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Neonatal sepsis: A review of the literature

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Neonatal sepsis contributes significantly to neonatal morbidity and mortality and is a major public health challenge around the world. Depending on the mode of occurrence, a distinction is made between maternal-transmitted infection and that acquired in the postnatal period. Although the etiologies maternally transmitted diseases are well understood, those of postnatal acquired infections are variable depending on the epidemiology of each hospital environment. On the one hand, risk factors for maternal-transmitted infections are maternal sepsis, prolonged premature rupture of membranes, chorioamnionitis, and bacteriuria in the mother during pregnancy. On the other hand, risk factors for postnatal acquired infections are prematurity, low birth weight, lack of hygiene, and invasive therapeutic interventions. The diagnosis is based on a series of anamnestic, clinical and biological features. Although the positive diagnosis is based on the isolation of the germ by culture on a body sample (blood, cerebrospinal fluid, urine, etc.); its low sensitivity leads to the use of markers of the acute phase of inflammation such as C-reactive protein, procalcitonin and interleukins. New molecular biology techniques are promising and offer precise diagnosis with rapid results. Empirical management is a function of microbial ecology while definitive treatment is guided by the results of microbial culture. This article presents the essential elements for understanding neonatal sepsis and discusses new diagnosis and therapeutic management. It offers a thorough reading based on the issue of infections in newborns.

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  • Published: 19 March 2020

Neonatal sepsis: need for consensus definition, collaboration and core outcomes

  • Eleanor J. Molloy   ORCID: orcid.org/0000-0001-6798-2158 1 , 2 , 3 , 4 ,
  • James L. Wynn 5 ,
  • Joseph Bliss 6 ,
  • Joyce M. Koenig 7 ,
  • Fleur M. Keij 8 ,
  • Matt McGovern 1 , 2 ,
  • Helmut Kuester 9 ,
  • Mark A. Turner 10 ,
  • Eric Giannoni 11 ,
  • Jan Mazela 12 ,
  • Marina Degtyareva 13 ,
  • Tobias Strunk 14 , 15 ,
  • Sinno H. P. Simons 8 ,
  • Jan Janota 16 ,
  • Franz B. Plotz 17 ,
  • Ages van den Hoogen 18 ,
  • Willem de Boode 19 ,
  • Luregn J. Schlapbach 20 , 21 &
  • Irwin K. M. Reiss 8

on behalf of the Infection, Inflammation, Immunology and Immunisation (I4) section of the ESPR

Pediatric Research volume  88 ,  pages 2–4 ( 2020 ) Cite this article

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A Correction to this article was published on 29 October 2020

This article has been updated

Overview of neonatal sepsis and definitions

Sepsis represents a major contributor to global mortality and has been declared as a priority by the WHO. 1 The highest sepsis incidence across all age groups is found in neonates affecting an estimated 3 million babies worldwide (22 per 1000 live births) with a mortality of 11–19% and unquantified long-term neurological defects. 2 , 3

However, international data are difficult to standardise in the absence of unified criteria for neonatal sepsis. Recently, in adults, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) have defined sepsis as a life-threatening organ dysfunction caused by a dysregulated response to infection. 4 The new consensus definition moved away from the concept of systemic inflammatory response syndrome, which formed part of the definition of sepsis in the past 20 years. Sepsis-3 criteria were developed and validated on large cohorts of electronic health record data-derived episodes from adults with sepsis. Despite the clear merits of the approach chosen by the Sepsis-3 taskforce, there are several pitfalls towards the translation of Sepsis-3 to neonates. The criteria to define infection and sepsis are essential in the neonatal population to limit overdiagnosis, but they are not part of the adult Sepsis-3 definitions. Sepsis-3 is based only on short-term outcomes but in neonates integration of predictors of long-term disability is critical. The criteria for organ dysfunction according to gestational and postnatal age need to be defined through systematic reviews and retrospective studies and validated in prospective studies.

The Sequential Organ Failure Assessment Score (SOFA) reflects changes in organ function altering from baseline. The pSOFA has been proposed and was found to be a reliable predictor of in-hospital mortality in children. 5 The recently described neonatal SOFA (nSOFA) predicted mortality on Very Low Birth Weight (VLBW) infants with late onset sepsis. 6 In this issue of the journal an international group has provided an overview of the diverse definitions of neonatal sepsis with the aim of working towards international consensus.

Why neonates are different

Neonates differ substantially to adults and older children due to altered immune function and potential intrauterine exposure to infection. 7 , 8 The fetus is immune privileged in utero often resulting in endotoxin tolerance. This is altered by labour from a predominantly Th2 response to a more “adult” immune phenotype with an enhanced pro-inflammatory response. 8 , 9 These differences are particularly prominent in preterm infants. However, neonatal immunology is not clearly delineated, and much has been extrapolated from research in umbilical cord blood that although easily accessible for study is more immunotolerant and does not entirely reflect postnatal immune responses. 10 There are difficulties in determining the true risk of neonatal sepsis as the in utero environment cannot be easily assessed. For example, the duration of rupture of membranes and the presence of intrauterine infection are hard to diagnose with certainty. Placental pathology is likewise not entirely predictive and also not usually available at the time of sepsis evaluation. The lack of specificity of the majority of clinical signs and symptoms further complicate the identification of sepsis on the neonate.

Although Sepsis-3 concentrates on organ dysfunction in the diagnosis of sepsis, microbiological results are often still included in neonatal sepsis. Blood culture is only positive in approximately 0.5% 11 , 12 due to the small blood volume for blood cultures and antenatal maternal antibiotic use. There is no reliable single marker of sepsis and mortality and morbidity are high so empiric antibiotics are commenced in infants at risk. However, there is a need to balance the risk of morbidity and mortality from untreated infection versus the short- and long-term adverse effect of exposure to antibiotics. The risks of overuse of antibiotics are well-described in the era of antibiotic resistance and the negative effects of altering the microbiome include an increased rate of serious complications including mortality and necrotising enterocolitis association with antibiotic exposure.

In addition, neonatal sepsis is a heterogeneous condition, related to differences in gestational age, timing and source of infection. Coagulase-negative Staphylococci are often considered a contaminant or commensal in adults and older children but are associated with significant morbidity in preterm neonates, including adverse neurodevelopment. 13 The difference in the NICU is that it may be more difficult to differentiate contamination from true infection and the long-term impact of these infections is greater on the developing brain. There are major differences between a baby arriving to the emergency room with a fever in the first month of life compared to a preterm infant born following severe chorioamnionitis and prolonged rupture of membranes. These varied populations of infants at risk of “neonatal sepsis” differ in many aspects of the disease, including clinical signs and symptoms, most likely pathogens and risk of mortality and long-term morbidity.

Current markers of neonatal sepsis

Surrogate biomarkers of sepsis are commonly used due to the limitations of blood cultures alone to diagnose sepsis. Maternal infectious status is also important and placental pathology can provide a diagnosis of chorioamnionitis, although the relationship between histologic chorioamnionitis and neonatal sepsis is complex and ill-defined. Markers of systemic inflammation and immune responses include serial white cell counts and immature-to-mature granulocyte (IT) ratio. 14 , 15 , 16 , 17 Serial full blood count values and IT ratios can predict the absence of early onset sepsis (EOS) with an AUC ~ 0.8 and negative predictive value for proven and suspected sepsis of 99% and 78%, respectively. 12 In addition, CRP and Procalcitonin demonstrate that biomarkers can be useful to shorten antibiotic treatment in patients who improve rapidly after treatment and have negative blood cultures. 17 , 18 , 19 In addition, a recent meta-analysis and systematic review demonstrated that use of the neonatal EOS calculator is associated with a substantial reduction in the use of empirical antibiotics for suspected EOS. 16

In view of the insensitivity of blood cultures alone to define neonatal infection, other techniques hold promise such as 16s rRNA and PCR which detects <3 copies bacterium. Positives identified by PCR were higher than by blood culture (10 versus 5%) and when blood culture was used as control, the sensitivity and specificity of PCR was 100% and 97.85%, respectively and the index of accurate diagnosis was 0.979. 19 Multiplex PCR ( n  = 803 infants and children) showed a positive test in 16% compared to 10% using blood culture. 20 This is further improved in CSF samples increasing detection from 9 to 45%. However, challenges still exist in the identification of clinically significant Gram-positive infections, understanding the significance of DNA of bacteria in the blood (DNAemia) and sustained inflammation on long-term outcomes.

Conclusions

The recent introduction of Sepsis-3 for adults has triggered plans to translate this to children and newborn infants and involvement in the Surviving Sepsis campaign ( www.survivingsepsis.org ). However, there are significant reasons that extrapolation is not appropriate in this setting. Sepsis is challenging for many reasons as it is not a single static disease but a dynamic continuum of inflammatory responses. This situation makes single biomarkers insufficient as different pathogens, immune status and duration of sepsis vary the systemic immune response.

Clinical trials have not routinely accounted for these variations and despite promise in defined subgroups have failed to prove benefit in larger populations. There are multiple definitions of neonatal sepsis used internationally that encompass clinical, microbiological and biochemical data as well as treatment initiation and duration. The difficulties in comparing early and late onset sepsis as well as differences between term and preterm infants make a single definition or management plan challenging. In EOS the presence of antenatal inflammation or chorioamnionitis may not be definitely recognised until the placental histology is completed and whether this information is included as a factor in early management is controversial. Histological confirmation of chorioamnionitis may or may not be helpful for the diagnosis of neonatal sepsis. 21

More recently the neurodevelopmental sequelae of infection have been highlighted apart from the immediate morbidity and mortality. The inflammatory response following sepsis and necrotising enterocolitis are associated with adverse neurological outcomes. Even coagulase-negative Staphloccoccal infections that were previously considered as contaminants and harmless skin commensals are associated with abnormal neurodevelopmental outcome in preterm infants. 22 Tertiary mechanisms of brain injury involve persistent dysregulated inflammation. Once inflammation is triggered, there can be a sustained response. 23

In addition to the lack of an internationally accepted consensus definition of neonatal sepsis, there are no definitions associated with long-term outcomes. This lack hinders ongoing collaborative research and benchmarking. Core outcomes are required to standardise clinical trials of sepsis and allow comparison between trials. In addition, prioritising research goals with families is essential. 24 , 25 Therefore a consensus definition is required that can be universally generalisable and validated in international datasets and correlated with neurodevelopmental outcomes.

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A Correction to this paper has been published: https://doi.org/10.1038/s41390-020-01221-8

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Acknowledgements

This research was funded in part by the National Children’s Research Centre, Dublin, Ireland. E.G. is supported by the Leenaards Foundation and E.J.M. by the Health Research Board of Ireland.

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E.J.M.: Manuscript conception and design and wrote the manuscript. Literature review and manuscript revision. Revised and edited the manuscript before submission. M.M., E.G., H.K., M.A.T., A.v.d.H., J.B., J.M.K., F.M.K., J.M., M.D., S.H.P.S., W.P.deB., T.S., I.K.M.R., J.L.W., J.J., F.B.P., L.J.S.: Significant contributions to the intellectual content and literature review of the manuscript. Revised and edited manuscript before submission.

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Molloy, E.J., Wynn, J.L., Bliss, J. et al. Neonatal sepsis: need for consensus definition, collaboration and core outcomes. Pediatr Res 88 , 2–4 (2020). https://doi.org/10.1038/s41390-020-0850-5

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literature review on neonatal sepsis

Exchange Transfusion in Neonatal Sepsis: A Narrative Literature Review of Pros and Cons

Affiliation.

  • 1 Department of Regional Neonatal-Perinatal Medicine, Hamamatsu University School of Medicine, Hamamatsu 4313192, Japan.
  • PMID: 35268331
  • PMCID: PMC8910835
  • DOI: 10.3390/jcm11051240

Neonatal sepsis remains a leading cause of morbidity and mortality worldwide. It is widely considered that exchange transfusion (ET) as an adjunctive treatment for neonatal sepsis has the ability to reduce mortality. This review summarizes the current knowledge regarding the efficacy of ET for neonatal sepsis. In neonatal sepsis, immune responses such as proinflammatory and anti-inflammatory cytokines play an important role in pathogenesis and can lead to septic shock, multiple organ failure, and death. Between the 1970s and 1990s several authors reported that ET was effective in the treatment of neonatal sepsis with sclerema. ET removes bacterial toxins and inflammatory cytokines from the blood by replacing it with fresh and immunologically abundant blood, thereby leading to improvement in tissue perfusion and oxygenation. Moreover, ET with fresh whole blood increases neutrophil count and immunoglobulin levels as well as enhancing neutrophil function. However, there is a lack of clear evidence for the clinical efficacy of ET. In addition, adverse events associated with ET have been reported. Although most complications are transient, ET can lead to life-threatening complications. Therefore, ET can be considered a last resort treatment to rescue neonates with severe sepsis with sclerema and disseminated intravascular coagulation.

Keywords: adverse event; neonatal sepsis; septic shock; whole blood exchange transfusion.

Publication types

  • jpchc-v6-id1042

Abbreviations

Introduction, epidemiology, risk factors and etiologies, clinical features, diagnostic approach of ns, treatment of ns, long-term prognosis.

literature review on neonatal sepsis

Review Article

J Pediatr & Child Health Care. 2021; 6(2): 1042.

Neonatal Sepsis: A Review of the Literature

Nyenga AM 1 , Mukuku O 2,3 * and Wembonyama SO 1,3

¹Department of Pediatrics, University of Lubumbashi, Lubumbashi, Democratic Republic of the Congo

²Institut Superieur des Techniques Medicales, Lubumbashi, Democratic Republic of Congo

³School of Public Health, University of Goma, Goma, Democratic Republic of Congo

*Corresponding author: Olivier Mukuku, Institut Superieur des Techniques Medicales, Lubumbashi, School of Public Health, University of Goma, Goma, Democratic Republic of Congo

Received: May 11, 2021; Accepted: June 03, 2021; Published: June 10, 2021

Neonatal sepsis contributes significantly to neonatal morbidity and mortality and is a major public health challenge around the world. Depending on the mode of occurrence, a distinction is made between maternal-transmitted infection and that acquired in the postnatal period. Although the etiologies maternally transmitted diseases are well understood, those of postnatal acquired infections are variable depending on the epidemiology of each hospital environment. On the one hand, risk factors for maternal-transmitted infections are maternal sepsis, prolonged premature rupture of membranes, chorioamnionitis, and bacteriuria in the mother during pregnancy. On the other hand, risk factors for postnatal acquired infections are prematurity, low birth weight, lack of hygiene, and invasive therapeutic interventions. The diagnosis is based on a series of anamnestic, clinical and biological features. Although the positive diagnosis is based on the isolation of the germ by culture on a body sample (blood, cerebrospinal fluid, urine, etc.); its low sensitivity leads to the use of markers of the acute phase of inflammation such as C-reactive protein, procalcitonin and interleukins. New molecular biology techniques are promising and offer precise diagnosis with rapid results. Empirical management is a function of microbial ecology while definitive treatment is guided by the results of microbial culture.

This article presents the essential elements for understanding neonatal sepsis and discusses new diagnosis and therapeutic management. It offers a thorough reading based on the issue of infections in newborns.

Keywords: Neonatal sepsis; Early onset sepsis; Late onset sepsis; Risk factors; Management

CSF: Cerebrospinal Fluid; EONS: Early Onset Sepsis; LONS: Late Onset Sepsis; NS: Neonatal Sepsis; PCR: Polymerase Chain Reaction; SIRS: Systemic Inflammatory Response Syndrome

Neonatal Sepsis (NS) is defined as a systemic inflammatory response syndrome in the presence or following a suspected or established infection with or without associated bacteremia, documented by a positive blood culture during the first 28 days of life [1,2].

The term ‘neonatal sepsis’ is used to denote a condition of bacterial, viral or fungal origin associated with hemodynamic changes and other clinical manifestations [3]. Despite several years of expertise, many challenges remain in the diagnostic approach to newborns suspected of having NS. These include the lack of a consensual definition of NS in everyday practice.

Traditionally, the definition of sepsis has included the isolation of a pathogen from a normally sterile body fluid such as blood or Cerebrospinal Fluid (CSF) [4,5]. However, given the understanding of the role of potent pro-inflammatory cytokines in the clinical characterization of sepsis, the term ‘Systemic Inflammatory Response Syndrome (SIRS)’ has also been used to define sepsis in neonates [2,4]. NS can be caused by bacterial, viral, and fungal microorganisms. Although the current description is clear on bacterial causes, the share of other microorganisms is no less important in the hospital environment. These include Candida and Enteroviruses responsible for severe pictures of NS [6-9].

Two categories are to be distinguished according to the mode of occurrence

Early Onset Sepsis (EONS): these are infections of the newborn resulting from vertical mother to infant transmission which occurs in the perinatal period (before or soon after delivery) and which can appear within the first week of postnatal life [3,10,11]. In this context, infection occurs in utero from transplacental transmission or more commonly vertically (ascending) from the vaginal environment after rupture of membranes. In addition, the newborn can become infected when exposed to pathogenic bacteria, viruses or fungi as they pass through the birth canal [12-15].

Postnatal acquired infections (Late Onset Sepsis [LONS]): contamination occurs after delivery following interactions with the hospital or community environment. It usually starts after 72 hours of age. The source of contamination is either nosocomial or community [4,14-16].

Analysis of several studies reports an estimate of NS of 2,202 (95% CI: 1,099 - 4,360) per 100,000 live births, with mortality between 11% and 19% in high- and middle-income countries [17]. However, the burden of NS varies greatly from one setting to another, depending on the level of organization of the health system and socio-demographic characteristics of the populations.

The reported incidence of NS ranges from 7.1 to 38 per 1,000 live births in Asia, 6.5 to 23 per 1,000 live births in Africa, and 3.5 to 8.9 per 1,000 live births in America South and the Caribbean. By comparison, reported rates in the United States and Australia vary from 1.5 to 3.5 per 1,000 for EONS and up to 6 per 1,000 live births for LONS, for a total of 6-9 per 1,000 for NS [18-22].

In the world, NS contributes significantly to neonatal morbidity and mortality; it constitutes a major public health challenge. The most common causes of death in the neonatal period are infections (35%), followed by prematurity (28%), intrapartum complications (24%), and asphyxia (23%) [2,23,24]. NS is responsible for 26% of deaths in children under-5, with the highest death rates in sub-Saharan Africa [25]. The data available is a mixture of official sources and studies both hospital and community [18].

In developing countries, statistics may be underestimated due to high rate of home deliveries and low percentage of attendance by skilled health workers. Establishing numbers and causes of neonatal deaths is therefore difficult given that a large number of newborns die at home without ever being in contact with health workers and without ever integrating the statistics.

Nonetheless, many studies report infections as one of the 3 leading causes of death both in the world and in Africa [26–31].

Risk factors for EONS

Anamnestic risk factors for EONS [11] are classified into two groups in decreasing order of risk (although this classification does not prejudge a systematic therapeutic approach).

Major criteria (strongly linked to NS): chorioamnionitis, twin with mother to infant infection, maternal temperature before or during labor >38°C, spontaneous prematurity <35 weeks, Prolonged Rupture of Membranes (PROM) more than 18 h, premature rupture of membranes before 37 weeks, and maternal group B streptococcus infections (GBS) colonization/GBS bacteriuria (during index pregnancy).

Minor criteria (little related to NS): rupture of membranes more than 12 hours but less than 18 hours, spontaneous prematurity less than 37 weeks and more than 35 weeks, abnormal fetal heartbeat or unexplained fetal asphyxia, and tinted or meconium amniotic fluid.

The existence of one of these criteria requires clinical monitoring, particularly close during the first 24 hours of postnatal life. Infection and mortality are inversely related to birth weight and gestational age [3,10].

Microorganisms most implicated in EONS are those found in maternal urogenital and digestive tracts. These are Streptococcus agalactiae (Group B streptococcus ) and Escherichia coli . Secondarily, Monocytogenic listeria, Nontypeable Haemophilus influenzae , and Gram-negative Enterobacteriaceae other than Escherichia coli are also implicated [3,10,11,19].

However, the application of a routine maternal screening program and intrapartum antibiotic prophylaxis in some countries has significantly reduced Streptococcus agalactiae in maternally transmitted NS [19,32].

Risk factors for LONS

In the hospital environment, several factors predispose to an increased risk of NS. These include stay in intensive care, prematurity, low birth weight, invasive medical procedures, mechanical ventilation, and use of parenteral fluid. Poorly disinfected hands and equipment are important vectors of germs [33,34].

In the community, the risk of NS is determined by poor hygiene in general (of the hands, bottle-feeding and poor umbilical cord care practices) [33,35,36].

Nevertheless, the important role of breastfeeding in preventing postnatal infection is proven [37-40]. Breast milk is believed to be an important vector of exchange between the maternal immune system and the newborn’s body. The practice of breastfeeding actively regulates immune and metabolic systems and the microflora in the newborn while providing multiple means of protection against various pathogens [40,41].

Bacterial aetiologies of LONS are very varied and depend on one setting to another. Coagulase-negative Staphylococci are the most reported in neonatal intensive care units [42,43]. Other germs such as methicillin-resistant Staphylococcus aureus and multidrugresistant Gram-negative bacteria ( Pseudomonas and Klebsiella ) are still common in developing countries unlike developed countries [44]. Some Gram-positive germs classically responsible for EONS (e.g. Group B streptococcus ) can be found in LONS in the community or due to manual transmission or by contaminated equipment in a hospital environment [3,45,46].

The over- and inappropriate use of antibiotics has favored the emergence of unusual germs and the emergence of multi-resistance to common antimicrobials [47,48]. Viruses are also a major cause of nosocomial infections, but most of the time they are underestimated. These include, in particular, Enteroviruses and Rotaviruses. Systemic fungal infections are increasingly reported, with Candida albicans leading the way [7,8,49].

Clinical features of NS are vague and ill-defined. Altered feeding behavior (refusal to breastfeed) is a common and early symptom, but not specific. Other signs are thermal disturbances (hypothermia or fever), lethargy, incessant crying, hypotonia, peripheral perfusion disorder (prolonged hair recoloration time), blunt neonatal archaic reflexes, cardiac arrhythmias (bradycardia or tachycardia), metabolic disorders such as hypoglycemia or hyperglycemia, and metabolic acidosis.

In the advanced-stage, signs of organ failure determine the severity of NS [1,3,10]. Symptoms specific to each system are:

• Central nervous system: these are a bulging of the anterior fontanel, a blank stare, a sharp and excessive cry, irritability, a coma, convulsions, and a retraction of the neck. The presence of these signs suggests the hypothesis of meningitis.

• Cardiac system: mainly hypotension and poor perfusion. Studies have emphasized the value of early diagnosis of NS using characteristic heart rate analysis over electrocardiographic monitoring. Griffin et al. [50] found that characteristic abnormal heart rate such as reduced variability and transient decelerations occurred 24 hours before symptoms appeared in NS. Another group experienced an asymmetric increase in the RR interval in 3-4 days preceding sepsis with a greater increase in the last 24 hours [50,51]. These tests may be useful for early indication of therapeutic management.

• Gastrointestinal system: These include vomiting, diarrhea, abdominal distension, paralytic ileus and ulcerative necrotizing enterocolitis.

• Hepatic system: Common hepatic signs are hepatomegaly and direct hyperbilirubinemia. A newborn with jaundice or direct bilirubinemia after 8 days of postnatal life is more likely to have a urinary tract infection [52,53].

• Renal system: acute renal failure may be noted.

• Haematological system: bleeding and petechiae or purpura may be observed.

• Skin system: Multiple pustule-like rashes, sclerema, mottling and oozing umbilicus have been reported. De Felice et al. used colorimetric analysis of skin color to assess the severity of sepsis [52,54].

The diagnosis of NS is based on a host of anamnestic, clinical, and biological arguments. History-taking information helps assess risk factors for sepsis in the newborn and in the mother. There is a significant correlation between some factors (maternal, environmental, and neonatal) and the occurrence of sepsis [55–57].

Prediction algorithms and scores have been developed to assess the risk of NS and thereby reduce exposure to empiric antibiotics. In addition, a good number of the cases of sepsis presented a poor clinical practice even asymptomatic in the immediate postnatal period [58– 60]. Clinical signs of sepsis in the newborn are nonspecific. Several non-infectious clinical pictures can constitute differential diagnoses. Likewise, features relating to the immaturity of some functions, in this case in prematurity, may coexist with an infectious process whose demarcation will not be easy in clinical practice. Nevertheless, a careful clinical examination makes it possible to formulate the diagnostic hypothesis and thus guide paraclinical investigations [3].

Several biological approaches are being studied in the development of NS. However, many of them do not have sufficient sensitivity and specificity to be used in isolation [61]. Isolation of the pathogen in a normally aseptic body sample (blood, cerebrospinal fluid, urine, etc.) is the gold standard in the diagnosis of sepsis [4,62]. However, the low sensitivity and the waiting time for results, especially for blood culture, limit its effectiveness in deciding whether to start treatment. Therefore, the use of biomarkers of the host’s response to infection, especially those of the acute phase of inflammation, is of great utility in clinical practice. The most widely used are white blood cell count, C-reactive protein, procalcitonin and interleukins. Understanding the kinetics of inflammatory markers during the infectious process as well as the significant thresholds is essential for a good interpretation. In addition, a combination of different biomarkers can increase sensitivity and specificity in the diagnosis of sepsis [61–63].

High sensitivity molecular diagnostic techniques are developed to overcome the limitations of microbial cultures. These new techniques target the early detection of the pathogen-specific nucleic acid. These are real-time Polymerase Chain Reaction (PCR), PCR followed by post-PCR treatment (matrix hybridization or mass spectroscopy), and Fluorescence In Situ Hybridization (FISH). These techniques have the advantage of being quick and requiring small amounts of blood sample. However, although promising, the cost and complexity of molecular biology analyzes do not currently allow their use in current practice and on a large scale [61,64].

Given the etiological diversity of sepsis in newborns, several cases can be envisaged in antimicrobial management. On the one hand, the antimicrobial therapeutic approach of NS can be distinguished according to whether they are suspected cases (empiric treatment) or cases with a pathogen well identified by culture (definitive treatment). On the other hand, the clinical picture and the mode of occurrence (EONS or LONS) must be taken into account in the choice of antibiotics.

To do this, a good anamnestic investigation and a careful clinical examination are essential. Under ideal conditions, a positive bacterial culture before starting treatment is an asset that would effectively and efficiently guide the choice of antibiotic. However, given the prognosis of NS, specimen collection and culture results should not delay initiation of treatment in symptomatic newborns.

Empirical treatment

By consensus, the empirical approach should be guided by data from antibiograms on bacteria commonly isolated in the neonatal care unit or in the community. Empiric treatment for EONS should consist of administration of Ampicillin and an aminoglycoside (most commonly Gentamicin) with a third or fourth generation cephalosporin. Piperacillin-Tazobactan and Ampicillin-Sulbactan are increasingly used in patients admitted to neonatal intensive care. However, given the low penetration of Tazobactan into the bloodbrain barrier, its indication is limited in meningitis, whereas the combination of Sulbactam (beta-lactamase inhibitor) with ampicillin seems to have a good diffusion in the central nervous system [3,65,66]. In the case of nosocomial infections, the most susceptible germs are of the group of coagulase negative Staphylococci compared to Staphylococcus aureus and Gram-negative bacteria. In order to reduce the use of Vancomycin (due to the emergence of resistance), an empirical treatment made of an antistaphylcoccal beta-lactam such as Nafcillin combined with an aminoglycoside is proposed before the results of bacterial cultures [67,68].

Definitive treatment

The definitive antimicrobial treatment will be chosen based on the germ identified (by the culture), its sensitivity (antibiogram) and its bioavailability at the main site (s) of infection. In general, the antibiotic of choice should have better systemic availability and good diffusion through the blood-brain barrier.

Ampicillin or any other antibiotic from the penicillin group is generally effective against group B streptococcus . Gentamycin is often used in common practice for a synergistic effect with ampicillin; whereas ampicillin alone has excellent efficacy against monocytogenic Listeria [10,69]. The third generation cephalosporins seem to be well indicated in the treatment of enterobacterial septicemia, especially if a meningeal transplant is suspected [3,70].

Inappropriate use of antibiotics has favored the emergence of strains resistant to several common antibiotics, especially from the beta-lactam class. This explains the increasingly frequent use of vancomycin, carbapenemes and combinations with sulbactan [47,48,71].

Preventive measures focus on the asepsis of the newborn. The hygiene of hands and equipment used, the reduction of manipulations and invasive procedures as well as early enteral feeding are important pillars [72]. Newborns at risk should be given special surveillance. Breastfeeding is the ideal natural way to help impart anti-infective, antiinflammatory and immunomodulatory properties to the newborn. Breast milk contains many bioactive molecules that protect against infection and inflammation in the form of cytokines, nucleotides, hormones, and growth factors. The anti-infective properties of breast milk are based on both soluble factors (immunoglobulins) and cellular elements [37,39]. Sound antimicrobial management and surveillance of antimicrobial resistance would improve the prognosis of NS.

In the long term, newborns with sepsis are prone to growth deficits and neurodevelopmental disorders. In the event of NS, newborns with low birth weight are at greater risk of developing cerebral palsy and neurodevelopmental delay [10,73].

On the one hand, sepsis affects the long-term neurodevelopmental prognosis, either by directly affecting the central nervous system or by causing severe systemic inflammatory lesion responsible for bronchopulmonary dysplasia, retinopathy of prematurity, and cerebral hemorrhages [74]. On the other hand, an association between the development of atopic diseases in childhood and a history of NS has been reported [75,76].

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literature review on neonatal sepsis

Citation: Nyenga AM, Mukuku O and Wembonyama SO. Neonatal Sepsis: A Review of the Literature. J Pediatr & Child Health Care. 2021; 6(2): 1042.

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Neonatal Sepsis

Muhammed ershad.

College of Medicine, Drexel University, 245 N 15th St, MS #1011, Philadelphia, PA 19102 USA

Ahmed Mostafa

Maricel dela cruz, david vearrier, purpose of review.

Neonatal sepsis is a diagnosis made in infants less than 28 days of life and consists of a clinical syndrome that may include systemic signs of infection, circulatory shock, and multisystem organ failure.

Recent Findings

Commonly involved bacteria include Staphylococcus aureus and Escherichia coli . Risk factors include central venous catheter use and prolonged hospitalization. Neonates are at significant risk of delayed recognition of sepsis until more ominous clinical findings and vital sign abnormalities develop. Blood culture remains the gold standard for diagnosis.

Neonatal sepsis remains an important diagnosis requiring a high index of suspicion. Immediate treatment with antibiotics is imperative.

Introduction

Neonatal sepsis is a diagnosis made in infants less than 28 days of life and consists of a clinical syndrome that may include systemic signs of infection, circulatory shock, and multisystem organ failure. Neonatal sepsis may be divided into two types: early-onset neonatal sepsis (EONS) and late-onset neonatal sepsis (LONS). EONS is typically described as infection and sepsis occurring within the first 24 hours to first week of life [ 1 – 3 ]. LONS has been labeled as after 24 hours or after the first week of life, up to 28 days or 1 month [ 4 – 6 ]. The literature varies in the definition of EONS and LONS, but most categorize EONS as within the first 72 hours of life and LONS as after this time period up to 28 days [ 7 – 10 ]. Some have proposed the need to create a unified definition worldwide to further develop accuracy in the diagnosis and treatment of EONS and LONS [ 11 , 12 •].

Classifications of neonates can be separated even further depending on age and weight. A newborn is an infant within the first 24 hours of life, while a neonate is up to 28 days old. Preterm infants are those born at a gestational age less than 37 weeks, and term infants are those born at or after 37 weeks of gestation. Low birth weight (LBW) is considered less than 2,500 grams and very low birth weight (VLBW) is less than 1,500 g. Extremely low birth weight (ELBW) is used to describe neonates less than 1,000 g. These designations become significant when discussing the etiology of and risk factors for neonatal sepsis. Neonatal sepsis can also be defined as clinically diagnosed or confirmed by positive culture in a typically sterile bodily fluid. The gold standard for the diagnosis of neonatal sepsis is a positive culture in the blood, urine, cerebrospinal fluid, peritoneal fluid, or any other sterile tissues [ 13 , 14 ].

We performed a search of the MEDLINE database for the keywords and titles, “neonatal sepsis,” “neonatal fever,” “newborn sepsis,” and “newborn fever,” covering the period January 1, 2018 to December 31, 2018, which resulted in a total of 1,107 citations. Limiting the search to articles published in the English language and including only human studies yielded a total of 1,055 citations. These 1,055 articles were manually reviewed for relevance and there were a total of 64 citations. The remaining 1,003 were not cited as they did not contain relevant information, contained outdated information, or were superseded by more recent articles.

Epidemiology

Worldwide, neonatal sepsis occurs in about 1 to 50 out of 1,000 live births and accounts for 3 to 30% of infant and child deaths annually [ 15 , 16 ]. In a prospective study performed between 1997 and 1999 at several neonatal centers in South Korea, the incidence rate of neonatal sepsis was 6 per 1,000 live births in those with positive cultures and 30 per 1,000 live births in clinically diagnosed neonatal sepsis [ 7 ]. Fatality rates in this study were 2.2% in culture-confirmed neonatal sepsis and 4.7% in clinically diagnosed neonatal sepsis [ 7 ]. An analysis performed in Taiwan from 2001 to 2006 found an incidence rate of 4 out of 1,000 live births in all those diagnosed with neonatal sepsis either clinically or by positive culture [ 8 ].

A retrospective study from the Netherlands showed a decrease in the incidence of EONS from 4% between 1978 to 1982 to 1.2% from 2003 to 2006 [ 17 ]. The incidence of LONS in this study increased from 7.1% between 1978 to 1982 to 13.9% from 2003 to 2006 [ 17 ]. A review from the United States (US) in 2012 reported that EONS occurs in 1.5 to 2% of VLBW infants and LONS in 21% of VLBW infants [ 18 ]. In an epidemiological study of culture positive diagnoses of neonatal sepsis in Switzerland from 2011 to 2015, the national incidence was 1.43 out of 1,000 live births with a mortality rate of up to 18% [ 19 ]. A systematic review that investigated the global burden of neonatal sepsis from 1979 to 2016 showed an annual incidence of three million cases of neonatal sepsis worldwide with a mortality rate of 19% [ 20 ].

The organisms and pathogens that are most associated with neonatal sepsis differ depending upon country involved. Pathogens range from gram positive and negative bacteria to viruses and fungi, with bacteria being the most frequently identified. The most commonly implicated bacteria include Staphylococcus aureus , coagulase negative staphylococci (CONS), Streptococcus pneumoniae , Streptococcus pyogenes , Escherichia coli , Klebsiella pneumoniae , Pseudomonas aeruginosa , Salmonella typhi , and Group B streptococcus (GBS) [ 21 ]. Viruses include echovirus, enterovirus, parechovirus, coxsackie virus, adenovirus, parainfluenza virus, rhinovirus, herpes simplex virus, respiratory syncytial virus, and coronavirus [ 21 ]. Candida albicans and other Candida species are the most common fungi associated with neonatal sepsis [ 22 ].

In the 1990s, the American Academy of Pediatrics (AAP) began to recommend the use of intrapartum antibiotic prophylaxis (IAP) to prevent perinatal GBS, and in 2002, the AAP and the American College of Obstetricians and Gynecologists instituted guidelines on the universal screening by culture of all pregnant women from 35- to 37-week gestation. Due to the widespread use of prophylactic antibiotics for neonates, particularly intrapartum antibiotic use in mothers with positive cultures for GBS, the incidence of GBS-associated neonatal sepsis has declined significantly, a decrease of 70% in the US [ 8 , 23 ]. During the same period, other countries such as Canada and Taiwan have recommended the universal use of IAP and have seen a decline in the incidence of neonatal sepsis secondary to GBS infection as well [ 1 , 24 ]. In such countries where IAP is utilized, the most common causative agents of neonatal sepsis are Escherichia coli and gram-positive organisms [ 1 , 24 ].

Risk Factors

In EONS, which is typically associated with vertical transmission of pathogens from mother to child, the most common pathogens are GBS, Escherichia coli , CONS, Haemophilus influenzae , and Listeria monocytogenes [ 3 , 5 , 25 , 26 ]. In LONS, which is most commonly associated with iatrogenic or nosocomial infections, the most common pathogens are CONS, followed by Staphylococcus aureus and Escherichia coli [ 3 , 17 , 19 , 24 ]. Risk factors include central venous catheter use and other invasive medical devices as well as prolonged hospitalization [ 27 ]. Other risk factors include preterm rupture of membranes, amnionitis, meconium aspiration, LBW, VLBW, ELBW, preterm birth, greater than three vaginal examinations during labor, fever in the mother during labor, or any other infection in the mother during labor [ 14 , 16 , 28 ]. In full-term infants, males have a greater incidence of sepsis compared to female infants, an association not found in preterm infants [ 21 ]. A study performed in the US found significant disparity and increased incidence of mortality secondary to neonatal sepsis among children from low household income backgrounds versus those from affluent households [OR 1.19, 95% confidence interval (1.05, 1.35)] [ 29 ••].

Clinical Findings

Considering the relatively subtle findings seen during the clinical assessment, neonates are at significant risk of delayed recognition of sepsis until more ominous clinical findings and vital sign abnormalities develop. In the early onset type, they may have a history of fetal distress including fetal tachycardia in the peripartum period. Soon after delivery, there may be other clinical clues such as meconium-stained amniotic fluid and low Apgar scores on initial neonatal assessment. The caretaker may give a history of feeding intolerance, irritability, excessive sleepiness, or “just not looking right.”

Vital sign derangements include both hypothermia and fever. Fever is more common in term babies whereas preterm babies more often demonstrate hypothermia. There may be tachycardia or bradycardia, signs of poor perfusion including cool and pale extremities, and a rapid thready pulse. Respiratory symptoms and signs are common in neonatal sepsis, including grunting, nasal flaring, use of accessory muscles of respiration, cyanosis, and episodes of apnea. Neurological symptoms and signs include lethargy, seizures, irregular respiration, high pitched cry, hypotonia, hypoactive deep tendon reflexes, and abnormal primitive reflexes. Gastrointestinal signs include decreased feeding, vomiting, diarrhea, jaundice, abdominal distension, and hepatosplenomegaly. Skin findings include petechiae, impetigo, cellulitis, and abscess. Underlying metabolic acidosis secondary to poor perfusion can manifest as tachypnea and respiratory distress in the absence of respiratory tract infection.

Diagnostic Testing

As the symptoms and signs of neonatal sepsis are often very subtle and vague, it is imperative to perform diagnostic testing in any neonate with significant risk factors and concerning signs and symptoms. There are various multivariate predictive scoring systems based on retrospective studies that may be used to predict the need for antibiotics and extensive laboratory evaluation of a neonate versus observation for concerning signs and symptoms. One such example is the EONS calculator based on a large retrospective population study performed in the US to support clinicians in the decision to start antibiotics in neonates suspected of having sepsis [ 30 ]. The newborn’s prior probability of EONS obtained from maternal risk factors such as chorioamnionitis and premature rupture of membranes is combined with findings based on the clinical examination, creating a scoring system that can determine the need for antibiotics and level of monitoring required (Table ​ (Table1). 1 ). This scoring system has been shown to reduce the proportion of newborns undergoing extensive laboratory evaluation and administration of antibiotics without any adverse effects [ 31 ••]. The number needed to treat (NNT) for the high-risk group requiring antibiotics determined by this scoring system was still 118, highlighting the challenges involved in coming up with better diagnostic tools in picking up EONS at an early stage [ 32 ].

EONS prediction calculator variables

Adapted from https://neonatalsepsiscalculator.kaiserpermanente.org/InfectionProbabilityCalculator.aspx

A complete blood count (CBC) should be performed to assess for total and differential white blood cell count (WBC), absolute and immature neutrophil count, and the ratio of immature to total neutrophil count. Although an absolute leukocytosis has low sensitivity for neonatal sepsis, they may aid in clinical decision-making in cases where a low-to-moderate clinical suspicion for sepsis is present. Interestingly, a low WBC count, low absolute neutrophil count (ANC), and an immature to total neutrophil ratio (I/T) of 0.2 or greater have been shown to be highly predictive of infection [ 33 ]. Obtaining an I / T 2 ratio by dividing I/T with the total neutrophil count has been shown to have better specificity and area under the curve than I/T and ANC alone in diagnosing EONS [ 33 ]. An I/T 2 ratio would account for both the elevated immature neutrophils and any neutropenia which can be worrying in the background of sepsis. The sensitivity, specificity, likelihood ratios, and the area under the curve for ANC, I/T, and I/T 2 were found to be highest after 4 hours of birth as compared to anytime earlier [ 33 ]. Limitations with I/T and I/T 2 include the skill of the laboratory personnel performing the manual counts as well as their limited specificity. It is also important to note that there are multiple variables that can affect the various components of WBC, including a crying neonate, gestational age, and arterial versus venous sample [ 34 ].

Blood culture remains the gold standard for confirmation of sepsis but is limited by low sensitivity and duration of time before a culture is determined to be positive (often around 24 to 72 hours). Fastidious organisms, maternal antibiotics, and small sample collection limit the sensitivity of blood cultures. False positives may occur due to inadequate skin antisepsis prior to sample collection. At least 0.5 mL of blood should be collected to improve the diagnostic yield. Samples should be collected from two different sites to reduce false positive results. If a central venous catheter is present, blood culture should be taken from both the line and a separate peripheral source, to assess for the differential time to positivity. This helps in distinguishing catheter-associated infections from other sources of infection, which has implications in clinical management.

Swab cultures from surface sites such as the eyes, ears, umbilicus, groin, throat, pharynx, and rectum may provide information about colonizing organisms. They, however, do not contribute to the decision on starting antibiotics, especially if the neonate appears well on clinical examination. Placental cultures may indicate the possible pathogen the fetus was exposed to but does not indicate infection [ 21 ]. Placental culture results should not, therefore, be used as a reason for antibiotic therapy. Urinary tract infections are uncommon in the first 72 hours of life. Urine cultures are therefore only performed in the evaluation of LONS [ 35 ]. Lumbar puncture (LP) should be routinely performed in neonates showing signs of EONS or LONS. About 23% of neonates with culture-positive bacteremia will have concomitant meningitis [ 36 ]. If LP has not been performed in a neonate whose blood culture is positive, it should be performed promptly. Negative blood cultures do not rule out meningitis, as 38% of these individuals will have positive cerebrospinal fluid (CSF) gram stain or culture [ 37 ]. False negative CSF gram stain and culture may occur in neonates treated with antibiotics prior to LP.

Acute phase reactants such as C-reactive protein (CRP), procalcitonin, interleukin levels (IL-6 and IL-8), presepsin, haptoglobin, and neutrophil CD64 have been investigated as potential biomarkers for neonatal sepsis. CRP may not be elevated in early stages of infection, due to the time taken for its synthesis in the liver and eventual appearance in the blood. Serial measurements of CRP combined with other acute phase reactants such as procalcitonin, IL-6, and IL-8 may improve its diagnostic accuracy [ 38 ].

Procalcitonin (PCT) is more specific than CRP for bacterial infections and rises more rapidly in response to infection than CRP. In normal birth weight infants, a PCT level greater than 0.5 ng/mL is associated with a nosocomial infection, whereas a level of greater than 2.4 ng/mL in VLBW infants should prompt antibiotic therapy [ 39 ]. It has been shown that procalcitonin-guided decision making is superior to standard care in reducing antibiotic therapy in neonates with suspected EONS [ 40 ]. PCT levels, however, can be elevated with non-infectious conditions such as respiratory distress syndrome, pneumothorax, intracranial hemorrhage, and hemodynamic instability [ 41 ]. Serial PCT concentration may be of utility in the evaluation of neonatal sepsis although PCT physiologically increases in the absence of infection over the first 48 hours of life [ 42 , 43 ].

Presepsin has been found to have a high level of diagnostic accuracy and has been recommended as a valuable marker in neonatal sepsis, albeit not as a single diagnostic test [ 44 •]. A meta-analysis performed to investigate the potential of IL-6 concluded that it could be used as a valid marker for early diagnosis of sepsis in neonatal care units [ 45 ].

Newer Diagnostic Techniques

Automated blood culture systems monitor continuously for positive signals, which improves time to detection of pathogens. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectroscopy can identify organisms in blood cultures much earlier, allowing antibiotic therapy specific to the organism(s) involved [ 46 ]. Multiplex polymerase chain reaction (PCR) can detect the identity of the bacteria or fungi, as well as the presence of antimicrobial resistance genes within hours of identification of the pathogen [ 47 ].

PCR can be performed on blood and other body fluids directly without the need to first culture causative organisms. Quantitative real-time amplification systems, known as qPCR, can be used to rapidly rule out the presence of organisms in body fluids, considering its high negative predictive value and a short time to results. The technique is based on 16S ribosomal deoxyribonucleic acid (DNA) amplification. qPCR utilizes a small sample volume and can be used for other bodily fluids such as pleural or peritoneal fluid. Disadvantages include the inability to perform antibiotic susceptibility testing, difficulty in differentiating a recent infection from an active infection, and the presence of contaminants that can give false positive results. Hence, clinical correlation should be made in the interpretation of these results.

Treatment and Management

Management varies depending on a number of factors including age, site of infection, suspected causative organism, microbial resistance patterns, and available resources. Consensus among authors exists that antibiotic therapy should be initiated as soon as neonatal sepsis is suspected, but there is no consensus regarding duration of treatment.

EONS Empiric Antibiotic Therapy

Recommendations from the Canadian Pediatric Society (CPS) and the AAP recommend initiating antibiotic therapy if clinical symptoms are present, with the AAP also recommending antibiotics in the presence of abnormal laboratory values or more than one risk factor (Table ​ (Table2) 2 ) [ 48 ]. The presence of maternal chorioamnionitis with no neonatal clinical signs warrants antibiotic initiation as per the AAP and only if present with laboratory abnormalities per the CPS. The US Center for Disease Control and Prevention (CDC) recommends empiric antibiotic therapy for all newborns with a maternal diagnosis of chorioamnionitis, regardless of the infant’s clinical condition [ 48 , 49 ]. Reevaluation at 48 hours and discontinuation of antibiotics if infection was unlikely was universally recommended [ 48 ].

Empiric antibiotic recommendations from the Canadian Pediatric Society and the American Academy of Pediatrics

Antibiotic therapy should include intravenous ampicillin for GBS, and coverage for Escherichia coli and other gram-negative bacteria implicated in neonatal sepsis, such as gentamicin, with local antibiotic resistance patterns considered [ 49 , 50 ]. The routine empirical use of broad-spectrum antibiotic agents should only be considered among term newborn infants who are critically ill until culture results are available. Elective genetic testing prior to aminoglycoside use is increasingly being considered to decrease the incidence of permanent hearing loss [ 51 ]. Further studies are required as this has not been evaluated in the neonatal setting. In low-resource settings, or when hospitalization is not possible, the use of intramuscular gentamicin and oral amoxicillin in lieu of intravenous medications has been recommended [ 52 ].

Treatment of LONS

Early diagnosis, appropriate antibiotic administration, and timely supportive management are the keys to successful treatment [ 53 ]. Most cases are attributable to Staphylococcus species and GBS, but about one-third are caused by gram-negative organisms. Most empiric antibiotic regimens include ampicillin, a third-generation cephalosporin, or meropenem, plus an aminoglycoside or vancomycin. In preterm infants, the most common isolates are CONS [ 54 ]. Vancomycin and teicoplanin are the antibiotics of choice for a proven and significant CONS infection, but their excessive use has been associated with the development of vancomycin-resistant enterococcus (VRE) infections and gram-negative infections. Their use as first-line antibiotics for nosocomial infection should be avoided. A combination of flucloxacillin and gentamicin can be used to treat the majority of cases caused by other organisms [ 51 ]. Clindamycin or metronidazole are sometimes added to cover anaerobic organisms in cases of necrotizing enterocolitis. Cefotaxime is commonly reserved for the treatment of infants with meningitis [ 53 ]. Infants with risk factors for candidal sepsis should receive fungal empiric therapy [ 10 ].

Treatment with a beta-lactam or beta-lactamase inhibitor combined with an aminoglycoside for Enterobacter, Serratia, or Pseudomonas sepsis is recommended by many experts [ 53 ]. Meropenem is recommended for preterm infants with systemic extended-spectrum beta-lactamase infections. In one study, prolonged intravenous infusion of meropenem (over 4 hours every 8 hours) in neonates with gram-negative LONS was associated with better clinical outcome compared to the conventional strategy (over 30 min every 8 h) [ 55 ].

Proven Bacterial Sepsis Without Meningitis

In blood culture-proven sepsis, it is reasonable to treat for 10–14 days. A shorter duration (7–10 days) of treatment may be considered in select situations, provided appropriate follow-up can be ensured [ 56 ]. Serial daily blood cultures should be performed until blood cultures are negative. Serial CRP measurements may also be used in deciding to discontinue antibiotics [ 56 , 57 ]. An infant with symptoms can have a false-negative blood culture if antibiotics are given prenatally to the mother or if the blood sample is collected improperly. Hence, antibiotics should be continued for symptomatic infants and those with positive blood culture [ 56 ]. Continuing empirical antibiotic therapy in response to laboratory test abnormalities alone is rarely justified, particularly among well-appearing term infants [ 50 ]. Prolonged duration of initial empirical antibiotic treatment has been associated with death and necrotizing enterocolitis among premature infants [ 58 ].

In resource-poor countries, empiric antibiotic therapy should be individualized for each hospital or region [ 56 ]. Consultation with a pediatric infectious disease specialist is warranted for failure of sterilization of the bloodstream (i.e., resistant or atypical organisms) and site-specific infections [ 50 ]. The use of pentoxifylline in neonatal sepsis was demonstrated to significantly decrease all-cause mortality during hospital stays in underdeveloped or developing countries, which warrants further investigation in large randomized clinical trials in capable countries [ 53 ].

Hydrocortisone has cytokine-suppressing effects, and may improve patient’s cardiovascular status, but has not been evaluated in prospective randomized clinical trials for the treatment of neonatal septic shock [ 53 ]. Immunotherapeutic interventions such as intravenous immunoglobulin (IVIG) infusion, IgM-enriched intravenous immunoglobulin, and granulocyte-macrophage colony-stimulating factor are not recommended [ 53 ].

Bacterial Meningitis

Intensive care with maintenance of cerebral perfusion, oxygenation, and prevention of hypoglycemia are crucial aspects of management [ 53 ]. Combinations of ampicillin, cefotaxime, and aminoglycosides have been suggested by different authors [ 51 , 53 , 56 ]. Cefotaxime plus an aminoglycoside is a good choice for the initial treatment of gram-negative meningitis, due to adequate central nervous system (CNS) penetration. Ceftriaxone may increase the risk of kernicterus in the first week of life and is to be avoided in that age range [ 59 ]. For uncomplicated meningitis, the duration of treatment is 14 days for GBS, Listeria monocytogenes , and Streptococcus pneumoniae , and 21 days for Pseudomonas aeruginosa and gram-negative enteric bacteria such as Escherichia coli . Longer duration of therapy is recommended in complicated cases or for delayed clinical improvement [ 60 ]. Consultation with a pediatric infectious disease specialist is warranted for cases that are complicated by meningitis. Neuroimaging options include cranial sonography and magnetic resonance imaging and may provide prognostic information [ 53 ].

Herpes Simplex Virus (HSV) Infection

Empiric treatment with intravenous acyclovir (20 mg/kg/dose every 8 h) is recommended in cases of aseptic meningitis or suspected meningoencephalitis. Dosage adjustments are warranted in patients less than 34 weeks gestational age or in patients with significant hepatic or renal failure. Treatment is continued for 14 days in localized infections, or 21 days for disseminated disease or CNS infections. In all cases of neonatal HSV, suppressive therapy with acyclovir (300 mg/m 2 per dose, orally, 3 times per day for 6 months) immediately following parenteral treatment may improve outcomes in CNS disease and reduce recurrence [ 53 ].

Congenital Pneumonia

Prompt diagnosis with recognition of risk factors, early administration of antibiotics, and supportive treatment are important for successfully treating congenital pneumonia. Commonly used antibiotics include ampicillin and gentamicin. Cephalosporins may be considered with failure of therapy with the aforementioned drugs or if Streptococcus pneumoniae is suspected. Supportive therapy includes surfactant replacement and nitric oxide inhalation for persistent pulmonary hypertension of the newborn [ 53 ].

Prevention Strategies

The only proven preventive strategy for EONS is the appropriate administration of maternal IAP [ 50 ]. Measures that have been postulated to decrease neonatal infection in intensive care units include the consumption of 50 mL/kg/day of fresh (non-donor) human milk, and probiotics, as well as the restriction of H2-blockers, fluconazole, and lactoferrin [ 61 ]. Neither GBS IAP nor the aforementioned preventive measures will prevent bacterial LONS [ 50 ]. Guidelines for prevention of perinatal transmission of HSV recommend cesarean delivery for women with active genital lesions or prodromal symptoms. It is also recommended that pregnant women with a history of genital herpes infection begin taking oral suppressive therapy at 36 weeks of gestation [ 62 ].

Though rates of neonatal sepsis have declined in some parts of the world, globally, it continues to be a significant problem. Testing modalities for the identification and diagnosis of neonatal sepsis continue to be developed, with new laboratory techniques still being tested. Monitoring and management of risk factors as well as IAP remain highly important in the prevention and control of infection in this vulnerable population. Treatment includes prompt antibiotic administration and supportive care in the appropriate hospital setting. Continued vigilance will be key in the diagnosis and management of neonatal sepsis.

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