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Metagenomic Sequencing Study Implicates Gut Microbes in Preterm Infant Bloodstream Infections

NEW YORK — Researchers have found that microbes that cause bacterial bloodstream infections (BSIs) in preterm infants likely originate in the infants' guts and unchecked usage of antibiotics could be the culprit.

Preemies who are hospitalized in neonatal intensive care units are particularly vulnerable to BSIs due to underdeveloped organs and overexposure to antibiotics. As a result, nearly half of them develop late-onset sepsis which increases their chances of dying.

"In contrast to early-onset sepsis, the incidence and mortality of late-onset sepsis in preterm infants have not diminished appreciably over the past 30 years," corresponding author Gautam Dantas, a professor of laboratory and genomic medicine at Washington University School of Medicine in St. Louis, and colleagues noted in a paper published Wednesday in Science Translational Medicine.

"It is therefore essential to better understand the pathogen sources and risk factors associated with late-onset sepsis to develop mitigation strategies for this highly consequential complication of preterm birth," they added.

Since previous studies had shown that BSI-causing pathogens are found in the NICU environment and in the gut microbiome of preemies, the researchers wanted to check if it was the infants' gut that was responsible.

They first analyzed 550 previously published fecal metagenomes from 115 hospitalized neonates and found that recent ampicillin, gentamicin, or vancomycin exposure was associated with increased abundance of Enterobacteriaceae and Enterococcaceae in infant guts.

Then they performed shotgun metagenomic sequencing on 462 longitudinal fecal samples from 19 preterm infants with BSIs and 37 infants without BSI (controls) admitted to the NICU at St. Louis Children's Hospital, Children's Hospital at Oklahoma University Medical Center, and Norton Children's Hospital in Louisville, Kentucky.

Additionally, they conducted whole genome sequencing on the bacterial strains that caused BSIs and used computational profiling to precisely track the identical strain within feces. This helped with identifying the strains of bacteria that had colonized the infants' guts prior to bloodstream infection.

In 58 percent of these cases, the researchers found a nearly identical disease-causing bacterial strain in the guts right before a BSI was diagnosed. In about 79 percent of cases, they found the disease-causing strain in the gut after the diagnosis.

It was also found that infants with BSI caused by Enterobacteriaceae were more likely than infants with BSI caused by other organisms to have had ampicillin, gentamicin, or vancomycin exposure in the 10 days before a BSI.

Based on these results, a key message is the need for appropriate usage of antibiotics in preemies, Dantas said in a statement.

"Antimicrobials are critical; we are going to need them to treat infections, but we need to carefully weigh whether and when to use antimicrobials in specific situations," Dantas said. "We need to make sure that when those antimicrobials are given, we have a very good reason."

The authors noted that in the future, it may be possible to develop a risk assessment tool to help physicians quantify the risk of future BSIs by identifying whether disease-causing bacteria already have colonized an infant's gut and to what degree.

Highlighting one of the limitations, the authors noted that this study didn't look at transmission of BSI pathogens from the skin. "We cannot exclude the possibility of short-term cutaneous or tracheal colonization before blood translocation," they noted.