Treatment With Tobramycin

Solution for Inhalation in

Bronchiectasis Patients With
Pseudomonas aeruginosa*
Leslie A. Couch, MD, FCCP

A randomized, placebo-controlled, multicenter trial

evaluated the safety and efficacy of 300 mg aerosolized tobramycin solution for inhalation (TSI) administered twice daily for 4 weeks in 74 bronchiectasis
patients colonized with Pseudomonas aeruginosa
(PA). Patients were evenly divided between TSI
therapy and placebo. After 2 weeks of treatment,
patients treated with TSI had a mean reduction in
sputum PA density of 4.8 log10. This reduction was
maintained for the duration of treatment. The placebo group showed no change in PA density during
the study. Two weeks after the end of therapy, PA
had been eradicated in 13 TSI-treated patients. PA
was not eradicated in any placebo patients. Among
those colonized with Staphylococcus aureus at baseline, 6 of 9 patients in the TSI group and 2 of 9
patients in the placebo group were culture negative
for this organism 2 weeks posttreatment. Sixty-two
percent of TSI-treated patients were judged by a
physician as having an improved general health
status, compared with 38% of placebo-treated patients. Dyspnea, wheezing, and chest tightness were
reported more frequently in the TSI-treated patient
group than in the placebo-treated patient group.
(CHEST 2001; 120:114S117S)
Key words: bronchiectasis; Pseudomonas aeruginosa; tobramycin solution for inhalation
Abbreviations: CF cystic fibrosis; MAC Mycobacterium aviumintracellulare; PA Pseudomonas aeruginosa; TSI tobramycin solution for inhalation

is a chronic disorder of the bronchi and

B ronchiectasis
bronchioles. It is characterized by permanent bron-

chial dilatation, microbial infection, and a persistent inflammatory response with the release of immune mediators and microbial toxins.1,2 This pathophysiologic
condition results in a decreased ability to clear secretions,
setting up a vicious cycle with infection and inflammation
becoming self-perpetuating.
Bronchiectasis is usually diagnosed in adult patients by
means of chest radiographs that reveal the tram lines that
are characteristic of this disease. More recently, highresolution CT scans have been used in the radiologic
diagnosis of bronchiectasis. Clinically, patients with bronchiectasis present with a productive cough that yields a
large volume of mucopurulent sputum. Hemoptysis is
*From the Department of Pulmonary and Critical Care Medicine, The University of Texas Health Center at Tyler, Tyler, TX.
Correspondence to: Leslie A. Couch, MD, FCCP, The University
of Texas Health Center at Tyler, 11937 US Hwy 271, Tyler, TX
75708-3154; e-mail: Leslie.couch@uthct.edu
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common, and patients may have pleuritic chest pain.

Fatigue is a frequent complaint in these chronically ill
patients, and acute exacerbations of airway symptomatology are common.
The causes of bronchiectasis are numerous. One of the
most common causes is a previous respiratory tract infection with adenovirus, measles, influenza, pertussis, Staphylococcus aureus, or Mycobacterium tuberculosis resulting
in lung damage. Aspiration of food or other foreign bodies
(commonly, following the loss of consciousness or as a
result of swallowing disorders or gastroesophageal reflux
disease) may result in bronchiectasis. Syndromes associated with bronchiectasis include primary ciliary dyskinesia
(Kartageners syndrome), immunodeficiency, middle-lobe
syndrome, and allergic bronchopulmonary aspergillosis.
The chronic nature of the infections in this disease
provides the rationale for using aerosolized antibiotics for
the treatment of bronchiectasis patients. Inhalation of
antibiotics maximizes the therapeutic effect in the lung
while minimizing systemic absorption and consequent
adverse effects such as ototoxicity and renal toxicity. The
need to minimize systemic effects is a particular concern
in the typical bronchiectasis patient as many are older and
already may have some degree of hearing loss or renal
insufficiency. In addition, such patients are frequently
receiving treatment for associated medical problems that
could interfere with systemic antibiotic therapy.

Materials and Methods

A randomized, placebo-controlled, multicenter study was conducted to evaluate the safety and microbiological efficacy of
aerosolized tobramycin solution for inhalation (TSI) (TOBI;
PathoGenesis Corporation; Seattle, WA) administered twice daily
for 4 weeks in bronchiectasis patients whose sputum contained
Pseudomonas aeruginosa (PA). This formulation of tobramycin is
sterile and nonpyrogenic, preservative-free, and stable. It is
available in 5-mL single-use ampules containing 300 mg tobramycin. The TSI aerosol was delivered using a jet nebulizer system
(PARI LC PLUS; PARI Respiratory Equipment, Inc; Richmond,
VA) and compressor (PulmoAid; DeVilbiss; Somerset, PA). Table
1 lists entry and exclusion criteria for the study.
Of the 125 patients who were screened, 74 were enrolled and
were divided equally between the two treatment groups. Patients
were treated with 300 mg TSI or a taste-masked placebo (1.25 mg
quinine sulfate) twice daily for 4 weeks. Patients were screened 2
weeks prior to the initial dose of the study drug (week 0 or
baseline), were dosed for 4 weeks, and were observed for 2 weeks
after their last dose. Thus, the total duration of the study was 8
weeks. At each visit, a culture for respiratory pathogens was
performed, and the density of PA in sputum was measured.
Pulmonary function testing (FEV1 and FVC) was performed at
baseline and at the final treatment visit (week 4). A clinical
assessment was made of the patients general medical condition
at the follow-up visit (week 6).

Microbiology Results
Microbiological Status at Screening
In addition to measuring the effects of TSI treatment on
clinical end points, this study sought to document the
sputum microbiology of bronchiectasis patients. Not surprisingly, inasmuch as the presence of this organism was
History and Evolution of Aerosolized Therapeutics

Table 1Entry Criteria for Aerosolized Tobramycin

in Bronchiectasis Study*
Inclusion
Age 18 yr
Production of 1 tablespoon purulent sputum/d
Confirmed diagnosis of bronchiectasis by CT
Presence of PA at density 104 CFU/g
Exclusion
Bronchiectasis due to CF
Allergic bronchopulmonary aspergillosis
Use of antibiotics within 2 wk of screening
History of aminoglycoside hypersensitivity
Glucose-6-phosphate dehydrogenase deficiency
Hemoptysis 60 mL within 4 wk prior to trial
Serum creatinine 2 mg/dL
BUN 40 mg/dL
Proteinuria 2 mg/dL
Pregnancy
Serious underlying medical illness (eg, liver failure or
decompensated heart failure)
*CFU colony-forming units.

an inclusion criterion, 85 of the 125 patients (68%) who

were screened for this study were shown to harbor PA in
their sputum. Other investigators35 have reported that the
percentage of patients with bronchiectasis who have PA
isolated from their sputum ranged from 10 to 34%.
Therefore, while the percentage of patients who were
colonized with different organisms in this study likely does
not represent the microbiology profile of all patients with
bronchiectasis, these data do provide insight into the
polymicrobial nature of their lung infections (Fig 1).

Patients infected with PA appeared to be less likely to be

infected with other typical respiratory pathogens, such as
S aureus and Haemophilus influenzae.
Patients also were screened for the presence of Mycobacterium since nontubercular mycobacteria frequently
infect adult bronchiectasis patients. Table 2 lists the
Mycobacterium isolates that were found at the initial
screening visit. Only 47 of the 125 patients screened for
the study produced a sputum sample of adequate size for
mycobacterial culture. Almost half (22 patients) of the 47
patients who were evaluated had a Mycobacterium
species isolated. Mycobacterium species other than
Mycobacterium avium-intracellulare (MAC) complex
that were identified included Mycobacterium gordonae
and Mycobacterium fortuitum. In one patient, a fastidious Mycobacterium species was isolated and is still
being identified.

PA Sputum Density
Figure 2 presents the mean change in sputum PA
density (log10 colony-forming units per gram) for both
TSI-treated patients and placebo-treated patients. Data
from a trial of TSI in cystic fibrosis (CF) patients6 are
shown for comparison.
At all time points during the study, patients treated with
TSI had significant reductions in sputum PA density. The
greatest reduction (4.8 log10) was observed after 2 weeks
of treatment, and this reduction was maintained through 4
weeks of treatment. Some regrowth of the organism was
noted after patients had been off-drug therapy for 2 weeks
(week 6). The placebo group essentially had no change in
sputum PA density throughout the study. At week 6 (2

Figure 1. Microbiology of screened patients.

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Table 2Initial Screening Visit Mycobacterium

Isolates

Characteristics
MAC isolated
Mycobacterium sp
not MAC
Both MAC and other
Mycobacterium sp
No Mycobacterium
isolated

TSI
(n 16)

Placebo
(n 15)

Screening
Failure
(n 16)

2
4

2
4*

5
3

10

*One of these isolates was subsequently identified as MAC.

weeks after the termination of TSI therapy), PA had been

eradicated from 13 patients receiving TSI and from no
patients receiving placebo.
Although a similar pattern of change in PA density was
seen in CF patients (ie, a maximum reduction seen after 2
weeks of treatment followed by regrowth of the organism
after therapy was discontinued), the reduction observed in
bronchiectasis patients was much greater. At the end of
the 4-week treatment period, a reduction of 4.54 log10 was
noted in TSI-treated bronchiectasis patients, compared
with a reduction of 1.9 log10 in TSI-treated CF patients.

S aureus
Nine patients (24%) in each group were colonized with
S aureus at baseline. During the 6 weeks of the study,
three patients (8%) in the TSI group and seven patients
(19%) in the placebo group became colonized with this
pathogen. Eight of the nine patients in the TSI group who

were colonized at baseline were culture-negative for this

organism at the end of treatment; for six of these eight
patients, cultures at the 2-week follow-up continued to be
negative for this organism. In the placebo group, two of
the nine patients who were positive for this organism at
baseline had negative cultures for S aureus at week 6.

H influenzae
At baseline, two patients (5%) in the TSI-treated group
and four patients (11%) in the placebo-treated group were
colonized with H influenzae. During the study, one TSI
patient had treatment-emergent isolation of H influenzae,
compared with nine patients in the placebo-treated group.
Both of the TSI-treated patients who were colonized at
baseline had cultures that were negative for this organism
at both the end of treatment and at the 2-week follow-up.
In the placebo-treated group, three of the four patients
who had been colonized at baseline had cultures that were
negative for this organism at the end of treatment; two of
these patients continued to be culture-negative at the
2-week follow-up.

Bacterial Resistance
At baseline, the tobramycin minimal inhibitory concentrations for PA in this population of patients resembled
those found in untreated reference populations. Although
no break point for resistance currently exists for inhaled
tobramycin therapy, 3 of 36 TSI-treated patients and 1 of
34 placebo-treated patients developed isolates with minimal inhibitory concentration values exceeding the resistance break point for tobramycin when given parenterally
( 16 g/mL). A break point for aerosol delivery may be
difficult to determine, as the mean sputum level of

Figure 2. Mean change in sputum PA density: bronchiectasis vs CF. CFU colony-forming units.
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History and Evolution of Aerosolized Therapeutics

Figure 3. Effect of treatment with aerosolized tobramycin on

pulmonary function: bronchiectasis vs CF.

Figure 4. Physician assessment of general health status in study

patients with bronchiectasis.

tobramycin in the TSI-treated patients was 1,370 mg/g

sputum (range, 25 to 5,655 mg/g).

sessed as improved. However, there was essentially no

change in microbial load in these patients, and, thus, these
improvements may reflect a placebo effect.

Clinical Results
Figure 3 shows the effect of treatment on pulmonary
function in both bronchiectasis and CF patients.6 In
contrast to the 11% improvement in FEV1 percent predicted observed for CF patients treated with TSI,6 patients
with bronchiectasis showed a small decline in pulmonary
function after 4 weeks of treatment. This lack of improvement in pulmonary function in bronchiectasis patients may
be due to differences in the nature of airway disease in
adult patients with bronchiectasis and in those with CF.

Adverse Events
Patients treated with TSI reported more treatmentemergent adverse events than those who received placebo.
The most common complaints were dyspnea, wheezing,
and chest pain. Half of the 12 TSI-treated patients who
developed dyspnea did so during the first 2 weeks of the
study period, while the remainder developed this symptom during the second 2 weeks of therapy. Three of 37
TSI-treated patients and none of the placebo-treated
patients withdrew from the study because of adverse
events.

Physician Assessment
The results of the general health status assessment for
the bronchiectasis patients are summarized in Figure 4.
The general health of patients was rated as improved,
worse, or unchanged in 62%, 22%, and 16%, respectively,
of the TSI group and in 38%, 13%, and 49%, respectively,
of the placebo group.
Patients in whom PA was eradicated after TSI therapy
were more likely to be assessed as clinically improved; 12
of 13 of the TSI patients (92%) with eradicated PA were
assessed as improved, while only 11 of the remaining 24
TSI patients (46%) were assessed as improved. Thirtyeight percent of the placebo-treated patients were as-

Conclusion
In summary, 4 weeks of treatment with aerosolized TSI
at a dose of 300 mg twice daily resulted in a 4.5 log10
reduction in PA density in sputum. Eradication of the
organism was sustained in 35% of the patients 2 weeks
after they stopped therapy. The TSI-treated patients also
showed improved general health status, as rated by physicians. Four weeks of this therapeutic regimen resulted in
no effect on pulmonary function. Although an increased
incidence of dyspnea, chest pain, and wheezing was noted
in the TSI group, only three patients withdrew from the
study as a result of these events.
This study raises some provocative questions regarding
the optimal duration of therapy in this patient population
as well as the minimal duration of therapy required to
produce an adequate antimicrobial effect. Further studies
also will be needed to assess additional end points such as
symptom scores and quality of life.

References
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bronchiectasis: a study of peripheral cells and lung secretions.
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2 Ip M, Liong E, Shum D. Sputum neutrophil activity in stable
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3 Nicotra MB, Rivera M, Dale AM, et al. Clinical, pathophysiologic, and microbiologic characterization of bronchiectasis
in an aging cohort. Chest 1995; 108:955961
4 Miszkiel KA, Wells AU, Rubens MB, et al. Effects of airway
infection by Pseudomonas aeruginosa: a computed tomographic study. Thorax 1997; 52:260 264
5 Wilson CV, Jones PW, OLeary CJ, et al. Effect of sputum
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N Engl J Med 1999; 340:2330

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