The Risks of Ongoing Antibiotic Treatment for Preterm Infants

Pablo J. Sanchez, MD
Pablo Sánchez, MD, a member of the Division of Neonatology at Nationwide Children’s and senior author of this study.

Each additional day of antibiotic therapy was associated with a 24 percent increase in the risk for late-onset sepsis, necrotizing enterocolitis (NEC), or death in preterm infants with very low birth weights, according to a new study published in The Journal of Pediatrics.

The study was a collaborative effort by researchers at the University of Texas Southwestern Medical Center, University of Texas Health Science Center San Antonio, Yale School of Medicine, and Nationwide Children’s Hospital.

“We need daily assessments of antibiotic use, whether the baby should be treated any longer, because there's no evidence for these standards of 48 hours or 7 or 14 days of therapy, and we really need to find what is the minimum duration that these babies will do well with,” says Pablo Sánchez, MD, a member of the Division of Neonatology at Nationwide Children’s and senior author of the study.

The study sought to determine if antibiotic use in the first 14 postnatal days in preterm (born at ≤ 326/7 weeks of gestation), very low weight (≤1500g) infants is associated with risk of late-onset sepsis, NEC, or death, as a composite primary outcome. It also used the CRIB II (Clinical Risk Index for Babies II) score, a validated risk-adjustment tool for predicting mortality in the NICU, to control for the severity of illness.

Of 374 infants included in the study, the average antibiotic exposure was 4.6 (±2.8) calendar days. Overall, 19% (70/374) of the infants developed the composite primary outcome of sepsis (14%, n=52), NEC (6%, n=24), or death (3%, n=11). Among these 70 infants, the median age at the onset of the outcome was 29 days (range, 15-101 days).

The median CRIB II score for all infants was 8 (IQR, 5-10), which corresponds to a predicted mortality risk of 5% (IQR, 1-12%). The CRIB II score could explain approximately 60% of the variation in the primary outcome (R2=0.59).

After controlling for the CRIB II score, and thus the severity of illness, in a multivariate analysis, each calendar day of antibiotic therapy was associated with increased risk for sepsis, NEC, or death after 14 days of age (OR, 1.24; 95% CI, 1.17-1.31).

Furthermore, after controlling for the CRIB II score, the variation in antibiotic use accounted for approximately 30% of the remaining risk for the primary outcome (sepsis, NEC, or death) after 14 days of age (R2=0.29)

Nationwide Children’s is implementing several strategies to minimize overall exposure of preterm infants to antibiotics, explains Dr. Sánchez, who is also a principal investigator in the Center for Perinatal Research at the Abigail Wexner Research Institute at Nationwide Children’s. This “stewardship bundle” will incorporate findings from this study and others, will include safety measures, and will entail auditing prescribers, requiring positive bacterial cultures to prescribe prolonged antibiotic therapy, testing for viruses, and using shorter durations of therapy -- such as five to seven days instead of the traditionally recommended 10 to 14 days.

“We have to realize that when an antibiotic is used appropriately, it's life saving, and when used inappropriately and for prolonged periods of time, it can have significant consequences related to intestinal dysbiosis, or changes in the bacterial microbiome. And we can certainly minimize these adverse associations by minimizing our therapy,” says Dr Sánchez.

Reference

Cantey JB, Pyle AK, Wozniak PS, Hynan LS, Sánchez PJ. Early antibiotic exposure and adverse outcomes in preterm, very low birth weight infants. The Journal of Pediatrics. 2018 Dec; 203:62-67.