Influence of timing of maternal antibiotic administration during caesarean section on infant microbial colonisation: a randomised controlled trial.

OBJECTIVE: Revised guidelines for caesarean section (CS) advise maternal antibiotic administration prior to skin incision instead of after umbilical cord clamping, unintentionally exposing the infant to antibiotics antenatally. We aimed to investigate if timing of intrapartum antibiotics contributes to the impairment of microbiota colonisation in CS born infants. DESIGN: In this randomised controlled trial, women delivering via CS received antibiotics prior to skin incision (n=20) or after umbilical cord clamping (n=20). A third control group of vaginally delivering women (n=23) was included. Faecal microbiota was determined from all infants at 1, 7 and 28 days after birth and at 3 years by 16S rRNA gene sequencing and whole-metagenome shotgun sequencing. RESULTS: Compared with vaginally born infants, profound differences were found in microbial diversity and composition in both CS groups in the first month of life. A decreased abundance in species belonging to the genera Bacteroides and Bifidobacterium was found with a concurrent increase in members belonging to the phylum Proteobacteria. These differences could not be observed at 3 years of age. No statistically significant differences were observed in taxonomic and functional composition of the microbiome between both CS groups at any of the time points. CONCLUSION: We confirmed that microbiome colonisation is strongly affected by CS delivery. Our findings suggest that maternal antibiotic administration prior to CS does not result in a second hit on the compromised microbiome. Future, larger studies should confirm that antenatal antibiotic exposure in CS born infants does not aggravate colonisation impairment and impact long-term health.

Exposure to intrauterine inflammation and late-onset sepsis in very preterm infants.

BACKGROUND: Late-onset sepsis is an important cause of mortality and morbidity in preterm infants. As these infants rely mostly on their innate immune system to fight off infection, enhancing this immune system by appropriate stimuli may prevent late-onset sepsis. However, it remains unclear which stimuli can enhance the neonatal immune system. This study aims to investigate the influence of intrauterine inflammation on late-onset sepsis. METHODS: This is a retrospective cohort study in a Neonatal Intensive Care Unit in the Netherlands. Between 2005 and 2016, 1014 infants with ≤32 weeks gestational age and/or with a birth weight ≤1500 g were included. Intrauterine inflammation was subdivided into histological chorioamnionitis, fetal inflammatory response, and funisitis. Logistic and Cox regression analyses were performed to investigate the influence of intrauterine inflammation on late-onset sepsis. RESULTS: Thirty-six percent of the included infants developed late-onset sepsis; 24% of placentas showed intrauterine inflammation. Late-onset sepsis incidence did not differ between infants with or without exposure to intrauterine inflammation after adjustment for gestational age (histological chorioamnionitis aHR 0.928 [CI: 0.727-1.185], p = 0.551; fetal inflammatory response aHR 1.011 [CI: 0.793-1.288], p = 0.930); funisitis aHR 0.965 [CI: 0.738-1.263], p = 0.797). CONCLUSIONS: Late-onset sepsis in very preterm infants seems not to be associated with intrauterine inflammation. IMPACT: Intrauterine inflammation is not protective of developing late-onset sepsis in premature infants. A large cohort study on the effect of intrauterine inflammation on neonatal outcome. This study adds to existing knowledge on finding appropriate stimuli to enhance the immune system of premature infants to improve neonatal outcome.

Umbilical cord blood culture in neonatal early-onset sepsis: a systematic review and meta-analysis.

BACKGROUND: Peripheral blood culture (PBC) is considered the gold standard for diagnosis of neonatal early-onset sepsis (EOS), but its diagnostic value can be questioned. We aimed to systematically asses the diagnostic test accuracy (DTA) of umbilical cord blood culture (UCBC) for EOS. METHODS: A systematic literature search was performed in PubMed, Embase, Web of Science, and the Cochrane Library. Studies performing UCBC for the diagnosis of EOS were included. RESULTS: A total of 1908 articles were screened of which 17 were included. Incidences of positive PBC and UCBC were low in all studies. There was a large heterogeneity in the consistency between positive PBC and UCBC outcomes. PBC had a pooled sensitivity of 20.4% (95% CI 0.0-40.9) and specificity of 100.0% (95% CI 100.0-100.0) compared to 42.6% (95% CI 12.7-72.4%) and 97.8% (95% CI 93.1-100.0) of UCBC for clinical EOS, defined as clinical sepsis regardless of PBC outcomes. CONCLUSIONS: This systematic review shows that, compared to PBC, UCBC has higher sensitivity and comparable specificity for clinical EOS and might be considered as diagnostic test for EOS. Due to the limited number of studies, low incidences of EOS cases, and the imperfect reference standards for EOS, results should be interpreted cautiously. IMPACT: This is the first systematic review and meta-analysis investigating the diagnostic test accuracy of umbilical cord blood culture for neonatal early-onset sepsis. Peripheral blood culture is considered the gold standard for diagnosis of neonatal early-onset sepsis, but its value for this specific diagnosis can be questioned. Umbilical cord blood culture has higher sensitivity and comparable specificity for diagnosis of neonatal early-onset sepsis compared to peripheral blood culture, circumventing the risk for iatrogenic anemia and consequently might be used as a diagnostic tool for early-onset sepsis. Quality of evidence was regarded as low due to imperfect diagnostic methods of neonatal early-onset sepsis.

Association between duration of early empiric antibiotics and necrotizing enterocolitis and late-onset sepsis in preterm infants: a multicenter cohort study.

The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics' effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age < 30 weeks) born in 9 centers in the Netherlands and Belgium between Oct. 2014 and Jan. 2019. EEAE association with NEC and LOS development was analyzed by multivariate regression. After excluding 56 EOS cases, 1259 infants were included. A total of 1122 infants (89.1%) were exposed to empirical antibiotics for the suspicion of EOS of whom 802 (63.7%) had short (≤ 72 h) and 320 (25.4%) prolonged EEAE (> 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19-0.80]; p = 0.01) and with prolonged EEAE (> 72 h) (aOR [95%CI]: 0.58 [0.35-0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85-0.97]; p = 0.003). CONCLUSION: Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored. WHAT IS KNOWN: • Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis. • The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated. WHAT IS NEW: • Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged. • A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (>72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life.

The association between clinical and biochemical characteristics of late-onset sepsis and bronchopulmonary dysplasia in preterm infants.

Studies in preterm infants have shown an association between late-onset sepsis (LOS) and the development of bronchopulmonary dysplasia (BPD). It is unknown whether clinical or biochemical characteristics during sepsis modulate the risk for BPD. This single-center retrospective cohort study included all patients with a gestational age < 30 weeks, born between 2009 and 2015, in whom empiric antimicrobial treatment was initiated > 72 h after birth and continued for at least 5 days, independent on microbiological results. The association between clinical and biochemical characteristics of LOS and the development of BPD in survivors were assessed with multivariate logistic regression analysis adjusted for early-onset sepsis, small for gestational age, and gestational age. Of the 756 admitted infants, 256 infants (mean GA: 27.0 weeks; birthweight: 924 grams) had at least one LOS episode, of whom 79 (30.9%) developed BPD. Analyses showed that only the need for and duration of mechanical ventilation during LOS were independently associated with an increased risk for BPD (adjusted OR 2.62, 95% CI 1.38, 4.96, p value 0.003, and OR 1.004, 95% CI 1.00, 1.007, p value 0.045, respectively).Conclusion: During a LOS, the need for and duration of mechanical ventilation are independently associated with the risk of developing BPD in preterm infants. What is Known: • Premature infants diagnosed with a late-onset sepsis are at higher risk of developing bronchopulmonary dysplasia • This association is mainly shown in infants with a positive blood culture What is New: • This study investigates the clinical and biochemical characteristics of late-onset sepsis and the development of bronchopulmonary dysplasia • The need for mechanical ventilation and duration of mechanical ventilation during late-onset sepsis are associated with an increased risk of developing bronchopulmonary dysplasia.

Early onset sepsis calculator implementation is associated with reduced healthcare utilization and financial costs in late preterm and term newborns.

The neonatal early onset sepsis (EOS) calculator is a novel tool for antibiotic stewardship in newborns, associated with a reduction of empiric antibiotic treatment for suspected EOS. We studied if implementation of the EOS calculator results in less healthcare utilization and lower financial costs of suspected EOS. For this, we compared two single-year cohorts of hospitalizations within 3 days after birth in a Dutch nonacademic teaching hospital, before and after implementation of the EOS calculator. All admitted newborns born at or after 35 weeks of gestation were eligible for inclusion. We analyzed data from 881 newborns pre-implementation and 827 newborns post-implementation. We found significant reductions in EOS-related laboratory tests performed and antibiotic days, associated with implementation of the EOS calculator. Mean length of hospital stay was shorter, and EOS-related financial costs were lower after implementation among term, but not among preterm newborns.Conclusion: In addition to the well-known positive impact on antibiotic stewardship, implementation of the EOS calculator is also clearly associated with reductions in healthcare utilization related to suspected EOS in late preterm and term newborns and with a reduction in associated financial costs among those born term.What is Known:• The early-onset sepsis (EOS) calculator is a novel tool for antibiotic stewardship in newborns, associated with a reduction in empiric antibiotic treatment for suspected EOS.What is New:• In newborns at risk for EOS, EOS calculator implementation is associated with a significant reduction in laboratory investigations related to suspected EOS and significantly shorter stay in those born term.• EOS calculator implementation in term newborns is associated with a mean reduction of €207 in costs for EOS-related care per admitted newborn.

Soluble CD14 subtype (sCD14-ST) as biomarker in neonatal early-onset sepsis and late-onset sepsis: a systematic review and meta-analysis.

BACKGROUND: Early diagnosis of bacterial sepsis in neonates is hampered by non-specific symptoms and the lack of rapid responding laboratory measures. The biomarker soluble CD14 subtype (sCD14-ST) seems promising in the diagnostic process of neonatal sepsis. In order to evaluate the differences in diagnostic accuracy of sCD14-ST between early onset sepsis (EOS) and late onset sepsis (LOS) we assessed this systematic review and meta-analysis. RESULTS: Twelve articles were included in the systematic review and 10 in the meta-analysis. There was a high risk of bias on patient selection, index test and/or flow and timing. The overall quality of the included studies was moderate. At sepsis onset a consequently higher level of sCD14-ST was found in septic neonates compared to healthy controls with significant higher levels in LOS compared to EOS. In the first 24 h after sepsis onset a significant increase in pooled means of plasma sCD14-ST levels was seen in EOS (t(71.6) = 7.3, p < .0001) while this was not seen in LOS or healthy controls. Optimal cut-off values ranged from 305 to 672 ng/l for EOS cases versus healthy controls. The pooled sensitivity was 81% (95%CI: 0.76-0.85), the pooled specificity was 86% (0.81-0.89) with an AUC of 0.9412 (SE 0.1178). In LOS optimal cut-off values ranged from 801 to 885 ng/l with a pooled sensitivity of 81% (0.74-0.86) and a pooled specificity of 100% (0.98-1.00). An AUC and SROC was not estimable in LOS because of the low number of studies. CONCLUSIONS: sCD14-ST is a promising and rapid-responding diagnostic biomarker for EOS and LOS. The difference in pooled means between EOS and LOS underlines the importance to consider EOS and LOS as two different disease entities, requiring separate analysis in original articles and systematic reviews.

Solar ultraviolet B exposure and global variation in tuberculosis incidence: an ecological analysis.

Epidemiological evidence supports vitamin D deficiency as a risk factor for tuberculosis. Differences in solar ultraviolet B (UV-B) exposure, the major source of vitamin D, might therefore partially explain global variation in tuberculosis incidence.In a global country-based ecological study, we explored the correlation between vitamin D-proxies, such as solar UV-B exposure, and other relevant variables with tuberculosis incidence, averaged over the period 2004-2013.Across 154 countries, annual solar UV-B exposure was associated with tuberculosis incidence. Tuberculosis incidence in countries in the highest quartile of UV-B exposure was 78% (95% CI 57-88%, p<0.001) lower than that in countries in the lowest quartile, taking into account other vitamin D-proxies and covariates. Of the explained global variation in tuberculosis incidence, 6.3% could be attributed to variations in annual UV-B exposure. Exposure to UV-B had a similar, but weaker association with tuberculosis notification rates in the multilevel analysis with sub-national level data for large countries (highest versus lowest quartile 29% lower incidence; p=0.057).The potential preventive applications of vitamin D supplementation in high-risk groups for tuberculosis merits further investigation.

Host immune response to tuberculous meningitis.

BACKGROUND: Tuberculous meningitis (TBM) is a severe complication of tuberculosis predominantly affecting young children. Early treatment is vital to prevent morbidity and mortality, emphasizing the importance of early diagnosis. The lack of sensitive methods for early diagnosis is the most common cause of delay. Attempts have been made to develop simplified tests for tuberculosis, but their diagnostic power remains poor. The clinical picture of TBM is mainly driven by the host's immune response to Mycobacterium tuberculosis; therefore, identification of disease-specific biomarkers may have diagnostic and therapeutic value and improve our understanding of its pathogenesis. METHODS: We investigated disease-specific biomarkers of childhood TBM in a cohort of children aged 3 months-13 years with symptoms and signs suggestive of meningitis. Cerebrospinal fluid (CSF) and serum from 56 patients with and 55 patients without TBM were assessed for 28 soluble mediators. RESULTS: Unsupervised hierarchical clustering analysis revealed a disease-specific pattern of biomarkers for TBM relative to other types of meningitis. A biomarker-based diagnostic prediction model for childhood TBM based on CSF concentrations of interleukin 13 (cutoff value, 37.26 pg/mL), vascular endothelial growth factor (cutoff value, 42.92 pg/mL), and cathelicidin LL-37 (cutoff value, 3221.01 pg/mL) is presented with a sensitivity of 0.52 and a specificity of 0.95. CONCLUSIONS: These data highlight the potential of biosignatures in the host's CSF for diagnostic applications and for improving our understanding of the pathogenesis of TBM to discover strategies to prevent immunopathological sequelae.

Uniform research case definition criteria differentiate tuberculous and bacterial meningitis in children.

BACKGROUND: Tuberculous meningitis (TBM) research is hampered by low numbers of microbiologically confirmed TBM cases and the fact that they may represent a select part of the disease spectrum. A uniform TBM research case definition was developed to address these limitations, but its ability to differentiate TBM from bacterial meningitis has not been evaluated. METHODS: We assessed all children treated for TBM from 1985 to 2005 at Tygerberg Children's Hospital, Cape Town, South Africa. For comparative purposes, a group of children with culture-confirmed bacterial meningitis, diagnosed between 2003 and 2009, was identified from the National Health Laboratory Service database. The performance of the proposed case definition was evaluated in culture-confirmed TBM and bacterial meningitis cases. RESULTS: Of 554 children treated for TBM, 66 (11.9%) were classified as "definite TBM," 408 (73.6%) as "probable TBM," and 72 (13.0%) as "possible TBM." "Probable TBM" criteria identified culture-confirmed TBM with a sensitivity of 86% and specificity of 100%; sensitivity was increased but specificity reduced when using "possible TBM" criteria (sensitivity 100%, specificity 56%). CONCLUSIONS: "Probable TBM" criteria accurately differentiated TBM from bacterial meningitis and could be considered for use in clinical trials; reduced sensitivity in children with early TBM (stage 1 disease) remains a concern.

Vitamin D deficiency among native Dutch and first- and second-generation non-Western immigrants.

UNLABELLED: The aim of this study was to determine the prevalence of 25-hydroxyvitamin D (25(OH)D) deficiency in a hospital-based population of both native Dutch and non-Western immigrants and to investigate the influence of immigrant status on the prevalence of vitamin D deficiency. A cross-sectional survey was conducted among 132 patients (1-18 years of age) visiting the paediatric outpatient department. Serum levels of 25(OH)D were measured using high-performance liquid chromatography. Cut-off levels of 30 and 50 nmol/l for serum 25(OH)D were evaluated. One third of the patients had serum 25(OH)D levels below 30 nmol/l, and half of the study population had serum levels below 50 nmol/l. Non-Western immigrants had an increased risk for vitamin D deficiency compared to their native Dutch peers [25(OH)D of <30 nmol/l, p = 0.03, odds ratio (OR) 3.87 (95 % confidence interval (CI) 1.13-13.29); 25(OH)D of <50 nmol/l, p = 0.02, OR 3.57 (95 % CI 1.26-10.14)] with the highest risk for first-generation non-Western immigrants. CONCLUSION: Vitamin D deficiency in the paediatric population is still a matter of concern in the Netherlands, in particular among first-generation non-Western immigrants. We therefore strongly recommend vitamin D supplementation for all non-Western immigrants, regardless of age, skin type or season. Health-care staff who work with non-Western immigrants should be aware of the prevalence and implications of vitamin D deficiency.

Cerebrospinal fluid inflammatory markers to differentiate between neonatal bacterial meningitis and sepsis: A prospective study of diagnostic accuracy.

OBJECTIVES: We evaluated the diagnostic accuracy of cerebrospinal fluid (CSF) inflammatory markers for diagnosing bacterial meningitis in neonates with sepsis and/or meningitis. METHODS: Cases were identified from a prospective multicenter study including patients aged 0-3 months with Group B Streptococcal (GBS) or Escherichia coli culture positive sepsis/meningitis. CSF CXCL10, MDC, IL-6, IL-8, IL-10, TNF- α, MIF, IL-1RA, CXCL13, IL-1ß, CRP and procalcitonin concentrations were measured with Luminex technology. RESULTS: In 61/373 patients (17%) residual CSF from the lumbar puncture was available, of whom 16 (26%) had definitive meningitis, 15 (25%) probable meningitis and 30 (49%) had sepsis. All biomarkers were detectable in CSF and showed significantly higher concentrations in definitive meningitis versus sepsis patients and six biomarkers in probable meningitis versus sepsis patients. Discrimination between definitive meningitis and sepsis was excellent for IL-1RA (area under the receiver operating characteristic curve [AUC] 0.93), TNF-α (AUC 0.92), CXCL10 (AUC 0.90), IL-1ß (AUC 0.92), IL-6 (AUC 0.94), IL-10 (AUC 0.93) and a combination of IL-1RA, TNF-α, CXCL-10 and CSF leukocyte count (AUC 0.95). CSF leukocyte count remained the predictor with the highest diagnostic accuracy (AUC 0.96). CONCLUSION: CSF inflammatory markers can be used to differentiate between neonatal sepsis and meningitis.

Technical Skills Curriculum in Neonatology: A Modified European Delphi Study.

INTRODUCTION: Simulation-based training (SBT) aids healthcare providers in acquiring the technical skills necessary to improve patient outcomes and safety. However, since SBT may require significant resources, training all skills to a comparable extent is impractical. Hence, a strategic prioritization of technical skills is necessary. While the European Training Requirements in Neonatology provide guidance on necessary skills, they lack prioritization. We aimed to identify and prioritize technical skills for a SBT curriculum in neonatology. METHODS: A three-round modified Delphi process of expert neonatologists and neonatal trainees was performed. In round one, the participants listed all the technical skills newly trained neonatologists should master. The content analysis excluded duplicates and non-technical skills. In round two, the Copenhagen Academy for Medical Education and Simulation Needs Assessment Formula (CAMES-NAF) was used to preliminarily prioritize the technical skills according to frequency, importance of competency, SBT impact on patient safety, and feasibility for SBT. In round three, the participants further refined and reprioritized the technical skills. Items achieving consensus (agreement of ≥75%) were included. RESULTS: We included 168 participants from 10 European countries. The response rates in rounds two and three were 80% (135/168) and 87% (117/135), respectively. In round one, the participants suggested 1964 different items. Content analysis revealed 81 unique technical skills prioritized in round two. In round three, 39 technical skills achieved consensus and were included. CONCLUSION: We reached a European consensus on a prioritized list of 39 technical skills to be included in a SBT curriculum in neonatology.

Heart Rate Characteristics Monitoring for Late-Onset Sepsis in Preterm Infants: A Systematic Review.

BACKGROUND: Early diagnosis of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) by monitoring heart rate characteristics (HRC) of preterm infants might reduce the risk of death and morbidities. We aimed to systematically assess the effects of HRC monitoring on death, LOS, and NEC. METHODS: A systematic search was performed in MEDLINE, Embase, Cochrane Library, and Web of Science. RESULTS: Fifteen papers were included in this review. Three of these papers reported results from the only identified randomized controlled trial (RCT). This RCT showed that HRC monitoring resulted in a small but significant reduction in mortality (absolute risk reduction 2.1% [95% confidence interval 0.01-4.14]) without any differences in neurodevelopmental impairment. The risk of bias was rated high due to performance and detection bias and failure to correct for multiple testing. Most diagnostic cohort studies showed high discriminating accuracy in predicting LOS but lacked sufficient quality and generalizability. No studies for the detection of NEC were identified. CONCLUSION: Supported by multiple observational cohort studies, the RCT identified in this systematic review showed that HRC monitoring as an early warning system for LOS might reduce the risk of death in preterm infants. However, methodological weaknesses and limited generalizability do not justify implementation of HRC in clinical care. A large international RCT is warranted.

Predictive performance of multiple organ dysfunction in asphyxiated newborns treated with therapeutic hypothermia on 24-month outcome: a cohort study.

BACKGROUND: Perinatal asphyxia may be followed by multiple organ dysfunction (MOD) and is often included in prognostication of the individual patient, but evidence of discriminating accuracy is lacking. The aim of this study was to assess whether MOD in asphyxiated neonates during therapeutic hypothermia (TH) predicts mortality or neurodevelopmental impairment (NDI) at 24 months of age and which peripartum variables are associated with the onset of MOD. METHODS: A retrospective analysis of a prospective cohort study of asphyxiated newborns undergoing TH was performed. MOD was defined as dysfunction of the brain (encephalopathy) combined with two or more organ systems. Outcome was routinely assessed by standardised developmental testing at the age of 24 months. The predictive accuracy of MOD on the combined outcome and its components (death and NDI) was expressed as areas under the receiver operating characteristic curves (AUROCs). The associations of peripartum variables and development of MOD were expressed as ORs and their CIs. RESULTS: 189 infants (median gestation 40 (range 36-42 weeks) with moderate to severe hypoxic ischaemic encephalopathy were included. 47% developed MOD. The prediction of the combined 24-month outcome or its components showed AUROCs <0.70. Associated with MOD were pH at birth (OR 0.97, CI 0.95 to 0.99), lactate at birth (OR 1.09, CI 1.04 to 1.15), Base Excess (BE) at birth (OR 0.94, CI 0.90 to 0.99) and epinephrine administration during resuscitation (OR 2.09, CI 1.02 to 4.40). CONCLUSION: MOD has a low discriminating accuracy in predicting mortality or NDI at 24 months age and might not be useful for prognostication. Signs of acid-base disturbance and adrenalin use at birth are associated with the development of MOD.

Benzylpenicillin concentrations in umbilical cord blood and plasma of premature neonates following intrapartum doses for group B streptococcal prophylaxis.

BACKGROUND AND METHOD: Dutch obstetrics guideline suggest an initial maternal benzylpenicillin dose of 2,000,000 IU followed by 1,000,000 IU every 4 h for group-B-streptococci (GBS) prophylaxis. The objective of this study was to evaluate whether concentrations of benzylpenicillin reached concentrations above the minimal inhibitory concentrations (MIC) in umbilical cord blood (UCB) and neonatal plasma following the Dutch guideline. RESULTS: Forty-six neonates were included. A total of 46 UCB samples and 18 neonatal plasma samples were available for analysis. Nineteen neonates had mothers that received intrapartum benzylpenicillin. Benzylpenicillin in UCB corresponded to concentrations in plasma drawn directly postpartum (R2 = 0.88, p < 0.01). A log-linear regression suggested that benzylpenicillin concentrations in neonates remained above the MIC threshold 0.125 mg/L up to 13.0 h after the last intrapartum dose. CONCLUSIONS: Dutch intrapartum benzylpenicillin doses result in neonatal concentrations above the MIC of GBS.

Appendicitis and its associated mortality and morbidity in infants up to 3 months of age: A systematic review.

Background and Aims: Although appendicitis is rare in young infants, the reported mortality is high. Primary aim of this systematic review was to provide updated insights in the mortality and morbidity (postoperative complications, Clavien-Dindo grades I-IV) of appendicitis in infants ≤3 months of age. Secondary aims comprised the evaluation of patient characteristics, diagnostic work-up, treatment strategies, comorbidity, and factors associated with poor outcome. Methods: This systematic review was reported according to the PRISMA statement with a search performed in Pubmed, Embase and Web of Science (up to September 5th 2022). Original articles (published in English ≥1980) reporting on infants ≤3 months of age with appendicitis were included. Both patients with abdominal appendicitis and herniated appendicitis (such as Amyand's hernia) were considered. Data were provided descriptively. Results: In total, 131 articles were included encompassing 242 cases after identification of 4294 records. Overall, 184 (76%) of the 242 patients had abdominal and 58 (24%) had herniated appendicitis. Two-hundred (83%) of the patients were newborns (≤28 days) and 42 (17%) were infants between 29 days and ≤3 months of age. Either immediate, or after initial conservative treatment, 236 (98%) patients underwent surgical treatment. Some 168 (69%) patients had perforated appendicitis. Mortality was reported in 20 (8%) patients and morbidity in an additional 18 (8%). All fatal cases had abdominal appendicitis and fatal outcome was relatively more often reported in newborns, term patients, patients with relevant comorbidity, nonperforated appendicitis and those presented from home. Conclusion: Mortality was reported in 20 (8%) infants ≤3 months of age and additional morbidity in 18 (8%). All patients with fatal outcome had abdominal appendicitis. Several patient characteristics were relatively more often reported in infants with poor outcome and adequate monitoring, early recognition and prompt treatment may favour the outcome.

Potential of Molecular Culture in Early Onset Neonatal Sepsis Diagnosis: A Proof of Principle Study.

Delay in the time-to-positivity of a peripheral blood culture (PBC), the gold standard for early onset neonatal sepsis (EOS) diagnosis, has resulted in excessive use of antibiotics. In this study, we evaluate the potential of the rapid Molecular Culture (MC) assay for quick EOS diagnosis. In the first part of this study, known positive and spiked blood samples were used to assess the performance of MC. In the in vivo clinical study, the second part of this study, all infants receiving antibiotics for suspicion of EOS were included. At initial EOS suspicion, a blood sample was collected for PBC and MC. MC was able to detect bacteria present in the spiked samples even when the bacterial load was low. In the clinical study, MC was positive in one infant with clinical EOS (Enterococcus faecalis) that was not detected by PBC. Additionally, MC was positive in two infants without clinical sepsis (Streptococcus mitis and multiple species), referred to as contamination. The other 37 samples were negative both by MC and PBC. MC seems to be able to detect bacteria even when the bacterial load is low. The majority of MC and PBC results were comparable and the risk for contamination and false positive MC results seems to be limited. Since MC can generate results within 4 h following sampling compared with 36-72 h in PBC, MC may have the potential to replace conventional PBC in EOS diagnostics in order to guide clinicians on when to discontinue antibiotic therapy several hours after birth.

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.

Group B Streptococcus Early-Onset Disease: New Preventive and Diagnostic Tools to Decrease the Burden of Antibiotic Use.

The difficulty in recognizing early-onset neonatal sepsis (EONS) in a timely manner due to non-specific symptoms and the limitations of diagnostic tests, combined with the risk of serious consequences if EONS is not treated in a timely manner, has resulted in a low threshold for starting empirical antibiotic treatment. New guideline strategies, such as the neonatal sepsis calculator, have been proven to reduce the antibiotic burden related to EONS, but lack sensitivity for detecting EONS. In this review, the potential of novel, targeted preventive and diagnostic methods for EONS is discussed from three different perspectives: maternal, umbilical cord and newborn perspectives. Promising strategies from the maternal perspective include Group B Streptococcus (GBS) prevention, exploring the virulence factors of GBS, maternal immunization and antepartum biomarkers. The diagnostic methods obtained from the umbilical cord are preliminary but promising. Finally, promising fields from the newborn perspective include biomarkers, new microbiological techniques and clinical prediction and monitoring strategies. Consensus on the definition of EONS and the standardization of research on novel diagnostic biomarkers are crucial for future implementation and to reduce current antibiotic overexposure in newborns.