NIH-funded Study Examines Interplay Between Immune Response and Antibiotic Dosage

Clinical pharmacologists study how host immune response to antibiotics may impact the respiratory system overtime in children with sepsis.

By Kate Knab

Clinical pharmacologists at Children's Hospital of Philadelphia are embarking on a new study to understand how immune phenotypes and host response to sepsis and multi-organ dysfunction syndrome (MODS) impacts an antibiotic's ability to perform effectively.

The study, called PediatRic sEpsiS induCed MODS: Relationship of Immune-phenotypes and antiBiotic Exposures, or PRESCRIBE, seeks to remove the guesswork from the traditional empiric prescription of antibiotics by understanding how specific amounts of antibiotics interact with the immune system to help critically ill children recover from sepsis.

In sepsis, the combination of the body's immune system response and the infection together influence outcomes. Host inflammatory responses can prevent our organ systems, such as the heart, lungs, brain, liver, and kidneys, from working normally, even if the infection is in a different part of the body.

"I think that we can improve how we administer antibiotics and the outcomes that children have by providing more tailored, individualized antibiotic dosing," said Kevin Downes, MD, lead principal investigator on the study. "That's ultimately what we're trying to achieve with this study."

CHOP is one of 15 institutions participating in the PRESCRIBE study through the Collaborative Pediatric Critical Care Research Network (CPCCRN). Supported by the CPCCRN and a grant from the National Institute of Child Health and Human Development, investigators will use data from PRESCRIBE's ongoing parent trial, PRECISE – which studies how a child's immune system responds to sepsis through personalized immunomodulation – to evaluate the nuanced relationship between antibiotics and their outcomes.

Dr. Downes, who is also a core faculty member of CHOP's Clinical Futures, a CHOP Research Institute Center of Emphasis, and his team of investigators will use pharmacokinetic (PK) studies to determine variability, how the host immune response to sepsis influences antibiotic concentrations, and how those concentrations affect organ dysfunction. However, drawing multiple milliliters of blood every day to complete conventional PK studies presents a challenge when working with children and infants in intensive care units. Dr. Downes will address this concern through multiplexed assays that use very small sample volumes ("microsampling").

"As a parent, if my child were asked to participate, I'd appreciate less invasive procedures when working with an otherwise very sick population," Dr. Downes said. "Our samples can be performed using capillary sticks, like finger sticks and heel sticks, that do not require drawing blood from veins. This allows us to be more precise when we collect the samples as well."

Although researchers will have to wait to perform certain analyses until data from the PRECISE trial is unblinded, they can still collect data for the PRESCRIBE study before children are randomized into PRECISE. These data will provide valuable information about dosing and antibiotic PK in the early stages of sepsis.

An additional, unique aim of the PRESCRIBE trial will explore the relationship between antibiotic concentrations and the respiratory microbiome. Lower respiratory infections are the most common cause of sepsis in children, and while pneumonia can be treated with a course of antibiotics, it is difficult to know at what point in time the infection has been treated successfully. This study will use next generation sequencing to dive into microbes on a genetic level to determine how much of their DNA is present in the lungs over the course of treatment.

"We are studying the interplay between the host immune system response and antibiotics to learn how it impacts a child's respiratory microbiome over time," Dr. Downes said.