Addition of Tobramycin Inhalation in the Treatment of Ventilator Associated Pneumonia

Study Overview
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Brief Summary
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This study evaluates the addition of tobramycin inhalation treatment to standard intravenous therapy in the treatment of ventilator associated pneumonia.

Detailed Description
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Rationale: Approximately 9-27% of mechanically ventilated patients in the intensive care unit (ICU) develop ventilator-associated pneumonia (VAP). Patients in whom VAP develops have a higher mortality rate up to 50%, stay longer in the intensive care unit (ICU), and require more resources than those without the disease. Despite the availability of modern ICU care and modern antibiotics, the overall clinical cure rate after 72 hours of antibiotic treatment for VAP is only 40%. The cure rate for Pseudomonas aeruginosa is even lower. It is unclear why VAP cure rates are so low. The ATS guidelines recommend IV antibiotic treatment (IV AB), especially directed against gram-negative microorganisms. However, the relatively poor response rates seen with intravenous therapy of VAP and the emergence of MDR organisms makes new treatment options desirable. The ATS/IDSA VAP guidelines recommend that adjunctive therapy with an inhaled aminoglycoside or polymyxin (colistin) for MDR Gram-negative pneumonia should be considered, especially in patients who are not improving. It is therefore necessary to investigate whether adjunctive therapy with inhalation Tobramycin could ameliorate prognosis. The recommendations by the Society of Infectious Diseases Pharmacists are similar.

Official Title
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Ventilator Associated Pneumonia: Addition of Tobramycin Inhalation Antibiotic Treatment to Standard IV Antibiotic Treatment

Conditions
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Ventilator Associated Pneumonia (VAP)

Intervention / Treatment
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* Drug: tobramycin inhalation
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Mechanical ventilation 48 hours or more New or progressive radiologic pulmonary infiltrate Together with at least two of the following three criteria (< 24 h): temperature >38°C leukocytosis >12,000/mm3 or leucopenia <4,000/mm3 purulent respiratory secretions Exclusion Criteria: patients with allergy to tobramycin pregnancy expected to die within 72 hours after enrollment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tobramycin inhalation<br>twice daily tobramycin inhalation (Bramitob) 300 mg and standard intravenous antibiotics treatment | Drug: tobramycin inhalation<br>* tobramycin inhalation 300 mg twice daily<br>* Other names: Bramitob;|
| Placebo Comparator: Placebo<br>twice daily placebo inhalation and standard intravenous antibiotics treatment | Drug: placebo<br>* NaCl 0.9% inhalation 4 ml twice daily<br>* Other names: NaCl 0.9% inhalation 4 ml;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| response after 72 h of treatment | non response is considered when at least one of the following is present No improvement of the arterial O2 tension to inspired O2 fraction ratio Persistence of fever (≥38°C) or hypothermia (<35.5°C) together with purulent respiratory secretions increase in the pulmonary infiltrates on chest radiograph of greater than or equal to 50% occurrence of septic shock or multiple organ dysfunction syndrome, defined as three or more organ system failures not present on Day 1 | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality rate | 30-day and 90- day mortality rate | day 30 | 
| Mortality rate | 30-day and 90- day mortality rate | day 90 | 
| ICU survival |  | day 90 | 
| Absence of hospital admittance at day 60 |  | day 60 | 
| Discharge from the ICU | Patients will be followed during ICU stay and evaluated at discharge from ICU, expected average time of discharge is 10 days | up to 60 days | 
| Ventilator free days at day 28 |  | up to 28 days | 
| Adverse events |  | day 1 | 
| Adverse events |  | day 4 | 
| Adverse events |  | day 8 | 
| Adverse events |  | day 14 | 
| Adverse events |  | day 30 | 
| Adverse events |  | day 90 | 
| Day of normalisation of CRP |  | day 1 | 
| Day of normalisation of CRP |  | day 4 | 
| Day of normalisation of CRP |  | day 8 | 
| Day of normalisation of CRP |  | day 14 | 
| Day of normalisation of CRP |  | day 30 | 
| Day of normalisation of CRP |  | day 90 | 
| Eradication of pathogens |  | day 4 | 
| Eradication of pathogens |  | day 8 | 
| Eradication of pathogens |  | day 14 | 
| Eradication of pathogens |  | day 30 | 
| Eradication of pathogens |  | day 90 | 
| Clinical Pulmonary Infectious Score (CPIS) |  | Day 1 | 
| Clinical Pulmonary Infectious Score (CPIS) |  | Day 4 | 
| Clinical Pulmonary Infectious Score (CPIS) |  | Day 8 | 
| Clinical Pulmonary Infectious Score (CPIS) |  | Day 14 | 
| Clinical Pulmonary Infectious Score (CPIS) |  | discharge ICU, expected average time of discharge is 10 days | 
| APACHE II score |  | Day 1 | 
| APACHE II score |  | Day 4 | 
| APACHE II score |  | Day 8 | 
| APACHE II score |  | Day 14 | 
| APACHE II score |  | discharge ICU, expected average time of discharge is 10 days | 
| Multiple Organ Dysfunction score (MODS) |  | Day 1 | 
| Multiple Organ Dysfunction score (MODS) |  | Day 4 | 
| Multiple Organ Dysfunction score (MODS) |  | Day 8 | 
| Multiple Organ Dysfunction score (MODS) |  | Day 14 | 
| Multiple Organ Dysfunction score (MODS) |  | discharge ICU, expected average time of discharge is 10 days | 
| Sequential Organ Failure Assessment score (SOFA) |  | Day 1 | 
| Sequential Organ Failure Assessment score (SOFA) |  | Day 4 | 
| Sequential Organ Failure Assessment score (SOFA) |  | Day 8 | 
| Sequential Organ Failure Assessment score (SOFA) |  | Day 14 | 
| Sequential Organ Failure Assessment score (SOFA) |  | discharge ICU, expected average time of discharge is 10 days | 
| Lung Injury Score (LIS) |  | Day 1 | 
| Lung Injury Score (LIS) |  | Day 4 | 
| Lung Injury Score (LIS) |  | Day 8 | 
| Lung Injury Score (LIS) |  | Day 14 | 
| Lung Injury Score (LIS) |  | discharge ICU, expected average time of discharge is 10 days | 
| Day of normalisation of procalcitonin (PCT) |  | day 1 | 
| Day of normalisation of procalcitonin (PCT) |  | day 4 | 
| Day of normalisation of procalcitonin (PCT) |  | day 8 | 
| Day of normalisation of procalcitonin (PCT) |  | day 14 | 
| Day of normalisation of procalcitonin (PCT) |  | day 30 | 
| Day of normalisation of procalcitonin (PCT) |  | day 90 | 
| Day of normalisation of chest X-ray |  | day 1 | 
| Day of normalisation of chest X-ray |  | day 4 | 
| Day of normalisation of chest X-ray |  | day 8 | 
| Day of normalisation of chest X-ray |  | day 14 | 
| Day of normalisation of chest X-ray |  | day 30 | 
| Day of normalisation of chest X-ray |  | day 90 |