The Impact of Environmental and Genetic Factors on Neonatal Late-Onset Sepsis

Abstract This study aimed to determine the effect of late-onset sepsis (LOS) on the development of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. A prospective cohort study was performed using data collected from 64 centres registered in the Korean national registry. LOS was defined as a positive blood culture and antibiotics treatment after 72 hours of life and prior to 36 weeks postmenstrual age (PMA). Data on the causative organisms were collected and analysed for respiratory outcomes. Among the 1,434 ELBW infants who survived to 36 weeks PMA, 481 (34%) developed LOS caused by bacteria (n = 405), fungi (n = 28), or both (n = 48). The incidence of BPD was significantly associated with LOS in both the entire cohort and the propensity score-matched cohort. Two or more LOS episodes were a risk factor for BPD. The impact of multiple episodes of LOS on BPD was prominent in infants who received mechanical ventilation for two weeks or less. The estimated odds ratios for BPD and severe BPD were greater with fungal LOS than with bacterial LOS. In conclusion, LOS, particularly complicated by multiple episodes and/or fungi, was a risk factor for BPD in ELBW infants.

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Cloxacillin versus vancomycin for presumed late-onset sepsis in the Neonatal Intensive Care Unit and the impact upon outcome of coagulase negative staphylococcal bacteremia: a retrospective cohort study

BMC Pediatrics ◽

10.1186/1471-2431-5-49 ◽

2005 ◽

Vol 5 (1) ◽

Cited By ~ 40

Author(s):

Sarah L Lawrence ◽

Virginia Roth ◽

Robert Slinger ◽

Baldwin Toye ◽

Isabelle Gaboury ◽

...

Keyword(s):

Intensive Care Unit ◽

Cohort Study ◽

Intensive Care ◽

Neonatal Intensive Care Unit ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Neonatal Intensive Care ◽

Late Onset ◽

Late Onset Sepsis ◽

The Impact

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Lactoferrin impact on gut microbiota in preterm infants with late-onset sepsis or necrotising enterocolitis: the MAGPIE mechanisms of action study

Efficacy and Mechanism Evaluation ◽

10.3310/eme08140 ◽

2021 ◽

Vol 8 (14) ◽

pp. 1-88

Author(s):

Nicholas Embleton ◽

Janet Berrington ◽

Stephen Cummings ◽

Jon Dorling ◽

Andrew Ewer ◽

...

Keyword(s):

Mass Spectrometry ◽

Liquid Chromatography ◽

Preterm Infants ◽

Late Onset ◽

Disease Onset ◽

Necrotising Enterocolitis ◽

Liquid Chromatography Mass Spectrometry ◽

Chromatography Mass Spectrometry ◽

Late Onset Sepsis ◽

The Impact

Background Preterm infants have high rates of morbidity, especially from late-onset sepsis and necrotising enterocolitis. Lactoferrin is an anti-infective milk protein that may act through effects on gut bacteria, metabolites and epithelial cell function. The impact of supplemental lactoferrin in reducing late-onset sepsis was explored in the Enteral LactoFerrin In Neonates (ELFIN) trial. Objectives The Mechanisms Affecting the Gut of Preterm Infants in Enteral feeding (MAGPIE) study was nested within the ELFIN trial and aimed to determine the impact of lactoferrin on gut microbiota and bacterial function, and changes preceding disease onset. We aimed to explore impacts on the stool bacteria and faecal/urinary metabolome using gas and liquid chromatography–mass spectrometry, and explore immunohistological pathways in resected tissue. Methods Preterm infants from 12 NHS hospitals were enrolled in the study, and daily stool and urine samples were collected. Local sample collection data were combined with ELFIN trial data from the National Perinatal Epidemiology Unit, Oxford. The longitudinal impact of lactoferrin in healthy infants was determined, and samples that were collected before disease onset were matched with samples from healthy control infants. Established, quality-controlled 16S ribonucleic acid, gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses were conducted. Validated databases and standardised workflows were used to identify bacteria and metabolites. Tissue samples from infants undergoing surgery and matched controls were analysed. Results We recruited 479 preterm infants (mean gestation of 28.4 ± 2.3 weeks) and collected > 33,000 usable samples from 467 infants. 16S ribonucleic acid bacterial analysis was conducted on samples from 201 infants, of whom 20 had necrotising enterocolitis and 51 had late-onset sepsis, along with samples from healthy matched controls to explore longitudinal changes. The greatest change in relative bacterial abundance over time was observed in Staphylococcus, which decreased from 42% at aged 7–9 days to only 2% at aged 30–60 days (p < 0.001). Small but significant differences in community composition were observed between samples in each ELFIN trial group (R 2 = 0.005; p = 0.04). Staphylococcus (p < 0.01), Haemophilus (p < 0.01) and Lactobacillus (p = 0.01) showed greater mean relative abundance in the placebo group than in the lactoferrin group. Gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses showed that lactoferrin had limited impact on the metabolome. Liquid chromatography–mass spectrometry showed significant metabolite differences between necrotising enterocolitis or late-onset sepsis infants and healthy controls. The resected gut tissue analysis revealed 82 differentially expressed genes between healthy and necrotic tissue. Limitations Although we recruited a large number of infants, collecting daily samples from every infant is challenging, especially in the few days immediately preceding disease onset. Conclusion We conducted a large mechanistic study across multiple hospital sites and showed that, although lactoferrin significantly decreased the level of Staphylococcus and other key pathogens, the impact was smaller than those of other clinical variables. Immunohistochemistry identified multiple inflammatory pathways leading to necrotising enterocolitis and showed that the use of NHS pathology archive tissue is feasible in the context of a randomised controlled trial. Future work We observed significant changes in the stool and urinary metabolome in cases preceding late-onset sepsis or necrotising enterocolitis, which provide metabolic targets for a future mechanistic and biomarker study. Trial registration Current Controlled Trials ISRCTN12554594. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 14. See the NIHR Journals Library website for further project information.

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Filling the Gaps: Current Research Directions for a Rational Use of Probiotics in Preterm Infants

Nutrients ◽

10.3390/nu10101472 ◽

2018 ◽

Vol 10 (10) ◽

pp. 1472 ◽

Cited By ~ 14

Author(s):

Arianna Aceti ◽

Isadora Beghetti ◽

Luca Maggio ◽

Silvia Martini ◽

Giacomo Faldella ◽

...

Keyword(s):

Preterm Infants ◽

Very Low Birth Weight ◽

Late Onset ◽

Future Research ◽

Low Birth Weight Infants ◽

Single Strain ◽

Safety Issues ◽

Long Term Effect ◽

Late Onset Sepsis ◽

The Impact

The use of probiotics among very low-birth-weight infants is constantly increasing, as probiotics are believed to reduce the incidence of severe diseases such as necrotizing enterocolitis and late-onset sepsis and to improve feeding tolerance. However, despite the enthusiasm towards these products in neonatal medicine, theoretical knowledge and clinical applications still need to be improved. The purpose of this review is to give an overview of the most important gaps in the current literature about potential uses of probiotics in preterm infants, highlighting promising directions for future research. Specifically, further well-designed studies should aim at clarifying the impact of the type of feeding (mother’s milk, donor milk, and formula) on the relationship between probiotic supplementation and clinical outcome. Moreover, future research is needed to provide solid evidence about the potential greater efficacy of multi-strain probiotics compared to single-strain products. Safety issues should also be addressed properly, by exploring the potential of paraprobiotics and risks connected to antibiotic resistance in preterm infants. Last, in light of increasing commercial and public interests, the long-term effect of routine consumption of probiotics in such a vulnerable population should be also evaluated.

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Ductal ligation timing and neonatal outcomes: a 12-year bicentric comparison

European Journal of Pediatrics ◽

10.1007/s00431-021-04004-3 ◽

2021 ◽

Author(s):

Silvia Martini ◽

Silvia Galletti ◽

Wilf Kelsall ◽

Emanuela Angeli ◽

Marta Agulli ◽

...

Keyword(s):

Multivariate Analysis ◽

Cardiac Surgery ◽

Late Onset ◽

Postoperative Mortality ◽

Cost Benefit ◽

Neonatal Outcomes ◽

Late Onset Sepsis ◽

Extremely Preterm ◽

Pda Ligation ◽

The Impact

AbstractPatent ductus arteriosus (PDA) is common among extremely preterm infants. In selected cases, surgical PDA ligation may be required. The timing for PDA ligation may depend upon a variety of factors, with potential clinical implications. We aimed to investigate the impact of different surgical PDA managements on ligation timing and neonatal outcomes. Inborn infants < 32 weeks of gestation and < 1500 g admitted at two tertiary Neonatal Intensive Care Units that underwent PDA ligation between 2007 and 2018 were enrolled in this retrospective cohort study and split into the following groups based on their surgical management: on-site bedside PDA ligation (ONS) vs. referral to an off-site pediatric cardiac surgery (OFS). Neonatal characteristics, surgical timing, and clinical outcomes of the enrolled infants were compared between the groups. Multivariate analysis was performed to evaluate the impact of PDA ligation timing on significantly different outcomes. Seventy-eight neonates (ONS, n = 39; OFS, n = 39) were included. Infants in the ONS group underwent PDA ligation significantly earlier than those in the OFS group (median age 12 vs. 36 days, p < 0.001) with no increase in postoperative mortality and complications. The multivariate analysis revealed a significant association between PDA ligation timing, late-onset sepsis prevalence (OR 1.045, 0.032), and oxygen need at discharge (OR 1.037, p = 0.025).Conclusions: Compared with off-site surgery, on-site bedside ligation allows an earlier surgical closure of PDA, with no apparent increase in mortality or complications. Earlier PDA ligation may contribute to reduced rates of late-onset sepsis and post-discharge home oxygen therapy, with possible cost-benefit implications. What is known:• Ineffective or contraindicated pharmacological closure of a hemodynamically significant PDA may require a surgical ligation.• Available literature comparing the effect of early vs. late PDA ligation on the main neonatal morbidities has yield contrasting results. What is new:• The availability of a cardiac surgery service performing bedside PDA ligation allows an earlier intervention compared to patient referral to an off-site center, with no difference in postoperative mortality and complications compared to off-site surgery.• Earlier PDA ligation was associated with a lower prevalence of late-onset sepsis and of oxygen need at discharge, with possible cost-benefit implications.

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Late-Onset Sepsis in Preterm Neonates is Associated with Higher Risks of Cerebellar Hemorrhage and Lower Motor Scores at 3 Years of Age

Oman Medical Journal ◽

10.5001/omj.2022.41 ◽

2021 ◽

Author(s):

Mais Kartam ◽

Alia Embaireeg ◽

Shahad Albalool ◽

Awrad Almesafer ◽

Majeda Hammoud ◽

...

Keyword(s):

Brain Injury ◽

Early Onset ◽

Late Onset ◽

Preterm Neonates ◽

Klebsiella Pneumonia ◽

Neurodevelopmental Outcomes ◽

Cerebellar Hemorrhage ◽

Late Onset Sepsis ◽

Early Onset Sepsis ◽

The Impact

Background: Sepsis is associated with adverse neonatal outcomes, including diffuse white matter injury (WMI) which may predispose to developmental delay. Objective: To evaluate the impact of late-onset sepsis (LOS) in preterm infants on brain injury and neurodevelopmental outcomes at 36 months corrected age (CA). Design: Retrospective cohort study. Setting: Neonatal Sepsis Registry at Neonatal Department, Al-Sabah Maternity hospital, Kuwait. Participants: A total of 203 neonates (gestational age (GA) between 24-32 weeks) were admitted between January 2017 and December 2017. Neonates were stratified into no sepsis, into early-onset sepsis (first onset of sepsis ≤72 hours postnatally), and LOS (>72 hours postnatally) 2 Main outcome: Brain injury and neurodevelopmental outcomes at 36 months CA were evaluated using Miller score and Bayley-III scales of infant development, respectively. Results: Sixteen neonates had early-onset sepsis with Klebsiella pneumonia and group-B streptococcus, and 93 developed LOS with K. pneumonia and gram-positive cocci in clusters. Intraventricular hemorrhage (n=68) and WMI (n=42) showed no group-wise differences. Higher cerebellar hemorrhage risk (adjusted odds ratio=4.6 (1.3-18.6); p=0.03) and lower motor composite scores (adjusted β=-9.5 (-16.4 to -2.7); p=0.007) were observed with LOS. Conclusions: LOS in preterm neonates is a significant risk factor predisposing to cerebellar hemorrhage and lower motor scores by three years of age.

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Screening for Third-Generation Cephalosporin-Resistant Bacteria Reduces the Incidence on Late-Onset Sepsis and Antibiotic use in Neonates

Klinische Pädiatrie ◽

10.1055/a-1128-0524 ◽

2020 ◽

Vol 232 (04) ◽

pp. 203-209 ◽

Cited By ~ 1

Author(s):

Ann Carolin Longardt ◽

Brar Piening ◽

Katharina von Weizsäcker ◽

Christof Dame ◽

Christoph Bührer ◽

...

Keyword(s):

Late Onset ◽

Antibiotic Use ◽

Generation Cephalosporin ◽

Multidrug Resistant ◽

Matched Pair ◽

Resistant Bacteria ◽

Third Generation ◽

Contact Precautions ◽

Late Onset Sepsis ◽

The Impact

Abstract Background The extensive use of antibiotics is reflected by an increasing prevalence of infections with multidrug-resistant bacteria, including third-generation cephalosporin-resistant bacteria (3GCRB). For neonatal intensive care units screening and enhanced barrier precautions are recommended to control the spread of multidrug-resistant Gram-negative bacteria, while evidence for efficacy of barrier precautions remains scarce in a non-outbreak setting. Objective To determine the impact of a screening program for maternal 3GCRB colonization and the effects of contact precautions and cohort nursing, concerning the risk of neonatal late-onset sepsis (LOS) and antibiotic use rates (AURs). Study Design In a retrospective matched-pair cohort study, data of neonates exposed to maternal 3GCRB colonization were compared with findings in non-exposed neonates. Results Of 3,144 neonates admitted, 184 neonates born to 3GCRB-positive mothers were eligible. Among them, 37 (20%) became 3GCRB positive during hospital stay. 3GCRB-exposed infants had a lower rate of LOS (6.5 vs. 14.1%, p=0.03) and lower AURs in that time period compared to controls (mean 0.009 vs. 0.025, p=0.006). When started within the first 72h after birth, days of therapy with meropenem were significantly lower in non-exposed vs. 3GCRB-exposed infants (mean 0.13 vs. 0.42; p=0.002). No invasive infections with 3GCRB occurred. Conclusions Neonates of 3GCRB-positive mothers do not have an increased a priori risk for invasive 3GCRB infection and may benefit from enhanced contact precautions measures.

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Fulminant Late-Onset Sepsis in a Neonatal Intensive Care Unit, 1988-1997, and the Impact of Avoiding Empiric Vancomycin Therapy

PEDIATRICS ◽

10.1542/peds.106.6.1387 ◽

2000 ◽

Vol 106 (6) ◽

pp. 1387-1390 ◽

Cited By ~ 128

Author(s):

M. G. Karlowicz ◽

E. S. Buescher ◽

A. E. Surka

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Neonatal Intensive Care Unit ◽

Neonatal Intensive Care ◽

Late Onset ◽

Vancomycin Therapy ◽

Late Onset Sepsis ◽

The Impact

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Growth outcomes of small for gestational age preterm infants before and after implementation of an exclusive human milk-based diet

Journal of Perinatology ◽

10.1038/s41372-021-01082-x ◽

2021 ◽

Author(s):

Lindsay Fleig ◽

Joseph Hagan ◽

Martin L. Lee ◽

Steven A. Abrams ◽

Keli M. Hawthorne ◽

...

Keyword(s):

Human Milk ◽

Preterm Infants ◽

Gestational Age ◽

Small For Gestational Age ◽

Late Onset ◽

Growth Failure ◽

Milk Diet ◽

Late Onset Sepsis ◽

Before And After ◽

The Impact

Abstract Objective Small for gestational age (SGA) preterm infants (PT) are at greatest risk for growth failure. Our objective was to assess the impact of an exclusive human milk diet (HUM) on growth velocities and neonatal morbidities from birth to discharge in a SGA population. Study design Multicenter, retrospective cohort study, subgroup analysis of SGA PT comparing a cow’s milk diet (CMD) with HUM diet. Results At birth 420 PT were classified as SGA (197 CMD group, 223 HUM group). Demographics and anthropometric measurements were similar. HUM group PT showed improvement in length Z score at discharge (p = 0.024) and reduction in necrotizing enterocolitis (NEC) (p = 0.004). Conclusion SGA PT fed a HUM diet had significantly decreased incidence of NEC, surgical NEC, and late-onset sepsis. Due to concerns about growth in a HUM diet, it is reassuring SGA infants fed the HUM diet had similar growth to CMD diet with trends toward improvement.

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