Decreasing Antibiotic Use in Infants With Suspected Ventilator-associated Infection (VAIN2)

This is a prospective study with three specific aims: (1) To convene a consensus conference to develop a guideline for antibiotic use in infants (age < 3 yrs) with suspected ventilator-associated infection; (2) To evaluate outcomes before and after implementation of the antibiotic guideline; (3) To evaluate changes in the tracheal microbiome over the course of mechanical ventilation

Study Overview

• Status: Completed
• Conditions: Microbial Colonization; Ventilator Associated Pneumonia; Nosocomial Infections in Children
• Intervention / Treatment: Behavioral: Development and implementation of an antibiotic guideline

Detailed Description

In 2011 the Centers for Disease Control (CDC) estimated antibiotic-resistant infections resulted in $20 billion in excess healthcare costs and more than 100,000 unnecessary deaths in the U.S. alone. Ventilator-associated infections (VAI) are the most commonly diagnosed hospital-acquired infections in the pediatric intensive care unit (PICU) and account for more than half of all antibiotic use. We believe the diagnosis is often in error and that much of the antibiotic use is unnecessary. Initiating broad-spectrum antibiotics is routine when VAI or other infection is suspected in the child on mechanical ventilation, but our data show when all other cultures are negative at 48-72 hours antibiotics are frequently still continued based on identification of bacteria in respiratory secretion cultures. The investigators have previously shown, however, that identification of bacteria in respiratory secretion cultures is common in asymptomatic children and continuing antibiotics on the basis of a "positive" respiratory secretion culture is not associated with a shorter hospital stay or improved survival.

Antibiotics are not benign. Antibiotics are expensive, have disproportionate adverse effects in younger children, often require placement of catheters that are themselves potential sources of infection, and their overuse has been associated with increasing resistance worldwide. Antibiotic exposure in young children has been associated with increased risk for obesity, types 1 and 2 diabetes, inflammatory bowel diseases, celiac disease, allergies, and asthma. Mouse studies have found that early antibiotic exposure disrupts the development of the early-life gut bacterial composition (microbiome), leading to metabolic perturbations that affect fat deposition and may alter normal immunologic development.

There is no diagnostic test for VAI and distinguishing tracheal bacterial colonization from actual infection is not straightforward. The normal lung is essentially sterile but placement of an endotracheal tube (ETT) compromises the lung's ability to clear aspirated secretions and allows a direct route for bacterial contamination from the mouth and throat. The resultant tracheal bacterial composition (the "microbiome") is largely unstudied but preliminary research suggests it consists of small numbers of a wide diversity of bacteria originating from the mouth. Loss of this bacterial diversity in conjunction with proliferation of pathological bacteria is thought to herald the conversion from colonization to infection.

The investigators believe that a positive respiratory culture alone in the absence of other indicators of infection is insufficient justification for continuing antibiotics and, consequently, much of the antibiotic use in VAI is both unnecessary and potentially harmful. To critically evaluate this belief and potentially decrease the use of unnecessary antibiotics we propose the following:

Aim 1: To develop a guideline to assess the likelihood of VAI and discontinue antibiotics when the risk is judged to be low Hypothesis 1.1: Using an iterative process PICU doctors can reach consensus on criteria to assess the likelihood of VAI and discontinue antibiotics when the risk of VAI is judged to be low

Aim 2: To assess the efficacy and safety of discontinuing antibiotics in children judged to have a low risk of VAI Hypothesis 2.1: Discontinuing antibiotics at 48-72 hours in children judged to have a low risk of VAI will result in fewer total days on antibiotics with no difference in survival, numbers of subsequent infection episodes, duration of need for mechanical ventilation and length of stay in the PICU compared to care prior to the implementation of the guideline.

Aim 3: To describe the longitudinal changes in the tracheal bacterial composition (the "microbiome") in children on mechanical ventilation Hypothesis 3.1: Loss of diversity in the tracheal microbiome will predate clinical signs and symptoms of VAI.

Hypothesis 3.2: Emergence of a dominant bacterial pathogen in the tracheal microbiome will be associated with clinical signs and symptoms of VAI.

Decreasing unnecessary antibiotic use has important implications for public health. Pediatric intensive care medicine is running out of effective antibiotics while also exposing our children to antibiotic risks, many of which are only now beginning to be understood. Avoidance of unnecessary antibiotic exposure in young children is critical and would be facilitated by a rational guideline for assessment of the risk and appropriate treatment for suspected VAI. As VAI is the most common reason for antibiotic use in the PICU, it is an obvious target for more careful antibiotic stewardship. Better understanding of the normal tracheal microbiome after placement of an endotracheal tube would also inform future decisions regarding appropriate antibiotic use when VAI is suspected. The most effective means of decreasing antibiotic resistance is avoidance of unnecessary use.

• Study Type: Observational
• Enrollment (Actual): 555

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H3T 1C5
      • Centre Hospitalier Universitaire Sainte-Justine
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Banner University Medical Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital of Los Angeles
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Health System - Holtz Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Children's Healthcare of Atlanta - Egleston Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children at Indiana University Health
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C.S. Mott Children's Hospital
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Children's Hospital - Washington University
  • New York
    • Buffalo, New York, United States, 14222
      • Children's Hospital of Buffalo
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Rainbow Babies & Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Children's Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Virginia
    • Richmond, Virginia, United States, 23219
      • Children's Hospital of Richmond at VCU
  • Washington
    • Seattle, Washington, United States, 98115
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Infants 0 - 3 years of age who have undergone a tracheal aspirate culture for suspected ventilator-associated infection and have had antibiotics initiated at that time.

Description

Inclusion Criteria:

• Age newborn -- 3 years in the Pediatric ICU
• on invasive mechanical ventilation > 48 hours
• evaluation for ventilator-associated infection that includes respiratory secretion cultures and microscopic evaluation of the gram-stained specimen
• antibiotics initiated for suspected ventilator-associated or other infection

Exclusion Criteria:

• Immune compromise --Other positive cultures (blood, urine, etc.) for which antibiotic continuation is appropriate

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Pre-antibiotic guideline; Infants for whom antibiotics have been initiated for suspected ventilator-associated infection prior to the implementation of the antibiotic guideline	Behavioral: Development and implementation of an antibiotic guideline; A consensus conference will develop and then implement a guideline for stopping vs. continuing antibiotics in infants with suspected ventilator-associated infection
After antibiotic guideline implementation; Infants for whom antibiotics have been initiated for suspected ventilator-associated infection after the implementation of the antibiotic guideline	Behavioral: Development and implementation of an antibiotic guideline; A consensus conference will develop and then implement a guideline for stopping vs. continuing antibiotics in infants with suspected ventilator-associated infection
Microbiome Study Group; Infants intubated and anticipated to require mechanical ventilation for at least several days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pediatric ICU-free days at 28 days	28 - number of days in PICU (death = 0 free days)	28 days after study enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antibiotic days in PICU	total number of antibiotic days with each antibiotic on each day = 1 antibiotic day (e.g., 3 antibiotics in one day = 3 antibiotic days)	28 days after study enrollment
Ventilator-free days at 28 days	28 - days on mechanical ventilation in PICU (death = 0 free days)	28 days after study enrollment
Infection and sepsis episodes	The number of infection and/or sepsis episodes after study enrollment	28 days after study enrollment

Collaborators and Investigators

• Sponsor: Virginia Commonwealth University
• Collaborators: The Gerber Foundation
• Investigators: Principal Investigator: Douglas F Willson, MD, Virginia Commonwealth University

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 20, 2017
• Primary Completion (ACTUAL): April 30, 2019
• Study Completion (ACTUAL): April 30, 2019

Study Registration Dates

• First Submitted: January 31, 2017
• First Submitted That Met QC Criteria: January 31, 2017
• First Posted (ESTIMATE): February 2, 2017

Study Record Updates

• Last Update Posted (ACTUAL): July 17, 2019
• Last Update Submitted That Met QC Criteria: July 15, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: ventilator associated pneumonia; ventilator associated infection; ventilator associated tracheitis; Lower respiratory infection
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Iatrogenic Disease; Healthcare-Associated Pneumonia; Infections; Communicable Diseases; Pneumonia; Pneumonia, Ventilator-Associated; Cross Infection; Anti-Infective Agents; Anti-Bacterial Agents
• Other Study ID Numbers: HM20009140

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