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Original Research: BRONCHIECTASIS |

Addition of Inhaled Tobramycin to Ciprofloxacin for Acute Exacerbations of Pseudomonas aeruginosa Infection in Adult Bronchiectasis* FREE TO VIEW

Diana Bilton, MD; Noreen Henig, MD, FCCP; Brian Morrissey, MD, FCCP; Mark Gotfried, MD, FCCP
Author and Funding Information

*From the Papworth Hospital NHS Trust (Dr. Bilton), Papworth Everard, Cambridge, UK; Stanford University Medical Center (Dr. Henig), Palo Alto, CA; University of California, Davis School of Medicine (Dr. Morrissey), Davis, CA; and the Department of Medicine and Pulmonary Associates (Dr. Gotfried), University of Arizona, Phoenix AZ.

Correspondence to: Diana Bilton, MD, Papworth Hospital, Adult CF Centre, Papworth Everard Cambridge, Cambridge CB38RE, UK; e-mail: drdianabilton@aol.com



Chest. 2006;130(5):1503-1510. doi:10.1378/chest.130.5.1503
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Rationale:Pseudomonas aeruginosa lung infection in patients with bronchiectasis, a chronic airway disease that is characterized by episodes of exacerbation, is associated with more severe disease and a higher utilization of health-care resources. Inhaled tobramycin solution reduces the number of acute exacerbations in patients with cystic fibrosis (CF)-related bronchiectasis with P aeruginosa infection but remains untested in the treatment of exacerbations in patients with non-CF bronchiectasis.

Objectives: This study tested the effect of adding inhaled tobramycin solution to oral ciprofloxacin (Cip) for the treatment of acute exacerbations of non-CF bronchiectasis in patients with P aeruginosa infection.

Methods: A double-blind, randomized, active comparator, parallel-design study conducted at 17 study centers (5 in the United Kingdom, and 12 in the United States) compared 2 weeks of therapy with Cip with either an inhaled tobramycin solution or placebo in 53 adults with known P aeruginosa infection who were having acute exacerbations of bronchiectasis.

Measurements: Clinical symptoms, pulmonary function, clinical efficacy, and sputum microbiology were investigated prospectively.

Main results: An inhaled solution of Cip with tobramycin, compared to placebo, achieved greater microbiological response but no statistically significant difference in clinical efficacy at days 14 or 21. Clinical and microbiological outcomes at the test of cure (ie, the clinical outcome assessment at day 21) were concordant when an inhaled tobramycin solution was added to therapy with Cip and compared to placebo (p = 0.01). Both subject groups had similar overall adverse event rates, but subjects receiving therapy with an inhaled tobramycin solution reported an increased frequency of wheeze (50%; placebo group, 15%).

Conclusions: The addition of an inhaled tobramycin solution to therapy with oral Cip for the treatment of acute exacerbations of bronchiectasis due to P aeruginosa improved microbiological outcome and was concordant with clinical outcome; the inability to demonstrate an additional clinical benefit may have been due to emergent wheeze resulting from treatment.

Figures in this Article

Bronchiectasis, which is a permanent dilation of the bronchial walls, often presents with chronic productive cough and chronic bacterial infection. Cycles of recurrent infection, local inflammation, and bronchial wall damage cause and perpetuate bronchiectasis. The initial insult to the lungs is linked to a variety of diseases including immunodeficiencies and local structural damage to the airway.12 Effective management of bronchiectasis requires treatment of the underlying cause (when known) and control of recurrent infection. The current management paradigm includes the promotion of bronchial hygiene, the reduction of bronchial inflammation, and administration of courses of directed antibiotic treatment aimed at pathogen reduction rather than eradication. These measures can improve patient quality of life,23 but neither can reverse bronchial dilation or cure the underlying pathology.

Bronchiectatic patients can be infected with a variety of bacterial species, including Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, and Moraxella catarrhalis. Chronic infection with P aeruginosa is observed in 24 to 33% of patients with bronchiectasis,1,4and is associated with poorer lung function, decreased quality of life, and more frequent hospitalization.56

It is estimated that 110,000 people in the United States may be receiving treatment for symptoms of bronchiectasis. Twenty percent of these patients account for nearly 80% of the total resources devoted to bronchiectasis management (approximately $600 million annually).7 These costs can be attributed in part to hospital admission for the treatment of acute exacerbations of bacterial infection that cannot be effectively managed in an outpatient setting. This is a particular problem for persons chronically infected with P aeruginosa who have become refractory to management with oral antipseudomonal antibiotics such as ciprofloxacin (Cip) and levofloxacin.

Previously, a single 28-day course of tobramycin inhalation solution (TIS) [TOBI; Chiron Corporation; Emeryville, CA] had been shown89 to dramatically reduce sputum bacterial load and lead to clinical improvement in stable subjects with P aeruginosa-infected non-cystic fibrosis (CF) bronchiectasis. Also, successive 14-day cycles of twice-daily therapy with TIS followed by 14-day rest periods had been shown to improve pulmonary symptom scores and quality of life in stable subjects.,3 In previous studies,3, 8 approximately 20 to 30% of subjects experienced reversible respiratory adverse events (AEs) that were associated with the inhalation of TIS. In this blinded, active-controlled study, we attempted to determine the effect of adding twice-daily TIS treatment to a 14-day outpatient regimen of oral Cip for the treatment of acute exacerbations of bronchiectasis in subjects chronically infected with P aeruginosa.

Design

A double-blind, randomized, active comparator, parallel-design study was conducted in 17 study centers (12 in the United States and 5 in the United Kingdom). Each center received Institutional Review Board or Ethics Committee approval prior to initiation. All subjects provided written informed consent before enrollment; confirmation of consent was obtained at the time of the exacerbation.

Population

Men and women between 18 and 80 years of age with bronchiectasis confirmed by the results of a central reading of a high-resolution CT scan of the chest were considered for this study. Patients with CF, allergic bronchopulmonary aspergillosis, active tuberculosis, glucose-6-phosphate dehydrogenase deficiency, significant renal disease, or a change in steroid therapy within 2 weeks of the acute exacerbation were excluded from the study. A history of chronic P aeruginosa lung infection, confirmed by a sputum culture that was positive for P aeruginosa both within the 12 months before screening and at the time of screening, was required for eligibility. In addition, the P aeruginosa isolate had to show Cip sensitivity (minimum inhibitory concentration [MIC], ≤ 4 μg/mL) at the time of study enrollment.

Subjects were not allowed to use TIS within the 28 days before screening, or at anytime between their screening visit and the time of the exacerbation. Maintenance therapy with antibiotics, including aerosolized antibiotics other than TIS, were allowed up until the time of the exacerbation; however, changes were not permitted within the 14 days before the exacerbation and were not permitted during the study.

Procedures

Data were collected on subjects’ baseline disease status during a period of stable respiratory health. Subjects were asked to return at the time of an acute exacerbation. Acute exacerbations were defined using the criteria in Table 1 . Subjects who did not experience an acute exacerbation within 2 months of the screening visit were rescreened for study eligibility.

The following three medications were used: (1) 750 mg of oral Cip; (2) 300 mg per 5 mL of TIS aerosolized with a jet nebulizer (PARI LC PLUS; Pari; Starnberg, Germany); and (3) 1.25 mg of quinine sulfate per 5 mL of inhalation solution (ie, the placebo) aerosolized a jet nebulizer (PARI LC PLUS; Pari). At the time of exacerbation, subjects were randomized to one of the following two active treatment arms: (1) therapy twice daily with TIS and twice daily with Cip (ie, the TIS/Cip arm); or (2) twice-daily therapy with placebo and Cip (ie, the placebo/Cip arm).

The first dose of study drug on day 1 was administered in the presence of study personnel. Subjects continued therapy with the study drugs at home for 14 days, returning on days 7 and 14. Spirometry was performed before and 30 min after study drug administration on days 1, 7, and 14 to assess acute bronchoreactivity. On days 3 and 16, a follow-up telephone call assessed subject status. Following the completion of therapy with the study medication, the conditions of subjects were reviewed after completing the last dose of study medication with visits on days 21 and 42.

Sputum samples were collected at every visit for visual inspection, Gram stain, and quantitative culture,10 and MICs were determined for Cip and tobramycin using broth microdilution. Hematology and blood chemistry samples were collected at each visit with the addition of serum tobramycin levels on days 1, 7, and 14. Symptoms were assessed by questionnaire at each visit, and each subject kept a structured respiratory symptoms diary throughout the course of the study.

End Points

Investigators completed two clinical outcome assessments. At day 14, investigators categorized each subject as “resolved” (ie, all signs and symptoms had returned to the preexacerbation state), “improved” (ie, but condition had not fully resolved or there were residual symptoms), or “not improved” (ie, if there was no change or condition had worsened). The primary efficacy end point was the clinical outcome assessment at day 21 (called the test of cure); at this time, each subject was categorized as “cured,” “failed,” or “indeterminate.” A cure was defined as a resolution or improvement of symptoms of acute exacerbation. Failure was defined as the persistence or worsening of symptoms of exacerbation, hospitalization, or the administration of additional antimicrobial therapy. Subjects with missing data, or without a clear cure or fail response were categorized as indeterminate. At the review on day 42, subjects were classified as at day 21, but, in addition, those subjects whose clinical outcome was cure on day 21, but who subsequently required retreatment with additional antibiotics, were classified as “relapse.”

The microbiological response was assessed at day 21 based on the sputum culture findings, and consisted of “eradicated” (ie, no P aeruginosa infection and/or unable to produce sputum), “persistent” (ie, has P aeruginosa infection and/or treated with additional antibiotics for continued infection), “superinfected” (ie, has a new pathogen and new or worsening symptoms of infection), or “indeterminate” (ie, unable to be otherwise classified).

Statistical Analysis

Demographic parameters were analyzed for significant differences in randomization between groups using both the χ2 test and the Fisher exact test. A logistic regression model with treatment (ie, TIS or placebo), country (ie, United Kingdom or United States), sex (male or female), and age group (≤ 65 years of age or > 65 years of age) as fixed effects compared the proportions of subjects whose day 21 clinical outcome was cure between the two treatment groups. The odds ratio, representing the likelihood of a cure in TIS/Cip subjects relative to placebo/Cip subjects, and p values were calculated. Differences in clinician outcome assessments on days 7, 14, and 42, in the microbiological outcome at day 21, and in the incidence of treatment-emergent AEs between study groups were analyzed using Cochran-Mantel-Haenszel, χ2, and Fisher exact two-sided statistical tests. Changes in sputum volume and P aeruginosa density from day 1 to days 7, 14, and 21 were analyzed using an analysis of covariance (ANCOVA) model with treatment, day 1 density (measured in colony-forming units) or volume, country, sex, and age as covariates. A Fisher exact test was performed to assess the statistical significance of the difference between TIS/Cip and placebo/Cip subjects in the proportion of concordant clinical and microbiological outcomes. Thus, subjects with concordant outcomes near 50% would indicate little or no association between the two outcomes for the treatment indicated.

Subject Demographics

Of 138 subjects screened, 53 were enrolled in the study, 26 were randomized to the TIS/Cip arm, and 27 were randomized to the placebo/Cip arm. Of those screened, 85 subjects were not randomized, 28 subjects either had no history of P aeruginosa infection or had no infection at screening, 24 subjects did not experience an exacerbation before the close of the study, 18 subjects had infection with Cip-resistant P aeruginosa, 4 subjects had no bronchiectasis on review of a high-resolution CT, 4 subjects failed to produce adequate sputum samples for analysis, 1 subject was hospitalized before randomization, 1 subject experienced an exacerbation within 7 days after undergoing screening, and the remaining 5 subjects were not randomized because of the withdrawal of consent or an inability to complete the tests at screening. A safety and efficacy analysis was performed on the study population, which included all randomized subjects who had received at least one dose of study medication. Efficacy analysis was also performed on the “per-protocol” population, which included all subjects with P aeruginosa infection on day 1 and had undergone clinical assessments at the test of cure on day 21. Exclusions from the “per-protocol” population included the following; subjects who failed on assessment at day 1 or 2; those who had not received at least 70% of the prescribed doses of therapy for any time point after days 1 and 2; or subjects who had experienced an exacerbation < 7 days after the last screening visit, which may have interfered with the baseline assessment. Treatment groups were similar with respect to age, sex, height, weight, and lung function (Table 2 ).

Forty-three subjects completed the study. Ten subjects (5 from each group) withdrew from the study prior to completing the study period. Seven of the withdrawals (five from the placebo/Cip arm, and 2 from the TIS/Cip arm) were due to AEs. Of these, three subjects (TIS/Cip, two subjects; placebo/Cip group, one subject) withdrew from the study due to possible drug-related AEs, and four of the placebo/Cip subjects withdrew on day 21 or later due to non-drug-related AEs. Three TIS/Cip subjects withdrew from the study due to “unsatisfactory therapeutic responses” after receiving 8, 8, and 15 days of dosing, respectively. One of the TIS/Cip subjects who had withdrawn at day 8 due to “unsatisfactory therapeutic responses,” also had an AE.

Efficacy Analyses

The clinical assessments at day 14 were similar in both the study and “per-protocol” populations, and did not demonstrate a significant difference in outcome between groups for either the resolution or improvement of symptoms by either χ2 test or two-sided Fisher exact test.

At the test of cure on day 21, 19 of 27 subjects (70.4%) treated with placebo/Cip were considered to be cured, compared with 13 of 26 subjects (50.0%) treated with TIS/Cip (Table 3 ). This 20.4% higher cure rate among placebo/Cip subjects was not statistically significant (odds ratio, 0.36; p = 0.091) by logistic regression when treatment, country, sex, and age group were incorporated as fixed effects. Five of 27 subjects (18.5%) who had been treated with placebo/Cip were considered to have failed therapy, compared to 10 of 26 TIS/Cip subjects (38.5%). Clinical outcomes for three subjects randomized to each study arm were either indeterminate or not evaluable at day 21. Differences between treatment groups did not reach statistical significance by either χ2 test or Fisher exact two-sided test (Table 3). At day 42 in both the study and per-protocol populations, there was no statistically significant difference in clinical outcome at day 42 between the TIS/Cip and placebo/Cip subjects (p = 0.49) [Table 4] .

Microbiological Analysis

More subjects treated with TIS/Cip (9 of 26 subjects; 34.6%) had P aeruginosa eradicated from their sputum than subjects treated with placebo/Cip (5 of 27 subjects; 18.5%), but the difference was not statistically significant (Table 5 ). A majority of patients in both groups had persistent P aeruginosa infection. One subject in the TIS/Cip arm had an apparent superinfection with S pneumoniae and was prescribed antibiotics on day 21 for new symptoms of an acute exacerbation.

Subjects treated with TIS/Cip had mean reductions in P aeruginosa of 3.67 log10 and 3.25 log10 cfu, respectively, on days 7 and 14. In comparison, subjects treated with placebo/Cip had mean reductions of 1.15 log10 cfu at day 7 and 0.52 log10 cfu at day 14 (Fig 1 ). One week after the completion of dosing, mean sputum bacterial densities remained reduced by 2.15 log10 cfu for TIS/Cip subjects and 0.95 log10 cfu for placebo/Cip subjects. Changes from baseline of mean sputum P aeruginosa density were significantly different between treatment groups at both day 7 (p < 0.001) and day 14 (p < 0.001), but not at day 21 (p = 0.111), as determined by ANCOVA with day 1 sputum density as a covariate and treatment group, country, sex, and age group as fixed effects. TIS/Cip subjects also showed a greater reduction in mean sputum volume at days 7 and 14 when compared with subjects treated with placebo/Cip, although this difference was not statistically significant. Other fixed effects were not significant by ANCOVA at any visit.

The isolation of treatment-emergent, antibiotic-resistant organisms was comparable between study arms. One TIS/Cip subject and two placebo/Cip subjects who had begun the study with Cip-susceptible P aeruginosa strains (MIC, ≤ 2 μg/mL) had Cip-resistant strains (MIC, ≥ 4 μg/mL) by the last study visit. One TIS/Cip subject who had begun the study with tobramycin-susceptible P aeruginosa (MIC, ≤ 8 μg/mL) had a resistant P aeruginosa infection (MIC, 16 μg/mL; National Committee for Clinical Laboratory Standards resistance breakpoint MIC, ≥ 16 μg/mL) at their last visit. Tobramycin-resistant P aeruginosa infection did not develop in placebo/Cip subjects during the course of the study.

The clinical and microbiological outcomes at day 21 (ie, test of cure) were significantly more frequently concordant for TIS/Cip subjects than for placebo/Cip subjects (p = 0.01) by Fisher exact test compared to the 50% concordance that would be expected by chance. Sixteen of 20 TIS/Cip subjects (80%) exhibited either clinical cure and eradication of P aeruginosa (9 subjects) or clinical failure and persistence of P aeruginosa (7 subjects). In contrast, less than half of the placebo/Cip subjects (9 of 22 subjects; 40.9%) had concordant outcomes (p = 0.52). Five subjects had clinical cure and eradication of P aeruginosa, and four subjects had clinical failure and persistence of P aeruginosa infection (Table 6 ).

Safety Analyses

No differences were observed in mean change from preexacerbation screening BUN or serum creatinine levels to day 14 levels for either treatment arm. On day 14, the mean serum tobramycin concentration collected 1 h posttreatment in TIS/Cip subjects was 1.14 μg/mL (SD, 0.68 μg/mL; range, 0.29 to 2.34 μg/mL). The serum and the sputum tobramycin concentrations were comparable at days 7 and 14, and were similar to those seen in patients with CF.11

Treatment-emergent AEs were common during the study, with 26 of 27 placebo/Cip subjects (96.3%) and 22 of 26 TIS/Cip subjects (84.6%) reporting at least one AE (Table 6). A majority of treatment-emergent AEs was associated with respiratory/thoracic/mediastinal complications that are typical of bronchiectasis and chronic pulmonary infection. Of all treatment-emergent AEs observed at > 15% incidence in either treatment group, only wheezing was reported at a higher frequency associated with TIS/Cip treatment (TIS/Cip subjects, 50.0%; placebo/Cip subjects, 14.8%; p < 0.01 [from ad hoc Fisher exact test). Those emergent AEs that were reported at a > 15% incidence in either study arm are listed in Table 7 .

Investigators attributed AEs in 11 of 27 placebo/Cip subjects (40.7%) and in 13 of 26 TIS/Cip subjects (50.0%) to study medication. Six of the 26 TIS/Cip subjects (24%) experienced wheeze or aggravation of wheeze either possibly or probably related to study medication, but none were reported in the placebo/Cip subjects. There was no apparent difference in the reporting of other treatment-related AEs between the two treatment groups. Six subjects experienced serious AEs, although an AE was considered by the investigator to be either possibly or probably related to treatment in only one, a placebo/Cip subject. Five of 27 placebo/Cip subjects (18.5%) and 3 of 26 TIS/Cip subjects (11.5%) experienced AEs that led to study withdrawal. Two of the TIS/Cip subjects withdrew from the study as a consequence of respiratory AEs (specifically, cough and wheeze) and one placebo/Cip subject withdrew because of dyspnea, which were considered to be probably related to treatment.

The development of treatment-emergent wheeze was not predicted by the measurement of acute changes in FEV1 measured 30 min postdose on day 1. Three TIS/Cip subjects and five placebo/Cip subjects experienced a > 10% drop in percent predicted FEV1 at any one of three study visits; however, none of these decreases was considered by the investigator to be an AE. There was no significant difference in FEV1 between the two treatment groups at day 7 or 14 (Fig 2 ).

A greater proportion of placebo/Cip subjects (4 of 27 subjects; 14.8%) compared to TIS/Cip subjects (2 of 26 subjects; 7.7%) required hospitalization and treatment for worsening symptoms such as dyspnea, cough, chest pain, or tightness that was associated with bronchiectasis and chronic infection.

This study represents the first randomized controlled trial of a nebulized antibiotic as adjunctive therapy for patients with an acute exacerbation of P aeruginosa infection in patients with non-CF bronchiectasis. In chronic airway infection with P aeruginosa in CF patients, clinical improvement is associated with a reduction in bacterial density rather than eradication.11The few comparable studies performed in patients with non-CF bronchiectasis1213 have shown that successful treatment does not depend on the eradication of organisms. We have presented the first study of an acute exacerbation of P aeruginosa infection in bronchiectasis patients in which quantitative microbiology measurements have been performed. There was evidence of superior microbiological efficacy during treatment in the patients receiving TIS/Cip compared to those receiving placebo/Cip with statistically significant differences in the change in bacterial density from day 0 to day 7, which were sustained at day 14 of treatment (Fig 1). The four-log reduction in bacterial density in the TIS/Cip group is highly significant. Although more subjects who were treated with TIS/Cip had P aeruginosa eradicated from their sputum (9 of 24 subjects) than subjects who were treated with placebo/Cip (5 of 25 subjects), this difference failed to reach statistical significance (Table 5).

Clinical success in treating bronchiectasis is usually defined in terms of a reduction in 24-h sputum volume, an improvement in sputum purulence, and an improvement in cough and dyspnea.1314 We hypothesized that the addition of TIS, which is a potent antipseudomonal agent known to achieve high sputum concentrations,11 to therapy with oral Cip to manage an acute exacerbation in a subject with bronchiectasis chronically infected with P aeruginosa that was susceptible to Cip would achieve superior clinical efficacy than therapy with Cip alone. Despite superior microbiological efficacy, a corresponding superior clinical efficacy was not demonstrated (Table 5, Fig 1).

The reasons for the disparity between microbiological and clinical efficacy found in this study are worth considering. A cure was defined as the resolution of symptoms of sputum purulence, and volume, cough, dyspnea, and wheeze to a baseline level. TIS/Cip-treated subjects were more likely to experience respiratory AEs, in particular, wheeze, although this was not a significant cause for withdrawal from the study. It is likely that treatment-related wheeze led to the classification of an outcome as clinical failure in some cases. It is also noteworthy that there was concordance between the clinical outcome and the microbiological outcome in the subjects treated with TIS/Cip compared to none seen in the placebo/Cip subjects (Table 6). Similarly, as a consequence of the exclusion of subjects with Cip-resistant organisms (13.0%) from the study, the 18.5% clinical failure rate for therapy with placebo/Cip in this study may represent a lower value than that experienced in clinical practice. The exclusion of Cip-resistant subjects in this study does not reflect the usual clinical practice. Therapy with Cip is frequently used to prevent hospitalization and the use of parenteral antibiotics before the results of antibiotic susceptibility are known. As the design of this study included a sputum screening, it was a stipulation of the regulatory bodies that patients with Cip-resistant organisms should be excluded in this first study of TIS in patients experiencing acute exacerbations. Further study of the role of TIS in managing Cip-resistant and nonresponding patients may be warranted as a method of reducing the need for IV antibiotics or hospitalization.

Lung function was not chosen as a major end point because previous studies15 have shown that patients with bronchiectasis may have a significant improvement in clinical symptoms without a significant change in FEV1. This is in keeping with a fixed reduction in FEV1 in patients with bronchiectasis occurring as a result of airway damage that is irreversible. FEV1 does, however, represent an important safety parameter, and there was no evidence that the emergent wheeze due to treatment was associated with acute bronchoconstriction immediately after treatment administration. Chest tightness and wheeze are side effects that have emerged in all the studies of TIS in patients with non-CF bronchiectasis,89 and is more common than those in the experience of CF patients.11 Most patients and their physicians, however, have not deemed this serious enough to stop therapy in this and previous studies.89

This study adds to our experience of the low level of systemic absorption of inhaled tobramycin solution in patients with non-CF bronchiectasis, including those in the older population.3 After Cip, there are few therapeutic alternatives to IV antibiotics for managing patients with acute exacerbations of bronchiectasis who are infected with P aeruginosa. This group of patients has more hospitalizations than groups of other patients with bronchiectasis despite similar numbers of exacerbations,6; therefore, endeavors to decrease the current failure rate of outpatient antibiotic therapy are worthwhile. This study does not demonstrate superior clinical efficacy for TIS when added to oral Cip, but in view of the superior microbiological efficacy achieved during treatment with TIS, the end points of time-to-next-exacerbation and time-to-next-exacerbation-requiring-hospitalization, which were not included in this study should be assessed in future studies. Furthermore, in clinical practice, when patients colonized with P aeruginosa have failed to respond to therapy with Cip, TIS may have a role in reducing the requirement for IV therapy. A pragmatic trial of TIS in patients who do not respond to Cip is warranted with appropriate attention to treatment-related AEs.

Participating Study Investigators

The authors present the data in the study on behalf of all the following participating investigators in this study: Wesley R. Bray, Marietta Pulmonary Medicine, Marietta, GA; Leslie Couch, University of Texas Health Center at Tyler, Tyler, TX; James D. DeMaio, Northwest Medical Specialties, Tacoma, WA; Graham Douglas, Aberdeen Royal Infirmary, Aberdeen, UK; Stuart Elborn, Belfast City Hospital, Belfast, Northern Ireland, UK; Gwen Huitt, National Jewish Medical & Research Center, Denver, CO; Dennis Lawlor, Consultants in Pulmonary Medicine, Olathe, KS; Keith Meyer, University of Wisconsin Hospital and Clinics, Madison, WI; Paul Scheinberg, Atlanta Pulmonary Group, Atlanta, GA; Geoffrey Serfilippi, Pulmonary and Critical Care Svcs Albany, NY; Jack Stewart, Pulmonary Consultants of Orange County, Orange, CA; Robert Stockley, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK; and Robert Wilson, Royal Brompton Hospital, London, UK.

Abbreviations: AE = adverse event; ANCOVA = analysis of covariance; CF = cystic fibrosis; Cip = ciprofloxacin; MIC = minimum inhibitory concentration; TIS = tobramycin inhalation solution

Chiron Corporation, manufacturers of Tobramycin Inhalation Solution (TOBI), sponsored this clinical study, and conducted data management and statistical analyses. Drs. Bilton and Gotfried have acted in the past as clinical consultants for Chiron Corporation. The authors did not receive compensation for either their participation as investigators in this study or for the writing of this article.

Table Graphic Jump Location
Table 1. Criteria Defining an Acute Exacerbation
Table Graphic Jump Location
Table 2. Study Population Demographics
* 

Values are given as mean (SD).

 

Values are given as No. (%).

 

Recorded at the screening visit.

Table Graphic Jump Location
Table 3. Clinical Assessments of Test of Cure (Day 21) in Study Population*
* 

Values are given as No. (%).

Table Graphic Jump Location
Table 4. Clinical Outcome of Study Population at Day 42*
* 

Values are given as No. (%).

Table Graphic Jump Location
Table 5. P aeruginosa Response to Study Treatment*
* 

Values are given as No. (%), unless otherwise indicated. Data include only subjects with cultures growing P aeruginosa at baseline.

 

Values given as two-sided χ 2 test/Fisher exact test for yes/no answers.

 

Subjects with negative culture findings with insufficient time elapsed between antibiotic administration and sputum collection at therapy withdrawal visit.

Figure Jump LinkFigure 1. Mean differences in the change of bacterial densities in sputum (in log10 colony-forming units per gram of sputum) between treatment groups. The number of subjects who submitted sputum samples that were able to be quantitatively cultured in parentheses at each time point. Bars = 95% confidence interval (CI) for means. Differences in bacterial density change at days 7 and 14 are statistically significant (p < 0.001).Grahic Jump Location
Table Graphic Jump Location
Table 6. Concordance of Clinical and Microbiological Outcome at Day 21
* 

Values are given as No. (%). Concordant outcomes = clinical cure and P. aeruginosa eradication OR clinical failure and P aeruginosa persistence; discordant outcomes = clinical cure and P aeruginosa persistence or clinical failure and P aeruginosa eradication.

 

Concordance was significant for the TIS/Cip group (p = 0.01). Six TIS/Cip group subjects had indeterminate or missing clinical or microbiological outcome data at day 21, and four of the six subjects had persistent P aeruginosa infection.

 

Concordance was no greater than expected by chance for the placebo/Cip group (p = 0.52). Five Placebo/Cip group subjects had indeterminate or missing clinical or microbiological outcome data at day 21, and two of the five subjects had persistent P aeruginosa infection.

Table Graphic Jump Location
Table 7. Number of Subjects With Treatment-Emergent AEs or Greater Incidence in Either Study Arm*
* 

Values are given as No. (%), unless otherwise indicated.

 

Ad hoc Fisher exact test.

 

Combined incidence of symptom and aggravated symptom.

Figure Jump LinkFigure 2. Mean pulmonary function for subjects with measurement data available for all visits. Bars = 95% confidence interval for means. No significant differences in mean pulmonary function (ie, FEV1) were observed at any visit. The number of subjects ast each time point is in parentheses.Grahic Jump Location

The authors thank the following Chiron Corporation employees for their support: Uta Meyer, Xin Yu, and Kevin Hou for statistical analyses; Sally Anne Jones, Barbara Schaeffler, Alistair Leigh, Kara MacGowan, Stephen Shrewsbury, and Lyn Waring for clinical operations support; and Dutch VanDevanter, Jill Van Dalfsen, and Debbi Humble for data analyses and critical reading of this manuscript.

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Hill, SL, Stockley, RA Effect of short and long term antibiotic response on lung function in bronchiectasis.Thorax1986;41,798-800. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Mean differences in the change of bacterial densities in sputum (in log10 colony-forming units per gram of sputum) between treatment groups. The number of subjects who submitted sputum samples that were able to be quantitatively cultured in parentheses at each time point. Bars = 95% confidence interval (CI) for means. Differences in bacterial density change at days 7 and 14 are statistically significant (p < 0.001).Grahic Jump Location
Figure Jump LinkFigure 2. Mean pulmonary function for subjects with measurement data available for all visits. Bars = 95% confidence interval for means. No significant differences in mean pulmonary function (ie, FEV1) were observed at any visit. The number of subjects ast each time point is in parentheses.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Criteria Defining an Acute Exacerbation
Table Graphic Jump Location
Table 2. Study Population Demographics
* 

Values are given as mean (SD).

 

Values are given as No. (%).

 

Recorded at the screening visit.

Table Graphic Jump Location
Table 3. Clinical Assessments of Test of Cure (Day 21) in Study Population*
* 

Values are given as No. (%).

Table Graphic Jump Location
Table 4. Clinical Outcome of Study Population at Day 42*
* 

Values are given as No. (%).

Table Graphic Jump Location
Table 5. P aeruginosa Response to Study Treatment*
* 

Values are given as No. (%), unless otherwise indicated. Data include only subjects with cultures growing P aeruginosa at baseline.

 

Values given as two-sided χ 2 test/Fisher exact test for yes/no answers.

 

Subjects with negative culture findings with insufficient time elapsed between antibiotic administration and sputum collection at therapy withdrawal visit.

Table Graphic Jump Location
Table 6. Concordance of Clinical and Microbiological Outcome at Day 21
* 

Values are given as No. (%). Concordant outcomes = clinical cure and P. aeruginosa eradication OR clinical failure and P aeruginosa persistence; discordant outcomes = clinical cure and P aeruginosa persistence or clinical failure and P aeruginosa eradication.

 

Concordance was significant for the TIS/Cip group (p = 0.01). Six TIS/Cip group subjects had indeterminate or missing clinical or microbiological outcome data at day 21, and four of the six subjects had persistent P aeruginosa infection.

 

Concordance was no greater than expected by chance for the placebo/Cip group (p = 0.52). Five Placebo/Cip group subjects had indeterminate or missing clinical or microbiological outcome data at day 21, and two of the five subjects had persistent P aeruginosa infection.

Table Graphic Jump Location
Table 7. Number of Subjects With Treatment-Emergent AEs or Greater Incidence in Either Study Arm*
* 

Values are given as No. (%), unless otherwise indicated.

 

Ad hoc Fisher exact test.

 

Combined incidence of symptom and aggravated symptom.

References

Pasteur, MC, Helliwell, SM, Houghton, SJ, et al (2000) An investigation into causative factors in patients with bronchiectasis.Am J Respir Crit Care Med162,1277-1284. [PubMed]
 
Barker, AF Bronchiectasis.N Engl J Med2002;346,1383-1393. [CrossRef] [PubMed]
 
Scheinberg, P, Shore, E A pilot study of the safety and efficacy of tobramycin solution for inhalation in patients with severe bronchiectasis.Chest2005;127,1420-1426. [CrossRef] [PubMed]
 
Ho, PL, Chan, KN, Ip, MSM, et al The effect ofPseudomonas aeruginosainfection on clinical parameters in steady-state bronchiectasis.Chest1998;114,1594-1598. [CrossRef] [PubMed]
 
Evans, SA, Turner, SM, Bosch, BJ, et al Lung function in bronchiectasis: the influence ofPseudomonas aeruginosa.Eur Respir J1996;9,1601-1604. [CrossRef] [PubMed]
 
Wilson, CB, Jones, PW, O’Leary, CJ, et al Effect of sputum bacteriology on the quality of life of patients with bronchiectasis.Eur Respir J1997;10,1754-1760. [CrossRef] [PubMed]
 
Weycker, D, Edelsberg, J, Oster, G, et al Prevalence and economic burden of bronchiectasis.Clin Pulm Med2005;12,205-209. [CrossRef]
 
Barker, AF, Couch, L, Fiel, SB, et al Tobramycin solution for inhalation reduces sputumPseudomonas aeruginosadensity in bronchiectasis.Am J Respir Crit Care Med2000;162,481-485. [PubMed]
 
Couch, LA Treatment with tobramycin solution for inhalation in bronchiectasis patients withPseudomonas aeruginosa.Chest2001;120(suppl),114S-117S
 
Burns, JL, Emerson, J, Stapp, JR, et al Microbiology of sputum from patients at cystic fibrosis centers in the United States.Clin Infect Dis1998;27,158-163. [CrossRef] [PubMed]
 
Ramsey, BW, Pepe, MS, Quan, JM, et al Intermittent administration of inhaled tobramycin in patients with cystic fibrosis: Cystic Fibrosis Inhaled Tobramycin Study Group.N Engl J Med1999;340,23-30. [CrossRef] [PubMed]
 
Hill, SL, Burnett, D, Hewetson, KA, et al The response of patients with purulent bronchiectasis to antibiotics for four months.Q J Med1988;66,163-173. [PubMed]
 
Tsang, KW, Chan, WM, Ho, PL, et al A comparative study on the efficacy of levofloxacin and ceftazidime in acute exacerbation of bronchiectasis.Eur Respir J1999;14,1206-1209. [CrossRef] [PubMed]
 
Hill, SL, Morrison, HM, Burnett, D, et al Short term response of patients with bronchiectasis to treatment with amoxycillin given in standard or high doses orally or by inhalation.Thorax1986;41,559-565. [CrossRef] [PubMed]
 
Hill, SL, Stockley, RA Effect of short and long term antibiotic response on lung function in bronchiectasis.Thorax1986;41,798-800. [CrossRef] [PubMed]
 
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