TAVeM2: Antimicrobial Treatment in Patients With Ventilator-associated Tracheobronchitis

Sponsor

University Hospital, Lille (Other)

Overall Status

Recruiting

CT.gov ID

NCT03012360

Collaborator

Ministry of Health, France (Other)

154

Enrollment

Location

Arms

66.7

Anticipated Duration (Months)

2.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Mechanical Ventilation Complication Critical Illness	Drug: ceftriaxone Drug: ciprofloxacin Drug: imipenem Drug: linezolid Drug: placebo	Phase 4

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

154 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Feb 8, 2018

Anticipated Primary Completion Date :

Sep 1, 2023

Anticipated Study Completion Date :

Sep 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: no antibiotic treatment for VAT 3 days of placebo	Drug: placebo 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
Experimental: antibiotic treatment for 3 days 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 2 g iv every 24h Drug: ciprofloxacin 400 mg iv every 8h Drug: imipenem 1 g iv every 8h Drug: linezolid 600 mg iv every 12h Drug: placebo 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

Arm

Intervention/Treatment

Placebo Comparator: no antibiotic treatment for VAT

3 days of placebo

Drug: placebo

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

Experimental: antibiotic treatment for 3 days

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

2 g iv every 24h

Drug: ciprofloxacin

400 mg iv every 8h

Drug: imipenem

1 g iv every 8h

Drug: linezolid

600 mg iv every 12h

Drug: placebo

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

Outcome Measures

Primary Outcome Measures

The percentage of patients with a transition from VAT to VAP, [from randomization to day 28 (4 weeks)]
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.

Secondary Outcome Measures

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)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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