Antimicrobial Treatment in Patients With Ventilator-associated Tracheobronchitis

Study Overview
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Brief Summary
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Antimicrobial treatment could be beneficial in patients with ventilator-associated tracheobronchitis (VAT). The hypothesis of this study is that antibiotic treatment for VAT (3 or 7 days), compared with no antibiotic treatment, would reduce the incidence of transition from VAT to ventilator-associated pneumonia (VAP).

Detailed Description
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The main objective of this randomized controlled multicenter double-blind trial is to assess the efficiency of two durations (3 or 7 days) of antibiotic treatment for VAT, compared with no antibiotic treatment, in reducing the incidence of transition from VAT to ventilator-associated pneumonia (VAP). Secondary objectives are to determine the impact of two durations (3 or 7 days) of antibiotic treatment for VAT, compared with no antibiotic treatment, on: duration of mechanical-ventilation free days duration of antibiotic free days length of ICU stay mortality at day 28 and day 90 incidence of ICU-acquired colonization related to multidrug resistant (MDR) bacteria incidence of ICU-acquired infection related to MDR bacteria incidence of ventilator-associated events After informed consent, patients will be randomized (1:1:1) to receive 0 (control group), 3 or 7 days (experimental groups) of antibiotic treatment for VAT Antibiotic treatment is standardized, based on the time of onset of VAT, and presence of risk factors for MDR bacteria: patients with early-onset VAT with no risk factor for MDR bacteria will receive ceftriaxone (2 g iv every 24h). patients with late-onset VAT (after day 4 of mechanical ventilation), or with at least one risk factor for MDR bacteria will receive imipenem (1 g iv every 8h), and ciprofloxacin (400 mg iv every 8h) as empirical treatment. When methicillin-resistant Staphylococcus aureus is suspected, linezolid (600 mg iv every 12h) will be added to empirical treatment. Patients randomized in control group will receive 7 days of placebo, and those randomized in the first experimental arm (3 days of antibiotics) will receive 4 days of placebo.

Official Title
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Antimicrobial Treatment in Patients With Ventilator-associated Tracheobronchitis: a Prospective Randomized Placebo-controlled Double-blind Multicenter Trial

Conditions
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Mechanical Ventilation Complication, Critical Illness

Intervention / Treatment
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* Drug: ceftriaxone
* Drug: ciprofloxacin
* Drug: imipenem
* Drug: linezolid
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All adult patients hospitalized in the ICU with a first episode of VAT diagnosed >48 hours after starting invasive mechanical ventilation are eligible for this study. VAT is defined using the following criteria: absence of new infiltrate on chest X ray two of the three following conditions: fever > 38.5 °C or <36.5, leucocyte count > than 12 000 cells per μL or <than 4000 cells per μL purulent tracheal secretions and positive tracheal aspirate (≥105 cfu/mL) Exclusion Criteria: long-term tracheostomy at ICU admission patients who develop VAP before VAT patients already receiving antibiotics active against all the microorganisms responsible for VAT severe immunosuppression pregnancy or breastfeeding patients <18 years patients already included in another study, with potential interaction with the primary objective of the current study known resistance to imipenem and ciprofloxacin of bacteria responsible for VAT treatment limitation decisions moribund patients (likely to die within 24 h) allergy to any of study drugs: hypersensitivity to any carbapenem, severe hypersensitivity (for example anaphylactic reaction or severe cutaneous reaction) to any other antibiotic form beta-lactam group (such as penicillin or cephalosporin), severe hypersensitivity (for example anaphylactic reaction) to any other antibiotic from beta-lactam group (penicillin, monobactam or carbapenem), hypersensitivity to quinolones

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: no antibiotic treatment for VAT<br>3 days of placebo | Drug: placebo<br>* The SSI 0.9% or dextrose 5% used are based on routine procedure in different participating centers.Placebo will be prepared using IV bags, with the same of quantity as IMP<br>|
| Experimental: antibiotic treatment for 3 days<br>Patients randomized in one of the two experimental groups will receive 3 days of antimicrobials. Antibiotic treatment is standardized, based on the time of onset of VAT, and presence of risk factors for MDR bacteria: patients with early-onset VAT (< 5 days of mechanical ventilation), with no risk factor for MDR will receive ceftriaxone . patients with late-onset VAT (≥5 days of mechanical ventilation), or with at least one risk factor for multidrug resistant bacteria will receive imipenem , and ciprofloxacin as empirical treatment. When methicillin-resistant Staphylococcus aureus (MRSA) is suspected linezolid will be added to empirical treatment. 3 days of imipenem and ciprofloxacin with optional linezolid, followed by 4 d of placebo | Drug: ceftriaxone<br>* 2 g iv every 24h<br>Drug: ciprofloxacin<br>* 400 mg iv every 8h<br>Drug: imipenem<br>* 1 g iv every 8h<br>Drug: linezolid<br>* 600 mg iv every 12h<br>Drug: placebo<br>* The SSI 0.9% or dextrose 5% used are based on routine procedure in different participating centers.Placebo will be prepared using IV bags, with the same of quantity as IMP<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of patients with a transition from VAT to VAP, | VAP is defined using the following criteria: new or progressive pulmonary infiltrate two of the following criteria: temperature >38°C or <36.5°C leukocyte count >12,000/μL or <4,000/μL purulent endotracheal aspirate positive tracheal aspirate (≥105 cfu/mL) or bronchoalveolar lavage (≥104 cfu/mL). VAP will be considered as subsequent to VAT, when it is diagnosed >24h after VAT occurrence. Only first episodes of VAP diagnosed >48h after starting mechanical ventilation will be taken into account. | from randomization to day 28 (4 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| duration of mechanical ventilation-free days |  | from randomization to day 28 (4 weeks) | 
| duration of antibiotic free-days |  | from randomization to day 28 (4 weeks) | 
| length of ICU stay |  | from randomization to day 28 (4 weeks) | 
| mortality |  | at day 28 and day 90 after randomization | 
| percentage of patients with ICU-acquired colonization related to MDR bacteria |  | from randomization to day 28 (4 weeks) | 
| percentage of patients with ventilator-associated events |  | from randomization to day 28 (4 weeks) | 
| percentage of patients with ICU-acquired infection related to MDR bacteria |  | from randomization to day 28 (4 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infectiology, Biology of infectious agents, Hygiene, Pneumology, Critical Care