Professional Documents
Culture Documents
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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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
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
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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
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
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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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
1 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
2 Ip M, Liong E, Shum D. Sputum neutrophil activity in stable
bronchiectasis. Med Sci Res 1992; 20:739 740
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
bacteriology on the quality of life of patients with bronchiectasis. Eur Respir J 1997; 10:1754 1760
6 Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.
N Engl J Med 1999; 340:2330
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