Advances in Neonatology

With the increasing recognition that overuse of antibiotics can change the microbiome of the preterm baby and lead to a range of unintended clinical consequences, and with scant evidence related to outcomes of this practice, the debate on when and how to administer antibiotics in newborns persists.

To this end, Richard A. Polin, MD, Chief of Neonatology and Perinatology and Executive Vice Chair of the Department of Pediatrics at NewYork-Presbyterian Morgan Stanley Children’s Hospital, is serving as one of three co-principal investigators on a new National Institutes of Health-funded multicenter study – NANO (NICU Antibiotics and Outcomes) – to look at the use of antibiotics in preterm babies and their effects on long-term outcomes.

“An ongoing challenge in the use of antibiotics in infants is the ability to distinguish an infectious process from a non-infectious disease,” says Dr. Polin. “This is particularly concerning in early-onset sepsis [EOS], a rare but highly morbid bloodstream infection that can occur in newborn infants during the first three days of life.”

Assessing Risk Factors for Early-Onset Sepsis

In a review article published in the June 2018 issue of the Journal of Perinatology, Dr. Polin, Thomas Hooven, MD, a neonatologist with a particular interest in infections in newborns, and Tara M. Randis, MD, MS, a former fellow in neonatology at NewYork-Presbyterian Morgan Stanley Children’s Hospital, explored the management of newborns with risk factors for EOS – a very common clinical scenario yet one that is considered one of the most controversial issues in neonatology. According to the authors, “a major concern with using an observation-based approach to the management of at-risk infants is that delayed antibiotic administration to initially asymptomatic infants who are truly infected will result in additional morbidity.”

Consequently, these infants are admitted to the NICU and typically undergo laboratory evaluation and receive empiric antibiotic therapy. But many in the field are concerned that “rule-out sepsis” practices could lead to overtreatment and a range of unintended clinical consequences, including necrotizing enterocolitis and late-onset sepsis, as well as complications resulting from the NICU admission itself. This has prompted a closer look at the role of serial observation of asymptomatic and mildly symptomatic newborns as a safe and cost-effective alternative to laboratory screening and empiric antibiotics as a matter of course.

Dr. Polin and his colleagues concluded in their review of existing evidence that “the differential between risk of serious harm from observing a well-appearing term or late-preterm newborn with risk factors for sepsis and the risk of less significant but common NICU complications argues in favor of the ongoing trend toward less aggressive management of newborns with sepsis risks.”

Fundamental to determining appropriate practices for managing newborns with a potential for developing EOS – presenting with or without symptoms – is defining standard and accurate guidelines for identifying at-risk newborns. More recently, Dr. Hooven and his colleague, Pamela I. Good, MD, focused on the need for more precise risk assessment tools and alternative management strategies that could decrease the number of infants exposed to blood draws and antibiotics during evaluations for EOS.

Their in-depth article reviewed clinical guidelines for the evaluation and management of EOS published over the past decade and include those from the Centers for Disease Control and Prevention, the American Academy of Pediatrics, and the National Institute for Health and Clinical Excellence, as well as numerous studies of both risk prediction models and serial observation. Each has their own set of pros and cons, but also offer insight that lead Dr. Hooven and his colleagues to note “the field is moving toward a new consensus that is rational, cost-effective, and safe for the patients.”

The NANO Trial is expected to be a major study that will direct the evidence – in favor of or against – antibiotic administration in such a vulnerable population.

The NANO Trial:

Examining Adverse Effects of Antibiotic Use on Long-Term Outcomes

“Timely diagnosis of early-onset sepsis [EOS] is particularly difficult in very low birthweight infants as there are no accepted biomarkers for the disease and because the clinical signs of EOS, such as respiratory failure, can overlap with non-infectious processes in preterm infants,” says Dr. Polin. “As a result, and despite lack of high quality data, the standard of care in many NICUs is to administer empiric antibiotics to preterm infants during the first two to seven days of life or until a workup for EOS has been completed.”

Dr. Polin and the multidisciplinary team members at NewYork-Presbyterian Morgan Stanley Children’s Hospital have substantial experience in the execution of single-center and multicenter clinical trials involving very low birthweight infants. “Our group also has more than 10 years of experience monitoring temporal changes in the gut microbiota of preterm infants,” adds Dr. Polin. “In previous NIH-sponsored studies, we have documented that empiric antibiotic exposure is associated with unambiguous changes in the microbiota favoring growth of pathogens.”

In addition, the team has demonstrated a dose-dependent relationship between empiric antibiotics and a combined outcome of late-onset sepsis, necrotizing enterocolitis, or mortality at 30 days. They also made the novel discovery that antibiotic exposure in very low birthweight infants is independently associated with poor weight gain in the NICU.

“The goal of the NANO trial is to study the longstanding clinical practice of empirically administering intravenous antibiotics to extremely low birthweight infants in the first days of life,” explains Dr. Polin. “We are going to test the hypothesis that the incidence of adverse outcomes is higher in very low birthweight infants receiving empiric antibiotics compared to infants receiving placebo.”

The trial, which opens in November 2019, will enroll 802 patients across five sites and targets a population of extremely low birthweight infants in whom the clinical decision to use or not use empiric antibiotics is currently most challenging. These are clinically stable infants who did not have a known exposure to intra-amniotic infection and were not born preterm for maternal indications.

The investigators seek to:

• determine if the incidence of late-onset sepsis and the combined incidence of late- onset sepsis, necrotizing enterocolitis, and death are higher in infants that receive empiric antibiotics compared to infants that receive placebo
• identify whether somatic growth is worse in infants receiving empiric antibiotics compared to infants receiving placebo
• collect and biobank cheek swabs and fecal samples for future analyses of genome and microbiome features that could mediate the relationship between empiric antibiotics, the gut microbiota, and clinical outcomes

According to Dr. Polin, if the trial determines that empiric antibiotic therapy either does not impact outcomes or worsens outcomes in premature infants, the findings could rapidly be translated into a sizeable decrease in the burden of antibiotic administration in NICUs. “Reducing antibiotic administration might not only benefit individual preterm infants, but could also support the broader battle against antibiotic resistance and nosocomial infections,” notes Dr. Polin. “But if the study demonstrates improved outcomes with antibiotic administration, this would provide physicians with the confidence to continue the still common, but unproven practice of administering empiric antibiotics.”