Gut microbiome and necrotizing enterocolitis: Understanding the connection to find a cure.

Necrotizing enterocolitis (NEC), a cause of death among premature babies, has defied therapeutics for decades. Bacterial analyses have expanded insights into NEC pathophysiology and roles of the gut microbiome. We discuss the contribution of the gut microbiome and potential therapeutics, notably lactadherin, that may promote gut homeostasis to alleviate NEC.

Risk factors and clinical analysis of peripherally inserted central catheter-related fungal colonization in premature infants.

We aimed to analyze the risk factors of positive peripherally inserted central catheter (PICC)-related fungal colonization in preterm infants. This retrospective study collected data from 2018 to 2020. The enrolled infants who underwent PICC insertion were born at < 32 weeks' gestation or birth weight < 1500 g. The demographics, PICC-related characteristics, and treatment information were collected. Univariate and multivariate analyses were performed to investigate risk factors for PICC-related fungal colonization. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off values for the duration of antibiotics and parenteral nutrition. In total, 124 premature infants underwent PICC insertion. Among them, 19 patients had positive results of fungi on the PICC tips. The duration of antibiotics (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.02-1.31), parenteral nutrition infusion (OR 1.27, 95% CI 1.05-1.54), and postnatal glucocorticoid exposure (OR 9.48, 95% CI 1.06-84.98) were independent risk factors for fungal colonization in PICCs. The ROC curves showed that the risk increased after 15 days of antibiotic use and 28 days of parenteral nutrition infusion. Appropriate clinical management should be used to prevent fungal colonization and fungemia.

Unraveling the Microbiome of Necrotizing Enterocolitis: Insights in Novel Microbial and Metabolomic Biomarkers.

Necrotizing enterocolitis (NEC) is among the most relevant gastrointestinal diseases affecting mostly prematurely born infants with low birth weight. While intestinal dysbiosis has been proposed as one of the possible factors involved in NEC pathogenesis, the role of the gut microbiota remains poorly understood. In this study, the gut microbiota of preterm infants was explored to highlight differences in the composition between infants affected by NEC and infants prior to NEC development. A large-scale gut microbiome analysis was performed, including 47 shotgun sequencing data sets generated in the framework of this study, along with 124 retrieved from publicly available repositories. Meta-analysis led to the identification of preterm community state types (PT-CSTs), which recur in healthy controls and NEC infants. Such analyses revealed an overgrowth of a range of opportunistic microbial species accompanying the loss of gut microbial biodiversity in NEC subjects. Moreover, longitudinal insights into preterm infants prior to NEC development indicated Clostridium neonatale and Clostridium perfringens species as potential biomarkers for predictive early diagnosis of this disease. Furthermore, functional investigation of the enzymatic reaction profiles associated with pre-NEC condition suggested DL-lactate as a putative metabolic biomarker for early detection of NEC onset. IMPORTANCE Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease occurring predominantly in premature infants whose etiology is still not fully understood. In this study, the analysis of infant fecal samples through shotgun metagenomics approaches revealed a marked reduction of the intestinal (bio)diversity and an overgrowth of (opportunistic) pathogens associated with the NEC development. In particular, dissection of the infant's gut microbiome before NEC diagnosis highlighted the potential involvement of Clostridium genus members in the progression of NEC. Remarkably, our analyses highlighted a gastrointestinal DL-lactate accumulation among NEC patients that might represent a novel potential functional biomarker for the early diagnosis of NEC.

Early-Onset Sepsis Among Very Preterm Infants.

OBJECTIVES: To determine the epidemiology and microbiology of early-onset sepsis (EOS) among very preterm infants using a nationally representative cohort from academic and community hospitals to inform empirical antibiotic guidance, highlight risk factors for infection, and aid in prognostication for infected infants. METHODS: Prospective observational study of very preterm infants born weighing 401 to 1500 g or at 22 to 29 weeks' gestational age from January 2018 to December 2019 in 753 Vermont Oxford Network centers. EOS was defined as a culture-confirmed bacterial infection of the blood or cerebrospinal fluid in the 3 days after birth. Demographics, clinical characteristics, and outcomes were compared between infants with and without EOS. RESULTS: Of 84 333 included infants, 1139 had EOS for an incidence rate of 13.5 per 1000 very preterm births (99% confidence interval [CI] 12.5-14.6). Escherichia coli (538 of 1158; 46.5%) and group B Streptococcus (218 of 1158; 18.8%) were the most common pathogens. Infected infants had longer lengths of stay (median 92 vs 66 days) and lower rates of survival (67.5% vs 90.4%; adjusted risk ratio 0.82 [95% CI 0.79-0.85]) and of survival without morbidity (26.1% vs 59.4%; adjusted risk ratio 0.66 [95% CI 0.60-0.72]). CONCLUSIONS: In a nationally representative sample of very preterm infants with EOS from 2018 to 2019, approximately one-third of isolates were neither group B Streptococcus nor E coli. Three-quarters of all infected infants either died or survived with a major medical morbidity. The profoundly negative impact of EOS on very preterm infants highlights the need for novel preventive strategies.

Premature neonatal gut microbial community patterns supporting an epithelial TLR-mediated pathway for necrotizing enterocolitis.

BACKGROUND: Necrotising enterocolitis (NEC) is a devastating bowel disease, primarily affecting premature infants, with a poorly understood aetiology. Prior studies have found associations in different cases with an overabundance of particular elements of the faecal microbiota (in particular Enterobacteriaceae or Clostridium perfringens), but there has been no explanation for the different results found in different cohorts. Immunological studies have indicated that stimulation of the TLR4 receptor is involved in development of NEC, with TLR4 signalling being antagonised by the activated TLR9 receptor. We speculated that differential stimulation of these two components of the signalling pathway by different microbiota might explain the dichotomous findings of microbiota-centered NEC studies. Here we used shotgun metagenomic sequencing and qPCR to characterise the faecal microbiota community of infants prior to NEC onset and in a set of matched controls. Bayesian regression was used to segregate cases from control samples using both microbial and clinical data. RESULTS: We found that the infants suffering from NEC fell into two groups based on their microbiota; one with low levels of CpG DNA in bacterial genomes and the other with high abundances of organisms expressing LPS. The identification of these characteristic communities was reproduced using an external metagenomic validation dataset. We propose that these two patterns represent the stimulation of a common pathway at extremes; the LPS-enriched microbiome suggesting overstimulation of TLR4, whilst a microbial community with low levels of CpG DNA suggests reduction of the counterbalance to TLR4 overstimulation. CONCLUSIONS: The identified microbial community patterns support the concept of NEC resulting from TLR-mediated pathways. Identification of these signals suggests characteristics of the gastrointestinal microbial community to be avoided to prevent NEC. Potential pre- or pro-biotic treatments may be designed to optimise TLR signalling.

Bloodstream Infections in Preterm Neonates and Mortality-Associated Risk Factors.

OBJECTIVE: To investigate the association of early (±4 hours after onset of bloodstream infection) clinical and laboratory variables with episode-related mortality (<7 days). STUDY DESIGN: This 2-site retrospective study included 142 neonates born at <35 weeks of gestational age with positive blood/cerebrospinal fluid (CSF) culture at >72 hours of age from organisms other than coagulase-negative Staphylococcus. Early variables were compared between those with bloodstream infection-related mortality and survivors. Multivariable analysis was conducted for the primary outcome, and the area under the curve (AUC) was estimated for relevant variables. RESULTS: The neonates who died were of lower gestational age at disease onset. After adjusting for relevant variables, lowest mean blood pressure (MBP) (aOR, 0.10; 95% CI, 1.02-1.19) and highest base deficit (aOR, 1.18; 95% CI, 1.06-1.32) were independently associated with mortality. The AUC was 0.87 (95% CI, 0.78-0.96) for base deficit, increasing to 0.91 (95% CI, 0.83-0.99) with the addition of MBP. CONCLUSION: Low MBP and high base deficit within ±4 hours of bloodstream infection onset identify preterm neonates at risk of mortality.

Lactant de 6 setmanes amb tumefacció preauricular I febre d'aparició sobtada / No disponible

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Which Patient in the Neonatal Intensive Care Unit should Receive Antifungal Prophylaxis Therapy?

BACKGROUND: Extremely preterm infants are at high risk for mortality and morbidity including neurodevelopmental impairment from invasive Candida infections. Prophylactic antifungal therapy has been shown to reduce both colonization and invasive candidemia in high-risk preterm infants. Prophylactic treatment should be started in the first 48 to 72 hours after birth to extremely low birth weight (ELBW) infants (weighing ≤ 1000 grams at birth) or below 27 weeks gestation age with risk factors, or in any NICU with moderate (5-10%) or high (≥ 10%) rates of invasive candidiasis. Studies demonstrated the benefits of fluconazole prophylaxis regarding its safety of the short-term and long-term without the development of fungal resistance. Empiric antifungal therapy may lower mortality and improve outcomes.

Gastrointestinal Zygomycosis in a Preterm Neonate Associated With Contaminated Probiotics.

A neonate of 29 weeks' gestation who received probiotics developed clinical signs suggesting surgical necrotizing enterocolitis. A specimen of resected ileum revealed fungal forms within the bowel wall. Rhizopus oryzae was detected via DNA sequencing from probiotic powder and tissue specimens from the infant. To our knowledge, this is the first report linking gastrointestinal zygomycosis to the administration of contaminated probiotics.

Neurodevelopmental outcomes following neonatal late-onset sepsis and blood culture-negative conditions.

OBJECTIVE: Determine risk of death or neurodevelopmental impairment (NDI) in infants with late-onset sepsis (LOS) versus late-onset, antibiotic-treated, blood culture-negative conditions (LOCNC). DESIGN: Retrospective cohort study. SETTING: 24 neonatal centres. PATIENTS: Infants born 1/1/2006-31/12/2014, at 22-26 weeks gestation, with birth weight 401-1000 g and surviving >7 days were included. Infants with early-onset sepsis, necrotising enterocolitis, intestinal perforation or both LOS and LOCNC were excluded. EXPOSURES: LOS and LOCNC were defined as antibiotic administration for ≥5 days with and without a positive blood/cerebrospinal fluid culture, respectively. Infants with these diagnoses were also compared with infants with neither condition. OUTCOMES: Death or NDI was assessed at 18-26 months corrected age follow-up. Modified Poisson regression models were used to estimate relative risks adjusting for covariates occurring ≤7 days of age. RESULTS: Of 7354 eligible infants, 3940 met inclusion criteria: 786 (20%) with LOS, 1601 (41%) with LOCNC and 1553 (39%) with neither. Infants with LOS had higher adjusted relative risk (95% CI) for death/NDI (1.14 (1.05 to 1.25)) and death before follow-up (1.71 (1.44 to 2.03)) than those with LOCNC. Among survivors, risk for NDI did not differ between the two groups (0.99 (0.86 to 1.13)) but was higher for LOCNC infants (1.17 (1.04 to 1.31)) compared with unaffected infants. CONCLUSIONS: Infants with LOS had higher risk of death, but not NDI, compared with infants with LOCNC. Surviving infants with LOCNC had higher risk of NDI compared with unaffected infants. Improving outcomes for infants with LOCNC requires study of the underlying conditions and the potential impact of antibiotic exposure.

Late-onset sepsis due to Salmonella Typhi in a preterm infant in a French neonatal unit.

We report a case of late-onset sepsis caused by Salmonella Typhi in a one-month old preterm infant hospitalised in our neonatal unit. An investigation of the index case was undertaken to identify the source of contamination. The patient made a complete recovery.

Preterm Twins Born to a Mother with Miliary Tuberculosis: Importance of Early Recognition and Prompt Response in Infection Control to Manage Congenital Tuberculosis Exposure in a Neonatal Intensive Care Unit.

Delayed diagnosis of congenital tuberculosis (TB) in the neonatal intensive care unit (NICU) is a serious problem in terms of infection control. Here, we report our preemptive infection control activities implemented after the diagnosis of miliary TB in a mother of preterm twins (index twins, NB1 and NB2) in the NICU. In addition, we reviewed previous case reports of congenital TB exposure in the NICU setting. Immediately after diagnosing miliary TB in the mother, the index twins were isolated before their TB diagnosis and received preemptive anti-TB medication; contact investigations were also conducted. Eventually, NB1 was diagnosed with congenital TB at 29 days of age, and NB2 showed no definite evidence of TB. Through contact investigation, 11 of the 16 exposed infants received isoniazid prophylaxis and no positive tuberculin skin test results were obtained after 3 months. One of the 31 exposed healthcare workers showed new interferon-gamma release assay conversion. Moreover, our case showed a much shorter contagious period compared to that in previous reports (8 versus 17-102 days). This suggests that a high index of suspicion and prompt measures can help prevent congenital TB outbreaks and reduce the burden of infection control activities in the NICU.

Assessment of Neonatal Intensive Care Unit Practices and Preterm Newborn Gut Microbiota and 2-Year Neurodevelopmental Outcomes.

Importance: In very preterm newborns, gut microbiota is highly variable with major dysbiosis. Its association with short-term health is widely studied, but the association with long-term outcomes remains unknown. Objective: To investigate in preterm newborns the associations among practice strategies in neonatal intensive care units (NICUs), gut microbiota, and outcomes at 2 years. Design, Setting, and Participants: EPIFLORE is a prospective observational cohort study that includes a stool sample collection during the fourth week after birth. Preterm newborns of less than 32 weeks of gestational age (GA) born in 2011 were included from 24 NICUs as part of the French nationwide population-based cohort, EPIPAGE 2. Data were collected from May 2011 to December 2011 and analyzed from September 2016 to December 2018. Exposures: Eight NICU strategies concerning sedation, ventilation, skin-to-skin practice, antibiotherapy, ductus arteriosus, and breastfeeding were assessed. A NICU was considered favorable to a practice if the percentage of that practice in the NICU was more than the expected percentage. Main Outcomes and Measures: Gut microbiota was analyzed by 16S ribosomal RNA gene sequencing and characterized by a clustering-based method. The 2-year outcome was defined by death or neurodevelopmental delay using a Global Ages and Stages questionnaire score. Results: Of 577 newborns included in the study, the mean (SD) GA was 28.3 (2.0) weeks, and 303 (52.5%) were male. Collected gut microbiota was grouped into 5 discrete clusters. A sixth cluster included nonamplifiable samples owing to low bacterial load. Cluster 4 (driven by Enterococcus [n = 63]), cluster 5 (driven by Staphylococcus [n = 52]), and cluster 6 (n = 93) were significantly associated with lower mean (SD) GA (26.7 [1.8] weeks and 26.8 [1.9] weeks, respectively) and cluster 3 (driven by Escherichia/Shigella [n = 61]) with higher mean (SD) GA (29.4 [1.6] weeks; P = .001). Cluster 3 was considered the reference. After adjustment for confounders, no assisted ventilation at day 1 was associated with a decreased risk of belonging to cluster 5 or cluster 6 (adjusted odds ratio [AOR], 0.21 [95% CI, 0.06-0.78] and 0.19 [95% CI, 0.06-0.62], respectively) when sedation (AOR, 10.55 [95% CI, 2.28-48.87] and 4.62 [1.32-16.18], respectively) and low volume of enteral nutrition (AOR, 10.48 [95% CI, 2.48-44.29] and 7.28 [95% CI, 2.03-26.18], respectively) was associated with an increased risk. Skin-to-skin practice was associated with a decreased risk of being in cluster 5 (AOR, 0.14 [95% CI, 0.04-0.48]). Moreover, clusters 4, 5, 6 were significantly associated with 2-year nonoptimal outcome (AOR, 6.17 [95% CI, 1.46-26.0]; AOR, 4.53 [95% CI, 1.02-20.1]; and AOR, 5.42 [95% CI, 1.36-21.6], respectively). Conclusions and Relevance: Gut microbiota of very preterm newborns at week 4 is associated with NICU practices and 2-year outcomes. Microbiota could be a noninvasive biomarker of immaturity.

Neonatal Microbiome and Its Relationship to Necrotizing Enterocolitis: A Review of the Science.

Necrotizing enterocolitis (NEC) occurs in many premature infants hospitalized in the neonatal intensive care unit. About 3% to 15% of very low-weight premature infants develop NEC, with an estimated 30% mortality rate for the cases requiring surgery. Currently, there is no known pathogenesis for NEC in the patient's populations. However, one of the most widely accepted hypotheses is having an abnormal fetal gut microbiome. The purpose of this review is to discuss some current methods of dysbiosis in the neonatal microbiome, such as maternal health, breastfeeding, and delivery method, and then to connect these to the occurrence of NEC in the infant and finally discuss some possibilities for limiting the occurrence of NEC in the future.

The infant microbiome and implications for central nervous system development.

Neurodevelopmental impairment remains a significant morbidity in former very low birth weight premature infants. There is increasing evidence the microbiome affects neurodevelopment but mechanistic causes are largely unknown. There are many factors which affect the developing microbiome in infants including mode of delivery, feeding, medications, and environmental exposures. The overall impact of these factors may differ between premature and term infants. The microbiome and brain have well recognized bidirectional communication pathways via neural, hormonal, and immunologic mechanisms. Understanding the interplay between these different pathways has been possible with the use of animal models, particularly germ-free mice. The intricate relationship between the microbiome and the brain remains a research priority not only to improve the care, but to also improve the long-term neurodevelopmental outcomes in this vulnerable population.

Epidemiology and microbiology of late-onset sepsis among preterm infants in China, 2015-2018: A cohort study.

OBJECTIVE: To describe the incidence, case-fatality rate and pathogen distribution of late-onset sepsis (LOS) among preterm infants in China. To investigate risk factors and short-term outcomes associated with LOS caused by Gram-positive bacteria, Gram-negative bacteria and fungi. METHODS: This cohort study included all infants born at <34 weeks' gestation and admitted to 25 tertiary hospitals in 19 provinces in China from May, 2015 to April, 2018. Infants were excluded who died or were discharged within 3 days of being born. RESULTS: A total of 1199 episodes of culture-positive LOS were identified in 1133 infants, with an incidence of 4.4% (1133/25,725). Overall, 15.4% (175/1133) of infants with LOS died and 10.0% (113/1133) of infants died within 7 days of LOS onset. Among 1214 isolated pathogens, Gram-negative bacteria were the most common (51.8%, 629/1214) and fungi accounted for 17.1% (207/1214). Use of central lines, longer duration of antibiotics and previous carbapenem exposure were related to increased risk of fungal LOS compared with Gram-positive bacteria. Gram-negative bacteria LOS was independently associated with increased risk of death, periventricular leukomalacia, bronchopulmonary dysplasia, and necrotizing enterocolitis. Fungal LOS was independently associated with increased risk of periventricular leukomalacia, bronchopulmonary dysplasia and necrotizing enterocolitis. CONCLUSIONS: Late-onset sepsis was a significant cause of morbidity and mortality in Chinese neonatal intensive care units, with a distinct pathogen distribution from industrial countries. Clinical guidelines on the prevention and treatment of LOS should be developed and tailored to these LOS characteristics in Chinese neonatal intensive care units.

Neonatal and Neurodevelopmental Outcomes Following Linezolid for Coagulase-negative Staphylococcal Infection: Real World Evidence.

BACKGROUND: Coagulase-negative staphylococci (CoNS) frequently causes late-onset sepsis in preterm infants. Vancomycin is the first-line therapy, but the emergence of reduced vancomycin-susceptibility strains has resulted in linezolid use, of which long-term safety in preterm infants is unknown. OBJECTIVE: Evaluate the association between linezolid exposure and neurodevelopmental impairment (NDI) or death at 18-21 months of corrected age, in preterm infants with CoNS sepsis. METHODS: Multicentric retrospective cohort study comparing long-term outcomes of preterm infants exposed to linezolid versus other antistaphylococcal antimicrobials. We included infants ≤28 weeks' gestational age (GA), with CoNS sepsis, admitted between January 2011 and June 2015 in 3 level-3 Canadian NICUs. Primary outcome was a composite of death or significant NDI (sNDI) at 18-21 months of corrected age. Secondary outcomes included NDI and individual components of the primary outcome. We assessed the relationship between linezolid exposure and outcomes using a multivariable logistic regression. RESULTS: Of 274 infants included, 67 (24.4%) were exposed to linezolid. Median GA was 26 weeks and clinical characteristics were similar between groups. There was no difference in composite outcome of death or sNDI among the infants of both groups, but significantly more death by 18-21 months in the linezolid group (29.9% vs. 17.6%; P = 0.01). CONCLUSIONS: Linezolid exposure was not associated with composite outcome of death or sNDI at 18-21 months. The association between linezolid and death may be due to indication bias. Further studies are warranted.