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Aerosol antibiotics – Not just for CF
Bruce K. Rubin MEngr, MD, MBA, FRCPC
Jessie Ball duPont Distinguished Professor and Chairman
Virginia Commonwealth University Department of Pediatrics
Physician in Chief; Children’s Hospital of Richmond
Richmond, VA, USA
Abbreviations
CF cystic fibrosis
CRS chronic rhinosinusitis
FEV1 forced expiratory volume in the first second of exhalation
TSI tobramycin solution for inhalation (TOBI)
VAP ventilator associated pneumonia
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Introduction
Aerosols can deliver high concentrations of antibiotics to the airway with low
systemic bioavailability, thus reducing toxicity. This approach is of particular vakue in
patients with cystic fibrosis (CF), who require frequent courses of antibiotic therapy. In
the phase 3 registration study, 468 patients with CF were enrolled in a 6-month masked,
placebo-controlled trial of preservative-free, non pyrogenic tobramycin solution for
inhalation (TSI) 300 mg, alternating between 4-week courses of tobramycin and placebo.
The forced expiratory volume in 1 second (FEV1) increased by more than 11% by the end
of 6 months, with a 36% reduction in the mean number of hospital days and a 10-fold
reduction in sputum bacterial density. Other antibiotics being prepared for aerosol
delivery include colistin, gentamicin, ciprofloxacin, levofloxacin, amikacin, and
aztreonam. Although aerosolized antibiotics may find a role in the therapy of patients
with diseases other than CF, the emergence of bacterial resistance to these antibiotics is a
risk, thus efficacy must be clearly demonstrated for a favorable cost benefit.
Non-CF bronchiectasis
Bronchiectasis is caused by reoccurring or continuous presence of bacteria in
association with airway obstruction. Although CF is the most common cause of
childhood bronchiectasis, there are many other causes. Secretions in the bronchiectasis
airway are similar to the pus found in the CF airway, and pulmonary complications and
progression of disease in non-CF bronchiectasis is similar to CF bronchiectasis, thus
many centers treat patients with bronchiectasis using aerosolized antibiotics. There have
been only a few small studies of aerosolized antibiotics to treat pseudomonas infection in
adults with non-CF bronchiectasis. Reported studies have been underpowered for long
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term outcomes of interest such as time to exacerbations, hospitalization, or frequency of
exacerbation. Although there is a reduction in sputum bacterial density while patients are
receiving TSI if Pseudomonas is the primary pathogen, this has not been associated with
improved quality of life, decreased need for additional antibiotics, or improvement in
pulmonary function. Dyspnea and wheezing appear to occur more commonly in adult
patients with non-CF bronchiectasis than in CF patients who receive TSI and there is a
concerning deterioration in airflow (FEV1) among patients with non-CF bronchiectasis
who receive TSI when compared to those who receive placebo aerosol. It is unknown if
other inhaled antibiotics such as colistin or aztreonam will be tolerated or have better
long term outcome for the treatment of non-CF bronchiectasis.
It is important when conducting studies not only to ensure that they have
sufficient power to detect clinically significant outcomes, but that the study population is
fairly homogeneous. For example, aerosolized antibiotics may not be the most effective
or efficient way to deliver antibiotics to a patient with isolated lobar bronchiectasis
resulting from a severe respiratory infection or retained foreign body. As well patients
with weakness, poor cough, underlying immunodeficiency, or other systemic causes of
bronchiectasis are at high risk of disease recurrence unless the underlying cause of the
bronchiectasis is treated along with treating the infection itself. Although the use of
aerosol antibiotics for patients with non-CF bronchiectasis is theoretically attractive, this
therapy cannot be recommended unless safety is improved and efficacy is assured.
Ventilator associated pneumonia (VAP)
VAP significantly increases intensive care morbidity, mortality, and costs. VAP is
thought to be caused by bacterial entry into injured airways producing tracheobronchitis
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that evolves into diffuse pneumonia. The use of aerosolized antibiotics is conceptually
attractive, especially when the infection is early and limited to the airway epithelium. The
clinical evidence for aerosolized antibiotics in preventing VAP is weak but suggestive.
However, there are concerns about antibiotic resistance developing with this approach.
These concerns, coupled with costs and other potential risks with aerosolized antibiotics,
has led several evidence based consensus groups to recommend against routine use in
VAP prevention until better data are available. Importantly, the clinical evidence that
aerosolized antibiotics can treat established VAP is negative and many consensus groups
recommend against this approach.
In children with chronic indwelling tracheostomy, bacterial isolated from routine
tracheostomy cultures usually change to different pathogens at the time of tracheitis
making it more difficult to anticipate and properly direct antimicrobial therapy. Although
it is possible that aerosolized antibiotics may be found to be useful in preventing VAP,
data are too few to support their routine use at this time.
Nasal and sinus disease
Chronic rhinosinusitis (CRS) is nearly universal in CF and is extremely common
in non-CF bronchiectasis and chronic obstructive pulmonary disease. CRS probably
contributes to morbidity in persons with these diseases. An uncontrolled pilot study of
aerosol therapy using a variety of different antibiotics suggested clinical benefit and more
rapid resolution of symptoms. Delivering aerosol to occluded sinus ostia is challenging
but newer nebulizer devices with pulsating airflow may overcome some of these
obstacles.
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Recommendations
Future studies should be powered with clinically significant outcomes in
populations with well defined and more uniform underlying diagnoses. Other goals
should be to develop strategies to enhance the lower respiratory deposition of
medications and the translocation of the antibiotic into the sputum and biofilm layer.
Strategies to decrease the development of resistance should also be evaluated; perhaps by
cycling antibiotics or by using aerosol antibiotics in combination with systemic
antibiotics.
It will be important to limit the therapy to targeted antibiotics given for a short a
time as possible. We also must identify which of the available antibiotics are most likely
to be effective, when they should be started, in which patients, at which dose, and for
how long.
References
1. Rubin BK. Overview of cystic fibrosis and non-CF bronchiectasis. Semin. Resp Crit
Care Med 2003;24:619-627.
2. Rubin BK. Aerosolized antibiotics for non-cystic fibrosis bronchiectasis. J Aerosol
Med Pulm Drug Deliv 2008;21:71-76.
3. MacIntyre N, Rubin BK. Should aerosolized antibiotics be used for the prevention and
therapy of ventilator associated pneumonia in patients who do not have cystic fibrosis?
Resp Care 2007; 52:416-22.
4. Kline JM,Woods CR, Ervin SE, Rubin BK, Kirse DJ. Surveillance tracheal aspirate
cultures do not reliably predict bacteria cultured at the time of an acute respiratory
infection in children with tracheostomy tubes. Chest 2011 (in press)
5. Robertson JM, Friedman EM, Rubin BK. Nasal and sinus disease in cystic fibrosis.
Paed. Respir. Rev. 2008;9:213-19
6. Scheinberg PA, Otsuji A. Nebulized antibiotics for the treatment of acute
exacerbations of chronic rhinosinusitis. Ear Nose Throat J. 2002;81:648-52