Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis

Design

Placebo-controlled, double-blind, randomized, phase II study

N= 74

Objective

To evaluate the microbiological efficacy and safety of inhaled tobramycin for treatment of patients with bronchiectasis and Pseudomonas aeruginosa 

Study Groups

Tobramycin inhalation (n= 37)

Placebo (n= 37)

Inclusion Criteria

Bronchiectasis, a minimum of 10⁴ colony-forming units of P. aeurginosa per gram 

Exclusion Criteria

Cystic fibrosis, allergic bronchopulmonary aspergillosis, acute pulmonary process requiring medical intervention, received antibiotics within 2 weeks of screening visit 

Methods

Patients were randomized to self administer either 5 mL of TSI (containing 300 mg tobramycin and 11.25 NaCl in sterile water for injection) or placebo (containg 1.25 mg quinine sulfate in NaCl) twice daily for 28 days using a PARI LC PLUS jet nebulizer. The placbo was chosen due to its similar taste to tobramycin. 

Follow-up visits occurred every 2 weeks during the 8 week study and patients were withdrawn if they required additional antibiotics during the study duration. Sputum samples were collected at all follow-ups and forced expiratory volume at one second (FEV₁) and forved vital capacity (FVC) measured at week 0 and week 4. Percent predicted values for FEV1 and FVC were done by dividing the actual measured values by predicted values from the Knudson equations for normal, healthy individuals based on age, height, and gender and multiplying by 100. 

Duration

Eight weeks of intervention 

Outcome Measures

Primary endpoint: change in P. aeruginosa density from baseline to week 4

Secondary endpoints: change in P. aeruginosa density from week 2 to week 6, investigator assessment of improved or not improved in condition at week 6, percent change in FEV₁ predicted and FVC from week 0 to week 4

Baseline Characteristics

Tobramycin inhalation (n= 37)

Placebo (n= 37)

Age, years

Female

White

P. aeruginosa log₁₀, cfu/g

FEV₁ % (predicted)

Duration of bronchiectasis, years

Smoking history 

Use of other treatments

Bronchodilators

Steroids

Chest physiotherapy

30 (81%)

20 (54%)

9 (24%)

31 (84%)

21 (57%)

5 (14%)

0.76

0.82

0.24

FEV₁= forced expiratory volume at one second 

Results

Tobramycin inhalation (n= 37)

Placebo (n= 37)

P-value

P. aeruginosa log₁₀, cfu/g

Change from baseline to week 4

Change from week 2 to week 6

-4.54

Approximately +1.6

+0.02

Approximately -0.15

<0.01

-

Improved medical condition*

Percent change in FEV₁

Percent change in FVC

*Improved medical condition was defined as eradicated (no P. aeruginosa at week 6) or decreased at least 2 log₁₀ at week 4.

FEV₁= forced expiratory volume at one second; FVC= forced vital capacity 

Adverse Events

Common Adverse Events: Cough (15 [41%] vs 9 [24%]); dyspnea (12 [32%] vs 3 [8%]); increased sputum (8 [22%] vs 5 [14%]); wheezing (6 [16%] vs 0); fever (4 [11%] vs 6 [16%])

Serious Adverse Events: Hemoptysis (5 [14%] vs 3 [8%]); chest pain (7 [19%] vs 0)

Study Author Conclusions

The results of this study, which were designed and powered to determine the microbiological efficacy of tobramycin solution for inhalation, show that tobramycin markedly reduced sputum P. aeruginosa density. Further investigation is necessary to define and demonstrate clinical efficacy and safety in non-CF patients with bronchiectasis.

InpharmD Researcher Critique

This was a relatively small study. The secondary endpoint of medical improvement was subjective. Another secondary endpoint, change in P. aeruginosa from week 2 to week 6, was approximated instead of objectively quantified. In addition, more patients treated with tobramycin experienced respiratory adverse events despite having been assessed as having medical improvement. 

Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa

Design

Randomized, double-blind, placebo-controlled, crossover trial 

N= 20

Objective

To determine whether direct aerosol delivery of tobramycin to the lower airways may control infection and produce only low systemic toxicity

Study Groups

Inhaled tobramycin (n= 20)

Placebo (n= 20)

Inclusion Criteria

Bronchiectasis, at least 3 positive cultures positive for Pseudomonas aeruginosa separated by one month each, hospitalized and completed 2 weeks of intravenous treatment with 2 PA susceptible antibiotics (ceftazidime 100 mg/kg/day and tobramycin 4 mg/kg/day)

Exclusion Criteria

Cystic fibrosis, tobramycin hypersensitivity, P. aeruginosa resistant to tobramycin, auditory threshold in either ear >20 dB at frequencies between 500 and 8000 Hz, serum creatinine ≥1.5 mg/dL

Methods

Patients were randomized to received either 300 mg of aerosolized tobramycin or placebo twice daily and crossed over to the other intervention. Each intervention lasted for 6 months with a 1 month washout period was required in between each cycle. Additional antibiotics were allowed if the patient had an exacerbation. 

Tobramycin, 100 mg/2mL, was diluted in NaCl 0.9% in order to make an 8 mL solution. Placebo was only 8 mL of NaCl 0.9%. Each treatment was administered via a jet nebulizer driven by a high-flow-rate compressor. 

Follow-ups occurred at months 1, 2, 4, and 6 for the first cylce, then at months 7, 8, 9, 11, and 13 for the second cycle. Patients were followed for an additional 6 months after study completion. Sputum and blood analyses were performed at each visit along with forced volume capacity (FVC) and forced expiratory volume in one second (FEV₁). 

Duration

12 months 

Outcome Measures

Baseline Characteristics

Tobramycin (n= 20)

Placebo (n= 20)

Died (n= 5)

Age, years (range)

Pseudomonas aeruginosa infection, months

Basline Pseudomonas aeruginosa density, cfu/mL

Lung function

Predicted FVC %

Predicted FEV1 %

56.63 ± 16.45

51.78 ± 16.45

56.63 ± 16.45

51.78 ± 16.45

35.8 ± 11.6

24.6 ± 4.2

<0.001

<0.001

Quality of Life (St. George Respiratory Questionnaire)

Symptoms

Activity

Impact

Total

53.8 ± 24.5

55.2 ± 28

32 ± 28

42.6 ± 25.2

56.1 ± 21.9

51.2 ± 28.6

31.4 ± 28.2

41.5 ± 25.12

-

-

-

-

0.76

0.66

0.95

0.89

FVC= forced volume capacity; FEV₁₌ forced expiratory volume in one second; cfu= colony forming unit 

Results

Tobramycin (n= 20)

Placebo (n= 20)

Exacerbations per patient

Hospital admissions  per patient

Days of hospital admission per patient

Days of additional antibiotic treatment per patient

Pseudomonas aeruginosa density, cfu/mL

Lung function

Change in FVC % (range)

Change in FEV1 % (range)

-3.50 (-5.95 to -1.02)

-5.45 (-8.03 to -2.87)

-1.20 (-4.38 to -1.98)

-1.30 (-4.88 to -2.28)

0.240

0.056

Change in St. George Respiratory Questionnaire scores*

Symptoms

Activity

Impact

Total

-2.40 ± 4.30

-4.29 ± 11.41

0.40 ± 1.46

-0.90 ± 3.93

-7.24 ± 16.32

0.66 ± 4.17

-0.61 ± 6.51

-0.83 ± 6.89

0.18

0.10

0.48

0.97

FVC= forced volume capacity; FEV₁₌ forced expiratory volume in one second; cfu= colony forming unit

*= St. George Respiratory Questionnaire consists of 76 items divided into 3 sections (range 0-100): Symptoms are related to respiratory symptoms, frequency and severity; Activity relates to activites that cause are are limited by breathlessness; Impact covers a range of aspects related to social activity and psychological disturbances resulting from airway disease. 

Adverse Events

Common Adverse Events: dyspnea (1 [5%]); wheezing (1 [5%]); tinnitis (1 [5%])

Serious Adverse Events: hemoptysis (1 [5%]); 

Percentage that Discontinued due to Adverse Events: Bronchospasm (3 [10%])

Study Author Conclusions

Aerosol administration of high-dose tobramycin in non-CF bronchiectatic patients for endobronchial infection with PA appears to be safe and decreases the risk of hospitalization and PA density in sputum. Nevertheless, pulmonary function and quality of life are not improved, and the risk of bronchospasm is appreciable.

InpharmD Researcher Critique

The sample size was small (N=30) and only 20 of those patients completed the trial. The formulation of tobramycin used contained the preservative metasulfite which may lead to airway irritation. 

A Pilot Study of the Safety and Efficacy of Tobramycin Solution for Inhalation in Patients With Severe Bronchiectasis

Design

Open-label clinical trial

N= 41

Objective

To evaluate the efficacy and safety of tobramycin solution for inhalation (TSI) in patients with severe bronchiectasis

Study Groups

Tobramycin inhalation (n= 41)

Inclusion Criteria

≥18 years of age, bronchiectasis affecting two or more lung segments, purulent sputum production, history of Pseudomonas aeruginosa in sputum, ≥4 courses of antibiotics for respiratory symptoms in the last 12 months

Exclusion Criteria

Use of TSI or smoking in previous 6 months, use of antibiotics in previous 2 weeks, or use of any investigational agents within 4 weeks

Methods

Patients self-administered tobramycin (300 mg/5mL) twice daily via a jet nebulizer for 3 cycles. Each cycle consisted of 14 days on treatment followed by 14 days off treatment. After the third cycle, patients were followed for an additional 40 weeks by chart review. 

If concomitant bronchodilators were used, they were administered at least 15 to 50 minutes before tobramycin treatment. The use of additional antibiotics was allowed at the discretion of the investigator. 

Duration

Treatment: 12 weeks

Follow-up: 40 weeks

Outcome Measures

Primary endpoint: pulmonary total symptom severity score 

Secondary endpoints: changes in severity and intensity of symptoms, change in St. George Respiratory Questionnaire, change in Pseudomonas aeruginosa cultures

Baseline Characteristics

Men (n= 14)

Women (n= 27)

Total (n= 41)

Age, years

White

Baseline FEV₁ %

Disease duration

Smoking history

Pulmonary total symptom severity score

SGRQ score

FEV₁= forced expiratory volume in one second; SGRQ= St. George Respiratory Questionnaire 

Results

Men (n= 14)

Women (n= 27)

Total (n= 41)

P-value

Change in pulmonary total symptom severity score

Symptoms

Cough

Severity

Intensity

Shortness of breath

Severity

Intensity

Sputum production

Severity

Intensity

Wheezing

Severity

Intensity

Fatigue

Severity

Intensity

-0.3 ± 0.8

-1.1 ± 3.5

-0.1 ± 0.8

-0.9 ± 3.2

-0.4 ± 0.9

-2.6 ± 4.0

0.0 ± 0.8

0.4 ± 3.2

0.0 ± 1.0

-0.3 ± 3.4

-0.5 ± 0.9

-2.0 ± 4.3

-0.3 ± 0.7

-1.2 ± 3.1

-0.7 ± 1.1

-3.0 ± 4.8

-0.3 ± 0.9

-1.1 ± 3.7

-0.2 ± 1.2

-1.6 ± 4.8

-0.4 ± 0.9

-1.7 ± 4.0

-0.2 ± 0.7

-1.1 ± 3.1

-0.6 ± 1.0

-2.9 ± 4.5

-0.2 ± 0.9

-0.6 ± 3.5

-0.1 ± 1.1

-1.2 ± 4.4

-

-

-

-

-

-

-

-

-

-

Change in SGRQ

Pseudomonas aeruginosa cultures

Eradicated at week 12 or withdrawal

Presumed eradicated at week 12 or withdrawal

Persistent

Intermediate 

-

-

-

-

-

-

-

-

3/27 (11.1%)

3/27 (11.1%)

12/27 (44.4%)

9/27 (33.3%)

-

-

-

-

SGRQ= St. George Respiratory Questionnaire 

Adverse Events

Common Adverse Events: Cough (18 [43.9%]); dyspnea (14 [34.1%]); increased sputum (12 [29.3%]); wheezing (11 [26.8%]); hoarseness (11 [26.8%]); fatigue (11 [26.8%]); headache (7 [17.1%]); pharyngitis (6 [14.6%]); nausea (6 [14.6%]); diarrhea (5 [12.2%])

Serious Adverse Events: dyspnea exacerbated (7 [17.1%]); chest pain (5 [12.2%])

Percentage that Discontinued due to Adverse Events: 10 (24.4%)

Study Author 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

InpharmD Researcher Critique

The study had a small sample size and no control group. Furthermore, only data from 27 patients were available to assess inhaled tobramycin's effect on Pseudomonas aeruginosa cultures. 

Aerosolized Tobramycin for Pseudomonas Aeruginosa Ventilator-Associated Pneumonia in Patients with Acute Respiratory Distress Syndrome

Design

Retrospective cohort study

N=44

Objective

To determine if tobramycin inhalation solution is effective in improving clinical outcomes compared in adult Intensive Care Unit (ICU) patients with acute respiratory distress syndrome (ARDS)

Study Groups

Tobramycin (n= 22)

Control (n= 22)

Inclusion Criteria

Aged ≥18 years; ICU patients; ARDS diagnosis via Berlin criteria moderate to severe; developed ventilator-associated pneumonia (VAP); positive culture of P. aeruginosa

Exclusion Criteria

< 18 years old; non-ICU patients

Methods

At a single institution in Japan, a retrospective cohort study was conducted to analyze adult ICU patients who developed ventilator-associated pneumonia caused by P. aeruginosa during the course of ARDS. Patients who received aerosolized tobramycin inhalation solution (TIS) were compared to patients who received systemic antibiotics alone.

Patients were matched on similar eligibility criteria and severity of ARDs (moderate or severe). In the TIS group, aerosolized TIS 240 mg was administered daily for 14 days using an ultrasonic nebulizer (Aeroneb®, Aerogen, Ireland) in combination with systemic antibiotics or alone. The duration of TIS therapy could be modified according to clinical response. The duration of systemic antibiotic therapy was not standardized. Patients in the TIS and control groups were managed with lung-protective mechanical ventilation strategies for ARDS.

Duration

July 2009 to December 2015

Outcome Measures

Recurrence of P. aeruginosa VAP; 28-day mortality; ICU mortality; Ventilator-free days on day 28 and day 90

Baseline Characteristics

Tobramycin (n= 22)

Control (n= 22)

Age, years

Male

ARDS severity

Moderate

Severe

17 (77%)

5 (23%)

17 (77%)

5 (23%)

Length of ICU stay, days (IQR)

At onset of ARDs

At onset of VAP

2.5 (1.25-8)

19 (13-31)

2 (1-11.7)

11 (5-16.8)

Duration of therapy, days

Aerosolized tobramycin

Systemic antibiotics

Total treatment duration

14.0 ± 6.1

7.2 ± 6.9

14.3 ± 5.9

N/A

14.0 ± 12.4

14.0 ± 12.4

Prescribed systemic antibiotics

Beta-lactams

Quinolones

Aminoglycosides

17 (77%)

6 (27%)

3 (14%)

19 (86%)

10 (46%)

9 (41%)

Initial inappropriate therapy

Results

Tobramycin (n= 22)

Control (n= 22)

P-value

Recurrence of P. aeruginosa

28-day mortality

ICU mortality

Ventilator-free days on day 28 (IQR)

Ventilator-free days on day 90 (IQR)

Adverse Events

Not reported

Study Author Conclusions

In conclusion, tobramycin inhalation solution has a therapeutic potential for P. aeruginosa VAP with ARDS by improving survival of patients without increasing resistance to antibiotics. Well-designed, prospective clinical trials are required to confirm the benefit of inhaled antibiotic therapy for patients who develop lung infection with P. aeruginosa during severe respiratory failure.

InpharmD Researcher Critique

As a result of the retrospective and non-randomized design, there is a potential for bias even though both study groups were similar in clinical features and severity of illness. The use of a historical control to match patients may have resulted in selection bias. Additionally, these results are limited by the small sample of patients from a single ICU in Japan.

Inhaled antibiotic therapy in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection by Pseudomonas aeruginosa

Design

Randomized, open-label, pilot study

N=17

Objective

To ascertain the long-term efficacy of home-inhaled antibiotic therapy in the outcome of non-CF patients with bronchiectasis and CBIPA who fail to respond satisfactorily to antibiotics by other routes

Study Groups

Inhaled antibiotics (n=7)

Symptomatic treatment (n=8)

Inclusion Criteria

Diagnosis of bronchiectasis confirmed by bronchography and/or thoracic computed axial tomography; required treatment due to respiratory exacerbations; required long-term therapy; previously treated with ciprofloxacin PO within the past 3 months due to exacerbation; at least 3 positive cultures over the past year

Exclusion Criteria

Methods

All patients completed a routine 2-week IV antibiotic treatment (ceftazidime 100 mg/kg/day and tobramycin 4 mg/kg/day) and standard protocols until respiratory status was stabilized. Then, patients were randomized to a 12-month course of the same antibiotics via inhalation (ceftazidime 1000 mg q12h and tobramycin 100 mg q12h) or symptomatic treatment.

All nebulized antibiotics were diluted in physiological saline to form a solution of approximately 8 mL. The solutions were administered separately twice a day using a jet nebulizer. Supplementary use of oral antibiotics was permitted if a patient had an exacerbation.

Duration

12 months

Outcome Measures

Baseline Characteristics

Inhaled antibiotics (n=7)

Symptomatic treatment (n=8)

Age, years

Male

Bronchiectasic lobes

Admissions in the past year

Admissions in the past 2 years

2.1 ± 1.1

2.3 ± 0.9

2.0 ± 0.9

2.1 ± 1.1

Pseudomonas aeruginosa was cultured in all samples from all patients.

Results

Inhaled antibiotics (n=7)

Symptomatic treatment (n=8)

P-value

Hospital admissions

Days of admission

0.6 ± 1.5

13.1 ± 34.8

2.5 ± 2.1

57.9 ± 41.8

0.023

0.033

Oral antibiotic use

Emergence of antibiotic-resistant bacteria

FVC, FEV₁, P_AO₂, and P_ACO₂, were similar in the two groups at the end of follow-up. The decline of these pulmonary function parameters was similar in both groups.

NS=not significant

Adverse Events

None of the patients presented impaired renal or auditory function at the end of the study.

Study Author Conclusions

This study suggests that long-term inhaled antibiotic therapy may be safe and lessen disease severity in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection by Pseudomonas aeruginosa which do not respond satisfactorily to antibiotics administered via other routes.

InpharmD Researcher Critique

Due to the rarity of this condition, the sample size is low and therefore a cross-over design could have been a possible option. However, this study lasted for 12 months, during which time the characteristics of the patients may have changed, therefore a crossover design could potentially have been flawed.

The use of placebo was not considered for different reasons: firstly, because of the difficulty in adequately matching for all the distinctive characteristics of the inhaled antibiotics used in the study; secondly, it was considered difficult to administer a placebo over such a long period of time; and finally, exactly how a nebulized placebo can influence long-term outcome remains unknown.

A strength of the study is that the decision to admit and discharge participants was made by physicians not participating in the study.

Aerosolized Tobramycin in the Treatment of Ventilator-Associated Pneumonia: A Pilot Study

Design

Randomized, double-blind, masked, pilot cohort study

N= 10

Objective

To evaluate the efficacy and safety of inhaled tobramycin (TOBI) in the treatment of ventilator-associated pneumonia (VAP) in a randomized, double-blind pilot study

Study Groups

Inhaled tobramycin (n= 5)

Intravenous tobramycin (n= 5)

Inclusion Criteria

Patients in the trauma intensive care unit with signs or symptoms of ventilator-associated pneumonia (VAP) or new infiltrate on chest radiograph after being intubated for 96 hours; had a simplified Clinical Pulmonary Score (CPIS) ≥6 or CPIS <6 with final confirmation of a positive bronchoalveolar lavage (BAL) result (≥10⁴ CFU of Pseudomonas aeruginosa or Acinetobacter spp. sensitive to tobramycin per milliliter of BAL fluid)

Exclusion Criteria

Age <18 years, pregnancy, use of immunosuppressive drugs, absolute neutrophil count ≤1,000/mm³, serum creatinine concentration ≥2 mg/dL or doubling of creatinine within the previous 72 hours, allergy to aminoglycosides, treatment with an aminoglycoside within the previous 72 hours, and previous enrollment in the study

Methods

The study was conducted at a trauma intensive care unit with patients who have VAP. Patients were randomized to receive tobramycin either intravenously or inhaled. Patients randomized to inhaled tobramycin received 300 mg (5 mL) q12h and placebo IV, while patients randomized to the intravenous group received IV tobramycin q24h (using individualized dosing) and placebo nebulization.

All patients also received either piperacillin/tazobactam or imipenem/cilastatin. Vancomycin was also allowed if the patient needed gram-positive antibiotic coverage.

Duration

Treatment duration: 14 days

Outcome Measures

Primary outcome: Resolution of pneumonia

Secondary outcomes: Average treatment duration, ventilator-free-days, mean creatinine concentration, PaO₂:FiO₂ ratio

Baseline Characteristics

Inhaled tobramycin (n= 5)

Age, years (range)

Male

APACHE II score

Days intubated before randomization

Results

Inhaled tobramycin (n= 5)

Intravenous tobramycin (n= 5)

P-value

Resolution of pneumonia

Average inhaled tobramycin duration, days

Ventilator-free days

Serum creatinine concentration, mg/dL

There was no significant difference in the PaO₂:FiO₂ ratio between groups.

Adverse Events

There were no observed adverse pulmonary effects from nebulized tobramycin

Study Author Conclusions

In this pilot study, aerosolized tobramycin appeared to be safe and effective for the treatment of VAP caused by P. aeruginosa or Acinetobacter spp. On the basis of these pilot data and encouraging experimental results on the benefit of inhaled antibiotics for the treatment of VAP, a larger study is warranted.

InpharmD Researcher Critique

Since this is a pilot study, these results are limited by the small sample size. The study mentioned that the two patients who failed therapy, also had a higher Multiple Organ Dysfunction Score (MODS) than the other patients. This could have skewed the results in favor of the inhaled cohort, especially with the small sample size.

Off-label use of inhaled tobramycin in Ontario, Canada

Design

Retrospective, cross-sectional study

N= 300

Objective

To examine changes in the apparent indication of inhaled tobramycin use over time

Study Groups

Users with CF (n= 163)

Users without CF with COPD (n= 137)

Inclusion Criteria

Patients eligible for the program with financial needs due to high drug costs and/or low income, residents ≥65 years old, diagnosis of cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD)

Exclusion Criteria

Patients who receive medications through private coverage or pay out of pocket, patients with neither CF nor COPD, persons with no reported indication for tobramycin

Methods

The study examined quarterly prescription claims for inhaled tobramycin reimbursed by the Ontario Public Drug Program (OPDP). The reports were stratified with a diagnosis of CF or COPD 5 years back from the date of the prescription. Patients with both CF and COPD were placed in the CF group.

Duration

April 2007 to March 2015

Outcome Measures

Change in number of prescriptions from 2007 to 2015 in OPDP

Baseline Characteristics

Users with CF (n= 163)

Users without CF with COPD (n= 137)

Median age, years (IQR)

Aged 65+

23 (21-76)

15 (9%)

76 (71-81)

128 (93%)

Number with only one prescription

IQR=interquartile range

Results

Users with CF (n= 163)

Users without CF with COPD (n= 137)

Number of prescriptions in 2007 (n= 5,853)

Number of prescriptions in 2014 (n= 324)

3042 (52%)

163 (54%)

2350 (40%)

137 (46%)

The study only provided an exact number of prescriptions for 2007 and 2014. The number of prescriptions for other years showed an overall increase in the number of prescription claims for both groups. Half of these claims were for off-label use, mostly among patients with COPD (40%).

Adverse Events

Not studied

Study Author Conclusions

There is a large amount of off-label use in patients with COPD, where there is little evidence of efficacy from clinical trials. Given the potential implications of off-label tobramycin use on both drug costs and patient outcomes, future research should explore the effectiveness and safety of inhaled tobramycin in these off-label indications, especially in patients with COPD.

InpharmD Researcher Critique

The study is based on the number of prescription claims in a database, so the actual indication for inhaled tobramycin is not certain. The study also does not include information on dosing or adverse events of inhaled tobramycin. COPD was the only off-label indication examined in this study. Other uses for tobramycin were mentioned but not documented.