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Preterm Infants Treated with Antibiotics Show Significant Drug Resistance, Depleted Gut Microbiome

NEW YORK (GenomeWeb) – Early treatment of preterm infants with antibiotics tends to deplete the number of species in their gut microbiome and correlates with antibiotic resistance, researchers at Washington University School of Medicine in St. Louis have found, calling into question the routine use of antibiotics in preemies.

The team, which published its work in Nature Microbiology today, sequenced the gut microbiomes of 84 prematurely born infants over the first few months of their lives and correlated the results with antibiotic treatments the children received. They also performed functional screens, which turned up almost 800 antibiotic resistance genes in the gut microbiota, many of which had not been previously classified as such.

"Our study demonstrates that even well-studied bacteria — the ones that we know cause disease or their close relatives — have many genes associated with antibiotic resistance that have not been characterized before," senior author Gautam Dantas, associate professor of pathology and immunology at WashU, said in a statement.

In treating preterm infants, who often have several medical problems, "the conventional wisdom has been antibiotics can’t hurt and they might help," said Barbara Warner, a professor of pediatrics and a neonatologist at St. Louis Children's Hospital. "But our new study demonstrates that wide-scale use of antibiotics in this population does not come without cost.”

For their study, the researchers used metagenomic sequencing to analyze 401 stool samples from 84 preterm infants, all born before 33 weeks of gestation. All but two of the infants had received antibiotic therapy within a day of their birth, and 39 percent received more antibiotics after their first week of life.

Compared to babies born at term, the preemies had 10-fold fewer gut bacterial species. Species richness in the preterm infants was generally reduced in response to antibiotic treatment, with the exception of vancomycin and gentamicin, which had varying effects.

To further study the development of drug resistance with antibiotic use, the researchers performed functional metagenomic selections, a culture-unbiased approach in which they screened metagenomic libraries constructed from 21 fecal samples of preterm infants against 16 clinically relevant antibiotics.

In that screen, they identified 794 genes that made the microbes resistant to a variety of the drugs — three quarters of these genes had not previously been associated with antibiotic resistance.

Combining those results with deep shotgun sequencing of all stool samples, the scientists found that multidrug resistant bacteria belonging to the Escherichia, Klebsiella, and Enterobacter genera, which are often associated with hospital infections, dominate the preterm infant gut microbiota.

Following antibiotic treatment, emerging resistance genes are generally unique to the specific treatment and are correlated with a single species, they found, with the exception of two drugs, which enrich for a large number of overlapping resistance genes.

Interestingly, all antibiotic treatments also lead to an enrichment of resistance genes for other, unrelated antibiotic drugs.

"While antibiotics can certainly still be lifesaving, we are becoming more aware of the risks they pose,” Warner said. “This study arms us with information that may help us push toward shorter antibiotic treatment courses and minimizing the use of broad-spectrum antibiotics."