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.

Can Presepsin Be Valuable in Reducing Unnecessary Antibiotic Exposure after Birth?

BACKGROUND: Due to a lack of rapid, accurate diagnostic tools for early-onset neonatal sepsis (EOS) at the initial suspicion, infants are often unnecessarily given antibiotics directly after birth. We aimed to determine the diagnostic accuracy of presepsin for EOS before antibiotic initiation and to investigate whether presepsin can be used to guide clinicians' decisions on whether to start antibiotics. METHODS: In this multicenter prospective observational cohort study, all infants who started on antibiotics for EOS suspicion were consecutively included. Presepsin concentrations were determined in blood samples collected at the initial EOS suspicion (t = 0). In addition to this, samples were collected at 3, 6, 12 and 24 h after the initial EOS suspicion and from the umbilical cord directly after birth. The diagnostic accuracy of presepsin was calculated. RESULTS: A total of 333 infants were included, of whom 169 were born preterm. We included 65 term and 15 preterm EOS cases. At the initial EOS suspicion, the area under the curve (AUC) was 0.60 (95% confidence interval (CI) 0.50-0.70) in the term-born infants compared to 0.84 (95% CI 0.73-0.95) in the preterm infants. A cut-off value of 645 pg/mL resulted in a sensitivity of 100% and a specificity of 54% in the preterm infants. The presepsin concentrations in cord blood and at other time points did not differ significantly from the concentrations at the initial EOS suspicion. CONCLUSIONS: Presepsin is a biomarker with an acceptable diagnostic accuracy for EOS (culture-proven and clinical EOS) in preterm infants and might be of value in reducing antibiotic exposure after birth when appended to current EOS guidelines. However, the small number of EOS cases prevents us from drawing firm conclusions. Further research should be performed to evaluate whether appending a presepsin-guided step to current EOS guidelines leads to a safe decrease in antibiotic overtreatment and antibiotic-related morbidity.

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.

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.

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.

The influence of timing of Maternal administration of Antibiotics during cesarean section on the intestinal Microbial colonization in Infants (MAMI-trial): study protocol for a randomised controlled trial.

BACKGROUND: A disturbance in the early colonisation of the gut by microorganisms is associated with an aberrant innate immune system and a variety of clinical conditions later in life. Several factors are considered to influence this initial colonisation, including maternally administered antibiotics during pregnancy and delivery. Recent revisions to international obstetric guidelines have resulted in the exposure of all infants born by caesarean section (CS) to broad-spectrum antibiotics perinatally. To date, the consequences of these new guidelines on neonatal gut colonisation and the associated short- and long-term health implications have not yet been addressed. The aim of this study is to investigate the influence of the timing of antibiotic administration during CS to the mother on the course of neonatal intestinal colonisation up to 2 years of age. METHODS/DESIGN: This single-centre randomised controlled trial will recruit 40 women scheduled for an elective CS. The subjects will be randomised to receive 1500 mg of cefuroxime intravenously either prior to the skin incision (n = 20) or after clamping of the umbilical cord (n = 20). Levels of cefuroxime in cord blood will be determined for exposed neonates. Faecal samples from the children will be collected on days 1, 7 and 28 days and at 2 years old and analysed by 16S sequencing. Shannon-diversity indices, absolute and relative abundances, and unsupervised and supervised classification methods will be used to evaluate the effect of the timing of intrapartum cefuroxime administration on the composition of the microbiota. The outcomes for both study groups will be compared to the intestinal microbiota of vaginally born infants (n = 20). To detect possible effects on health state, a questionnaire on health-related issues will be taken at the age of 2 years. DISCUSSION: In the proposed study, changes in the intestinal microbiota of 40 children born by CS will be followed until the age of 2 years. Research on this topic is necessary since significant effects relating to the timing of antibiotic administration on microbial colonisation may conflict with the current guidelines, as this may have health consequences later in life. TRIAL REGISTRATION: Netherlands Clinical Trial Registry, NTR6000 . Retrospectively registered on 25 July 2016.