Antimicrobial Treatment in Patients With Ventilator-associated Tracheobronchitis (TAVeM2)

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

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).

Study Overview

• Status: Recruiting
• Conditions: Critical Illness; Mechanical Ventilation Complication
• Intervention / Treatment: Drug: placebo; Drug: ceftriaxone; Drug: ciprofloxacin; Drug: imipenem; Drug: linezolid

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 Type: Interventional
• Enrollment (Anticipated): 154
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Saad NSEIR, MD,PhD; Phone Number: +33 3 20 44 40 84; Email: saadalla.nseir@chru-lille.fr

Study Locations

• France
  • Lille, France
    • Recruiting
    • Hôpital Roger Salengro, CHRU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

1. absence of new infiltrate on chest X ray
2. 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
3. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / 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: 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; 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

What is the study measuring?

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	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)

Collaborators and Investigators

• Sponsor: University Hospital, Lille
• Collaborators: Ministry of Health, France

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 8, 2018
• Primary Completion (ANTICIPATED): September 1, 2023
• Study Completion (ANTICIPATED): September 1, 2023

Study Registration Dates

• First Submitted: December 13, 2016
• First Submitted That Met QC Criteria: January 4, 2017
• First Posted (ESTIMATE): January 6, 2017

Study Record Updates

• Last Update Posted (ACTUAL): August 17, 2022
• Last Update Submitted That Met QC Criteria: August 16, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Infectiology; Critical Care; Hygiene; Pneumology; Biology of infectious agents
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Linezolid; Ceftriaxone; Ciprofloxacin; Imipenem
• Other Study ID Numbers: 2015_66; 2016-000735-41 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No