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

Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation
Author:
Mohan Pammi, MD, PhD
Section Editors:
Joseph A Garcia-Prats, MD
Morven S Edwards, MD
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Mar 2022. | This topic last updated: Apr 06, 2021.

INTRODUCTION — Neonatal sepsis remains a major cause of neonatal mortality and morbidity in preterm and very low birth weight (VLBW) infants [1-5]. As a result, clinical care providers should have a very low threshold for evaluation and treatment for possible sepsis in preterm and VLBW infants since delays in diagnosis or treatment may worsen clinical outcomes.

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".)

Systemic infections due to virus and fungi in the preterm infant, as well as sepsis in the term and late preterm infant, are also discussed separately. (See "Nosocomial viral infections in the neonatal intensive care unit" and "Clinical manifestations and diagnosis of Candida infection in neonates" and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants" and "Management and outcome of sepsis in term and late preterm infants".)

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

Preterm infants are those born at less than 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 infants".)

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 in the first 72 hours of age

Late-onset sepsis (LOS) is defined as sepsis that occurs after the first 72 hours of age

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 — 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 — 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 [8-11]. 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) [4,11]:

According to gestational age:

-Gestational age <25 weeks – 41 percent

-Gestational age 25 to 28 weeks – 21 percent

-Gestational age 29 to 32 weeks – 10 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

The incidence of EOS in VLBW infants has remained stable since the 1990s; however, the incidence of LOS decreased from 2005 to 2012 for preterm infants in each gestational age category [11].

These estimated rates are based on data from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network's prospective registry of infants born at 26 network centers in the United States between 1993 and 2012. Registries of preterm infants born in other developed countries (including Canada, England, Germany, Israel, Australia, and New Zealand) have yielded similar estimates [9,10,12-14].

ETIOLOGIC AGENTS

Early-onset sepsis

Group B Streptococcus (GBS) and Escherichia coli – GBS and E. coli are the most common causes of neonatal early-onset sepsis (EOS) (table 1) [8,10]. In very preterm infants, the incidence of EOS with E. coli is higher than with GBS [8-10,15]. This was illustrated in a study of the previously mentioned 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 remained the most common cause of EOS [9]. However, the second most common etiologic agent in the Canadian cohort was coagulase-negative staphylococci (CoNS) rather than GBS, which was the third most common pathogen.

CoNS – The importance of CoNS as an EOS pathogen is uncertain because it is difficult to ascertain whether a positive blood culture for CoNS is due to sepsis or is a contaminant. Differences between the NICHD and CNN studies are likely due to study design since the criterion for antibiotic therapy for more than five days was included in the NICHD study but not in the CNN study [8,9]. As a result, in the CNN study, a positive blood culture for CoNS would always be considered an episode of sepsis rather than a result of contamination. In contrast, more than one-half of the 149 positive cultures for CoNS in the NICHD study were considered to be due to contaminates and only three cases of EOS due to CoNS were thought to be true infections (defined as >1 positive culture for CoNS) [8]. (See 'Blood culture' below.)

The challenge of distinguishing true CoNS neonatal infection was illustrated by a retrospective study from a single tertiary center that identified 134 neonates with a positive CoNS culture from blood or a usual sterile site between 2000 and 2002 [16]. Of the first 149 episodes, 40 were considered proven (defined as two positive cultures and more than one sign of clinical sepsis [temperature instability, cardiorespiratory or gastrointestinal disturbances, lethargy or irritability]), 55 were considered probable (defined as isolation of CoNS from one positive culture that was deemed a probable pathogen after review of clinical data and laboratory data by two pediatric infectious disease specialists), and 54 were considered due to contamination. In this cohort, risk factors for proven and probable CoNS were birth weight <2000 g, gestational age <34 weeks, and central venous line.

Late-onset sepsis — In preterm infants, the most common pathogen associated with late-onset sepsis (LOS) is CoNS (table 1). In the previously discussed NICHD study of VLBW infants with LOS, nearly one-half of the cases were caused by CoNS (48 percent), followed by other gram-positive bacteria (22 percent; Staphylococcus aureus, Enterococcus, GBS), gram-negative bacteria (18 percent; E. coli, Klebsiella, Pseudomonas, Enterobacter, Serratia), and fungi (12 percent; Candida albicans and Candida parapsilosis) [4]. Similar findings were noted in a report based on data from the national neonatal infection surveillance system in Germany [17].

Candidal and viral infections in the newborn 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 "Nosocomial viral infections in the neonatal intensive care unit".)

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

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

RISK FACTORS

Risk factors associated with prematurity — In addition to the maternal and neonatal risk factors associated with sepsis in all neonates regardless of gestation and birth weight (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Maternal risk factors'), 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 [6,18].

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 line 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 the previously discussed National Institute of Child Health and Human Development (NICHD) Neonatal Research Network study of 1313 very low birth weight (VLBW) infants born with late-onset sepsis (LOS) [4]. In this cohort, LOS was associated with the use of central venous line, parenteral nutrition, umbilical catheterization, and mechanical ventilation. The risk also rose as the duration of use of these interventions increased.

A prevalence 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 [18]:

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)

Central venous line (RR 2.37, 95% CI 1.61-3.50)

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

Urinary catheter, chest tube, and tracheotomy were not associated with an increased risk of neonatal intensive care unit-acquired infections

Type of central line (ie, peripherally inserted central catheter [PICC] versus umbilical venous catheter [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 did not differ 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) [19].

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 [16]. (See 'Etiologic agents' above.)

Risk factors for all neonates — The following maternal and neonatal risk factors, regardless of gestational age, are associated with neonatal sepsis and are discussed in greater detail separately. These factors are particularly pertinent to group B streptococcal (GBS) infection. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Maternal risk factors'.)

Intrapartum maternal temperature ≥38°C (100.4°F)

Delivery at <37 weeks gestation

Chorioamnionitis (see "Intraamniotic infection (clinical chorioamnionitis)", section on 'Diagnosis')

Five-minute Apgar score ≤6 [20]

Evidence of fetal distress

Maternal GBS colonization

Membrane rupture ≥18 hours – The risk of proven sepsis increases tenfold to 1 percent when membranes are ruptured beyond 18 hours [21]

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

Increase in ventilatory support in the mechanically ventilated patient

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) that showed that most infants on the first day of sepsis had new-onset apnea or bradycardia (n = 27) and changes in respiratory support (need for oxygen [n = 18] or ventilatory support [n = 21]) [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, which may result in death within 48 hours. In a retrospective study from a single center from 1988 to 1997, 49 of 825 episodes of neonatal late-onset sepsis (LOS) were fulminant (defined as lethal within 48 hours) [25]. The isolated bacterial pathogen and their relative frequencies were Pseudomonas species (56 percent), E. coli (19 percent), Enterobacter species (14 percent), Klebsiella species (13 percent), S. aureus (6 percent), and CoNS (1 percent) [25]. Of note, this cohort included neonates of all birth weights and gestational ages.

In the previously mentioned study of neonatal CoNS infection, the most frequent presenting signs that prompted evaluations included hypoxia, apnea, bradycardia, lethargy, and gastric residuals.

Novel monitoring techniques using algorithms to detect pathologic heart rate variability and respiratory instability and decrease spontaneous infant movement 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 dysfunction, acute respiratory distress syndrome, or dysfunction in two or more organ systems (defined as multiorgan failure). In severely septic patients, systemic inflammatory host response produces proinflammatory and antiinflammatory mediators, which contribute to multiorgan dysfunction, and is referred to as systemic inflammatory response syndrome. In the preterm infant, evidence suggests that inflammation plays an important role in necrotizing enterocolitis and cerebral and pulmonary injury, which may result in systemic inflammatory response syndrome [27-31]. (See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis".)

Septic shock results in inadequate tissue perfusion because of the loss of fluid from the vascular to extravascular space. This leads to reduced systemic vascular resistance and, potentially, myocardial dysfunction. (See "Neonatal shock: Etiology, clinical manifestations, and evaluation", section on 'Distributive shock'.)

Core 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

DIAGNOSIS — The isolation of a pathogenic bacterium from a blood culture is the only method to truly confirm the diagnosis of neonatal sepsis.

However, there is a significant time lag before blood culture results are available and blood cultures may lead to false-negative results in approximately 10 percent of septic cases [32,33]. As a result, clinical assessment and laboratory tests are used to identify neonates at significant risk for sepsis so that empiric antibiotic treatment may be initiated while awaiting blood culture results.

In addition, a small 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. A complete course of antibiotic therapy is generally warranted in neonates with a clinical diagnosis of "probable sepsis" unless an alternative diagnosis (table 2) is established that explains the findings. (See 'Differential diagnosis' below and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Probable sepsis'.)

EVALUATION — Because the signs and symptoms of sepsis are subtle and nonspecific, laboratory evaluation is performed in any infant with identifiable risk factors, with physical findings consistent with sepsis, or who deviates in any way from the usual pattern of activity or feeding. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants".)

Blood culture — The blood culture makes the definitive diagnosis of sepsis and can be obtained by venipuncture or arterial puncture or by sampling from a newly inserted umbilical artery or vascular access catheter. The sensitivity of blood culture to detect neonatal bacteremia is dependent upon 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 blood sample volume for culture, 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) [34,35].

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.

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 [16]). (See 'Etiologic agents' above.)

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

Cerebrospinal fluid (CSF) culture – A lumbar puncture should be considered in all neonates for whom blood culture evaluation for sepsis is performed because clinical signs suggesting meningitis can be lacking in young infants. The 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 3). (See "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Evaluation'.)

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 infants", section on 'Urine culture'.)

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 or in the occasional patient from whom it is difficult to obtain an adequate blood sample for culture. The most commonly used tests are neutrophil counts and C-reactive proteins (CRPs). Other tests that have been evaluated include cytokines (interleukin-6, interleukin-8, tumor necrosis factor-alpha) and procalcitonin; however, these studies are primarily used in the research setting and are not routinely available in hospital laboratories [36,37]. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", 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 infants", 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) [38]. 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) [38]. However, sensitivity also 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 greater than 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) [39]. CRP levels do not seem to be affected by gestational age [40], and serial CRPs have been found to be useful to follow resolution of infection and guide antibiotic therapy [37,41-44]. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Other inflammatory markers'.)

Molecular diagnostic methods — Molecular techniques (eg, polymerase chain reaction, microarrays, and fluorescence in situ hybridization analysis techniques) may offer a more timely, reliable method for diagnosis than blood cultures as they have a more rapid turnaround time, require smaller volumes of blood, and are not affected by the administration of antepartum antibiotics [45-48]. In one study that used a positive blood culture as the gold standard, the sensitivity and specificity of polymerase chain reaction testing for the bacterial 16S rRNA gene were 96 and 99.4 percent, respectively, with a nine-hour turnaround time [46]. In addition, the amount of blood needed for testing was much smaller, with volumes as small as 200 microL. However, these tests are more expensive and are not available in most hospital laboratories, which mitigate the more rapid turnaround time.

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 "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn")

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")

Our approach — In our practice, a presumptive diagnosis of sepsis is made on the presence of neonatal symptoms and risk factors. (See 'Risk factors' above and 'Signs and symptoms' above.)

Based on the available literature, our evaluation of symptomatic preterm infants who are suspected to have sepsis usually consists of blood cultures (usually two separate tests), culture of CSF, and complete blood count with differential. Further evaluation may include testing for inflammation (eg, CRP) and, in infants with late-onset infection, cultures of other sites such as skin lesion or urine culture in infants greater than six days of age. Empiric antibiotic therapy is started pending culture results. (See 'Evaluation' above and "Management and outcome of sepsis in term and late preterm infants", section on 'Initial empiric therapy'.)

In asymptomatic preterm infants with risk factors for EOS, our approach is similar to that for an asymptomatic term infant with a more limited evaluation, consisting of a blood culture followed by the administration of empiric antibiotic therapy. If any signs of sepsis develop or the baby clinically deteriorates after the initiation of antibiotics, reevaluation with a complete blood count and differential, CSF culture, and repeat blood culture is undertaken. Cultures from other sites (eg, urine and skin lesions) are obtained as clinically indicated.

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.

The differential diagnosis for neonatal sepsis in the preterm infant is similar to that seen in the term or near-term infant (table 2). 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 infants", 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 "Nosocomial viral infections in the neonatal intensive care unit", section on 'Etiology and clinical manifestations')

Spirochetal infections – Syphilis (see "Congenital syphilis: Clinical features 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 5th to 6th 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 10th to 12th 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 — Neonatal sepsis is a major cause of neonatal mortality and morbidity in preterm and very low birth weight (VLBW) infants (birth weight <1500 g).

The risk of neonatal sepsis increases with decreasing gestational age and birth weight. (See 'Incidence' above.)

Neonatal sepsis is typically classified by the infant's age into early-onset sepsis (EOS; ≤3 days of life) due to maternal vertical transmitted bacteria and late-onset sepsis (LOS; >3 days of life) due to bacteria acquired at birth or from environmental horizontal transmission. EOS occurs in approximately 2 percent and LOS in approximately 10 to 40 percent of VLBW infants, depending upon birth weight and gestational age. (See 'Pathogenesis' above and 'Incidence' above.)

In preterm infants, group B Streptococcus (GBS) and gram-negative infections (typically Escherichia coli) are the most common bacteria causing EOS and coagulase-negative staphylococci (CoNS) is the most common bacteria causing LOS (table 1). (See 'Etiologic agents' above.)

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 lines as well as umbilical arterial and venous catheterization). (See 'Risk factors associated with prematurity' above.)

In preterm infants, the spectrum of symptoms of neonatal sepsis ranges from nonspecific subtle findings (eg, mild increase in apnea) to fulminant septic shock. 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. (See 'Clinical manifestations' above.)

The isolation of a pathogen from a blood culture is the only method to confirm the diagnosis of neonatal sepsis. (See 'Diagnosis' above.)

Evaluation of neonates with suspected sepsis should include review of risk factors and clinical findings as well as a laboratory evaluation that minimally includes a blood culture. Other laboratory tests include a complete blood count with a differential, lumbar puncture prior to antibiotic therapy to determine whether meningitis is present, urine culture for infants >6 days of age, and culture of any other potential foci of infection (eg, pustule). Empiric antibiotic therapy is generally initiated while awaiting culture results. (See 'Evaluation' above.)

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.)

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Topic 88740 Version 21.0

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