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Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection

Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection
Literature review current through: May 2024.
This topic last updated: Oct 16, 2023.

INTRODUCTION — Cystic fibrosis (CF) is a multisystem disorder caused by pathogenic variants in the CF 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]. One of the major drivers of CF lung disease is infection [3]. The approach to treating infection in CF is multifaceted, involving antibiotics, chest physiotherapy, inhaled medications to promote secretion clearance, and antiinflammatory 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).

The use of antibiotics to treat chronic pulmonary infections in CF will be reviewed here. Treatment of acute pulmonary exacerbations and other aspects of pulmonary disease in CF are discussed in separate topic reviews:

(See "Cystic fibrosis: Management of pulmonary exacerbations".)

(See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations".)

(See "Cystic fibrosis: Overview of the treatment of lung disease".)

(See "Cystic fibrosis: Management of advanced lung disease".)

(See "Cystic fibrosis: Treatment with CFTR modulators".)

(See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)

The diagnosis and pathophysiology of CF and its manifestations in other organ systems are also discussed separately. (See "Cystic fibrosis: Clinical manifestations and diagnosis" and "Cystic fibrosis: Genetics and pathogenesis" and "Cystic fibrosis: Nutritional issues" and "Cystic fibrosis: Assessment and management of pancreatic insufficiency" and "Cystic fibrosis: Overview of gastrointestinal disease" and "Cystic fibrosis: Hepatobiliary disease" and "Cystic fibrosis-related diabetes mellitus".)

PATHOGENS — Most patients with CF develop chronic bacterial infection within the airways (table 1). The prevalence of each bacterial type varies with the age of the patient (figure 2) and geographic region of the United States, with methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and nontuberculous mycobacteria (NTM) being more prevalent in the South [4].

Pseudomonas aeruginosa — For reasons that are poorly understood, the CF airway is particularly susceptible to P. aeruginosa, with infection occurring as early as the first year of life. The prevalence of P. aeruginosa increases with age, such that more than 60 percent of adults are chronically infected [2]. Of note, the prevalence and incidence of new chronic infections appears to have decreased among adolescents and adults in the United States [5-7]. (See "Epidemiology, microbiology, 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 [8,9]. 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 [10,11]. Protocols for early detection and eradication have had considerable success. (See 'Pseudomonas aeruginosa' below and 'Infection prevention and control' below.)

Staphylococcus aureus — S. aureus is the bacterial pathogen most frequently identified in respiratory secretions of CF infants and children [2]. It remains a significant pathogen throughout adulthood. In children under six years of age infected with P. aeruginosa, coinfection with S. aureus has an independent and additive effect on airway inflammation [12].

Methicillin-resistant Staphylococcus aureus — MRSA has become more prevalent in the CF population, increasing from 9.2 percent in 2002 to 24.6 percent in 2019 [2]. 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 in one second [FEV1]) in children but not in adults [13], while another study reported that MRSA had no effect on the rate of FEV1 decline [14].

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 [15]. 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 coinfection with Burkholderia cepacia complex or P. aeruginosa.

Early detection and eradication of MRSA has shown some promise. (See 'Methicillin-resistant Staphylococcus aureus' below.)

Burkholderia cepacia complex — Advances in bacterial genetics have revealed that B. cepacia, which was originally thought to be a single species, is now known to constitute multiple separate species, collectively known as B. cepacia complex [16]. The species most commonly isolated from the sputum of CF patients are B. multivorans and B. cenocepacia [6,7,17]. The original strain identified many years ago retains the species name, B. cepacia, but is rarely found in patients with CF. B. gladioli, another Burkholderia species not belonging to the B. cepacia complex, is the third most frequent Burkholderia species identified in respiratory secretions of CF patients.

Chronic infection with B. cenocepacia complex bacteria is associated with an accelerated decline in pulmonary function and shortened survival in CF [18]. Much of the worse outcome is attributable to the highly transmissible ET-12 (Edinburgh/Toronto-12) strain [19]. Lung transplantation in patients infected with B. cenocepacia often leads to recurrent and often severe infection with poor outcomes [20,21], causing most transplantation centers to consider it a relatively strong contraindication to transplantation [22]. (See "Bacterial infections following lung transplantation", section on 'Burkholderia cepacia'.)

Nontuberculous mycobacteria — NTM can be isolated from the sputum in 10 to 20 percent of patients with CF, with increasing prevalence with age and substantial geographic variation [2,23-25]. The incidence of NTM-positive cultures has increased substantially over decades in populations with CF as well as in the general population. Mycobacterium avium complex is identified in up to 75 percent of these patients. The other frequently identified pathogen is Mycobacterium abscessus complex (which includes the subspecies M. abscessus, M. abscessus bolletii, and M. abscessus massiliense) and has become more common than M. avium complex in some populations [26-30]. (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. NTM may be transiently, intermittently, or continuously present in patients without apparent clinical sequelae. However, on average, the rate of decline in FEV1 is greater in patients infected with M. abscessus than a control population [28,31]. The impact on lung function appears to be less in patients with other species of NTM [26,28,32]. A subset of patients develop progressive inflammatory lung damage, known as NTM pulmonary disease, for which specific treatment is warranted in selected cases [32]. (See 'Nontuberculous mycobacteria' below.)

Other pathogens — Other pathogens have been identified in respiratory secretions of CF patients, with varying prevalence (table 1 and figure 2) [2,6,7]. These include:

Nontypeable Haemophilus influenzae

Stenotrophomonas maltophilia

Achromobacter species

Aspergillus species

Other species identified in the respiratory secretions of occasional CF patients include non-Cepacia complex Burkholderia species (Burkholderia gladioli and Burkholderia 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 [33]. Furthermore, nonculture-based molecular genetic techniques have identified microorganisms in respiratory secretions of patients with CF that were previously unrecognized as being present [34]. Both culture-based and genetic methods have revealed high densities of anaerobic bacteria in respiratory secretions from CF patients [35-37]. Investigations are ongoing to determine the role of this complex microbiota in driving pulmonary exacerbations and disease progression.

CONSEQUENCES OF CYSTIC FIBROSIS LUNG INFECTION — Once established in the 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. The same may be true for methicillin-resistant S. aureus (MRSA), but this will require further study. (See 'Prevention and eradication' below.)

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 B. cenocepacia connotes an even worse prognosis than chronic infection with P. aeruginosa. (See 'Burkholderia cepacia complex' above.)

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

A subset of patients with nontuberculous mycobacteria (NTM) infection, especially M. abscessus, develop progressive inflammatory lung damage known as NTM pulmonary disease, which is associated with worsening pulmonary function and can be difficult to eradicate. (See 'Nontuberculous mycobacteria' below.)

Several mechanisms may contribute to the persistence of bacteria in CF patients despite aggressive treatment including poor penetration of antibiotics into purulent airway secretions, native or acquired antibiotic resistance, CF-related defects in mucosal defenses, and/or biofilms produced by the bacteria that may render antibiotics ineffective or interfere with host defenses.

PERIODIC SURVEILLANCE CULTURES — We suggest performing bacterial cultures of expectorated sputum or throat swabs at least every three months during routine clinic visits, consistent with guidelines from the Cystic Fibrosis Foundation (CFF) [38-40]. We also suggest performing cultures at least annually for nontuberculous mycobacteria (NTM) [24] and fungi for patients who can spontaneously expectorate sputum. More frequent cultures are appropriate for patients with deteriorating respiratory status or who are not responding adequately to standard treatment for a pulmonary exacerbation. We use the culture results as follows:

To monitor for the acquisition of P. aeruginosa, which we treat with an eradication protocol (see 'Pseudomonas aeruginosa' below)

To initiate chronic treatment with inhaled antibiotics for patients chronically infected with P. aeruginosa (see 'Inhaled antibiotics' below)

To guide selection of antibiotics in the event of an acute exacerbation (see 'Pseudomonas aeruginosa' below and "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations", section on 'Respiratory secretion cultures')

To initiate evaluation and possible treatment of patients who are newly positive for NTM (see 'Nontuberculous mycobacteria' above)

PREVENTION AND ERADICATION

Once a patient becomes chronically infected with P. aeruginosa, treatment strategies are unsuccessful at eradicating it. Variable success has been reported for methicillin-resistant S. aureus (MRSA). Early studies of highly effective CF transmembrane conductance regulator (CFTR) modulators have reported inconsistent results regarding whether they reduce the acquisition and prevalence of CF pathogens [41-43].

Pseudomonas aeruginosa — Strategies to prevent P. aeruginosa from chronically infecting the airways of CF patients include:

Prevention of acquisition – We recommend measures to prevent transmission of P. aeruginosa among CF patients. (See 'Infection prevention and control' below.)

We do not recommend prophylactic use of antibiotics targeting P. aeruginosa or S. aureus in an attempt to prevent P. aeruginosa acquisition [40,44]. Clinical trials of this approach did not show benefit:

A randomized trial evaluated the effects of treating children without P. aeruginosa infection with cycles of oral ciprofloxacin and inhaled colistin [45]. 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.

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 [46]. To test this hypothesis, a randomized trial of oral cephalexin was performed in young children [47]. 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. Furthermore, a retrospective study of registry data from the United Kingdom studied children less than approximately four years old who either did or did not receive chronic flucloxacillin [48]. The risk of acquiring Staphylococcus was not reduced with chronic flucloxacillin, but the risk of acquiring P. aeruginosa increased.

Early eradication – We recommend using a protocol to detect and treat P. aeruginosa when it is first acquired, regardless of age or whether there are associated clinical signs or symptoms [49,50]. We perform cultures of expectorated sputum or throat swabs every three months during routine clinic visits. When P. aeruginosa is first detected, we treat with inhaled tobramycin alone (300 mg administered twice daily) for 28 days, rather than a regimen including ciprofloxacin or other antibiotics. Repeat cultures should be performed within four weeks after completion of treatment. The therapy is repeated only if surveillance cultures show recurrence of P. aeruginosa [51].

This practice of early eradication is supported by considerable clinical evidence and has been incorporated into the Cystic Fibrosis Foundation (CFF) clinical guidelines [50,52]. Treatment of patients as young as one year of age [49] with newly acquired P. aeruginosa typically achieves initial eradication in 70 to 90 percent of subjects after a 28-day cycle of inhaled tobramycin [51-54]. The longest observational study reported that 70 percent of patients treated with an early eradication protocol remained free of P. aeruginosa 12 months after the initial treatment (sustained eradicators) [55]. During the following five years, 77 percent of sustained eradicators remained free of chronic P. aeruginosa and only 17 percent developed mucoid species. There were minimal differences in clinical outcomes during this follow-up period, but longer studies may be needed to detect such differences. Other trials found no additional benefit for longer duration of inhaled tobramycin [52]. The certainty and generalizability of these findings were extended by a placebo-controlled trial that included 51 children less than seven years old who received inhaled tobramycin or placebo for 28 days [56]. Following treatment, 85 percent of patients receiving tobramycin were P. aeruginosa-free compared with 24 percent of those receiving placebo, with no difference in adverse events between groups.

There is no consensus regarding the approach to patients with newly acquired P. aeruginosa whose initial treatment fails to eradicate the infection. A stepwise protocol has been studied in children, in which children who failed to achieve eradication after a 28-day course of inhaled tobramycin were given a second 28-day course of inhaled tobramycin [57]. Those who remained positive after the second course were additionally treated with 14 days of intravenous antibiotics followed by 28 days of inhaled tobramycin. Patients who had worsening symptoms at any time during the protocol were treated with intravenous antibiotics. For those who remained asymptomatic during the study, successful eradiation was achieved in 77 percent of patients after initial treatment, 33 percent of those who progressed through step 2, and 42 percent of those who finished step 3. Given these overall favorable results and the absence of direct comparisons with other regimens, this is a reasonable approach to treating children who fail the initial attempt of eradicating a new P. aeruginosa infection.

Other regimens to eradicate P. aeruginosa using antibiotics other than tobramycin have been evaluated:

Four weeks of inhaled aztreonam led to outcomes similar to those reported for tobramycin [58].

The combination of inhaled tobramycin and ciprofloxacin was not more effective than tobramycin alone [51,52].

The combination of inhaled colistin and oral ciprofloxacin was similar in effect to inhaled tobramycin with oral ciprofloxacin [52,54].

The combination of 28 days of inhaled tobramycin plus 18 months of oral azithromycin resulted in greater weight gain and longer time to the first pulmonary exacerbation compared with tobramycin alone but no difference in eradication rate or other clinical outcomes [59].

The combination of intravenous antibiotics (ceftazidime and tobramycin) and inhaled colistimethate sodium was not more effective than an oral antibiotic (ciprofloxacin) in combination with inhaled colistimethate sodium [60].

Methicillin-resistant Staphylococcus aureus — Chronic infection with MRSA is associated with declines in pulmonary function and increased risk of death, but the pathogen is difficult to eradicate once the infection is established. (See 'Methicillin-resistant Staphylococcus aureus' above.)

This observation has motivated development of protocols designed to eradicate both early and established MRSA infection:

Early eradication – Based on preliminary results, we believe it is reasonable to offer a treatment regimen to highly selected patients who have acquired MRSA within the previous six months, who can follow a demanding treatment protocol and who can tolerate rifampin without problems from drug-drug interactions. The long-term benefits of eradication are not known.

The limited evidence supporting this approach includes several uncontrolled studies using a variety of treatment regimens that reported successful eradication of newly acquired MRSA [61,62]. The only controlled clinical trial reported elimination of MRSA from sputum cultures at one month follow-up in 22 subjects (82 percent) in the treatment group, compared with 19 (26 percent) of those in the control group (p<0.001) [63]. However, by six months, there was no difference in the prevalence of MRSA infection between the two groups. This and one other randomized trial were included in a meta-analysis, which concluded that short-term MRSA eradication is possible, but that the long-term clinical implications are unclear [64]. A subsequent study randomized 69 subjects to either an observation group or to a group receiving rifampin, sulfamethoxazole/trimethoprim, and nasal mupirocin [65]. There was a trend toward eradication of MRSA in the treatment group, but only 52 percent of the subjects completed the trial, thus limiting the validity of conclusions.

No studies have compared different eradication protocols. Nevertheless, it would be reasonable to select the regimen used in the above mentioned randomized study that showed successful eradication [63], which consisted of oral rifampin, oral trimethoprim-sulfamethoxazole or minocycline, nasal mupirocin, chlorhexidine oral rinses and body wipes, and environmental decontamination. (See "Rifamycins (rifampin, rifabutin, rifapentine)", section on 'Drug interactions'.)

Eradication of chronic infection – Combined oral, inhaled, and topical antibiotics have been tested for their ability to eradicate chronic MRSA infection from patients with CF. In a randomized study, subjects with chronic MRSA infection received either inhaled vancomycin or placebo for 28 days [66]. Both groups received oral and topical anti-MRSA antibiotics and undertook environmental cleaning to limit MRSA re-exposure. The rate of MRSA eradication one month after treatment, the primary endpoint, was 20 percent in both groups.

CHRONIC PULMONARY INFECTION (PSEUDOMONAS AND BURKHOLDERIA SPP) — Once P. aeruginosa or B. cepacia complex bacteria become established in the airways of a patient with CF for more than a few months, the organisms usually persist for years despite aggressive attempts at eradication. Chronic treatment with inhaled antibiotics helps to reduce the Pseudomonas bacterial burden and thus lessen its impact [67]. Because most classes of antibiotics that show in vitro activity against P. aeruginosa are ineffective when administered orally, delivery by inhalation presents an attractive alternative to intravenous administration. Unfortunately, there are no chronic treatment regimens directed at established Burkholderia species infections that have been shown to improve outcomes.

Inhaled antibiotics — We recommend chronic treatment with cyclic inhaled antibiotics for patients with chronic P. aeruginosa infection. Our approach to selecting the regimen is described below, followed by the evidence and other considerations for different types of aerosolized antibiotics.

We use the following approach to prescribing inhaled antibiotics for patients with chronic P. aeruginosa infection:

Tobramycin – Inhaled tobramycin is our first-line choice because of the extensive information supporting the efficacy of tobramycin and its good safety record following many years of use [39,40,44,68]. The standard inhalation solution is given as a 300 mg dose, administered by nebulizer twice daily for 28 days, alternating with 28 days off treatment. A powdered form is also available. But, of note, there is growing concern that the efficacy of inhaled tobramycin may be reduced in patients on chronic oral azithromycin. (See 'Oral azithromycin' below.)

Aztreonam lysine – Inhaled aztreonam lysine can be used as an alternative to inhaled tobramycin in selected patients. The dose is 75 mg by inhalation three times daily for 28 days, alternating with 28 days off treatment. (See 'Inhaled aztreonam lysine' below.)

In our practice, we prescribe aztreonam particularly when:

The patient does not tolerate inhaled tobramycin

The patient's pulmonary status is deteriorating despite inhaled tobramycin

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

The patient is considered more likely to be adherent to inhaled aztreonam because of personal preference for its mode of delivery despite the need to take it three times per day compared with twice per day for tobramycin

Colistin – Because no colistin preparation has been approved by the US Food and Drug Administration (FDA) for use by inhalation in the United States, we first prescribe tobramycin and/or aztreonam. We reserve colistin for those patients who are not doing well on these treatments or do not tolerate tobramycin and aztreonam. By contrast, in Europe, colistin is frequently used as a primary inhaled antibiotic treatment [69]. A commonly used dose is 150 mg (colistimethate base) for children ≥10 years and 75 mg for younger children, administered twice daily for 28 days, alternating with 28 days off of treatment. (See 'Inhaled colistin' below.)

Continuous alternating inhaled antibiotics – For patients with deteriorating pulmonary status and/or rapidly recurrent pulmonary exacerbations despite cycling between 28 days on and 28 days off of a single inhaled antibiotic, it has become common practice for clinicians to prescribe continuous treatment by alternating between two different antibiotics (eg, tobramycin and aztreonam), each for a 28-day period.

This approach was evaluated in a randomized clinical trial in patients with a wide range of pulmonary function (forced expiratory volume in one second [FEV1] 25 to 75 percent predicted), in which 28 days of inhaled aztreonam or placebo alternated with 28-day cycles of inhaled tobramycin [70]. The study was terminated early because of inability to meet recruitment targets, in part because many clinicians and patients had already adopted continuously alternating therapy into their treatment regimen [71]. The study found a trend toward reduced pulmonary exacerbation rate from continuous therapy, but it did not reach statistical significance.

A retrospective analysis of 89 patients using chronic inhaled antibiotics found that 49 were alternating between two antibiotics every four weeks, while the remaining patients were using one antibiotic with four weeks off treatment between courses. The most frequently used combinations were colistin with either tobramycin or aztreonam. The rate of change in FEV1 percent predicted before initiating continuous alternating antibiotics was -0.9 points and improved to +1.1 points [72].

Although there is insufficient evidence to support the practice of alternating inhaled antibiotics for all patients with chronic P. aeruginosa infection, many experts feel that it is reasonable practice for patients with advanced lung disease or those with frequent pulmonary exacerbations or accelerated decline in pulmonary status.

We typically base the choice of inhaled antibiotics on the above considerations and clinical response, rather than on in vitro susceptibility testing. This is because antibiotic resistance as measured by in vitro susceptibility testing does not preclude a clinically beneficial response to inhaled medications. This was illustrated by studies of patients participating in clinical trials of inhaled tobramycin or aztreonam that included patients 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 [73,74]. 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. Furthermore, the ability of in vitro susceptibility results to predict clinical improvement for P. aeruginosa is in question. (See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations", section on 'Respiratory secretion cultures'.)

Considerations and techniques for delivering medications by inhalation are discussed separately. (See "Delivery of inhaled medication in children" and "Delivery of inhaled medication in adults".)

Inhaled tobramycin — Chronic treatment with inhaled tobramycin is a well-established first-line treatment for patients who are infected with P. aeruginosa [39,40,75].

Dosing and administration:

The standard inhalation solution of tobramycin is 300 mg in 4 or 5 mL, administered via nebulizer twice daily, in cycles of 28 days on therapy alternating with 28 days off.

Peak serum levels following inhaled tobramycin in patients with normal renal function are generally <2 mcg/mL, so renal and ototoxicity are rare. However, patients with impaired renal function can accumulate high serum levels of tobramycin, leading to further renal injury and ototoxicity. Annual hearing tests are suggested for all children and adults with CF who are exposed to aminoglycosides, including inhaled tobramycin [76].

A powdered form of tobramycin (tobramycin inhalation powder) can be prescribed as 112 mg contained in four capsules, inhaled twice daily using a specially designed apparatus [77]. This preparation significantly reduces the time required to administer each dose compared with the aerosolized form [78]. However, the frequency of cough in subjects participating in the clinical study (25.3 percent) was higher with the powdered form compared with the nebulized liquid (4.3 percent), leading to a higher rate of drug discontinuation. A subsequent study followed subjects for up to one year of treatment and reported somewhat lower frequency of cough (13.6 percent initially, with further improvement thereafter), possibly due to an alteration in the manufacturing process [79].

Efficacy – Large trials have demonstrated that chronic treatment with inhaled tobramycin improves lung function, reduces acute pulmonary exacerbations, and improves quality-of-life outcomes [80-84]. 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 efficacy of inhaled tobramycin was demonstrated in a randomized trial in 520 patients with stable CF and a wide range of pulmonary function [80]. Twice-daily treatment with 300 mg of inhalation tobramycin solution (TOBI) was administered via jet nebulizer in cycles of 28 days on the medication followed by 28 days off for 24 weeks. 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. Adverse effects included 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, ongoing use of inhaled tobramycin was associated with greater improvement in FEV1 and with an increase in body mass index [81]. 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 [83]. 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 [81,82]. Peak serum tobramycin concentrations averaged <1 mcg/mL, and no nephrotoxicity or ototoxicity was detected. A registry study reported that receiving inhaled tobramycin solution correlated with improved survival [85]. The association persisted when adjusted for patient demographics, lung function, comorbidities, microbiology, medical resource use, and other CF treatments, using a multivariate logistic regression model for mortality.

Inhaled aztreonam lysine — Inhaled aztreonam lysine is an alternative choice for chronic treatment of patients with chronic P. aeruginosa infection. It is appropriate for use in patients for whom inhaled tobramycin is not effective or not well tolerated. Aztreonam is a monobactam antibiotic with antipseudomonal activity. The lysine salt formulation is used to avoid airway inflammation.

Aztreonam is 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. The FDA-approved package insert stipulates that aztreonam must be administered using this nebulizer, which is provided to the patient together with the first supply of drug. Although the shortened delivery time is certainly helpful to patients, this benefit is no longer unique, because of the subsequent approval of a powdered form of tobramycin. Also, to achieve full benefit, the aztreonam must be administered three times per day, rather than twice per day for tobramycin. Furthermore, to maintain the efficiency of the aztreonam nebulizer, the system must be carefully cleaned after each use, which adds additional time to the treatments.

The efficacy of inhaled aztreonam lysine was demonstrated in two large clinical trials, in which patients with chronic pseudomonal lung infection were given either inhaled aztreonam lysine (75 mg) or placebo either two or three times daily for 28 days [86,87]. All patients were older than six years, had had FEV1 between 25 and 75 percent predicted, and had received 28 days of inhaled tobramycin prior to the trial. The group treated with inhaled aztreonam had a longer time before needing additional antipseudomonal antibiotics (92 days) compared with those given placebo (71 days) [86]. Furthermore, patient-reported respiratory symptom scores, FEV1, and Pseudomonas density in sputum samples also improved in the group given aztreonam. In an open-label follow-up study, 271 of the participants in these trials were given aztreonam by inhalation either two or three times per day for 28 days, followed by 28 days off treatment, for up to nine cycles [88]. Patients treated with aztreonam three times daily had greater improvements in FEV1 and better patient-reported respiratory symptom scores than those receiving aztreonam twice daily. A separate randomized study showed that the benefit of inhaled aztreonam was greatest in patients with more severe lung disease (FEV1 <90 percent predicted) compared with those with milder lung disease (FEV1 ≥90 percent predicted) [89].

Inhaled colistin — Inhaled colistin (colistimethate sodium) is used to treat chronic P. aeruginosa infection in CF. In the United States, it is delivered by nebulizing an intravenous formulation (an off-label use). Outside of the United States, formulations designed for inhalation are available, either as a powder intended for suspension in liquid and nebulization, or as capsules containing a dry powder that is directly inhaled. Potential adverse effects include bronchospasm, particularly among patients with a history of wheezing, atopy, or asthma [90]. (See "Polymyxins: An overview", section on 'Inhaled administration'.)

Colistin is a polypeptide antibiotic with antipseudomonal activity, which is preserved against many multidrug-resistant strains, including aminoglycoside-resistant strains. Unlike when administered intravenously, inhaled colistin does not appear to have significant renal toxicity and neurotoxicity. The dose is 150 mg, typically diluted in 2 mL of sterile water and administered by nebulizer twice per day for 28 days, alternating with 28 days off treatment.

There are few data comparing nebulized colistin to placebo. A randomized, blinded, placebo-controlled trial of 40 subjects received twice-daily colistin compared with placebo for three months [91]. Eleven subjects did not complete the study. A score reflecting symptoms was significantly better in the colistin group, but FEV1 was not significantly different. Better evidence exists evaluating the dry powder formulation: In a phase 3 trial, 380 subjects were randomized to twice-daily inhaled colistin for 24 weeks without interruption versus twice-daily tobramycin that was cycled on and off every four weeks [92]. There was no difference in FEV1, the primary endpoint. These results led to regulatory approval of the dry powder formulation in the European Union. Inhaled colistin is being studied in combination with other antibiotics for various clinical situations.

Comparison of different inhaled antibiotics — Few studies have compared the effectiveness of different inhaled antibiotics, so firm conclusions cannot be made.

Tobramycin versus colistin – Two randomized trials comparing inhaled tobramycin with colistin in patients with chronic P. aeruginosa infection yielded conflicting results. In one trial, treatment with inhaled tobramycin for one month improved lung function (FEV1 percent predicted), whereas inhaled colistin did not [93]. An open-label five-month extension showed persistence of the superiority of tobramycin over colistin [94]. Contrasting results were found in a different trial of 380 subjects who were treated with three 28-day cycles of inhaled nebulized tobramycin or a powered preparation of colistimethate over a total of 24 weeks [92]. Colistin was found to be noninferior to tobramycin for the primary endpoint, which was change in mean FEV1 percent predicted from baseline to week 24. Additional clinical trials will be needed to resolve whether there is an efficacy difference between tobramycin and colistimethate.

Tobramycin versus aztreonam – One randomized trial in 268 patients suggested an advantage of switching from inhaled tobramycin to aztreonam. After three 28-day cycles of treatment, the group treated with aztreonam had mean FEV1 percent predicted that was 7.8 percent higher than the tobramycin group (95% CI 3.86-11.73, p<0.001) [95]. A potentially confounding factor is that during the year prior to enrollment, 85 percent of the patients enrolled in this study had been treated with inhaled tobramycin and some had been treated with colistimethate. Apparently none had received aztreonam. Therefore, this study reflects primarily the effects of switching from tobramycin to aztreonam, rather than the effect of each treatment in previously untreated patients. Unfortunately, there are no studies comparing tobramycin with aztreonam in patients who are naïve to both drugs or who have been receiving chronic aztreonam but not tobramycin.

Colistin versus other inhaled antibiotics – A United Kingdom CF registry study found no difference in safety indicators of patients prescribed dry powder colistin with those receiving any other inhaled antibiotics [41].

Oral azithromycin — Azithromycin is a macrolide antibiotic that has been shown in randomized trials to have clinical benefit including for those with chronic P. aeruginosa infection, 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 has antiinflammatory properties or that it alters the Pseudomonas phenotype without inhibiting bacterial growth. 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 'Azithromycin'.)

Of note, concern has been raised that chronic use of oral azithromycin may reduce the efficacy of inhaled or intravenous tobramycin. Retrospective analyses of data collected in trials of inhaled aztreonam and tobramycin found that patients receiving oral azithromycin showed less improvement in FEV1 from inhaled tobramycin compared with inhaled aztreonam [96,97]. However, a prospective clinical trial of azithromycin versus placebo on relative change from baseline in FEV1 following four weeks of inhaled tobramycin found no significant effect from azithromycin (NCT02677701) (see "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Azithromycin'). In contrast, an antagonistic effect of azithromycin has been reported for intravenous tobramycin used to treat pulmonary exacerbations. (See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations", section on 'Managing the chronically prescribed antibiotics'.)

There is no consensus within the CF community on how to respond to this provocative but as yet inconclusive information [98]. Options include avoiding chronic azithromycin for patients who are likely to be prescribed tobramycin in the near future, prescribing azithromycin but selecting antibiotics other than tobramycin to treat pulmonary exacerbations, or continuing the current practice of prescribing both azithromycin and tobramycin while waiting for more definitive data.

Practices that are not recommended — The following interventions have been advocated to control the progression of pulmonary disease. We do not recommend their use, due to lack of evidence for benefit and potential risks including induction of antibiotic resistance.

Other oral antibiotics — We suggest not prescribing chronic or intermittent oral antibiotics other than azithromycin, because their uncertain benefits do not outweigh the problems caused by induction of antibiotic resistance and side effects. Despite the lack of experimental evidence, it is the practice of some clinicians 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 [99]. This is particularly true for fluoroquinolones, which have a high propensity to induce both reversible and permanent resistance in P. aeruginosa.

Intermittent courses of prophylactic antibiotics have been advocated as a means of conferring benefit with less risk of subsequent resistance. However, there are few 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 FEV1, the number of hospitalizations, or the requirement for intravenous antibiotics [100].

Periodic hospitalizations — We advise against regularly planned hospitalizations for preventive therapy, which may include intravenous antibiotics and intensified airway clearance therapies (referred to as "clean outs") [101]. This practice was frequently used in the past but has been generally abandoned in North America and many other settings due to lack of proof of benefit, high cost of treatment, and disruption of patients' daily lives. 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.

The practice of periodic hospitalization for clean out was pioneered by clinicians in the Danish Cystic Fibrosis Center in Copenhagen [102]. Patients chronically infected with P. aeruginosa were admitted to a hospital for two weeks every three to four months to receive intravenous and inhaled antibiotics. 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.

Only a few randomized trials have examined periodic elective hospitalization, and these have failed to show benefit compared with hospitalization of patients only when they are clinically worsening [103-105]. A trial of 19 subjects with modestly elevated titer of anti-Pseudomonas immunoglobulin G (IgG; implying recent infection) were sequentially assigned to usual care or to be hospitalized with intravenous antipseudomonal antibiotics every four months. After one year, FEV1 did not differ between groups [105]. A larger prospective trial randomly assigned 60 patients to receive either regular antipseudomonal antibiotics every three months (clean out) or antibiotics only when indicated by clinical deterioration (symptomatically treated) [104]. After three years of follow-up, no significant differences in spirometry or survival were noted between the two groups. Of note, the number of days of intravenous antibiotics in the clean out group was only slightly higher (1.2 to 1.5 times) than the symptomatically treated group. In the earlier Danish report, patients treated with periodic hospitalization for clean out received approximately 1.9 times the amount of intravenous antibiotics as compared with their historical controls [102]. Some authors have suggested that the United Kingdom study did not adequately test the role of scheduled therapy, because the intensity of antibiotic therapy in the symptomatically treated group was relatively high [106].

OTHER SPECIFIC PATHOGENS

Aspergillus species — Cultures of sputum from patients with CF often yield Aspergillus species, but there is insufficient evidence to recommend treatment solely on its presence [107]. We do consider treatment when criteria are met for allergic bronchopulmonary aspergillosis [108-110] (see "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis", section on 'Diagnosis of ABPA in cystic fibrosis' and "Treatment of allergic bronchopulmonary aspergillosis"). The practice of using azoles varies among lung transplant centers for patients with Aspergillus in respiratory secretions, with some using them pre-transplant and many post-transplant [111]. (See "Prophylaxis of infections in solid organ transplantation" and "Fungal infections following lung transplantation".)

Results of observational studies are conflicting regarding the consequences of detecting Aspergillus in respiratory secretions, with several studies suggesting no association between the presence of Aspergillus and the clinical course in patients without allergic symptoms [112-115], while another study did find this association [116]. However, it is not clear whether this association is causal or whether Aspergillus is merely a marker of more severe lung disease.

Studies have generally failed to show a benefit of treating Aspergillus in patients without allergic symptoms. A small trial randomized subjects with persistently positive Aspergillus cultures to 24 weeks of itraconazole therapy versus placebo [117]. No statistically significant improvement in time to next pulmonary exacerbation or in forced expiratory volume in one second (FEV1) were noted with itraconazole treatment, but the study was limited by the small number of participants and the observation that 43 percent of the subjects treated with itraconazole did not achieve what was considered to be therapeutic blood levels. No randomized trials have been performed testing efficacy of voriconazole or posaconazole in CF patients. However, the better bioavailability of voriconazole has led many clinicians to use it in place of itraconazole [118]. Regardless, drug level monitoring is recommended for itraconazole, voriconazole, and posaconazole due to patient-to-patient variation in drug absorption and metabolism. (See "Pharmacology of azoles".)

Of note, itraconazole, voriconazole, and posaconazole are strong inhibitors of cytochrome P450 3A4, the predominant enzyme that metabolizes elexacaftor, tezacaftor, and ivacaftor (see "Pharmacology of azoles"). Dose reduction of these CF transmembrane conductance regulator (CFTR) modulators is required when co-administered with these antifungal agents. These azoles can induce liver injury, and voriconazole is associated with vision changes and photosensitivity reactions. (See "Ivacaftor: Drug information" and "Tezacaftor and ivacaftor: Drug information" and "Elexacaftor, tezacaftor, and ivacaftor co-packaged with ivacaftor: Drug information".)

Nontuberculous mycobacteria — Nontuberculous mycobacteria (NTM) can be isolated from the sputum in 10 to 20 percent of individuals with CF, including M. avium complex and M. abscessus complex (see 'Nontuberculous mycobacteria' above). Those with sputum samples that are smear-positive for acid-fast bacilli (AFB) are likely to have a higher burden of bacteria than those who are smear-negative. The clinical implications of detecting NTM in sputum samples of patients with CF are variable, but in some cases, the infection is associated with declining pulmonary status and warrants treatment.

Progressive inflammatory lung damage, known as NTM pulmonary disease, occurs in a subset of patients with NTM, causing increased cough, sputum production, shortness of breath, and deteriorating pulmonary function tests. Fever, night sweats, and weight loss are uncommon in CF patients with NTM disease, but if these features are present, they support this diagnosis. It is estimated that between 20 to 59 percent of CF patients with positive NTM cultures meet diagnostic criteria for NTM pulmonary disease [119]. Although radiographic features of NTM pulmonary disease overlap with those seen in the general CF population, high-resolution computed tomography (HRCT) findings that suggest concomitant NTM lung disease are prominent nodular infiltrates, tree-in-bud opacities in lung regions having minimal bronchiectasis, and parenchymal cavities.

Identifying CF patients who might have NTM pulmonary disease is best done by routine screening for all CF patients and by early evaluation of the subgroup of patients who have signs and symptoms suggesting NTM pulmonary disease. An expert panel convened jointly by the Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) has published a comprehensive set of recommendations for the screening, diagnosis, and management of NTM in CF, with which we concur [24].

Screening – To detect NTM in patients with CF, we recommend that all expectorating patients have their sputum screened annually by examining smears stained for AFB and culture. Oropharyngeal swabs are not recommended. The recommendations by the CFF/ECFS panel regarding collection and processing of the samples should be followed [24]. If NTM are isolated, they should be further identified using molecular techniques. Patients screening positive and those with a clinical suspicion of NTM pulmonary disease suggested by worsening pulmonary symptoms or accelerated decline in FEV1 should be further evaluated to determine if they fulfill diagnostic criteria for NTM lung disease, as detailed below.

Importantly, for any patient taking chronic azithromycin who screens positive for NTM or who is suspected of being infected with NTM, the azithromycin should be temporarily halted pending further diagnostic evaluation to reduce the risk that monotherapy will induce resistance of the NTM to azithromycin. A single-center retrospective study reported that initial isolates of mycobacterium avium complex in CF patients receiving chronic azithromycin therapy are unlikely to be macrolide resistant [120]. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Azithromycin'.)

Diagnosis – Diagnostic criteria for NTM pulmonary disease in CF patients are the same as for the general population, as initially outlined by the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) [32] and endorsed by the CFF/ECFS expert panel [24]. These criteria require symptoms suggesting active NTM disease, imaging studies (HRCT) consistent with NTM pulmonary disease, and microbiologic identification of NTM (table 2) [32] (see "Overview of nontuberculous mycobacterial infections", section on 'Diagnostic criteria'). Other pathogens and comorbidities should be considered as potential contributors to the patient's symptoms and radiologic findings.

When clinical features suggest NTM pulmonary disease, the patient should have respiratory secretions tested for NTM and an HRCT performed (algorithm 1) [24]. The microbiologic evaluation follows a stepwise approach, starting with examination of expectorated or induced sputum. If the results of sputum testing are negative and imaging is suspicious for NTM pulmonary disease, bronchoscopy should be performed, with bronchial washing or bronchoalveolar lavage targeted to lung regions appearing suspicious for NTM disease on HRCT. The microbiologic criteria for diagnosis of NTM pulmonary disease require isolation of NTM from sputum on two occasions or from bronchial wash/alveolar lavage on one occasion [32]. Transbronchial lung biopsies should not be performed routinely, because the risks of complications including pneumothorax and hemoptysis likely exceed the diagnostic benefit.

Those patients with NTM detected during annual sputum screening should be scrutinized carefully for evidence of active NTM pulmonary disease. Additional sputum samples should be examined by AFB staining and culture. Those with suspicious symptoms, worsening pulmonary function test results, or repeatedly positive AFB cultures should have an HRCT performed. The diagnosis of NTM pulmonary disease should be made if the accumulated data fulfill the ATS/IDSA criteria.

Treatment – If the diagnostic criteria for NTM pulmonary disease are fulfilled, treatment for NTM should be seriously considered. However, prior to initiating treatment, it is appropriate to provide a course of intensified treatment targeting the bacteria other than NTM that infect the patient's airways (see "Cystic fibrosis: Management of pulmonary exacerbations"). If such treatment returns the patient to a baseline level of symptoms and lung function, NTM treatment may be deferred but with close follow-up. Unfortunately, eradication of NTM from airway secretions of CF patients is difficult to achieve, particularly in those infected with M. abscessus, and drug toxicities are frequent [31,121,122]. The decision to initiate NTM therapy needs to be individualized for each patient based on assessment of risks and benefits and consultation with infectious diseases specialists with CF experience. Some patients may be better served if left untreated [123].

If the decision is made to treat NTM pulmonary disease in a patient with CF, the approach to treatment is similar to that for patients without CF, except that daily rather than intermittent antibiotic therapy is preferred [24]. Other details of treatment in patients without CF are discussed separately. (See "Treatment of Mycobacterium avium complex pulmonary infection in adults".)

Transplant considerations – Infection with M. avium complex appears to have no adverse impact on patients with CF who undergo lung transplantation [124-126]. However, M. abscessus complex infection can complicate lung transplantation, causing soft tissue and mediastinal abscesses that can recur despite treatment with surgical drainage and antibiotics. The CFF/ECFS guidelines recommend that assessment for NTM pulmonary disease be included in any lung transplant evaluation and that NTM be treated prior to transplant if detected [24]. Current or previous positive cultures for NTM should not preclude consideration for transplant, and patients with evidence of eradication or sequential negative cultures during treatment may be eligible for transplant listing, although there are significant variations in policy among centers [126]. Persistent M. avium complex or M. abscessus complex infection despite optimal treatment is not an absolute contraindication for transplantation. Referral of candidates to centers having special expertise in transplanting patients with these organisms should be considered.

INFECTION PREVENTION AND CONTROL — Evidence is accumulating that a variety of respiratory pathogens can be transmitted among individuals with CF within the health care system, despite implementation of infection control guidelines similar to those that were published in 2003 by the Cystic Fibrosis Foundation (CFF). In particular, highly transmissible strains of P. aeruginosa have been reported in Europe, Canada, and Australia [127,128], and infection with these strains is associated with increased health care needs and antibiotic use as compared with infection with sporadic strains [10,129] (see 'Pseudomonas aeruginosa' above). Spread of Burkholderia species, methicillin-resistant S. aureus (MRSA), and multidrug-resistant M. abscessus between CF patients has been detected in individual CF centers [29,33,130,131]. Less commonly, strains of S. maltophilia, Achromobacter species, and other Gram-negative pathogens may be shared by individuals with CF.

The possibility of transmission of M. abscessus between patients was explored in a study that employed whole-genome analysis of 1080 clinical isolates of M. abscessus from 517 CF patients attending centers in Europe, the United States, and Australia [29]. Isolates obtained from these widely scattered sites were found to have near-identical sequences. These findings led the authors to suggest worldwide person-to-person transmission of M. abscessus clones between CF patients. However, the study did not exclude another likely explanation for their findings, which is that the clones are distributed globally in the environment and that patients become infected from them locally without direct patient-to-patient transmission. Following publication of this article, the CFF has made no new recommendations beyond the existing guidelines, which are designed to limit spread of all infectious agents between CF patients.

To minimize risk of transmission, the CFF has published updated guidelines for infection prevention and control to be applied to all individuals with CF, regardless of respiratory tract culture results [130]. Although few of the guidelines have been tested to determine their independent effectiveness in limiting transfer of microorganisms, implementation of sets of enhanced guidelines has been successful at terminating transmission at individual CF centers experiencing spread of specific bacteria. The new guidelines include:

Contact precautions – Clinicians should always use contact precautions (ie, gown and gloves) when caring for individuals with CF in ambulatory and inpatient settings.

Spacing of patients – Individuals with CF should be separated from each other by at least six feet in all settings to reduce the risk of droplet transmission of CF pathogens. This includes measures so that patients do not spend time in a waiting room or common area. Inpatients with CF should be housed in a single-patient hospital room.

Hand hygiene – All individuals with CF, family members, and friends should perform hand hygiene where there is potential for contamination of hands with pathogens (eg, entering and exiting CF clinic, examination room, or hospital room or after performing chest physiotherapy).

Masks – All individuals with CF should routinely wear a surgical mask when in a health care setting [132]. Reusable cloth masks that some patients obtain commercially provide inadequate protection and are not recommended for use in health care settings.

In addition, the guideline includes specific measures for pulmonary function testing and sterilization of hospital equipment [130].

PREVENTIVE CARE — Inflammation induced by viral upper respiratory tract infections appears to initiate exacerbations of CF lung disease. For all infants with CF, immunoprophylaxis with nirsevimab is recommended during the first respiratory syncytial virus (RSV) season (similar to all infants), and selected infants should also receive nirsevimab during the second RSV season. Annual immunization against influenza is also recommended for all people with CF beginning at six months of age, unless they have strong contraindications to receiving the vaccine. Although people with CF become infected with Streptococcus pneumoniae only rarely, the availability and safety of the vaccine make its use advisable in this population. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Prevention of infection' and "Respiratory syncytial virus infection: Prevention in infants and children", section on 'Immunoprophylaxis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cystic fibrosis".)

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 5th to 6th 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 10th to 12th 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 education: Cystic fibrosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Common pathogens – Cystic fibrosis (CF) lung disease is characterized by persistent bacterial infection. Staphylococcus aureus and Pseudomonas aeruginosa are the most prevalent pathogens (figure 2 and table 1). (See 'Pathogens' above.)

Sputum cultures – Cultures of expectorated sputum or throat swabs should be performed at least every three months during routine clinic visits.

When P. aeruginosa is first detected, we recommend prompt treatment using an early eradication protocol, rather than delayed or no treatment (Grade 1B). We suggest using inhaled tobramycin alone (300 mg in 5 mL, administered twice daily) for 28 days, rather than a regimen including other antibiotics (Grade 2C). The therapy is repeated only if surveillance cultures show recurrence of P. aeruginosa. (See 'Prevention and eradication' above.)

The results of sputum cultures are used to guide selection of antibiotics in the event of an acute exacerbation. (See 'Periodic surveillance cultures' above and "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations".)

Pseudomonas infection – For patients with persistent P. aeruginosa infection, we recommend chronic treatment with inhaled tobramycin, rather than no inhaled antibiotic (Grade 1B). Inhaled aztreonam lysine is a reasonable alternative, as is inhaled colistin. The inhaled antibiotic is typically cycled between 28 days on and 28 days off treatment. For patients with deteriorating pulmonary status and/or recurrent pulmonary exacerbations despite cyclic treatment with a single inhaled antibiotic, it is becoming common practice to administer inhaled antibiotics continuously, by alternating 28 days of one antibiotic with 28 days of another. (See 'Inhaled antibiotics' above.)

Not recommended

Chronic oral antibiotics – We suggest against prescribing chronic or intermittent oral antibiotic therapy other than oral azithromycin (Grade 2C). Evidence of benefit is lacking, and there is concern about promoting antibiotic resistance with this therapy. (See 'Other oral antibiotics' above.)

Indications for chronic treatment with oral azithromycin are discussed separately. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Azithromycin'.)

Periodic hospitalizations – In addition, we suggest against performing regularly scheduled elective hospitalizations for antibiotics and intensified chest physiotherapy ("clean outs") (Grade 2C). Limited clinical trial data suggest that this treatment approach is not more effective than hospitalization only for acute pulmonary exacerbations. (See 'Periodic hospitalizations' above.)

Nontuberculous mycobacteria (NTM) – NTM are increasingly identified in patients with CF. The clinical implications of detecting NTM in sputum samples of patients with CF are variable, but in some cases, the infection is associated with declining pulmonary function and warrants treatment. All expectorating patients should have annual screening for NTM in sputum. Those testing positive and patients with a clinical suspicion of NTM pulmonary disease suggested by unexplained worsening of symptoms or pulmonary function test results should be further evaluated. For any patient taking chronic azithromycin who screen positive for NTM or who is suspected of being infected with NTM, azithromycin should be temporarily held pending further evaluation to reduce the risk that monotherapy will induce resistance of the NTM to azithromycin. (See 'Nontuberculous mycobacteria' above.)

Infection control – To reduce transmission of pathogens, the Cystic Fibrosis Foundation (CFF) recommends the following measures for all CF patients, regardless of a patient's respiratory tract culture results (see 'Infection prevention and control' above):

Clinicians use contact precautions (gown and surgical masks) at all times

Patients wear surgical masks in the health care setting

Patients with CF should not congregate within or outside of the health care setting and should be separated by at least six feet, and inpatients with CF should be housed in single-patient rooms

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Topic 6371 Version 72.0

References

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