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

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

Ventilator-associated pneumonia (VAP) remains the most common hospital-acquired infection worldwide, affecting up to 40% of mechanically ventilated patients and contributing to increased morbidity, prolonged hospital stays, and high mortality rates. Standard prevention strategies rely on VAP prevention "bundles", which focus on general supportive care measures such as head-of-bed elevation, sedation interruption, and oral care. While these measures reduce some risk, they do not specifically target the underlying microbial mechanisms driving VAP.

Emerging evidence supports the use of inhaled antibiotic (iABx) prophylaxis to suppress or eliminate airway pathogens. Several randomized controlled trials have shown that inhaled antimicrobials can reduce the incidence of VAP. However, the effectiveness of this approach is inconsistent when applied to all ventilated patients. Studies indicate that the greatest benefit occurs when inhaled antimicrobials are targeted toward patients with airway colonization by specific VAP pathogens.

Traditional airway microbiome diagnostics have been a major barrier to implementing targeted prophylaxis because they are slow, costly, and require advanced expertise. Recently, a novel diagnostic method-ON-Time rapid microbiome sequencing-has been developed, offering accurate, cost-effective, and rapid (approximately 4.2 hours) results that can identify key VAP pathogens within the airway microbiome of ICU patients such as Enterobacteriaceae organisms, Pseudomonas spp., Acinetobacter spp., Stenotrophomonas maltophilia, Staphylococcus aureus, and others. The ability to define the airway microbiome of ICU patients including whether they harbour potential VAP pathogens provides a unique opportunity to tailor prophylactic antibiotics in a personalized and timely manner.

Thus, microbiome-guided prophylaxis represents a novel precision medicine approach to preventing VAP by selecting the right patient. This pilot trial aims to test the feasibility of implementing such an approach to prevent VAP in critically ill patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Critical Illness; Mechanical Ventilation
• Intervention / Treatment: Drug: Microbiome-guided inhaled antibiotic prophylaxis; Drug: Placebo

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Braedon McDonald, MD, PhD, FRCPC; Phone Number: 403-220-6885; Email: bamcdona@ucalgary.ca
• Study Contact Backup: Name: Ranjani Somayaji, BScPT, MD, MPH, FRCPC; Phone Number: 403-220-8559; Email: rsomayaj@ucalgary.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Microbiome-guided inhaled antibiotic prophylaxis; Participants randomized to "microbiome-guided antibiotic prophylaxis" will be administered inhaled antibiotics tailored to their airway microbiome composition.	Drug: Microbiome-guided inhaled antibiotic prophylaxis; Participants will receive inhaled antibiotics (tobramycin, aztreonam, and/or vancomycin - based on protocolled matching of VAP pathogens to appropriate antibiotics) for up to 5 days guided by analysis of airway microbiome composition.
Placebo Comparator: Placebo control; Participants randomized to "placebo control" will be administered inhaled 0.9% saline placebo.	Drug: Placebo; Participants randomized to "placebo control" arm will receive inhaled placebo twice daily for 5 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility: Adherence to protocol as measured by proportion of participants with endotracheal aspirate (ETA) microbiome sequencing results and initiation of microbiome-guided inhaled antimicrobial prophylaxis (or placebo) within <36h from ICU admission.	Proportion of participants with endotracheal aspirate (ETA) microbiome sequencing results and initiation of microbiome-guided inhaled antimicrobial prophylaxis (or placebo) within <36h from ICU admission.	ICU admission to hour 36.
Safety: As defined by proportion of participants who develop treatment-emergent adverse events (TEAE) related to inhaled antimicrobials (or placebo).	Proportion of participants who develop treatment-emergent adverse events (TEAE) related to inhaled antimicrobials (or placebo).	Enrolment to day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP)	Incidence of VAP/HAP from the time of enrolment to day 28, including early-onset VAP/HAP (enrolment to day 4) and late onset VAP/HAP (day 5 to day 28).	Enrolment to day 28
All-cause mortality	All-cause mortality from enrolment to day 28.	Enrolment to day 28
VAP/HAP-free survival	Composite outcome of VAP/HAP or death from enrolment to day 28	Enrolment to day 28
Ventilator-free day	Days free of mechanical ventilation from the time of enrolment to day 28.	Enrolment to day 28
ICU-free and hospital-free days	Number of days spent outside of ICU and number of days spent outside of hospital from enrolment to day 28	Enrolment to day 28
Extubation failure	Re-intubation within 7 days following extubation from enrolment to day 28	Enrolment to day 28
Ventilator-associated complications and infection-related ventilator-associated complications	Incidence of ventilator-associated complications (VAC), and infection-related ventilator-associated complications (IVAC) from enrolment to day 28.	Enrolment to day 28
Non-pneumonia hospital-acquired infections (HAIs)	Incidence of other hospital-acquired infections (HAIs) from enrolment to day 28	Enrolment to day 28
Illness severity	Daily maximum sequential organ failure assessment (SOFA) score from enrolment to day 28.	Enrolment to day 28
Lung injury severity	Daily maximum PaO2/FiO2 and/or SaO2/FiO2 respiratory ratio from the time of enrolment to day 28.	Enrolment to day 28
Additional safety outcomes	Additional safety outcomes including any serious adverse events (SAEs), degree of hypoxemia (daily PaO2/FiO2 and/or SaO2/FiO2 respiratory ratio), clinically significant bronchospasm, ICU-acquired infections with antibiotic resistant bacteria.	Enrolment to day 28

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biological (microbiome and immune) outcomes	Pre-treatment versus longitudinal post-treatment assessment of metagenomic composition and function of the airway microbiome (including antimicrobial gene and virulence gene counts), immune analysis, and metabolomics, as well as systemic immune response analysis.	Enrolment to day 14

Collaborators and Investigators

• Sponsor: University of Calgary

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): April 30, 2027
• Study Completion (Estimated): April 30, 2028

Study Registration Dates

• First Submitted: March 5, 2026
• First Submitted That Met QC Criteria: March 5, 2026
• First Posted (Actual): March 11, 2026

Study Record Updates

• Last Update Posted (Actual): March 11, 2026
• Last Update Submitted That Met QC Criteria: March 5, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Microbiome; Critical Illness; Ventilator-associated pneumonia; Inhaled Antibiotics
• Additional Relevant MeSH Terms: Healthcare-Associated Pneumonia; Pathologic Processes; Disease Attributes; Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Pneumonia; Cross Infection; Iatrogenic Disease; Pathological Conditions, Signs and Symptoms; Critical Illness; Pneumonia, Ventilator-Associated
• Other Study ID Numbers: REB25-1758

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
• product manufactured in and exported from the U.S.: No