Management of neonates at risk of early onset sepsis: a probability-based approach and recent literature appraisal : Update of the Swiss national guideline of the Swiss Society of Neonatology and the Pediatric Infectious Disease Group Switzerland.

In Switzerland and other high-income countries, one out of 3000 to 5000 term and late preterm neonates develops early onset sepsis (EOS) associated with a mortality of around 3%, while incidence and mortality of EOS in very preterm infants are substantially higher. Exposure to antibiotics for suspected EOS is disproportionally high compared to the incidence of EOS with consequences for future health and antimicrobial resistance (AMR). A safe reduction of unnecessary antibiotic treatment has to be a major goal of new management strategies and guidelines. Antibiotics should be administered immediately in situations with clinical signs of septic shock. Group B streptococcus (GBS) and Escherichia coli (E. coli) are the leading pathogens of EOS. Amoxicillin combined with an aminoglycoside remains the first choice for empirical treatment. Serial physical examinations are recommended for all neonates with risk factors for EOS. Neonates without any clinical signs suggestive of EOS should not be treated with antibiotics. In Switzerland, we do not recommend the use of the EOS calculator, a risk stratification tool, due to its unclear impact in a population with an observed antibiotic exposure below 3%. Not all neonates with respiratory distress should be empirically treated with antibiotics. Isolated tachypnea or respiratory distress starting immediately after delivery by elective caesarean section or a clearly assessed alternative explanation than EOS for clinical signs may point towards a low probability of sepsis. On the other hand, unexplained prematurity with risk factors has an inherent higher risk of EOS. Before the start of antibiotic therapy, blood cultures should be drawn with a minimum volume of 1 ml in a single aerobic blood culture bottle. This standard procedure allows antibiotics to be stopped after 24 to 36 h if no pathogen is detected in blood cultures. Current data do not support the use of PCR-based pathogen detection in blood as a standard method. Lumbar puncture is recommended in blood culture-proven EOS, critical illness, or in the presence of neurological symptoms such as seizures or altered consciousness. The accuracy of a single biomarker measurement to distinguish inflammation from infection is low in neonates. Therefore, biomarker guidance is not a standard part of decision-making regarding the start or stop of antibiotic therapy but may be used as part of an algorithm and after appropriate education of health care teams. Every newborn started on antibiotics should be assessed for organ dysfunction with prompt initiation of respiratory and hemodynamic support if needed. An elevated lactate may be a sign of poor perfusion and requires a comprehensive assessment of the clinical condition. Interventions to restore perfusion include fluid boli with crystalloids and catecholamines. Neonates in critical condition should be cared for in a specialized unit. In situations with a low probability of EOS, antibiotics should be stopped as early as possible within the first 24 h after the start of therapy. In cases with microbiologically proven EOS, reassessment and streamlining of antibiotic therapy in neonates is an important step to minimize AMR. CONCLUSION:  This guideline, developed through a critical review of the literature, facilitates a probability-based approach to the management of neonates at risk of early onset sepsis. WHAT IS KNOWN: • Neonatal exposure to antibiotics is disproportionally high compared with the incidence of early onset sepsis with implications for future health and antimicrobial resistance. WHAT IS NEW: • A probability-based approach may facilitate a more balanced management of neonatal sepsis and antibiotic stewardship.

Diagnosis and Management of Neonatal Bacterial Sepsis: Current Challenges and Future Perspectives.

Sepsis remains the second cause of death among neonates after the pathological consequences of extreme prematurity. In this review we summarized knowledge about pathogens causing early-onset sepsis (EOS) and late-onset sepsis (LOS), the role of perinatal risk factors in determining the EOS risk, and the tools used to reduce unnecessary antibiotics. New molecular assays could improve the accuracy of standard blood cultures, providing the opportunity for a quick and sensitive tool. Different sepsis criteria and biomarkers are available to date, but further research is needed to guide the use of antibiotics according to these tools. Beyond the historical antibiotic regimens in EOS and LOS episodes, antibiotics should be based on the local flora and promptly modulated if specific pathogens are identified. The possibility of an antibiotic lock therapy for central venous catheters should be further investigated. In the near future, artificial intelligence could help us to personalize treatments and reduce the increasing trend of multidrug-resistant bacteria.

Utilizing Predictive Factors as a Screening Tool for Early-Onset Sepsis in Neonates.

INTRODUCTION: Neonatal early-onset sepsis (EOS) is a severe condition that affects newborns within the first three days of life, with high mortality rates, particularly in low- and middle-income countries (LMICs). In Vietnam, the diagnosis and management of EOS are challenged by ambiguous clinical signs and limited access to blood culture testing facilities. Early identification of at-risk neonates using a predictive risk factor model is crucial for improving neonatal care and reducing mortality. OBJECTIVES: This study aims to identify maternal and neonatal risk factors associated with EOS and develop a predictive screening tool to facilitate the early detection of at-risk neonates in Vietnam. MATERIALS AND METHODS: A nested case-control study was conducted on 225 neonates at the central neonatal unit in a principal tertiary hospital in southwestern Vietnam over a two-year period. Risk factors were identified using univariable and multivariable logistic regression analyses. A predictive nomogram was developed and evaluated for discrimination, calibration, and decision curve analysis (DCA). RESULTS: The study identified eight significant risk factors for EOS, including maternal genital infections during the third trimester, urinary tract infections (UTIs) during pregnancy, hypertension during pregnancy, insufficient maternal weight gain, rupture of membranes (ROM) ≥18 hours, meconium-stained amniotic fluid, first-minute APGAR score <7, and preterm birth <34 weeks. The predictive model demonstrated excellent discrimination with an area under the curve (AUC) of 0.913 (95% CI: 0.876-0.95, p<0.001) and good calibration (Hosmer-Lemeshow test with χ²(df)=5.496 (5), p=0.358). The model-based nomogram showed high sensitivity (82.7%) and specificity (83.3%) at an optimal cutoff of 0.25. The DCA illustrates the model's good clinical utility, providing a higher net benefit across most threshold probability ranges (0.0-0.96). CONCLUSIONS: This study presents a robust predictive model for the early identification of neonates at risk of EOS in Vietnam, based on key maternal and neonatal risk factors. The model, with demonstrated accuracy and reliability, holds significant potential for improving neonatal outcomes through timely interventions. Future research should aim at external validation and inclusion of broader clinical data to enhance the model's applicability and generalizability.

Antibiotic Management for Early-Onset Sepsis in Neonates With Gestational Ages of ≥ 34 Weeks: The Kaiser Sepsis Calculator Versus the 2010 CDC Guidelines.

INTRODUCTION: The traditional approach to neonatal early-onset sepsis (NEOS) management, involving maternal risk factors and nonspecific neonatal symptoms, usually leads to unnecessary antibiotic use. This study addresses these concerns by evaluating the Kaiser sepsis calculator (KSC) in guiding antibiotic therapy for NEOS, especially in high-incidence facilities (over 4/1,000 live births), by comparing it against the 2010 Centers for Disease Control and Prevention (CDC) guidelines for neonates ≥34 weeks with suspected sepsis, thereby emphasizing its implications for personalized patient care. METHODS: This is a prospective observational study. All neonates of 34 gestational weeks or more, presenting with either maternal risk factors or sepsis symptoms within 12 hours of birth, were included in the study. The analysis focused on antibiotic recommendations by the 2010 CDC guidelines versus those by the KSC at presumed (0.5/1,000) and actual (16/1,000) sepsis incidence rates. RESULTS: NEOS was identified in 14 cases (14.1%). Compared to the KSC, at an incidence rate of 16 per 1,000, the KSC resulted in a significant 32.3% reduction in antibiotic treatment (74 cases (74.7%) vs. 42 cases (42.4%), respectively; p < 0.001). The calculator advised immediate antibiotic utilization for 13 out of 14 (92.9%) diagnosed cases, suggesting further evaluation for the remaining cases. When a presumed incidence of 0.5/1,000 was applied, the KSC indicated antibiotics less frequently than when using the actual rate of 16/1,000 (p<0.001) with two missed NEOS cases. CONCLUSIONS: Using the KSC led to a decrease of 32 cases (32.3%) in unnecessary antibiotic prescriptions compared to adherence to 2010 CDC guidelines. However, setting a presumed incidence below the actual rate risked missing NEOS. The calculator was effective when actual local incidence rates were used, ensuring no missed cases needing antibiotics.

Exploring factors influencing delayed first antibiotic treatment for suspected early-onset sepsis in preterm newborns: a study before quality improvement initiative.

BACKGROUND: Early-onset sepsis (EOS) is a serious illness that affects preterm newborns, and delayed antibiotic initiation may increase the risk of adverse outcomes. PURPOSE: The objective of this study was to examine the present time of antibiotic administration in preterm infants with suspected EOS and the factors that contribute to delayed antibiotic initiation. METHODS: In this retrospective study in China, a total of 82 early preterm infants with suspected EOS between December 2021 and March 2023 were included. The study utilized a linear regression analytical approach to identify independent factors that contribute to delayed antibiotic administration. RESULTS: The mean gestational age and birth weight of the study population were 29.1 ± 1.4 weeks and 1265.7 ± 176.8 g, respectively. The median time of initial antibiotic administration was 3.8 (3.1-5.0) hours. Linear regression revealed that severe respiratory distress syndrome (RDS) (ß = 0.07, P = 0.013), penicillin skin test (PST) timing (ß = 0.06, P < 0.001) and medical order timing (ß = 0.04, P = 0.017) were significantly associated with the initial timing of antibiotic administration. CONCLUSIONS: There is an evident delay in antibiotic administration in preterm infants with suspected EOS in our unit. Severe RDS, PST postponement and delayed medical orders were found to be associated with the delayed use of antibiotics, which will be helpful for quality improvement efforts in the neonatal intensive care unit (NICU).

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.

Epidemiology and Outcomes of Neonatal Sepsis: Experience from a Tertiary Australian NICU.

INTRODUCTION: Neonatal sepsis is associated with significant mortality and morbidity. Low-middle-income countries are disproportionately affected, but late-onset sepsis (LOS) still occurs in up to 20% of infants <28 weeks in high-income countries. Understanding site-specific data is vital to guide management. METHODS: A retrospective cohort study was conducted at King Edward Memorial Hospital (KEMH), Perth. Infants admitted between January 2012 and June 2022 were included. Data were extracted from routine electronic databases. Incidence and aetiology of sepsis were determined and the association of sepsis with neonatal outcomes analysed. RESULTS: During the study period, 23,395 newborns were admitted with a median gestation of 37 weeks and birth weight of 2,800 g. There were 370 sepsis episodes in 350 infants; 102 were early-onset sepsis (EOS) (1.6 per 1,000 live births), predominantly Streptococcus agalactiae (35, 34.3%) and Escherichia coli (27, 26.5%); 268 were LOS (0.9 per 1,000 inpatient days), predominantly coagulase-negative staphylococci (CONS) (156, 57.6%) and E. coli (30, 11.1%). The incidence of LOS declined from 2012 to 2022 (p = 0.002). Infants with EOS had increased brain injury (25.7% vs. 4.1%; p = 0.002) and mortality (18.8% vs. 1.6%; p < 0.001). Those with LOS had increased hospital stay (median 95 vs. 15 days; p < 0.001), mortality (15.3% vs. 1.6%; p = 0.018), necrotising enterocolitis (NEC) (7.4% vs. 0.5%; p < 0.001), and chronic lung disease (CLD) (58.1% vs. 5.9%; p = 0.005). Infants <28 weeks with sepsis were at increased risk of neurodevelopmental impairment compared to those without infection (43.2% vs. 30.9%, p = 0.027). CONCLUSIONS: While we observed a reduction in LOS incidence, sepsis remains associated with higher mortality, and in survivors with longer hospital stay and increased risk of brain injury, NEC, CLD, and neurodevelopmental impairment.

Fetal inflammatory response syndrome predicts early-onset sepsis and cystic periventricular leukomalacia in preterm neonates: A retrospective study.

BACKGROUND: Fetal inflammatory response syndrome (FIRS), the fetal equivalent of chorioamnionitis, is associated with poorer neonatal outcomes. FIRS is diagnosed through placental histology, namely by the identification of funisitis (inflammation of the umbilical cord) and chorionic vasculitis (inflammation of fetal vessels within the chorionic plate). The aim of this study was to identify and evaluate associations between FIRS and neonatal outcomes in preterm neonates. METHODS: We performed a retrospective cohort study at a level III neonatal intensive care unit (NICU), from January 1st 2008 to December 31st 2022, involving all inborn neonates with a gestational age below 30 weeks. We compared preterm neonates based on whether their placental histology described funisitis with chorionic vasculitis (FCV) or not. RESULTS: The study included 113 preterms, 27 (23.9%) of those had FCV and 86 (76.1%) did not. After adjusting to gestational age, prolonged rupture of membranes and preeclampsia, FCV was independently associated with the development of early-onset sepsis (OR = 7.3, p = 0.021) and cystic periventricular leukomalacia (OR = 4.6, p = 0.004). CONCLUSION: The authors identified an association between FIRS and the development of early-onset sepsis and cystic periventricular leukomalacia, highlighting the importance of early detection and management of this condition in order to improve long-term neonatal outcomes.

Heart rate and oxygen saturation patterns in very low birth weight infants with early onset sepsis and histologic chorioamnionitis.

BACKGROUND: Chorioamnionitis and early onset sepsis (EOS) in very low birth weight (VLBW,< 1500 g) infants may cause a systemic inflammatory response reflected in patterns of heart rate (HR) and oxygenation measured by pulse oximetry (SpO2). Identification of these patterns might inform decisions about duration of antibiotic therapy after birth. OBJECTIVE: Compare early HR and SpO2 patterns in VLBW infants with or without early onset sepsis (EOS) or histologic chorioamnionitis (HC). STUDY DESIGN: Retrospective study of placental pathology and HR and SpO2 in the first 72 h from birth in relation to EOS status for inborn VLBW NICU patients 2012-2019. RESULT: Among 362 VLBW infants with HR and SpO2 data available, clinical, or culture-positive EOS occurred in 91/362 (25%) and HC in 81/355 (22%). In univariate analysis, EOS was associated with higher mean HR, lower mean SpO2, and less negative skewness of HR in the first 3 days after birth. HC was associated with higher standard deviation and skewness of HR but no difference in SpO2. In multivariable modeling, significant risk factors for EOS were mean HR, gestational age, HC, mean SpO2, and skewness of SpO2. CONCLUSION: HR and SpO2 patterns differ shortly after birth in VLBW infants exposed to HC or with EOS, likely reflecting a systemic inflammatory response.

Antibiotic Treatment for Well-Appearing Infants Born at ≥35 Weeks' Gestation to Mothers with Chorioamnionitis Before and After Implementation of Neonatal Early-Onset Sepsis Calculator.

Purpose: Our quality improvement study aimed to determine whether application of a neonatal early-onset sepsis calculator (NSC) among well-appearing infants born at ≥35 weeks' gestation to mothers with chorioamnionitis decreases the number of lab evaluations (LEs) and antibiotic treatments (Abxs) without missing early-onset sepsis. Methods: We compared 2 years (January 1, 2019-January 3, 2021) of data from a historical-control group before implementation of the NSC to 1 year (January 4, 2021-December 31, 2021) of data from a calculator group after implementation of the NSC to evaluate whether LE and Abx decreased following implementation of the NSC on January 4, 2021. A P-value of <0.05 was considered statistically significant for the chi-squared test, Fisher's exact test, Student's t-test, and Mann-Whitney U test used for the analyses. Results: In the historical-control group, 94% of infants received LE and Abx. Retrospective application of the NSC in the historical-control group decreased LE from 94% to 21% and Abx from 94% to 13%. In the calculator group, 14% and 5% of infants received LE and Abx, respectively, and none of the blood culture was positive. Median time from birth to antibiotic initiation was significantly longer (14.5 vs 3.8 hours; P=0.0037) with no increase in median length of stay (2.3 vs 2.4 days; P=0.02) after NSC implementation. No significant difference in neonatal intensive care unit admission was identified between groups (4% vs 1%; P=0.15). Conclusions: There was a significant decrease in LE and Abx among well-appearing infants born at ≥35 weeks' gestation to mothers with chorioamnionitis after implementation of the NSC without missing early-onset sepsis. There was no increase in neonatal intensive care unit admission or length of hospital stay in infants who received antibiotics later after they appeared equivocal or clinically ill in the calculator group. Larger prospective studies that include follow ups are needed to confirm that early-onset sepsis is not missed.

Evaluation of systemic inflammatory indices in the diagnosis of early onset neonatal sepsis in very low birth weight infants.

BACKGROUND: Previously, not six systemic inflammatory indices were evaluated in the diagnosis of early onset sepsis (EOS) in very low birth weight (VLBW, <1500g) premature infants. OBJECTIVES: We evaluated the effectiveness of systemic inflammatory indices in the diagnosis of EOS in VLBW infants. METHODS: Premature infants with birth weight <1500 g were included in the study. Six systemic inflammatory indices including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), pan-immune-inflammation value (PIV), and systemic inflammation response index (SIRI) were compared in patients with EOS (treatment group) and without EOS (control group). RESULTS: Of 917 infants enrolled, 204 infants were in the EOS group and 713 infants comprised the control group. NLR, MLR and SIRI values were significantly higher in the EOS group than in the control group (p < 0.001). The AUC value of SIRI for the predictivity of EOS was 0.803. CONCLUSIONS: The SIRI can be used together with other parameters as both an easily accessible and the reliable systemic inflammatory indices in the diagnosis of EOS in VLBW preterm infants.

Antibiotic use in infants at risk of early-onset sepsis: results from a unicentric retrospective cohort study.

BACKGROUND: Antibiotic use for early-onset sepsis represents a high percentage of antibiotic consumption in the neonatal setting. Measures to assess infants at risk of early-onset sepsis are needed to optimize antibiotic use. Our primary objective was to assess the impact of a departmental guideline on antibiotic use among term infants with suspected EOS not confirmed, in our neonatal unit. METHODS: Retrospective cohort study, to compare antibiotic use in term infants during a baseline period of January to December 2018, and a postintervention period from October 2019, to September 2020, respectively. The primary outcome was antibiotic use measured by days of therapy, the antibiotic spectrum index, the antibiotic use rate, and the length of therapy. RESULTS: We included 71 infants in the baseline period and 66 infants in the postintervention period. Compared to those in the baseline period, there was a significant reduction in overall antibiotic measures in the postintervention period, (P < 0.001). The total days of therapy/1000 patient-days decreased from 63/1000 patient-days during the baseline period to 25.8/1000 patient-days in the postintervention period, representing a relative reduction of 59%. The antibiotic use rate decreased by more than half of the infants, from 3.2% during the baseline period to 1.3% in the postintervention period. CONCLUSIONS: The use of a departmental guideline to assess infants at risk of early-onset sepsis based on their clinical condition and prompt discontinuation of antibiotics, is a simple and low-cost measure that contributed to an important decrease in antibiotic use.

Early-onset neonatal sepsis: Effectiveness of classification based on ante- and intrapartum risk factors and clinical monitoring.

INTRODUCTION: In 2017, the French public health authority HAS published new guidelines for the management of newborns at risk of early bacterial neonatal infection. These guidelines were based on ante- and intrapartum risk factors and clinical monitoring. In January 2021, we implemented a new protocol based on these guidelines in our tertiary maternity unit. OBJECTIVES: To assess the impact of the protocol implemented on neonates' antibiotic prescriptions. METHOD: An "old protocol" group comprising newborns hospitalized between July 1, 2020 and December 31, 2020, was compared to a "new protocol" group formed between January 14, 2021 and July 13, 2021. Data were collected on infectious risk factors, antibiotic prescriptions, and emergency room visits within 2 weeks for an infection or suspected infection. RESULTS: The "old protocol" population comprised 1565 children and the "new protocol" population 1513. Antibiotic therapy was prescribed for 29 newborns (1.85 %) in the old protocol group versus 15 (0.99 %) in the new one (p = 0.05). The median duration was 5 days and 2 days respectively (p = 0.08). With the new protocol, newborns in category B were about 20 times more likely (p = 0.01), and those in category C about 54 times more likely (p = 0.005) to have an infection than those classified in categories N or A. CONCLUSION: This study demonstrates that clinical monitoring criteria enable reduced use and duration of antibiotic therapy and are reliable.

Diagnostic value of maternal, cord blood and neonatal biomarkers for early-onset sepsis: a systematic review and meta-analysis.

BACKGROUND: An accurate diagnosis of early-onset sepsis (EOS) is challenging because of subtle symptoms and the lack of a good diagnostic tool, resulting in considerable antibiotic overtreatment. A biomarker, discriminating between infected and non-infected newborns at an early stage of the disease, could improve EOS prediction. Numerous biomarkers have been tested, but have never been compared directly. OBJECTIVES: We aimed to provide a comprehensive overview of early biomarkers and their diagnostic value in maternal samples, umbilical cord blood, and neonatal serum. DATA SOURCES: PubMed-Medline, EMBASE, The Cochrane Library, and Web of Science were searched up to 1 March 2023, without restrictions on publication date, population, or language. STUDY ELIGIBILITY CRITERIA: Articles describing the diagnostic value of at least one biomarker in the detection of EOS in neonates, independent of gestational age, were included. ASSESSMENT OF RISK OF BIAS: The QUADAS-2 tool was used to assess study quality. METHODS OF DATA SYNTHESIS: Three independent researchers assessed the articles using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Meta-analysis was performed with all manuscripts describing diagnostic accuracy using a random-effects model. RESULTS: Of 2296 identified articles, 171 reports were included in the systematic review and 69 in the meta-analysis. Literature showed mixed and inconsistent evidence for most biomarkers and sample types, because of a lack of a uniform EOS case definition, small sample sizes, and large heterogeneity between studies. Interesting markers were procalcitonin (pooled sensitivity 79%, 95% CI 71-84%; specificity 91%, 95% CI 83-96%, n = 11) and interleukin (IL)-6 (pooled sensitivity 83%, 95% CI 71-90%; specificity 87%, 95% CI 78-93%, n = 8) in umbilical cord blood and presepsin (pooled sensitivity 82%, 95% CI 62-93%; specificity 86%, 95% CI 73-93%, n = 3) and serum amyloid A (pooled sensitivity 92%, 95% CI 75-98%; specificity 96%, 95% CI 78-99%, n = 4) in neonatal serum. Studies on the combination of biomarkers were scarce. CONCLUSIONS: A biomarker stand-alone test is currently not reliable for direct antibiotic stewardship in newborns, although several biomarkers show promising initial results. Further research into biomarker combinations could lead to an improved EOS diagnosis, reduce antibiotic overtreatment, and prevent associated health-related problems.

Sustaining the Continued Effectiveness of an Antimicrobial Stewardship Program in Preterm Infants.

BACKGROUND: There are wide variations in antibiotic use in neonatal intensive care units (NICUs). Limited data are available on antimicrobial stewardship (AS) programs and long-term maintenance of AS interventions in preterm very-low-birth-weight (VLBW) infants. METHODS: We extended a single-centre observational study carried out in an Italian NICU. Three periods were compared: I. "baseline" (2011-2012), II. "intervention" (2016-2017), and III. "maintenance" (2020-2021). Intensive training of medical and nursing staff on AS occurred between periods I and II. AS protocols and algorithms were maintained and implemented between periods II and III. RESULTS: There were 111, 119, and 100 VLBW infants in periods I, II, and III, respectively. In the "intervention period", there was a reduction in antibiotic use, reported as days of antibiotic therapy per 1000 patient days (215 vs. 302, p < 0.01). In the "maintenance period", the number of culture-proven sepsis increased. Nevertheless, antibiotic exposure of uninfected VLBW infants was lower, while no sepsis-related deaths occurred. Our restriction was mostly directed at shortening antibiotic regimens with a policy of 48 h rule-out sepsis (median days of early empiric antibiotics: 6 vs. 3 vs. 2 in periods I, II, and III, respectively, p < 0.001). Moreover, antibiotics administered for so-called culture-negative sepsis were reduced (22% vs. 11% vs. 6%, p = 0.002), especially in infants with a birth weight between 1000 and 1499 g. CONCLUSIONS: AS is feasible in preterm VLBW infants, and antibiotic use can be safely reduced. AS interventions, namely, the shortening of antibiotic courses in uninfected infants, can be sustained over time with periodic clinical audits and daily discussion of antimicrobial therapies among staff members.

An Overview of Antibiotic Therapy for Early- and Late-Onset Neonatal Sepsis: Current Strategies and Future Prospects.

Neonatal sepsis is a clinical syndrome mainly associated with a bacterial infection leading to severe clinical manifestations that could be associated with fatal sequalae. According to the time of onset, neonatal sepsis is categorized as early- (EOS) or late-onset sepsis (LOS). Despite blood culture being the gold standard for diagnosis, it has several limitations, and early diagnosis is not immediate. Consequently, most infants who start empirical antimicrobial therapy do not have an underlying infection. Despite stewardship programs partially reduced this negative trend, in neonatology, antibiotic overuse still persists, and it is associated with several relevant problems, the first of which is the increase in antimicrobial resistance (AMR). Starting with these considerations, we performed a narrative review to summarize the main findings and the future prospects regarding antibiotics use to treat neonatal sepsis. Because of the impact on morbidity and mortality that EOS and LOS entail, it is essential to start an effective and prompt treatment as soon as possible. The use of targeted antibiotics is peremptory as soon as the pathogen in the culture is detected. Although prompt therapy is essential, it should be better assessed whether, when and how to treat neonates with antibiotics, even those at higher risk. Considering that we are certainly in the worrying era defined as the "post-antibiotic era", it is still essential and urgent to define novel strategies for the development of antibacterial compounds with new targets or mechanisms of action. A future strategy could also be to perform well-designed studies to develop innovative algorithms for improving the etiological diagnosis of infection, allowing for more personalized use of the antibiotics to treat EOS and LOS.

Early procalcitonin assays may reduce antibiotic exposure in premature newborn infants.

AIM: The diagnosis of early-onset neonatal sepsis (EOS) remains difficult. The main aim was to study the effect of a new algorithm for EOS, which includes the level of procalcitonin in umbilical cord blood, on the exposure to antibiotic therapy of premature newborn infants. METHODS: This was a monocentric, observational and retrospective study with before-and-after design. The duration and dose of antibiotic therapy provided as well as the morbidity and mortality were compared in two groups, one included 01 May 2015-30 November 2015 when procalcitonin was not used, and one after the change 01 November 2016-30 May 2017 when procalcitonin was used in a hospital setting in Nice, France. RESULTS: Sixty newborn infants were included in the before group and 54 in the after group. Antibiotic therapy was stopped after 24 h for 18 newborn infants in the after group and four in the before group, and after 48 h for 26 newborn infants in the after group and 10 in the before group. CONCLUSION: The implementation of a new decision-making algorithm including early procalcitonin assay of premature newborn infants significantly reduced exposure to antibiotics without modifying mortality or morbidity.

Does perinatal management have the potential to reduce the risk of intraventricular hemorrhage in preterm infants?

Background: Intraventricular hemorrhage (IVH) is an important cause of neurodevelopmental impairment in preterm infants. A number of risk factors for IVH have already been proposed; however, some controversies regarding optimal perinatal management persist. This study aimed to identify perinatal and neonatal attributes associated with IVH in a representative population of preterm infants. Methods: Perinatal data on 1,279 very preterm infants (<32 weeks of gestation) admitted to a tertiary neonatal intensive care unit were analyzed. The records were assessed using univariate analysis and logistic regression model to evaluate the risk factors for any and high-grade IVH (grade III-IV according to the classification by Papile) within the first week after birth. Results: The incidence of any IVH was 14.3% (183/1,279); the rate of low-grade (I-II) and high-grade (III-IV) IVH was 9.0% (115/1,279) and 5.3% (68/1,279), respectively. Univariate analysis revealed multiple factors significantly associated with intraventricular hemorrhage: lower gestational age and birth weight, absence of antenatal steroids, vaginal delivery, low Apgar score at 5 min, delivery room intubation, surfactant administration, high frequency oscillation, pulmonary hypertension, pulmonary hemorrhage, tension pneumothorax, persistent ductus arteriosus, hypotension and early onset sepsis. Logistic regression confirmed lower gestational age, vaginal delivery, ductus arteriosus and early onset sepsis to be independent predictors for any IVH. Pulmonary hemorrhage, tension pneumothorax and early onset sepsis were independent risk factors for high-grade IVH. Complete course of antenatal steroids was associated with a lower risk for any (odds ratio 0.58, 95% confidence interval 0.39-0.85; P = .006) and for high-grade intraventricular hemorrhage (odds ratio 0.36, 95% confidence interval 0.20-0.65; P < .001). Conclusion: The use of antenatal steroids and mode of delivery are crucial in the prevention of IVH; however, our study did not confirm the protective effect of placental transfusion. Severe respiratory insufficiency and circulatory instability remain to be powerful contributors to the development of IVH. Early detection and management of perinatal infection may also help to reduce the rate of brain injury and improve neurodevelopment in high-risk newborns.

Application of Advanced Molecular Methods to Study Early-Onset Neonatal Sepsis.

Early-onset sepsis (EOS) is a global health issue, considered one of the primary causes of neonatal mortality. Diagnosis of EOS is challenging because its clinical signs are nonspecific, and blood culture, which is the current gold-standard diagnostic tool, has low sensitivity. Commonly used biomarkers for sepsis diagnosis, including C-reactive protein, procalcitonin, and interleukin-6, lack specificity for infection. Due to the disadvantages of blood culture and other common biomarkers, ongoing efforts are directed towards identifying innovative molecular approaches to diagnose neonates at risk of sepsis. This review aims to gather knowledge and recent research on these emerging molecular methods. PCR-based techniques and unrestricted techniques based on 16S rRNA sequencing and 16S-23S rRNA gene interspace region sequencing offer several advantages. Despite their potential, these approaches are not able to replace blood cultures due to several limitations; however, they may prove valuable as complementary tests in neonatal sepsis diagnosis. Several microRNAs have been evaluated and have been proposed as diagnostic biomarkers in EOS. T2 magnetic resonance and bioinformatic analysis have proposed potential biomarkers of neonatal sepsis, though further studies are essential to validate these findings.

Effect of Serial Clinical Observation Complemented by Point-of-Care Blood Culture Volume Verification on Antibiotic Exposure in Newborns.

Objective. This study evaluated the effects of serial clinical observation strategy complemented by point-of-care verification of blood culture volume in managing term and near-term newborns at risk for early-onset sepsis. Methods. We used a "before-and-after" approach. Infants born at ≥35 0/7 weeks' gestation were eligible. Our strategy was based on serial clinical observation complemented with point-of-care verification of blood culture volume. Two separate 12-month periods were analyzed. The number of infants exposed to antibiotics started during the first 3 days of life was compared before and after introducing the strategy. Results. During the post-intervention period, 0.6% of infants received antibiotic therapy, compared to 4.1% during the pre-intervention period (P < .001; relative risk [RR]: 0.15; 95% CI: 0.08-0.28). Conclusion. Serial clinical observation complemented with verification of blood culture volume might reduce antibiotic utilization in newborns in the early postnatal period.