Infants with sepsis exposed to antibiotics have altered gut microbiomes

WASHINGTON — Neonates with sepsis were exposed to more antibiotics throughout their NICU admissions than controls and were found to have microbiome dysbiosis, researchers reported.

Hope Hendricks, MD, a pediatric infectious diseases fellow at Vanderbilt University Medical Center, presented findings from the study at IDWeek. In her remarks, Hendricks noted that research in the area of neonatal infections is important because of the “the clear morbidity and mortality, increased risk for antibiotic adverse events and for resistant infections in this patient population.”

“We know that premature neonates are at high risk for serious bacterial infections, receive frequent and [broad-spectrum] antibiotic courses, and that the literature previously has shown that alterations to the maturing gut microbiome in the form of dysbiosis precede serious clinical complications, including [necrotizing enterocolitis] and sepsis,” Hendricks said in her presentation.

Hendricks and colleagues established an infant stool biorepository, and for the study they collected more than 1,300 stool samples from 265 infants in NICUs weighing less than 2 kilos at birth and aged younger than 2 months. They sought to characterize how antibiotic exposure affected the development of intestinal dysbiosis in infants with bloodstream infections (BSI) compared with control infants, who had less than 5 days of antibiotic exposure, no BSI or necrotizing enterocolitis.

According to Hendricks, 2 to 5 weeks after collecting the samples, the researchers observed that the control infants had more anaerobes — or healthy gut colonizers — than case infants who provided samples before developing sepsis. Later, at the 6- to-13-week point, control samples continued to have an increasing anaerobe presence, but the case samples had developed an abundance of Enterococcus species.

“When we look at much older samples, in the cases after the sepsis event at 14 to 20 weeks’ postnatal age, we see a recovery of anaerobes but a persistence of the Enterococcus abundance,” Hendricks said.

The authors also found that in seven of eight BSI cases, the causative pathogen was identified in the pre-BSI stool sample. In two additional BSI cases, the patients did not have a pre-BSI stool sample. In six of the cases, identified to have high beta-lactam exposure, three had notable increases in the relative abundance of Enterococcus species.

However, the abundance antibiotic resistance genes in the intestinal flora of infants did not differ between cases and controls, according to the researchers.

Hendricks and colleagues also examined how antibiotic exposure played a role in the altered gut microbiomes of neonatal sepsis. To do that, they relied primarily on the Antibiotic Spectrum Index (ASI), a tool developed by Gerber and colleagues that classifies commonly used antibiotics based on their activity against certain pathogens. Based on the index, they assigned a score for each infant, giving an estimate of how much antibiotic exposure had occurred.

“When we use this ASI score, we can see that sepsis cases had much higher antibiotic exposure,” Hendricks said.

The total cohort in the biorepository of 363 infants had an average cumulative ASI score of 63 for their total NICU admission, whereas cases before their sepsis event had an average score of 84.

“We found that compared [with] noninfected controls, neonatal sepsis cases had lower alpha diversity, less abundant anaerobes and more frequent and broader spectrum antibiotics,” Hendricks said. “Those cases with high beta-lactam use had Enterococcus predominance in the stool, which begs the question of whether Enterococcus-sparing antibiotic regimens play a heightened role in gut dysregulation and potential future infectious events, and whether antibiotic metrics in the future could account for this differential harm to the microbiome.”

References:

Gerber JS, et al. Infect Control Hospital Epidemiol. 2017;doi:10.1017/ice.2017.94.

Hendricks H, et al. Abstract 779. Presented at: IDWeek; Oct. 19-23, 2022; Washington (hybrid meeting).