Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation

INTRODUCTION — Neonatal sepsis remains a major cause of neonatal mortality and morbidity in preterm and very low birth weight (VLBW) infants [1-5].

The clinical features and diagnosis of bacterial sepsis in the preterm infant will be reviewed here. The management and prevention of bacterial sepsis in the preterm infant are discussed separately. (See "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation".)

Sepsis in term and late preterm neonates is discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates" and "Management and outcome of sepsis in term and late preterm neonates".)

TERMINOLOGY — The following terms will be used throughout this topic:

●Preterm infants are those born at <34 weeks gestation.

●Late preterm infants (also called near-term infants) are those born between 34 and 36 completed weeks of gestation. Sepsis in late preterm infants is discussed in a separate topic review. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)

●Very low birth weight (VLBW) infants are those with birth weights <1500 g.

●Sepsis is defined as isolation of a pathogenic bacterium from a blood culture in a patient with signs or symptoms consistent with clinical sepsis.

•Early-onset sepsis (EOS) is defined as sepsis that occurs within the first 72 hours after birth

•Late-onset sepsis (LOS) is defined as sepsis that occurs at >72 hours of after birth

●Health care-associated infections are defined as infections (eg, sepsis) acquired in the hospital while receiving treatment for other conditions [6].

PATHOGENESIS

Early-onset sepsis (EOS) — Early-onset infection is usually due to vertical transmission by ascending contaminated amniotic fluid or during vaginal delivery from bacteria colonizing or infecting the mother's lower genital tract [7]. The risk for sepsis increases from 1 to 4 percent in neonates born to mothers with chorioamnionitis.

Maternal group B streptococcal (GBS) bacteriuria during the current pregnancy, prior delivery of an infant with GBS disease, and maternal colonization are some risk factors for early-onset GBS sepsis. (See "Group B streptococcal infection in neonates and young infants", section on 'Risk factors'.)

Late-onset sepsis (LOS) — Late-onset infections can be acquired by the two following mechanisms:

●Maternal vertical transmission, resulting in initial neonatal colonization that evolves into later infection.

●Horizontal transmission from direct contact with care providers or environmental sources (ie, health care-associated infections). Disruption of the intact skin or mucosa, which can be due to invasive procedures (eg, intravascular catheter), increases the risk of late-onset infection. (See 'Risk factors' below.)

INCIDENCE — The risk of sepsis increases with decreasing gestational age and birth weight [8-12]. In the United States, estimated rates of culture-proven sepsis among preterm very low birth weight (VLBW) infants are as follows:

●Early-onset sepsis (EOS) [3,5,8,11]:

•According to gestational age:

-Gestational age <25 weeks – 3.5 percent

-Gestational age 25 to 28 weeks – 1.9 percent

-Gestational age ≥29 weeks – 1 percent

•According to birth weight:

-Birth weight <400 to 500 g – 1.7 percent

-Birth weight 501 to 750 g – 2.2 percent

-Birth weight 751 to 1000 g – 1.9 percent

-Birth weight 1001 to 1250 g – 1.5 percent

-Birth weight 1251 to 1500 g – 0.8 percent

●Late-onset sepsis (LOS) [11,12]:

•According to gestational age:

-Gestational age ≤23 weeks – 32 percent

-Gestational age 24 to 25 weeks – 22 percent

-Gestational age 26 to 27 weeks – 11 percent

-Gestational age 28 to 29 weeks – 5 percent

-Gestational age >29 weeks – 2 percent

•According to birth weight:

-Birth weight <400 to 500 g – 43 percent

-Birth weight 501 to 750 g – 43 percent

-Birth weight 751 to 1000 g – 28 percent

-Birth weight 1001 to 1250 g – 15 percent

-Birth weight 1251 to 1500 g – 7 percent

These incidence rates are based on data from two prospective registries in the United States (the National Institute of Child Health and Human Development Neonatal Research Network and the Vermont Oxford Network). Registries of preterm infants born in other developed countries (including Canada, England, Germany, Israel, Australia, and New Zealand) have yielded similar estimates [9,10,13-15].

The incidence of EOS in VLBW infants has remained stable since the 1990s; however, the incidence of LOS has decreased since the early 2000s among preterm infants in each gestational age category [11].

ETIOLOGIC AGENTS

Pathogens in EOS — Escherichia coli and group B streptococcus (GBS) are the most common causes of neonatal early-onset sepsis (EOS) (table 1) [8,10]. In very preterm infants, E. coli is more common as an EOS pathogen compared with GBS [8-10,16]. This was illustrated in a study of the National Institute of Child Health and Human Development (NICHD) registry, in which the incidences of EOS due to E. coli and GBS in very low birth weight (VLBW) infants were 5.1 and 2.1 per 1000 live births, respectively. For larger preterm infants with birth weights between 1500 and 2500 g, the incidences were 0.5 versus 0.4 per 1000 live births [8]. In a study from the Canadian Neonatal Network (CNN), similar to studies from other countries, E. coli and GBS were among the most common pathogens [9]. In this study, coagulase-negative staphylococci (CoNS) were also commonly isolated. The relevance of CoNS as a pathogen in EOS is discussed below. (See 'CoNS: Pathogen or contaminant?' below.)

Pathogens in LOS — In preterm infants, the most common pathogens associated with late-onset sepsis (LOS) are CoNS, Staphylococcus aureus, and gram-negative bacteria (E. coli, Klebsiella, Enterobacter) (table 1). In a prospective observational study of very preterm infants born from 2018 through 2020, the relative frequencies of different pathogens among the 10,501 infants with LOS were as follows [12]:

●CoNS (29 percent)

●S. aureus (23 percent)

●E. coli (12 percent)

●Klebsiella (8 percent)

●Enterococcus (5 percent)

●GBS (5 percent)

●Enterobacter (4 percent)

●Pseudomonas (3 percent)

●Serratia (2 percent)

●Fungi (5 percent)

Similar findings were noted in a report based on data from the national neonatal infection surveillance system in Germany [17].

Candidal and viral infections are also important causes of late-onset infections in preterm neonates. These pathogens are discussed separately:

●(See "Epidemiology and risk factors for Candida infection in neonates".)

●(See "Clinical manifestations and diagnosis of Candida infection in neonates".)

●(See "Treatment of Candida infection in neonates".)

●(See "Neonatal herpes simplex virus infection: Clinical features and diagnosis".)

●(See "Neonatal herpes simplex virus infection: Management and prevention".)

●(See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Neonates'.)

CoNS: Pathogen or contaminant? — While CoNS is commonly isolated in culture in preterm neonates, it may or may not reflect true infection. In some cases, the positive culture may be due to contamination or colonization of a catheter hub (eg, when blood cultures are drawn from indwelling catheters).

The challenge of distinguishing true CoNS neonatal infection was illustrated in a retrospective study from a single tertiary center that identified 134 neonates with 149 episodes of positive CoNS culture from blood or a usual sterile site [18]. Of these, 27 percent were considered proven infection (defined as two positive cultures and ≥2 clinical signs of sepsis [temperature instability, cardiorespiratory or gastrointestinal disturbances, lethargy or irritability]), 37 percent were considered probable infection (based upon blinded review of clinical nd laboratory data by two pediatric infectious disease specialists), and 36 percent were felt to reflect contamination. In this cohort, risk factors for proven and probable CoNS infection included birth weight <2000 g, gestational age <34 weeks, and presence of a central venous catheter.

CoNS is most relevant as a pathogen in LOS; the importance of CoNS as a pathogen in EOS is unclear. The two studies described above (from the NICHD and CNN registries) reported markedly different rates of EOS due to CoNS. In the NICHD study, CoNS accounted for <1 percent of EOS cases; whereas in the CNN study, CoNS accounted for 11 percent of cases of EOS in preterm neonates [8,9]. These disparate findings are likely explained by differences in how EOS was defined in each study. The NICHD study required both a positive culture and ≥5 days of antibiotic therapy to define an episode of true EOS, whereas the CNN study required only a positive culture [8,9]. Thus, while there were 149 positive blood cultures for CoNS in the NICHD study, only 3 were felt to represent true infection [8]. By contrast, all cases of CoNS bacteremia in the CNN study were classified as EOS [9].

Obtaining two blood cultures can help to distinguish between true CoNS infection versus contaminant, as discussed below. (See 'Blood culture' below.)

RISK FACTORS

Risk factors associated with prematurity — Preterm infants are at increased risk for developing sepsis compared with term infants for the following reasons [6]:

●Immunocompromised host – Preterm infants have low levels of circulating maternal immunoglobulin G (IgG) because of the loss of transplacental transfer that occurs during the third trimester of pregnancy. Even in the presence of adequate IgG concentrations, opsonization and complement functions are reduced in preterm infants.

●Epithelial mucosal barrier – The epithelial barriers in preterm infants are immature. In these infants, the skin and mucosal barriers are thin and delicate, readily break down, and provide minimal protection. Therapeutic interventions that increase the risk of health care-associated (ie, nosocomial) infection are more likely to be used in preterm infants [6,19].

●Invasive devices – Invasive procedural devices, such as central venous and arterial catheterizations, urinary catheters, tracheal intubation, and feeding tubes, further compromise the epithelial barrier. In addition, total parenteral nutrition through central venous catheters (CVC) and administration of histamine blockers and proton pump inhibitors are associated with an increased risk of sepsis. The administration of lipids may also be an independent risk factor for bacterial and fungal sepsis. The use of invasive technology increases with decreasing gestational age, thereby increasing the risk of infection.

These points were illustrated in a study from National Institute of Child Health and Human Development (NICHD) Neonatal Research Network that included 1313 very low birth weight (VLBW) infants with late-onset sepsis (LOS) [4]. In this cohort, LOS was associated with the use of CVCs, parenteral nutrition, umbilical venous and arterial catheters (UVCs and UACs), and mechanical ventilation. The risk correlated with the duration of use of these interventions.

A study conducted in 29 neonatal intensive care units in the United States identified the following risk factors in 94 patients with 116 health care-associated infections after adjusting for birth weight [19]:

●Total parenteral nutrition (relative risk [RR] 3.66, 95% CI 2.47-5.41)

●Mechanical ventilation (RR 3.2, 95% 2.12-4.82)

●Arterial catheter (RR 2.43, 95% 1.50-3.95)

●CVC (RR 2.37, 95% CI 1.61-3.50)

●Peripheral intravenous catheter (RR 2.02, 95% CI 1.38-2.95)

●Urinary catheter, chest tube, and tracheostomy were not independently associated with LOS in this cohort

Type of central line (ie, peripherally inserted central catheter [PICC] versus UVC) does not appear to impact the risk of infection. In a retrospective matched cohort study of 540 preterm infants (<30 weeks gestation), the rates of catheter-associated bloodstream infection were similar among infants who received a PICC on the first day after birth (day 1), those who received a UVC on day 1, and those who received a UVC on day 1 that was then changed for a PICC after four days or more (9.3, 7.8, and 8.2 per 1000 catheter days, respectively) [20].

As discussed above, risk factors of coagulase-negative staphylococci (CoNS) neonatal infection included gestational age <34 weeks, birth weight <2000 g, and central venous line [18]. (See 'CoNS: Pathogen or contaminant?' above.)

Maternal risk factors for EOS — Maternal factors that are associated with an increased risk of EOS in the neonate, regardless of gestational age, include intra-amniotic infection (clinical chorioamnionitis), intrapartum maternal fever, maternal group B streptococcus (GBS) colonization, preterm birth, and prolonged rupture of the membranes (PROM). Though the duration of ruptured membranes is commonly considered when assessing the neonate's risk of infection, it is unclear whether PROM is an independent risk factor for sepsis in the absence of intra-amniotic infection [21].

These factors are particularly pertinent to GBS infection. The approach to identifying pregnancies at risk for neonatal EOS and indications for maternal intrapartum antibiotic prophylaxis (IAP) are discussed separately. (See "Prevention of early-onset group B streptococcal disease in neonates", section on 'Identification of pregnancies at increased risk for early-onset neonatal GBS' and "Prevention of early-onset group B streptococcal disease in neonates", section on 'Intrapartum antibiotic prophylaxis'.)

Maternal GBS screening and IAP reduce but do not eliminate the risk of GBS infection in the neonate.

CLINICAL MANIFESTATIONS

Signs and symptoms — In preterm infants, the spectrum of symptoms of neonatal sepsis ranges from nonspecific subtle findings (eg, mild increase in apnea) to fulminant septic shock.

Nonspecific signs observed in preterm infants with sepsis include [22,23]:

●Respiratory distress that ranges from mild tachypnea to respiratory failure

●Increased respiratory support requirement

●Lethargy or hypotonia

●Increase in apnea

●Feeding intolerance

●Temperature instability

●Hypotension or evidence of poor perfusion

●Increase in heart rate

Because the signs and symptoms of sepsis can be subtle and nonspecific, any deviation from an infant's usual pattern of activity or feeding should be regarded as a possible indication of systemic bacterial infection. This was illustrated in a retrospective review of preterm infants with culture-proven coagulase-negative staphylococci (CoNS) bacteremia in which most infants on the first day of sepsis had new-onset apnea or bradycardia or new or increased respiratory support needs [24].

The underlying etiologic agent may also influence the clinical presentation. For example, gram-negative sepsis is associated with a more fulminant course of severe sepsis and/or septic shock with a high risk of mortality [25].

Clinical signs associated with CoNS infection tend to be more subtle. In the previously mentioned study of neonatal CoNS infections, the most frequent presenting signs that prompted evaluation included hypoxia, apnea, bradycardia, lethargy, and increased gastric residuals [24].

Novel monitoring techniques using algorithms to detect pathologic heart rate variability, respiratory instability, and/or decrease spontaneous movement in the infant have shown promise in predicting onset of sepsis in preterm neonates [26]. However, further study is needed before this strategy is routinely used in clinical practice.

Severe sepsis and septic shock — Sepsis is considered severe when it is associated with cardiovascular or pulmonary compromise or multiorgan failure (ie, dysfunction in two or more organ systems).

Clinical findings of neonatal shock include (see "Neonatal shock: Etiology, clinical manifestations, and evaluation", section on 'Distributive shock'):

●Cool extremities, acrocyanosis, and pallor

●Changes in heart rate (initially tachycardia and, in the later stages, which may be terminal, bradycardia)

●Neurologic changes such as lethargy, irritability, and nonresponsiveness

●Hypotension

●Oliguria

In patients with severe sepsis, the host response is to produce systemic pro- and anti-inflammatory mediators, which contribute to multiorgan dysfunction. This is referred to as systemic inflammatory response syndrome (SIRS). (See "Sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis".)

In the preterm infant, evidence suggests that systemic inflammation can contribute to the development of other neonatal morbidities such as necrotizing enterocolitis, lung disease, and intraventricular hemorrhage [27-31]. (See "Neonatal necrotizing enterocolitis: Pathology and pathogenesis" and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis".)

Septic shock results in inadequate tissue perfusion and lactic acidosis. Shock in this setting is likely multifactorial, resulting from reduced systemic vascular resistance, reduced circulating intravascular volume due to capillary leak and third spacing, and, potentially, myocardial dysfunction. (See "Neonatal shock: Etiology, clinical manifestations, and evaluation", section on 'Distributive shock'.)

EVALUATION

Asymptomatic neonates at risk for EOS — The approach to evaluating preterm neonates who have risk factors for early-onset group B streptococcus infection is summarized in the figure (algorithm 1) and discussed in detail separately. (See "Management of neonates at risk for early-onset group B streptococcal infection", section on 'Neonates <35 weeks gestation'.)

Symptomatic neonates — Because the signs and symptoms of sepsis are subtle and nonspecific, laboratory evaluation is performed in any infant with physical findings consistent with sepsis or who deviates significantly from the usual pattern of activity or feeding.

Blood culture — The blood culture makes the definitive diagnosis of sepsis and can be obtained by venous or arterial puncture or by sampling from a newly inserted arterial or venous catheter. The sensitivity of blood culture to detect neonatal bacteremia depends on the number of cultures obtained and volume of blood used to inoculate each culture bottle. However, sensitivity may be impaired because of inability to obtain adequate volume of blood, especially from sick very low birth weight (VLBW) infants. In addition, the use of antepartum antibiotics may negatively impact blood culture sensitivity.

A minimum volume of 0.5 mL of blood is required for blood cultures, but a higher volume may be required to detect low colony-count sepsis (<4 colony-forming units/mL) [32,33].

Obtaining more than one blood culture is helpful in the interpretation of blood culture results. If coagulase-negative staphylococci (CoNS) are isolated from two or more blood cultures, true bacteremia is more likely than contamination of the specimen, which may be reflected by a single positive blood culture [18].

However, in preterm infants, because of the difficulty in obtaining an adequate blood volume for culture, the result from only a single positive blood culture may be available. In this setting, it is challenging to decide whether or not there is true infection from CoNS [6]. The clinician must decide on further management based on the clinical setting (eg, response to empiric therapy and clinical suspicion for infection based on gestational age and other risk factors [18]). (See 'CoNS: Pathogen or contaminant?' above.)

Other cultures — Cultures of other sites may be indicated in the preterm infant who is suspected of having sepsis.

●Cerebrospinal fluid (CSF) culture – Lumbar puncture (LP) is not necessary for every preterm neonate undergoing sepsis evaluation if the index of suspicion for infection is low (eg, a neonate undergoing evaluation due to increased episodes of apnea who otherwise appears clinically well). However, LP should be performed if the neonate is ill appearing or has other concerning findings (irritability, bulging fontanelle, seizures). In addition, LP should be performed if the blood culture is positive. In some cases, it may not be feasible to perform LP because the neonate is too unstable to tolerate the procedure. In these cases, the LP should be deferred until the neonate is stable.

If LP is performed, CSF should be sent for Gram stain, routine culture, cell count with differential, and protein and glucose concentrations. The interpretation of CSF needs to account for variations due to gestational age, chronologic age, and birth weight (table 2). (See "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Evaluation'.)

●Urine culture – Urine culture obtained by catheter or bladder tap should be included in the sepsis evaluation for infants >6 days of age. A urine culture need not be routinely performed in the evaluation of an infant ≤6 days of age, because a positive urine culture in this setting is a reflection of high-grade bacteremia rather than an isolated urinary tract infection. (See "Urinary tract infections in neonates", section on 'Epidemiology' and "Urinary tract infections in neonates", section on 'Preterm infants' and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Urine culture'.)

●Other sites – In patients with late-onset infection, cultures should be obtained from any other potential foci of infection (eg, purulent eye drainage; pustules; skin lesions; bone, joint, or peritoneal fluid; or tracheal aspirates in mechanically ventilated infants).

Inflammatory markers — Efforts have not been successful in identifying tests that can accurately and rapidly predict neonatal sepsis while awaiting blood culture results. The most widely studied tests are neutrophil counts, C-reactive protein (CRP), and procalcitonin. Other tests that have been evaluated include interleukin-6, interleukin-8, and tumor necrosis factor-alpha levels; however, these studies are primarily used in the research setting and are not routinely available in hospital laboratories [34,35]. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Laboratory tests'.)

Neutrophil counts — Both the absolute neutrophil and the ratio of immature to total neutrophil counts (I/T ratio) have been used as markers for neonatal sepsis. However, as is true for term and late preterm infants, these tests are not useful to accurately predict neonatal sepsis. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Complete blood count'.)

This was illustrated in a multicenter study of 166,092 infants that included both term and preterm infants with a mean gestational age of 34.6 weeks who were suspected to have early-onset sepsis (EOS) [36]. Although the probability of a positive blood culture within the first three days of age increased with a low white blood cell count (<5000/microL), absolute neutropenia (<1000 neutrophils/microL), and an elevated I/T ratio, sensitivities of all indices were poor and insufficient to accurately diagnose neonatal sepsis.

In another analysis of the same cohort of patients, late-onset sepsis (LOS; defined as a positive culture between day of age 4 and 120) was associated with both low and high white blood cell counts (<1000 and >50,000/microL), high absolute neutrophil count (>17,670/microL), elevated I/T ratio of 0.2 or higher, and low platelet count (<50,000/microL) [36]. However, the sensitivity of these indices was inadequate to reliably make the diagnosis of LOS.

C-reactive protein — CRP is an acute phase reactant synthesized in the liver that increases in inflammatory conditions, including sepsis. Although an elevated CRP (>1 mg/dL) is 90 percent sensitive in detecting neonatal sepsis, its poor specificity makes it a poor predictor for neonatal sepsis as it is elevated in other noninfectious inflammatory conditions (eg, maternal fever, fetal distress) [37]. CRP levels do not seem to be affected by gestational age [38], and serial CRPs have been found to be useful to follow resolution of infection and guide antibiotic therapy [35,39-42]. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Other inflammatory markers'.)

Molecular diagnostic methods — Molecular techniques (eg, polymerase chain reaction [PCR]) may offer a reliable and more timely method for diagnosis than bacterial cultures as they have a more rapid turnaround time, require smaller sample volumes, and are not affected by the administration of antepartum antibiotics [43,44]. While molecular methods are increasingly used to assist in the diagnosis of central nervous system (CNS) infections in infants and children, there role in the routine evaluation of suspected neonatal sepsis (ie, to detect bacteremia) is limited.

The role of PCR testing in neonatal meningitis is discussed separately. (See "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Polymerase chain reaction'.)

Other studies — Other studies are often obtained to differentiate sepsis from conditions with similar presentations. (See 'Differential diagnosis' below.)

These include:

●Chest radiography in patients with respiratory distress to differentiate from pneumonia and respiratory distress syndrome (see "Neonatal pneumonia" and "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis")

●Serum glucose to differentiate from hypoglycemia (see "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Clinical presentation')

●Metabolic screening to differentiate from inborn errors of metabolism (see "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management")

●Pulse oximetry screening and echocardiography to differentiate from critical congenital heart disease (see "Identifying newborns with critical congenital heart disease")

DIAGNOSIS

●Proven sepsis – The diagnosis of sepsis is based upon isolating a pathogenic organism in culture. Only a small fraction of neonates who undergo sepsis evaluation are ultimately diagnosed with proven sepsis.

●Probable sepsis – A subset of neonates have sterile blood cultures yet have a clinical course consistent with sepsis. In these infants, a clinical diagnosis of "probable sepsis" can be made based upon clinical assessment, subsequent laboratory tests, and the clinical course. These infants should also be evaluated for other causes of their clinical findings (table 3). (See 'Differential diagnosis' below.)

If no alternative diagnosis is established to explain the findings, a complete course of antibiotic therapy is generally warranted in neonates with a clinical diagnosis of "probable sepsis". (See "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Antibiotic therapy'.)

●Unlikely infection – Neonates with mild and/or transient symptoms who remain clinically well with negative cultures at 36 to 48 hours are unlikely to have sepsis. Empiric antibiotic therapy should be discontinued after 36 to 48 hours in these neonates.

DIFFERENTIAL DIAGNOSIS — Because the findings are nonspecific, it is often difficult to differentiate neonatal sepsis from other diseases. As a result, empiric antibiotic therapy is started until blood culture results are available. (See "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Empiric antibiotic therapy'.)

The differential diagnosis for neonatal sepsis in the preterm infant is similar to that seen in the term or near-term infant (table 3). Clinical history, appropriate culture(s), molecular diagnostic assays, serology, imaging, and screening studies usually distinguish neonatal sepsis from other systemic infections as well as metabolic and other conditions, which may present with similar findings. (See 'Evaluation' above and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Differential diagnosis'.)

●Fungal infection – Candidiasis (see "Clinical manifestations and diagnosis of Candida infection in neonates")

●Viral infections – Enteroviruses, herpes simplex virus, cytomegalovirus, influenza viruses, and respiratory syncytial virus (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis" and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Neonates')

●Spirochetal infections – Syphilis (see "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis")

●Parasitic infections – Congenital malaria and toxoplasmosis (see "Congenital toxoplasmosis: Clinical features and diagnosis", section on 'Clinical features' and "Malaria in pregnancy: Epidemiology, clinical manifestations, diagnosis, and outcome", section on 'Vertical transmission')

●Other bacterial infections include urinary tract infection (particularly in the setting of a congenital genitourinary tract malformation), osteomyelitis or septic arthritis, pneumonia, and tuberculosis

●Noninfectious conditions include neonatal respiratory distress, inborn errors of metabolism, critical congenital heart disease, and hypoglycemia (see 'Other studies' above)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sepsis in neonates" and "Society guideline links: Group B streptococcal infection in pregnant women and neonates".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Sepsis in newborn babies (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Importance – Neonatal sepsis is a major cause of neonatal mortality and morbidity in preterm and very low birth weight (VLBW; <1500 g) infants. The risk of neonatal sepsis increases with decreasing gestational age (GA) and birth weight (BW). (See 'Introduction' above and 'Incidence' above.)

●Early- versus late-onset infection – Neonatal sepsis is classified by the infant's age at the time of onset of symptoms:

•Early-onset sepsis (EOS; onset within 72 hours after birth) – EOS occurs in approximately 2 percent of VLBW infants. It is due to maternal vertical transmitted bacteria. Group B Streptococcus (GBS) and Escherichia coli are the most commonly isolated pathogens (table 1). (See 'Early-onset sepsis (EOS)' above and 'Incidence' above and 'Pathogens in EOS' above.)

•Late-onset sepsis (LOS; onset at >72 hours after birth) – LOS occurs in approximately 10 to 40 percent of VLBW infants, depending upon GA and BW. LOS is due to bacteria acquired at birth or from environmental horizontal transmission. Coagulase-negative staphylococci (CoNS), Staphylococcus aureus, and gram-negative bacteria (E. coli, Klebsiella,) are the most commonly isolated pathogens (table 1). (See 'Late-onset sepsis (LOS)' above and 'Incidence' above and 'Pathogens in LOS' above.)

●Risk factors – Risk factors that increase the likelihood of sepsis in preterm infants compared with term infants include their decreased immunocompetence, poorer epithelial mucosal barrier, and increased prevalence of invasive procedures and interventions associated with infection (eg, central venous catheters, mechanical ventilation). (See 'Risk factors associated with prematurity' above.)

●Clinical manifestations – In preterm infants, the spectrum of symptoms of neonatal sepsis ranges from nonspecific subtle findings (eg, mild increase in apnea) to fulminant septic shock. The most frequent signs observed in preterm infants with sepsis include:

•Respiratory distress that ranges from mild tachypnea to respiratory failure

•Increased respiratory support requirement

•Lethargy or hypotonia

•Increase in apnea

•Feeding intolerance

•Temperature instability

•Hypotension or evidence of poor perfusion

•Increase in heart rate

Because the signs and symptoms of sepsis can be subtle and nonspecific, systemic bacterial infection should be suspected if the neonate deviates significantly from the usual pattern of activity or feeding. (See 'Clinical manifestations' above.)

●Evaluation

•Asymptomatic neonates at risk for EOS – The approach to evaluating preterm neonates who have risk factors for early-onset GBS infection is summarized in the figure (algorithm 1) and discussed in greater detail separately. (See "Management of neonates at risk for early-onset group B streptococcal infection", section on 'Neonates <35 weeks gestation'.)

•Symptomatic neonates – The laboratory evaluation of neonates with clinically suspected sepsis minimally includes a blood culture. Other tests may include lumbar puncture, inflammatory markers (eg, C-reactive protein, white blood cell count with differential), urine culture (for infants >6 days of age), chest radiograph (if there are respiratory symptoms), and cultures of any other potential foci of infection (eg, skin pustule, tracheal aspirates in mechanically ventilated infants). Empiric antibiotic therapy is generally initiated while awaiting culture results. (See 'Evaluation' above and "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Empiric antibiotic therapy'.)

●Diagnosis – The diagnosis of sepsis is based upon isolating a pathogenic organism in culture. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of neonatal sepsis includes other systemic infections, inborn errors of metabolism, critical congenital heart disease, and neonatal respiratory distress. These conditions are differentiated from sepsis by the clinical history and laboratory evaluation, including culture. (See 'Differential diagnosis' above.)