Search

Sildenafil is used to treat pulmonary hypertension in neonatal intensive care unit (NICU) settings. As multiple intravenous (IV) medications are co-administered in NICU settings, we sought to investigate the physicochemical compatibility of sildenafil with a range of IV drugs. Sildenafil 600 mcg/mL or 60 mcg/mL was mixed 1:1 with the secondary drug solution to simulate Y-site co-administration procedures. Physical compatibility was evaluated by visual observation against a black and white background and under polarized light for two hours for changes in colour, precipitation, haze and evolution of gas. Chemical compatibility was determined from sildenafil concentrations, using a validated, stability-indicating high-performance liquid chromatography assay. Sildenafil 600 mcg/mL was physicochemically compatible with 29 of the 45 drugs tested at 'high-end' clinical concentrations and physically incompatible with 16 drugs and six '2-in-1' parenteral nutrition solutions. Sildenafil 600 mcg/mL was compatible with lower, clinically relevant concentrations of calcium gluconate, heparin and hydrocortisone. Aciclovir, amoxicillin, ampicillin, ibuprofen lysine, indometacin, phenobarbitone and rifampicin were incompatible with sildenafil 600 mcg/mL, however these IV medications were compatible with sildenafil 60 mcg/mL. Sildenafil 600 mcg/mL and 60 mcg/mL were incompatible with amphotericin, flucloxacillin, furosemide, ibuprofen, meropenem and sodium bicarbonate. Sildenafil compatibility with commonly used syringe filters was also investigated. Sildenafil solution was compatible with nylon syringe filters, however, absorption/adsorption loss occurred with polyethersulfone and cellulose ester filters. [ABSTRACT FROM AUTHOR]

Background: Composition of leukocyte populations in the first month of life remains incompletely characterised, particularly in preterm infants who go on to develop late-onset sepsis (LOS). Aim: To characterise and compare leukocyte populations in preterm infants with and without LOS during the first month of life. Study design: Single-centre prospective observational cohort study. Participants: Infants born <30 weeks gestational age (GA). Outcome measures: Peripheral blood samples were collected at 1, 7, 14, 21 and 28 days of life. Leukocyte populations were characterised using 5-fluorophore-6-marker flow cytometry. Absolute leukocyte counts and frequency of total CD45+ leukocytes of each population were adjusted for GA, birth weight z-scores, sex and total leukocyte count. Results: Of 119 preterm infants enrolled, 43 (36%) had confirmed or clinical LOS, with a median onset at 13 days (range 6–26). Compared to infants without LOS, the adjusted counts and frequency of neutrophils, basophils and non-cytotoxic T lymphocytes were generally lower and immature granulocytes were higher over the first month of life in infants who developed LOS. Specific time point comparisons identified lower adjusted neutrophil counts on the first day of life in those infants who developed LOS more than a week later, compared to those without LOS, albeit levels were within the normal age-adjusted range. Non-cytotoxic T lymphocyte counts and/or frequencies were lower in infants following LOS on days 21 and 28 when compared to those who did not develop LOS. Conclusion: Changes in non-cytotoxic T lymphocytes occurred following LOS suggesting sepsis-induced immune suppression. [ABSTRACT FROM AUTHOR]

Pentoxifylline (PTX) is administered as 6- or 12-hour intravenous infusions in the treatment of sepsis or necrotizing enterocolitis in neonates; however, there is a paucity of formal stability data for PTX in the end-use solution. We investigated PTX stability in the simulated clinical conditions of neonatal intensive care, where PTX injection is diluted to 5 mg/mL and administered via syringe pump. A stability-indicating high performance liquid chromatography (HPLC) assay was established for PTX. The clinical simulation stability study comprised PTX 5 mg/mL in 20 mL syringes and was conducted at three temperatures, all protected from light: refrigerator (4°C); room temperature (22°C) and incubator/humidicrib (35°C). PTX stability also was evaluated at room temperature and exposed to light. Samples were drawn at pre-determined times over a 10 day period and stored frozen (-80°C) until assayed by HPLC. A single exponential equation was fitted to the concentration-time data to determine PTX stability. Forced degradation studies confirmed that PTX was stable at elevated temperature (up to 45°C), exposed to light and under acidic stress for up to 10 days, but subject to degradation under alkali and oxidative stress. PTX injection 5 mg/mL in 0.9% w/v sodium chloride or 5% w/v glucose was found to be stable when protected from light at 22°C and 35°C, and exposed to light at 22°C for at least 7 days. These data provide clinically relevant evidence that PTX injection is stable in the end-use, ICU/incubator clinical conditions for at least 24 hours. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the physicochemical compatibility of caffeine citrate and caffeine base injections with 43 secondary intravenous (IV) drugs used in Neonatal Intensive Care Unit (NICU) settings. Methods: Caffeine citrate (20 mg/mL or 10 mg/mL) or caffeine base injection (10 mg/mL) were mixed in a volume ratio of 1:1 with the secondary drug solution to simulate Y-site co-administration procedures in NICUs. Physical compatibility was evaluated based on visual observation for 2 h, against a black and white background and under polarised light, for changes in colour, precipitation, haze and evolution of gas. Chemical compatibility was determined from caffeine concentration measurements, using a validated high-performance liquid chromatography assay. Results: Six of the 43 secondary drugs tested (aciclovir, amphotericin (liposomal), furosemide, hydrocortisone, ibuprofen and ibuprofen lysine) were physically incompatible with caffeine citrate undiluted injection (20 mg/mL), at their high-end, clinically relevant concentrations for NICU settings. However, when tested at lower concentrations, hydrocortisone (1 mg/mL) was physicochemically compatible, whereas furosemide (0.2 mg/mL) was physically incompatible with caffeine citrate. The six drugs which showed physical incompatibility with caffeine citrate 20 mg/mL injection were also physically incompatible with caffeine citrate 10 mg/mL solution. All 43 secondary drugs tested were physicochemically compatible with caffeine base injection. Conclusions: Most secondary test drugs, except aciclovir, amphotericin (liposomal), furosemide, hydrocortisone, ibuprofen and ibuprofen lysine, were physicochemically compatible with caffeine citrate injection. Caffeine base injection was physicochemically compatible with all 43 test drugs tested. [ABSTRACT FROM AUTHOR]

Background Late-onset sepsis (LOS) with Staphylococcus epidermidis is common in preterm infants, but the immunological mechanisms underlying heightened susceptibility are poorly understood. Our aim is to characterize the ontogeny of cytokine responses to live S. epidermidis in preterm infants with and without subsequent Gram-positive LOS. Methods We conducted a prospective, observational cohort study of preterm infants (<30 weeks gestational age [GA]) with blood sampling on Days 1, 7, 14, 21, and 28 of life. Cytokine responses in peripheral whole blood stimulated with live S. epidermidis were analyzed by 11-plex immunoassay. Results Of 129 infants (mean GA, 26.2 weeks; mean birth weight, 887g), 23 (17.8%) had confirmed LOS with Gram-positive organisms and 15 (11.6%) had clinical sepsis, with median onsets at 13 and 15 days, respectively. Blood cytokine responses to an in vitro S. epidermidis challenge were similar between infected and uninfected infants on Day 1, but diverged thereafter. Infants with subsequent LOS displayed broadly reduced S. epidermidis– induced responses from Day 7 onwards, compared to those who did not develop LOS. This pattern was observed with chemokines (interleukin [IL]-8, monocyte chemotactic protein–1, and macrophage inflammatory protein–1α), pro-inflammatory cytokines (IL-1, IL-6, and tumor necrosis factor–α) and the regulatory cytokine IL-10. Conclusions Cytokine responses to a live S. epidermidis challenge are impaired in infants with LOS and precede the onset of clinical illness. Quantifying pathogen-specific cytokine responses at Day 7 may identify those high-risk preterm infants at the greatest risk of LOS, and prospective replication is warranted. [ABSTRACT FROM AUTHOR]

Background: Preterm infants are at a high risk of developing late-onset sepsis (LOS). Lactoferrin is one of the most abundant endogenous antimicrobial proteins expressed in breast milk, stools, and blood, and a candidate for preventive intervention. Large clinical trials have recently investigated whether enteral supplementation with bovine lactoferrin reduces LOS. Aim: To characterize lactoferrin levels in preterm infants with and without LOS during the first month of life. Methods: Very preterm and term infants were recruited and serial biosamples collected during the first month of life. Lactoferrin levels were determined by immunoassay in cord blood and peripheral blood on days 1, 7, 14, 21, and 28; in the stools on days 1 and 28; and in the mother's breast milk on days 7 and 21. Furthermore, we assessed the capacity of the peripheral blood to release lactoferrin in response to an in vitro challenge with live Staphylococcus epidermidis, lipopolysaccharide, and fibroblast-stimulating lipopeptide 1. Results: Plasma lactoferrin levels were higher in cord blood and day 1 peripheral blood and declined during the first month of life. Plasma lactoferrin levels were similar in term infants and in preterm infants with (n = 32) and without LOS (n = 53). S. epidermidis-induced lactoferrin levels were lower following the sepsis episode. Conclusions: Endogenous lactoferrin expression in preterm infants does not appear to affect their risk of developing LOS. These findings are in line with the lack of benefit recently observed in large trials of enteral supplementation with bovine lactoferrin to prevent LOS. [ABSTRACT FROM AUTHOR]

Background: Host immune responses during late-onset sepsis (LOS) in very preterm infants are poorly characterised due to a complex and dynamic pathophysiology and challenges in working with small available blood volumes. We present here an unbiased transcriptomic analysis of whole peripheral blood from very preterm infants at the time of LOS. Methods: RNA-Seq was performed on peripheral blood samples (6–29 days postnatal age) taken at the time of suspected LOS from very preterm infants <30 weeks gestational age. Infants were classified based on blood culture positivity and elevated C-reactive protein concentrations as having confirmed LOS (n = 5), possible LOS (n = 4) or no LOS (n = 9). Bioinformatics and statistical analyses performed included pathway over-representation and protein-protein interaction network analyses. Plasma cytokine immunoassays were performed to validate differentially expressed cytokine pathways. Results: The blood leukocyte transcriptional responses of infants with confirmed LOS differed significantly from infants without LOS (1,317 differentially expressed genes). However, infants with possible LOS could not be distinguished from infants with no LOS or confirmed LOS. Transcriptional alterations associated with LOS included genes involved in pathogen recognition (mainly TLR pathways), cytokine signalling (both pro-inflammatory and inhibitory responses), immune and haematological regulation (including cell death pathways), and metabolism (altered cholesterol biosynthesis). At the transcriptional-level cytokine responses during LOS were characterised by over-representation of IFN-α/β, IFN-γ, IL-1 and IL-6 signalling pathways and up-regulation of genes for inflammatory responses. Infants with confirmed LOS had significantly higher levels of IL-1α and IL-6 in their plasma. Conclusions: Blood responses in very preterm infants with LOS are characterised by altered host immune responses that appear to reflect unbalanced immuno-metabolic homeostasis. [ABSTRACT FROM AUTHOR]

Introduction: Deficiencies in innate immune responses may contribute to the increased susceptibility to infection in preterm infants. In vivo cytokine profiles in response to sepsis in very preterm infants are not fully understood. Aims: To characterise plasma pro- and anti-inflammatory cytokine concentrations and pre-defined ratios in very preterm infants with late-onset sepsis (LOS). Methods: In this observational study, peripheral blood samples were collected at the time of evaluation for suspected LOS from 31 preterm infants (<30 weeks gestational age). Plasma cytokine concentrations were determined by 12-plex immunoassay. Results: IL-10, IFN-γ, IL-12p70, IP-10, IL-6 and CCL2 were elevated in the majority infants with LOS (n = 12) compared to those without LOS (n = 19). There was no difference in TNF-α, IL-1β, IL-17AF, IL-8 and IL-15 concentrations between groups. IL-10/TNF-α ratios were increased, while CCL2/IL-10 and IL-12p70/IL-10 ratios were decreased in infants with LOS compared to those without. Conclusion: Very preterm infants have a marked innate inflammatory response at the time of LOS. The increase in IL-10/TNF-α ratio may indicate early immune hypo-responsiveness. Longitudinal studies with a larger number of participants are required to understand immune responses and clinical outcomes following LOS in preterm infants. [ABSTRACT FROM AUTHOR]

Our objective was to establish and test a machine learning‐based screening process that would be applicable to systematic reviews in pharmaceutical sciences. We used the SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type) model, a broad search strategy, and a machine learning tool (Research Screener) to identify relevant references related to y‐site compatibility of 95 intravenous drugs used in neonatal intensive care settings. Two independent reviewers conducted pilot studies, including manual screening and evaluation of Research Screener, and used the kappa‐coefficient for inter‐reviewer reliability. After initial deduplication of the search strategy results, 27 597 references were available for screening. Research Screener excluded 1735 references, including 451 duplicate titles and 1269 reports with no abstract/title, which were manually screened. The remainder (25 862) were subject to the machine learning screening process. All eligible articles for the systematic review were extracted from <10% of the references available for screening. Moderate inter‐reviewer reliability was achieved, with kappa‐coefficient ≥0.75. Overall, 324 references were subject to full‐text reading and 118 were deemed relevant for the systematic review. Our study showed that a broad search strategy to optimize the literature captured for systematic reviews can be efficiently screened by the semi‐automated machine learning tool, Research Screener. [ABSTRACT FROM AUTHOR]

Supplementation with probiotics in preterm infants reduces necrotizing enterocolitis and sepsis. Bovine lactoferrin is a promising supplement that may further reduce disease burden, but its effects on probiotic bacteria in human breast milk has not been evaluated. We aimed to characterise the antimicrobial activity of bovine and human lactoferrin in human breast milk against probiotics and typical neonatal sepsis pathogens. Lactoferrin levels were determined by enzyme linked immunosorbent assay in fresh and pasteurised human breast milk. The neonatal pathogens Staphylococcus epidermidis and Escherichia coli, and the probiotic Bifidobacterium breve strain M-16V were cultured in human breast milk or infant formula in the presence or absence of clinically relevant doses of bovine or human lactoferrin. Standard microbiological methods were used to determine the effects of lactoferrin on bacterial growth. Unpasteurised human breast milk contained significantly higher lactoferrin levels and resulted in superior inhibition of pathogenic bacterial growth compared to infant formula and pasteurised human breast milk. Human lactoferrin was significantly more effective at inhibiting bacterial growth, when compared to bovine lactoferrin. Supplementation with human lactoferrin or high dose bovine lactoferrin inhibited growth of the probiotic strain B. breve M-16V in pasteurised human breast milk. Although unpasteurised human breast milk and human lactoferrin had the greatest antimicrobial activity against all bacterial species tested, higher doses of bovine lactoferrin also showed activity against B. breve and. S. epidermidis. This study suggests that simultaneous administration of lactoferrins and probiotics may affect colonisation with probiotic bacteria, warranting further investigations. [ABSTRACT FROM AUTHOR]

The most abundant fatty acid ester in coconut oil, monolaurin (glycerol 1-monolaurate), has well-documented antimicrobial activity, but this has not been tested systematically against neonatal pathogens [[3]]. Here, we demonstrate that topical co-conut oil increases plasma levels of monolaurin, and that this fatty acid ester, in concentrations present in coconut oil applied topically (~280 µg•mL SP -1 sp ), is highly active against prototypical gram-positive late-onset sepsis pathogens such as I S. epidermidis i and I S. aureus i as well as I C. albicans i . [Extracted from the article]

Background: Early-onset sepsis (EOS) is a potentially fatal condition that affects about 0.3–0.8/1,000 infants born at ≥35 weeks’ gestation in developed countries. Current EOS management algorithms result in 8–15% of infants receiving antibiotics for suspected sepsis. The Neonatal Sepsis Calculator provides evidence-based estimates of individual sepsis risk, but data on its clinical application is limited. Objectives: To evaluate the feasibility, safety, and effect on the newborn infants that were investigated and that received antibiotic treatment for suspected EOS following the introduction of the Neonatal Sepsis Calculator. Methods: This was a prospective, observational, single-centre cohort study comparing the rates of newborn infants born at ≥35 weeks’ gestation requiring evaluation and/or treatment for suspected EOS in a large tertiary perinatal centre before versus after the prospective introduction of the Neonatal Sepsis Calculator (Epoch 1: October 2014 to January 2015 vs. Epoch 2: July to December 2016). Results: There were 1,732 and 2,502 eligible infants born during Epochs 1 and 2, respectively. Of these, 425 (24.2%) and 530 (21.2%), respectively, were admitted to the neonatal unit. The proportion of infants investigated for sepsis decreased from 15.2 to 11.1%, and that of infants treated with antibiotics from 12.0 to 7.6%. One case of EOS occurred during each Epoch. Conclusions: The implementation of the Neonatal Sepsis Calculator was feasible and safe in our unit. Application of this clinical decision support tool may reduce the number of infants undergoing investigations and empirical treatment for suspected EOS. [ABSTRACT FROM AUTHOR]

Background: The immature fragile skin of preterm infants represents an inadequate protective barrier. The emollient and anti-infective properties of coconut oil make it a potentially beneficial topical agent for this population. Objectives: Our aim was to evaluate feasibility, safety, and the effects of topical coconut oil on skin condition in very preterm infants. Methods: An open-label randomised controlled trial in preterm infants <30 weeks' gestation was conducted. Enrolled infants were randomised to receive either routine care or topical coconut oil (5 mL/kg) twice daily for 21 days, starting within 24 h of birth. The neonatal skin condition was the primary outcome, and was assessed using the Neonatal Skin Condition Score (NSCS) on days 1, 7, 14, and 21. The number of coconut oil applications was recorded to assess clinical feasibility and all enrolled infants were monitored for adverse effects of topical coconut application, such as skin irritation. Results: A total of 72 infants born <30 weeks' gestation were enrolled (36 infants per arm), with comparable demographic characteristics. Topical application of coconut oil was feasible and without adverse effects. The NSCS was maintained in the coconut oil group throughout the intervention period, but deteriorated from a median (IQR) of 3 (3-4) on day 1 to 4 (4-4) on day 21 in the control group (p = 0.01). There were no differences in common neonatal outcomes, including sepsis, necrotising enterocolitis, retinopathy of prematurity, chronic lung disease, and mortality. Conclusions: Topical coconut oil maintained a better skin condition in very preterm infants without adverse effects. This simple, safe, and affordable intervention warrants further investigation. [ABSTRACT FROM AUTHOR]

Advances in bioanalytical methods are facilitating micro-volume and dried blood spot (DBS) analysis of drugs in biological matrices for pharmacokinetic studies in children and neonates. We sought to develop a UPLC–MS/MS assay for simultaneous measurement of caffeine, pentoxifylline (PTX) and three metabolites of PTX in both plasma and DBS. Caffeine, PTX, the metabolites M1 (lisofylline), M4 and M5, and the internal standards (caffeine-d 9 and PTX-d 6 ) were separated using a Waters Aquity T3 UPLC C 18 column and gradient mobile phase (water-methanol-formic acid). Retention times for caffeine, M5, M4, PTX and M1 were 1.6, 1.7, 1.9, 2.0 and 2.1 min, respectively, with a run time of 5 min. The precision (≤10%) and accuracy (≤15%) across the concentration range 0.1–50 mg/L for caffeine, PTX and the three metabolites in plasma and DBS were within accepted limits, as were the limits of quantification (100 μg/L for caffeine and 10 μg/L for PTX, M1, M4 and M5). Caffeine, PTX and the metabolites were stable in DBS for >34 days at room and refrigerated temperatures. Plasma and DBS samples were obtained from 24 preterm infants recruited into a clinical pharmacokinetic study of PTX. Paired analysis indicated that DBS concentrations were 9% lower than concurrent plasma concentrations for caffeine, 7% lower for PTX (consistent with the blood:plasma ratio) and 13% lower for M1 (lisofylline). The validated UPLC–MS/MS method is suitable for micro-volume plasma and DBS analysis of caffeine, PTX and its metabolites for pharmacokinetic studies in paediatric patients. [ABSTRACT FROM AUTHOR]

Aim: To characterise the secreted and inducible antimicrobial protein and peptide (APP) levels in a prospective cohort of preterm infants (<30 weeks gestational age) with or without Bifidobacterium breve M16V supplementation during the first month of life.Methods: We analysed serial biosamples of infants who did (n = 13) or did not receive (n = 62) B. breve (3 × 109 cfu/day). Peripheral blood was obtained on days 1, 14 and 28, and infant stool prior to commencement of probiotic supplementation and on day 21. Levels of APP (bactericidal/permeability inducing protein (BPI), beta defensins 1 and 2, lactoferrin, human cathelicidin, secretory phospholipase A2) in plasma and stool were determined. Further, we characterised induced APP levels in whole blood cultured with live S. epidermidis or with agonists of Toll-like receptors 2/6 and 4.Results: Stool, plasma and stimulated blood APP levels changed significantly during the first month of life. Supplementation with B. breve did not affect basal or stimulated APP levels except for a transient increase in inducible BPI.Conclusion: Supplementation with B. breve does not appear to act via modulation of systemic or enteric APP expression in preterm infants although small effects cannot be excluded. Further work with other probiotic preparations is warranted. [ABSTRACT FROM AUTHOR]

Objective: We investigated the levels and antimicrobial activity of antimicrobial proteins and peptides (AMPs) in breast milk consumed by preterm infants, and whether deficiencies of these factors were associated with late-onset neonatal sepsis (LOS), a bacterial infection that frequently occurs in preterm infants in the neonatal period. Study design: Breast milk from mothers of preterm infants (≤32 weeks gestation) was collected on days 7 (n = 88) and 21 (n = 77) postpartum. Concentrations of lactoferrin, LL-37, beta-defensins 1 and 2, and alpha-defensin 5 were measured by enzyme-linked immunosorbent assay. The antimicrobial activity of breast milk samples against Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, and Streptococcus agalactiae was compared to the activity of infant formula, alone or supplemented with physiological levels of AMPs. Samples of breast milk fed to infants with and without subsequent LOS were compared for levels of AMPs and inhibition of bacterial growth. Results: Levels of most AMPs and antibacterial activity in preterm breast milk were higher at day 7 than at day 21. Lactoferrin was the only AMP that limited pathogen growth >50% when added to formula at a concentration equivalent to that present in breast milk. Levels of AMPs were similar in the breast milk fed to infants with and without LOS, however, infants who developed LOS consumed significantly less breast milk and lower doses of milk AMPs than those who were free from LOS. Conclusions: The concentrations of lactoferrin and defensins in preterm breast milk have antimicrobial activity against common neonatal pathogens. [ABSTRACT FROM AUTHOR]

Preterm birth and infectious diseases are the most common causes of neonatal and early childhood deaths worldwide. The rates of preterm birth have increased over recent decades and account for 11% of all births worldwide. Preterm infants are at significant risk of severe infection in early life and throughout childhood. Bacteraemia, inflammation, or both during the neonatal period in preterm infants is associated with adverse outcomes, including death, chronic lung disease, and neurodevelopmental impairment. Recent studies suggest that bacteraemia could trigger cerebral injury even without penetration of viable bacteria into the CNS. Here we review available evidence that supports the concept of a strong association between bacteraemia, inflammation, and cerebral injury in preterm infants, with an emphasis on the underlying biological mechanisms, clinical correlates, and translational opportunities. [ABSTRACT FROM AUTHOR]

Aim To evaluate mononuclear cell expression and function of the cytosolic nucleotide-binding oligomerization domain-containing receptors, NOD1 and NOD2, in very preterm and full-term infants. Methods NOD1 and NOD2 gene and protein expression in very preterm infants, term infants and healthy adult, cord and peripheral blood mononuclear cells (C/ PBMC) were quantified using q PCR and flow cytometry. Cytokine responses of purified infant and adult monocytes to NOD1- and NOD2-specific agonists were assessed using a multiplex immunoassay (Bioplex). Results NOD1 and NOD2 were expressed by a range of infant and adult mononuclear cell types, including T- and B cells, with highest expression in classical ( CD14++ CD16−) and intermediate ( CD14++ CD16+) monocytes. NOD1 and NOD2 expression levels by monocytes from very preterm infant were similar to those in term infants or adults. Monocyte production of TNF α, IL-6 and IL-1 β induced by activation of NOD1 and NOD2 was similar between very preterm infants, term infants and adults. Conclusion Monocyte expression and function of NOD1 and NOD2 in very preterm infants are intact and comparable/equivalent to term infants and adults. Functional deficiencies in monocyte NOD signalling pathways are unlikely to contribute to the increased susceptibility to bacterial sepsis in preterm infants. [ABSTRACT FROM AUTHOR]

Background:In vitro investigations of human innate immune responses to extracellular bacteria commonly utilise killed preparations in preference to live organisms. The effects of the bacterial preparation method on the activation of innate signalling pathways by the common opportunistic pathogen Staphylococcus epidermidis (SE) are unknown.Materials and methods: Mononuclear cell cytokine expression patterns induced by live (LSE), heat-killed (HKSE) and ethanol-killed SE (EKSE) were characterized at the transcriptional and translational level. Toll-like receptor (TLR)-activating capacity of the preparations was analysed using TLR-transfected human embryonic kidney cells.Results: Live SE activated NF-κB, STAT1, type I interferon, and inflammasome pathways. Killed preparations engaged the NF-κB pathway, but had significantly lower capacity to activate other innate immune pathways.Conclusions: Killing of extracellular bacteria has significant qualitative and quantitative effects on key aspects of innate responses in vitro. Interpretation of in vitro data and extrapolation of findings should take into account the potential effects of bacterial preparation and should not assume that responses to killed bacteria are predictive of responses to live organisms. [ABSTRACT FROM PUBLISHER]

Neonates, particularly those born prematurely, are exquisitely vulnerable to life-threatening infections. This increased susceptibility to infection is maintained into childhood. Despite the considerable human and economic cost of infection-related neonatal morbidity and mortality, the mechanisms underlying this heightened susceptibility are only partly understood. It is increasingly recognised that innate immune responses are key to the protection against infection early in life, and emerging data suggest that such responses are deficient in the newborn and especially in preterm infants. Here we review the current understanding of the maturation of the innate immune response in human neonates highlighting the clinical relevance and possible avenues for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: Staphylococcus epidermidis (SE) is a nosocomial pathogen that causes catheter-associated bacteremia in the immunocompromised, including those at the extremes of age, motivating study of host clearance mechanisms. SE-derived soluble components engage TLR2; but additional signaling pathways have also been implicated, and TLR2 can play complex, at times detrimental, roles in host defense against other Staphylococcal spp. The role of TLR2 in responses of primary blood leukocytes to live SE and in clearance of SE bacteremia, the most common clinical manifestation of SE infection, is unknown. Methodology/Principal Findings: We studied TLR2-mediated recognition of live clinical SE strain 1457 employing TLR2- transfected cells, neutralizing anti-TLR antibodies and TLR2-deficient mice. TLR2 mediated SE-induced cytokine production in human embryonic kidney cells, human whole blood and murine primary macrophages, in part via recognition of a soluble TLR2 agonist. After i.v. challenge with SE, early (1 h) cytokine/chemokine production and subsequent clearance of bacteremia (24–48 h) were markedly impaired in TLR2-deficient mice. Conclusions/Significance: TLR2 mediates recognition of live SE and clearance of SE bacteremia in vivo. [ABSTRACT FROM AUTHOR]

Background: Erythropoietin (Epo) was originally defined as a hematopoietic growth factor, but also has potent tissue-protective properties. The cytokine-modulating actions of Epo have received scant attention. We hypothesized that Epo significantly influences the in vitro cytokine production in both neonates and adults. Methods: The effects of Epo were investigated using a standardized in vitro whole blood assay. Production of various cytokines was assessed by means of intracellular cytokine detection (IL-2, -6, -8, IFN-γ and TNF-α) in preterm infants, term neonates and adults. Furthermore, synthesis of IL-4, -5 and -10 in adults was investigated via cytometric bead array. Results: Epo significantly inhibits the production of various cytokines in preterm infants, term neonates and adults. In CD3+ lymphocytes, Epo predominantly decreases the number of IL-2-positive cells in all age groups. Similarly, in CD14+ cells, Epo significantly diminishes the number of IL-6- and TNF-α-producing cells. Furthermore, Epo significantly inhibits the synthesis of IL-4, IL-5 and IL-10 in adults. Conclusion: rhEpo has significant inhibitory potential on the production of various cytokines by leukocytes in preterm and term infants as well as in adults. The described effect likely contributes to the tissue protective properties of Epo. [ABSTRACT FROM AUTHOR]

An association between early-onset neonatal Group B streptococcal (GBS) sepsis and subsequent diagnosis of late-onset diaphragmatic hernia has been reported. We report one such case and review the literature. The index case involved a male preterm neonate in whom late-onset right diaphragmatic was diagnosed on day 21 following early-onset GBS sepsis. Our literature review identified 40 cases of such an association. The typical description involves near term male neonates, who improved from an early-onset GBS sepsis only to have a secondary respiratory deterioration leading to the diagnosis of late-onset right diaphragmatic hernia. With surgical repair, this condition has an excellent survival rate. In conclusion, the pathophysiological mechanisms underlying the association remain to be elucidated. Awareness of the associated pleural effusion is important to avoid inadvertent organ injury due to chest drains. [ABSTRACT FROM AUTHOR]

Background: Vitamin C (ascorbic acid) is an essential water-soluble nutrient which primarily exerts its effect on immune homeostasis as physiological antioxidant. However, conflicting data exist regarding the effect of vitamin C on the expression of pro-inflammatory cytokines.Methods: It was the aim of this study to investigate the impact of vitamin C on intracytoplasmic production of pro-inflammatory cytokines in monocytes and lymphocytes by flow cytometry after human whole blood assay.Results: Vitamin C dose dependently inhibited the LPS-induced number of monocytes producing IL-6 (e.g., 41.0% reduction, p<0.001, 20 mM vitamin C) and TNF-α (e.g., 26.0% reduction, p<0.005, 20 mM vitamin C). Simultaneously, the number of lymphocytes producing IL-2 after PMA/ionomycin stimulation was dose dependently reduced (e.g., 24.2% inhibition, p<0.005, 20 mM vitamin C). Notably, the number of IL-1 and IL-8 producing monocytes as well as TNF-α and IFN-γ producing lymphocytes were not significantly affected by 20 mM vitamin C.Conclusions: These data suggest that vitamin C selectively influences intracytoplasmic cytokine production and therefore, further studies are needed to elucidate the underlying mechanisms of immunomodulation, i.e. regulation of NFκB activation which is mandatory for the induction of pro-inflammatory cytokines. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Background Objectives Search Strategy Selection Criteria Data Collection and Analysis Main Results Conclusions While a systematic review exists detailing neonatal sepsis outcomes from clinical trials, there remains an absence of a qualitative systematic review capturing the perspectives of key stakeholders.Our aim is to identify outcomes from qualitative research on any intervention to prevent or improve the outcomes of neonatal sepsis that are important to parents, other family members, healthcare providers, policymakers, and researchers as a part of the development of a core outcome set (COS) for neonatal sepsis.A literature search was carried out using MEDLINE, EMBASE, CINAHL, and PsycInfo databases.Publications describing qualitative data relating to neonatal sepsis outcomes were included.Drawing on the concepts of thematic synthesis, texts related to outcomes were coded and grouped. These outcomes were then mapped to the domain headings of an existing model.Out of 6777 records screened, six studies were included. Overall, 19 outcomes were extracted from the included studies. The most frequently reported outcomes were those in the domains related to parents, healthcare workers and individual organ systemas such as gastrointestinal system. The remaining outcomes were classified under the headings of general outcomes, miscellaneous outcomes, survival, and infection.The outcomes identified in this review are different from those reported in neonatal sepsis clinical trials, thus highlighting the importance of incorporating qualitative studies into COS development to encapsulate all relevant stakeholders' perspectives. [ABSTRACT FROM AUTHOR]

Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis. [ABSTRACT FROM AUTHOR]

The article discusses how pentoxifylline (PTX) is a methylxanthine with immunomodulating properties that may be beneficial in neonatal sepsis, with mechanisms including inhibition of TLR-mediated inflammation, mainly in cord blood.

Neonatal sepsis is a serious public health problem; however, there is substantial heterogeneity in the outcomes measured and reported in research evaluating the effectiveness of the treatments. Therefore, we aim to develop a Core Outcome Set (COS) for studies evaluating the effectiveness of treatments for neonatal sepsis. Since a systematic review of key outcomes from randomised trials of therapeutic interventions in neonatal sepsis was published recently, we will complement this with a qualitative systematic review of the key outcomes of neonatal sepsis identified by parents, other family members, parent representatives, healthcare providers, policymakers, and researchers. We will interpret the outcomes of both studies using a previously established framework. Stakeholders across three different groups i.e., (1) researchers, (2) healthcare providers, and (3) patients' parents/family members and parent representatives will rate the importance of the outcomes in an online Real-Time Delphi Survey. Afterwards, consensus meetings will be held to agree on the final COS through online discussions with key stakeholders. This COS is expected to minimize outcome heterogeneity in measurements and publications, improve comparability and synthesis, and decrease research waste. [ABSTRACT FROM AUTHOR]

The structure and function of infant skin is not fully developed until 34 weeks of gestation, and this immaturity is associated with risk of late-onset sepsis (LOS). Topical coconut oil improves preterm-infant skin integrity and may reduce LOS. However, data on early-life skin-microbiome succession and potential effects of emollient skin care in preterm infants are scarce. We therefore collected skin-microbiome samples from the ear, axilla, and groin on days 1, 7, 14, and 21 from preterm infants born <30 weeks of gestation as part of a randomized clinical trial of standard skin care vs. topical coconut oil. We found that within-sample microbiome diversity was highest on day 1 after birth, with a subsequent decline and emergence of Staphylococcus genus dominance from day 7. Moreover, microbiome assembly was less diverse in infants receiving coconut oil vs. standard skin care. Our study provides novel data on preterm-infant skin-microbiome composition and highlights the modifying potential of emollient skin care. [ABSTRACT FROM AUTHOR]

Preterm infants are at risk of increased trans-epidermal water loss and infections due to epidermal immaturity. The emollient and anti-infective properties of coconut oil make it a potentially beneficial topical agent for this population. We aimed to systematically review randomised trials assessing the effects of topical coconut oil in preterm infants. Medline, EMBASE, Cochrane Central Register of Controlled Trials and CINAHL were searched. Seven trials (n = 727 infants) were included. The majority of trials included relatively mature infants (gestation > 32 weeks, birth weight > 1200 g). The duration of intervention (5-31 days) and outcomes of interest varied among included studies. Meta-analysis using random effects model found significantly lower incidence of hospital-acquired blood stream infections (HABSI) in the coconut oil group (11/164 vs 32/166; relative risk 0.35, 95% confidence interval 0.18, 0.67, p = 0.001; I2 = 0%, two RCTs). Overall, infants in the coconut oil group had decreased water loss, decreased infection rates, better growth and skin condition. There were no significant adverse effects associated with coconut oil application. The overall quality of evidence was considered moderate for the outcome of HABSI and low for the outcome of physical growth based on GRADE guidelines.Conclusion: Topical coconut oil application to the skin may be beneficial in preterm infants, but the quality of evidence is low to moderate. Adequately powered randomised controlled trials, especially in very preterm (< 32 weeks) and extremely preterm (< 28 weeks) infants, are needed. What is Known: • Coconut oil has been used traditionally for topical application in terms of infants in Asian countries What is New: • This systematic review found that topical application of coconut oil may reduce the risk of infection and improve weight gain and skin condition in preterm infants. However, the quality of evidence was considered to be moderate to low based on GRADE guidelines. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article about the association of prematurity with mortality in childhood and early adulthood.

The article presents a case study of 33-week gestational age female infant who was delivered by non-elective caesarean section for intrauterine growth restriction. It reveals that the infant was given continuous positive airway pressure support and empiric penicillin and gentamicin. It further mentions that within 12 hours of starting antibiotic treatment streptococcal cellulitis was improved in the infant.

Background: Reduced gestational age and low birthweight are associated with an increased risk of neonatal infections. However, the long-term risk of infection, especially in late preterm infants or those at near-normal birthweight, is unknown. We estimated whether rates of infection-related admissions to hospital for children in Western Australia were associated with age, gestational age, birthweight, and birth length.Methods: We did a population-based, data-linkage study using total-linked, registry data from the Western Australia Birth Register of all liveborn, non-Indigenous Australian singleton births recorded from Jan 1, 1980, to Dec 31, 2010. We followed up individuals from birth-related hospital discharge to age 18 years, death, or end of 2010, and linked to data about subsequent admissions to hospital or death registrations. Gestational age was assessed from both the last menstrual period and from estimates based on ultrasonography. We categorised birthweight by 500 g bands and birth length by 5 cm bands, and approximated the reference ranges for both to the 50th percentile. Because size at birth and gestational age are strongly associated, we calculated Z scores for gestational-specific and sex-specific birthweight, birth length, and ponderal index. Our primary outcomes were the number and type of infection-related admissions to hospital. We used multilevel negative binomial regression to generate rate ratios (RR) for such admissions, identified by codes from the International Classification of Diseases, versions 9 and 10-AM. We adjusted the RRs for maternal age at delivery, birth year, birth season, parity, sex, 5-min Apgar score, delivery method, socioeconomic status, and bronchopulmonary dysplasia.Findings: Of 719 311 liveborn singletons included in the analysis and followed up for 8 824 093 person-years, 365 867 infection-related admissions to hospital occurred for 213 683 (30%) children. Of the 719 311 children included in the analysis, 137 124 (19%) had one infection-related admission to hospital, 43 796 (6%) had two, 16 679 (2%) had three, and 16 084 (2%) had four or more. The 365 867 admissions to hospital included a diagnosis of infection of the upper respiratory tract for 174 653 (48%), the lower respiratory tract for 74 297 (20%), the gastrointestinal tract for 44 755 (12%), and a viral infection for 37 213 (10%). Infection-related rates of admissions to hospital increased by 12% for each week reduction in gestational age less than 39-40 weeks (RR 1·12, 95% CI 1·12-1·13), by 19% for each 500 g reduction in birthweight less than 3000-3500 g (1·19, 1·18-1·21), and by 41% for each 5 cm reduction in birth length less than 45-50 cm (1·41, 1·38-1·45). Gestational age-specific and sex-specific birthweight Z scores lower than the 25th to 50th percentile and birth length Z scores lower than the 10th to 25th percentile were associated with increased rates of infection-related admissions to hospital (eg, 1st-5th percentile RR 1·15, 95% CI 1·12-1·19, and 1·11, 1·07-1·14, respectively). Ponderal index Z scores lower than the 25th to 50th percentile were also associated with increased rates of infection-related admissions (eg, 1st-5th percentile RR 1·08, 95% CI 1·04-1·12). A gestational age of 41 weeks or later, a birthweight or birth length Z score above the 50th percentile, or a ponderal index Z score between the 75th and 95th percentile, were associated with modestly reduced rates of infection-related admissions to hospital.Interpretation: Children who were born with reduced gestational age, birthweight, and birth length have persistently increased rates of infection-related admissions to hospital until age 18 years. Pregnancy outcomes should be optimised to prevent infection occurring in this population, especially in resource-limited settings where suboptimum intrauterine growth and moderate prematurity are common.Funding: Australian National Health and Medical Research Council. [ABSTRACT FROM AUTHOR]

Presents the case report of a 11-year-old girl with intractable anaemia and short stature. Complaints such as recurrent headaches and heat intolerance; Results of blood tests; Diagnosis of cystinosis; Treatment of cystinosis.

Preterm infants are at increased risk for invasive neonatal bacterial infections. S. epidermidis, a ubiquitous skin commensal, is a major cause of late-onset neonatal sepsis, particularly in high-resource settings. The vulnerability of preterm infants to serious bacterial infections is commonly attributed to their distinct and developing immune system. While developmentally immature immune defences play a large role in facilitating bacterial invasion, this fails to explain why only a subset of infants develop infections with low-virulence organisms when exposed to similar risk factors in the neonatal ICU. Experimental research has explored potential virulence mechanisms contributing to the pathogenic shift of commensal S. epidermidis strains. Furthermore, comparative genomics studies have yielded insights into the emergence and spread of nosocomial S. epidermidis strains, and their genetic and functional characteristics implicated in invasive disease in neonates. These studies have highlighted the multifactorial nature of S. epidermidis traits relating to pathogenicity and commensalism. In this review, we discuss the known host and pathogen drivers of S. epidermidis virulence in neonatal sepsis and provide future perspectives to close the gap in our understanding of S. epidermidis as a cause of neonatal morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: The proportion of births via cesarean section (CS) varies worldwide and in many countries exceeds WHO-recommended rates. Long-term health outcomes for children born by CS are poorly understood, but limited data suggest that CS is associated with increased infection-related hospitalisation. We investigated the relationship between mode of birth and childhood infection-related hospitalisation in high-income countries with varying CS rates.Methods and Findings: We conducted a multicountry population-based cohort study of all recorded singleton live births from January 1, 1996 to December 31, 2015 using record-linked birth and hospitalisation data from Denmark, Scotland, England, and Australia (New South Wales and Western Australia). Birth years within the date range varied by site, but data were available from at least 2001 to 2010 for each site. Mode of birth was categorised as vaginal or CS (emergency/elective). Infection-related hospitalisations (overall and by clinical type) occurring after the birth-related discharge date were identified in children until 5 years of age by primary/secondary International Classification of Diseases, 10th Revision (ICD-10) diagnosis codes. Analysis used Cox regression models, adjusting for maternal factors, birth parameters, and socioeconomic status, with results pooled using meta-analysis. In total, 7,174,787 live recorded births were included. Of these, 1,681,966 (23%, range by jurisdiction 17%-29%) were by CS, of which 727,755 (43%, range 38%-57%) were elective. A total of 1,502,537 offspring (21%) had at least 1 infection-related hospitalisation. Compared to vaginally born children, risk of infection was greater among CS-born children (hazard ratio (HR) from random effects model, HR 1.10, 95% confidence interval (CI) 1.09-1.12, p < 0.001). The risk was higher following both elective (HR 1.13, 95% CI 1.12-1.13, p < 0.001) and emergency CS (HR 1.09, 95% CI 1.06-1.12, p < 0.001). Increased risks persisted to 5 years and were highest for respiratory, gastrointestinal, and viral infections. Findings were comparable in prespecified subanalyses of children born to mothers at low obstetric risk and unchanged in sensitivity analyses. Limitations include site-specific and longitudinal variations in clinical practice and in the definition and availability of some data. Data on postnatal factors were not available.Conclusions: In this study, we observed a consistent association between birth by CS and infection-related hospitalisation in early childhood. Notwithstanding the limitations of observational data, the associations may reflect differences in early microbial exposure by mode of birth, which should be investigated by mechanistic studies. If our findings are confirmed, they could inform efforts to reduce elective CS rates that are not clinically indicated. [ABSTRACT FROM AUTHOR]

Preterm infants are particularly susceptible to bacterial late‐onset sepsis (LOS). Diagnosis by blood culture and inflammatory markers have sub‐optimal sensitivity and specificity and prolonged reporting times. There is an urgent need for more rapid, accurate adjunctive diagnostics in LOS to improve management and minimise antibiotic exposure. We measured the diagnostic performance of secretory phospholipase A2 type IIA (sPLA2‐IIA) in very preterm infants (<30 weeks gestational age) with suspected LOS. Plasma sPLA2‐IIA levels were elevated in infants with LOS (n = 28) compared to those without LOS (n = 21; median 30,970 vs. 2534 pg/ml, p < 0.0001). The mean area under the curve was 0.884 (95% CI: 0.771, 0.977) with a sensitivity of 0.907 (95% CI: 0.667, 1.00) and specificity of 0.804 (95% CI: 0.600, 1.00). The positive and negative predictive values were 0.833 (95% CI: 0.664, 0.927) and 0.842 (95% CI: 0.624, 0.945), respectively. This pilot study suggests that sPLA2‐IIA may have clinical utility for the early diagnosis of LOS in very preterm infants, potentially informing clinical management and antibiotic stewardship. [ABSTRACT FROM AUTHOR]

Pentoxifylline (PTX) is a candidate adjuvant medication for the treatment of sepsis and necrotizing enterocolitis in preterm infants. There is only limited data on safety and compatibility with other commonly used intravenous medications. This retrospective single-center study of 198 preterm infants (September 2012–September 2018) was performed at a level IV neonatal intensive care unit. Electronic data of all preterm infants who received pentoxifylline for sepsis or necrotizing were extracted from routine databases. We analyzed a total of 1081 PTX treatment days from 217 treatment episodes in 198 preterm infants (mean gestational age 27 weeks; mean birth weight 1060 g). At a mean daily dose of 28 mg/kg, no clinically relevant side effects were observed. PTX therapy was not associated with clinically significant changes of blood biochemistry and hematology parameters. Concomitant infusion of PTX with other common NICU medications was well tolerated, and there was no evidence of incompatibility. Conclusion: Intravenous PTX is compatible with standard NICU drugs and well tolerated in critically ill preterm infants. What is Know: •Currently, there are no evidence-based adjuvant medications available that target the harmful inflammatory host response in neonatal sepsis or necrotizing enterocolitis. •Pentoxifylline (PTX) is a candidate adjuvant medication for the treatment of sepsis and necrotizing enterocolitis in preterm infants; however, safety data are rare and PTX is currently used off-label. What is New: •Here we report on our experience in the pragmatic routine use of PTX as adjuvant therapy in 198 preterm infants with sepsis or NEC. •Concomitant infusion of PTX with other common NICU medications was well tolerated, and there was no evidence of incompatibility. No clinically relevant side effects were observed. [ABSTRACT FROM AUTHOR]

Aims: Infection‐induced inflammation is associated with adverse long‐term outcomes in preterm infants. Pentoxifylline (PTX) is a candidate for adjunct immunomodulatory therapy in preterm infants with late‐onset sepsis (LOS) and necrotizing enterocolitis (NEC), but pharmacokinetic data in this population are extremely limited. This study aims to characterize the pharmacokinetic properties of intravenous PTX and its metabolites in preterm infants. Method: An open label pilot clinical study of intravenous PTX as an adjunct therapy in preterm infants (gestation <32 weeks) with suspected LOS or NEC was undertaken. PTX was infused for 12 h for two days (60 mg kg−1 per 12 h), and in infants with confirmed diagnosis of LOS or NEC, for 6 h for another 4 days (30 mg kg−1 per 6 h). Plasma concentrations of PTX and its principal metabolites from collected blood samples were measured using a validated LCMS assay. NONMEM was used to analyse the data using population pharmacokinetic modelling. Results: The preterm infants (n = 26) had a median (range) gestation of 24.8 weeks (23.3–30.4) and birthweight of 689 g (370–1285). PTX was well tolerated and without treatment‐limiting adverse effects. Changes in size (weight) and maturation were successfully modelled for PTX and metabolites. After allometric scaling, clearance increased with postmenstrual age, increasing by approximately 30% per week for PTX and M1 (lisofylline) and simulations of current dosing demonstrated a six‐fold difference in exposure between 24 and 35 weeks postmenstrual age. Conclusions: The developed model can be used to explore dosing strategies based on size and maturation for preterm infants. A population pharmacokinetic model was developed to characterize the six‐fold range in exposure in the studied infants despite using a weight‐based dosing regimen for these critically ill preterm infants. [ABSTRACT FROM AUTHOR]

Abstract: Preterm infants are uniquely susceptible to late‐onset sepsis that is frequently caused by the skin commensal Staphylococcus epidermidis. Innate immune responses, particularly from monocytes, are a key protective mechanism. Impaired cytokine production by preterm infant monocytes is well described, but few studies have comprehensively assessed the corresponding monocyte transcriptional response. Innate immune responses in preterm infants may be modulated by inflammation such as prenatal exposure to histologic chorioamnionitis which complicates 40–70% of preterm pregnancies. Chorioamnionitis alters the risk of late‐onset sepsis, but its effect on monocyte function is largely unknown. Here, we aimed to determine the impact of exposure to chorioamnionitis on the proportions and phenotype of cord blood monocytes using flow cytometry, as well as their transcriptional response to live S. epidermidis. RNA‐seq was performed on purified cord blood monocytes from very preterm infants (<32 weeks gestation, with and without chorioamnionitis‐exposure) and term infants (37–40 weeks), pre‐ and postchallenge with live S. epidermidis. Preterm monocytes from infants without chorioamnionitis‐exposure did not exhibit an intrinsically deficient transcriptional response to S. epidermidis compared to term infants. In contrast, chorioamnionitis‐exposure was associated with hypo‐responsive transcriptional phenotype regarding a subset of genes involved in antigen presentation and adaptive immunity. Overall, our findings suggest that prenatal exposure to inflammation may alter the risk of sepsis in preterm infants partly by modulation of monocyte responses to pathogens. [ABSTRACT FROM AUTHOR]

Escherichia coli and Staphylococcus epidermidis are predominant causes of neonatal sepsis, particularly affecting preterm infants. Susceptibility to infection has been attributed to 'immature' innate monocyte defences, but no studies have assessed global transcriptional responses of neonatal monocytes to these pathogens. Here, we aimed to identify and characterise the neonatal monocyte transcriptional responses to E. coli and S. epidermidis and the role of common modifiers such as gestational age (GA) and exposure to chorioamnionitis (a common complication of preterm birth) to better understand early life innate immune responses. RNA-sequencing was performed on purified cord blood monocytes from very preterm (< 32 weeks GA) and term infants (37-40 weeks GA) following standardised challenge with live S. epidermidis or E. coli. The major transcriptional changes induced by either pathogen were highly conserved between infant groups and stimuli, highlighting a common extant neonatal monocyte response to infection, largely mediated by TLR/NF-κB/TREM-1 signalling. In addition, we observed an activated interferon-centred immune response specific to stimulation with E. coli in both preterm and term infants. These data provide novel insights into the functionality of neonatal monocytes at birth and highlight potential pathways that could be targeted to reduce the harmful effects of bacterial-induced inflammation in sepsis. E. coli and S. epidermidis elicit common transcriptional changes in cord monocytes. The common transcriptional response is mediated by TLR/NF-κB/TREM-1 signalling. IFN genes are differentially regulated by E. coli and S. epidermidis in monocytes. These responses are largely unaffected by GA or exposure to chorioamnionitis. Key messages: [ABSTRACT FROM AUTHOR]

Background: A host defense function for Alkaline phosphatases (ALPs) is suggested by the contribution of intestinal ALP to detoxifying bacterial lipopolysaccharide (endotoxin) in animal models in vivo and the elevation of ALP activity following treatment of human cells with inflammatory stimuli in vitro. However the activity of ALP in human plasma (primarily tissue-nonspecific ALP; TNAP) on lipopolysaccharide and other microbial products has not been assessed, nor has its expression been studied in preterm newborns, a vulnerable population at high risk of sepsis. In this context, the aim of our study was to characterize the activity of TNAP on Toll-like receptor (TLR) agonists and assess the concentrations of plasma ALP during late-onset sepsis in preterm newborns. Methods: Recombinant human TNAP was incubated with microbial products and phosphate release was measured by malachite green assay. Plasma ALP activity was measured serially in a cohort of preterm (N = 129) infants at high risk of late-onset sepsis (LOS). Results: TNAP dephosphorylates poly-inosine:cytosine (Toll-like receptor (TLR) 3 agonist) and LPS from Klebsiella pneumoniae and Salmonella minnesota (TLR4 agonists). Plasma ALP significantly increased postnatally over the first 4 weeks of life in preterm and term newborns. Bacteremic LOS in preterm infants (gestational age ≤ 30 weeks) was associated with significantly elevated plasma ALP at 4 weeks postnatal age. Conclusions: TNAP, the main circulating isozyme of ALP, de-phosphorylates TLR agonists, demonstrates a post-natal age dependent increase in preterm and term plasma across the first 4 weeks of life, and is elevated in association with preterm LOS. [ABSTRACT FROM AUTHOR]

Background: Extremely preterm infants are highly susceptible to bacterial infections but breast milk provides some protection. It is unknown if leukocyte numbers and subsets in milk differ between term and preterm breast milk. This study serially characterised leukocyte populations in breast milk of mothers of preterm and term infants using multicolour flow cytometry methods for extended differential leukocyte counts in blood. Methods: Sixty mothers of extremely preterm (<28 weeks gestational age), very preterm (28–31 wk), and moderately preterm (32–36 wk), as well as term (37–41 wk) infants were recruited. Colostrum (d2–5), transitional (d8–12) and mature milk (d26–30) samples were collected, cells isolated, and leukocyte subsets analysed using flow cytometry. Results: The major CD45+ leukocyte populations circulating in blood were also detectable in breast milk but at different frequencies. Progression of lactation was associated with decreasing CD45+ leukocyte concentration, as well as increases in the relative frequencies of neutrophils and immature granulocytes, and decreases in the relative frequencies of eosinophils, myeloid and B cell precursors, and CD16- monocytes. No differences were observed between preterm and term breast milk in leukocyte concentration, though minor differences between preterm groups in some leukocyte frequencies were observed. Conclusions: Flow cytometry is a useful tool to identify and quantify leukocyte subsets in breast milk. The stage of lactation is associated with major changes in milk leukocyte composition in this population. Fresh preterm breast milk is not deficient in leukocytes, but shorter gestation may be associated with minor differences in leukocyte subset frequencies in preterm compared to term breast milk. [ABSTRACT FROM AUTHOR]

Background: The relationship between histological chorioamnionitis and haematological and biochemical markers in mothers and infants at delivery, and in infants postnatally, is incompletely characterised. These markers are widely used in the diagnosis of maternal and neonatal infection. Our objective was to investigate the effects of histological chorioamnionitis (HCA) on haematological and biochemical inflammatory markers in mothers and infants at delivery, and in infants post-delivery. Methods: Two hundred and forty seven mothers, delivering 325 infants, were recruited at the only tertiary perinatal centre in Western Australia. Placentae were assessed for evidence of HCA using a semi-quantitative scoring system. Maternal high sensitivity C-reactive protein (hsCRP), procalcitonin, and umbilical cord hsCRP, procalcitonin, white cell count and absolute neutrophil count were measured at delivery. In infants where sepsis was clinically suspected, postnatal CRP, white cell count and absolute neutrophil count were measured up to 48 hours of age. The effect of HCA on maternal, cord and neonatal markers was evaluated by multivariable regression analysis. Results: The median gestational age was 34 weeks and HCA was present in 26 of 247 (10.5%) placentae. Mothers whose pregnancies were complicated by HCA had higher hsCRP (median 26 (range 2-107) versus 5.6 (0-108) mg/L; P<0.001). Histological chorioamnionitis was associated with higher umbilical cord hsCRP (75th percentile 2.91 mg/L (range 0-63.9) versus 75th percentile 0 mg/L (0-45.6); P<0.001) and procalcitonin (median 0.293 (range 0.05-27.37) versus median 0.064 (range 0.01-5.24) ug/L; P<0.001), with a sustained increase in neonatal absolute neutrophil count (median 4.5 (0.1- 26.4)6109/L versus 3.0 (0.1-17.8)6109/L), and CRP up to 48 hours post-partum (median 10 versus 6.5 mg/L) (P<0.05 for each). Conclusion: Histological chorioamnionitis is associated with modest systemic inflammation in maternal and cord blood. These systemic changes may increase postnatally, potentially undermining their utility in the diagnosis of early-onset neonatal infection. [ABSTRACT FROM AUTHOR]