Gut and Lung Microbiota in Preterm Infants: Immunological Modulation and Implication in Neonatal Outcomes.
Tirone Chiara,Pezza Lucilla,Paladini Angela,Tana Milena,Aurilia Claudia,Lio Alessandra,D'Ippolito Silvia,Tersigni Chiara,Posteraro Brunella,Sanguinetti Maurizio,Di Simone Nicoletta,Vento Giovanni
Frontiers in immunology
In recent years, an aberrant gastrointestinal colonization has been found to be associated with an higher risk for postnatal sepsis, necrotizing enterocolitis (NEC) and growth impairment in preterm infants. As a consequence, the reasons of intestinal dysbiosis in this population of newborns have increasingly become an object of interest. The presence of a link between the gut and lung microbiome's development (gut-lung axis) is emerging, and more data show as a gut-brain cross talking mediated by an inflammatory milieu, may affect the immunity system and influence neonatal outcomes. A revision of the studies which examined gut and lung microbiota in preterm infants and a qualitative analysis of data about characteristic patterns and related outcomes in terms of risk of growing impairment, Necrotizing Enterocolitis (NEC), Bronchopulmonary Dysplasia (BPD), and sepsis have been performed. Microbiota take part in the establishment of the gut barrier and many data suggest its immune-modulator role. Furthermore, the development of the gut and lung microbiome (gut-lung axis) appear to be connected and able to lead to abnormal inflammatory responses which have a key role in the pathogenesis of BPD. Dysbiosis and the gut predominance of facultative anaerobes appear to be crucial to the pathogenesis and subsequently to the prevention of such diseases.
10.3389/fimmu.2019.02910
Meconium microbiota predicts clinical early-onset neonatal sepsis in preterm neonates.
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians
BACKGROUND:Early-onset neonatal sepsis (EONS) remains one of the leading causes of morbidity and mortality related to premature birth, and its diagnosis remains difficult. Our goal was to evaluate the intestinal microbiota of the first meconium of preterm newborns and ascertain whether it is associated with clinical EONS. METHODS:In a controlled, prospective cohort study, samples of the first meconium of premature infants with a gestational age (GA) ≤32 weeks was obtained at Hospital de Clínicas de Porto Alegre and DNA was isolated from the samples. 16S rDNA based microbiota composition of preterm infants with a clinical diagnosis of EONS was compared to that of a control group. RESULTS:40 (48%) premature infants with clinical diagnosis of EONS and 44 (52%) without EONS were included in the analysis. The most abundant phylum detected in both groups, , was more prevalent in the sepsis group ( = .034). 14% of variance among bacterial communities ( = .001) correlated with EONS. The genera most strongly associated with EONS were and . A single genus, , was most strongly associated with the control group. CONCLUSION:These findings suggest that the first-meconium microbiota is different in preterm neonates with and without clinical EONS.
10.1080/14767058.2020.1774870
Gut microbiota and sepsis: from pathogenesis to novel treatments.
Current opinion in gastroenterology
PURPOSE OF REVIEW:This review summarizes recent progress in our understanding of the role of the gut microbiota in sepsis pathogenesis and outlines the potential role of microbiota-targeted therapies. RECENT FINDINGS:The composition of the gut microbiome is profoundly distorted during sepsis, with a loss of commensal bacteria and an overgrowth of potential pathogenic micro-organisms. These alterations also extend to nonbacterial intestinal inhabitants. Disruptions of these intestinal communities are associated with both an increased susceptibility to develop sepsis, as well as a higher risk of adverse outcomes. Preclinical studies have characterized the effects of several microbiota-derived metabolites (such as D-lactate, butyrate, and deoxycholic acid) on enhancing the host immune response during critical illness. Microbiota-targeted therapies (e.g. probiotics or fecal microbiota transplantation) might be of benefit, but can also be associated with increased risks of bloodstream infections. SUMMARY:Emerging evidence display an important role of gut micro-organisms (including bacteria, fungi, eukaryotic viruses, and bacteriophages) and their derived metabolites in both the susceptibility to, as well as outcomes of sepsis. Despite recent progress in the mechanistic understanding of microbiota-mediated protection, clinical breakthroughs in the development of microbiota-based prognostic tools or therapies are thus far lacking in the field of sepsis.
10.1097/MOG.0000000000000781
Analysis of gut microbiota alteration and application as an auxiliary prognostic marker for sepsis in children: a pilot study.
Translational pediatrics
BACKGROUND:Emerging evidence suggests that gut microbiota dysbiosis plays a role in sepsis. Recent advances in sequencing technology enable the characterization of the gut microbiota and can provide clues for the pathogenesis of sepsis, which may help develop biomarkers for diagnosis or prognosis prediction in children with sepsis. METHODS:The gut microbiota from 25 children with sepsis and 15 age- and sex-matched healthy controls were extracted and sequenced by high-throughput Illumina Hiseq, targeting the 16S rDNA genes. The differences of gut microbiota between the two groups were analyzed to assess if the gut microbiota can be used as an auxiliary prognostic marker for sepsis. RESULTS:The diversity of gut microbiota in children with sepsis was significantly lower than that of healthy controls (P<0.001). The overall community structure of gut microbiota was also altered considerably. On the genus level, children with sepsis had more opportunistic pathogens, such as and , while fewer beneficial bacterial, such as , , , , and , were detected. Further analysis of the association between the gut microbiota and clinical features revealed that the pathogens from bacteria culture correlated to the dominant bacteria genus detected in the intestinal flora. Furthermore, the gut microbiota diversity was negatively associated with the antibiotic therapy duration, but did not correlate with type of antibiotics used. Finally, gut microbiota disturbance was correlated with increased mortality rate. CONCLUSIONS:Overall, we confirmed that gut microbiota disturbance occurred in the children with sepsis, and changes in the fecal microbiota were closely related to clinical characteristics. Elucidation of such dysbiosis could improve our understanding of sepsis pathogenesis and help develop microbiota-based diagnosis, monitoring, and therapy for sepsis.
10.21037/tp-21-51
The Potential Impact of the Gut Microbiota on Neonatal Brain Development and Adverse Health Outcomes.
Children (Basel, Switzerland)
Over the past decade, microbiome research has significantly expanded in both scope and volume, leading to the development of new models and treatments targeting the gut-brain axis to mitigate the effects of various disorders. Related research suggests that interventions during the critical period from birth to three years old may yield the greatest benefits. Investigating the substantial link between the gut and brain during this crucial developmental phase raises fundamental issues about the role of microorganisms in human health and brain development. This underscores the importance of focusing on the prevention rather than the treatment of neurodevelopmental and neuropsychiatric disorders. The present review examines the gut microbiota from birth to age 3, with a particular focus on its potential relationship with neurodevelopment. This review emphasizes the immunological mechanisms underlying this relationship. Additionally, the study investigates the impact of the microbiome on cognitive development and neurobehavioral issues such as anxiety and autism. Importantly, it highlights the need to integrate mechanistic studies of animal models with epidemiological research across diverse cultures to better understand the role of a healthy microbiome in early life and the implications of dysbiosis. Furthermore, this review summarizes factors contributing to the transmission of gut microbiome-targeted therapies and their effects on neurodevelopment. Recent studies on environmental toxins known to impact neurodevelopment are also reviewed, exploring whether the microbiota may mitigate or modulate these effects.
10.3390/children11050552
Gut microbiome dysbiosis in neonatal sepsis.
Progress in molecular biology and translational science
Sepsis is a highly heterogeneous, life-threatening organ dysfunction primarily caused by a dysregulated immune response to counter bacterial, viral, or fungal infections, resulting in haemodynamic changes and significant morbidity and mortality across all ages. In recent times, it has become one of the foremost causes of morbidity and mortality among newborns globally. The neonates, particularly the preterm neonates, due to their immature immune systems and non-canonical microbial community acquisition in the gastrointestinal tract and other body habitats, are adversely affected compared to the elderly with immunocompromised conditions. The neonates could acquire microbiota in utero or during delivery from the mother's genital tract or postnatally from contact with hospital personnel and the immediate hospital environment after the birth. Other factors that may enhance the risk include early colonization of microbiota by pathogens that trigger dysbiosis of the gut microbiome accompanied by a dysregulated immune response, organ dysfunction, and potential death. The sepsis-linked mortality could be prevented by timely diagnosis, selective antibiotic therapy, and supportive postnatal care. Infections due to antibiotic-resistant bacteria severely restrict possible therapeutic options, thus extending hospital stays. A comprehensive analysis of the infecting pathogens, cognate host responses, and the microbiota present would certainly help formulate appropriate interventions.
10.1016/bs.pmbts.2022.07.010
Clinical implications of preterm infant gut microbiome development.
Nature microbiology
Perturbations to the infant gut microbiome during the first weeks to months of life affect growth, development and health. In particular, assembly of an altered intestinal microbiota during infant development results in an increased risk of immune and metabolic diseases that can persist into childhood and potentially into adulthood. Most research into gut microbiome development has focused on full-term babies, but health-related outcomes are also important for preterm babies. The systemic physiological immaturity of very preterm gestation babies (born earlier than 32 weeks gestation) results in numerous other microbiome-organ interactions, the mechanisms of which have yet to be fully elucidated or in some cases even considered. In this Perspective, we compare assembly of the intestinal microbiome in preterm and term infants. We focus in particular on the clinical implications of preterm infant gut microbiome composition and discuss the prospects for microbiome diagnostics and interventions to improve the health of preterm babies.
10.1038/s41564-021-01025-4
Connection between gut microbiome and brain development in preterm infants.
Lu Jing,Claud Erika C
Developmental psychobiology
Dysbiosis of the gut microbiome in preterm infants predisposes the neonate to various major morbidities including neonatal necrotizing enterocolitis and sepsis in the neonatal intensive care unit, and adverse neurological outcomes later in life. There are parallel early developmental windows for the gut microbiota and the nervous system during prenatal to postnatal of life. Therefore, preterm infants represent a unique population in which optimization of initial colonization and microbiota development can affect brain development and enhance neurological outcomes. In this review, we will first discuss the factors affecting the assembly of neonatal gut microbiota and the contribution of dysbiosis in preterm infants to neuroinflammation and neurodevelopmental disorders. We then will discuss the emerging pathways connecting the gut microbiome and brain development. Further we will discuss the significance of current models for alteration of the gut microbiome (including humanized gnotobiotic models and exposure to antibiotics) to brain development and functions. Understanding the role of early optimization of the microbiome in brain development is of paramount importance for developing microbiome-targeted therapies and protecting infants from prematurity-related neurodevelopmental diseases.
10.1002/dev.21806
Preterm infants at low risk for early-onset sepsis differ in early fecal microbiome assembly.
Gut microbes
Antibiotics are administered near-universally to very low birth weight (VLBW) infants after birth for suspected early-onset sepsis (EOS). We previously identified a phenotypic group of VLBW infants, referred to as low-risk for EOS (LRE), whose risk of EOS is low enough to avoid routine antibiotic initiation. In this cohort study, we compared 18 such infants with 30 infants categorized as non-LRE to determine if the lower risk of pathogen transmission at birth is accompanied by differences in microbiome acquisition and development. We did shotgun metagenomic sequencing of 361 fecal samples obtained serially. LRE infants had a higher human-to-bacterial DNA ratio than non-LRE infants in fecal samples on days 1-3 after birth, confirming lower bacterial acquisition among LRE infants. The microbial diversity and composition in samples from days 4-7 differed between the groups with a predominance of in LRE infants and Enterobacteriaceae sp. in non-LRE infants. Compositional differences were congruent with the distribution of virulence factors and antibiotic resistant genes. After the first week, the overall composition was similar, but changes in relative abundance for several taxa with increasing age differed between groups. Of the nine late-onset bacteremia episodes, eight occurred in non-LRE infants. Species isolated from the blood culture was detected in the pre-antibiotic fecal samples of the infant for all episodes, though these species were also found in infants without bacteremia. In conclusion, LRE infants present a distinct pattern of microbiome development that is aligned with their low risk for EOS. Further investigation to determine the impact of these differences on later outcomes such as late-onset bacteremia is warranted.
10.1080/19490976.2022.2154091
The role of the gut microbiota in sepsis.
Haak Bastiaan W,Wiersinga W Joost
The lancet. Gastroenterology & hepatology
For decades, the gut was thought to play an important role in sepsis pathogenesis. Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Organ failure assessment for sepsis focuses on respiratory, cardiovascular, hepatic, renal, neurological, and haematological systems. Unfortunately, symptoms of gut failure are non-specific and are therefore not assessed. The composition of the intestinal microbiome, however, is affected by sepsis, and might contribute to the development of organ failure. Experimental work underscores the role of the microbiota in maintaining gut-barrier function, and modulation of the innate and adaptive immune system. Translation of these preclinical findings into functional characterisations will be essential to understand how disruption of commensals affects susceptibility and outcome of sepsis. In this Review, we identify knowledge gaps which, if addressed, will help researchers understand the role of the microbiota in sepsis, and provide microbiota-targeted tools to improve sepsis management.
10.1016/S2468-1253(16)30119-4
The gut microbiome's role in the development, maintenance, and outcomes of sepsis.
Adelman Max W,Woodworth Michael H,Langelier Charles,Busch Lindsay M,Kempker Jordan A,Kraft Colleen S,Martin Greg S
Critical care (London, England)
The gut microbiome regulates a number of homeostatic mechanisms in the healthy host including immune function and gut barrier protection. Loss of normal gut microbial structure and function has been associated with diseases as diverse as Clostridioides difficile infection, asthma, and epilepsy. Recent evidence has also demonstrated a link between the gut microbiome and sepsis. In this review, we focus on three key areas of the interaction between the gut microbiome and sepsis. First, prior to sepsis onset, gut microbiome alteration increases sepsis susceptibility through several mechanisms, including (a) allowing for expansion of pathogenic intestinal bacteria, (b) priming the immune system for a robust pro-inflammatory response, and (c) decreasing production of beneficial microbial products such as short-chain fatty acids. Second, once sepsis is established, gut microbiome disruption worsens and increases susceptibility to end-organ dysfunction. Third, there is limited evidence that microbiome-based therapeutics, including probiotics and selective digestive decontamination, may decrease sepsis risk and improve sepsis outcomes in select patient populations, but concerns about safety have limited uptake. Case reports of a different microbiome-based therapy, fecal microbiota transplantation, have shown correlation with gut microbial structure restoration and decreased inflammatory response, but these results require further validation. While much of the evidence linking the gut microbiome and sepsis has been established in pre-clinical studies, clinical evidence is lacking in many areas. To address this, we outline a potential research agenda for further investigating the interaction between the gut microbiome and sepsis.
10.1186/s13054-020-02989-1
Crosstalk between gut microbiota and sepsis.
Burns & trauma
Sepsis is an overwhelming inflammatory response to microbial infection. Sepsis management remains a clinical challenge. The role of the gut microbiome in sepsis has gained some attention. Recent evidence has demonstrated that gut microbiota regulate host physiological homeostasis mediators, including the immune system, gut barrier function and disease susceptibility pathways. Therefore, maintenance or restoration of microbiota and metabolite composition might be a therapeutic or prophylactic target against critical illness. Fecal microbiota transplantation and supplementation of probiotics are microbiota-based treatment methods that are somewhat limited in terms of evidence-based efficacy. This review focuses on the importance of the crosstalk between the gastrointestinal ecosystem and sepsis to highlight novel microbiota-targeted therapies to improve the outcomes of sepsis treatment.
10.1093/burnst/tkab036
Metagenomics Approaches to Investigate the Neonatal Gut Microbiome.
Frontiers in pediatrics
Early infancy is critical for the development of an infant's gut flora. Many factors can influence microbiota development during the pre- and postnatal periods, including maternal factors, antibiotic exposure, mode of delivery, dietary patterns, and feeding type. Therefore, investigating the connection between these variables and host and microbiome interactions in neonatal development would be of great interest. As the "unculturable" era of microbiome research gives way to an intrinsically multidisciplinary field, microbiome research has reaped the advantages of technological advancements in next-generation sequencing, particularly 16S rRNA gene amplicon and shotgun sequencing, which have considerably expanded our knowledge about gut microbiota development during early life. Using omics approaches to explore the neonatal microbiome may help to better understand the link between the microbiome and newborn diseases. Herein, we summarized the metagenomics methods and tools used to advance knowledge on the neonatal microbiome origin and evolution and how the microbiome shapes early and late individuals' lives for health and disease. The way to overcome limitations in neonatal microbiome studies will be discussed.
10.3389/fped.2022.886627
Early-life gut microbiota and neurodevelopment in preterm infants: a narrative review.
Frontiers in nutrition
Infants born preterm are at a high risk of both gut microbiota (GM) dysbiosis and neurodevelopmental impairment. While the link between early dysbiosis and short-term clinical outcomes is well established, the relationship with long-term infant health has only recently gained interest. Notably, there is a significant overlap in the developmental windows of GM and the nervous system in early life. The connection between GM and neurodevelopment was first described in animal models, but over the last decade a growing body of research has also identified GM features as one of the potential mediators for human neurodevelopmental and neuropsychiatric disorders. In this narrative review, we provide an overview of the developing GM in early life and its prospective relationship with neurodevelopment, with a focus on preterm infants. Animal models have provided evidence for emerging pathways linking early-life GM with brain development. Furthermore, a relationship between both dynamic patterns and static features of the GM during preterm infants' early life and brain maturation, as well as neurodevelopmental outcomes in early childhood, was documented. Future human studies in larger cohorts, integrated with studies on animal models, may provide additional evidence and help to identify predictive biomarkers and potential therapeutic targets for healthy neurodevelopment in preterm infants.
10.3389/fnut.2023.1241303
Necrotizing enterocolitis, gut microbes, and sepsis.
Gut microbes
Necrotizing enterocolitis (NEC) is a devastating disease in premature infants and the leading cause of death and disability from gastrointestinal disease in this vulnerable population. Although the pathophysiology of NEC remains incompletely understood, current thinking indicates that the disease develops in response to dietary and bacterial factors in the setting of a vulnerable host. As NEC progresses, intestinal perforation can result in serious infection with the development of overwhelming sepsis. In seeking to understand the mechanisms by which bacterial signaling on the intestinal epithelium can lead to NEC, we have shown that the gram-negative bacterial receptor toll-like receptor 4 is a critical regulator of NEC development, a finding that has been confirmed by many other groups. This review article provides recent findings on the interaction of microbial signaling, the immature immune system, intestinal ischemia, and systemic inflammation in the pathogenesis of NEC and the development of sepsis. We will also review promising therapeutic approaches that show efficacy in pre-clinical studies.
10.1080/19490976.2023.2221470
Gut Injury and the Microbiome in Neonates.
Pammi Mohan,Hollister Emily,Neu Josef
Clinics in perinatology
The causes of neonatal gut injury are multifactorial and include ischemia, tissue hypoxia due to anemia, excessive inflammation, deficiency of growth factors, and food protein sensitivity. The developing intestinal microbiome plays a role in some of these forms of intestinal injury but knowledge of its relative role in each remains poorly understood. Commensal bacteria are required for normal immune development and immune tolerance. Dysbiosis in the neonatal gut that alters the patterns of commensal and pathogenic bacteria may accentuate gut injury.
10.1016/j.clp.2020.02.010
Establishment of an ideal gut microbiota to boost healthy growth of neonates.
Nguyen Thi Thanh Binh,Chung Hea-Jong,Kim Hyeon-Jin,Hong Seong-Tshool
Critical reviews in microbiology
For decades, supporting the optimal growth of low birth weight (LBW) infants has been considered one of the most important paediatric challenges, despite advances in neonatal intensive care technology and nutrition interventions. Since gut microbiota affects such diverse phenotypes in adults, the difference in gut microbiota composition between normal infants and LBW infants raises the possibility of gut microbiota playing an important role in different growth rates of neonates. Based on the concept that probiotics are generally beneficial to the health, numerous studies have been made on probiotics as a supplement to the diet of the LBW infants. However, clinical results on the effects of probiotics on LBW infant growth are either inconsistent or contradictory with each other, and thus the contribution of gut microbiota in neonatal growth has remained inconclusive. In this review, recent researches on neonatal gut microbiota are discussed to develop a new strategy for targeting gut microbiota as a solution to growth retardation in LBW infants. We also discuss how to establish the ideal gut microbiota to support optimal growth of LBW infants.
10.1080/1040841X.2018.1561643
Gut Dysbiosis, Bacterial Colonization and Translocation, and Neonatal Sepsis in Very-Low-Birth-Weight Preterm Infants.
Lee Chien-Chung,Feng Ye,Yeh Yuan-Ming,Lien Reyin,Chen Chyi-Liang,Zhou Ying-Li,Chiu Cheng-Hsun
Frontiers in microbiology
Gut dysbiosis may precede neonatal sepsis, but the association is still not well-understood. The goal of this study is to investigate the association between gut microbiota and neonatal sepsis, and to seek the evidence of colonization of pathogenic bacteria in the gut before evolving into an invasive infection. A prospective cohort study examined fecal microbiota composition in preterm infants with and without sepsis. Thirty-two very-low-birth-weight (VLBW) preterm infants and 10 healthy term infants as controls were enrolled. The fecal samples collected from the participants at the first, fourth, and seventh weeks of life underwent 16S rRNA amplicon sequencing for measurement of the diversity and composition of the microbiota. The bacterial isolates causing neonatal sepsis were genome sequenced. PCR was performed to confirm the translocation of the bacteria from the gut to the blood. The results showed that VLBW preterm infants with sepsis had lower microbial diversity in the gut at birth compared to preterm infants without sepsis and term infants. The composition of gut microbiome in preterm infants was similar to healthy terms at birth but evolved toward dysbiosis with increasing and decreasing weeks later. The strain-specific PCR confirmed the presence of causative pathogens in the gut in 4 (40%) out of 10 VLBW preterms with sepsis before or at onset of sepsis, and persistence of the colonization for weeks after antibiotic treatment. The same bacterial strain could horizontally spread to cause infection in other infants. Prolonged antibiotic exposure significantly reduced beneficial and in the gut. In conclusion, preterm infants with gut dysbiosis are at risk for neonatal sepsis, and the causative pathogens may be from the gut and persist to spread horizontally. The association of increased abundance and decrease in microbiome diversity suggests the need for interventions targeting the gut microbiome to prevent dysbiosis and sepsis in VLBW preterm infants.
10.3389/fmicb.2021.746111
The impact of gut microbiota on morbidities in preterm infants.
The Kaohsiung journal of medical sciences
The gut microbiota undergoes substantial development from birth, and its development in the initial years of life has a potentially lifelong effect on the health of the individual. However, various factors can disrupt the development of the gut microbiota, leading to a condition known as dysbiosis, particularly in preterm infants. Current studies involving adults have suggested that the gut microbiota not only influences the gut but also has multidimensional effects on remote organs; these pathways are often referred to as the gut-organ axis. Imbalance of the gut microbiota may lead to the development of multiple diseases. Recent studies have revealed that gut dysbiosis in preterm infants may cause several acute morbidities-such as necrotizing enterocolitis, late-onset sepsis, bronchopulmonary dysplasia, and retinopathy of prematurity-and it may also influence long-term outcomes including neurodevelopment and somatic growth. This review mainly presents the existing evidence regarding the relationships between the gut microbiota and these morbidities in preterm infants and explores the role of the gut-organ axis in these morbidities. This paper thus offers insights into the future perspectives on microbiota interventions for promoting the health of preterm infants.
10.1002/kjm2.12878
The Problem of Microbial Dark Matter in Neonatal Sepsis.
Sinnar Shamim A,Schiff Steven J
Emerging infectious diseases
Neonatal sepsis (NS) kills 750,000 infants every year. Effectively treating NS requires timely diagnosis and antimicrobial therapy matched to the causative pathogens, but most blood cultures for suspected NS do not recover a causative pathogen. We refer to these suspected but unidentified pathogens as microbial dark matter. Given these low culture recovery rates, many non-culture-based technologies are being explored to diagnose NS, including PCR, 16S amplicon sequencing, and whole metagenomic sequencing. However, few of these newer technologies are scalable or sustainable globally. To reduce worldwide deaths from NS, one possibility may be performing population-wide pathogen discovery. Because pathogen transmission patterns can vary across space and time, computational models can be built to predict the pathogens responsible for NS by region and season. This approach could help to optimally treat patients, decreasing deaths from NS and increasing antimicrobial stewardship until effective diagnostics that are scalable become available globally.
10.3201/eid2611.200004
The Microbiota-Gut Axis in Premature Infants: Physio-Pathological Implications.
Cells
Intriguing evidence is emerging in regard to the influence of gut microbiota composition and function on host health from the very early stages of life. The development of the saprophytic microflora is conditioned by several factors in infants, and peculiarities have been found for babies born prematurely. This population is particularly exposed to a high risk of infection, postnatal antibiotic treatment, feeding difficulties and neurodevelopmental disabilities. To date, there is still a wide gap in understanding all the determinants and the mechanism behind microbiota disruption and its influence in the development of the most common complications of premature infants. A large body of evidence has emerged during the last decades showing the existence of a bidirectional communication axis involving the gut microbiota, the gut and the brain, defined as the microbiota-gut-brain axis. In this context, given that very few data are available to demonstrate the correlation between microbiota dysbiosis and neurodevelopmental disorders in preterm infants, increasing interest has arisen to better understand the impact of the microbiota-gut-brain axis on the clinical outcomes of premature infants and to clarify how this may lead to alternative preventive, diagnostic and therapeutic strategies. In this review, we explored the current evidence regarding microbiota development in premature infants, focusing on the effects of delivery mode, type of feeding, environmental factors and possible influence of the microbiota-gut-brain axis on preterm clinical outcomes during their hospital stay and on their health status later in life.
10.3390/cells11030379
DECIPHERING GUT MICROBIOTA IN PATIENTS WITH SEVERE SEPSIS AND SEPTIC SHOCK.
Shock (Augusta, Ga.)
ABSTRACT:Introduction: Gut microbiota dysbiosis is associated with susceptibility to sepsis and poor outcomes. However, changes to the intestinal microbiota during sepsis and their value as biomarkers are unclear. In this study, we compared the intestinal microbiota of patients with sepsis and healthy controls. Methods: Stool was collected from patients with sepsis (subdivided according to mortality) and controls. Microbiome diversity and composition were analyzed by 16S rRNA gene pyrosequencing. The α-diversity of the intestinal microbiome was determined using operational taxonomic unit counts and the Chao1, Shannon, and ACE indices. Adjusted Cox regression analyses assessed 6-month mortality risk factors. Results: Fifty-nine patients (14 in-hospital deaths) and 29 healthy controls were enrolled. Operational taxonomic unit counts and Chao1 and ACE indices were lower in the nonsurvivor than in the other groups. The controls showed a higher Shannon and lower Simpson index than did the sepsis group. The genus Blautia was more abundant in controls than in the sepsis group, and Faecalibacterium less abundant in the nonsurvivor than in the other groups. Regression analysis associated low Shannon index with 6-month mortality. Conclusions: Survivors of sepsis, nonsurvivors, and healthy controls have different gut microbiomes, and a low Shannon index is a risk factor for 6-month mortality.
10.1097/SHK.0000000000002241
The Role of Gut Microbiota in the Clinical Outcome of Septic Patients: State of the Art and Future Perspectives.
International journal of molecular sciences
Sepsis is a life-threatening multiple-organ dysfunction caused by a dysregulated host response to infection, with high mortality worldwide; 11 million deaths per year are attributable to sepsis in high-income countries. Several research groups have reported that septic patients display a dysbiotic gut microbiota, often related to high mortality. Based on current knowledge, in this narrative review, we revised original articles, clinical trials, and pilot studies to evaluate the beneficial effect of gut microbiota manipulation in clinical practice, starting from an early diagnosis of sepsis and an in-depth analysis of gut microbiota.
10.3390/ijms24119307
Profound Pathogen-Specific Alterations in Intestinal Microbiota Composition Precede Late-Onset Sepsis in Preterm Infants: A Longitudinal, Multicenter, Case-Control Study.
El Manouni El Hassani Sofia,Niemarkt Hendrik J,Berkhout Daniel J C,Peeters Carel F W,Hulzebos Christian V,van Kaam Anton H,Kramer Boris W,van Lingen Richard A,Jenken Floor,de Boode Willem P,Benninga Marc A,Budding Andries E,van Weissenbruch Mirjam M,de Boer Nanne K H,de Meij Tim G J
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
BACKGROUND:The role of intestinal microbiota in the pathogenesis of late-onset sepsis (LOS) in preterm infants is largely unexplored but could provide opportunities for microbiota-targeted preventive and therapeutic strategies. We hypothesized that microbiota composition changes before the onset of sepsis, with causative bacteria that are isolated later in blood culture. METHODS:This multicenter case-control study included preterm infants born under 30 weeks of gestation. Fecal samples collected from the 5 days preceding LOS diagnosis were analyzed using a molecular microbiota detection technique. LOS cases were subdivided into 3 groups: gram-negative, gram-positive, and coagulase-negative Staphylococci (CoNS). RESULTS:Forty LOS cases and 40 matched controls were included. In gram-negative LOS, the causative pathogen could be identified in at least 1 of the fecal samples collected 3 days prior to LOS onset in all cases, whereas in all matched controls, this pathogen was absent (P = .015). The abundance of these pathogens increased from 3 days before clinical onset. In gram-negative and gram-positive LOS (except CoNS) combined, the causative pathogen could be identified in at least 1 fecal sample collected 3 days prior to LOS onset in 92% of the fecal samples, whereas these pathogens were present in 33% of the control samples (P = .004). Overall, LOS (expect CoNS) could be predicted 1 day prior to clinical onset with an area under the curve of 0.78. CONCLUSIONS:Profound preclinical microbial alterations underline that gut microbiota is involved in the pathogenesis of LOS and has the potential as an early noninvasive biomarker.
10.1093/cid/ciaa1635
Gut microbiota in preterm infants with late-onset sepsis and pneumonia: a pilot case-control study.
BMC microbiology
BACKGROUND:Late-onset sepsis (LOS) and pneumonia are common infectious diseases, with high morbidity and mortality in neonates. This study aimed to investigate the differences in the gut microbiota among preterm infants with LOS, or pneumonia, and full-term infants. Furthermore, this study aimed to determine whether there is a correlation between intestinal pathogenic colonization and LOS. METHODS:In a single-center case‒control study, 16 S rRNA gene sequencing technology was used to compare gut microbiota characteristics and differences among the LOS group, pneumonia group, and control group. RESULTS:Our study revealed that the gut microbiota in the control group was more diverse than that in the LOS group and pneumonia group (P < 0.05). No significant differences in diversity were detected between the LOS and pneumonia groups (P > 0.05). Compared with the control group, the abundances of Akkermansia, Escherichia/Shigella, and Enterococcus increased, while the abundances of Bacteroides and Stenotrophomonas decreased in the LOS and pneumonia groups. The pathogenic bacteria in infants with LOS were consistent with the distribution of the main bacteria in the intestinal microbiota. An increase in Escherichia/Shigella abundance may predict a high risk of LOS occurrence, with an area under the curve (AUC) of 0.773. CONCLUSION:Changes in the gut microbiota composition were associated with an increased risk of LOS and pneumonia. The dominant bacteria in the gut microbiota of the LOS group were found to be associated with the causative pathogen of LOS. Moreover, preterm infants exhibiting an elevated abundance of Escherichia/Shigella may be considered potential candidates for predicting the onset of LOS.
10.1186/s12866-024-03419-w
Development of the Neonatal Intestinal Barrier, Microbiome, and Susceptibility to NEC.
Microorganisms
The function of the intestinal barrier is partially dependent on host maturity and the colonization patterns of the microbiome to which it is exposed. Premature birth and stressors of neonatal intensive care unit (NICU)-related support (e.g., antibiotics, steroids, etc.) can alter the host internal environment resulting in changes in the intestinal barrier. Pathogenic microbial proliferation and breach of the immature intestinal barrier are proposed to be crucial steps in the development of neonatal diseases such as necrotizing enterocolitis. This article will review the current literature on the intestinal barrier in the neonatal gut, the consequences of microbiome development for this defense system, and how prematurity can influence neonatal susceptibility to gastrointestinal infection.
10.3390/microorganisms11051247
Therapeutic Potential of the Gut Microbiota in the Management of Sepsis.
Critical care (London, England)
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2020. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2020. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.
10.1186/s13054-020-2780-3
Neonatal infection induces long-lasting dysbiosis of the gut microbiota in a mouse model.
Frontiers in microbiology
Early life is a "critical window" for gut microbiota development, antibiotic use during this period exerts a profound effect on gut microbial dysbiosis and asthma. In clinical practice, antibiotics are usually used in patients with bacterial infections, we previously showed that neonatal pneumonia promoted adult-onset asthma in mice model, while it remains unclear whether neonatal infection have long-term effects on gut microbiota. Neonatal BALB/c mice were inoculated with 5*10 CFU D39 to establish non-lethal pneumonia model. At 2, 3, 8 weeks of age, feces in the cecum were prepared for 16S rRNA sequencing, lungs were collected for histopathologic and lung function analysis. -infected neonatal mice exhibited histopathologic lesions in their lungs and increased airway hyperresponsiveness, obvious alterations in alpha and beta diversities in the entire gut microbiota, and changes of the community structure during the breastfeeding period, infancy, and adulthood. Furthermore, gut microbial composition was modified after neonatal infection, with a decreased relative abundance of Lactobacillus in the breastfeeding period and infancy; in adulthood, the relative abundance of Allobaculum diminished while that of Proteobacteria was augmented. Neonatal infection induced a long-term alteration in microbial community composition.
10.3389/fmicb.2022.961684
Microbiota Signals during the Neonatal Period Forge Life-Long Immune Responses.
Phillips-Farfán Bryan,Gómez-Chávez Fernando,Medina-Torres Edgar Alejandro,Vargas-Villavicencio José Antonio,Carvajal-Aguilera Karla,Camacho Luz
International journal of molecular sciences
The microbiota regulates immunological development during early human life, with long-term effects on health and disease. Microbial products include short-chain fatty acids (SCFAs), formyl peptides (FPs), polysaccharide A (PSA), polyamines (PAs), sphingolipids (SLPs) and aryl hydrocarbon receptor (AhR) ligands. Anti-inflammatory SCFAs are produced by Actinobacteria, Bacteroidetes, Firmicutes, Spirochaetes and Verrucomicrobia by undigested-carbohydrate fermentation. Thus, fiber amount and type determine their occurrence. FPs bind receptors from the pattern recognition family, those from commensal bacteria induce a different response than those from pathogens. PSA is a capsular polysaccharide from B. fragilis stimulating immunoregulatory protein expression, promoting IL-2, STAT1 and STAT4 gene expression, affecting cytokine production and response modulation. PAs interact with neonatal immunity, contribute to gut maturation, modulate the gut-brain axis and regulate host immunity. SLPs are composed of a sphingoid attached to a fatty acid. Prokaryotic SLPs are mostly found in anaerobes. SLPs are involved in proliferation, apoptosis and immune regulation as signaling molecules. The AhR is a transcription factor regulating development, reproduction and metabolism. AhR binds many ligands due to its promiscuous binding site. It participates in immune tolerance, involving lymphocytes and antigen-presenting cells during early development in exposed humans.
10.3390/ijms22158162
Neonatal sepsis and the skin microbiome.
Journal of perinatology : official journal of the California Perinatal Association
Neonatal sepsis is a major cause of morbidity and mortality in preterm infants. Preterm and very low birth weight infants are particularly susceptible to sepsis due to their immature skin barrier, naive immune system, exposure to broad-spectrum antibiotics, and insertion of medical devices. Neonatal intestinal dysbiosis has been linked to neonatal sepsis; however, the cutaneous microbiome likely plays a role as well, as common sepsis pathogens also dominate the skin flora. This review summarizes our current understanding of the infant skin microbiome and common causative pathogens in neonatal sepsis, as well as the relationship between the two. A better understanding of the role of the skin microbiome in the pathogenesis of neonatal sepsis may guide future prophylaxis and treatment.
10.1038/s41372-022-01451-0
The role of the preterm intestinal microbiome in sepsis and necrotising enterocolitis.
Masi Andrea C,Stewart Christopher J
Early human development
Late-onset sepsis (LOS) and necrotising enterocolitis (NEC) account for the highest number of deaths in premature infants and often cause severe morbidity in survivors. NEC is an inflammatory mediated condition, but its pathophysiology remains poorly understood. There is increasing evidence that in LOS the causative organism most often translocates from the gut. No causative microorganism has been consistently associated with either LOS or NEC, but an aberrant gut microbiome development could play a pivotal role. A low bacterial diversity and a delay in anaerobic bacteria colonization may predispose preterm infants to disease development. Conversely, a predominance of Bifidobacterium species and breast milk feeding might help to prevent disease onset. With numerous studies reporting conflicting results, further research is needed to better understand the role of microorganisms and type of feeding in the health status of preterm infants.
10.1016/j.earlhumdev.2019.104854
Longitudinal development of the gut microbiome and metabolome in preterm neonates with late onset sepsis and healthy controls.
Stewart Christopher J,Embleton Nicholas D,Marrs Emma C L,Smith Daniel P,Fofanova Tatiana,Nelson Andrew,Skeath Tom,Perry John D,Petrosino Joseph F,Berrington Janet E,Cummings Stephen P
Microbiome
BACKGROUND:Late onset sepsis (LOS) in preterm infants is associated with considerable morbidity and mortality. While studies have implicated gut bacteria in the aetiology of the disease, functional analysis and mechanistic insights are generally lacking. We performed temporal bacterial (n = 613) and metabolomic (n = 63) profiling on extensively sampled stool from 7 infants with LOS and 28 matched healthy (no LOS or NEC) controls. RESULTS:The bacteria isolated in diagnostic blood culture usually corresponded to the dominant bacterial genera in the gut microbiome. Longitudinal changes were monitored based on preterm gut community types (PGCTs), where control infants had an increased number of PGCTs compared to LOS infants (P = 0.011). PGCT 6, characterised by Bifidobacteria dominance, was only present in control infants. Metabolite profiles differed between LOS and control infants at diagnosis and 7 days later, but not 7 days prior to diagnosis. Bifidobacteria was positively correlated with control metabolites, including raffinose, sucrose, and acetic acid. CONCLUSIONS:Using multi-omic analysis, we show that the gut microbiome is involved in the pathogenesis of LOS. While the causative agent of LOS varies, it is usually abundant in the gut. Bifidobacteria dominance was associated with control infants, and the presence of this organism may directly protect, or act as a marker for protection, against gut epithelial translocation. While the metabolomic data is preliminary, the findings support that gut development and protection in preterm infants is associated with increased in prebiotic oligosaccharides (e.g. raffinose) and the growth of beneficial bacteria (e.g. Bifidobacterium).
10.1186/s40168-017-0295-1
Preventing dysbiosis of the neonatal mouse intestinal microbiome protects against late-onset sepsis.
Nature medicine
Late-onset sepsis (LOS) is thought to result from systemic spread of commensal microbes from the intestines of premature infants. Clinical use of probiotics for LOS prophylaxis has varied owing to limited efficacy, reflecting an incomplete understanding of relationships between development of the intestinal microbiome, neonatal dysbiosis and LOS. Using a model of LOS, we found that components of the developing microbiome were both necessary and sufficient to prevent LOS. Maternal antibiotic exposure that eradicated or enriched transmission of Lactobacillus murinus exacerbated and prevented disease, respectively. Prophylactic administration of some, but not all Lactobacillus spp. was protective, as was administration of Escherichia coli. Intestinal oxygen level was a major driver of colonization dynamics, albeit via mechanisms distinct from those in adults. These results establish a link between neonatal dysbiosis and LOS, and provide a basis for rational selection of probiotics that modulate primary succession of the microbiome to prevent disease.
10.1038/s41591-019-0640-y
Exploring the Role of Gut Bacteria in Health and Disease in Preterm Neonates.
International journal of environmental research and public health
The mortality rate of very preterm infants with birth weight <1500 g is as high as 15%. The survivors till discharge have a high incidence of significant morbidity, which includes necrotising enterocolitis (NEC), early-onset neonatal sepsis (EONS) and late-onset neonatal sepsis (LONS). More than 25% of preterm births are associated with microbial invasion of amniotic cavity. The preterm gut microbiome subsequently undergoes an early disruption before achieving bacterial maturation. It is postulated that bacterial gut colonisation at birth and postnatal intestinal dysbacteriosis precede the development of NEC and LONS in very preterm infants. In fact, bacterial colonization patterns in preterm infants greatly differ from term infants due to maternal chorioamnionitis, gestational age, delivery method, feeding type, antibiotic exposure and the environment factor in neonatal intensive care unit (NICU). In this regard, this review provides an overview on the gut bacteria in preterm neonates' meconium and stool. More than 50% of preterm meconium contains bacteria and the proportion increases with lower gestational age. Researchers revealed that the gut bacterial diversity is reduced in preterm infants at risk for LONS and NEC. Nevertheless, the association between gut dysbacteriosis and NEC is inconclusive with regards to relative bacteria abundance and between-sample beta diversity indices. With most studies show a disruption of the Proteobacteria and Firmicutes preceding the NEC. Hence, this review sheds light on whether gut bacteria at birth either alone or in combination with postnatal gut dysbacteriosis are associated with mortality and the morbidity of LONS and NEC in very preterm infants.
10.3390/ijerph17196963
Link between gut microbiota and neonatal sepsis.
Journal of the Formosan Medical Association = Taiwan yi zhi
In neonates, the gastrointestinal tract is rapidly colonized by bacteria after birth. Gut microbiota development is critical during the first few years of life. However, disruption of gut microbiota development in neonates can lead to gut dysbiosis, characterized by overcolonization by pathogenic bacteria and delayed or failed maturation toward increasing microbial diversity and Fermicutes dominance. Gut dysbiosis can predispose infants to sepsis. Pathogenic bacteria can colonize the gut prior to sepsis and cause sepsis through translocation. This review explores gut microbiota development in neonates, the evidence linking gut dysbiosis to neonatal sepsis, and the potential role of probiotics in gut microbiota modulation and sepsis prevention.
10.1016/j.jfma.2023.09.019
Interaction Between Altered Gut Microbiota and Sepsis: A Hypothesis or an Authentic Fact?
Journal of intensive care medicine
Sepsis, as an important public health concern, is one of the leading causes of death in hospitals around the world, accounting for 25% of all deaths. Nowadays, several factors contribute to the development of sepsis. The role of the gut microbiota and the response state of the aberrant immune system is dominant. The effect of the human microbiome on health is undeniable, and gut microbiota is even considered a body organ. It is now clear that the alteration in the normal balance of the microbiota (dysbiosis) is associated with a change in the status of immune system responses. Owing to the strong association between the gut microbiota and its metabolites particularly short-chain fatty acids with many illnesses, the gut microbiota has a unique position in the research of microbiologists and even clinicians. This review aimed to analyze studies' results on the association between microbiota and sepsis, with a substantial understanding of their relationship. As a result, an extensive and comprehensive search was conducted on this issue in existing databases.
10.1177/08850666221102796
[Intestinal microbiome and its relationship with necrotizing enterocolitis in very low birth weight preterm infants].
Wang C,Cui M L,Wang S N,Zhu X P
Zhonghua er ke za zhi = Chinese journal of pediatrics
To explore the composition of intestinal microflora prior to onset of necrotizing enterocolitis (NEC) in very low birth weight preterm infants. This was a multicenter prospective nested case-control study. A total of 46 very low birth weight preterm infants (birth weight <1 500 g and gestional age <35 weeks) within 24 h of life admitted into Neonatal Intensive Care Unit of Children's Hospital of Soochow University and Suzhou Municipal Hospital from April 20 to November 20, 2018 were enrolled. Baseline clinical data and fecal samples of these infants were collected. The subsequent sampling time points were 1st, 4th and 7th day in the first week of life then once per week consecutively. The endpoint of sampling was NEC occurrence, patient discharge or the 8th week post-discharge, whichever came first. Fecal samples were analyzed by 16 S rDNA high-throughput nucleotide sequencing. The control cases were infants without NEC who were matched to the NEC cases with a ratio of 1∶1. The operational taxonomic units (OTU), sequence number and shannon diversity index of the fecal samples were analyzed. Continuous variables were compared with -test or non-parametric test, and χ test or Fisher's exact test was used for categorical variables. There were 23 patients in each group. The gestational age was (29.4±1.8) weeks in NEC group and (29.9±1.6) weeks in control group, including 13 males (57%) and 11 males (48%) in each group, respectively. Species abundance showed that the in both groups decreased temporarily at 7 days of age and then increased with age in control group, but not in NEC group, the in both groups increased at 7 days of age and then decreased in control group, but kept increasing in NEC group. Regarding the other levels of taxonomy, compared with that of the control group, the NEC group had lower abundance of , γ- and at 7 days of age, while higer abundance of at 14 days of age, meanwhile, lower and at 21 days of age, lower , and and higher and γ- at 28 days of age, these differences were all statistically significant (=43.00, 43.00, 45.00, 80.00, 74.00, 76.00, 19.00, 8.00, 36.00, 25.00, 25.00,all <0.05). The shannon index of NEC group was both lower than that of the controls at 21 days of age (2.4 (1.4, 3.0) 3.1 (2.6, 4.0), =67.00, =0.027) and 28 days of age (2.4 (1.4, 2.8) 3.9 (3.3, 4.2), =12.00, 0.001). The intestinal microflora profile of very low birth weight preterm infants has already changed prior to NEC development. The emergence of differential flora and the reduction of microflora diversity may facilitate early identification and prevention of NEC.
10.3760/cma.j.cn112140-20211104-00928
Therapeutic Potential of the Gut Microbiota in the Prevention and Treatment of Sepsis.
Haak Bastiaan W,Prescott Hallie C,Wiersinga W Joost
Frontiers in immunology
Alongside advances in understanding the pathophysiology of sepsis, there have been tremendous strides in understanding the pervasive role of the gut microbiota in systemic host resistance. In pre-clinical models, a diverse and balanced gut microbiota enhances host immunity to both enteric and systemic pathogens. Disturbance of this balance increases susceptibility to sepsis and sepsis-related organ dysfunction, while restoration of the gut microbiome is protective. Patients with sepsis have a profoundly distorted composition of the intestinal microbiota, but the impact and therapeutic potential of the microbiome is not well-established in human sepsis. Modulation of the microbiota consists of either resupplying the pool of beneficial microbes by administration of probiotics, improving the intestinal microenvironment to enhance the growth of beneficial species by dietary interventions and prebiotics, or by totally recolonizing the gut with a fecal microbiota transplantation (FMT). We propose that there are three potential opportunities to utilize these treatment modalities over the course of sepsis: to decrease sepsis incidence, to improve sepsis outcome, and to decrease late mortality after sepsis. Exploring these three avenues will provide insight into how disturbances of the microbiota can predispose to, or even perpetuate the dysregulated immune response associated with this syndrome, which in turn could be associated with improved sepsis management.
10.3389/fimmu.2018.02042
Gut Microbiome in Sepsis.
Surgical infections
The gut has been hypothesized to be the "motor" of multiple organ dysfunction in sepsis. Although there are multiple ways in which the gut can drive systemic inflammation, increasing evidence suggests that the intestinal microbiome plays a more substantial role than previously appreciated. An English language literature review was performed to summarize the current knowledge of sepsis-induced gut microbiome dysbiosis. Conversion of a normal microbiome to a pathobiome in the setting of sepsis is associated with worsened mortality. Changes in microbiome composition and diversity signal the intestinal epithelium and immune system resulting in increased intestinal permeability and a dysregulated immune response to sepsis. Clinical approaches to return to microbiome homeostasis may be theoretically possible through a variety of methods including probiotics, prebiotics, fecal microbial transplant, and selective decontamination of the digestive tract. However, more research is required to determine the efficacy (if any) of targeting the microbiome for therapeutic gain. The gut microbiome rapidly loses diversity with emergence of virulent bacteria in sepsis. Restoring normal commensal bacterial diversity through various therapies may be an avenue to improve sepsis mortality.
10.1089/sur.2022.420
Gut Microbiota and Mucosal Immunity in the Neonate.
Dzidic Majda,Boix-Amorós Alba,Selma-Royo Marta,Mira Alex,Collado Maria Carmen
Medical sciences (Basel, Switzerland)
Gut microbiota colonization is a complex, dynamic, and step-wise process that is in constant development during the first years of life. This microbial settlement occurs in parallel with the maturation of the immune system, and alterations during this period, due to environmental and host factors, are considered to be potential determinants of health-outcomes later in life. Given that host⁻microbe interactions are mediated by the immune system response, it is important to understand the close relationship between immunity and the microbiota during birth, lactation, and early infancy. This work summarizes the evidence to date on early gut microbiota colonization, and how it influences the maturation of the infant immune system and health during the first 1000 days of life. This review will also address the influence of perinatal antibiotic intake and the importance of delivery mode and breastfeeding for an appropriate development of gut immunity.
10.3390/medsci6030056
Neonatal gut microbiome and immunity.
Current opinion in microbiology
Early life is a critical time window for the neonatal gut to be progressively populated with different bacterial species that collectively promote gut maturation. A fully developed and healthy gut microbiome in neonates is an important driver for the development of other aspects of health. Unlike the relatively stable gut microbiome in adults, the developing gut microbiome in neonates exhibits higher plasticity and adaptability. This also underscores the unique window of opportunity for intervention or preventive measures to improve long-term health through modulations of the gut microbiome in early life. Better understanding of the neonatal gut microbiome - how it arises and how it impacts immune cell development - will help us appreciate the underpinnings of immune-related diseases. Here, we examine recent findings on the neonatal gut microbiome and discuss their implications for understanding this important driver of the maturation of the immune system and immunity against infections in early life.
10.1016/j.mib.2020.05.011
Recent advances in understanding the neonatal microbiome.
F1000Research
The neonatal developmental window represents a key time for establishment of the gut microbiota. First contact with these microbes within the infant gastrointestinal tract signifies the start of a critical mutualistic relationship, which is central for short- and longer-term health. Recent research has provided insights into the origin of these microbial pioneers, how they are maintained within the gut environment, and how factors such as antibiotics or preterm birth may disrupt the succession of beneficial microbes. The acquisition, colonisation, and maintenance of the early life microbiota, and subsequent interactions with the host is a rapidly developing research area. In this review we explore some of these key topics which have been illuminated by recent research, and we highlight some of the important unresolved questions which currently limit our overall understanding of the neonatal gut microbiome.
10.12688/f1000research.22355.1
Gut microbiota differences in five-year-old children that were born preterm with a history of necrotizing enterocolitis: A pilot trial.
iScience
The study explores the long-term effects of necrotizing enterocolitis (NEC) on gut microbiota in preterm infants by analyzing stool samples from 5-year-old children using shotgun metagenomic sequencing. It compares children with a history of NEC, treated surgically or medically, to preterm controls without NEC. Findings reveal persistent gut microbiota dysbiosis in NEC children, with reduced species diversity and evenness, especially in those treated surgically. The surgical NEC group had a lower Shannon index, indicating less microbial diversity. Significant differences in taxonomic profiles were observed, mainly influenced by surgical treatment. These results underscore the lasting impact of NEC and its treatment on gut microbiota, suggesting a need for strategies addressing long-term dysbiosis.
10.1016/j.isci.2024.110325
Antibiotic resistance genes in the gut microbiota of mothers and linked neonates with or without sepsis from low- and middle-income countries.
Nature microbiology
Early development of the microbiome has been shown to affect general health and physical development of the infant and, although some studies have been undertaken in high-income countries, there are few studies from low- and middle-income countries. As part of the BARNARDS study, we examined the rectal microbiota of 2,931 neonates (term used up to 60 d) with clinical signs of sepsis and of 15,217 mothers screening for bla, bla, bla and bla-like genes, which were detected in 56.1%, 18.5%, 0% and 4.1% of neonates' rectal swabs and 47.1%, 4.6%, 0% and 1.6% of mothers' rectal swabs, respectively. Carbapenemase-positive bacteria were identified by MALDI-TOF MS and showed a high diversity of bacterial species (57 distinct species/genera) which exhibited resistance to most of the antibiotics tested. Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae/E. cloacae complex, the most commonly found isolates, were subjected to whole-genome sequencing analysis and revealed close relationships between isolates from different samples, suggesting transmission of bacteria between neonates, and between neonates and mothers. Associations between the carriage of antimicrobial resistance genes (ARGs) and healthcare/environmental factors were identified, and the presence of ARGs was a predictor of neonatal sepsis and adverse birth outcomes.
10.1038/s41564-022-01184-y
Importance of the Gut Microbiome in Preterm Infants.
Nestle Nutrition Institute workshop series
Birth represents the start of an incredible journey for the individual and the microbes which reside within and upon them. This interaction between human and microbe is essential for healthy development. Term infants are colonized by bacteria at birth, and thereafter the diet is the most important factor shaping the gut microbiome, in particular receipt of human milk. Human milk contains viable bacteria and numerous components that modulate the bacterial community, including human milk oligosaccharides (HMOs) which promote the growth of Bifidobacteriumspecies. Notably, Bifidobacteriumspp. are the primary bacterium used in probiotic supplements, owing to their association with positive outcomes in cohort studies and range of beneficial properties in mechanistic experiments. Preterm infants born <32 weeks' gestation encounter an unnatural beginning to life, with housing in "sterile" incubators, higher rates of caesarean delivery and antibiotic use, and complex nutritional provision. This reduces Bifidobacteriumabundance and overall microbial diversity. However, this also presents an opportunity to use probiotics and prebiotics (e.g., HMOs) to restore "normal" development. Much work has focused in this area over the past two decades and, while more work is needed, there is promise in symbiotic intervention to modulate the microbiome and reduce disease in preterm infants.
10.1159/000519396
A systematic review of associations between gut microbiota composition and growth failure in preterm neonates.
Gut microbes
Growth failure is among the most prevalent and devastating consequences of prematurity. Up to half of all extremely preterm neonates struggle to grow despite modern nutrition practices. Although elegant preclinical models suggest causal roles for the gut microbiome, these insights have not yet translated into biomarkers that identify at-risk neonates or therapies that prevent or treat growth failure. This systematic review aims to identify features of the neonatal gut microbiota that are positively or negatively associated with early postnatal growth. We identified 860 articles, of which 14 were eligible for inclusion. No two studies used the same definitions of growth, ages at stool collection, and statistical methods linking microbiota to metadata. In all, 58 different taxa were associated with growth, with little consensus among studies. Two or more studies reported positive associations with Enterobacteriaceae, , , , and , and negative associations with , and . was positively associated with growth in five studies and negatively associated with growth in three studies. To gain insight into how the various definitions of growth could impact results, we performed an exploratory secondary analysis of 245 longitudinally sampled preterm infant stools, linking microbiota composition to multiple clinically relevant definitions of neonatal growth. Within this cohort, every definition of growth was associated with a different combination of microbiota features. Together, these results suggest that the lack of consensus in defining neonatal growth may limit our capacity to detect consistent, meaningful clinical associations that could be leveraged into improved care for preterm neonates.
10.1080/19490976.2023.2190301
Challenges in developing a consensus definition of neonatal sepsis.
McGovern Matthew,Giannoni Eric,Kuester Helmut,Turner Mark A,van den Hoogen Agnes,Bliss Joseph M,Koenig Joyce M,Keij Fleur M,Mazela Jan,Finnegan Rebecca,Degtyareva Marina,Simons Sinno H P,de Boode Willem P,Strunk Tobias,Reiss Irwin K M,Wynn James L,Molloy Eleanor J,
Pediatric research
Sepsis remains a leading cause of morbidity and mortality in the neonatal population, and at present, there is no unified definition of neonatal sepsis. Existing consensus sepsis definitions within paediatrics are not suited for use in the NICU and do not address sepsis in the premature population. Many neonatal research and surveillance networks have criteria for the definition of sepsis within their publications though these vary greatly and there is typically a heavy emphasis on microbiological culture. The concept of organ dysfunction as a diagnostic criterion for sepsis is rarely considered in neonatal literature, and it remains unclear how to most accurately screen neonates for organ dysfunction. Accurately defining and screening for sepsis is important for clinical management, health service design and future research. The progress made by the Sepsis-3 group provides a roadmap of how definitions and screening criteria may be developed. Similar initiatives in neonatology are likely to be more challenging and would need to account for the unique presentation of sepsis in term and premature neonates. The outputs of similar consensus work within neonatology should be twofold: a validated definition of neonatal sepsis and screening criteria to identify at-risk patients earlier in their clinical course. IMPACT: There is currently no consensus definition of neonatal sepsis and the definitions that are currently in use are varied.A consensus definition of neonatal sepsis would benefit clinicians, patients and researchers.Recent progress in adults with publication of Sepsis-3 provides guidance on how a consensus definition and screening criteria for sepsis could be produced in neonatology.We discuss common themes and potential shortcomings in sepsis definitions within neonatology.We highlight the need for a consensus definition of neonatal sepsis and the challenges that this task poses.
10.1038/s41390-020-0785-x
Neonatal sepsis in low-income countries: epidemiology, diagnosis and prevention.
Popescu Constantin Radu,Cavanagh Miranda M M,Tembo Bentry,Chiume Msandeni,Lufesi Norman,Goldfarb David M,Kissoon Niranjan,Lavoie Pascal M
Expert review of anti-infective therapy
: Sepsis accounts for up to one-third of neonatal deaths in the world each year. The World Health Organization acknowledges neonatal sepsis as a major global health concern, and that the highest burden occurs in low- and middle-income countries (LMICs). Despite major research and clinical progress in this area, we still lack accurate diagnostic tools for neonatal sepsis, complicating the management of this condition.: The purpose here is to review the latest data on the incidence, diagnosis, prevention, and management of neonatal sepsis in LMIC. We discuss the limitations of current diagnostic tests - including their lack of availability - and how this may influence global estimates of cases. We review the benefits of antenatal, intrapartum, and post-natal preventive measures. We briefly discuss the management, highlighting the emergence of antimicrobial resistance. Finally, we expose some high priority areas.: Neonatal sepsis is a challenging condition requiring a multifaceted approach to address the major diagnostic issues, but also the underlying socio-economic causes that nourish epidemic cases in LMIC. Focusing on antibiotics as a main pillar of intervention is likely to engender antimicrobial resistance, eventually hindering the appreciable gains LMICs have achieved in neonatal health outcomes.
10.1080/14787210.2020.1732818
Hemodynamic dysfunction in neonatal sepsis.
Kharrat Ashraf,Jain Amish
Pediatric research
Cardiovascular disturbances are a frequent occurrence in neonatal sepsis. Preterm and term infants are particularly vulnerable due to the unique features of their cardiovascular function and reserve, compared to older children and adults. The clinical manifestations of neonatal sepsis are a product of the variable inflammatory pathways involved (warm vs. cold shock physiology), developmental state of the cardiovascular system, and hormonal responses. Targeted neonatal echocardiography has played an important role in advancing our knowledge, may help delineate specific hemodynamic phenotypes in real-time, and supports an individualized physiology-based management of sepsis-associated cardiovascular dysfunction. IMPACT: Cardiovascular dysfunction is a common sequela of sepsis. This review aims to highlight the pathophysiological mechanisms involved in hemodynamic disturbance in neonatal sepsis, provide insights from targeted neonatal echocardiography-based clinical studies, and suggest its potential incorporation in day-to-day management.
10.1038/s41390-021-01855-2
Biomarkers for the Diagnosis of Neonatal Sepsis.
Cantey Joseph B,Lee John H
Clinics in perinatology
Neonatal sepsis is a major cause of morbidity and mortality in neonates and is challenging to diagnose. Infants manifest nonspecific clinical signs in response to sepsis; these signs may be caused by noninfectious conditions. Time to antibiotics affects neonatal sepsis outcome, so clinicians need to identify and treat neonates with sepsis expeditiously. Clinicians use serum biomarkers to measure inflammation and infection and assess the infant's risk of sepsis. However, current biomarkers lack sufficient sensitivity or specificity to be consider useful diagnostic tools. Continued research to identify novel biomarkers as well as novel ways of measuring them is sorely needed.
10.1016/j.clp.2021.03.012
Diagnosis of neonatal sepsis: the past, present and future.
Pediatric research
Sepsis remains a significant cause of neonatal mortality and morbidity, especially in low- and middle-income countries. Neonatal sepsis presents with nonspecific signs and symptoms that necessitate tests to confirm the diagnosis. Early and accurate diagnosis of infection will improve clinical outcomes and decrease the overuse of antibiotics. Current diagnostic methods rely on conventional culture methods, which is time-consuming, and may delay critical therapeutic decisions. Nonculture-based techniques including molecular methods and mass spectrometry may overcome some of the limitations seen with culture-based techniques. Biomarkers including hematological indices, cell adhesion molecules, interleukins, and acute-phase reactants have been used for the diagnosis of neonatal sepsis. In this review, we examine past and current microbiological techniques, hematological indices, and inflammatory biomarkers that may aid sepsis diagnosis. The search for an ideal biomarker that has adequate diagnostic accuracy early in sepsis is still ongoing. We discuss promising strategies for the future that are being developed and tested that may help us diagnose sepsis early and improve clinical outcomes. IMPACT: Reviews the clinical relevance of currently available diagnostic tests for sepsis. Summarizes the diagnostic accuracy of novel biomarkers for neonatal sepsis. Outlines future strategies including the use of omics technology, personalized medicine, and point of care tests.
10.1038/s41390-021-01696-z
Recognising early onset neonatal sepsis: an essential step in appropriate antimicrobial use.
van Herk Wendy,Stocker Martin,van Rossum Annemarie M C
The Journal of infection
Early diagnosis and timely treatment of early onset neonatal sepsis (EOS) are essential to prevent life threatening complications. Subtle, nonspecific clinical presentation and low predictive values of biomarkers complicate early diagnosis. This uncertainty commonly results in unnecessary and prolonged empiric antibiotic treatment. Annually, approximately 395,000 neonates (7.9% of live term births) are treated for suspected EOS in the European Union, while the incidence of proven EOS varies between 0.01 and 0.53 per 1000 live births. Adherence to guidelines for the management of suspicion of EOS is poor. Pragmatic approaches to minimise overtreatment in neonates with suspected EOS, using combined stratified risk algorithms, based on maternal and perinatal risk factors, clinical characteristics of the neonate and sequential biomarkers are promising.
10.1016/j.jinf.2016.04.026
The Accuracy of 16S rRNA Polymerase Chain Reaction for the Diagnosis of Neonatal Sepsis: A Meta-Analysis.
BioMed research international
OBJECTIVE:To determine the accuracy of 16S rRNA polymerase chain reaction (PCR) for the diagnosis of neonatal sepsis through a systematic review and meta-analysis. METHODS:Studies involving 16S rRNA PCR tests for the diagnosis of neonatal sepsis were searched in the PubMed, Medline, Embase, and Cochrane Library databases. The methodological quality of the identified studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2), and the sensitivity, the specificity, the positive likelihood ratio (PLR), the negative likelihood ratio (NLR), the diagnostic odds ratio (DOR), and the area under the curve (AUC) of operator characteristic (SROC) curves were determined. Heterogeneity between studies was analyzed by metaregression. Stata 14.0 and Meta-disc 1.4 software were used for the analyses. RESULTS:This meta-analysis included 19 related studies. The analysis found a sensitivity of 0.98 (95% CI: 0.85-1), specificity of 0.94 (95% CI: 0.87-0.97), PLR of 16.0 (95% CI: 7.6-33.9), NLR of 0.02 (95% CI: 0.00-0.18), DOR of 674 (95% CI: 89-5100), and AUC of 0.99 (95% CI: 0.97-0.99). Metaregression analysis identified Asian countries, arterial blood in blood samples, and sample size > 200 as the main sources of heterogeneity. This meta-analysis did not uncover publication bias. Sensitivity analysis showed that the study was robust. Fagan's nomogram results showed clinical usability. CONCLUSIONS:The results from this meta-analysis indicate that 16S rRNA PCR testing is effective for the rapid diagnosis of neonatal sepsis.
10.1155/2021/5550387
Early-Onset Sepsis Among Very Preterm Infants.
Pediatrics
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). (538 of 1158; 46.5%) and group B (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 nor . 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.
10.1542/peds.2021-052456
Results of a strategy based on clinical observation of newborns at risk of early-onset neonatal sepsis.
Early human development
BACKGROUND:Serial clinical observation of asymptomatic newborns at risk of early-onset sepsis is an alternative option for which there is limited scientific evidence. AIMS:To evaluate the rate of protocol compliance, the impact on blood tests, percentage of hospitalizations and subsequent procedures, and course of diagnosed early-onset sepsis cases of a protocol based on serial clinical observation. METHODS:Retrospective observational study comparing an 18-month period under this protocol against a previous protocol based on laboratory tests. SUBJECTS:6895 asymptomatic newborns with over 35 weeks of gestation. OUTCOME MEASURES:number of evaluations performed on each subject at risk, percentage of patients undergoing blood draws and hospitalization rates. RESULTS:Some of the evaluations included in the protocol were omitted in 51.6 % of the newborns undergoing the physical examinations. The implementation of this new approach was associated with a decrease in the percentage of patients undergoing blood draws from 16.8 % to 0.7 % (p < 0.001) with no differences in the progression of the five cases of sepsis studied in each period. The serial clinical observation protocol was associated with a significant increase in hospitalizations for suspected infection, although with no difference in the rate of lumbar punctures performed or antibiotic treatments administered. CONCLUSION:Compliance with the serial clinical observation protocol can be difficult. This approach often detects newborns with abnormal clinical data that are not explained by early-onset sepsis. Clinical observation is a safe option that minimizes the rate of blood draws.
10.1016/j.earlhumdev.2023.105714
Microbiological comparison of blood culture and amplification of 16S rDNA methods in combination with DGGE for detection of neonatal sepsis in blood samples.
García-Gudiño Isela,Yllescas-Medrano Eucario,Maida-Claros Rolando,Soriano-Becerril Diana,Díaz Nestor F,García-López Guadalupe,Molina-Hernández Anayansí,Flores-Herrera Oscar,Zavala-Díaz de la Serna Francisco J,Del Rosario Peralta-Pérez María,Flores-Herrera Héctor
European journal of pediatrics
It is estimated that 15% of all newborns admitted to the neonatal intensive care unit (NICU) for suspected sepsis receive multiple broad-spectrum antibiotics without pathogen identification. The gold standard for bacterial sepsis detection is blood culture, but the sensitivity of this method is very low. Recently, amplification and analysis of the 16S ribosomal DNA (rDNA) bacterial gene in combination with denaturing gradient gel electrophoresis (DGGE) has proven to be a useful approach for identifying bacteria that are difficult to isolate by standard culture methods. The main goal of this study was to compare two methods used to identify bacteria associated with neonatal sepsis: blood culture and broad range 16S rDNA-DGGE. Twenty-two blood samples were obtained from newborns with (n = 15) or without (n = 7) signs and symptoms of sepsis. Blood samples were screened to identify pathogenic bacteria with two different methods: (1) bacteriological culture and (2) amplification of the variable V3 region of 16S rDNA-DGGE. Blood culture analysis was positive in 40%, whereas 16S rDNA-DGGE was positive in 87% of neonatal sepsis cases. All 16S rDNA-DGGE positive samples were associated with some other signs of neonatal sepsis. CONCLUSION:Our study shows that the molecular approach with 16S rDNA-DGGE identifies twofold more pathogenic bacteria than bacteriological culture, including complex bacterial communities associated with the development of bacterial sepsis in neonates. What is Known: • Neonatal sepsis affects 2.3% of birth in the NICU with a high mortality risk. • Evidence supports the use of molecular methods as an alternative to blood culture for identification of bacterial associated neonatal sepsis. What is New: • The DGGE gel is a good methodological approach for the identification of bacterial in neonatal blood samples. • This study describes the pattern of electrophoretic mobility obtained by DGGE gels and allows to determine the type of bacteria associated in the development of neonatal sepsis.
10.1007/s00431-017-3036-3
Late Neonatal Sepsis in Very-low-birth-weight Premature Newborns Is Associated With Alterations in Neurodevelopment at Twenty-five Months of Age.
The Pediatric infectious disease journal
AIM:To evaluate the impact of late-onset sepsis (LOS) on the neurodevelopment of very-low-birth-weight (VLBW) premature infants. METHODS:This is a retrospective cohort study of VLBW premature infants. The Mental Development Index (MDI) was determined for a population of 546 VLBW infants, at 14 and 25 months of age, and evaluated using the Bayley test. A history of meningitis or early neonatal sepsis was considered an exclusion criterion. The study parameters analyzed included perinatal variables, the development of neonatal comorbidities and a history of LOS. Multivariate linear regression and multinomial logistic regression analyses were performed. RESULTS:LOS was observed in 115 newborns, among whom microbiological testing showed that 65.0% presented Gram-positive bacteria, with Staphylococcus epidermidis being responsible for 55.4%. There was a significant association between the 25-month MDI and a history of LOS. This represents a decrease of 7.9 points in the MDI evaluation of newborns with a history of LOS. The latter history is also associated with the following neurodevelopmental alternations: mild motor disorders [odds ratio (OR): 2.75; 95% confidence intervals (CI): 1.07-7.05], moderate cognitive delay (OR: 3.07; 95% CI: 1.17-8.00) and cerebral palsy (OR: 2.41; 95% CI: 1.09-5.35). CONCLUSIONS:In our study cohort, LOS was associated with alterations in neurodevelopment, including reduced MDI, together with motor and cognitive disorders and cerebral palsy. To improve neurodevelopmental outcomes in this group of newborns, neonatal intensive care unit personnel should focus attention on preventing hospital-acquired infections.
10.1097/INF.0000000000004262
Risk Factors for Neonatal Sepsis in Pregnant Women with Premature Rupture of the Membrane.
Ocviyanti Dwiana,Wahono William Timotius
Journal of pregnancy
BACKGROUND:Premature rupture of the membrane (PROM) is associated with high maternal as well as perinatal morbidity and mortality risks. It occurs in 5 to 10% of all pregnancy while incidence of amniotic membrane infection varies from 6 to 10%. This study aimed to determine the incidence of neonatal sepsis in Cipto Mangunkusumo Hospital and the risk factors. METHODS:A cross-sectional study was done in Cipto Mangunkusumo Hospital, Jakarta, from December 2016 to June 2017. The study used total sampling method including all pregnant women with gestational age of 20 weeks or more experiencing PROM, who came to the hospital at that time. Samples with existing comorbidities such as diabetes mellitus or other serious systemic illnesses such as heart disease or autoimmune condition were excluded from the analysis. RESULTS:A total of 405 pregnant women with PROM were included in this study. There were 21 cases (5.2%) of neonatal sepsis. The analysis showed that risk of neonatal sepsis was higher in pregnant women with prolonged rupture of membrane for ≥ 18 hours before hospital admission (OR 3.08), prolonged rupture of membrane for ≥ 15 hours during hospitalization (OR 7.32), and prolonged rupture of membrane for ≥ 48 hours until birth (OR 5.77). The risk of neonatal sepsis was higher in preterm pregnancy with gestational age of <37 weeks (OR 18.59). CONCLUSION:Risk of neonatal sepsis is higher in longer duration of prolonged rupture of membrane as well as preterm pregnancy.
10.1155/2018/4823404
Factors influencing antibiotic duration in culture-negative neonatal early-onset sepsis.
Songer Corinne N,Calip Gregory S,Srinivasan Nishant,Barbosa Vanessa M,Pham Jennifer T
Pharmacotherapy
STUDY OBJECTIVE:Little guidance exists on the treatment duration of culture-negative early-onset sepsis (CN-EOS) in neonates, which may lead to prolonged antimicrobial therapy and adverse outcomes. Our objective was to identify risk factors associated with prolonged antibiotic therapy in CN-EOS in neonates. DESIGN:This was a retrospective, matched cohort study of neonates treated with empiric antibiotic therapy for EOS. Infants were sampled with matching of gestational age (GA) into short (≤3 days) and prolonged (>3 days) antibiotic course. Primary outcomes were to identify predictive factors that may be associated with prolonged therapy and compare rates of late-onset sepsis (LOS) and mortality. Secondary outcomes included necrotizing enterocolitis, feeding intolerance, and early development assessment. Predictors associated with prolonged antibiotic therapy were identified using multivariable-adjusted logistic regression. MEASUREMENTS AND MAIN RESULTS:Three hundred infants were included with 150 infants in each group. Mean GA and birthweights were 34.2 ± 4.7 weeks and 2293 ± 991 g, respectively. Male gender, 5-min Apgar <7, immature-to-total neutrophil ratio ≥0.2, C-reactive protein (CRP) ≥10 mg/L, need for vasopressors, and mechanical ventilation were identified as significant predictors for prolonged antibiotics in all infants. Independent of GA, elevated CRP (OR 40.84, 95% CI 15.28-109.15, p < 0.001), need for vasopressors (OR 13.48, 95% CI 3.86-47.15, p < 0.001), and mechanical ventilation (OR 12.98, 95% CI 4.91-34.35, p < 0.001) remained significant predictors of prolonged antibiotic use. Infants in the prolonged courses experienced significant delays in achieving independent oral feeding compared with infants receiving short-course antibiotics (median 17.5 vs. 8 days, p = 0.002, respectively). There were no significant differences in LOS, mortality, or other neonatal comorbidities. CONCLUSIONS:Elevated CRP levels, need for vasopressors, and mechanical ventilation were associated with prolonged antibiotic use in neonates presumptively treated for CN-EOS. Further research is warranted in identifying selective biomarkers for EOS and evaluating whether early antibiotic discontinuation for CN-EOS, despite abnormal laboratory tests/illness severity, is safe and justified.
10.1002/phar.2507
Long-term impact of serious neonatal bacterial infections on neurodevelopment.
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
BACKGROUND:Neonatal bacterial infections have long been recognized as an important cause of acute morbidity and mortality, but long-term neurodevelopmental consequences have not been comprehensively described and discussed. OBJECTIVES:We aimed to summarize evidence on the pathogenesis, diagnosis, and epidemiology of long-term sequelae after neonatal bacterial sepsis and meningitis. We also discuss approaches for future studies to quantify the public health impact of neonatal infection-associated neurodevelopmental impairment. SOURCES:We identified studies, both research articles and reviews, which provide mechanistic information on the long-term disease, as well as epidemiological studies that describe the frequency of neurodevelopmental impairment in children with and, for comparison, without a history of neonatal bacterial infection. Tools currently used in clinical practice and research settings to assess neurodevelopmental impairment were also reviewed. CONTENT:We first enumerate potential direct and indirect mechanisms that can lead to brain injury following neonatal infections. We then discuss summary data, either frequencies or measures of association, from epidemiological studies. Risk factors that predict long-term outcomes are also described. Finally, we describe clinical approaches for identifying children with neurodevelopmental impairment and provide an overview of common diagnostic tools. IMPLICATIONS:The limited number of studies that describe the long-term consequences of neonatal infections, often undertaken in high-income settings and using variable designs and diagnostic tools, are not sufficient to inform clinical practice and policy prioritization. Multi-country studies with follow-up into adolescence, standardized diagnostic approaches, and local comparator groups are needed, especially in low and middle-income countries where the incidence of neonatal sepsis is high.
10.1016/j.cmi.2023.04.017
Antibiotic stewardship for early-onset sepsis.
Kuzniewicz Michael W,Puopolo Karen M
Seminars in perinatology
Antibiotics are administered to the vast majority of preterm newborns and to a substantial proportion of term infants in the hours after birth due to risk for early-onset sepsis. The approaches taken to determine which newborns should be evaluated for early-onset sepsis, and what type and duration of antibiotics are administered, are important elements of neonatal antibiotic stewardship. The use of multivariate prediction models for sepsis risk assessment among infants born ≥35 weeks' gestation can safely reduce the use of empiric antibiotic therapy. Approaches incorporating serial physical examination may also contribute to decreasing empiric antibiotic exposure among such infants. Among infants born <35 weeks' gestation, delivery characteristics can be used to identify preterm infants at low enough risk of early infection that empiric therapies are not required. Data informing the epidemiology, microbiology and antibiotic susceptibility patterns of early-onset sepsis pathogens can be used to optimize antibiotic choice for empiric and targeted antibiotic therapy to ensure that effective therapies are administered, while decreasing the risks associated with broad-spectrum antibiotic exposure. Optimal use of blood culture and time to positivity data can also contribute to decreasing the risks associated with prolonged antibiotic administration in the face of sterile cultures.
10.1016/j.semperi.2020.151325
[Early neonatal sepsis and associated factors].
Anaya-Prado Roberto,Valero-Padilla Cuauhtémoc,Sarralde-Delgado Augusto,Sánchez-González Jorge Manuel,Montes-Velázquez Leonora,Gil-Villarreal Francisco
Revista medica del Instituto Mexicano del Seguro Social
BACKGROUND:Early-onset neonatal sepsis (EONS) is an infectious disease of low incidence but high morbidity and mortality with severe consequences to the newborn prognosis. Identifying the associated factors related to EONS allows to start a timely treatment and to take preventive measures. METHODS:In this case and controls study we identified all the newborns (NB) with and without EONS (cases and controls), diagnosed through blood culture in a period of three years. We studied risk factors such as: low gestational age, gender, weight, maternal infections, and premature rupture of membranes. RESULTS:Our study consisted of 27 cases and 36 controls, with a mean age of 32.43 and 33.19 weeks of gestation (WOG), respectively (p > 0.05). Of these, 22 and 29 of the cases and controls had a gestational age < 37 WOG, (p > 0.05). However, maternal infection (odds ratio [OR] 1.76), respiratory distress syndrome (OR 4.72), the need of resuscitation (OR 2.9), intubation (OR 5.1) and ventilation support (OR 2.6) were statistically different between both groups (p < 0.05). The most isolated microorganism was Staphylococcus coagulase negative (42.3%). CONCLUSIONS:Risk factors associated with EONS were maternal infection, the need of resuscitation, and intubation to ventilation support.
The neonatal gut microbiome and global health.
Gut microbes
The role of gut microbiome in health, a century-old concept, has been on the center stage of medical research recently. While different body sites, disease conditions, and populations have been targeted, neonatal and early infancy appear to be the most suitable period for such interventions. It is intriguing to note that, unlike traditional use in diarrhea and maintenance of gastrointestinal health, microbiome-mediating therapies have now addressed the most serious medical conditions in young infants such as necrotizing enterocolitis and neonatal sepsis. Unfortunately, almost all new endeavors in this space have been carried out in the Western world leaving behind millions of neonates that can benefit from such manipulations while serving as a large resource for further learning. In this review, an attempt has been made to quantify the global burden of neonatal morbidity and mortality, examples presented on interventions that have failed as a result of drawing from studies conducted in the West, and a case made for manipulating the neonatal gut microbiome to address the biggest killers in early life. A brief comparative analysis has been made to demonstrate the differences in the gut microbiota of North and South and a large clinical trial of synbiotics conducted by our group in a South Asian setting has been presented. Although challenging, the value of conducting such global health research is introduced with an intent to invite medical scientists to engage in well-planned, scientifically robust research endeavors. This can bring about innovation while saving and serving the most vulnerable citizens now and protecting them from the negative health consequences in the later part of their lives, ultimately shaping a resilient and equitable world as pledged by 193 United Nations member countries in 2015.
10.1080/19490976.2024.2352175
Delivery Characteristics and the Risk of Early-Onset Neonatal Sepsis.
Pediatrics
BACKGROUND AND OBJECTIVES:Multiple strategies are used to identify newborn infants at high risk of culture-confirmed early-onset sepsis (EOS). Delivery characteristics have been used to identify preterm infants at lowest risk of infection to guide initiation of empirical antibiotics. Our objectives were to identify term and preterm infants at lowest risk of EOS using delivery characteristics and to determine antibiotic use among them. METHODS:This was a retrospective cohort study of term and preterm infants born January 1, 2009 to December 31, 2014, with blood culture with or without cerebrospinal fluid culture obtained ≤72 hours after birth. Criteria for determining low EOS risk included: cesarean delivery, without labor or membrane rupture before delivery, and no antepartum concern for intraamniotic infection or nonreassuring fetal status. We determined the association between these characteristics, incidence of EOS, and antibiotic duration among infants without EOS. RESULTS:Among 53 575 births, 7549 infants (14.1%) were evaluated and 41 (0.5%) of those evaluated had EOS. Low-risk delivery characteristics were present for 1121 (14.8%) evaluated infants, and none had EOS. Whereas antibiotics were initiated in a lower proportion of these infants (80.4% vs 91.0%, P < .001), duration of antibiotics administered to infants born with and without low-risk characteristics was not different (adjusted difference 0.6 hours, 95% CI [-3.8, 5.1]). CONCLUSIONS:Risk of EOS among infants with low-risk delivery characteristics is extremely low. Despite this, a substantial proportion of these infants are administered antibiotics. Delivery characteristics should inform empirical antibiotic management decisions among infants born at all gestational ages.
10.1542/peds.2021-052900
Gram-negative neonatal sepsis in low- and lower-middle-income countries and WHO empirical antibiotic recommendations: A systematic review and meta-analysis.
Wen Sophie C H,Ezure Yukiko,Rolley Lauren,Spurling Geoff,Lau Colleen L,Riaz Saba,Paterson David L,Irwin Adam D
PLoS medicine
BACKGROUND:Neonatal sepsis is a significant global health issue associated with marked regional disparities in mortality. Antimicrobial resistance (AMR) is a growing concern in Gram-negative organisms, which increasingly predominate in neonatal sepsis, and existing WHO empirical antibiotic recommendations may no longer be appropriate. Previous systematic reviews have been limited to specific low- and middle-income countries. We therefore completed a systematic review and meta-analysis of available data from all low- and lower-middle-income countries (LLMICs) since 2010, with a focus on regional differences in Gram-negative infections and AMR. METHODS AND FINDINGS:All studies published from 1 January 2010 to 21 April 2021 about microbiologically confirmed bloodstream infections or meningitis in neonates and AMR in LLMICs were assessed for eligibility. Small case series, studies with a small number of Gram-negative isolates (<10), and studies with a majority of isolates prior to 2010 were excluded. Main outcomes were pooled proportions of Escherichia coli, Klebsiella, Enterobacter, Pseudomonas, Acinetobacter and AMR. We included 88 studies (4 cohort studies, 3 randomised controlled studies, and 81 cross-sectional studies) comprising 10,458 Gram-negative isolates from 19 LLMICs. No studies were identified outside of Africa and Asia. The estimated pooled proportion of neonatal sepsis caused by Gram-negative organisms was 60% (95% CI 55% to 65%). Klebsiella spp. was the most common, with a pooled proportion of 38% of Gram-negative sepsis (95% CI 33% to 43%). Regional differences were observed, with higher proportions of Acinetobacter spp. in Asia and Klebsiella spp. in Africa. Resistance to aminoglycosides and third-generation cephalosporins ranged from 42% to 69% and from 59% to 84%, respectively. Study limitations include significant heterogeneity among included studies, exclusion of upper-middle-income countries, and potential sampling bias, with the majority of studies from tertiary hospital settings, which may overestimate the burden caused by Gram-negative bacteria. CONCLUSIONS:Gram-negative bacteria are an important cause of neonatal sepsis in LLMICs and are associated with significant rates of resistance to WHO-recommended first- and second-line empirical antibiotics. AMR surveillance should underpin region-specific empirical treatment recommendations. Meanwhile, a significant global commitment to accessible and effective antimicrobials for neonates is required.
10.1371/journal.pmed.1003787
Early onset neonatal sepsis and its associatited factors: a cross sectional study.
BMC pregnancy and childbirth
BACKGROUND:Sepsis is the 3rd leading cause of neonatal mortality in Ethiopia contributing to 16% of neonatal death. In a hospital study, neonatal sepsis was the leading diagnosis at admission and the second leading cause of neonatal death at the neonatal intensive care unit. Among other factors repeated vaginal examination during labor is known to contribute to sepsis in low-income settings. However, there is limited evidence in the Ethiopian setting. OBJECTIVE:The objective of this study was to examine the association between early-onset neonatal sepsis and repeated vaginal examinations. METHODS:The study was conducted at Gandhi Memorial Hospital, a public maternity and newborn care hospital. We followed 672 mother-newborn pairs by phone until 7 days of age to detect clinical sepsis. Data were analyzed using SPSS version 20 software. Adjusted odds ratio risk (AOR) with a corresponding 95% confidence interval (CI) was used to show the strength of associations and variables with p-value < 0.05 were considered to be statistically significant. RESULTS:The incidence of early-onset neonatal sepsis was found to be 20.83% (95% CI 17.60, 24.00). Having a frequent vaginal examination (four or more times) during labor and delivery, prolonged rupture of membranes, induced labor and gestational age < 37 weeks were strongly associated with the development of early-onset neonatal sepsis, (AOR 2. 69;95 CI: 1.08, 6.70) AOR 5.12(95% CI 1.31, 20.00), AOR of 5.24 (95% CI 1.72, AOR4.34 (95% CI 1.20, 15.68), 16.00), respectively. CONCLUSION:Frequent digital vaginal examination prolonged rupture of membranes, induced labor and gestational age < 37 weeks significantly increases the risk of early onset neonatal sepsis. We also recommend further study using neonatal blood culture to better diagnose early onset neonatal sepsis objectively.
10.1186/s12884-024-06820-5
How to assess early-onset neonatal sepsis? Comparison of three detection strategies.
Anales de pediatria
INTRODUCTION:Early-onset neonatal sepsis (EONS) can cause significant morbidity and mortality, especially if it is not detected early. Given the decrease in its incidence in the past few decades, it is important to find a balance between reducing the use of diagnostic tests and continuing to detect affected patients. We compared 3 detection strategies in patients with risk factors (RFs) for infection: laboratory screening (S1), the Neonatal Sepsis Risk Calculator (S2) and clinical observation (S3). PATIENTS AND METHODS:Retrospective observational study in neonates born at 34 weeks of gestation or later and with RFs or symptoms compatible with EONS. We analysed outcomes in our unit with the use of laboratory screening (S1) and compared them with the other two strategies (S2 and S3) to contemplate whether to modify our protocol. RESULTS:The study included 754 patients, and the most frequent RFs were prolonged rupture of membranes (35.5%) and maternal colonization by Streptococcus agalactiae (38.5%). Strategies S2 and S3 would decrease the performance of laboratory tests (S1, 56.8% of patients; S2, 9.9%; S3, 22.4%; P < 0.01), hospital admissions (S1, 11%; S2, 6.9%; S3, 7.9%; P < 0.01) and the use of antibiotherapy (S1, 8.6%; S2, 6.7%; S3, 6.4%; P < 0.01). Sepsis was diagnosed in 13 patients, and it would have been detected with S2 and S3 except in 1 patient who had asymptomatic bacteriemia by Enterococcus faecalis. No patient with mild and self-limited symptoms in whom antibiotherapy was not started received a diagnosis of sepsis later on. CONCLUSION:Close clinical observation seems to be a safe option and could reduce the use of diagnostic tests, hospital admission and unnecessary antibiotherapy. The watchful waiting approach in patients with mild and self-limiting symptoms in the first hours post birth does not appear to be associated with failure to identify sepsis.
10.1016/j.anpede.2022.10.009
Global incidence and mortality of neonatal sepsis: a systematic review and meta-analysis.
Archives of disease in childhood
BACKGROUND:Neonates are at major risk of sepsis, but data on neonatal sepsis incidence are scarce. We aimed to assess the incidence and mortality of neonatal sepsis worldwide. METHODS:We performed a systematic review and meta-analysis. 13 databases were searched for the period January 1979-May 2019, updating the search of a previous systematic review and extending it in order to increase data inputs from low-income and middle-income countries (LMICs). We included studies on the population-level neonatal sepsis incidence that used a clinical sepsis definition, such as the 2005 consensus definition, or relevant ICD codes. We performed a random-effects meta-analysis on neonatal sepsis incidence and mortality, stratified according to sepsis onset, birth weight, prematurity, study setting, WHO region and World Bank income level. RESULTS:The search yielded 4737 publications, of which 26 were included. They accounted for 2 797 879 live births and 29 608 sepsis cases in 14 countries, most of which were middle-income countries. Random-effects estimator for neonatal sepsis incidence in the overall time frame was 2824 (95% CI 1892 to 4194) cases per 100 000 live births, of which an estimated 17.6% 9 (95% CI 10.3% to 28.6%) died. In the last decade (2009-2018), the incidence was 3930 (95% CI 1937 to 7812) per 100 000 live births based on four studies from LMICs. In the overall time frame, estimated incidence and mortality was higher in early-onset than late-onset neonatal sepsis cases. There was substantial between-study heterogeneity in all analyses. Studies were at moderate to high risk of bias. CONCLUSION:Neonatal sepsis is common and often fatal. Its incidence remains unknown in most countries and existing studies show marked heterogeneity, indicating the need to increase the number of epidemiological studies, harmonise neonatal sepsis definitions and improve the quality of research in this field. This can help to design and implement targeted interventions, which are urgently needed to reduce the high incidence of neonatal sepsis worldwide.
10.1136/archdischild-2020-320217
[Lethality by neonatal sepsis, risk factors and microbiological characteristics].
Andes pediatrica : revista Chilena de pediatria
INTRODUCTION:Neonatal sepsis is one of the leading causes of death in this population and is related to gestational and perinatal factors as well as factors inherent in the newborn. OBJECTIVE:To associate perinatal, neonatal, and microbiological factors to sepsis mortality. PATIENTS AND METHOD:Retrospective ca se-control study of hospitalized newborns with confirmed neonatal sepsis through blood cultures, from 2013 to 2019. Cases were defined as those patients with confirmed sepsis that presented a fa tal outcome and controls as those newborns with confirmed sepsis without a fatal outcome. Cases and controls were compared regarding maternal, perinatal, neonatal, and microbiological factors for quantitative variables in order to identify the trend and concentration of the variables studied. RESULTS:Eleven cases were identified and three controls were randomly assigned to each case, stra tified by gestational age groups. The median birth weight and gestational age were 1,004 grams and 28 weeks, respectively. Escherichia coli was identified in 21% of the patients, Candida parapsilosis in 16%, and Staphylococcus aureus in 14%. There was a statistically significant association between sepsis lethality and vaginal delivery (P = 0.023), infection before 7 days of life (P = 0.025), and Can dida parapsilosis infection (P = 0.049). The multivariate analysis determined a statistically significant association between neonatal sepsis lethality and vaginal delivery and microbiological identification of Candida parapsilosis. CONCLUSION:Neonatal sepsis lethality was more frequent in the group of extremely preterm infants, newborns withhistory of vaginal delivery, early microbiological isolation, and t infection with Candida parapsilosis.
10.32641/aodespedlatr.v92i5.2610
Game changer or gimmick: inflammatory markers to guide antibiotic treatment decisions in neonatal early-onset sepsis.
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
BACKGROUND:The diagnosis of neonatal early-onset sepsis (EOS) is challenging, and inflammatory markers are widely used to guide decision-making and therapies. OBJECTIVES:This narrative review presents the current state of knowledge regarding the diagnostic value and potential pitfalls in the interpretation of inflammatory markers for EOS. SOURCES:PubMed until October 2022 and searched references in identified articles using the search terms: neonatal EOS, biomarker or inflammatory marker, and antibiotic therapy or antibiotic stewardship. CONTENT:In situations with a high or low probability of sepsis, the measurements of inflammatory markers have no impact on the decision to start or stop antibiotics and are just gimmick, whereas they may be a game changer for neonates with intermediate risk and therefore an unclear situation. There is no single or combination of inflammatory markers that can predict EOS with high probability, allowing us to make decisions regarding the start of antibiotics based only on inflammatory markers. The main reason for the limited accuracy is most probably the numerous noninfectious conditions that influence the levels of inflammatory markers. However, there is evidence that C-reactive protein and procalcitonin have good negative predictive accuracy to rule out sepsis within 24 to 48 hours. Nevertheless, several publications have reported more investigations and prolonged antibiotic treatments with the use of inflammatory markers. Given the limitations of current strategies, using an algorithm with only moderate diagnostic accuracy may have a positive impact, as reported for the EOS calculator and the NeoPInS algorithm. IMPLICATIONS:As the decision regarding the start of antibiotic therapy is different from the process of stopping antibiotics, the accuracy of inflammatory markers needs to be evaluated separately. Novel machine learning-based algorithms are required to improve accuracy in the diagnosis of EOS. In the future, inflammatory markers included in algorithms may be a game changer reducing bias and noise in the decision-making process.
10.1016/j.cmi.2023.02.021
Effect of oropharyngeal colostrum therapy on neonatal sepsis in preterm neonates: A systematic review and meta-analysis.
Journal of pediatric gastroenterology and nutrition
Various studies have shown that oropharyngeal colostrum application (OPCA) is beneficial to preterm neonates. We performed a systematic review and meta-analysis to assess whether OPCA reduces the incidence of culture-proven neonatal sepsis in preterm neonates. Randomized controlled trials comparing OPCA with placebo or standard care in preterm neonates were included. Medline, Embase, Web of Science, Cumulated Index to Nursing and Allied Health Literature, Scopus, and CENTRAL were searched for studies published up to June 15, 2023. We used the Cochrane Risk of Bias tool, version 2, for risk of bias assessment, the random-effects model (RevMan 5.4) for meta-analysis, and Gradepro software for assessing the certainty of evidence. Twenty-one studies involving 2393 participants were included in this meta-analysis. Four studies had a low risk of bias, whereas seven had a high risk. Oropharyngeal colostrum significantly reduced the incidence of culture-proven sepsis (18 studies, 1990 neonates, risk ratio [RR]: 0.78, 95% confidence interval [95% CI]: 0.65, 0.94), mortality (18 studies, 2117 neonates, RR: 0.73, 95% CI: 0.59, 0.90), necrotizing enterocolitis (NEC) (17 studies, 1692 neonates, RR: 0.59, 95% CI: 0.43, 0.82), feeding intolerance episodes (four studies, 445 neonates, RR: 0.59, 95% CI: 0.38, 0.92), and the time to full enteral feeding (19 studies, 2142 neonates, mean difference: -2 to 21 days, 95% CI: -3.44, -0.99 days). There was no reduction in intraventricular hemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia, ventilator-associated pneumonia, neurodevelopmental abnormalities, hospital stay duration, time to full oral feeding, weight at discharge, pneumonia, and duration of antibiotic therapy. The certainty of the evidence was high for the outcomes of culture-positive sepsis and mortality, moderate for NEC, low for time to full enteral feeding, and very low for feeding intolerance. OPCA reduces culture-positive sepsis and mortality (high certainty), NEC (moderate certainty), and time to full enteral feeding (low certainty) in preterm neonates. However, scarcity of data from extremely premature infants limits the generalizability of these results to this population.
10.1002/jpn3.12085
miRNA-23b as a biomarker of culture-positive neonatal sepsis.
Fatmi Ahlam,Rebiahi Sid Ahmed,Chabni Nafissa,Zerrouki Hanane,Azzaoui Hafsa,Elhabiri Yamina,Benmansour Souheila,Ibáñez-Cabellos José Santiago,Smahi Mohammed Chems-Eddine,Aribi Mourad,García-Giménez José Luis,Pallardó Federico V
Molecular medicine (Cambridge, Mass.)
BACKGROUND:Neonatal sepsis remains an important cause of morbidity and mortality. The ability to quickly and accurately diagnose neonatal sepsis based on clinical assessments and laboratory blood tests remains difficult, where haemoculture is the gold standard for detecting bacterial sepsis in blood culture. It is also very difficult to study because neonatal samples are lacking. METHODS:Forty-eight newborns suspected of sepsis admitted to the Neonatology Department of the Mother-Child Specialized Hospital of Tlemcen. From each newborn, a minimum of 1-2 ml of blood was drawn by standard sterile procedures for blood culture. The miRNA-23b level in haemoculture was evaluated by RT-qPCR. RESULTS:miR-23b levels increased in premature and full-term newborns in early onset sepsis (p < 0.001 and p < 0.005 respectively), but lowered in late onset sepsis in full-term neonates (p < 0.05) compared to the respective negative controls. miR-23b levels also increased in late sepsis in the negative versus early sepsis negative controls (p < 0.05). miR-23b levels significantly lowered in the newborns who died from both sepsis types (p < 0.0001 and p < 0.05 respectively). In early sepsis, miR-23b and death strongly and negatively correlated (correlation coefficient = - 0.96, p = 0.0019). In late sepsis, miRNA-23b and number of survivors (correlation coefficient = 0.70, p = 0.506) positively correlated. CONCLUSIONS:Lowering miR-23b levels is an important factor that favours sepsis development, which would confirm their vital protective role, and strongly suggest that they act as a good marker in molecular diagnosis and patient monitoring.
10.1186/s10020-020-00217-8
Experimental Neonatal Sepsis Causes Long-Term Cognitive Impairment.
Comim Clarissa M,Bussmann Regina M,Simão Silvia R,Ventura Letícia,Freiberger Viviane,Patrício Janini J,Palmas Daphne,Mendonça Bruna P,Cassol Omar J,Quevedo João
Molecular neurobiology
Neonatal sepsis is a major cause of morbidity and mortality in neonatal intensive care units. Treatment with antibiotics reduces mortality and morbidity, but neonatal sepsis remains a serious life-threatening condition. The objective of this study was to evaluate cognitive impairment in adult mice submitted to sepsis in the neonatal period. To this aim, 2-day-old male C57BL/6 mice were submitted to sepsis by injection of 25 μg of LPS. Sixty days after, the learning and memory were evaluated. It was observed that the mice submitted to neonatal sepsis presented impairment of habituation, aversive, and object recognition memories, and had an increase of immobility time in forced swimming test in adulthood. In conclusion, this study shows that the neonatal sepsis causes long-term brain alterations. These alterations can persist to adulthood in an animal model due to a vulnerability of the developing brain.
10.1007/s12035-015-9495-5
Look Who's Talking: Host and Pathogen Drivers of Virulence in Neonatal Sepsis.
Joubert Isabella A,Otto Michael,Strunk Tobias,Currie Andrew J
International journal of molecular sciences
Preterm infants are at increased risk for invasive neonatal bacterial infections. , 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 strains. Furthermore, comparative genomics studies have yielded insights into the emergence and spread of nosocomial strains, and their genetic and functional characteristics implicated in invasive disease in neonates. These studies have highlighted the multifactorial nature of traits relating to pathogenicity and commensalism. In this review, we discuss the known host and pathogen drivers of virulence in neonatal sepsis and provide future perspectives to close the gap in our understanding of as a cause of neonatal morbidity and mortality.
10.3390/ijms23020860
Application of Advanced Molecular Methods to Study Early-Onset Neonatal Sepsis.
International journal of molecular sciences
Early-onset sepsis (EOS) is a global health issue, considered one of the primary causes of neonatal mortality. Diagnosis of EOS is challenging because its clinical signs are nonspecific, and blood culture, which is the current gold-standard diagnostic tool, has low sensitivity. Commonly used biomarkers for sepsis diagnosis, including C-reactive protein, procalcitonin, and interleukin-6, lack specificity for infection. Due to the disadvantages of blood culture and other common biomarkers, ongoing efforts are directed towards identifying innovative molecular approaches to diagnose neonates at risk of sepsis. This review aims to gather knowledge and recent research on these emerging molecular methods. PCR-based techniques and unrestricted techniques based on 16S rRNA sequencing and 16S-23S rRNA gene interspace region sequencing offer several advantages. Despite their potential, these approaches are not able to replace blood cultures due to several limitations; however, they may prove valuable as complementary tests in neonatal sepsis diagnosis. Several microRNAs have been evaluated and have been proposed as diagnostic biomarkers in EOS. T2 magnetic resonance and bioinformatic analysis have proposed potential biomarkers of neonatal sepsis, though further studies are essential to validate these findings.
10.3390/ijms25042258
An Immunological Perspective on Neonatal Sepsis.
Trends in molecular medicine
Despite concerted international efforts, mortality from neonatal infections remains unacceptably high in some areas of the world, particularly for premature infants. Recent developments in flow cytometry and next-generation sequencing technologies have led to major discoveries over the past few years, providing a more integrated understanding of the developing human immune system in the context of its microbial environment. We review these recent findings, focusing on how in human newborns incomplete maturation of the immune system before a full term of gestation impacts on their vulnerability to infection. We also discuss some of the clinical implications of this research in guiding the design of more-accurate age-adapted diagnostic and preventive strategies for neonatal sepsis.
10.1016/j.molmed.2016.02.001
[Advances in clinical management of neonatal sepsis].
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics
Neonatal sepsis, as a significant cause of various complications and adverse outcomes in neonates, remains a serious health burden both domestically and internationally. Strategies such as antibiotic prophylaxis during delivery, the utilization of early-onset sepsis risk calculators, and quality improvement initiatives in neonatal wards are beneficial in alleviating the disease burden of neonatal sepsis. This paper provides a review of the epidemiology, risk factors, and recent advances in clinical management of neonatal sepsis.
10.7499/j.issn.1008-8830.2309145
Recognition and management of neonatal sepsis.
Crocker Luke William,White Ayesha,Heaton Paul Anthony,Horta Débora Pascoal,Paul Siba Prosad
British journal of nursing (Mark Allen Publishing)
Neonatal sepsis results from acute bacterial or viral infection occurring in the first 28 days of life. It causes significant morbidity and mortality, although the outcome can be improved by early recognition and prompt treatment by health professionals. This article describes the most common causes of sepsis, and explains why neonates are particularly vulnerable to infection. It highlights the non-specific way in which an infant with a serious infection may present, indicating the crucial features to elicit during history taking and examination, and emphasising the 'red-flag' signs and symptoms that should increase suspicion of a serious illness. The authors have adapted National Institute for Health and Care Excellence guidelines to produce an evidence-based approach to the management of an infant with suspected sepsis, and describe the roles of nurses in ensuring effective treatment and best outcomes for these babies.
10.12968/bjon.2021.30.7.410
When to Include a Lumbar Puncture in the Evaluation for Neonatal Sepsis.
Aleem Samia,Greenberg Rachel G
NeoReviews
Meningitis is a devastating infection in infants and is linked to adverse long-term outcomes. The prevalence of meningitis is variable and depends on gestational age, postnatal age, and clinical setting. Early diagnosis and treatment with appropriate antibiotics are crucial to decrease the risk of morbidity and mortality. Lumbar punctures are essential for the diagnosis of meningitis, but clinicians may defer lumbar puncture if the risk for meningitis is low or if there are substantial concerns regarding the risk associated with the procedure. Awareness of the epidemiology and microbiology of meningitis in infants, as well as valid contraindications to performing a lumbar puncture, is necessary to avoid missed diagnoses and procedure-related adverse effects.
10.1542/neo.20-3-e124
Early-versus late-onset sepsis in neonates - time to shift the paradigm?
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
BACKGROUND:Neonatal sepsis is traditionally classified as early-onset sepsis (EOS) and late-onset sepsis (LOS) disease categories. This paradigm was based on observed epidemiological data from high income settings. However, increasing availability of microbiology results from diverse settings challenges these assumptions, necessitating re-examination of neonatal sepsis classifications. OBJECTIVES:To review the literature describing the aetiology of EOS and LOS in hospitalized neonates with stratification of pathogen spectrum by low- (LIC), middle- (MIC) and high-income (HIC) country settings, to critically re-examine the continued appropriateness of the 'EOS vs. LOS' sepsis paradigm in all settings. SOURCES:PubMed was searched for peer-reviewed English full-text articles published from inception up until 8 August 2022. CONTENT:Studies often report on either EOS or LOS, rather than both. We identified only 49 original articles reporting on pathogen distribution of both EOS and LOS in the same hospital setting. Clear differences in sepsis aetiology were shown between LIC, MIC and HIC settings, with increasing importance of Klebsiella pneumoniae and decreasing importance of Group B Streptococcus in the first 72 hours of life in LIC and MIC. IMPLICATIONS:The concept of 'EOS vs. LOS' may be less useful for predicting the pathogen spectrum of neonatal sepsis in LIC and MIC, but the paradigm has shaped reporting of neonatal sepsis, and our understanding. Future neonatal sepsis reporting should utilize strengthening the reporting of observational studies in epidemiology for newborn infection (STROBE-NI) reporting guidelines and clearly describe timing of infection by day, and variation in pathogen spectrum across the neonatal period. Data identified in this review challenge the generalizability of the prevailing EOS/LOS paradigm in LIC and MIC.
10.1016/j.cmi.2023.07.023
Management of Neonates Born at ≥35 0/7 Weeks' Gestation With Suspected or Proven Early-Onset Bacterial Sepsis.
Puopolo Karen M,Benitz William E,Zaoutis Theoklis E, ,
Pediatrics
The incidence of neonatal early-onset sepsis (EOS) has declined substantially over the last 2 decades, primarily because of the implementation of evidence-based intrapartum antimicrobial therapy. However, EOS remains a serious and potentially fatal illness. Laboratory tests alone are neither sensitive nor specific enough to guide EOS management decisions. Maternal and infant clinical characteristics can help identify newborn infants who are at risk and guide the administration of empirical antibiotic therapy. The incidence of EOS, the prevalence and implications of established risk factors, the predictive value of commonly used laboratory tests, and the uncertainties in the risk/benefit balance of antibiotic exposures all vary significantly with gestational age at birth. Our purpose in this clinical report is to provide a summary of the current epidemiology of neonatal sepsis among infants born at ≥35 0/7 weeks' gestation and a framework for the development of evidence-based approaches to sepsis risk assessment among these infants.
10.1542/peds.2018-2894
Neonatal sepsis: need for consensus definition, collaboration and core outcomes.
Molloy Eleanor J,Wynn James L,Bliss Joseph,Koenig Joyce M,Keij Fleur M,McGovern Matt,Kuester Helmut,Turner Mark A,Giannoni Eric,Mazela Jan,Degtyareva Marina,Strunk Tobias,Simons Sinno H P,Janota Jan,Plotz Franz B,van den Hoogen Ages,de Boode Willem,Schlapbach Luregn J,Reiss Irwin K M,
Pediatric research
10.1038/s41390-020-0850-5
Advancement in biomarker based effective diagnosis of neonatal sepsis.
Artificial cells, nanomedicine, and biotechnology
Neonatal sepsis is considered as alarming medical emergency and becomes the common global reason of neonatal mortality. Non-specific symptoms and limitations of conventional diagnostic methods for neonatal sepsis mandate fast and reliable method to diagnose disease for point of care application. Recently, disease specific biomarkers have gained interest for rapid diagnosis that led to the development of electrochemical biosensor with enhanced specificity, sensitivity, cost-effectiveness and user-friendliness. Other than conventional biomarker C-reactive protein to diagnose neonatal sepsis, several potential biomarkers including Procalcitonin (PCT), Serum amyloid A (SAA) and other candidates are extensively investigated. The present review provides insights on advancements and diagnostic abilities of protein and nucleotide based biomarkers with their incorporation in developing electrochemical biosensors by employing novel fabrication strategies. This review provides an overview of most promising biomarker and its capability for neonatal sepsis diagnosis to fulfil future demand to develop electrochemical biosensor for point-of-care applications.
10.1080/21691401.2023.2252016
Updates in Late-Onset Sepsis: Risk Assessment, Therapy, and Outcomes.
NeoReviews
Neonatal late-onset sepsis (LOS) continues to threaten morbidity and mortality in the NICU and poses ongoing diagnostic and therapeutic challenges. Early recognition of clinical signs, rapid evaluation, and prompt initiation of treatment are critical to prevent life-threatening deterioration. Preterm infants-born at ever-decreasing gestational ages-are at particularly high risk for life-long morbidities and death. This changing NICU population necessitates continual reassessments of diagnostic and preventive measures and evidence-based treatment for LOS. The clinical presentation of LOS is varied and nonspecific. Despite ongoing research, reliable, specific laboratory biomarkers facilitating early diagnosis are lacking. These limitations drive an ongoing practice of liberal initiation of empiric antibiotics among infants with suspected LOS. Subsequent promotion of multidrug-resistant microorganisms threatens the future of antimicrobial therapy and puts preterm and chronically ill infants at even higher risk of nosocomial infection. Efforts to identify adjunctive therapies counteracting sepsis-driven hyperinflammation and sepsis-related functional immunosuppression are ongoing. However, most approaches have either failed to improve LOS prognosis or are not yet ready for clinical application. This article provides an overview of the epidemiology, risk factors, diagnostic tools, and treatment options of LOS in the context of increasing numbers of extremely preterm infants. It addresses the question of whether LOS could be identified earlier and more precisely to allow for earlier and more targeted therapy and discusses rational approaches to antibiotic therapy to avoid overuse. Finally, this review elucidates the necessity of long-term follow-up of infants with a history of LOS.
10.1542/neo.23-10-e738
Neonatal sepsis and cardiovascular dysfunction I: mechanisms and pathophysiology.
Pediatric research
The highest incidence of sepsis across all age groups occurs in neonates leading to substantial mortality and morbidity. Cardiovascular dysfunction frequently complicates neonatal sepsis including biventricular systolic and/or diastolic dysfunction, vasoregulatory failure, and pulmonary arterial hypertension. The haemodynamic response in neonatal sepsis can be hyperdynamic or hypodynamic and the underlying pathophysiological mechanisms are heterogeneous. The diagnosis and definition of both neonatal sepsis and cardiovascular dysfunction complicating neonatal sepsis are challenging and not consensus-based. Future developments in neonatal sepsis management will be facilitated by common definitions and datasets especially in neonatal cardiovascular optimisation. IMPACT: Cardiovascular dysfunction is common in neonatal sepsis but there is no consensus-based definition, making calculating the incidence and designing clinical trials challenging. Neonatal cardiovascular dysfunction is related to the inflammatory response, which can directly target myocyte function and systemic haemodynamics.
10.1038/s41390-023-02926-2
What's new in the management of neonatal early-onset sepsis?
Archives of disease in childhood. Fetal and neonatal edition
The expert guidelines highlighted in this review provide an evidence-based framework for approaching at-risk infants and allow for a more limited and standardised approach to antibiotic use. While these guidelines have significantly reduced antibiotic utilisation worldwide, optimally each unit would individualise their approach to early onset sepsis (EOS) based on the neonatal population they serve and available resources. As advancements in EOS research continue and limitations with sepsis prediction tools are addressed, it is inevitable that our risk stratification and management guidelines will become more precise.
10.1136/archdischild-2021-323532
Effect of Intrapartum Azithromycin vs Placebo on Neonatal Sepsis and Death: A Randomized Clinical Trial.
JAMA
Importance:Neonatal sepsis is a leading cause of neonatal mortality. New interventions are needed to decrease neonatal sepsis and mortality in regions with highest burden. Objective:To evaluate the efficacy of intrapartum azithromycin to reduce neonatal sepsis or mortality, as well as neonatal and maternal infections. Design, Setting, and Participants:This double-blind, placebo-controlled, randomized clinical trial enrolled and followed up birthing parents and their infants at 10 health facilities in The Gambia and Burkina Faso, West Africa, between October 2017 and May 2021. Interventions:Participants were assigned at random to receive oral azithromycin (2 g) or placebo (ratio 1:1) during labor. Main Outcomes and Measures:The primary outcome was a composite of neonatal sepsis or mortality, with the former defined based on microbiologic or clinical criteria. Secondary outcomes were neonatal infections (skin, umbilical, eye and ear infections), malaria, and fever; postpartum infections (puerperal sepsis, mastitis), fever, and malaria; and use of antibiotics during 4-week follow-up. Results:The trial randomized 11 983 persons in labor (median age, 29.9 years). Overall, 225 newborns (1.9% of 11 783 live births) met the primary end point. The incidence of neonatal mortality or sepsis was similar in the azithromycin and placebo groups (2.0% [115/5889] vs 1.9% [110/5894]; risk difference [RD], 0.09 [95% CI, -0.39 to 0.57]), as was the incidence of neonatal mortality (0.8% vs 0.8%; RD, 0.04 [95% CI, -0.27 to 0.35]) and neonatal sepsis (1.3% vs 1.3%; RD, 0.02 [95% CI, -0.38 to 0.43]). Newborns in the azithromycin group compared with the placebo group had lower incidence of skin infections (0.8% vs 1.7%; RD, -0.90 [95% CI, -1.30 to -0.49]) and need for antibiotics (6.2% vs 7.8%; RD, -1.58 [95% CI, -2.49 to -0.67]). Postpartum parents in the azithromycin group had lower incidence of mastitis (0.3% vs 0.5%; RD, -0.24 [95% CI, -0.47 to -0.01]) and puerperal fever (0.1% vs 0.3%; RD, -0.19 [95% CI, -0.36 to -0.01]). Conclusions and Relevance:Azithromycin administered orally during labor did not reduce neonatal sepsis or mortality. These results do not support routine introduction of oral intrapartum azithromycin for this purpose. Trial Registration:ClinicalTrials.gov Identifier: NCT03199547.
10.1001/jama.2022.24388
Neonatal bacterial sepsis.
Lancet (London, England)
Neonatal sepsis remains one of the key challenges of neonatal medicine, and together with preterm birth, causes almost 50% of all deaths globally for children younger than 5 years. Compared with advances achieved for other serious neonatal and early childhood conditions globally, progress in reducing neonatal sepsis has been much slower, especially in low-resource settings that have the highest burden of neonatal sepsis morbidity and mortality. By contrast to sepsis in older patients, there is no universally accepted neonatal sepsis definition. This poses substantial challenges in clinical practice, research, and health-care management, and has direct practical implications, such as diagnostic inconsistency, heterogeneous data collection and surveillance, and inappropriate treatment, health-resource allocation, and education. As the clinical manifestation of neonatal sepsis is frequently non-specific and the current diagnostic standard blood culture has performance limitations, new improved diagnostic techniques are required to guide appropriate and warranted antimicrobial treatment. Although antimicrobial therapy and supportive care continue as principal components of neonatal sepsis therapy, refining basic neonatal care to prevent sepsis through education and quality improvement initiatives remains paramount.
10.1016/S0140-6736(24)00495-1
Neonatal Early-Onset Sepsis.
NeoReviews
Early-onset sepsis (EOS) is a significant cause of morbidity and mortality among newborn infants, particularly among those born premature. The epidemiology of EOS is changing over time. Here, we highlight the most contemporary data informing the epidemiology of neonatal EOS, including incidence, microbiology, risk factors, and associated outcomes, with a focus on infants born in high-income countries during their birth hospitalization. We discuss approaches to risk assessment for EOS, summarizing national guidelines and comparing key differences between approaches for term and preterm infants. Lastly, we analyze contemporary antibiotic resistance data for EOS pathogens to inform optimal empiric treatment for EOS.
10.1542/neo.23-10-e756
Neonatal sepsis: within and beyond China.
Chinese medical journal
Sepsis remains a significant cause of neonatal morbidity and mortality in China. A better understanding of neonatal sepsis in China as compared with other industrialized and non-industrialized countries may help optimize neonatal health care both regionally and globally. Literature cited in this review was retrieved from PubMed using the keywords "neonatal sepsis," "early-onset (EOS)" and "late-onset (LOS)" in English, with the focus set on population-based studies. This review provides an updated summary regarding the epidemiology, pathogen profile, infectious work-up, and empirical treatment of neonatal sepsis within and beyond China. The incidence of neonatal EOS and the proportion of Group B Streptococcus (GBS) within pathogens causing EOS in China seem to differ from those in developed countries, possibly due to different population characteristics and intrapartum/postnatal health care strategies. Whether to adopt GBS screening and intrapartum antibiotic prophylaxis in China remains highly debatable. The pathogen profile of LOS in China was shown to be similar to other countries. However, viruses as potential pathogens of neonatal LOS have been underappreciated. Growing antimicrobial resistance in China reflects limitations in adapting antibiotic regimen to local microbial profile and timely cessation of treatment in non-proven bacterial infections. This review stresses that the local epidemiology of neonatal sepsis should be closely monitored in each institution. A prompt and adequate infectious work-up is critically important in diagnosing neonatal sepsis. Adequate and appropriate antibiotic strategies must be overemphasized to prevent the emergence of multi-resistant bacteria in China.
10.1097/CM9.0000000000000935
Neonatal sepsis.
Shane Andi L,Sánchez Pablo J,Stoll Barbara J
Lancet (London, England)
Neonatal sepsis is the cause of substantial morbidity and mortality. Precise estimates of neonatal sepsis burden vary by setting. Differing estimates of disease burden have been reported from high-income countries compared with reports from low-income and middle-income countries. The clinical manifestations range from subclinical infection to severe manifestations of focal or systemic disease. The source of the pathogen might be attributed to an in-utero infection, acquisition from maternal flora, or postnatal acquisition from the hospital or community. The timing of exposure, inoculum size, immune status of the infant, and virulence of the causative agent influence the clinical expression of neonatal sepsis. Immunological immaturity of the neonate might result in an impaired response to infectious agents. This is especially evident in premature infants whose prolonged stays in hospital and need for invasive procedures place them at increased risk for hospital-acquired infections. Clinically, there is often little difference between sepsis that is caused by an identified pathogen and sepsis that is caused by an unknown pathogen. Culture-independent diagnostics, the use of sepsis prediction scores, judicious antimicrobial use, and the development of preventive measures including maternal vaccines are ongoing efforts designed to reduce the burden of neonatal sepsis.
10.1016/S0140-6736(17)31002-4