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

• ClinicalTrials.gov Identifier: NCT03041207
• Recruitment Status: Completed
• First Posted: February 2, 2017
• Last Update Posted: July 17, 2019
• Sponsor: Virginia Commonwealth University
• Collaborator: The Gerber Foundation
• Information provided by (Responsible Party): Virginia Commonwealth University

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment
Ventilator Associated Pneumonia; Nosocomial Infections in Children; Microbial Colonization	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 Design

• Study Type: Observational
• Actual Enrollment: 555 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Decreasing Antibiotic Use in Infants With Suspected Ventilator-associated Infection
• Actual Study Start Date: March 20, 2017
• Actual Primary Completion Date: April 30, 2019
• Actual Study Completion Date: April 30, 2019

Groups and Cohorts

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

Outcome Measures

Primary Outcome Measures :

1. Pediatric ICU-free days at 28 days [ Time Frame: 28 days after study enrollment ]
   28 - number of days in PICU (death = 0 free days)

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: up to 3 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• 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.

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Banner University Medical Center

Tucson, Arizona, United States, 85724

United States, Arkansas

Arkansas Children's Hospital

Little Rock, Arkansas, United States, 72202

United States, California

Children's Hospital of Los Angeles

Los Angeles, California, United States, 90027

Children's Hospital of Orange County

Orange, California, United States, 92868

United States, Connecticut

Connecticut Children's Medical Center

Hartford, Connecticut, United States, 06106

United States, Florida

University of Miami Health System - Holtz Children's Hospital

Miami, Florida, United States, 33136

United States, Georgia

Children's Healthcare of Atlanta - Egleston Hospital

Atlanta, Georgia, United States, 30329

United States, Illinois

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States, 60611

United States, Indiana

Riley Hospital for Children at Indiana University Health

Indianapolis, Indiana, United States, 46202

United States, Michigan

C.S. Mott Children's Hospital

Ann Arbor, Michigan, United States, 48109

Helen DeVos Children's Hospital

Grand Rapids, Michigan, United States, 49503

United States, Missouri

St. Louis Children's Hospital - Washington University

Saint Louis, Missouri, United States, 63110

United States, New York

Children's Hospital of Buffalo

Buffalo, New York, United States, 14222

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

University Hospitals Rainbow Babies & Children's Hospital

Cleveland, Ohio, United States, 44106

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

Penn State Children's Hospital

Hershey, Pennsylvania, United States, 17033

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

United States, Virginia

Children's Hospital of Richmond at VCU

Richmond, Virginia, United States, 23219

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98115

United States, Wisconsin

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Canada, Quebec

Centre hospitalier universitaire Sainte-Justine

Montréal, Quebec, Canada, H3T 1C5

Sponsors and Collaborators

Virginia Commonwealth University

The Gerber Foundation

Investigators

• Principal Investigator: Douglas F Willson, MD; Virginia Commonwealth University

More Information

• Responsible Party: Virginia Commonwealth University
• ClinicalTrials.gov Identifier: NCT03041207
• Other Study ID Numbers: HM20009140
• First Posted: February 2, 2017
• Last Update Posted: July 17, 2019
• Last Verified: July 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Virginia Commonwealth University:

ventilator associated infection; ventilator associated pneumonia; ventilator associated tracheitis; Lower respiratory infection

Additional relevant MeSH terms:

Infection; Communicable Diseases; Pneumonia, Ventilator-Associated; Cross Infection; Pneumonia; Lung Diseases; Respiratory Tract Diseases; Respiratory Tract Infections; Iatrogenic Disease; Disease Attributes; Pathologic Processes; Anti-Bacterial Agents; Anti-Infective Agents