Microbiome-guided Prophylaxis to Reduce Ventilator-Associated Pneumonia in Intensive Care Units: A Pilot Randomized Controlled Trial

Research Question:

Is it feasible and safe to implement a randomized controlled trial of microbiome-guided inhaled antimicrobial prophylaxis to prevent VAP in mechanically ventilated ICU patients?

Primary Objective:

To assess the feasibility of conducting a full-scale randomized controlled trial, including protocol adherence, timely microbiome result reporting, and timely initiation and completion of the assigned intervention, and safety.

Secondary Objectives:

To explore the impact of microbiome-guided inhaled prophylaxis on airway microbiome composition and to estimate clinical outcomes including VAP incidence, ventilator-free days, ICU and hospital length of stay, and mortality up to 28 days.

Hypothesis:

Microbiome-guided inhaled antimicrobial prophylaxis is feasible and may be superior to standard care in reducing airway pathogen burden and VAP incidence.

Methods:

This is a single-centre, randomized, placebo-controlled pilot trial enrolling 70 mechanically ventilated adult ICU patients at Foothills Medical Centre in Calgary, AB, Canada. Participants will be randomized 1:1 to microbiome-guided inhaled antibiotic prophylaxis (intervention arm) or matching placebo (control arm). Endotracheal aspirates (ETA) will be collected at enrolment for rapid microbiome sequencing and analysis. In the intervention arm, participants with airway microbiome positive for VAP pathogens will receive inhaled tobramycin, participants with airway S. aureus will receive inhaled vancomycin, while those without pathogens will receive inhaled saline placebo. Treatment responsiveness will be determined on day 3 with repeat airway microbiome sequencing and analysis, and in participants with persistent airway pathogens, inhaled tobramycin will be changed to inhaled aztreonam, while those with airway S. aureus will continue to receive inhaled vancomycin. Total duration of intervention will be 5 days. Participants randomized to control arm, will undergo identical ETA sampling for airway microbiome sequencing but results will remain blinded, and participants will receive inhaled saline placebo for 5 days. Clinicians and participants will be blinded to microbiome results and allocation. Participants will be followed for up to 28 days for primary feasibility and safety outcomes (see section below for additional details), as well as secondary clinical outcomes and biological outcomes (airway microbiome and immune analyses).

Inclusion criteria

• Adult (>18 years old) admitted to FMC ICU
• Mechanically ventilated via endotracheal tube
• Expected duration of mechanical ventilation >72 hours (as determined by the attending ICU physician)

Exclusion criteria

• Goals of care designation that limits the use of life-sustaining interventions
• Life expectancy <72 hours (in the opinion of the attending ICU physician)
• Suspected or confirmed pneumonia (community-acquired [CAP], hospital-acquired [HAP], or ventilator-associated [VAP])
• Severe chronic lung disease (diagnosis of chronic lung disease with home oxygen or home mechanical ventilation, or FEV1 <30% on outpatient pulmonary function testing, or medical research council dyspnea scale grade 4 or higher symptoms attributed to lung disease)
• Contraindication to interventional agents: for inhaled tobramycin - severe acute kidney injury (AKI, KDIGO stage 3) or chronic kidney disease (CKD, stage 4 or higher with eGFR <30 mL/min measured as outpatient) not receiving renal replacement therapy (RRT), severe allergy/hypersensitivity to aminoglycosides; for aztreonam - severe allergy/hypersensitivity to beta-lactams, for vancomycin - severe allergy/hypersensitivity.
• Tracheostomy
• Pregnancy
• >48 hours from initiation of mechanical ventilation at the time of enrolment
• Concurrently enrolled in another interventional clinical trial of antimicrobial or immune modulator therapy