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What is the role of tobramycin inhalation in adults for indications outside of cystic fibrosis? Is there any evidence for other indications (e.g., tracheitis)?

Comment by InpharmD Researcher

Tobramycin has been studied off-label for non-cystic fibrosis bronchiectasis, as post-transplant prophylaxis, in patients who are chronically colonized by P. aeruginosa (without CF), and for ventilator-associated pneumonia in patients with acute respiratory distress syndrome. These studies of off-label inhaled tobramycin are mainly pilot studies that consist of small sample sizes.
Background

Cystic fibrosis is the only pulmonary condition FDA-approved for inhaled tobramycin, but there are tobramycin has also been used for non-cystic fibrosis bronchiectasis. While data is limited, tobramycin has potential use as a long-term nebulized antibiotic if patients are chronically colonized by P. aeruginosa and in patients who experience 3 or more exacerbations a year that cause significant morbidity. Inhaled tobramycin has also been studied as post-transplant prophylaxis in patients with pretransplant infection with multidrug-resistant organisms (P. aeruginosa or Burkholderia cepacia). A small uncontrolled study has also evaluated tobramycin inhalation for overlapping bronchiectasis with purulent sputum production and chronic infection with Pseudomonas aeruginosa. [1-3]

A meta-analysis reviewed five randomized controlled trials on the use of inhaled tobramycin in patients with non-cystic fibrosis bronchiectasis. The analysis demonstrated a high heterogeneity among the studies (I^2=75%), so the authors did not report the overall pooled results. Two studies demonstrated decreased P. aeruginosa sputum density compared to placebo. The results of three studies reported inhaled tobramycin to be associated with P. aeruginosa eradication after a median of 4.3 weeks (odds ratio 4.87; 95% confidence interval 1.04 to 22.77; I^2=40%). The data also reports antibiotic resistance to tobramycin, suggesting inhaled tobramycin leads to resistant P. aeruginosa strains. Additionally, tobramycin showed an increase in all non-fatal adverse effects including bronchospasm that lead to subject withdrawals from the interventional group. The authors conclude there is not enough evidence to confirm the benefit of inhaled tobramycin. [4]

A 2011 poster abstract presents a pilot study of inhaled tobramycin to prevent airway stenosis after lung transplantation. Of 22 patients who received inhaled tobramycin, (2×80mg for the first 7 postoperative days), 7 patients (31.8%) developed airway complications. Of a historical cohort matched for age, gender, and diagnosis lead to transplant, 15/22 patients (68.2%) who did not receive post-transplant tobramycin developed airway complications. This resulted in a significant decrease in the development of postoperative stenosis with inhaled tobramycin (P=0.034). [5]

A case report described a 63-year-old man who developed renal toxicity after inhaled tobramycin following bilateral lung transplantation because of idiopathic pulmonary fibrosis. The patient had multiple bronchial infections caused by Pseudomonas aeruginosa, so inhaled tobramycin was started at a dose of 300 mg BID. Ten days after starting tobramycin, his creatinine level rose from 2.5 to 3.5 mg/dL despite cyclosporine adjustments. Tobramycin was withdrawn, and his creatinine decreased to his previous value within 1 week. [6]

A second case described a 55-year-old man who received a lung transplant due to emphysema. Inhaled tobramycin was started because of repeated bronchial infections by P. aeruginosa following a bronchiolitis obliterans diagnosis. After starting tobramycin, his creatinine rose to 4 mg/dL, potassium levels reached 7 mEq/L, and the patient required temporary hemodialysis. His renal function returned to normal 15 days after tobramycin was stopped. [6]

References:

[1] Quon BS, Goss CH, Ramsey BW. Inhaled antibiotics for lower airway infections. Ann Am Thorac Soc. 2014;11(3):425-434.
[2] Bothra M, Lodha R, Kabra SK. Tobramycin for the treatment of bacterial pneumonia in children. Expert Opin Pharmacother. 2012;13(4):565-571. doi:10.1517/14656566.2012.656090
[3] Vendrell M, Muñoz G, de Gracia J. Evidence of inhaled tobramycin in non-cystic fibrosis bronchiectasis. Open Respir Med J. 2015;9:30-36. Published 2015 Mar 31. doi:10.2174/1874306401509010030
[4] Sangiovanni S, Morales EI, Fernández-Trujillo L. Inhaled tobramycin for chronic infection with pseudomonas aeruginosa in non-cystic fibrosis bronchiectasis: A systematic review and meta-analysis. Respir Med. 2021;176:106283.
[5] Yarmus L, Shah A, Merlo C, Orens J, Feller-Kopman D, McDyer J. Inhaled tobramycin for the prevention of airway stenosis after lung transplantation: A pilot study. European Respiratory Journal. 2011;38(Suppl 55):p3069.
[6] Laporta R, Ussetti P, Carreño MC. Renal toxicity due to inhaled tobramycin in lung transplant recipients. J Heart Lung Transplant. 2006;25(5):608.

Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

What is the role of tobramycin inhalation in adults for indications outside of cystic fibrosis? Is there any evidence for other indications (e.g., tracheitis)?

Please see Tables 1-7 for your response.


 

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)

P-value

Age, years

66.6 ± 13.0 63.2 ± 13.5 0.27

Female

23 (62%) 22 (59%) 1.00 

White

36 (97%) 32 (86%) 0.20 

P. aeruginosa log10, cfu/g

7.1 ± 1.4 6.7 ± 1.6 0.33

FEV1 % (predicted)

56.2 ± 21.2 53.3 ± 22.1 0.57

Duration of bronchiectasis, years

14.1 ± 15.4 18.7 ± 17.0 0.23

Smoking history 

24 (65%) 16 (43%) 0.10

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*

23 (62%) 14 (38%)

Percent change in FEV1

-2.2% 1.5% 0.41

Percent change in FVC

-2.8% 2.2% 0.19

*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. 



References:

Barker AF, Couch L, Fiel SB, et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med. 2000;162(2 Pt 1):481-485. doi:10.1164/ajrccm.162.2.9910086

 

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

Number of exacerbations, number and days of hospital admissions, lung function based on FVC and FEV1, days of antibiotic treatment, quality of life as determined by St. George Respiratory Questionnaire, density of PA in sputum 

Baseline Characteristics

 

Tobramycin (n= 20)

Placebo (n= 20)

Died (n= 5)

P-value

Age, years (range)

64.5 (38-75) 64.5 (38-75) 65.6 (61-72) 0.740

Pseudomonas aeruginosa infection, months

48 ± 43.15 48 ± 43.15 43.4 ± 10.57 0.670

Basline Pseudomonas aeruginosa density, cfu/mL

>106 >106 - -

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)

P-value

 

Exacerbations per patient

0.9 1.3 0.330  

Hospital admissions  per patient

0.15 ± 0.37 0.75 ± 1.16 0.038  

Days of hospital admission per patient

2.05 ± 5.03 12.65 ± 21.8 0.047  

Days of additional antibiotic treatment per patient

8.4 ± 11.2 19.1 ± 24.4 0.052  

Pseudomonas aeruginosa density, cfu/mL

Between 10 and 106 Between 10 and 106 0.038  

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. 



References:

Drobnic ME, Suñé P, Montoro JB, Ferrer A, Orriols R. Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa. Ann Pharmacother. 2005;39(1):39-44. doi:10.1345/aph.1E099

 

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

63.1 ± 12.7 66.2 ± 13.5 65.2 ± 13.1  

White

14 (100%) 25 (92.6%) 39 (95.1%)  

Baseline FEV1 %

43.1 ± 28.1 56.1 ± 20.7 51.7 ± 24.0  

Disease duration

18.1 ± 24.1 12.1 ± 15.9  14.2 ± 19.0  

Smoking history

11 (78.6%) 11 (40.7%) 22 (53.7%)  

Pulmonary total symptom severity score

8.3 ± 3.9 9.7 ± 4.0 9.2 ± 4.0  

SGRQ score

57.6 ± 21.4 57.1 ± 19.6 57.4 ± 20.0  

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

-0.7 ± 3.1 -2.0 ± 3.5 -1.5 ± 3.4 0.006

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

-7.9 -10.5 -9.8 ± 13.9 0.001

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. 



References:

Scheinberg P, Shore E. A pilot study of the safety and efficacy of tobramycin solution for inhalation in patients with severe bronchiectasis. Chest. 2005;127(4):1420-1426. doi:10.1378/chest.127.4.1420

 

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

67.8 ± 18.8 71.5 ± 11.3  

Male

16 (73%) 19 (86%)  

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

2 (9%) 3/19 (16%)  
IQR=interquartile range

Results

 

Tobramycin (n= 22)

Control (n= 22)

P-value

Recurrence of P. aeruginosa

5 (22.7%) 11/21 (52.4%) 0.042

28-day mortality

3 (14.3%) 12 (63.2%) <0.01

ICU mortality

5 (22.7%) 14 (63.6%) <0.01

Ventilator-free days on day 28 (IQR)

1 (0-15) 0 (0-1) 0.072

Ventilator-free days on day 90 (IQR)

20.5 (0-77) 0 (0-4.25) 0.086

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.



References:

Migiyama Y, Hirosako S, Tokunaga K, et al. Aerosolized tobramycin for Pseudomonas aeruginosa ventilator-associated pneumonia in patients with acute respiratory distress syndrome. Pulm Pharmacol Ther. 2017;45:142-147.

 

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

Positive for cystic fibrosis mutations; immunodeficiency, enzymatic deficient, or congenital disease as the cause of the bronchiectasis; beta-lactam or aminoglycoside hypersensitivity; bacterial resistance in the antibiogram; kidney failure

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

Hospital administration; number of hospitalization days; oral antibiotic use; emergence of bacterial resistance

Baseline Characteristics

 

Inhaled antibiotics (n=7)

Symptomatic treatment (n=8)

 

Age, years

62.0 ± 8.5 61.4 ± 10.3  

Male

6 (86%) 4 (50%)  

Bronchiectasic lobes

4.0 ± 1.5 3.0 ± 1.3  

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

1.1 ± 1.2 4.0 ± 4.5 NS

Emergence of antibiotic-resistant bacteria

1 (14%) 4 (50%) NS

FVC, FEV1, PAO2, and PACO2, 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.



References:

Orriols R, Roig J, Ferrer J, et al. Inhaled antibiotic therapy in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection by Pseudomonas aeruginosa. Respir Med. 1999;93(7):476-480. doi:10.1016/s0954-6111(99)90090-2

 

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)

Intravenous tobramycin (n= 5) P-value

Age, years (range)

52.6 ± 24 53.6 ± 21.4 0.96

Male

4 (80%) 2 (40%)  --

APACHE II score

17 ± 1.26 15 ± 3.3 0.53

Days intubated before randomization

17 ± 20.2 13.2 ± 13.3 0.89

Results

 

Inhaled tobramycin (n= 5)

Intravenous tobramycin (n= 5)

P-value

Resolution of pneumonia

5 (100%) 3 (60%)  --

Average inhaled tobramycin duration, days

13.6 ± 0.9  --  --

Ventilator-free days

24 ± 3 14 ± 13 0.12

Serum creatinine concentration, mg/dL

0.79 ± 0.17 1.6 ± 1.46 0.25

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.



References:

Hallal A, Cohn SM, Namias N, et al. Aerosolized tobramycin in the treatment of ventilator-associated pneumonia: a pilot study. Surg Infect (Larchmt). 2007;8(1):73-82.

 

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

58 (36%) 37 (27%)

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.



References:

Tadrous M, Khuu W, Paterson JM, Mamdani MM, Juurlink DN, Gomes T. Off-label use of inhaled tobramycin in Ontario, Canada. Thorax. 2016;71(9):862-864. doi:10.1136/thoraxjnl-2015-208145


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