Study objective: To evaluate the efficacy and safety of tobramycin solution for inhalation (TSI) in patients with severe bronchiectasis.
Design: Open-label clinical trial consisting of three treatment cycles (14 days of drug therapy, and 14 days off drug) and an additional 40-week follow-up by chart review.
Setting: Nine clinical sites throughout the United States.
Subjects: Forty-one adult patients ([greater than or equal to] 18 years old) with diffuse bronchiectasis affecting two or more lung segments and a history of Pseudomonas aeruginosa infection.
Interventions: TSI, 300 mg tobramycin per dose bid.
Measurements and results: During the 12-week treatment period, significant improvements (reduction of 1.5 U [p = 0.006]) occurred in mean pulmonary total symptom severity score, a composite score that assesses the severity of cough, shortness of breath, sputum production, fatigue, and wheezing. Significant improvements (reduction of 9.8 U [p < 0.001]) were also observed in St. George Respiratory Questionnaire scores, which measure health-related quality of life. Eradication or presumed eradication of P aeruginosa occurred in 6 of 27 evaluable subjects (22.2%). Tobramycin-resistant P aeruginosa developed in two subjects (minimal inhibitory concentration [greater than or equal to] 16 [micro]g/mL). Ten subjects withdrew from the study due to adverse events; in nine of these subjects, adverse events were considered probably or possibly related to treatment. The most common adverse events were cough, wheezing, and dyspnea.
Conclusions: TSI therapy resulted in significant improvements in respiratory symptoms and health-related quality of life in subjects with severe bronchiectasis, but some subjects did not tolerate TSI therapy. Bronchiectasis patients receiving this therapy should be monitored for signs of intolerance.
Key words: bronchiectasis; chronic pulmonary disease; clinical trial; Pseudomonas aeruginosa; St. George Respiratory Questionnaire; tobramycin solution for inhalation; treatment
Abbreviations: ITT = intention to treat; LRCF = last result carried forward; SGRQ = St. George Respiratory Questionnaire; TSI = tobramycin solution for inhalation
Bronchiectasis, the abnormal and permanent dilation of the bronchi, is a chronic lung condition that can be difficult to manage. In most patients with bronchiectasis, airway damage is related to a combination of infection and the associated release of inflammatory mediators. (1) Accordingly, antibiotic therapy is frequently required to reduce infection and inflammation and to ease symptoms. Several different bacteria are commonly isolated from the sputum of patients with bronchiectasis, including Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, and Moraxella catarrhalis. Of these, P aeruginosa infection is one of the most frequently observed (2,3) and, by releasing proinflammatory cytokines, pseudomonal colonization is associated with more severe disease, as indicated by lung function tests, quality-of-life measures, number of hospital admissions, and CT imaging. (4-6)
Management of chronic infections in bronchiectasis patients is variable, and based both on the infecting species and individual clinician experience. Tobramycin solution for inhalation (TSI) has been shown to be an effective outpatient therapy for long-term treatment of pseudomonal infections in patients with cystic fibrosis. (7,8) A placebo-controlled, double-blind, randomized study (9,10) of 4 weeks of treatment with TSI in subjects with bronchiectasis and P aeruginosa infection found that TSI-treated subjects showed significantly greater clinical improvement and a significantly higher rate of Pseudomonas eradication than subjects receiving placebo. However, subjects in the TSI group experienced higher incidences of cough, dyspnea, and wheezing than placebo subjects, and a slightly higher rate of development of tobramycin-resistant Pseudomonas strains (11% vs 3% for placebo).
We sought to further characterize the efficacy and safety profile of TSI in patients with severe bronchiectasis in an open-label, multicenter, clinical trial. Our data suggest that TSI may be a useful treatment option in some patients with bronchiectasis.
MATERIALS AND METHODS
This open-label study was conducted between June 2000 and January 2002 at nine sites in the United States. The institutional review board at each site approved the study protocol and informed consent document. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice according to International Conference on Harmonisation guidelines. All subjects gave informed consent.
Subjects were required to be at least 18 years of age and to have a diagnosis of diffuse bronchiectasis affecting two or more lung segments by conventional CT or high-resolution CT scan of the chest. In addition, subjects were required to have purulent sputum production, a history of P aeruginosa in sputum, and four or more courses of antibiotics for respiratory symptoms in the past 12 months, including either one course of IV antibiotics or one course of failed oral antibiotics requiring additional antibiotic therapy for relief of symptoms. Subjects who had used TSI or smoked tobacco within 6 months of the baseline visit, used any antibiotics within 2 weeks of the baseline visit, or used any investigational agents within 4 weeks of the baseline visit were excluded from the study. Other key exclusion criteria included a diagnosis of cystic fibrosis or allergic bronchopulmonary aspergillosis at entry, known hypersensitivity to aminoglycosides, unexpected chest radiograph findings, and history of renal disease or cancer.
Subjects enrolled in this study received three treatment cycles with TSI (300 rag/5 mL tobramycin per dose) using a reusable air jet nebulizer (PARI LC Plus; PARI Respiratory Equipment; Richmond, VA) with a compressor (Pulmo-Aide; DeVilbiss; Somerset, PA). Each treatment cycle consisted of twice-daily dosing for 14 days, followed by 14 days off treatment (Fig 1). Following the third cycle, the subjects were followed up for an additional 40 weeks by chart review. The total duration of the study was 52 weeks. Treatment administration began on day 0 (baseline visit).
[FIGURE 1 OMITTED]
Subjects were given nose clips and trained in self-administration of study medication, use and cleaning of the nebulizer, and use of the compressor. The first close was administered in the hospital in the presence of the research coordinator or investigator. Subjects were instructed to self-administer the rest of the study treatments at home two times per day, approximately 12-h apart, and not < 6-h apart. No restrictions for dosing were made regarding the time of clay or relationship to meals. Those subjects receiving concomitant bronchodilators were asked to administer their bronchodilator 15 to 30 min before TSI treatment. Subjects were not allowed to use aerosolized/inhaled antibiotics other than study drug throughout the trial. Other antibiotics could be administered at the discretion of the investigator after study initiation. The use of investigational agents was not allowed at any time during the trial. Subjects were not allowed to use > 80 mg/d of furosemide at baseline or during the study, or to initiate or discontinue antidepressant therapy during the study. Other concomitant medications and therapies were permitted during this trial.
Baseline assessments were performed either during screening or before the first dose of study treatment on day 0 of the study. Efficacy assessments were performed at 2-week intervals throughout the study. Microbiological samples were obtained at week 0 and week 12 (or withdrawal visit). Sputum was cultured for the presence of P aeruginosa and other typical respiratory pathogens. Tobramycin minimal inhibitory concentration values for P aeruginosa were determined at week 0 and week 12 (or withdrawal visit). Subjects were examined at week 0 for baseline symptoms, and questioned concerning new conditions or changes in existing conditions at weeks 2, 6, 10, and 12. Clinical laboratory variables (serum chemistry, hematology, estimated creatinine clearance, and urine dipstick tests for proteinuria) were assessed at week 0 and at week 10 (or withdrawal visit). Acute broncho-constriction was evaluated by measuring FE[V.sub.1] before and 30 min after TSI dosing.
The change in the mean pulmonary total symptom severity score from week 0 to week 10 was assessed based on subject responses to the Patient Symptoms Questionnaire, which employs symptom frequency and severity scales described for the validated Memorial Symptoms Assessment Scale. (11) Symptom severity was scored on a scale of 0 (not applicable or symptom not present) to 4 (very severe) for each of five symptoms (cough, shortness of breath, sputum production [frequency and severity], fatigue, and wheezing), and a composite score (range, 0 to 20) was obtained as the sum of the severity scores for each symptom. Secondary efficacy end points included changes in the severity and intensity (frequency times severity) of individual symptoms and change in the St. George Respiratory Questionnaire (SGRQ), a self-administered questionnaire that has been validated in patients with airways disease, including specifically in patients with bronchiectasis. (12,13) The SGRQ assesses health-related quality of life in patients with chronic pulmonary disease by evaluating three health domains: symptoms (distress due to respiratory symptoms); activity (effects of disturbances to mobility and physical activity); and impacts (the effect of disease on factors such as employment, personal control of one's health, and need for medication). A composite total score is derived as the sum of domain scores for symptoms, activity, and impact, with 0 the best possible score and 100 the worst possible score. A reduction in score of 4 U is generally recognized as a clinically meaningful improvement in quality of life. (12) Other secondary efficacy end points were changes in sputum characteristics and sputum clinical microbiology from baseline. Safety end points included incidence of treatment-emergent adverse events, change in clinical laboratory tests from week 0 to week 10, and acute changes in FE[V.sub.1] 30 min after the first dose of TSI.
Treatment compliance was determined by assessments of unused drug and empty ampules returned by the subjects at week 2 and week 6, and calculated as the percentage of doses taken relative to the number of doses prescribed under the twice-daily treatment regimen for the duration of the subject's participation. In eases in which TSI vials were not returned, the dose corresponding to that vial was considered to have been administered.
For efficacy variables, the overall change from week 0 to week 10 in the intention-to-treat (ITT) population was analyzed using a paired t test to determine if the change was significantly different from zero. The statistical test was a two-tailed test, and the criterion for statistical significance was [alpha] = 0.05. The ITF analysis was performed for all subjects, using the last result carried forward (LRCF) for noncompleters, and was repeated separately for all men and all women.
Of the 106 subjects screened for the study, 41 met eligibility requirements and were enrolled at nine sites. The most common reason for exclusion in screened subjects was the absence of a history of P aeruginosa infection (n = 18), followed by an inability to travel to the clinic (n = 11). Demographic characteristics of the 41 enrolled subjects are shown in Table 1. Subjects were primarily elderly (mean age, 65.2 years), of white (not of Hispanic) origin, and had long-standing disease. The most common bronchiectasis etiology was virulent bacterial and viral infections (24 subjects), followed by other causes (8 subjects), and tuberculosis (5 subjects). All 41 subjects had a history of previous antibiotic use for respiratory events and had been prescribed anti-pseudomonal medications in the 24 mouths before study initiation.
Of the 41 enrolled subjects, 31 subjects (75.6%) completed the full three cycles of TSI treatment. Ten subjects (24.4%; 6 men and 4 women) withdrew before study completion due to adverse events. All 41 subjects received at least one dose of study treatment and were included in the ITT population for efficacy and safety analyses.
Eleven of 41 ITT subjects (26.8%) were administered antipseudomonal antibiotics other than study drug during the treatment phase for symptoms of pulmonary infection. Eight of these subjects received only oral fluoroquinolones (levofloxacin or ciprofloxacin), two subjects received IV antibiotics (ceftriaxone or piperacillin/tazobactam) in addition to oral fluoroquinolones, and one subject received only IV ceftriaxone.
Subjects were generally compliant with treatment during the study. Forty of 41 subjects (97.6%) were at least 80% compliant. The one subject who was < 80% compliant experienced numerous adverse events and was withdrawn during the second treatment cycle due to adverse events.
Between week 0 and week 10, mean pulmonary total symptom severity scores improved (decreased) by a mean [+ or -] SD of 1.5 [+ or -] 3.4 points as assessed by LRCF analysis of the ITT population (Fig 2; p = 0.006). Subgroup analyses suggested that women derived a greater benefit from TSI treatment, with a mean change of -2.0 [+ or -] 3.5 points (p = 0.008) vs - 0.7 [+ or -] 3.1 points (p = 0.408) for men. However, both men and women achieved nearly identical symptom scores following treatment (7.6 points and 7.7 points, respectively); the greater symptom severity of women at baseline (Table 1) accounted for the greater decrease in symptom scores in this subgroup. Men appeared to respond more gradually than women. Among women, reductions in pulmonary total symptom severity score were observed at the earliest time point (2 weeks) and were sustained throughout the study. Among men, reductions were not observed until the 4-week time point, and maximum response was not achieved until week 10.
[FIGURE 2 OMITTED]
The severity and intensity (frequency times severity) of all individual symptoms (cough, shortness of breath, sputum production, wheezing, and fatigue) decreased between baseline and week 10 in the total study population (Table 2). The greatest reduction in severity and intensity was seen in sputum production. In general, women experienced greater reductions in symptom severity and intensity than men.
Sputum color improved in 18 subjects (43.9%; 13 women and 5 men) and worsened in 2 (4.9%; 1 woman and 1 man) between baseline and week 10 or last assessment. In the remaining 21 subjects (51.2%; 13 women and 8 men), sputum color was unchanged. Reduction in sputum amount was observed in 25 subjects (61.0%; 18 women and 7 men) between baseline and week 10 or last assessment, whereas 7 subjects (17.1%; 6 women and 1 man) exhibited increased sputum production and 9 subjects (22.0%; 3 women and 6 men) remained unchanged. The percentages of subjects who showed reduction in sputum volume at the end of each cycle of TSI treatment were 59.5% at 2 weeks, 64.5% at 6 weeks, and 65.8% at 10 weeks.
The respiratory quality of life of subjects was assessed by use of the SGRQ. This questionnaire evaluates three domains of health--symptoms, activity, and impacts--and provides a total score on a scale of 0 to 100, with 0 representing the best possible score and 100 the worst possible score. SGRQ scores indicated that the health-related quality of life of subjects improved significantly during the study, decreasing from a baseline value of 57.4 to 46.2 at week 10 or last analysis (mean change, - 9.8 [+ or -] 13.9; p < 0.001). Each domain of the SGRQ (symptoms, activity, and impacts) showed clinically significant reductions ([greater than or equal to] 4 U), with the most profound changes being observed in the symptoms and impacts domains (Fig 3). As with symptom severity assessments, greater reductions in SGRQ scores were observed in women vs men (total SGRQ score reduction of 10.5 vs 7.9, respectively), with the greatest difference occurring in symptoms score (-14.3 vs -7.5, respectively).
[FIGURE 3 OMITTED]
To be evaluable for microbiological response, subjects must have had P aeruginosa isolated in baseline sputum samples, completed at least 5 days of treatment during the study, had no major protocol violations, and achieved at least 80% compliance with study treatment administration requirements. Of the 41 subjects, 27 subjects (65.9%; 20 women and 7 men) were evaluable for microbiologic response.
The impact of therapy on P aeruginosa cultures is shown in Table 3. Of the 27 subjects who were microbiologically evaluable, 6 subjects (22.2%) were considered to have P aeruginosa eradicated (three confirmed, and three presumed) at week 12 or withdrawal.
None of these six subjects received concomitant antibiotics during the treatment period. LRCF analysis of change in total pulmonary symptom severity scores suggested that P aeruginosa eradication was not necessary for improvement in pulmonary status. The 21 subjects with confirmed or presumed persistence of P aeruginosa had a mean improvement in total symptom severity score of 2.2 (SD, 3.9); while the 6 subjects with eradicated or presumed eradicated P aeruginosa had a lesser improvement of only 0.8 (SD, 3.2). More dramatic differences were observed for differences in health-related quality-of-life outcomes, in which total SGRQ scores were reduced only 3.3 U (SD, 5.5) for the 6 subjects with eradicated P aeruginosa and 9.9 U (SD, 14.0) for 18 of the 21 subjects with persistent P aeruginosa completing the SGRQ.
A TSI resistance breakpoint for P aeruginosa has not been established. The resistance breakpoint for parenteral administration of tobramycin ([greater than or equal to] 16 [micro]g/ mL) was therefore used to determine the number of subjects who acquired resistant P aeruginosa infections during the course of the study. Two subjects who began the study with tobramycin-susceptible P aeruginosa had resistant P aeruginosa at their last visit (minimal inhibitory concentrations of 16 [micro]g/mL and 128 [micro]g/mL, respectively).
During the 12-week treatment period, 39 of 41 subjects (95.1%) reported treatment-emergent adverse events regardless of causality. Table 4 shows treatment-emergent adverse events affecting > 10% of the total subject population. The most common of these involved the respiratory system, including cough (43.9%), dyspnea (34.1%), and increased sputum (29.3%). Compared with men, a greater percentage of women experienced hoarseness (14.3% vs 33.3%), increased sputum (14.3% vs 37.0%), headache (7.1% vs 22.2%), and rhinorrhea (0% vs 14.8%).
Adverse events considered by the investigator to be possibly, probably, or definitely related to TSI treatment occurred in 35 of 41 subjects (85.4%). The most common of these were hoarseness and cough (26.8% each), increased sputum (22%), dyspnea and wheezing (17.1% each), pharyngitis (14.6%), and fatigue (12.2%). Of the 10 withdrawals due to adverse events, 9 were determined to be probably (four subjects) or possibly (five subjects) related to TSI administration. Four subjects had doses withheld due to adverse events believed to be treatment related, but all four subjects completed the study.
Thirty-nine study subjects were followed up for an additional 40 weeks in order to capture time to administration of IV antibiotics. Ten of 39 subjects received IV antibiotics within the 40-week observation period (0, 0, 7, 55, 67, 80, 86, 141, 182, and 278 days after last dose of TSI). Two of these 10 subjects withdrew from the study early, with administration of IV antipseudomonal antibiotics occurring within a week of withdrawal in response to clinical symptoms. Both subjects were evaluated as having persistent Pseudomonas infection at the time of withdrawal. Six of the remaining eight subjects receiving IV antibiotics during the observation period received antipseudomonal antibiotics, one immediately after cessation of treatment.
Five subjects (three men and two women) died during the study due to underlying disease, one subject during the 12-week treatment period and four subjects during the 40-week follow-up period. None of the deaths were considered related to drug treatment.
Laboratory evaluations found that creatinine clearance decreased during the treatment period (mean [+ or -] SD decrease of 11.0 [+ or -] 24.2 mL/min). Men had higher baseline creatinine clearance and greater changes during treatment, on the average, than women (mean, - 14.2 [+ or -] 27.7 mL/min vs - 9.9 [+ or -] 23.4 mL/min). No similar trends were noted for any other laboratory test. There were no substantial changes in mean vital signs for the complete subject population or for men and women separately during the 12-week treatment period.
Pulmonary Function Tests
Three subjects experienced a decrease of [greater than or equal to] 10% in FE[V.sub.1] percentage of predicted within 30 min after the first TSI treatment at week 0, with two of these subjects experiencing decreases [greater than or equal to] 20%. One additional subject experienced severe bronchospasm immediately after the second dose of study treatment, although there was no such reaction to the first dose. This event was considered probably related to study treatment, and caused study treatment to be stopped.
The optimal management (antibiotic treatment) of bronchiectasis remains an evolving field. Controlling P aeruginosa colonization is an important goal, as pseudomonal infections are associated with a more rapid decline in lung function in an already significantly impaired population, as well as a reduced quality of life. (4,5) In small studies, (14-17) several therapies have demonstrated modest success in the treatment of pseudomonal infections in subjects with bronchiectasis, including erythromycin, meropenem, fluoroquinolones, and aerosolized gentamicin. The use of aerosolized antibiotics is particularly attractive, as this mode of administration has the potential to deliver high concentrations to the site of infection. In a study of gentamicin therapy in subjects with bronchiectasis, gentamicin delivered by a dry powder inhaler or a nebulizer was effective in decreasing P aeruginosa density, whereas no decline in bacterial counts was observed following IV gentamicin. (17)
The individuals studied in this pilot trial had reached a stage in their disease progression where control of symptoms associated with chronic P aeruginosa lung infections was a prominent management issue. All 41 ITT subjects had received at least four courses of antibiotics in the previous 12 months, including either one IV antibiotic course or one failed oral course that required additional/alternative therapy for symptom relief. Despite previous administration of multiple courses of antipseudomonal antibiotics, these patients continued to be chronically infected, suggesting that reduction of clinical symptoms of infection can be achieved by antibiotic therapy in the absence of "sterilization" of the lung.
The data from this pilot open-label trial confirm and extend the findings from the randomized, placebo-controlled study reported by Barker and colleagues (9) and Couch, (10) which found that TSI therapy resulted in clinical and bacteriological improvement in subjects with bronchiectasis and P aeruginosa infection. In our study, three cycles of TSI treatment led to eradication or presumed eradication of P aeruginosa in 26% of treated subjects (Table 3), a rate similar to the 35% noted by Barker et al. (9) We further found that TSI treatment was associated with significant decreases in disease severity, as indicated by mean pulmonary total symptom severity scores (Fig 2), and significant, clinically relevant improvements in health-related quality of life, as assessed by the SGRQ (Fig 3).
The inability to culture P aeruginosa following treatment (commonly referred to in the clinical literature as eradication) is a substantial microbiological outcome. It is highly unlikely, however, that eradication is equivalent to sterilization for bronchiectasis patients, and the results of this study would suggest that eradication is not necessary to achieve clinical benefit of inhaled antibiotic therapy. Clinical benefit measured as change in total pulmonary symptom severity score or change in health-related quality of life appeared unrelated to eradication outcome for those 27 subjects with evaluable microbiology.
Antibiotic therapy can reduce clinical symptoms of infection, but does not address underlying defects that leave bronchiectasis patients vulnerable to chronic bacterial lung infections. Thus, whether bacterial loads have been reduced so far as to be undetectable or whether true sterilization has occurred following treatment, these patients will be expected to again culture Pseudomonas in the future. As was also noted in the previous study, (9,10) TSI treatment was associated with a low level of development of tobramycin resistance. Resistant P aeruginosa were isolated from 2 subjects, and increases in susceptibility of fourfold or greater were observed in 4 of 21 evaluable subjects (Table 3). The development of resistance is not unexpected in a chronically ill patient population requiring frequent treatment with antibiotics (as an inclusion criteria, all subjects had received four or more courses of antibiotics in the previous 12 months).
TSI treatment was associated with respiratory adverse events in approximately one third to one half of subjects, including cough, dyspnea, increased sputum, and wheezing (Table 4), and 24% of subjects withdrew from the study due to adverse events. The development of adverse events was not predictable based on subject demographics or disease severity. Women tended to experience more respiratory adverse events than men (Table 4) but did not show an increase in serious adverse events. Somewhat paradoxically, women also derived greater clinical benefit from treatment (Fig 2; Table 2).
Bronchiectasis is a progressive disease in which management of clinical symptoms becomes increasingly challenging. Pilot studies such as this can be useful for identifying new treatment modalities, but they are limited by their relatively short duration compared to that of disease progression in an affected population. Although this study suggests that TSI therapy is associated with significant clinical benefits, our current state of knowledge does not allow us to identify prospectively those patients who cannot tolerate treatment, or whether safety and efficacy can be extrapolated over extended periods of time. Accordingly, physicians who use TSI to treat patients with bronchiectasis should be aware that some patients may not tolerate this therapy, and should educate and monitor patients for signs of intolerance. Both our study and the previous study (9,10) were conducted in patients with long-standing, severe disease, and it is possible that patients with milder disease may experience fewer side effects and show better responses to TSI therapy. We believe that data from this pilot study, along with the findings from Barker and colleagues (9) and Couch, (10) support further studies to identify patients with bronchiectasis most likely to benefit from TSI therapy.
The members of the PC-TNDS-008 Study Group are as follows: Martin Kubiet, Central Florida Pulmonary Group, Orlando, FL; Geoffrey Serfilippi, Pulmonary and Critical Care Services, Albany NY; Stuart Garay, NY Pulmonary Associates, New York, NY; Mark Robbins, University of Virginia, Charlottesville, VA; Imre Noth, University of Chicago Hospitals, Chicago, IL; Timothy Aksamit, Mayo Clinic, Rochester, MN; Joseph Shaver, Acute Care Consultants of Augusta, Augusta, GA; Atul Mehta, The Cleveland Clinic Foundation, Cleveland, OH; Dan Olson, Medical College of Ohio, Toledo, OH; Paul Hassoun, New England Medical Center, Boston, MA; Allen Fein, North Shore University Hospital, Manhasset, NY.
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(16) Darley ESR, Bowker KE, Lovering AM, et al. Use of meropenem 3 g once daily for outpatient treatment of infective exacerbations of bronchiectasis. J Antimicrob Chemother 2000; 45:247-250
(17) Crowther Labiris NR, Holbrook AM, Chrystyn H, et al. Dry powder versus intravenous and nebulized gentamicin in cystic fibrosis and bronchiectasis: a pilot study. Am J Respir Crit Care Med 1999; 160:1711-1716
Paul, Scheinberg, MD, FCCP; and Eric Shore, MD; on behalf of the PC-TNDS-008 Study Group ([dagger])
* From the Atlanta Pulmonary Group (Dr. Scheinberg), Atlanta, GA; and the Physician's Research Center, Inc. (Dr. Shore), Hartford, CT.
([dagger]) A list of study group members is given in the Appendix. Chiron Corporation, manufacturers of Tobramycin Solution for Inhalation (TOBI), sponsored this clinical study, and conducted data management and statistical analyses. Drs. Scheinberg and Shore have acted in the past as clinical consultants for Chiron Corporation, but did not receive compensation for either their participation as investigators in this study or the writing of this article.
Manuscript received Marcia 10, 2004; revision accepted September 23, 2004.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: firstname.lastname@example.org).
Correspondence to: Paul Scheinberg, MD, Atlanta Pulmonary Group, 5667 Peachtree Dunwoody Rd, Suite 350, Atlanta, GA 30350; e-mail: pscheinberg@SJHA.org
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