Neonatal sepsis may be categorized as early-onset or late-onset. Of newborns with early-onset sepsis, 85% present within 24 hours, 5% present at 24-48 hours, and a smaller percentage present within 48-72 hours. Onset is most rapid in premature neonates.
Early-onset sepsis is associated with acquisition of microorganisms from the mother. Transplacental infection or an ascending infection from the cervix may be caused by organisms that colonize the mother’s genitourinary (GU) tract; the neonate acquires the microorganisms as it passes through the colonized birth canal at delivery. The microorganisms most commonly associated with early-onset infection include the following :
Trends in the epidemiology of early-onset sepsis show a decreasing incidence of GBS disease. This can be attributed to the implementation of a prenatal screening and treatment protocol for GBS.
In a 2009 study involving 4696 women, prenatal cultures showed a GBS colonization rate of 24.5%, with a positive culture rate of 18.8% at the time of labor. As many as 10% of prenatally culture-negative women were found to have positive cultures at the time of labor. With intrapartum antibiotic prophylaxis rates of 93.3%, 0.36 of 1000 infants developed early-onset GBS disease.[2, 3]
Late-onset sepsis occurs at 4-90 days of life and is acquired from the caregiving environment. Organisms that have been implicated in causing late-onset sepsis include the following:
Trends in late-onset sepsis show an increase in coagulase-negative streptococcal sepsis; most of these isolates are susceptible to first-generation cephalosporins. The infant’s skin, respiratory tract, conjunctivae, gastrointestinal (GI) tract, and umbilicus may become colonized from the environment, and such colonization to the possibility of late-onset sepsis from invasive microorganisms. Vectors for such colonization may include vascular or urinary catheters, other indwelling lines, or contact with caregivers who have bacterial colonization.
Pneumonia is more common in early-onset sepsis, whereas meningitis and bacteremia are more common in late-onset sepsis. Premature and ill infants are more susceptible to sepsis and subtle nonspecific initial presentations; considerable vigilance is therefore required in these patients so that sepsis can be effectively identified and treated.
When neonatal sepsis is suspected, treatment should be initiated immediately because of the neonate’s relative immunosuppression. Begin antibiotics as soon as diagnostic tests are performed (see Treatment).
For patient education information, see Sepsis (Blood Infection).
The infectious agents associated with neonatal sepsis have changed since the mid-20th century. During the 1950s, S aureus and E coli were the most common bacterial pathogens among neonates in the United States. Over the ensuing decades, GBS replaced S aureus as the most common gram-positive organism that caused early-onset sepsis.
During the 1990s, GBS and E coli continued to be associated with neonatal infection; however, coagulase-negative Staphylococcus epidermidis is now more frequently observed. Additional organisms, such as L monocytogenes, Chlamydia pneumoniae, H influenzae, Enterobacter aerogenes, and species of Bacteroides and Clostridium have also been identified in neonatal sepsis.
Meningoencephalitis and neonatal sepsis can also be caused by infection with adenovirus, enterovirus, or coxsackievirus. Additionally, sexually transmitted diseases (eg, gonorrhea, syphilis, herpes simplex virus [HSV] infection, cytomegalovirus [CMV] infection, hepatitis, human immunodeficiency virus [HIV] infection, rubella, toxoplasmosis, trichomoniasis, and candidiasis) have all been implicated in neonatal infection.
Bacterial organisms with increased antibiotic resistance have also emerged and have further complicated the management of neonatal sepsis. The colonization patterns in nurseries and personnel are reflected in the organisms currently associated with nosocomial infection. In neonatal intensive care units (NICUs), infants with lower birth weight and infants who are less mature have an increased susceptibility to these organisms.
S epidermidis, a coagulase-negative Staphylococcus, is increasingly seen as a cause of nosocomial or late-onset sepsis, especially in the premature infant, in whom it is considered the leading cause of late-onset infections. Its prevalence is likely related to several intrinsic properties of the organism that allow it to readily adhere to the plastic mediums found in intravascular catheters and intraventricular shunts.
The bacterial capsule polysaccharide adheres well to the plastic polymers of the catheters. Also, proteins found in the organism (AtlE and SSP-1) enhance attachment to the surface of the catheter. The adherence creates a capsule between microbe and catheter, preventing C3 deposition and phagocytosis.
Biofilms are formed on indwelling catheters by the aggregation of organisms that have multiplied under the protection provided by the adherence to the catheter. Slimes are produced at the site from the extracellular material formed by the organism, which provides a barrier to host defense as well as to antibiotic action, making coagulase-negative staphylococcal bloodstream infection (BSI) more difficult to treat. The toxins formed by this organism have also been associated with necrotizing enterocolitis.
In addition to being a cause of neonatal sepsis, coagulase-negative Staphylococcus is ubiquitous as part of the normal skin flora. Consequently, it is a frequent contaminant of blood and cerebrospinal fluid (CSF) cultures. When a culture grows this organism , the clinical setting, colony counts, and the presence of polymorphonuclear neutrophils (PMNs) on Gram staining of the submitted specimen often help differentiate true infection and positive culture from a false-positive or contaminated specimen.
In addition to the specific microbial factors mentioned above, numerous host factors predispose the newborn to sepsis. These factors are especially prominent in the premature infant and involve all levels of host defense, including cellular immunity, humoral immunity, and barrier function.
PMNs are vital for effective killing of bacteria. However, neonatal PMNs are deficient in chemotaxis and killing capacity. Decreased adherence to the endothelial lining of blood vessels reduces their ability to marginate and leave the intravascular space to migrate into the tissues. Once in the tissues, they may fail to degranulate in response to chemotactic factors.
Furthermore, neonatal PMNs are less deformable and thus are less able to move through the extracellular matrix of tissues to reach the site of inflammation and infection. The limited capacity of neonatal PMNs for phagocytosis and killing of bacteria is further impaired when the infant is clinically ill. Finally, neutrophil reserves are easily depleted because of the diminished response of the bone marrow, especially in the premature infant.
Neonatal monocyte concentrations are at adult levels; however, macrophage chemotaxis is impaired and continues to exhibit decreased function into early childhood. The absolute numbers of macrophages are decreased in the lungs and are likely decreased in the liver and spleen as well. The chemotactic and bactericidal activity and the antigen presentation by these cells are also not fully competent at birth. Cytokine production by macrophages is decreased, which may be associated with a corresponding decrease in T-cell production.
Although T cells are found in early gestation in fetal circulation and increase in number from birth to about age 6 months, these cells represent an immature population. These naive cells do not proliferate as readily as adult T cells do when activated, and they do not effectively produce the cytokines that assist with B-cell stimulation and differentiation and granulocyte/monocyte proliferation.
Formation of antigen-specific memory function after primary infection is delayed, and the cytotoxic function of neonatal T cells is 50-100% as effective as that of adult T cells. At birth, neonates are deficient in memory T cells. As the neonate is exposed to antigenic stimuli, the number of these memory T cells increases.
Natural killer (NK) cells are found in small numbers in the peripheral blood of neonates. These cells are also functionally immature in that they produce far lower levels of interferon gamma (IFN-γ) upon primary stimulation than adult NK cells do. This combination of findings may contribute to the severity of HSV infections in the neonatal period.
The fetus has some preformed immunoglobulin, which is primarily acquired through nonspecific placental transfer from the mother. Most of this transfer occurs in late gestation, so that lower levels are found with increasing prematurity. The neonate’s ability to generate immunoglobulin in response to antigenic stimulation is intact; however, the magnitude of the response is initially decreased, rapidly rising with increasing postnatal age.
The neonate is also capable of synthesizing immunoglobulin M (IgM) in utero at 10 weeks’ gestation; however, IgM levels are generally low at birth, unless the infant was exposed to an infectious agent during the pregnancy, which would have stimulated increased IgM production.
Immunoglobulin G (IgG) and immunoglobulin E (IgE) may be synthesized in utero. Most of the IgG is acquired from the mother during late gestation. The neonate may receive immunoglobulin A (IgA) from breastfeeding but does not secrete IgA until 2-5 weeks after birth. Response to bacterial polysaccharide antigen is diminished and remains so during the first 2 years of life.
Complement protein production can be detected as early as 6 weeks’ gestation; however, the concentration of the various components of the complement system varies widely from one neonate to another. Although some infants have had complement levels comparable to those in adults, deficiencies appear to be greater in the alternative pathway than in the classic pathway.
The terminal cytotoxic components of the complement cascade that lead to killing of organisms, especially gram-negative bacteria, are deficient. This deficiency is more marked in preterm infants. Mature complement activity is not reached until infants are aged 6-10 months. Neonatal sera have reduced opsonic efficiency against GBS, E coli, and Streptococcus pneumoniae because of decreased levels of fibronectin, a serum protein that assists with neutrophil adherence and has opsonic properties.
The physical and chemical barriers to infection in the human body are present in the newborn but are functionally deficient. Skin and mucous membranes are broken down easily in the premature infant. Neonates who are ill, premature, or both are at additional risk because of the invasive procedures that breach their physical barriers to infection.
Because of the interdependence of the immune response, these individual deficiencies of the various components of immune activity in the neonate conspire to create a hazardous situation for the neonate exposed to infectious threats.
In overwhelming sepsis, there may be an initial early phase characterized by pulmonary hypertension, decreased cardiac output, and hypoxemia. These cardiopulmonary disturbances may be due to the activity of granulocyte-derived biochemical mediators, such as hydroxyl radicals and thromboxane B2 (an arachidonic acid metabolite).
These biochemical agents have vasoconstrictive actions that result in pulmonary hypertension when they are released in pulmonary tissue. A toxin derived from the polysaccharide capsule of type III Streptococcus has also been shown to cause pulmonary hypertension.
The intestines can be colonized by organisms in utero or at delivery through swallowing of infected amniotic fluid. The immunologic defenses of the GI tract are not mature, especially in the preterm infant. Lymphocytes proliferate in the intestines in response to mitogen stimulation; however, this proliferation is not fully effective in responding to a microorganism, because antibody response and cytokine formation are immature until approximately 46 weeks.
Necrotizing enterocolitis has been associated with the presence of a number of species of bacteria in the immature intestine. Overgrowth of these organisms in the neonatal lumen is a component of the multifactorial pathophysiology of necrotizing enterocolitis.
Ventriculitis is the initiating event in meningitis, with inflammation of the ventricular surface. Exudative material usually appears at the choroid plexus and is external to the plexus. Ependymitis then occurs, with disruption of the ventricular lining and projections of glial tufts into the ventricular lumen. Glial bridges may develop by these tufts and cause obstruction, particularly at the aqueduct of Sylvius.
The lateral ventricles may become multiloculated, a process that is similar to formation of abscesses. Multiloculated ventricles can isolate organisms in an area, making treatment more difficult.
Meningitis is likely to arise at the choroid plexus and extend via the ventricles through aqueducts and into the subarachnoid space to affect the cerebral and cerebellar surfaces. The high glycogen content in the neonatal choroid plexus provides an excellent medium for the bacteria. When meningitis develops from ventriculitis, effective treatment is complicated because adequate antibiotic levels in the cerebral ventricles are difficult to achieve. When ventricular obstruction is present, it causes additional problems.
Arachnoiditis is the next phase of the process and is the hallmark of meningitis. The arachnoid is infiltrated by inflammatory cells producing an exudate that is thick over the base of the brain and more uniform over the rest of the brain. Early in the infection, the exudate primarily contains PMNs, bacteria, and macrophages. It is prominent around the blood vessels and extends into the brain parenchyma.
In the second and third weeks of infection, the proportion of PMNs decreases; the dominant cells are histiocytes, macrophages, and some lymphocytes and plasma cells. Exudate infiltration of cranial roots 3-8 occurs.
After this period, the exudate decreases. Thick strands of collagen form, and arachnoid fibrosis occurs, which is responsible for obstruction. Hydrocephalus results. Early-onset GBS meningitis is characterized by much less arachnoiditis than late-onset GBS meningitis is.
Vasculitis extends the inflammation of the arachnoid and ventricles to the blood vessels surrounding the brain. Occlusion of the arteries rarely occurs; however, venous involvement is more severe. Phlebitis may be accompanied by thrombosis and complete occlusion. Multiple fibrin thrombi are especially associated with hemorrhagic infarction. This vascular involvement is apparent within the first days of meningitis and becomes more prominent during the second and third weeks.
Cerebral edema may occur during the acute state of meningitis and may be severe enough to diminish the ventricular lumen substantially. The cause is unknown but is likely to be related to vasculitis and the increased permeability of blood vessels. It may also be related to cytotoxins of microbial origin. Herniation of edematous supratentorial structures does not generally occur in neonates, because of the cranium’s distensibility.
Infarction is a prominent and serious feature of neonatal meningitis, occurring in 30% of infants who die. Lesions occur because of multiple venous occlusions, which are frequently hemorrhagic. The loci of infarcts are most often in the cerebral cortex and underlying white matter but may also be subependymal within the deep white matter. Neuronal loss occurs, especially in the cerebral cortex, and periventricular leukomalacia may subsequently appear in areas of neuronal cell death.
The microorganisms most commonly associated with early-onset neonatal sepsis include the following :
Risk factors implicated in neonatal sepsis reflect the level stress and illness experienced by the fetus at delivery, as well as the hazardous uterine environment surrounding the fetus before delivery. The most common risk factors associated with early-onset neonatal sepsis are as follows:
Other factors that are associated with or predispose to early-onset neonatal sepsis include the following :
Organisms that have been implicated in causing late-onset neonatal sepsis include the following:
Late-onset sepsis is associated with the following risk factors :
The principal pathogens in neonatal meningitis are GBS (36% of cases), E coli (31%), and Listeria species (5-10%). Other organisms that may cause meningitis include the following:
The incidence of culture-proven sepsis in the United States is approximately 2 per 1000 live births. Of the 7-13% of neonates who are evaluated for neonatal sepsis, only 3-8% have culture-proven sepsis. This disparity arises from the cautious approach to management of neonatal sepsis.
Because early signs of sepsis in the newborn are nonspecific, diagnostic studies are often ordered and treatment initiated in neonates before the presence of sepsis has been proved. Moreover, because the American Academy of Pediatrics (AAP), the American Academy of Obstetrics and Gynecology (AAOG), and the Centers for Disease Control and Prevention (CDC) all have recommended sepsis screening or treatment for various risk factors related to GBS infections, many asymptomatic neonates now undergo evaluation.
Because mortality from untreated sepsis can be as high as 50%, most clinicians believe that the hazard of untreated sepsis is too great to allow them to wait for confirmation in the form of positive culture results. Therefore, most clinicians initiate treatment while awaiting culture results.
The implementation of a prenatal screening and treatment protocol for GBS has resulted in a decreasing incidence of GBS sepsis. This has changed the epidemiology of early-onset sepsis (see the image below).
Incidence of early-onset and late-onset invasive group B Streptococcus (GBS) disease.
Black infants have an increased incidence of GBS disease and late-onset sepsis. This is observed even after the risk factors of low birth weight and decreased maternal age have been controlled for. In all races, the incidence of bacterial sepsis and meningitis, especially with gram-negative enteric bacilli, is higher in males than in females.
Premature infants have an increased incidence of sepsis. The incidence of sepsis is significantly higher in infants with a birth weight of less than 1000 g (26 per 1000 live births) than in infants with a birth weight of 1000-2000 g (8-9 per 1000 live births). The risk of death or meningitis from sepsis is higher in infants with low birth weight than in full-term neonates.
With early diagnosis and treatment, term infants are not likely to experience long-term health problems associated with neonatal sepsis; however, if early signs or risk factors are missed, mortality increases. Residual neurologic damage occurs in 15-30% of neonates with septic meningitis.
Mortality from neonatal sepsis may be as high as 50% for infants who are not treated. Infection is a major cause of fatality during the first month of life, contributing to 13-15% of all neonatal deaths. Low birth weight and gram-negative infection are associated with adverse outcomes. Neonatal meningitis occurs in 2-4 cases per 10,000 live births and contributes significantly to mortality from neonatal sepsis; it is responsible for 4% of all neonatal deaths.
In preterm infants who have had sepsis, impaired neurodevelopment is a concern. Proinflammatory molecules may negatively affect brain development in this patient population. In a large study of about 6000 premature infants who weighed less than 1000 g at birth, preterm infants with sepsis who did not have meningitis had higher rates of cognitive deficits, cerebral palsy, and other neurodevelopmental disabilities than infants who did not have sepsis.[11, 12]
Infants with meningitis may acquire hydrocephalus or periventricular leukomalacia. They may also have complications associated with the use of aminoglycosides, such as hearing loss or nephrotoxicity.
An awareness of the many risk factors associated with neonatal sepsis prepares the clinician for early identification and effective treatment, thereby reducing mortality and morbidity. Among these risk factors are the following:
The most common cause of neonatal bacterial sepsis is GBS. There are 9 serotypes, each of which is related to the polysaccharide capsule of the organism. Types I, II, and III are commonly associated with neonatal GBS infection. The type III strain has been shown to be most highly associated with central nervous system (CNS) involvement in early-onset infection, whereas types I and V have been associated with early-onset disease without CNS involvement.
The GBS organism colonizes the maternal gastrointestinal (GI) tract and birth canal. Approximately 25% of women have asymptomatic GBS colonization during pregnancy. GBS is responsible for approximately 50,000 maternal infections per year in women, but only 0.36-2 neonates per 1000 live births are infected.
Women with heavy GBS colonization and chronically positive GBS culture results have the highest risk of perinatal transmission. Also, heavy colonization at 23-26 weeks’ gestation is associated with prematurity and low birth weight. Colonization at delivery is associated with neonatal infection.
Intrapartum chemoprophylaxis for women with positive culture results for GBS has been shown to decrease the transmission of the organism to the neonate during delivery. Mothers may have a negative prenatal culture for GBS but a positive one at the time of labor.
PROM may occur in response to an untreated urinary tract infection (UTI) or birth canal infection. Other risk factors are previous preterm delivery, uterine bleeding in pregnancy, and heavy cigarette smoking during pregnancy. Rupture of membranes without other complications for more than 24 hours before delivery is associated with a 1% increase in the incidence of neonatal sepsis; however, when chorioamnionitis accompanies the rupture of membranes, the incidence of neonatal infection is quadrupled.
A multicenter study demonstrated that clinical chorioamnionitis and maternal colonization with GBS are the most important predictors of subsequent neonatal infection after PROM. Seaward et al found that more than 6 vaginal digital examinations, which may be carried out as part of the evaluation for PROM, were associated with neonatal infection even when considered separately from the presence of chorioamnionitis.
When membranes have ruptured prematurely before 37 weeks’ gestation, a longer latent period precedes vaginal delivery, increasing the likelihood that the infant will be infected. The duration of membrane rupture before delivery and the likelihood of neonatal infection are inversely related to gestational age. Thus, the more premature an infant is, the longer the delay between rupture of membranes and delivery and the higher the likelihood of neonatal sepsis.
In addition to the relation between preterm PROM and neonatal sepsis, there are other associations between prematurity and neonatal sepsis that increase the risk for premature infants.
Preterm infants are more likely to require invasive procedures, such as umbilical catheterization and intubation. Prematurity is associated with infection from cytomegalovirus (CMV), herpes simplex virus (HSV), hepatitis B virus (HBV), Toxoplasma,Mycobacterium tuberculosis, Campylobacter fetus, and Listeria species. Intrauterine growth retardation and low birth weight are also observed in CMV infection and toxoplasmosis.
Premature infants have less immunologic ability to resist and combat infection. Consequently, they are more susceptible to infection caused by common organisms such as coagulase-negative Staphylococcus— an organism usually not associated with severe sepsis.
The relationship between chorioamnionitis and other risk variables is strong. Suspect chorioamnionitis in the presence of fetal tachycardia, uterine tenderness, purulent amniotic fluid, an elevated maternal white blood cell (WBC) count, and an unexplained maternal temperature higher than 100.4°F (38°C).
The clinical signs of neonatal sepsis are nonspecific and are associated with the characteristics of the causative organism and the body’s response to the invasion. These nonspecific clinical signs of early sepsis are also associated with other neonatal diseases, such as respiratory distress syndrome (RDS), metabolic disorders, intracranial hemorrhage, and a traumatic delivery. In view of the nonspecificity of these signs, it is prudent to provide treatment for suspected neonatal sepsis while excluding other disease processes.
To obtain the most information from the examination, systematic physical assessment of the infant is best performed in a series that should include observation, auscultation, and palpation, in that order. Changes in findings from one examination to the next provide important information about the presence and evolution of sepsis.
Inflammatory lesions are observed post mortem in the lungs of infants with congenital and intrauterine pneumonia. They may result not from the action of the microorganisms themselves but, rather, from aspiration of amniotic fluid containing maternal leukocytes and cellular debris. Tachypnea, irregular respirations, moderate retraction, apnea, cyanosis, and grunting may be observed.
Neonates with intrauterine pneumonia may also be critically ill at birth and require high levels of ventilatory support. The chest radiograph may depict bilateral consolidation or pleural effusions.
Neonates who are infected during the birth process may acquire pneumonia through aspiration of microorganisms during delivery. Klebsiella species and S aureus are especially likely to generate severe lung damage, producing microabscesses and empyema. Early-onset GBS pneumonia has a particularly fulminant course, with significant mortality in the first 48 hours of life.
Intrapartum aspiration may lead to infection with pulmonary changes, infiltration, and destruction of bronchopulmonary tissue. This damage is partly due to the granulocytes’ release of prostaglandins and leukotrienes. Fibrinous exudation into the alveoli leads to inhibition of pulmonary surfactant function and respiratory failure, with a presentation similar to that of RDS. Vascular congestion, hemorrhage, and necrosis may occur. Infectious pneumonia is also characterized by pneumatoceles within the pulmonary tissue.
Coughing, grunting, costal and sternal retractions, nasal flaring, tachypnea or irregular respiration, rales, decreased breath sounds, and cyanosis may be observed. Radiographic evaluation may demonstrate segmental or lobar atelectasis or a diffuse reticulogranular pattern, much like what is observed in RDS. Pleural effusions may be observed in advanced disease.
Postnatally acquired pneumonia may occur at any age. Because these infectious agents exist in the environment, the likely cause depends heavily on the infant’s recent environment. If the infant has remained hospitalized in a neonatal intensive care unit (NICU), especially with endotracheal intubation and mechanical ventilation, the organisms may include Staphylococcus or Pseudomonas species.
Additionally, these hospital-acquired organisms frequently demonstrate multiple antibiotic resistances. Therefore, the choice of antibiotic agents in such cases requires knowledge of the likely causative organisms and the local antibiotic-resistance patterns.
In overwhelming sepsis, an initial early phase characterized by pulmonary hypertension, decreased cardiac output, and hypoxemia may occur. This phase is followed by further progressive decreases in cardiac output with bradycardia and systemic hypotension. The infant manifests overt shock with pallor, poor capillary perfusion, and edema. These late signs of shock are indicative of severe compromise and are strongly associated with mortality.
Hypoglycemia, hyperglycemia, metabolic acidosis, and jaundice are all metabolic signs that commonly accompany neonatal sepsis. The infant has an increased glucose requirement as a result of the septic state. The infant may also be malnourished as a consequence of diminished energy intake. Hypoglycemia accompanied by hypotension may be secondary to an inadequate response from the adrenal gland and may be associated with a low cortisol level.
Metabolic acidosis is due to a conversion to anaerobic metabolism with the production of lactic acid. When infants are hypothermic or are not kept in a neutral thermal environment, efforts to regulate body temperature can cause metabolic acidosis. Jaundice occurs in response to decreased hepatic glucuronidation caused by both hepatic dysfunction and increased erythrocyte destruction.
Meningitis is the common manifestation of CNS infection. Acute and chronic histologic features are associated with specific organisms.
Meningitis due to early-onset neonatal sepsis usually occurs within 24-48 hours and is dominated by nonneurologic signs. Neurologic signs may include stupor and irritability. Overt signs of meningitis occur in only 30% of cases. Even culture-proven meningitis may not demonstrate white blood cell (WBC) changes in the cerebrospinal fluid (CSF).
Meningitis due to late-onset disease is more likely to demonstrate neurologic signs (80-90%); however, many of these physical examination findings are subtle or inapparent. Neurologic signs include the following:
Temperature instability is observed with neonatal sepsis and meningitis, either in response to pyrogens secreted by the bacterial organisms or from sympathetic nervous system instability. The neonate is most likely to be hypothermic. The infant may also have decreased tone, lethargy, and poor feeding. Signs of neurologic hyperactivity are more likely when late-onset meningitis occurs.
Laboratory studies used to evaluate for early-onset and late-onset sepsis include a complete blood count (CBC) and differential, blood and cerebrospinal fluid (CSF) cultures, and measurement of levels of C-reactive protein (CRP) and possibly other infection markers. In some cases, serial CBC and CRP studies may be appropriate. A Gram stain provides early identification of the gram-negative or gram-positive status of the organism for preliminary identification.
Because of the low incidence of meningitis in the newborn with negative blood culture results, clinicians may elect to culture the CSF of only those infants with documented or presumed sepsis. However, data from large studies show a 38% rate of culture-positive meningitis in neonates with negative blood culture results and suspected sepsis. Accordingly, a lumbar puncture should be part of the evaluation of an infant with suspected sepsis.
Emerging technology using polymerase chain reaction (PCR), though not yet available clinically, could eventually help achieve faster identification of sepsis and the causative organism than can be achieved with blood culture alone. Rapid pathogen detection with multiplex PCR may facilitate more timely selection of targeted antibiotic therapy while limiting exposure to broad-spectrum antibiotics.
Imaging studies employed in the workup of neonatal sepsis may include chest radiography to evaluate pulmonary involvement, as well as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography of the head in cases of meningitis.
Aerobic and anaerobic cultures are appropriate for most of the bacterial pathogens associated with neonatal sepsis. Anaerobic cultures are especially important in neonates who have abscesses, processes with bowel involvement, massive hemolysis, or refractory pneumonia.
Bacterial culture results should generally reveal the organism of infection within 36-48 hours; subsequent initial identification of the organism occurs within 12-24 hours of the growth. Single-site blood cultures are effective for isolating bacteria in neonates with sepsis. Urine cultures are most appropriate for the investigation of late-onset sepsis.
A CBC and differential may be ordered serially to determine changes associated with the infection (eg, thrombocytopenia or neutropenia) or to monitor the development of a left shift or changes in the ratio of immature to total neutrophils. Such serial monitoring of the CBC may be useful in aiding the differentiation of sepsis from nonspecific abnormalities due to the stress of delivery.
The platelet count in the healthy newborn is rarely lower than 100,000/µL in the first 10 days of life (normal, ≥150,000/μL). Thrombocytopenia (platelet counts < 100,000/µL) may be a presenting sign of neonatal sepsis and can last as long as 3 weeks; 10-60% of infants with sepsis have thrombocytopenia.
Because of the appearance of newly formed platelets, mean platelet volume (MPV) and platelet distribution width (PDW) are significantly higher in neonatal sepsis after 2-3 days of life. These measures may assist in determining the cause of thrombocytopenia. However, because of the myriad of causes of thrombocytopenia and its late appearance in neonatal sepsis, the presence of thrombocytopenia generally does not aid the diagnosis of neonatal sepsis.
White blood cell counts and ratios
Although white blood cell (WBC) counts and ratios are more sensitive for determining sepsis than platelet counts are, they remain very nonspecific and have a low positive predictive value. Normal WBC counts may be initially observed in as many as 50% of cases of culture-proven sepsis. Infants who are not infected may also demonstrate abnormal WBC counts related to the stress of delivery or to any of several other factors.
A differential may be of use in diagnosing sepsis; however, these counts are largely dependent on the laboratory technician performing them. The total neutrophil count (polymorphonuclear cells [PMNs] and immature forms) is slightly more sensitive for determining sepsis than the total leukocyte count (percent lymphocyte + monocyte/PMNs + bands).
Abnormal neutrophil counts at the time of symptom onset are observed in only two thirds of infants; therefore, the neutrophil count does not provide adequate confirmation of sepsis. Neutropenia is also observed with maternal hypertension, severe perinatal asphyxia, and periventricular or intraventricular hemorrhage.
Neutrophil ratios have been more useful in diagnosing neonatal sepsis; of these, the immature-to-total (I/T) ratio is the most sensitive (60-90%). All immature neutrophil forms are counted. The maximum acceptable I/T ratio for excluding sepsis in the first 24 hours is 0.16. In most newborns, the ratio falls to 0.12 within 60 hours of birth. Because elevated I/T ratios may be observed with other physiologic events, their positive predictive value is limited; thus, in the diagnosis of sepsis, an elevated I/T ratio should be used in combination with other signs.
levels of CRP, an acute-phase protein associated with tissue injury, are elevated at some point in 50-90% of infants with systemic bacterial infections. CRP levels rise secondary to macrophage, T-cell, and adipocyte production of interleukin (IL)–6. This is especially true of infections with abscesses or cellulitis of deep tissue.
CRP levels usually begin to rise within 4-6 hours of the onset of infection, become abnormal within 24 hours of infection, peak within 2-3 days, and remain elevated until the inflammation is resolved. The CRP level is not recommended as a sole indicator of neonatal sepsis but may be used as part of a sepsis workup or as a serial study during infection to assess the response to antibiotics, determine the duration of therapy, or identify a relapse of infection.
Immunoglobulin M (IgM) concentration in serum may be helpful in determining the presence of an intrauterine infection, especially if the infection has been present for some time. Elevated IgM levels in umbilical cord serum suggest intrauterine infection.
Evidence on the use of infection markers such as CD11b, CD64, IL-6, and IL-8 for evaluation of sepsis in neonates shows that they may be helpful as adjunctive markers. Their value may be further enhanced by performing serial measurements and using combinations of tests. At present, however, the consensus is that these tests should not be used alone to determine the need for antibiotic therapy, though in some cases they may prove useful in determining when to stop antibiotic therapy.
levels of other acute-phase reactants (eg, procalcitonin and serum amyloid) are often elevated with the onset of sepsis. The evidence is too sparse and the clinical laboratory availability too limited to support routine use of these levels as markers for neonatal sepsis. They may, however, be used in combination with other acute-phase reactants, such as CRP.
Disseminated intravascular coagulation (DIC) can occur in infected infants. Predicting which infants will be affected at the onset of sepsis is difficult.
Infants with DIC show abnormalities in the prothrombin time (PT), the partial thromboplastin time (PTT), and fibrinogen and D-dimer levels, and they may need blood products, including fresh frozen plasma (FFP) and cryoprecipitate, to replace coagulation factors consumed in association with DIC. If infants show signs consistent with impaired coagulation (eg, gastric blood, bleeding from intravenous [IV] or laboratory puncture sites, or other bleeding), coagulation should be evaluated by checking these values.
Lumbar puncture is warranted for early- and late-onset sepsis, though clinicians may be unsuccessful in obtaining sufficient or clear fluid for all the studies. Infants may be positioned on their side or in a sitting position with support. The insertion site should be between L3 and L4 to ensure that it is below the lowest point of the spinal cord in infants.
If positive culture results are obtained, a follow-up lumbar puncture is often performed within 24-36 hours after initiation of antibiotic therapy to document CSF sterility. If organisms are still present, modification of the drug type or dosage may be required for adequate treatment of the meningitis. An additional lumbar puncture within 24-36 hours of the change in therapy is necessary if organisms are still present.
CSF findings in infective neonatal meningitis are as follows:
The CSF WBC count is within the reference range in 29% of group B Streptococcus (GBS) meningitis infections but in only 4% of gram-negative meningitis infections. Reference-range CSF protein and glucose concentrations are found in about 50% of patients with GBS meningitis but in only 15-20% of patients with gram-negative meningitis. CSF culture is critical, in that neonatal meningitis often occurs in patients without bacteremia and with normal CSF findings.
The decrease in CSF glucose concentration does not necessarily reflect serum hypoglycemia. Glucose concentration abnormalities are more severe in late-onset disease and with gram-negative infections.
No consensus has been reached regarding the inclusion of herpes simplex virus (HSV) PCR testing of CSF as part of a routine sepsis workup in the neonate. Currently, HSV PCR is reserved for infants with CNS abnormalities, skin vesicles, and CSF abnormalities or for infants who have clinical symptoms but have negative cultures and do not respond to antibiotics. However, vesicles are not present in as many as one third of CNS HSV and disseminated HSV cases. Further research in this area is needed to provide clear practice recommendations.
Chest radiography may reveal segmental or lobar infiltrate but more commonly reveals a diffuse, fine, reticulogranular pattern, much like that seen in respiratory distress syndrome (RDS). Pleural effusions may also be observed.
CT scanning or MRI may be needed late in the course of complex neonatal meningitis to document obstructive hydrocephalus, the site where the obstruction is occurring, and the occurrence of major infarctions or abscesses. Signs of chronic disease (eg, ventricular dilation, multicystic encephalomalacia, and atrophy) may also be demonstrated on CT scanning or MRI.
Head ultrasonography in neonates with meningitis may reveal evidence of ventriculitis, abnormal parenchymal echogenicities, extracellular fluid, and chronic changes. Serially, head ultrasonography can reveal the progression of complications.
When neonatal sepsis is suspected, treatment should be initiated immediately because of the neonate’s relative immunosuppression. Begin antibiotics as soon as diagnostic tests are performed.
A neonate with sepsis may require treatment aimed at the overwhelming systemic effects of the disease. Cardiopulmonary support and intravenous (IV) nutrition may be required during the acute phase of the illness until the infant’s condition stabilizes. Monitoring of blood pressure, vital signs, hematocrit, platelets, and coagulation studies is vital. Not uncommonly, blood product transfusion, including packed red blood cells (PRBCs), platelets, and fresh frozen plasma (FFP), is indicated.
An infant with temperature instability needs thermoregulatory support with a radiant warmer or incubator. Once the infant is stable from a cardiopulmonary standpoint, parental contact is important.
Surgical consultation for central line placement may be necessary in infants who require prolonged IV antimicrobial therapy for sepsis, if peripheral IV access cannot be maintained. If an abscess is present, surgical drainage may be necessary; IV antibiotic therapy cannot adequately penetrate an abscess, and antibiotic treatment alone is ineffective.
The infant may require transfer to a level III perinatal center, especially if he or she requires cardiopulmonary support, parenteral nutrition, or prolonged IV access. The multidisciplinary services available at larger centers may be necessary if the neonate’s condition is acutely compromised.
Additional therapies have been investigated for the treatment of neonatal sepsis, including granulocyte transfusion, IV immune globulin (IVIg) infusion, exchange transfusion, and the use of recombinant cytokines. However, no substantial clinical trials have shown that these treatments are beneficial.
In the United States and Canada, the current approach to the treatment of early-onset neonatal sepsis includes combined IV aminoglycoside and expanded-spectrum penicillin antibiotic therapy. This provides coverage for gram-positive organisms, especially group B Streptococcus (GBS), and gram-negative bacteria, such as Escherichia coli. The specific antibiotics to be used are chosen on the basis of maternal history and prevalent trends of organism colonization and antibiotic susceptibility in individual nurseries.
If an infection appears to be nosocomial (late-onset sepsis), antibiotic coverage should be directed at organisms implicated in hospital-acquired infections, including S aureus, S epidermidis, and Pseudomonas species. Most strains of S aureus produce beta-lactamase, which makes them resistant to penicillin G, ampicillin, carbenicillin, and ticarcillin. Vancomycin has been favored for this coverage; however, concern exists that overuse of this drug may lead to vancomycin-resistant organisms, thereby eliminating the best response to penicillin-resistant organisms. For this reason, some clinicians prefer oxacillin therapy in this setting.
Cephalosporins are attractive in the treatment of nosocomial infection because of their lack of dose-related toxicity and their ability to reach adequate serum and cerebrospinal fluid (CSF) concentrations; however, their use has led to resistance in gram-negative organisms. Ceftriaxone displaces bilirubin from serum albumin and should be used with caution in infants with significant hyperbilirubinemia. Resistance and sensitivities for the organism isolated from cultures are used to select the most effective drug.
Zaidi et al compared the failure rates of 3 clinic-based antibiotic regimens in 0- to 59-day-old infants with possible serious bacterial infections in Karachi, Pakistan. In a randomized study, the researchers found that outpatient therapy with injectable antibiotics is an effective alternative when hospitalization is not possible. Procaine penicillin/gentamicin was superior to oral trimethoprim-sulfamethoxazole, while ceftriaxone was more expensive and less effective than penicillin/gentamicin.
Aminoglycosides and vancomycin both have the potential to produce ototoxicity and nephrotoxicity and should therefore be used with caution. The serum drug level is assessed around the third dose or at 48 hours after the start of treatment to determine whether levels are within the therapeutic range. The drug dosage or interval may have to be adjusted to optimize the drug serum levels. Infants who received aminoglycosides should undergo audiology screening before discharge.
If the infant’s clinical condition has not improved, a serum level may also be warranted to ensure that a therapeutic level has been reached. In addition, renal function and hearing screening should be considered after completion of the therapeutic course to determine whether any short- or long-range toxic effects of these drugs have occurred.
If culture results are negative but the infant is at significant risk for or has clinical signs of sepsis, the clinician must decide whether to provide continued treatment. In most cases, 2-3 days of negative culture results should allow the clinician to be confident that sepsis is absent; however, a small number of infants shown to have had sepsis by postmortem examination had negative culture results during their initial sepsis evaluation.
Management is further complicated if the mother received antibiotic therapy before delivery, especially if she received the therapy within several hours of delivery. This may result in negative culture results in an infant who actually has bacteremia or sepsis. With this in mind, the need for continued therapy should be based not on a single test, but on a review of all diagnostic data, including the following:
Treatment for 7-10 days may be appropriate, even if culture results remain negative at 48-72 hours.
Infants with bacterial meningitis often require different dosages of antibiotics and longer courses of treatment. In addition, these infants may require an antimicrobial that has better penetration of the blood-brain barrier so that therapeutic drug concentrations can be achieved in the CSF.
To determine whether the CSF is sterile, a follow-up lumbar puncture is recommended within 24-36 hours after initiation of antibiotic therapy. If organisms are still present, modification of the drug type or dosage is required to treat the meningitis adequately. Continue antibiotic treatment for 2 weeks after sterilization of the CSF or for a minimum of 2 weeks with gram-positive meningitis and 3 weeks with gram-negative meningitis.
Meningitis complicated by seizures or persistent positive cultures may require extended IV antimicrobial therapy. Chloramphenicol or trimethoprim-sulfamethoxazole has been shown to be effective in the treatment of highly resistant bacterial meningitis. Trimethoprim-sulfamethoxazole should not be used if hyperbilirubinemia and kernicterus are of concern in the newborn.
If hydrocephalus is associated with neonatal meningitis and if there is progressive accumulation of CSF, a ventriculoperitoneal (VP) shunt may be necessary to drain off the excess fluid. The immediate complications of shunt placement are overdrainage, equipment failure, disconnection, migration of catheter, and shunt infection. Abdominal obstruction, omental cysts, and perforation of the bladder, gallbladder, or bowel are uncommon.
The VP shunt may cause long-term neurologic complications, including slit-ventricle syndrome, seizures, neuro-ophthalmologic problems, and craniosynostosis. Nevertheless, the outcome for children with VP shunt placement is generally good with careful follow-up.
Additional therapies that have been investigated for the treatment of neonatal sepsis include the following:
Granulocyte transfusion has been shown to be suitable for infants with significant depletion of the storage neutrophil pool; however, documentation of storage pool depletion requires bone marrow aspiration, and the granulocyte transfusion must be administered quickly if it is to be beneficial. The number of potential adverse effects (eg, graft-versus-host reaction, transmission of cytomegalovirus [CMV] or hepatitis B, and pulmonary leukocyte sequestration) is considerable. Consequently, this therapy remains experimental.
The rationale for IVIg infusion is that it could provide type-specific antibodies, thereby improving opsonization and phagocytosis of bacterial organisms and enhancing complement activation and chemotaxis of neonatal neutrophils. It has been studied as a possible therapy for neonatal sepsis, but at present, the data do not support its routine use for this purpose. The main difficulties with IVIg therapy are as follows:
In addition, dose-related problems with IVIg infusion limit its usefulness in neonatal populations. Research has demonstrated no improvement in outcomes for neonates with sepsis who receive IVIg therapy.
Administration of recombinant human cytokines to stimulate granulocyte progenitor cells has been studied as an adjunct to antibiotic therapy. It has shown promise in animal models, especially for GBS sepsis, but pretreatment or immediate treatment is required to demonstrate its efficacy. The use of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) has been studied in clinical trials, but the use of these agents in clinical neonatology remains experimental.
Because of gastrointestinal (GI) symptoms, feeding intolerance, or poor feeding, it may be necessary to give the neonate nothing by mouth (nil per os; NPO) during the first days of treatment. Consider parenteral nutrition to ensure that the patient’s intake of calories, protein, minerals, and electrolytes is adequate during this period.
For the infant whose condition is seriously compromised, feeding may be restarted via a nasogastric tube For most infants, breast milk is the enteral diet recommended by the American Academy of Pediatrics (AAP).
The Committee on Infectious Diseases of the AAP recommends that obstetric care include a strategy for managing early-onset GBS disease. Women with GBS bacteriuria should be treated during pregnancy when the condition is diagnosed and during the intrapartum period. The committee also recommends that women who have previously given birth to an infant with invasive GBS disease receive antibiotic prophylaxis during labor and delivery.
To minimize the risk of early-onset GBS disease, practitioners should obtain screening vaginal and rectal cultures at 35-37 weeks’ gestation in all pregnant women unless the patients have had GBS bacteriuria in the current pregnancy or have previously had a child with invasive GBS disease. Implementation of a screening protocol has led to a significant decrease in the incidence of neonatal GBS disease (see the first image below). Recommendations have been formulated for antibiotic prophylaxis regimens (see the second image below).
Indications for intrapartum group B Streptococcus (GBS) antibiotic prophylaxis.
Recommended regimens for intrapartum antimicrobial prophylaxis for perinatal group B Streptococcus (GBS) disease prevention.
Other methods of preventing late-onset sepsis, particularly in the preterm neonate, are under investigation. Administration of lactoferrin, the major whey protein in mammalian milk, is thought to have properties that contribute to innate immune host defenses.
An infectious disease consultation is useful, especially if the infant is not responding to treatment, is infected with an unusual organism, or has had a complicated clinical course. If neonatal meningitis is identified, consultation with a pediatric neurologist may be necessary for assistance with outpatient follow-up of neurologic sequelae. Inpatient consultation may be necessary if meningitis is complicated by seizures.
Consultation with a pediatric pharmacologist may be helpful for obtaining advice on the most appropriate antibiotic or dosage to use if changes in the drug regimen prove necessary because of inadequate or toxic drug levels obtained with therapeutic monitoring. A pediatric surgical consultation may be necessary if sepsis is complicated by abscess, if the differential diagnosis includes necrotizing enterocolitis (NEC), or if central line placement is required.
The primary care provider (PCP) should evaluate the infant with neonatal sepsis within 1 week of discharge from the hospital. The infant can be evaluated for superinfection and bacterial colonization associated with antibiotic therapy, especially if the therapy was prolonged. The PCP should evaluate growth and determine whether the feeding regimen and activity have returned to normal.
The Joint Commission on Infant Hearing of the AAP recommends that infants who received aminoglycosides should receive follow-up audiology testing, in addition to audiology screening before hospital discharge. Screen these infants at 3 months—but no later than 6 months—after discharge to determine whether damage has occurred.
If neonatal sepsis was associated with meningitis, prolonged hypoxia, extracorporeal membrane oxygenation therapy, or brain abscess formation, the infant should be observed for several years to assess neurodevelopment. If problems are found, the child should receive appropriate early intervention services and therapies.
The antibiotics commonly used to treat neonatal sepsis include ampicillin, gentamicin, cefotaxime, vancomycin, metronidazole, erythromycin, and piperacillin. The choice of antibiotic agents should be based on the specific organisms associated with sepsis, the sensitivities of the bacterial pathogen, and the prevailing nosocomial infection trends in the nursery. Viral infections, such as herpes and fungal infections, can masquerade as bacterial infections.
Clinical Context: Ampicillin is a beta-lactam antibiotic that is bactericidal for susceptible organisms, such as group B Streptococcus (GBS), Listeria, non–penicillinase-producing Staphylococcus, some strains of Haemophilus influenzae, and meningococci. Some publications recommend ampicillin (in combination with gentamicin) as first-line therapy for suspected sepsis in the newborn.
Clinical Context: Gentamicin is an aminoglycoside that is bactericidal for susceptible gram-negative organisms, such as Escherichia coli and Pseudomonas, Proteus, and Serratia species. It is effective in combination with ampicillin for GBS and Enterococcus. Some publications recommend gentamicin (in combination with ampicillin) as first-line therapy for suspected sepsis in the newborn.
Clinical Context: Cefotaxime is a third-generation cephalosporin with excellent in vitro activity against GBS and E coli and other gram-negative enteric bacilli. Good concentrations can be achieved in serum and cerebrospinal fluid (CSF). Concern exists that emergence of drug-resistant gram-negative bacteria may occur more rapidly with cefotaxime coverage than with traditional penicillin and aminoglycoside coverage.
Clinical Context: Vancomycin is a bactericidal agent that is effective against most aerobic and anaerobic gram-positive cocci and bacilli. It is especially important in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) and is recommended when coagulase-negative staphylococcal sepsis is suspected. However, therapy with rifampin, gentamicin, or cephalothin may be required in cases of endocarditis or CSF shunt infection with coagulase-negative staphylococci.
Clinical Context: Chloramphenicol has been shown to be effective in the treatment of highly resistant bacterial meningitis. It inhibits protein synthesis by binding reversibly to 50S ribosomal subunits of susceptible organisms, which, in turn, prevents amino acids from being transferred to growing peptide chains.
Clinical Context: Oxacillin is a bactericidal antibiotic that inhibits cell wall synthesis. It is used in the treatment of infections caused by penicillinase-producing staphylococci. It may be given as initial therapy when a staphylococcal infection is suspected.
Clinical Context: Metronidazole is an antimicrobial that has been shown to be effective against anaerobic infections, especially Bacteroides fragilis meningitis, ventriculitis, and endocarditis. This agent is also useful in the treatment of infections caused by Trichomonas vaginalis.
Clinical Context: Piperacillin is an acylampicillin with excellent activity against Pseudomonas aeruginosa. It is also effective against Klebsiella pneumoniae, Proteus mirabilis, B fragilis, Serratia marcescens, and many strains of Enterobacter. Administer it in combination with an aminoglycoside.
Clinical Context: Erythromycin is a macrolide antimicrobial agent that is primarily bacteriostatic and is active against most gram-positive bacteria, such as Neisseria species, Mycoplasma pneumoniae, Ureaplasma urealyticum, and Chlamydia trachomatis. It is not well concentrated in the CSF.
Clinical Context: Trimethoprim-sulfamethoxazole has been shown to be effective in the treatment of highly resistant bacterial meningitis. Trimethoprim-sulfamethoxazole inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. Trimethoprim-sulfamethoxazole should not be used if hyperbilirubinemia and kernicterus are of concern in the newborn.
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Neonatal doses for antibiotics may be based on several variables (eg, postmenstrual age [PMA], postnatal age, and weight).
Clinical Context: Acyclovir is used for treatment of mucosal, cutaneous, and systemic HSV-1 and HSV-2 infections.
Clinical Context: Zidovudine is a thymidine analogue that inhibits viral replication. It is used to treat patients with HIV infection.
A viral infection, such as that from herpes simplex virus (HSV), may masquerade as bacterial sepsis. At the onset of the infection, treatment must be initiated promptly to effectively inhibit the replicating virus.
Clinical Context: Fluconazole is used to treat susceptible fungal infections, including oropharyngeal, esophageal, and vaginal candidiasis. It is also used for systemic candidal infections and cryptococcal meningitis. Fluconazole has fungistatic activity. It is a synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal CYP450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes.
Clinical Context: Amphotericin B is used to treat severe systemic infections and meningitis caused by susceptible fungi, such as Candida and Aspergillus species, Histoplasma capsulatum, and Cryptococcus neoformans. This agent is a polyene produced by a strain of Streptomyces nodosus; it can be fungistatic or fungicidal. Amphotericin B binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak and subsequent fungal cell death.
Liposomal amphotericin B (AmBisome) may be considered for patients with systemic fungal infections resistant to amphotericin B or for patients with renal or hepatic failure. This product consists of amphotericin B within a single-bilayer liposomal drug delivery system.
Fungal infections can masquerade as bacterial infections or may appear at the end of prolonged antibacterial therapy. Their mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide, which is toxic to the fungal cell.