Factors Associated with Prolonged Antibiotic Therapy in Neonates with Suspected Early-Onset Sepsis

Early-onset sepsis (EOS) is a rare but profoundly serious bacterial infection. Neonates at risk of EOS are often treated with antibiotics. The start of empiric antibiotic therapy can successfully be reduced by the implementation of the EOS calculator. However, once started, antibiotic therapy is often continued despite a negative blood culture. To decrease the burden of antibiotic therapy, it is necessary to know whether the clinician’s reasons are based on objective factors. Therefore, we performed a retrospective single-centre cohort study to identify the factors associated with prolongation of antibiotic therapy in neonates with suspected EOS but a negative blood culture. Maternal, clinical, and laboratory data of neonates with a gestational age of ≥32 weeks, admitted between January 2019 and June 2021, were collected. Among neonates with a negative blood culture, we compared neonates with prolonged (≥3 days) to neonates with discontinued (&lt;3 days) antibiotic therapy. The clinician’s reported reasons for prolonging therapy were explored. Blood cultures were positive in 4/146 (2.7%), negative in 131/146 (89.7%), and not obtained in 11/146 (7.5%) of the neonates. The incidence of EOS was 0.7 per 1000 neonates. Of the 131 neonates with a negative blood culture, 47 neonates (35.9%) received prolonged antibiotic therapy. In the prolonged group, the mean gestational age was higher (38.9 versus 36.8 weeks), and spontaneous preterm birth was less prevalent (21.3% versus 53.6%). Prolonged treatment was associated with late onset of respiratory distress, respiratory rate, hypoxia, apnoea and bradycardia, pale appearance, behavioural change, and elevated CRP levels. The most reported reasons were clinical appearance (38.3%), elevated CRP levels (36.2%), and skin colour (10.6%). Prolonging empiric antibiotic therapy despite a negative blood culture is common in suspected EOS. Clinical signs associated with prolongation are uncommon and the reported reasons for prolongation contain subjective assessments and arbitrary interpretations that are not supported by the guideline recommendations as arguments for prolonged therapy.</p

Factors Associated with Prolonged Antibiotic Therapy in Neonates with Suspected Early-Onset Sepsis

Early-onset sepsis (EOS) is a rare but profoundly serious bacterial infection. Neonates at risk of EOS are often treated with antibiotics. The start of empiric antibiotic therapy can successfully be reduced by the implementation of the EOS calculator. However, once started, antibiotic therapy is often continued despite a negative blood culture. To decrease the burden of antibiotic therapy, it is necessary to know whether the clinician’s reasons are based on objective factors. Therefore, we performed a retrospective single-centre cohort study to identify the factors associated with prolongation of antibiotic therapy in neonates with suspected EOS but a negative blood culture. Maternal, clinical, and laboratory data of neonates with a gestational age of ≥32 weeks, admitted between January 2019 and June 2021, were collected. Among neonates with a negative blood culture, we compared neonates with prolonged (≥3 days) to neonates with discontinued (&lt;3 days) antibiotic therapy. The clinician’s reported reasons for prolonging therapy were explored. Blood cultures were positive in 4/146 (2.7%), negative in 131/146 (89.7%), and not obtained in 11/146 (7.5%) of the neonates. The incidence of EOS was 0.7 per 1000 neonates. Of the 131 neonates with a negative blood culture, 47 neonates (35.9%) received prolonged antibiotic therapy. In the prolonged group, the mean gestational age was higher (38.9 versus 36.8 weeks), and spontaneous preterm birth was less prevalent (21.3% versus 53.6%). Prolonged treatment was associated with late onset of respiratory distress, respiratory rate, hypoxia, apnoea and bradycardia, pale appearance, behavioural change, and elevated CRP levels. The most reported reasons were clinical appearance (38.3%), elevated CRP levels (36.2%), and skin colour (10.6%). Prolonging empiric antibiotic therapy despite a negative blood culture is common in suspected EOS. Clinical signs associated with prolongation are uncommon and the reported reasons for prolongation contain subjective assessments and arbitrary interpretations that are not supported by the guideline recommendations as arguments for prolonged therapy.</p

Requirement of respiratory support in acute bronchiolitis in infants is linked to endothelial and neutrophil activation

BACKGROUND: Evidence shows that activation of pulmonary vascular endothelium and neutrophils are involved in the pathophysiology of acute bronchiolitis. We hypothesized that levels of markers of endothelial activation and leukocyte counts are associated with requirement and duration of respiratory support. METHODS: Thirty-four infants with bronchiolitis and eight controls were included. Nasopharyngeal swabs and blood samples were taken at admission. Serum levels of Angiopoietin (Ang)-1, Ang-2, sP-selectin, sE-selectin, vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), and leukocyte counts were measured. For univariate analysis, bronchiolitis cases were grouped into two groups, namely those not requiring and those requiring any form of respiratory support. To control for known risk factors for poor outcome (i.e., age, prematurity, and congenital heart disease), and for days post symptom onset, linear regression analysis was performed with duration of any type of respiratory support in days. RESULTS: Ang-2 levels, Ang-2/Ang-1 ratios, sE-selectin levels, immature neutrophil count, and neutrophil/lymphocyte ratio (NLR) were higher in acute bronchiolitis versus controls. Ang-2, and NLR levels were significantly higher, and lymphocyte counts significantly lower, in infants that required respiratory support versus those that did not. Ang-2 levels (β: .32, 95% confidence interval [CI]: 0.19-1.19) and NLR (β: .68, 95% CI: 0.17-1.19) were positive predictors for the duration of respiratory support. CONCLUSIONS: Markers of endothelial and neutrophil activation are associated with respiratory support for acute bronchiolitis. Admission Ang-2 levels and NLR may be promising markers to determine requirement of respiratory support and deserve further study

Barriers and Facilitators to the Implementation of the Early-Onset Sepsis Calculator:A Multicenter Survey Study

Prior studies demonstrated the neonatal early-onset sepsis (EOS) calculator’s potential in drastically reducing antibiotic prescriptions, and its international adoption is increasing rapidly. To optimize the EOS calculator’s impact, successful implementation is crucial. This study aimed to identify key barriers and facilitators to inform an implementation strategy. A multicenter cross-sectional survey was carried out among physicians, residents, nurses and clinical obstetricians of thirteen Dutch hospitals. Survey development was prepared through a literature search and stakeholder interviews. Data collection and analysis were based on the Consolidated Framework for Implementation Research (CFIR). A total of 465 stakeholders completed the survey. The main barriers concerned the expectance of the department’s capacity problems and the issues with maternal information transfer between departments. Facilitators concerned multiple relative advantages of the EOS calculator, including stakeholder education, EOS calculator integration in the electronic health record and existing positive expectations about the safety and effectivity of the calculator. Based on these findings, tailored implementation interventions can be developed, such as identifying early adopters and champions, conducting educational meetings tailored to the target group, creating ready-to-use educational materials, integrating the EOS calculator into electronic health records, creating a culture of collective responsibility among departments and collecting data to evaluate implementation success and innovation results.</p

Stratified Management for Bacterial Infections in Late Preterm and Term Neonates:Current Strategies and Future Opportunities Toward Precision Medicine

Bacterial infections remain a major cause of morbidity and mortality in the neonatal period. Therefore, many neonates, including late preterm and term neonates, are exposed to antibiotics in the first weeks of life. Data on the importance of inter-individual differences and disease signatures are accumulating. Differences that may potentially influence treatment requirement and success rate. However, currently, many neonates are treated following a “one size fits all” approach, based on general protocols and standard antibiotic treatment regimens. Precision medicine has emerged in the last years and is perceived as a new, holistic, way of stratifying patients based on large-scale data including patient characteristics and disease specific features. Specific to sepsis, differences in disease susceptibility, disease severity, immune response and pharmacokinetics and -dynamics can be used for the development of treatment algorithms helping clinicians decide when and how to treat a specific patient or a specific subpopulation. In this review, we highlight the current and future developments that could allow transition to a more precise manner of antibiotic treatment in late preterm and term neonates, and propose a research agenda toward precision medicine for neonatal bacterial infections.</p

Personalized Infant Risk Prediction for Severe Respiratory Syncytial Virus Lower Respiratory Tract Infection Requiring Intensive Care Unit Admission

BACKGROUND: Currently, there are no available tools to identify infants at the highest risk of significant morbidity and mortality from respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) who would benefit most from RSV prevention products. The objective was to develop and internally validate a personalized risk prediction tool for use among all newborns that uses readily available birth/postnatal data to predict RSV LRTI requiring intensive care unit (ICU) admission. METHODS: We conducted a population-based birth cohort study of infants born from 1995 to 2007, insured by the Tennessee Medicaid Program, and who did not receive RSV immunoprophylaxis during the first year of life. The primary outcome was severe RSV LRTI requiring ICU admission during the first year of life. We built a multivariable logistic regression model including demographic and clinical variables available at or shortly after birth to predict the primary outcome. RESULTS: In a population-based sample of 429 365 infants, 713 (0.2%) had severe RSV LRTI requiring ICU admission. The median age of admission was 66 days (interquartile range, 37-120). Our tool, including 19 variables, demonstrated good predictive accuracy (area under the curve, 0.78; 95% confidence interval, 0.77-0.80) and identified infants who did not qualify for palivizumab, based on American Academy of Pediatrics guidelines, but had higher predicted risk levels than infants who qualified (27% of noneligible infants with >0.16% predicted probabilities [lower quartile for eligible infants]). CONCLUSIONS: We developed a personalized tool that identified infants at increased risk for severe RSV LRTI requiring ICU admission, expected to benefit most from immunoprophylaxis

Incidence of Antibiotic Exposure for Suspected and Proven Neonatal Early-Onset Sepsis between 2019 and 2021:A Retrospective, Multicentre Study

Management of suspected early-onset sepsis (EOS) is undergoing continuous evolution aiming to limit antibiotic overtreatment, yet current data on the level of overtreatment are only available for a select number of countries. This study aimed to determine antibiotic initiation and continuation rates for suspected EOS, along with the incidence of culture-proven EOS in The Netherlands. In this retrospective study from 2019 to 2021, data were collected from 15 Dutch hospitals, comprising 13 regional hospitals equipped with Level I-II facilities and 2 academic hospitals equipped with Level IV facilities. Data included birth rates, number of neonates started on antibiotics for suspected EOS, number of neonates that continued treatment beyond 48 h and number of neonates with culture-proven EOS. Additionally, blood culture results were documented. Data were analysed both collectively and separately for regional and academic hospitals. A total of 103,492 live-born neonates were included. In 4755 neonates (4.6%, 95% CI 4.5–4.7), antibiotic therapy was started for suspected EOS, and in 2399 neonates (2.3%, 95% CI 2.2–2.4), antibiotic treatment was continued beyond 48 h. Incidence of culture-proven EOS was 1.1 cases per 1000 live births (0.11%, 95% CI 0.09–0.14). Overall, for each culture-proven EOS case, 40.6 neonates were started on antibiotics and in 21.7 neonates therapy was continued. Large variations in treatment rates were observed across all hospitals, with the number of neonates initiated and continued on antibiotics per culture-proven EOS case varying from 4 to 90 and from 4 to 56, respectively. The high number of antibiotic prescriptions compared to the EOS incidence and wide variety in clinical practice among hospitals in The Netherlands underscore both the need and potential for a novel approach to the management of neonates with suspected EOS.</p

Machine learning used to compare the diagnostic accuracy of risk factors, clinical signs and biomarkers and to develop a new prediction model for neonatal early-onset sepsis

Background: Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs. Study Design: Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier. Results: One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (±8.8%) and an area-under-the-precision-recall-curve of 28.42% (±11.5%). The predictive performance of the model with RFs alone was comparable with random. Conclusions: Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics