(Chest. 2001;120:114S-117S.)
© 2001
American College of Chest Physicians
Treatment With Tobramycin Solution for Inhalation in Bronchiectasis Patients With Pseudomonas aeruginosa*
Leslie A. Couch, MD, FCCP
*
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{at}uthct.edu
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Abstract
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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.
Key Words: bronchiectasis • Pseudomonas aeruginosa • tobramycin solution for inhalation
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Introduction
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Bronchiectasis
is a chronic disorder of the bronchi and bronchioles. It is
characterized by permanent bronchial 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, high-resolution 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
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 (Kartagener’s 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.
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Materials and Methods
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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 patient’s general
medical condition at the follow-up visit (week 6).
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Microbiology Results
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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 an inclusion criterion, 85 of the 125 patients (68%)
who were screened for this study were shown to harbor PA in their
sputum. Other investigators3
4
5
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 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.
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Bacterial Resistance
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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 µg/mL). A break point
for aerosol delivery may be difficult to determine, as the mean sputum
level of tobramycin in the TSI-treated patients was 1,370 mg/g
sputum (range, 25 to 5,655 mg/g).
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Clinical Results
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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.
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Adverse Events
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Patients treated with TSI reported more treatment-emergent 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.
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Physician Assessment
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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.
Thirty-eight percent of the placebo-treated patients were assessed as
improved. However, there was essentially no change in microbial load in
these patients, and, thus, these improvements may reflect a placebo
effect.
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Conclusion
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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.
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Footnotes
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Abbreviations: CF = cystic
fibrosis; MAC = Mycobacterium avium-intracellulare;
PA = Pseudomonas aeruginosa; TSI = tobramycin
solution for inhalation
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References
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Stockley RA, Shaw J, Hill SL, et al. Neutrophil chemotaxis in bronchiectasis: a study of peripheral cells and lung secretions. Clin Sci (Lond) 1988; 74:645–650
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Ip, M, Liong, E, Shum, D (1992) Sputum neutrophil activity in stable bronchiectasis. Med Sci Res 20,739-740
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Nicotra, MB, Rivera, M, Dale, AM, et al (1995) Clinical, pathophysiologic, and microbiologic characterization of bronchiectasis in an aging cohort. Chest 108,955-961[Abstract/Free Full Text]
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Miszkiel, KA, Wells, AU, Rubens, MB, et al (1997) Effects of airway infection by Pseudomonas aeruginosa: a computed tomographic study. Thorax 52,260-264[Abstract]
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Wilson, CV, Jones, PW, O’Leary, CJ, et al (1997) Effect of sputum bacteriology on the quality of life of patients with bronchiectasis. Eur Respir J 10,1754-1760[Abstract]
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Ramsey, BW, Pepe, MS, Quan, JM, et al (1999) Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 340,23-30[Abstract/Free Full Text]
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Abstract
Introduction
