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

Sponsor

Virginia Commonwealth University (Other)

Overall Status

Completed

CT.gov ID

NCT03041207

Collaborator

The Gerber Foundation (Other)

555

Enrollment

Locations

25.3

Actual Duration (Months)

24.1

Patients Per Site

Patients Per Site Per Month

Study Details

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	Phase
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 :

Mar 20, 2017

Actual Primary Completion Date :

Apr 30, 2019

Actual Study Completion Date :

Apr 30, 2019

Arms and Interventions

Arm	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

Arm

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

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

Secondary Outcome Measures

Antibiotic days in PICU [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)
Ventilator-free days at 28 days [28 days after study enrollment]
28 - days on mechanical ventilation in PICU (death = 0 free days)
Infection and sepsis episodes [28 days after study enrollment]
The number of infection and/or sepsis episodes after study enrollment

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 3 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

	Site	City	State	Country	Postal Code
1	Banner University Medical Center	Tucson	Arizona	United States	85724
2	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202
3	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027
4	Children's Hospital of Orange County	Orange	California	United States	92868
5	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
6	University of Miami Health System - Holtz Children's Hospital	Miami	Florida	United States	33136
7	Children's Healthcare of Atlanta - Egleston Hospital	Atlanta	Georgia	United States	30329
8	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
9	Riley Hospital for Children at Indiana University Health	Indianapolis	Indiana	United States	46202
10	C.S. Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
11	Helen DeVos Children's Hospital	Grand Rapids	Michigan	United States	49503
12	St. Louis Children's Hospital - Washington University	Saint Louis	Missouri	United States	63110
13	Children's Hospital of Buffalo	Buffalo	New York	United States	14222
14	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
15	University Hospitals Rainbow Babies & Children's Hospital	Cleveland	Ohio	United States	44106
16	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
17	Oregon Health and Science University	Portland	Oregon	United States	97239
18	Penn State Children's Hospital	Hershey	Pennsylvania	United States	17033
19	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
20	Children's Hospital of Richmond at VCU	Richmond	Virginia	United States	23219
21	Seattle Children's Hospital	Seattle	Washington	United States	98115
22	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
23	Centre hospitalier universitaire Sainte-Justine	Montréal	Quebec	Canada	H3T 1C5