Cystic Fibrosis - Antibiotic Therapy For Chronic Pulmonary Infection - UpToDate

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Cystic fibrosis: Antibiotic therapy for chronic pulmonary

infection
AUTHOR: Richard H Simon, MD
SECTION EDITOR: James F Chmiel, MD, MPH
DEPUTY EDITOR: Alison G Hoppin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2023.

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".)
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● (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
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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

GRAPHICS
Median predicted survival of patients with cystic fibrosis
This chart depicts the birth year on the x-axis and median predicted survival for that birth cohort on
the y-axis. The median predicted survival for a given birth year is the age at which one-half of the
those born that year are predicted to survive beyond, given the age distribution of deaths that
occurred during that specific year and assuming no future changes in mortality rate. Statistics from
1940 to 1978 are collected from Davis et al [1] . Statistics from 1990 to 2022 are collected from the
Cystic Fibrosis Foundation Patient Registry [2] .
Data from:
1. Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med 1996; 154:1229.
2. 2022 Patient Registry Annual Data Report. Cystic Fibrosis Foundation. https://www.cff.org/medical-
professionals/patient-registry (Accessed on November 8, 2023).
Graphic 61930 Version 18.0

Microorganisms isolated from respiratory secretions of patients with cystic

fibrosis, all ages
Organism Percent with positive respiratory

cultures
Staphylococcus aureus 60.8%
Methicillin-resistant S. aureus (MRSA) 15.6%
Pseudomonas aeruginosa 26.0%
Multidrug-resistant P. aeruginosa (MDR-PA) 3.3%
Stenotrophomonas maltophilia 5.0%
Burkholderia cepacia complex 1.3%
Achromobacter (Alcaligenes) xylosoxidans 2.4%
Nontuberculous mycobacteria (NTM) 10.3%*
* For NTM, this represents the percentage of patients with 1 or more mycobacterial species isolated
among those who had at least 1 mycobacterial culture performed during 2022.
Data from: 2022 Patient Registry Annual Data Report. Cystic Fibrosis Foundation. https://www.cff.org/medical-
professionals/patient-registry (Accessed January 8, 2024).

Prevalence of bacteria identified in respiratory secretions from patients with

cystic fibrosis, by age cohort
The graph shows the proportion of individuals in various age groups who had positive cultures for
each of these bacterial species during 2019. We did not include data from the 2020 and 2021 Cystic
Fibrosis Foundation Patient Registry reports, which may be misleading because many fewer cultures
were collected during that period due to the COVID-19 pandemic.
P. aeruginosa: Pseudomonas aeruginosa; H. influenza: Haemophilus influenza; B. cepacia complex:

Burkholderia cepacia complex; S. aureus: Staphylococcus aureus; MRSA: methicillin-resistant S. aureus;
Achromobacter: Achromobacter xylosoxidans; S. maltophilia: Stenotrophomonas maltophilia; MDR-PA:
multidrug-resistant P. aeruginosa; COVID-19: coronavirus disease 2019.
Reproduced with permission from: Cystic Fibrosis Foundation Patient Registry: 2019 Annual Data Report, Bethesda, MD.
Copyright © 2020 Cystic Fibrosis Foundation.

Clinical and microbiologic criteria for diagnosing nontuberculous

mycobacterial pulmonary disease [1]
Clinical and radiologic criteria (all required)
1. Pulmonary or systemic symptoms
and
2. Nodular or cavitary opacities on chest radiograph or bronchiectasis with multiple small nodules on
high-resolution computed tomography
and
3. Appropriate exclusion of other diagnoses
Microbiologic criteria (at least one required)*
1. Positive culture results from at least two separate expectorated sputum samples. If the results are
nondiagnostic, consider repeat sputum AFB smears and cultures.
or
2. Positive culture result from at least one bronchial wash or lavage.
or
3. Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous

inflammation or AFB) and positive culture for NTM; or biopsy showing mycobacterial histopathologic
features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are
culture positive for NTM.
Additional considerations
Expert consultation should be obtained when NTM are recovered that are infrequently encountered
or that usually represent environmental contamination.
Patients who are suspected of having NTM lung disease but do not meet the diagnostic criteria
should be followed until the diagnosis is firmly established or excluded.
Making the diagnosis of NTM lung disease does not, per se, necessitate the institution of therapy,
which is a decision based on potential risks and benefits of therapy for individual patients.
AFB: acid-fast bacilli; NTM: nontuberculous mycobacteria.
When 2 positive cultures are obtained, the isolates should be the same NTM species (or subspecies
*
in the case of M. abscessus) in order to meet disease criteria.
Originally reproduced with permission from: Griffith DE, Aksamit T, Brown-Elliott BA, et al. An Official ATS/IDSA Statement:
Diagnosis, treatment and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175:367.
Copyright © 2007 American Thoracic Society.
Updated with information from:
1. Daley CL, Iaccarino JM, Lange C, et al. Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official
ATS/ERS/ESCMID/IDSA Clinical Practice Guideline: Executive Summary. Clin Infect Dis 2020; 71:e1.

Algorithm for investigation of nontuberculous mycobacteria pulmonary

disease in patients with cystic fibrosis
An algorithm for the investigation of individuals with clinical suspicion of NTM-PD, suggested by the
United States Cystic Fibrosis Foundation and the European Cystic Fibrosis Society.
NTM-PD: nontuberculous mycobacteria pulmonary disease; CF: cystic fibrosis; AFB: acid-fast bacilli;
FEV1: forced expiratory volume in one second; HRCT: high-resolution computed tomography; CT:
computed tomography.
From: Floto RA, Olivier KN, Saiman L, et al. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus
recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis. Thorax 2016; 71:i1.
Reproduced through the Creative Commons Attribution (CC BY 4.0) license.

Contributor Disclosures
Richard H Simon, MD No relevant financial relationship(s) with ineligible companies to
disclose. James F Chmiel, MD, MPH Grant/Research/Clinical Trial Support: Cystic Fibrosis Foundation
[Cystic fibrosis]; National Institutes of Health [Asthma; cystic fibrosis]; Vertex [Cystic fibrosis].
Consultant/Advisory Boards: Cystic Fibrosis Foundation [Cystic fibrosis]; Microbion [Cystic fibrosis];
Phylaxis [Cystic fibrosis]. Other Financial Interest: American Board of Pediatrics [Honorarium received
for service on credentialing committee]; American Thoracic Society [Course Director for Fellows Track
Symposium]; Cystic Fibrosis Foundation [Honorarium received for service on clinical research
committee]. All of the relevant financial relationships listed have been mitigated. Alison G Hoppin,
MD No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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Cystic fibrosis: Antibiotic therapy for chronic pulmonary

Literature review current through: Dec 2023.

Cystic fibrosis (CF) is a multisystem disorder caused by pathogenic variants in the CF

● (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".)

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

Staphylococcus aureus — S. aureus is the bacterial pathogen most frequently identified in

Methicillin-resistant Staphylococcus aureus — MRSA has become more prevalent in the

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Burkholderia cepacia complex — Advances in bacterial genetics have revealed that B.

Chronic infection with B. cenocepacia complex bacteria is associated with an accelerated

Nontuberculous mycobacteria — NTM can be isolated from the sputum in 10 to 20 percent

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Other pathogens — Other pathogens have been identified in respiratory secretions of CF

● Nontypeable Haemophilus influenzae

CONSEQUENCES OF CYSTIC FIBROSIS LUNG INFECTION

Although chronic infection of the CF airway is sometimes referred to as "airway colonization,"

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● A subset of patients with nontuberculous mycobacteria (NTM) infection, especially M.

Several mechanisms may contribute to the persistence of bacteria in CF patients despite

PERIODIC SURVEILLANCE CULTURES

We suggest performing bacterial cultures of expectorated sputum or throat swabs at least

● To monitor for the acquisition of P. aeruginosa, which we treat with an eradication

● To guide selection of antibiotics in the event of an acute exacerbation (see

PREVENTION AND ERADICATION

Pseudomonas aeruginosa — Strategies to prevent P. aeruginosa from chronically infecting

● Prevention of acquisition – We recommend measures to prevent transmission of P.

We do not recommend prophylactic use of antibiotics targeting P. aeruginosa or S.

• A randomized trial evaluated the effects of treating children without P. aeruginosa

● Early eradication – We recommend using a protocol to detect and treat P. aeruginosa

or symptoms [49,50]. We perform cultures of expectorated sputum or throat swabs

There is no consensus regarding the approach to patients with newly acquired P.

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• The combination of 28 days of inhaled tobramycin plus 18 months of oral

• The combination of intravenous antibiotics (ceftazidime and tobramycin) and

Methicillin-resistant Staphylococcus aureus — Chronic infection with MRSA is associated

● Early eradication – Based on preliminary results, we believe it is reasonable to offer a

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No studies have compared different eradication protocols. Nevertheless, it would be

CHRONIC PULMONARY INFECTION (PSEUDOMONAS AND BURKHOLDERIA

Once P. aeruginosa or B. cepacia complex bacteria become established in the airways of a

● Tobramycin – Inhaled tobramycin is our first-line choice because of the extensive

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● Aztreonam lysine – Inhaled aztreonam lysine can be used as an alternative to inhaled

In our practice, we prescribe aztreonam particularly when:

• The patient does not tolerate inhaled tobramycin

● Continuous alternating inhaled antibiotics – For patients with deteriorating

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A retrospective analysis of 89 patients using chronic inhaled antibiotics found that 49

Although there is insufficient evidence to support the practice of alternating inhaled

Considerations and techniques for delivering medications by inhalation are discussed

Inhaled tobramycin — Chronic treatment with inhaled tobramycin is a well-established

● Dosing and administration:

• The standard inhalation solution of tobramycin is 300 mg in 4 or 5 mL, administered

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• A powdered form of tobramycin (tobramycin inhalation powder) can be prescribed

The efficacy of inhaled tobramycin was demonstrated in a randomized trial in 520