Neonatal Sepsis

Background

Neonatal sepsis may be categorized as early onset (day of life 0-3) or late onset (day of life 4 or later). Of newborns with early-onset sepsis, 85% present within 24 hours (median age of onset 6 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. Infection can occur via hematogenous, transplacental spread from an infected mother or, more commonly, via ascending infection from the cervix. Organisms that colonize the mother’s genitourinary (GU) tract may be acquired by the neonate as it passes through the colonized birth canal at delivery. The microorganisms most commonly associated with early-onset infection include the following^[1] :

• Group B Streptococcus (GBS)
• Escherichia coli
• Coagulase-negative Staphylococcus
• Haemophilus influenzae
• Listeria monocytogenes

Trends in the epidemiology of early-onset sepsis show a decreasing incidence of GBS disease following the widespread adoption of prenatal screening and treatment protocols.^{[2, 3, 4]}

In a 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.^[5] As many as 10% of prenatally culture-negative women were found to have positive cultures at the time of labor. In the study, intrapartum antibiotic prophylaxis occurred appropriately in 93.3% of cases, with 0.36 of 1000 infants developing early-onset GBS disease.^[5]

Late-onset sepsis occurs at 4-90 days of life and is acquired from the environment. Organisms that have been implicated in late-onset sepsis include the following:

• Coagulase-negative Staphylococcus
• Staphylococcus aureus
• E coli
• Klebsiella
• Pseudomonas
• Enterobacter
• Candida
• GBS
• Serratia
• Acinetobacter
• Anaerobes
• Many additional less-common organisms

Trends in late-onset sepsis show an increase in coagulase-negative streptococcal sepsis, with most isolates showing susceptibility to first-generation cephalosporins.^[2] The infant’s skin, respiratory tract, conjunctivae, gastrointestinal tract, and umbilicus may become colonized via contact with the environment or caregivers.

Pneumonia is more common in early-onset sepsis, whereas meningitis and bacteremia are more common in late-onset sepsis. Early-onset sepsis is 10 to 20 times more likely to occur in premature, very low birthweight infants.^[6] Premature infants often have nonspecific, subtle symptoms; considerable vigilance is therefore required in these patients so that sepsis can be identified and treated in a timely manner.

For patient education information, see Sepsis.

• References

Pathophysiology

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, Group B Streptococcus (GBS) replaced S aureus as the most common gram-positive organism causing early-onset sepsis.

Currently, GBS and E coli continue to be the most commonly identified microorganisms associated with neonatal infection. Additional organisms, such as coagulase-negative Staphylococcus epidermidis, 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 emerged and have further complicated the management of neonatal sepsis.^[7] 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 younger gestational ages 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 commonly required for the care of these infants.

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.^{[8, 9]}

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 S epidermidis 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 presentation, colony counts, and the presence of polymorphonuclear neutrophils (PMNs) on Gram staining of the submitted specimen often help differentiate true infection from contaminated culture specimens.

In addition to the specific microbial factors mentioned above, numerous host factors predispose the newborn to sepsis.^[10] These factors are especially prominent in the premature infant and involve all levels of host defense, including cellular immunity, humoral immunity, and barrier function. Immature immune defenses and environmental and maternal factors contribute to the risk for neonatal sepsis, morbidity, and mortality, particularly in preterm and/or very low birthweight (VLBW) infants.^{[10, 11]}  There may also be a genetic association.^[10]

Cellular immunity

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.^[12]

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.^[13]

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.

Humoral immunity

The fetus has some preformed immunoglobulin (Ig), which is primarily acquired through nonspecific placental transfer from the mother. Most of this transfer occurs in late gestation, such 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.^[14]

The neonate is also capable of synthesizing 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.^[15]

IgG and IgE also may be synthesized in utero. Most IgG is acquired from the mother during late gestation. The neonate may receive 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.^[16]

The terminal cytotoxic components of the complement cascade that lead to the killing of organisms, especially gram-negative bacteria, are deficient. This deficiency is more marked in preterm infants. Mature complement activity is not attained until infants reach 6-10 months of life. 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.

Barrier function

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, the individual deficiencies of the various components of immune activity in the neonate conspire to create a hazardous situation when the neonate is exposed to infectious threats.

Gastrointestinal involvement in sepsis

The intestines are colonized by organisms in utero or at delivery through swallowing of, and exposure to, amniotic fluid and genitourinary tract secretions. The immunologic defenses of the gastrointestinal 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, as antibody response and cytokine formation are immature until approximately 46 weeks' gestation.

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 can be a component of the multifactorial pathophysiology of necrotizing enterocolitis.

Meningitis

Ventriculitis

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 near these tufts and cause obstruction, particularly at the aqueduct of Sylvius.

The lateral ventricles may become loculated, a process that is similar to the formation of abscesses. Multiloculated ventricles can lead to the development of localized pockets of infection, 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, particularly if ventricular obstruction is present.

Arachnoiditis

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 typically 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 can extend 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 can occur in cranial roots 3-8.

After this period, the exudate decreases. Thick strands of collagen form along with arachnoid fibrosis, ultimately leading to obstruction of CSF flow. Hydrocephalus results. Early-onset GBS meningitis is characterized by much less arachnoiditis than late-onset GBS meningitis.

Vasculitis

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 can be severe. Phlebitis may be accompanied by thrombosis and complete vessel 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 of infection.

Cerebral edema

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

Infarction is a prominent and serious feature of advanced 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.^[17]

• References

Etiology

Early-onset neonatal sepsis

The microorganisms most commonly associated with early-onset neonatal sepsis include the following^[1] :

• Group B Streptococcus (GBS)
• E coli
• Coagulase-negative Staphylococcus
• H influenzae
• L monocytogenes

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 include, but are not limited to, the following:

• Maternal GBS colonization (particularly in the setting of inadequate prophylactic treatment)
• Premature rupture of membranes (PROM)
• Preterm rupture of membranes
• Prolonged rupture of membranes
• Premature birth
• Maternal urinary tract infection (UTI)
• Chorioamnionitis
• Maternal fever greater than 38ºC (100.4ºF)

Other factors that are associated with or predispose to early-onset sepsis include the following^{[18, 19]} :

• Low Apgar score (< 6 at 1 or 5 minutes)
• Poor prenatal care
• Poor maternal nutrition
• Low socioeconomic status
• Black mother
• History of recurrent abortion
• Maternal substance abuse
• Low birth weight
• Difficult delivery
• Birth asphyxia
• Meconium staining
• Congenital anomalies

Late-onset neonatal sepsis

Organisms that have been implicated in causing late-onset neonatal sepsis include the following:

• Coagulase-negative staphylococci
• S aureus
• E coli
• Klebsiella
• Pseudomonas
• Enterobacter
• Candida
• GBS
• Serratia
• Acinetobacter
• Anaerobes
• Many additional less-common organisms

Late-onset sepsis is associated with the following risk factors^[20] :

• Prematurity
• Central venous catheterization (duration >10 days)
• Urinary catheterization
• Chronic mechanical ventilation
• Failure to advance enteral feeding
• nasal cannula or continuous positive airway pressure (CPAP)
• Use of H₂ -receptor blocker or proton pump inhibitor (PPI)
• Gastointestinal tract pathology

Meningitis

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:

• S pneumoniae
• S aureus
• S epidermidis
• H influenzae
• Pseudomonas species
• Klebsiella species
• Serratia species
• Enterobacter species
• Proteus species

• References

Epidemiology

The incidence of culture-proven early-onset sepsis in the United States is approximately 0.3-2 per 1000 live births. Of the 7%-13% of neonates who are evaluated for neonatal sepsis, only 3%-8% of those screened will have culture-proven sepsis. This disparity arises from the cautious approach to management of neonatal sepsis.^[21]

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 proven. Moreover, because the American Academy of Pediatrics (AAP),^{[22, 23]} the American College of Obstetricians and Gynecologists (ACOG),^[24]  and the Centers for Disease Control and Prevention (CDC)^[25] all have recommended sepsis screening or treatment for various risk factors related to Group B Streptococcus (GBS) infections, many asymptomatic neonates now undergo evaluation and are exposed to antibiotics.

Mortality from untreated sepsis can be as high as 50%, leading many clinicians to err on the side of treating asymptomatic infants based on historical and maternal risk factors alone. This approach has been questioned in the past several years as more evidence emerges on the deleterious impact of unnecessary antibiotic exposure, including interference with the establishment of breast feeding, alternations in gut microbiome, increases in the incidence of childhood obesity, and development of antimicrobial resistance, amongst others.^[26]  

The implementation of a prenatal screening and treatment protocol for GBS has resulted in a dramatic decrease in the incidence of GBS sepsis. This has changed the epidemiology of early-onset sepsis (see the image below).

View Image

Neonatal sepsis. Incidence of early-onset and late-onset invasive group B Streptococcus (GBS) disease. Graph from Verani JR, McGee L, Schrag SJ, for t....

Age-, race-, and sex-related demographics

Premature infants have an increased incidence of sepsis, with a significantly higher occurrence in infants with a birth weight lower than 1500 g (11-22.7 per 1000 live births) than in infants born at 37 weeks or later (0.3-0.98 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.

Black infants have an increased incidence of GBS disease and late-onset sepsis. This is observed even after other risk factors such as low birth weight and younger maternal age have been controlled for. This finding may be in part due to higher carriage rates of GBS among black women, but this factor does not explain all of the variation.^[19]

In all races, the incidence of bacterial sepsis and meningitis, especially with gram-negative enteric bacilli, is higher in males than in females.

• References

Prognosis

With early diagnosis and treatment of neonatal sepsis, most term infants will not experience associated long-term health problems. 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 mortality during the first month of life, contributing to 13%-15% of all neonatal deaths. Low birth weight and gram-negative infection are associated with worse outcomes.^[27] 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.^[28] Proinflammatory molecules may negatively affect brain development in this patient population. In a large study of 6093 premature infants who weighed less than 1000 g at birth, preterm infants with sepsis who did not have meningitis had higher rates of cerebral palsy (odds ratio [OR] 1.4-1.7), developmental delay (OR 1.3-1.6), and vision impairment (OR 1.3-2.2) as well as other neurodevelopmental disabilities than infants who did not have sepsis.^{[29, 30]}

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.

• References

History

An awareness of the many risk factors associated with neonatal sepsis prepares the clinician for early identification and effective treatment, thereby reducing morbidity and mortality. Among these risk factors are the following:

• Maternal group B Streptococcus (GBS) status
• Prolonged and/or premature rupture of membranes (PPROM)
• Premature delivery
• Chorioamnionitis

Maternal GBS status

The most common cause of neonatal bacterial sepsis remains GBS, despite a decreased overall incidence in the age of universal GBS prophylaxis. There are nine 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 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 GBS culture results has been shown to reduce 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.^[5]

Premature rupture of membranes

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 increases four-fold.

A multicenter study demonstrated that clinical chorioamnionitis and maternal colonization with GBS are the most important predictors of subsequent neonatal infection after PROM.^[31] Exposure to more than six vaginal digital examinations, which may be carried out as part of the evaluation for PROM, is associated with neonatal infection even when considered separately from the presence of chorioamnionitis.^[31]

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.

Prematurity

In addition to the relationship 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. Preterm delivery 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.

Chorioamnionitis

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 38°C (100.4°F).

The diagnosis of chorioamnionitis has been a trigger point for sepsis evaluation and initiation of empiric antibiotics based on guidelines from the Centers for Disease Control and Prevention (CDC),^[25] American College of Obstetricians and Gynecologists (ACOG),^{[24, 32]}  and American Academy of Pediatrics (AAP).^[22] This approach has been criticized based upon the low incidence of culture-positive early-onset sepsis and the growing evidence of deleterious effects from unnecessary antibiotic exposure. In 2015, a panel of experts recommended that the term “chorioamnionitis” be replaced with “intrauterine inflammation or infection or both” (triple I), emphasizing that isolated maternal fever does not automatically equate to chorioamnionitis.^[33]

A newer approach to this issue has used a multivariate predictive model that takes into account maternal GBS status, appropriateness of intrapartum GBS coverage, gestational age, duration of rupture of membranes, highest intrapartum maternal temperature, along with the neonate’s examination following birth.  This model, commonly referred to as the “Kaiser Sepsis Calculator” has allowed for a dramatic reduction in the use of empiric antibiotics (from 5.0% of all births before implementation to 2.8% of all births afterward) and obtaining blood cultures (12.8% of all births before implementation to < 5% of all births afterward), without an increase in the rate of morbidity or mortality or readmissions for early-onset sepsis.^{[34, 35]}

• References

Physical Examination

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 can also be associated with other neonatal diseases, such as respiratory distress syndrome (RDS), metabolic disorders, intracranial hemorrhage, and a traumatic delivery, making the diagnosis based on physical examination alone difficult.

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.^[36]

Congenital pneumonia and intrauterine infection

Inflammatory lesions are observed postmortem in the lungs of infants with congenital and intrauterine pneumonia. These 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, retractions, apnea, cyanosis, and grunting may be observed.

Neonates with intrauterine pneumonia may be critically ill immediately upon birth and require high levels of ventilatory support. The chest radiograph may depict bilateral consolidation or pleural effusions.

Congenital pneumonia and intrapartum infection

Neonates who are infected during the birth process may acquire pneumonia through aspiration of microorganisms from the maternal genitourinary tract during delivery. Klebsiella species and S aureus are especially likely to generate severe lung damage, producing microabscesses and empyema. Early-onset group B streptococcal (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 release of prostaglandins and leukotrienes from granulocytes. 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, retractions, nasal flaring, tachypnea or irregular respiration, rales, decreased breath sounds, and cyanosis may be observed.  Infants who aspirate meconium, blood, or other proinflammatory material during labor may be symptomatic at birth, whereas infants primarily impacted by an infectious process may not show symptoms in the first hours after birth. 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.

Postnatal infection

Postnatally acquired pneumonia may occur at any age. 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, Pseudomonas species, Klebsiella, or others.

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 local antibiotic-resistance patterns.

Cardiac signs

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.

Metabolic signs

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. 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.

Neurologic signs

Meningitis is the common manifestation of central nervous system (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 may include the following:

• Impairment of consciousness (ie, stupor with or without irritability)
• Coma
• Seizures
• Bulging anterior fontanelle
• Extensor rigidity
• Focal cerebral signs
• Cranial nerve signs
• Nuchal rigidity
• Central apnea or periodic breathing

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.

• References

Approach Considerations

Laboratory studies used to evaluate for early-onset and late-onset sepsis include a complete blood cell (CBC) count and differential, measurement of levels of C-reactive protein (CRP) and other infection markers. Culture of blood, urine, and cerebrospinal fluid (CSF) samples remains the gold standard.^[37] A Gram stain may provide early identification of the gram-negative or gram-positive status of the organism for preliminary identification. DNA-based identification techniques are becoming available and may supplement culture results and provide rapid diagnostic information.^[38] Rapid pathogen detection with multiplex polymerase chain reaction (PCR) may facilitate more timely selection of targeted antibiotic therapy while limiting exposure to broad-spectrum antibiotics.^[39]

Because of the low incidence of meningitis in the newborn with negative blood culture results, clinicians may elect to culture the cerebrospinal fluid (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 considered when evaluating the infant with suspected sepsis.

Imaging studies employed in the workup of neonatal sepsis should target the neonate's symptoms and may include chest radiography to evaluate pulmonary involvement, as well as computed tomography (CT) scanning, magnetic resonance imaging (MRI), and ultrasonography of the head in cases of meningitis.

• References

Laboratory Studies

Cultures

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. In one study, anaerobic infections were responsible for 16% of early-onset sepsis amongst very low birthweight infants.^[40]  

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, although obtaining two cultures from separate sites has been shown to be useful in determining if commensal species represent true infection or a contaminated sample.^[40]  Blood culture from the umbilical cord may be considered. This route is attractive because larger volumes of blood may be drawn without concern, optimizing recovery of the offending organisms. However, contaminants have been reported at high rates in some, studies and specimen handling can be challenging.^[41] Urine cultures are most appropriate for the investigation of late-onset sepsis.

Complete blood cell (CBC) count and differential

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, although the sensitivity and specificity of these markers is low. Serial monitoring of the CBC may be useful in aiding the differentiation of sepsis from nonspecific abnormalities due to the stress of delivery.

Platelet count

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 count < 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.^[42]  However, thrombocytopenia is an insensitive and nonspecific finding as well as a late indicator of serious bacterial infection, making its utility in the initial workup of neonatal sepsis questionable.

Because of the appearance of newly formed platelets, mean platelet volume (MPV) and platelet distribution width are significantly higher in neonatal sepsis after 2-3 days of life. These measures may assist in determining the cause of thrombocytopenia. However, owing to the myriad of causes of thrombocytopenia and its late appearance in neonatal sepsis, the presence of thrombocytopenia 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 low WBC count (< 5,000/µL) is associated with a higher likelihood ratio for sepsis than an elevated WBC count (>20,000/µL).^[43]

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), although the overall likelihood ratio remains low. 

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 may have some limited utility in the diagnosis of neonatal sepsis. 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. In addition, the specificity of the I/T ratio is only 50%-75%, limiting its clinical usefulness. 

The utility of the CBC increases after the first 4 hours of age, with the WBC count findings, I/T ratio, presence of thrombocytopenia, and low absolute neutrophil count (ANC) all having significantly improved likelihood ratios in this later timeframe. Delaying the CBC until 4 hours or later may be prudent if the intent of its use is to make decisions regarding the likelihood of infection. In this context, decisions about antibiotic treatment should largely be based upon clinical findings and maternal risk factors.^[43]

C-reactive protein (CRP), procalcitonin, and other markers

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.^[44] 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 sera suggest intrauterine infection. The clinical availability of such testing and access to timely results limits this assay’s utility.

Evidence on the use of infection markers such as CD11b, soluble CD14 subtype, CD64, IL-6, IL-8, IL-10, and granulocyte-colony stimulating factor (G-CSF) for evaluation of sepsis in neonates shows that they may be helpful as adjunctive tests.^{[45, 46, 47, 48]} 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, although 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. Procalcitonin, a pro-peptide of calcitonin produced in monocytes and in the liver, may be more sensitive than CRP. It is more specific to bacterial infection than viral infection. Levels of procalcitonin can be elevated in infants with respiratory distress syndrome and in infants of diabetic mothers, and it should be used in conjunction with the entire clinical situation and not as a single determinant of treatment initiation or duration. Procalcitonin may be used in combination with other acute-phase reactants, such as CRP.^{[19, 49, 50, 51]}

Coagulation studies

Disseminated intravascular coagulation (DIC) can occur in infected infants. Predicting which infants will be affected at the onset of sepsis is difficult.^[52]

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 or laboratory puncture sites, or other bleeding), coagulation should be evaluated by checking these values.

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Lumbar Puncture and CSF Analysis

Lumbar puncture may be warranted in the workup of early- and late-onset sepsis, although clinicians may be unsuccessful in obtaining sufficient or clear cerebrospinal fluid (CSF) for all the studies. If positive culture results are obtained, a follow-up lumbar puncture is often performed within 24-36 hours after the 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 remain present.

CSF analysis

CSF findings in infective neonatal meningitis are as follows:

• Elevated white blood cell (WBC) count (predominantly polymorphonuclear neutrophils [PMNs])
• Elevated protein level
• Decreased glucose concentration
• Positive culture results
• Positive polymerase chain reaction (PCR)-based results

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. Obtaining a CSF culture is critical, in that neonatal meningitis is commonly present in neonates without bacteremia and with normal CSF findings.^[53]

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.

Herpes simplex virus (HSV) PCR testing

No consensus has been reached regarding the inclusion of HSV PCR testing of CSF as part of a routine sepsis workup in the neonate. Practice in this area is variable, with some centers reserving HSV PCR for infants with CSF abnormalities or for infants with clinical symptoms but who have negative cultures and do not respond to antibiotics.^[54] However, vesicles are not present in as many as one third of cases of CNS HSV and disseminated HSV. Further research in this area is needed to provide clear practice recommendations.

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Imaging Studies

Chest radiography

Chest radiography of infants with concomitant congenital pneumonia may reveal segmental or lobar infiltrate, but it more commonly reveals a diffuse, fine, reticulogranular pattern, much like that seen in respiratory distress syndrome (RDS). Pleural effusions may also be observed.

Head computed tomography (CT) scanning or magnetic resonance imaging (MRI)

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 dilatation, multicystic encephalomalacia, and atrophy) may also be demonstrated on CT scan or MRI.

Head ultrasonography

Head ultrasonography in neonates with meningitis may reveal evidence of ventriculitis, abnormal parenchymal echogenicities, extracellular fluid, and chronic changes. Serial head ultrasonography can reveal the progression of complications.

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Approach Considerations

Historically, the treatment approach for suspected neonatal sepsis has included early aggressive initiation of antibiotics because of the neonate’s relative immunosuppression. 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 proven. Moreover, because the American Academy of Pediatrics (AAP),^{[22, 23]} the American College of Obstetricians and Gynecologists (ACOG),^[24] and the Centers for Disease Control and Prevention (CDC)^[25] all have recommended sepsis screening or treatment for various risk factors related to group B Streptococcus (GBS) infections, many asymptomatic neonates now undergo evaluation and are exposed to antibiotics.

This approach has been questioned in recent years as more evidence emerges on the deleterious impact of unnecessary antibiotic exposure, including interference with the establishment of breast feeding, alternations in gut microbiome, increased incidence of childhood obesity and development of antimicrobial resistance amongst others.^[26]  Furthermore, amongst very low birth weight infants who were initially treated with antibiotics but subsequently proved to have negative cultures, there was an increased risk of mortality and stage 3 retinopathy of prematurity.^[55]

A newer approach to this issue has used a multivariate predictive model which considers maternal GBS status, appropriateness of intrapartum GBS coverage, gestational age, duration of rupture of membranes, highest intrapartum maternal temperature, along with the neonate’s postpartum examination findings. This model, commonly referred to as the “Kaiser Sepsis Calculator” has allowed for a significant reduction in the use of empiric antibiotics (from 5.0% of all births before implementation to 2.8% of all births thereafter) and obtaining blood cultures (12.8% of all births before implementation to < 5% of all births thereafter), without an increase in the rate of morbidity or mortality or readmissions for early-onset sepsis.^{[34, 35]}

Use of this approach should be limited to term and late preterm infants of 34 weeks’ gestation or later. Use of the sepsis calculator should be implemented at an institutional level, taking into account local resources and the incidence of early-onset sepsis. A standardized approach will lead to improved risk identification as well as needed buy-in from important stakeholders, such as obstetricians, nursing staff, and other care team members.

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Medical Care

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, platelet countss, and coagulation profile 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.

Central line or peripherally inserted central catheter 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 as IV antibiotic therapy cannot adequately penetrate an abscess, and antibiotic treatment alone is often ineffective.

The infant may require transfer to a level III or IV 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, plasmapheresis, and the use of recombinant cytokines. However, no substantial clinical trials have shown these treatments to be  beneficial.

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Antibiotic Therapy

In the United States and Canada, the current approach to the treatment of early-onset neonatal sepsis includes the administration of combined intravenous (IV) aminoglycoside and expanded-spectrum penicillin antibiotic therapy. This regimen provides coverage for gram-positive organisms, especially group B Streptococcus (GBS), and gram-negative bacteria, such as E 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 hospitals.

Antimicrobial resistance is increasing in the general population worldwide, and infections are rising in neonatal units due to multidrug- and extensively multidrug-resistant bacteria, posing a significant treatment dilemma.^[56]  Reserving broad-spectrum therapy for high-risk infants and quickly de-escalating once culture results are available is one strategy for improving neonatal outcomes.^[57]

If an infection appears to be nosocomial, as is common in 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 or nafcillin 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 the rapid induction of antibiotic resistance in gram-negative organisms. Ceftriaxone displaces bilirubin from serum albumin and should be used with caution in infants with significant hyperbilirubinemia due to the risk of kernicterus or bilirubin encephalopathy. Selection of the most effective drug is based on resistance and sensitivities for the organism isolated from cultures. Studies linking early cefotaxime exposure to an increased risk of neonatal death support the practice of limiting cephalosporin use to case-specific, targeted circumstances, such as in infants with findings concerning for concomitant meningitis.^[58]

Zaidi et al compared the failure rates of three clinic-based antibiotic regimens in 0- to 59-day-old infants with possible serious bacterial infections in Karachi, Pakistan.^[59] 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, whereas ceftriaxone was more expensive and less effective than penicillin/gentamicin.^[59]

Aminoglycosides and vancomycin both have the potential to produce ototoxicity and nephrotoxicity and should therefore be used with caution. Monitor serum drug levels during treatment to minimize the risk of these complications. The drug dosage or interval may have to be adjusted to achieve therapeutic drug serum levels. Infants who received aminoglycosides should undergo audiology and renal function screening before discharge 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, 36-48 hours 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.

Although there remains concern that intrapartum maternal antibiotic administration may decrease the reliability of neonatal culture results, studies have failed to demonstrate a change in culture sensitivity or time to positive culture.^{[40, 60]}  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:

• Culture results
• Maternal and intrapartum risk factors
• CSF results
• Complete blood cell (CBC) count and differential
• C-reactive protein (CRP) trends
• Radiographs
• Clinical progress

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Additional Considerations for Meningitis

Infants with bacterial meningitis often require higher 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, such as cephalosporins, so that therapeutic drug concentrations can be achieved in the cerebrospinal fluid (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 adequately treat the meningitis. 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.  Consultation with an infectious disease specialist can be helpful in such situations.

Meningitis complicated by seizures or persistent positive cultures may require extended intravenous antimicrobial therapy. Chloramphenicol or trimethoprim-sulfamethoxazole has been shown to be effective in the treatment of highly resistant bacterial meningitis. Note that trimethoprim-sulfamethoxazole should not be used if hyperbilirubinemia and kernicterus are of concern in the newborn.

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Investigational Therapies

Additional therapies that have been investigated for the treatment of neonatal sepsis include the following:

• Granulocyte transfusion
• Intravenous (IV) immunoglobulin (Ig) infusion
• Exchange transfusion
• Recombinant cytokine administration

Granulocyte transfusion

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.

IVIg infusion

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:

• The effect has been transient.
• Clinically available IVIg solutions do not contain type-specific antibody.
• The adverse effects associated with the infusion of any blood product can occur.

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.^[61]

Recombinant human cytokine administration

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 group B Streptococcus (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.

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Prevention

The American College of Obstetrics and Gynecology (ACOG)^[32] and the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP)^[23] recommends that obstetric care include a strategy for managing early-onset group B streptoccocal (GBS) disease. Women with GBS bacteriuria should be treated during pregnancy when the condition is diagnosed and during the intrapartum period. It is also recommended that women who have previously given birth to an infant with invasive GBS disease receive antibiotic prophylaxis during labor and delivery.

Universal screening for GBS during pregnancy is now ubiquitous in the United States. The Centers for Disease Control and Prevention (CDC) created guidelines for the use of intrapartum antibiotic prophylaxis to prevent GBS infection in 1996,^[62] which were subsequently updated in 2002, and 2010.^{[3, 25]}

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.^{[2, 3, 4]} Recommendations have been formulated for antibiotic prophylaxis regimens. See the images below.

View Image

Neonatal sepsis. Indications and nonindications for intrapartum antibiotic prophylaxis to prevent early-onset group B streptococcal (GBS) disease. Tab....

View Image

Neonatal sepsis. Recommended regimens for intrapartum antibiotic prophylaxis for prevention of early-onset group B streptococcal (GBS) disease. Diagra....

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Consultations

An infectious disease consultation may be useful, especially if the infant is not responding to treatment, is infected with an unusual organism, or has had a complicated clinical course such as concomitant meningitis. In such cases, neurology consult may also be helpful in the presence of seizures, and to ensure outpatient follow-up of neurologic sequelae.

Consultation with a pharmacist 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.

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Long-Term Monitoring

The primary care provider (PCP) should evaluate the infant with a history of neonatal sepsis within 1 week of discharge from the hospital. The infant can be assessed for superinfection and bacterial colonization associated with antibiotic therapy, especially if the therapy was prolonged. The PCP should evaluate the infant's growth and determine whether the feeding regimen and activity have returned to normal.

The Joint Commission on Infant Hearing of the American Academy of Pediatrics (AAP)^[63]  and the American Academy of Audiology^[64]  recommends that infants who received aminoglycosides should receive follow-up audiology testing, in addition to audiology screening before hospital discharge. Screen these infants between 3 and 6 months of 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 his/her neurodevelopment. If problems are found, the child should receive appropriate early intervention services and therapies.

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Medication Summary

The antibiotics commonly used to treat neonatal sepsis include ampicillin, gentamicin, cefotaxime, vancomycin, erythromycin, and piperacillin. The choice of antibiotic agents should be based on the specific organisms associated with sepsis, the sensitivities of the pathogen, and the prevailing nosocomial infection trends in the nursery. Viral infections, such as herpes and fungal infections, can masquerade as bacterial infections.

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Ampicillin

• Dosing, Interactions, etc.

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.

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Gentamicin

• Dosing, Interactions, etc.

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.

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Cefotaxime (Claforan)

Clinical Context:  Cefotaxime is a third-generation cephalosporin with excellent in vitro activity against GBS and E coli and other gram-negative enteric bacilli. Therapeutic 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.

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Vancomycin

• Dosing, Interactions, etc.

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.

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Chloramphenicol

• Dosing, Interactions, etc.

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.

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Oxacillin

• Dosing, Interactions, etc.

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.

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Piperacillin

• Dosing, Interactions, etc.

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. It is most often given in combination with the beta-lactamase inhibitor tazobactam.

• References

Erythromycin base (Erythrocin, Ery-Tab, EryPed, E.E.S.)

• Dosing, Interactions, etc.

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.

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Trimethoprim/sulfamethoxazole (Bactrim DS, Septra DS)

• Dosing, Interactions, etc.

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.

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Class Summary

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).

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Acyclovir (Zovirax)

• Dosing, Interactions, etc.

Clinical Context:  Acyclovir is used for treatment of mucosal, cutaneous, and systemic HSV-1 and HSV-2 infections.

• References

Zidovudine (Retrovir)

• Dosing, Interactions, etc.

Clinical Context:  Zidovudine is a thymidine analogue that inhibits viral replication. It is used to treat patients with HIV infection.

• References

Class Summary

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.

• References

Fluconazole (Diflucan)

• Dosing, Interactions, etc.

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.

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Amphotericin B (AmBisome)

• Dosing, Interactions, etc.

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.

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Class Summary

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.

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