with BMIs above

the 85th percentile are considered overweight [ 8 ]. There are rare CF patients who are overweight and even obese [ 8 ]. For children younger than two years of age, the same percentile criteria are applied to weight-for-height rather than BMI. For adults with CF, the target is a BMI at or above 22 for women, and 23 for men [ 7 ].

Another important indicator of nutritional sufficiency is the achievement of full genetic potential for height. This can be estimated by a variety of methods, one of which is the mid-parental target height prediction ( calculator 1 ). This and other methods for calculating height potential are discussed separately. (See "Diagnostic approach to short stature", section on 'Prediction of height potential' .)

Anticipatory guidance to optimize nutrition should be provided to all children with CF. Those who do not meet target goals for BMI, whose linear growth is less than expected for their genetic potential, or whose growth rates begin to plateau require additional attention. These patients should be given intensive counseling to optimize nutrition. They should also be further evaluated to identify reasons for nutritional deficits and potential contributors to malnutrition, including inadequate pancreatic enzyme replacement therapy and small bowel bacterial overgrowth. (See 'Pathophysiology' above.)

As soon as a decline in growth parameters is documented, intervention should begin. (See 'Nutrition support' below.)

Blood tests  — Several laboratory tests are recommended as part of the evaluation for nutritional status. The CFF has developed a panel of recommended tests and testing intervals ( table 2 ) [ 2,9 ].

Evaluation for comorbidities

Bone disease  — Bone disease, characterized by decreased mineral density, increased fracture rates, and kyphosis, is common in patients with cystic fibrosis, even among those with pancreatic sufficiency [ 10,11 ]. Sixty percent of young adults have a kyphosis angle of >40 degrees, contributing to height loss (mean 5.9 cm), chest wall deformities, and reduced lung function [ 12 ]. Children and adolescents with CF also have higher than expected rates of fractures [ 13 ]. In a meta-analysis of studies of adults with CF (median age 28 years), the pooled prevalence of vertebral and non-vertebral fractures were 14 percent and 20 percent, respectively [ 14 ].

Patients with CF have the following multiple risk factors for developing bone disease [ 15 ]:

Failure to thrive Delayed pubertal development Malabsorption of calcium, magnesium, vitamin D, and vitamin K Hepatobiliary disease Reduced weight-bearing activity Chronic corticosteroid use Inadequate intake of nutrients

The risk for bone disease increases with advancing age and severity of lung disease and malnutrition. As an example, the average bone density of adults with severe CF-related

pulmonary disease is more than 2 SD below the expected value, and vertebral compression and other pathological fractures are common [12 ].

To monitor for bone health, children with CF should have yearly determination of calcium, phosphorus, intact parathyroid hormone, and 25 hydroxyvitamin D levels ( table 2 ) [ 11 ]. In addition, children older than eight years should have an evaluation of bone density using dual-energy X-ray absorptiometry (DXA) if risk factors are present (eg, BMI <10 th percentile for age, FEV1 <50 percent predicted, glucocorticoid use of ≥5 mg daily for ≥90 days/year, delayed puberty, or a history of fractures).

DXA scanning is now widely available. Standards have been developed for the pediatric age group, and the findings are expressed as Z-scores to reflect age-specific standards (rather than T-scores as in adults). However, interpretation remains problematic, and requires adjustment for bone size and pubertal status; the unadjusted DXA Z-score for age and gender may systematically underestimate bone density in shorter patients [ 16 ]. (See "Overview of dual-energy x-ray absorptiometry", section on 'Children' .)

All individuals with CF should be counseled to ensure that intake of the recommended amounts of calcium, phosphorus, vitamin K, and vitamin D is achieved to support bone health ( table 3 and table 4 ). Weightbearing exercise should be encouraged and low levels of vitamin D or vitamin K should be treated aggressively. (See 'Vitamin D' below and 'Vitamin K' below.)

In our practice, we take the following additional measures depending on the results of the DXA scanning:

If the DXA scan shows bone density within a healthy range (Z-score ≥-1), we repeat the DXA scan every two years in growing children. The interval could be increased to every five years for adults with initial results in a healthy range [ 11 ].

If the DXA scan shows borderline bone mineral density (Z-score -1 to -2), additional measures are taken to diagnose and treat any endocrine contributors to the bone disease (CF related diabetes, hypogonadism) and to minimize use of glucocorticoid medications. Additional low-impact, weight-bearing exercise is encouraged. Patients receive supplemental calcium, phosphorus and vitamin D ( table 3 and table 4 ). DXA scans are repeated annually in growing children, and every two to four years in adults.

If the DXA scan shows markedly decreased bone mineral density (Z-score ≤-2), vitamin D, phosphorus, and calcium status are reviewed and vigorously replaced, in addition to the other measures described above. DXA scans are repeated annually until normalized.

Some groups have suggested that bisphosphonate treatment be considered for CF patients with markedly decreased bone mineral density [ 11 ]. Bisphosphonates are essentially anti-reabsorptive agents. Although the exact mechanism of low bone density in CF is not known, in growing children with CF the problem may be decreased bone formation rather than increased reabsorption. Giving bisphosphonates in this setting would lead to slow bone turnover. Moreover, there are increasing concerns about the use of bisphosphonates in children, because these agents form bone with abnormal characteristics, have extremely long half-lives, and the long-term risks and benefits have not been fully explored [ 17 ]. For these reasons, we do not use bisphosphonates for children or adolescents in our practice.

There is some evidence to support the use of bisphosphonates in adult patients with CF and bone disease. In a systematic review that included 237 adult subjects, oral and intravenous bisphosphonate treatment improved bone mineral density by 5 to 8 percent at several sites over 24 months of therapy [ 18 ]. However, fracture rates were not different between treated and untreated individuals. Intravenous administration of bisphosphonates was associated with severe bone pain and flu-like symptoms. Larger trials will be needed to determine if there are effects on fracture rates.

Pulmonary function testing  — Pulmonary function testing (PFT) is not a measure of nutritional status, but there is a close correlation between PFT results and nutritional status ( figure 3 ). It is unclear whether worsening lung function causes nutritional deterioration (by decreasing intake or by increasing requirements) or whether deteriorating nutritional status causes poor performance on PFT testing (by weakening respiratory musculature or other mechanisms) [ 19-21 ]. In either case, the two are so closely linked that any child with worsening PFTs should be carefully evaluated for nutritional inadequacies.

CF-related diabetes mellitus  — Many patients with CF develop CF-related diabetes (CFRD); the risk increases with age and varies with CF genotype and severity. CFRD is associated with clinical deterioration, including poor growth, deterioration of nutritional status, worsening lung function, and early death [ 22 ]. However, deterioration of nutritional status is not inevitable [ 23 ]. The prevalence and risk factors for CFRD are discussed separately. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'CF-related diabetes' .)

The CFF and American Diabetes Association recommend annual screening for CFRD beginning at age 10 years, carried out at a time of clinical stability [ 24 ]. An oral glucose tolerance test (OGTT) should be used for screening because either fasting plasma glucose or hemoglobin A1C has low sensitivity in this patient group. Recommendations from the UK Cystic Fibrosis Trust are similar, except that routine screening begins at 12 years of age [ 25 ]. In addition, patients with an acute pulmonary exacerbation requiring intravenous antibiotics and/or systemic glucocorticoids should be screened for CFRD by measuring fasting and 2 hour postprandial blood glucose levels for the first 48 hours of treatment [ 24 ]. Women with CF who are pregnant or patients undergoing transplantation should have additional screening for CFRD.

OGTT results are interpreted as for non-CF related diabetes (two-hour plasma glucose 140 to 200 mg/dL constitutes impaired glucose tolerance; >200 mg/dLconstitutes diabetes mellitus). Patients with abnormal results of the OGTT should have confirmatory testing on a different day. Hemoglobin A1C ≥6.5 percent or fasting plasma glucose ≥126 mg/dL can be used as a confirmatory test, but if these are normal the OGTT should be repeated [ 24 ]. In patients with an acute pulmonary exacerbation, the diagnosis of CFRD is made if fasting plasma glucose levels are ≥126 or if two hour postprandial glucose levels are ≥200mg/dL for more than 48 hours.

Continuous glucose monitoring is a new technique that might be more sensitive than OGTT for detecting abnormal hyperglycemia. However, this technique requires a sophisticated device and is probably not practical for routine clinical screening [ 26,27 ]. (See "Blood

glucose self-monitoring in management of adults with diabetes mellitus", section on 'Continuous glucose monitoring' .)

Small intestine bacterial overgrowth  — Individuals with CF may be susceptible to small intestine bacterial overgrowth (SIBO), primarily because of decreased intestinal motility. The disorder can contribute to malnutrition by decreasing appetite, and by interfering with fat absorption. SIBO should be considered in patients with suggestive clinical symptoms and/or deterioration in nutritional status. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Small intestine bacterial overgrowth' .)

NUTRIENT DEFICITS AND GOALS

Calories  — In the past, the caloric requirement of a CF patient was estimated to be 130 percent of recommended dietary allowance (RDA) for calories [ 28 ]. This is now considered an unwarranted simplification. A number of recent studies used open and closed indirect calorimetry and doubly-labeled water to determine energy expenditures. These studies consistently show that energy expenditure is directly associated with the severity of the CF gene mutation and inversely associated with pancreatic function [ 29-31 ]. A wide range of energy expenditures are reported in individuals with CF, ranging from normal to 150 percent of normal, depending on the CF mutation, the patient's age and current state of health.

Each patient should have a nutritional regimen tailored to his or her needs [ 32 ]. Ideally, energy expenditure should be measured for each individual; however, techniques of determining energy expenditure can be difficult, especially in patients with CF. Measurement of resting energy expenditure requires either endotracheal intubation or a tight fitting hood to collect expired gases. CF patients do not tolerate either method well. A handheld apparatus for measuring resting energy expenditure is available [ 33 ]. To date, this device has not been tested in CF patients, and its use could be limited by chronic cough and by problems with contamination. However, if the technique proves feasible and accurate in this population, it could allow more exact matching of patients' needs with nutritional recommendations.

Fat soluble vitamins  — CF liver disease and pancreatic dysfunction lead to fat malabsorption that predisposes patients to deficiencies of the fat-soluble vitamins: A, D, E, and K [ 34 ].

The Cystic Fibrosis Foundation (CFF) recommends supplementation of these vitamins for all children with cystic fibrosis ( table 5 and table 4 ) [ 9 ]. These doses are considerably higher than those recommended for individuals without CF. Supplements should be started as soon as CF is diagnosed, including in asymptomatic infants and in individuals without pancreatic insufficiency. Several different commercially available vitamin supplements provide doses within the target range ( table 6A-B ).

Vitamin A  — Because vitamin A is fat-soluble and requires bile acids for absorption, patients with CF are at risk for vitamin A deficiency. However, except at the time of diagnosis, vitamin A deficiency is a rare occurrence in CF. Toxicity from vitamin A supplements is probably a more important clinical issue, as discussed below.

Physiology — Vitamin A is important for vision, gene expression, reproduction, embryonic development, growth, and immune function. It exists as "preformed vitamin A" (retinol, retinal, retinoic acid, and retinyl ester) and as "provitamin A" (food composition data is available for alpha-carotene, beta-carotene and cryptoxanthin; other forms of provitamin A are found in nature for which no food composition data is available). Most supplements contain preformed vitamin A. (See "Overview of vitamin A" .)

Recommended intake — Supplementing CF patients with a water miscible or water soluble form of vitamin A has been a routine component of care for many years, and is recommended by the CFF in the doses found in the table (1 mcg retinol activity equivalent = 3.33 international units vitamin A) ( table 5 ).

Several reports show that vitamin A may reach toxic levels in some CF patients taking supplements [ 35,36 ]. This is particularly concerning because long-term vitamin A toxicity results in bone mineral loss and liver abnormalities, as well as other abnormalities; complications that CF patients cannot afford. Many of the supplements used for patients with CF provide total doses of vitamin A that are well in excess of the CFF recommended intake ( table 6A ). However, in some supplements, part of the vitamin A is provided in the form of beta-carotene . Beta-carotene is a provitamin A, and because its conversion to vitamin A is physiologically regulated, it has a lower risk for toxicity than preformed vitamin A [ 34 ].

Monitoring — The CFF recommends measurement of serum retinol annually in all patients with CF ( table 2 ), and that serum retinol binding protein and retinyl esters also be measured in those with liver disease [ 2,34,37 ]. However, serum retinol is a better marker of deficiency than excess. The optimal forms and dosing of vitamin A supplements, and approach to monitoring is a subject of active study.

Vitamin D  — Vitamin D deficiency is common among patients with CF, and is probably a major contributor to bone disease [ 10,11 ]. (See 'Bone disease'above.)

Physiology — Vitamin D3 (cholecalciferol) is the form in most over-the-counter supplements in the United States, and is also the form produced in the skin by sunlight ( figure 4 ). Vitamin D2 (ergocalciferol) is available by prescription and is in some over-the-counter supplements. Both forms are effective in increasing serum vitamin D levels, and it is unclear if one preparation is more efficacious than the other. The CFF recommends vitamin D3 (cholecalciferol) as an oral supplement, because a small study suggests that it is somewhat more likely to achieve target 25-hydroxyvitamin D levels in patients with CF than vitamin D2 (ergocalciferol) [ 38 ]. Vitamin D2 and vitamin D3 are hydroxylated in the liver to 25-hydroxyvitamin D (calcidiol), the major circulating form of the hormone. 25-hydroxyvitamin D is then converted in the kidney to the biologically active form of the vitamin, 1,25-dihydroxyvitamin D. In addition to its important role in bone health, vitamin D also has a role in muscle function, innate immunity, cardiovascular disease, and diabetes [ 39 ]. The metabolism and biological roles of vitamin D are discussed in detail separately. (See "Overview of vitamin D" and "Metabolism of vitamin D" .)

Recommended intake — CF clinical practice guidelines recommend that all individuals with CF take vitamin D supplements: recommended doses are 400 to 500 international units daily

for patients younger than one year and 800 to 1000 international units daily for those 1 to 10 years of age. For those 10 years and older, the recommended daily intake is 800 to 2000 international units ( table 4 ) [ 38 ].

There is some evidence that the dose of 800 international units daily that was previously recommended for children older than four years is not adequate; among children taking the recommended doses, at least 45 percent had vitamin D insufficiency (25-OH vitamin D levels <30 ng/mL) [ 40 ]. Even with high dose ergocalciferol treatment (50,000 international units three times weekly for eight weeks) vitamin D levels remained below the target range in 57 percent of patients. Similarly, a report from three Canadian CF centers documented that 95 percent of CF patients had suboptimal vitamin D status despite having vitamin D intake above 400 international units [ 10 ]. Strategies for repletion of vitamin D are discussed separately. (See "Treatment of vitamin D deficiency in adults" .)

Monitoring — Vitamin D status should be assessed annually in all patients with CF by measuring serum 25-hydroxyvitamin D, preferably at the end of winter (table 2 ) [ 2,11 ]. Desirable levels are 30 to 60 ng/mL (75 to 150 nmol/L). If levels fall below 30 ng/mL, assure adherence to previously recommended supplements and supplement with vitamin D2 (cholecalciferol) ( table 4 ) [ 11,38,40 ]. However, whether achieving 25-OH vitamin D levels in the recommended target range (30 to 60 ng/mL) will cause clinically important improvements in bone health has not been established.

Vitamin E  — Patients with CF are at risk for vitamin E deficiency, as they are for other fat-soluble vitamins. Because vitamin E functions as an antioxidant, some have proposed that deficiency of this vitamin may promote inflammation and contribute to CF lung disease.

Physiology — Vitamin E is a fat soluble vitamin with eight different forms, each of which has its own profile of activity. The form most commonly used as a supplement is alpha tocopherol acetate. All forms of vitamin E act as anti-oxidants at cell membranes, preventing membrane damage. Gamma tocopherol may play an important and complementary role to alpha-tocopherol in scavenging free radicals [ 41 ]. (See "Overview of vitamin E" .)

Recommended intake — The CFF recommends the following intake of vitamin E (as alpha tocopherol) as shown in the following table ( table 5 ) [ 2 ].

These doses are about 20-fold higher than the recommended intake for healthy individuals, and are generally effective in preventing vitamin E deficiency (as measured by alpha tocopherol levels) [ 42 ].

The known role of vitamin E as an antioxidant has generated interest in the possibility that higher doses of vitamin E, or different forms of vitamin E, alone or in combination with other antioxidants, might reduce inflammation and end-organ damage in CF. This hypothesis is supported by some studies showing a correlation between vitamin E status, polyunsaturated fatty acid status, and inflammation in patients with CF [ 42 ]. However, clinical efficacy for this approach has not been established, and supplements in excess of the above dosing ranges are not generally recommended.

Monitoring — The CFF currently recommends annual measurements of serum alpha tocopherol to monitor vitamin E status in patients with CF ( table 2 ) [ 2 ]. Serum vitamin E

levels are strongly influenced by concentration of serum lipids, and do not accurately reflect tissue vitamin levels, and patients with CF typically have lower serum cholesterol than the reference population. Therefore, the alpha-tocopherol:cholesterol ratio or alpha tocopherol:total serum lipid ratio may be a better measure of sufficiency. (See "Overview of vitamin E", section on 'Measurement' .)

Vitamin K  — Vitamin K deficiency can cause coagulation abnormalities and may also contribute to bone disease in patients with CF. Several reports demonstrate a direct correlation between vitamin K status and measures of bone health [ 34,43-45 ]. (See 'Bone disease' above.)

Physiology — Vitamin K is a fat-soluble vitamin found in a variety of green vegetables, and is also synthesized by intestinal bacteria. Patients with CF are at risk for vitamin K deficiency because of fat malabsorption, and also because of disturbances in the bowel flora caused by small intestine bacterial overgrowth, or frequent use of antibiotics.

Vitamin K is a cofactor required for the activity of several key proteins in the coagulation pathways, including prothrombin. Because vitamin-K dependent carboxylation occurs in the liver, its action can be further reduced in patients with severely impaired hepatic function. Vitamin K-dependent carboxylation is also necessary for function of osteocalcin and other bone-related proteins. (See "Overview of vitamin K" .)

Recommended intake — The CFF recommends vitamin K supplementation of 0.3 to 0.5 mg daily for infants, children, and adolescents with CF [ 2 ]. Adults should be supplemented with 2.5 to 5 mg weekly, and additional supplementation may be necessary during antibiotic therapy ( table 5 ) [ 37 ]. These doses are over 100-fold higher than the recommended intake for individuals without CF.

Monitoring — The CFF recommends annual screening for vitamin K deficiency in patients with liver disease, hemoptysis, or hematemesis; screening consists of measuring serum prothrombin time and, if possible, also PIVKA-II (Proteins induced by vitamin K absence) levels ( table 2 ). In our practice, we perform these screening tests annually in all CF patients even if there is no known liver disease or bleeding diathesis, because patients may have CF-related liver disease for some time before it becomes clinically apparent.

PIVKA-II is more sensitive than prothrombin time in detecting vitamin K deficiency. Using this measure, 82 percent of patients with CF were found to have suboptimal vitamin K status, despite meeting the goals for vitamin K intake recommended by the CFF [ 10 ].

Essential fatty acids  — Essential fatty acid (EFA) deficiency may contribute to inflammatory pathways in CF, and there is preliminary evidence that supplementation may be beneficial.

Routine EFA supplementation or monitoring is not currently recommended for patients with CF [ 2,9 ]. However, patients at high risk for EFA deficiency, such as infants with growth failure or other suggestive symptoms, should be evaluated by measuring the triene:tetraene ratio or other biomarker of EFA status (table 2 ). Diets rich in EFA, including cold-water fish and vegetable oils (eg, flax, canola, or soy), are encouraged [ 2 ].

Physiology — Long chain polyunsaturated fatty acids of the omega-3 and the omega-6 series are termed "essential" because they cannot be synthesized by humans. Fatty acids of the omega-3 series are found as components of cell membranes and exhibit profound anti-inflammatory effects. Fish oil is a rich source of the metabolically active omega-3 fatty acid, docosahexaenoic acid (DHA). Fish oil is found to be beneficial in a number of chronic inflammatory states, such as rheumatoid arthritis and inflammatory bowel disease.

EFA deficiency is characterized by scaly dermatitis, alopecia, thrombocytopenia, and growth failure. Overt symptoms of EFA deficiency such as these are uncommon in patients with CF, but there is some evidence for subclinical EFA deficiency in this population. As an example, biochemical markers of EFA deficiency are correlated with poor growth and pulmonary status [ 46,47 ]. EFA deficiency is more common among infants and in patients with pancreatic insufficiency. A systematic review found that short-term supplementation of omega-3 fatty acids improved several indices of CF lung disease, and concluded that the supplements were probably beneficial and have few adverse effects [ 48 ].

Monitoring — EFA status is usually measured using a triene:tetraene ratio (eicosatrienoic acid:arachidonic acid). However, some investigators have suggested that serum linoleic acid (an omega-6 fatty acid), expressed as a molar percent of total serum phospholipid fatty acids, is a more clinically relevant biomarker of EFA deficiency [ 46 ]. In a group of patients with CF, linoleic acid concentration above 21 moles percent was associated with better growth, body composition, and lung function.

Sodium  — Individuals with CF are prone to hyponatremic dehydration under conditions of heat stress, especially with exercise. This was described in five patients during a summer heat wave in 1948 who developed heat exhaustion with low serum sodium [ 49 ]. The risk for hyponatremic dehydration is increased during infancy and in hot climates [ 50 ]. A similar picture can develop in infants without heat stress [ 51 ]. To avoid these potentially life-threatening complications, routine supplementation with sodium chloride is recommended, depending upon the patient’s age and climate conditions ( table 7 ) [ 9 ].

Fluoride  — Infants and children with CF require fluoride for dental health at the same levels as healthy children [ 9 ]. Vitamins formulated for CF do not generally include fluoride. Fluoride supplements should be supplied separately beginning at 6 months of age, if the fluoride concentration of the water supply is not adequate. (See "Preventive dental care and counseling for infants and young children", section on 'Fluoride' .)

Zinc  — For infants with CF under two years of age who are not growing well despite adequate energy intake and pancreatic enzyme supplementation, the CF foundation suggests a trial of zinc supplementation (1 mg elemental zinc/kg/day in divided doses for six months). This suggestion is based on expert consensus, inferred from the positive effects of zinc on growth in some other clinical settings. (See "Zinc deficiency and supplementation in children and adolescents", section on 'Enhancement of growth' .)

Rarely, infants with undiagnosed CF may present with a dermatitis caused by zinc deficiency, often in combination with EFA deficiency and/or protein-energy malnutrition. The dermatitis resembles acrodermatitis enteropathica. (See "Zinc deficiency and supplementation in children and adolescents", section on 'Other'.)

NUTRITION SUPPORT

Oral  — All individuals with CF should be given dietary advice about a balanced diet with adequate calories to ensure growth at or above the 50 th percentile for age. Caloric goals will often be higher than those for the general population. Pancreatic enzyme replacement therapy should be provided for those with pancreatic insufficiency. (See 'Growth' above and 'Calories' above and "Cystic fibrosis: Assessment and management of pancreatic insufficiency" .)

For infants with cystic fibrosis, human milk feeding is specifically encouraged [ 9 ]. If infants are fed formula, a standard infant formula may be used; formulas containing extensively hydrolyzed protein are not helpful unless the infant has a milk protein intolerance in addition to CF. If weight gain is inadequate, the energy content of the formula or human milk should be increased using standard methods. (See "Management of failure to thrive (undernutrition) in children younger than two years", section on 'For infants' .)

Parents should be educated to use behavioral techniques to promote positive feeding behaviors [ 9 ]. These include:

Providing attention and praise for positive eating behaviors Gentle persistence when offering new foods (offer a new food 10 or more times

before giving up) Ignoring negative eating behaviors such as food refusal Offer meals and substantive snacks on a regular schedule Keep mealtimes relaxed and time-limited; do not enforce specific goals for intake at

each meal

For patients with suboptimal growth, the initial intervention is to provide more intensive dietary advice to increase caloric intake [ 9 ]. A number of studies support this approach and show nutritional benefit through counseling, with the use of behavior modification strategies to support dietary change [ 52-56 ]. As an example, a small randomized trial found that a behavioral intervention substantially increased caloric intake in toddlers and preschool-aged children with CF as compared with standard care, and that these effects persisted 12 months after the intervention [ 57,58 ]. The behavioral techniques included differential attention (parents praised children for desired eating behaviors and ignored non-eating behaviors) and contingencies (rewards to motivate children to meet energy goals). A larger multicenter trial of children aged 4 to 12 years assessed the efficacy of a similar behavioral intervention designed to promote energy intake [ 59,60 ]. The group receiving the behavioral intervention achieved improved energy intake and weight gain at the end of a nine-week intervention, and a slower rate of decline in BMI z-score over the subsequent two years, as compared with control patients receiving nutritional education alone.

In addition to nutritional and behavioral counseling, patients with suboptimal growth should also be assessed for the possibility of emerging pancreatic insufficiency or inadequate replacement therapy. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency" .)

For infants with CF under two years of age who are not growing well despite adequate energy intake and pancreatic enzyme supplementation, the CF foundation suggests a trial of zinc supplementation. (See 'Zinc' above.)

If dietary counseling is not successful, a liquid supplement that is high in calories and protein can be added to the diet. A variety of supplements are available and are appropriate for use by patients with CF ( table 8 ). These supplements are often less efficacious than expected because the supplements tend to displace ordinary food rather than being taken in addition to a usual diet [ 61 ], and patients often complain of taste fatigue with oral supplements. As an example, a systematic review found that calorie-protein supplements do not confer benefits above dietary advice and monitoring in CF patients who have moderate malnutrition [ 62 ].

Enteral feedings  — When oral nutrition support fails, enteral nutrition (EN) (tube feeding) should be employed. Aspects of enteral nutrition that are specific to patients with CF are outlined here. An overview of enteral nutrition in children is presented separately. (See "Enteral nutrition in infants and children" .)

EN is widely used for patients with CF and perceived as helpful [ 63-65 ]. This practice is supported by a number of observational studies that suggest improved nutritional status and stabilization of lung function in CF patients receiving EN, as illustrated by the following examples [ 64,66,67 ]:

A series of 14 patients with moderate to severe lung disease were compared with age- and disease-matched contemporary controls, with a mean follow-up of 1.1 years [ 68 ]. The patients receiving EN experienced a weight percentile increase, while growth percentiles declined in the comparison group. The FEV1 in the EN group did not change, while the FEV1 of the comparison group worsened.

A series of 53 patients with CF, ten of whom were children, showed an increase in expected weight and stabilization of lung function, but these outcomes were not compared to a control group [ 64 ].

No randomized studies of EN have been performed in patients with CF. Therefore, the clinical benefits and potential adverse consequences, including effects on quality of life, have not been rigorously addressed [ 66 ].

Route  — EN is usually provided to patients with CF via gastrostomy tube (G-tube), because nasogastric tubes are usually poorly tolerated due to chronic cough, nasal polyps, and the sensation of suffocating. Gastrojejunostomy and jejunostomy feeding may also be used, but these tubes are more difficult to place and maintain in position. Additionally, jejunal feeds must be given continuously rather than in boluses, making the route inconvenient for ambulatory patients.

G-tubes can be placed surgically, endoscopically, or by an interventional radiologist, with minimal risk. If general anesthesia is not advisable for a particular patient, the procedure can be performed under sedation and local anesthesia. A skin-level device (or "button") can be used so that the patient can disconnect from all tubing between feeds, to optimize mobility and cosmesis.

Schedule  — Schedules for tube feeding vary and should take into account the patient's activities and other therapies. Feeds can be instilled continuously, as boluses, or a combination of these two regimens.

For the school-age child, a frequently employed schedule supplies approximately 40 percent of daily requirements via a slow infusion overnight, and the remainder of the requirement is supplied through food taken by mouth during the day. If the child is unable to meet the daily caloric requirements, the nighttime infusions can be lengthened or the rate of infusion increased so that a greater percentage of the requirements are delivered overnight.

For the younger patient who is at home during the day, nutritional requirements can be supplied through a combination of nighttime continuous feeds, daytime meals, and daytime bolus feeds. If the child fails to ingest the prescribed amount at any daytime meal, a bolus feed is added to compensate.

CF patients often have a complex care schedule because of their need for multiple medications and frequent pulmonary therapies. Feeding schedules should take these other elements of therapy into account.

Formula  — No one class of formula has been shown to be superior to another. Some formulas supply protein that is either elemental (free amino acids) or semi-elemental ( table 9 ). The protein in a semi-elemental formula may be extensively hydrolyzed (containing short peptides) or partially hydrolyzed (containing longer peptide chains). However, more extensive protein digestion does not have a clinical advantage as long as pancreatic enzyme replacement is given, and it may have the disadvantage of increasing the osmolarity of the formula. In one study, a non-elemental formula plus pancreatic enzyme replacement was as well absorbed as a semi-elemental formula without pancreatic enzymes [ 69 ].

Concentrated formulas with 1.5 to 2 Kcal/mL have the advantage of delivering more calories in a smaller volume. Since nighttime urination is a problem when using high-volume overnight feeds, a smaller volume can make the feeding schedule more tolerable. When using the more concentrated formulas, care must be exercised to avoid carbohydrate overload and possible inadequate supply of free water. Use of formulas with concentrated carbohydrates may uncover CF related diabetes (CFRD). Similarly, in established diabetics, these formulas may complicate diabetes treatment. The complications encountered because of CFRD are surmountable and should not preclude the use of EN.

Enzyme replacement  — As with other aspects of EN in CF, there is little information on the best way to administer pancreatic enzyme replacement therapy (PERT) in conjunction with EN. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency", section on 'Pancreatic enzyme replacement therapy' .)

In the absence of evidence-based guidelines, we suggest the following approach:

Start by calculating the grams of long chain triglycerides (LCT) being administered. LCT is the main determinant of the lipase requirement, becausemedium chain triglycerides (MCT) require relatively low concentrations of lipase to hydrolyze the fatty acids from the glycerol backbone. Therefore, MCT accounts for little of the fat malabsorption in CF.

Supply 1600 to 2000 lipase units per gram LCT ( table 10 ). (See "Pancrelipase: Pediatric drug information" .)

For cycled and continuous overnight feeds, administer three-fourths of the enzymes at the beginning of the feeding and one-fourth of the enzymes at the end of the feeding.

For bolus feedings, administer the calculated amount of enzymes just prior to the feeding.

For continuous 24-hour feedings, divide the total calculated lipase into six doses, and give each dose at four hour intervals.

Parenteral nutrition  — Parenteral nutrition (PN) should be prescribed for CF patients when GI function is inadequate to supply complete nutrition. This could occur during times of extreme metabolic stress, such as post-transplantation or following GI surgical procedures. The PN solution should contain a balance of amino acids, dextrose, lipids, vitamins, and trace elements to provide appropriate nutrition.

One study observed that PN promoted weight gain in patients with CF but was also associated with higher rates of sepsis [ 70 ]. Moreover, after PN was discontinued, weight decreased again, and no long term gain was achieved. PN should not be a part of palliative care.

INFORMATION FOR PATIENTS  — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topic (see "Patient information: Cystic fibrosis (The Basics)" )

SUMMARY AND RECOMMENDATIONS  — Nutritional issues in CF are pervasive, and are not fully explained by pancreatic insufficiency or overcome by pancreatic enzyme replacement therapy.

Early recognition and intensive treatment of undernutrition in patients with CF can minimize the damaging effects of malnutrition on lung disease, longevity, and quality of life. (See 'Introduction' above.)

Pancreatic insufficiency is an important contributor to malnutrition in most individuals with cystic fibrosis. Diagnosing and managing this problem is an important step in nutritional management. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency" .)

CF-related liver disease, bile salt abnormalities, CF-related diabetes and small bowel bacterial overgrowth also compromise nutrient absorption, while inflammatory lung disease increases energy needs. (See 'Pathophysiology' above.)

All patients with CF should have regular nutritional assessments at three monthly intervals for early detection of nutritional deterioration ( table 1 ). Anthropometric measurements are tracked against standard curves, and laboratory tests are performed to monitor for specific deficiencies ( table 2 ). (See 'Assessing and monitoring nutrition' above.)

Bone disease is common in patients with cystic fibrosis, and progresses with age. All individuals with CF should be counseled to ensure recommended intake of calcium, phosphorus, vitamin K, and vitamin D to support bone health ( table 3 and table 4 ). In addition, serum levels of calcium, phosphorus, intact parathyroid hormone, and 25 hydroxyvitamin D should be measured annually; bone density should be measured in children older than eight years (table 2 ). (See 'Bone disease' above.)

We recommend that all individuals with cystic fibrosis take supplements to meet disease-specific recommended intakes for fat-soluble vitamins ( table 5and table 4 ) ( Grade 1B ). Several different commercially available vitamin supplements provide doses within the target range ( table 6A-B ). The currently available supplements may provide excessive amounts of vitamin A, and suboptimal amounts of vitamin D and K. In addition, serum retinol, vitamin E, and prothrombin time (PT) or PIVKA-II should be monitored annually to assess for deficiency. (See 'Fat soluble vitamins' above.)

Because of sodium losses in sweat, individuals with CF are prone to hyponatremic dehydration under conditions of heat stress. Most patients will need supplementation of sodium chloride to compensate for estimated sodium losses, which depend on the patient's age and climate conditions ( table 7 ). (See 'Sodium' above.)

All individuals with CF should be given dietary counseling to ensure a balanced diet with adequate calories to ensure good growth, and caloric goals will often be higher than for the general population. Patients with growth failure can be managed with a series of interventions, beginning with intensive counseling, and escalating to nutritional supplements via the oral or enteral route. Parenteral nutrition has a limited role in the management of this disease (see 'Nutrition support' above).