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

Official title

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

Overview

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.

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).

Interventions

• 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.
• Drug Placebo
  Participants randomized to "placebo control" arm will receive inhaled placebo twice daily for 5 days.

Primary outcome measures

• 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. [Time frame: 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). [Time frame: Enrolment to day 7]

Secondary outcome measures (11)

• Ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) [Time frame: Enrolment to day 28]
• All-cause mortality [Time frame: Enrolment to day 28]
• VAP/HAP-free survival [Time frame: Enrolment to day 28]
• Ventilator-free day [Time frame: Enrolment to day 28]
• ICU-free and hospital-free days [Time frame: Enrolment to day 28]
• Extubation failure [Time frame: Enrolment to day 28]
• Ventilator-associated complications and infection-related ventilator-associated complications [Time frame: Enrolment to day 28]
• Non-pneumonia hospital-acquired infections (HAIs) [Time frame: Enrolment to day 28]
• Illness severity [Time frame: Enrolment to day 28]
• Lung injury severity [Time frame: Enrolment to day 28]
• Additional safety outcomes [Time frame: Enrolment to day 28]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Prevention

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07463339 · REB25-1758

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗