Sepsis is a leading cause of morbidity and mortality in neonates, especially in middle and lower-income countries, as infants’ immature immune systems predispose them to a high risk of sepsis.1
When suspicion of a severe infection is present, a timely diagnosis is essential. Procalcitonin (PCT), a host response biomarker that is sensitive and specific to bacterial infection, can complement clinical assessment to provide answers when minutes matter most.2
Categorized by the time of presentation after birth, neonatal sepsis is considered either early-onset sepsis or late-onset sepsis. Early-onset sepsis is sepsis at or before 72 hours of life and late-onset sepsis is identified as sepsis at or after 72 hours of life.3
Early-onset sepsis occurs when pathogens from the mother are transmitted to the fetus or newborn before or during delivery.
Even with guidelines around screening for maternal group B. Streptococcus (GBS) colonization, GBS continues to be the most common organism that causes EOS. According to most EOS management guidelines, approximately 10% of the total neonatal population are exposed to antibiotics in the first postnatal days with subsequent increase of neonatal and pediatric comorbidities. Reducing empiric antibiotics in uninfected infants is critical, because overuse of antibiotics can lead to the emergence of resistant flora and changes in the infant’s microbiome. Furthermore, separating hospitalized infants from their parents may cause unnecessary stress to both the infant and parents.4,5
In healthy neonates, plasma PCT concentrations increase gradually after birth, reaching peak values at about 24 hours of age and then decreasing to normal values below 0.5 μg/L within 72 hours of age.7 Because PCT shows a physiological elevation in newborns right after birth, age-specific PCT reference values apply.7,8
The early treatment of neonatal sepsis is vital to improving patient outcomes. For this reason, antibiotic treatment in newborn infants with risk factors for infection is started soon after birth, even when reliable infection markers are absent. This results in a considerable number of patients being exposed to unnecessary antibiotic therapy.
In fact, culture-proven early-onset sepsis was found in less than 0.1% of patients. However, a much higher percentage (4.0% – 7.4%) of late-preterm to term neonates are given intravenous antibiotics within their first three days of life when sepsis is suspected.7 With two consecutive, normal PCT values, clinicians can now safely stop antibiotic treatment for near-term and term neonates with low likelihood of bacterial infection.
Age-adjusted B·R·A·H·M·S™ PCT cut-off values in newborns.7
It has been shown in randomized controlled trials that by using a PCT-aided approach, the duration of antibiotic treatment could be shortened significantly without negative impact on the outcome.6,7
Serial PCT measurements allow clinicians to significantly shorten the duration of empiric antibiotic therapy in term and near-term infants with suspected early-onset sepsis.6
*Multivariate regression analysis showed that the duration of antibiotic therapy and hospital stay depended on Study group, Risk category, Gestational age (term or late preterm), Participating center. Duration of hospital stay also depended on birth weight.
Upon suspicion of early-onset sepsis, 4.0–7.4% of late-preterm and term neonates are given intravenous antibiotics within the first three days of life in high-income countries. However, the prevalence of culture-proven early-onset sepsis is less than 0.1%, which suggests that antibiotic treatment is unnecessary in many neonates. Unnecessary antibiotic use in neonates has substantial short-term effects, such as an increase in hospital admission rates, neonatal and parental discomfort, medical costs, and the use of resources.8
Furthermore, evidence is accumulating that antibiotic treatment in early life has also significant long-term effects as it disturbs the microbial flora that colonize the neonate. This disruption might be associated with health problems such as eczema, allergies, inflammatory bowel diseases, and obesity.9
NeoPInS has been the largest randomized controlled, interventional, multi-centric clinical trial addressing the use of PCT for antibiotic stewardship in neonates. During this clinical trial, 18 hospitals in Europe and North America investigated whether PCT-aided decision-making can safely shorten the duration of antibiotic therapy in newborns with suspected early onset sepsis.
The trial included 1,710 infants with a gestational age of 34 weeks or older who presented with signs of early-onset sepsis. Patients were randomized in a 1:1 ratio to either routine care with antibiotics or to a decision-making protocol based on levels of the biomarker PCT. The results demonstrate that PCT-aided decision-making leads to a significant reduction in the duration of empirical antibiotic therapy (15% for intention-to-treat to 19% for per-protocol analysis). Hospital stay in term and near-term neonates with suspected early-onset sepsis was also reduced.
Throughout the trial, no sepsis-associated deaths occurred and the rate of possible reinfection was similar (less than 1%) in both study groups (standard of care and PCT-aided)—clear evidence that PCT-aided decision-making was superior to standard care in reducing antibiotic therapy in neonates with suspected early-onset sepsis.
Late-onset sepsis (LOS) is generally caused by the transmission of pathogens from the environment to the baby after delivery, including after contact with healthcare providers or caregivers. A percentage of LOS may also be caused by a late manifestation of vertically transmitted infection. In addition, infants requiring intravascular catheter insertion, or other invasive procedures that disrupt the mucosa, are at increased risk for developing LOS.3
In one study, using the B·R·A·H·M·S PCT cut-off level of 0.5 μg/L was valuable for the diagnosis of LOS in neonates. The sensitivity of PCT for this diagnosis was 84.4%, specificity was 93.9%, positive predictive value was 82.6%, and negative predictive value was 94.6%.10
According to the data, the likelihood of infection increases from 25.6% to 84.4% when PCT is positive, while the likelihood of infection declines from 25.6% to 5.3% when the PCT level is below 0.5 µg/L.10