Clinical trial NCT03041207: Decreasing Antibiotic Use in Infants With Suspected Ventilator-associated Infection
Official title: Decreasing Antibiotic Use in Infants With Suspected Ventilator-associated Infection
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Ventilator Associated Pneumonia
Nosocomial Infections in Children
Microbial Colonization
Keywords: ventilator associated infection
ventilator associated pneumonia
ventilator associated tracheitis
Lower respiratory infection
Lead sponsor: Virginia Commonwealth University
Sponsor class: OTHER
Collaborators: name: The Gerber Foundation
First posted: 2017-02-02
Enrollment: 555
Sex: ALL
Maximum age (years): 3
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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

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.

Eligibility 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

Primary outcomes:
measure: Pediatric ICU-free days at 28 days
timeFrame: 28 days after study enrollment
Secondary outcomes:
measure: Antibiotic days in PICU
timeFrame: 28 days after study enrollment
measure: Ventilator-free days at 28 days
timeFrame: 28 days after study enrollment
measure: Infection and sepsis episodes
timeFrame: 28 days after study enrollment
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Banner University Medical Center
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: Miami
country: United States
facility: University of Miami Health System - Holtz Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Egleston Hospital
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children at Indiana University Health
state: Indiana
city: Ann Arbor
country: United States
facility: C.S. Mott Children's Hospital
state: Michigan
city: Grand Rapids
country: United States
facility: Helen DeVos Children's Hospital
state: Michigan
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital - Washington University
state: Missouri
city: Buffalo
country: United States
facility: Children's Hospital of Buffalo
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Rainbow Babies & Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Hershey
country: United States
facility: Penn State Children's Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Richmond
country: United States
facility: Children's Hospital of Richmond at VCU
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Montréal
country: Canada
facility: Centre hospitalier universitaire Sainte-Justine
state: Quebec
Study officials:
affiliation: Virginia Commonwealth University
name: Douglas F Willson, MD
role: PRINCIPAL_INVESTIGATOR
References: