Beatriz Larru, MD, PhD and Theoklis E. Zaoutis, MD, MSCE

Developmental Immunology

Except in the case of congenital infection, all pathogen encounters in the neonatal period are first-time encounters. For those first-time exposures to pathogens, neonates are dependent on the innate immune system. The innate immune system comprises cells and mechanisms that defend in a nonspecific manner. T- and B-cell responses are part of the specific (adaptive) immune system. The adaptive immune response allows the immune system to remember specific pathogens. ¹²³

There are two types of effector CD4⁺ helper cells: T_h1 and T_h2. Each of these is responsible for eliminating a specific kind of pathogen. The T_h1 response leads to cell-mediated immunity (important defense against viruses and intracellular pathogens.) T_h1 responses are considered proinflammatory. T_h2 responses activate B cells to make antibodies, leading to humoral immunity (important defense against extracellular bacteria, parasites, and toxins). T_h2 responses are antiinflammatory. T_h2 inflammatory responses are favored in the fetus, dampening the fetal immune response and preventing alloimmune reactions between mother and fetus (e.g., miscarriage). Decreased production of T_h1 cytokines increases the susceptibility to infection and contributes to the poor response to vaccines. ⁴

The nonspecific innate immune system includes host defense mechanisms that operate effectively without prior exposure. It includes the following:

The vernix caseosa is a waxy coating in newborns that is secreted by fetal sebaceous glands. It contains antimicrobial peptides that act as a microbicidal shield. The lipids and acid pH of the neonatal skin inhibit microbial growth and reach maturity by week 2 to 4 in term neonates (later in premature infants). Small breaks in the integrity of the skin can serve as entry points for infection. ⁶⁷⁸

Complement components are synthesized as early as 6 to 14 weeks of gestation. However, neonatal plasma concentrations of complement components are diminished, ranging from 10% to 70% of adult levels. A relative deficiency in complement might contribute to the inability of newborns to limit the replication of many bacterial strains in the blood because opsonization is impaired; these differences are greater in preterm than in term neonates.

Overall activity and components of the alternative pathway are more consistently decreased than those of the classical pathway. This finding is especially problematic for neonates who are exposed to organisms with polysaccharide capsules, such as Escherichia coli K1 and group B Streptococcus (GBS) and who cannot rely on classical pathway activation owing to the lack of specific antibodies. ⁹

CRP is a soluble protein that facilitates clearance of infected cells and microorganisms by phagocytes. It is produced by the liver and is part of the acute-phase response. It does not cross the placenta. Neonates can produce CRP, and levels reach concentration similar to that of adults in the first days of life in term neonates.

The pluripotent hematopoietic stem cells are generated from embryonic para-aortic tissue, fetal liver (by 4 weeks’ gestation) and bone marrow (by 11 weeks’ gestation). The yolk site is a major site of production of erythrocytes and phagocytes (by 3 weeks’ gestation). Liver hematopoiesis ceases by week 20 and continues only in bone marrow. All major lineages of the hematopoietic cells that are part of the immune system are present in the fetus by the beginning of the second trimester ( Fig. 13-1). ¹⁰¹¹

Circulating monocytes first appear in the fetal blood at 18 to 20 weeks’ gestation; by week 30 they increase to 3% to 7% of the circulating formed blood cells. By birth values exceed 500/mm³, which is higher than in most adults. Monocytes undergo tissue-specific differentation into mononuclear macrophages, which utilize a respiratory burst (biosynthesis of O₂^– and H₂O₂) to kill organisms.

The microbicidal activity of macrophages can be regulated by cytokines (interferon gamma [IFN-gamma], granulocyte-macrophage colony-stimulating factor [GM-CSF], and tumor necrosis factor alpha [TNF-alpha]). The ability of mononuclear phagocytes to generate reactive oxygen intermediates is normal in neonates. However, IFN-gamma production and response to exogenous IFN-gamma are diminished in newborns. ¹²

T-cell precursors differentiate into immunocompetent T cells within the thymus. Before entering the thymus, stem cells lack antigen receptors and do not express CD3, CD4, or CD8 on their surface. Prothymocytes do not initially express CD4 or CD8 (double negatives); however, during the process of differentialtion they express both CD4 and CD8 (double positives) and then proceed to express either CD4 or CD8. A double-positive cell will differentiate into a CD4-positive one if it comes into contact with a cell bearing class II major histocompatibility complex (MHC) proteins but will differentiate into a CD8-positive cell if it comes into contact with a cell bearing class I MHC proteins.

The double-negative and double-positive cells are located in the cortex of the thymus, whereas the single-positive cells are located in the medulla, from which they migrate out of the thymus into the blood. The thymic education of T cells includes negative selection; self-reactive cells are removed to prevent autoimmune reactions and positive selection; CD4-positive and CD8-positive cells bearing antigen receptors that do not react with self MHC proteins are eliminated.

In healthy neonates the number of eosinophils increases postnatally, reaching a maximum at 3 to 4 weeks, when it represents a larger percentage (10% to 20%) of total granulocytes than in adults. This physiologic eosinophilia does not suggest the presence of allergic diseases or helminthic infections as strongly as they do in adults and is not associated with increased amounts of circulating immunoglobulin (Ig) E. ¹³

By week 12 of gestation, lymphocytes obtained from the human thymus respond to mitogens and foreign histocompatibility antigens. Furthermore, fetal cells stimulated with alloantigens exhibit normal antigen-specific cytotoxicity. In contrast, the phenotypic appearance and proportion of circulating cells are diminished, and the production of some cytokines such as interleukin (IL)-12 is reduced in neonates. The most significant defect appears to be a deficiency of memory T cells, which may be responsible for the deficient production of IFN-gamma in the neonate. The mother does not transfer T-cell–specific immunity to the fetus. ¹⁴

Immature polymorphonuclear neuthrophils (PMNs) (metamyelocytes and band forms) and mature bone marrow PMNs constitute a reserve pool of cells that may be rapidly mobilized into the circulation in response to inflammation. The rate of proliferation of neuthrophil precursors in the human neonate seems to be near maximal, and therefore their capacity to increase numbers in response to infection might be limited. As a result, rather than develop neutrophilia, as might occur in the septic adult, the neonate will rapidly develop neutropenia as a result of exhaustion or depletion of the storage pools. ¹⁵

Circulating PMNs increase dramatically after birth, peak at 12 to 24 hours, and then decline slowly by 72 hours in a neonate without complications. The fraction of immature forms remains constant at about 15%. A limited ability to accelerate neutrophil production in response to infection and impaired migration of PMNs to areas of microbial invasion in tissues contribute to the higher risk of developing overwhelming sepsis in neonates (especially premature infants). However, phagocytosis and microbial killing by PMNs seem not to be greatly impaired unless the neonates are critically ill. ¹⁶

The IgG content of the fetus and the newborn infant is mainly maternal in origin and is predominantly transferred during the latter third of pregnancy. Levels of all classes of IgG fall rapidly after birth, and the respective concentrations derived from maternal placental transfer and active production by the young infant are approximately equal by 2 months’ postnatal age. By 10 to 12 months of age, catabolism of passively acquired IgG is complete, and the infant produces all the circulating IgG ( Fig. 13-2).

In humans the antigens can be divided into three groups depending on the nature of the immune response: (1) thymus-dependent (TD) antigens, which include most protein antigens; (2) thymus-independent type 1 (TI-1) antigens, which bind directly to B lymphocytes and do not require T cells for antibody production; and (3) thymus-independent type 2 (TI-2) antigens, which are mostly polysaccharides composed of multiple identical subunits and require small numbers of T lymphocytes for antibody production to occur. The response to TI-2 antigens appears last chronologically at approximately 6 months of age, accounting for the poor neonatal response to polysaccharide vaccines and to the higher risk of infection with encapsulated organisms such as GBS. ¹⁷

The defenses against viral infections involve numerous mechanisms, including antibody neutralization of extracellular virus, direct cytolysis of infected cells by natural killer (NK) cells, antibody-dependent cellular cytotoxicity and specific cell-mediated cytotoxicity through T lymphocytes. Neonates have deficits in virtually all of these components. Infants infected with herpes simplex virus (HSV) at the time of delivery depend on the presence of passively acquired maternal antibodies, which are low in mothers with primary infection. This is the scenario in which the most severe neonatal infection occurs.

NK cells appear early in gestation and reach normal numbers by mid to late gestation; however, they are largely immature in phenotype, consisting of 50% CD56-negative cells. These cells are deficient in their ability to kill virus-infected cells and to produce critical cytokines such as IFN-gamma. Furthermore, virus-specific T-cell–mediated immunity is also diminished or delayed in the neonates with decreased T-cell killing and production of IFN-gamma. Consequently, infection with HSV in the neonate can result in a rapidly progressive, fulminant, and often fatal infection. ¹⁸

An unusually severe course of infection or an unusual pathogen, recurrent pyogenic infections, and recurrent upper and lower respiratory tract infections might be caused by immunodeficiency resulting from a congenital neutropenia or dysfunctional neutrophils. A summary of the most important diseases is shown in Table 13-1. ¹⁹

Neonatal Sepsis Epidemiology

Early-onset sepsis begins at 3 days of age (or even sooner) when organisms ascend from the birth canal after overt or occult rupture of membranes. Early-onset sepsis usually manifests as fulminant systemic illness and is associated with mortality rates of 3% to 50% (highest in premature infants). Infection with gram-negative pathogens and low-birth-weight infants are at higher risk of mortality. ²⁰²¹

Since consensus guidelines were developed in 1996 and subsequently revised in 2002 and 2010, the incidence of early-onset Streptococcus agalactiae (GBS) infections has declined from 1.7 in 1000 live births to 0.28 in 1000 live births, a 70% reduction in the incidence of early-onset GBS sepsis. During the same period, however, intrapartum antibiotic administration has been associated with an increased incidence of drug-resistant neonatal sepsis, particularly ampicillin-resistant gram-negative disease in very-low-birth-weight (VLBW) infants (<1500 g) ( Fig. 13-3). Whether the increase in gram-negative sepsis is due to intrapartum antibiotic prophylaxis remains controversial. ²²²³

Among VLBW infants the incidence of early-onset sepsis increases with decreasing gestational age (15 cases in 1000 live births for preterm versus 2.5 cases in 1000 live births for term infants). Compared with data derived before the inception of guidelines for the prevention of GBS disease, there has been a significant reduction in early-onset GBS disease, from 5.9 to 1.7 cases per 1000 live births, with a concomitant increase in E. coli sepsis from 3.2 to 6.8 per 1000 live births. Approximately 85% of the E. coli isolates have been resistant to ampicillin. When the years 1991 through 1993 were compared with 1998 through 2000, there was also an increase in the incidence of early-onset fungal disease, from 0.1 to 0.4 per 1000 live births. ²⁴²⁵

Low parity, spontaneous labor, longer length of labor and membrane rupture, multiple digital examinations, meconium-stained fluid, internal fetal or uterine monitoring, and presence of genital tract infections. The incidence of chorioamnionitis is inversely related with gestational age. ²⁶

The major risk factors for early-onset neonatal sepsis are preterm birth (the factor most closely associated with early-onset neonatal sepsis), maternal colonization with GBS, prolonged rupture of membranes (>18 hours before labor), and maternal signs or symptoms of chorioamnionitis. Other variables include ethnicity (e.g., African-American women have higher rates of colonization with GBS), low socioeconomic status, male sex, and low Apgar scores. Infant birth weight is inversely related to risk of early-onset sepsis ( Table 13-2).

The presence of any of these factors alone is not an indication for a complete sepsis work-up and antibiotic therapy; however, combinations of risk factors are clearly cumulative and should give rise to the suspicion of sepsis. ²⁷

As a general rule, presence of a major risk factor (e.g., premature rupture of fetal membranes or maternal GBS colonization) leads to an attack rate of about 1% for proven sepsis or 2% for proven or highly suspected sepsis. If a second risk factor is present, the attack rate rises to 4% to 6% for proven and 10% for proven or highly suspected sepsis. Further risk factors are additive; the presence of three risk factors raises the sepsis risk 25-fold over baseline.

The pathogenesis of early-onset sepsis has changed over the last decades as intrapartum antibiotic prophylaxis protocols have become widely used. GBS and gram-negative enteric bacilli, predominantly E. coli, are the most common pathogens for early-onset disease. In preterm infants who weigh less than 1500 grams, E. coli is more common than GBS. Coagulase-negative staphylococci (CoNS); Staphylococcus aureus; Enterococcus, Klebsiella, and Enterobacter species; Pseudomonas aeruginosa; and fungi (especially Candida albicans) are the major pathogens for late-onset diseases (onset after 72 hours). ²⁸²⁹³⁰

CoNS have increased as pathogens in the NICU as the survival of extremely-low-birth-weight infants (<1000 grams) has improved. CoNS bacteremia is associated with indwelling vascular lines. CoNS produce a biofilm that facilitates adherence to the catheter and protects them from antibiotic and host immune responses. ³¹

Clinical manifestations of GBS late-onset neonatal sepsis are more insidious, and meningitis is frequently part of the clinical picture. Late-onset disease is associated with GBS serotype III and has a lower mortality rate than early sepsis. With increase survival of extremely-low-birth-weight neonates, very-late-onset disease (>98 days) has also been described ( Table 13-3).

See Table 13-4.

Diagnosis of Neonatal Sepsis

The most sensitive criteria for the clinical diagnosis of chorioamnionitis is maternal fever higher than 38° C (100.4° F). The presence of two or more of the following criteria also supports the diagnosis; maternal leukocytosis (>15000 cells/mm³), maternal tachycardia (> 100 bpm), fetal tachycardia (>160 bpm), uterine tenderness, and foul odor of the amniotic fluid. If maternal fever and two or more of the criteria are present, there is a significant sepsis risk for the neonate, with reported attack rates ranging from 6% to 20%. This issue is further confounded by the use of epidural anesthesia, which is associated with a fourfold increased incidence of maternal fever without increasing the neonatal sepsis rate. ³³

The clinical diagnosis of sepsis in the neonate is difficult because many of the signs are nonspecific. They include fever, respiratory distress, jaundice, lethargy, irritability, anorexia or vomiting, hypotonia, “not looking well,” abdominal distention, hypothermia, hypoglycemia, apnea, seizures, shock, petechiae, and purpura. There is considerable overlap with noninfectious conditions, and some infants may exhibit transiently abnormal clinical signs during the transition to postnatal life.

The temperature of a neonate with sepsis might be elevated; depressed; or, as is frequently observed, within normal limits. Term infants are more likely to have fever than premature infants, whereas the latter are more prone to exhibit hypothermia. Fever is generally considered as a rectal temperature higher than 38° C (100.4° F). Fever can also be due to many other noninfectious causes, such as elevation in ambient temperature.

Diagnostic testing can assist with the decision to discontinue treatment. Isolation of the microorganism from a sterile site, such as blood or cerebrospinal fluid (CSF) remains the most valid method of diagnosis of bacterial sepsis. ³⁴³⁵

Body surface cultures have very limited sensitivity, specificity, and predictive value and do not establish invasive systemic infection. They reveal only colonization and are poorly correlated with pathogens isolated from blood.

In studies of neonates who died, the postmortem diagnosis of sepsis was confirmed by antemortem blood cultures in only 80% of cases. The current extensive use of maternal antibiotics further confounds the reliability of the newborn blood culture. ³⁶

A minimum of 1 mL of blood should be drawn to establish the diagnosis of bacteremia when a single pediatric blood culture bottle is used. Dividing the specimen in half and inoculating the aerobic and anaerobic bottles is likely to reduce sensitivity (0.5 mL of blood will not reliably detect 4 colony-forming units/mL) and is not recommended.

In early-onset sepsis, positive urine cultures are attributable to seeding of the kidneys during an episode of bacteremia unlike the urinary tract infections (UTIs) in older infants, which are usually ascending infections. Therefore urine cultures yield very limited information about the source of infection in early sepsis and should not be part of the sepsis work-up. However, suprapubic aspiration or bladder catheterization should be performed in all infants in whom late-onset sepsis is suspected. ³⁷³⁸³⁹

The decision to perform a lumbar puncture in neonates with suspected early-onset sepsis remains controversial. Infants with clinical signs that can be attributed to noninfectious conditions such as respiratory distress syndrome have a very low likelihood of meningitis. However, up to 23% of infants with bacteremia have concomitant meningitis and often have no clinical signs directly referable to the central nervous system (CNS). Furthermore, up to 38% of infants with meningitis have a negative blood culture. Therefore the presence of a positive blood culture cannot serve as indication to do a lumbar puncture.

Because neonatal meningitis is a low-incidence disease (0.25 in 1000 live births), an informal meta-analysis of published reports showed that it would be necessary to do at least 1000 lumbar punctures to diagnose one case that would be missed by lack of symptoms or a negative blood culture result. A rational approach would be to perform a lumbar puncture in infants with positive blood cultures, those who deteriorate with antimicrobial treatment, and those whose clinical or laboratory data strongly suggest bacterial sepsis if they do not have any contraindication for the procedure.

The cell content and chemistry of neonatal CSF differs from those of older infants. The cell content of CSF particularly in the first week is higher, and polymorphonuclear leukocytes are often present in CSF of normal newborns. In a recent study the upper reference limit of the CSF white blood cell (WBC) count was 12 cells/mm³ in preterm infants and 14 cells/mm³ in term infants. Most well infants will have cell counts lower than 10 cells/mm³. Adjusting the cell count for the number of red cells does not improve its diagnostic utility. Preterm infants have protein concentrations that are inversely correlated with their gestational age. Uninfected term newborns have protein concentrations in the CSF lower than 100 mg/dL, with a physiologic decline with postnatal age reaching values of healthy older infants before the third month of life. CSF glucose concentrations in normoglycemic uninfected neonates are similar to those of older infants (70% to 80% of a simultaneous peripheral blood glucose). Meningitis can occur in neonates with completely normal CSF values. ⁴⁰

Elevated WBC counts or abnormal neutrophil indices (low absolute neutrophil counts [neutropenia], elevated band counts, and high immature-to-total neutrophil [I/T] ratios) have a poor positive predictive value for the diagnosis of early-onset sepsis. They are useful for excluding infants without infections rather than identifying infected ones. Neutropenia is the index with the best specificity. The definition of neutropenia changes with age, type of delivery, site of sampling, and altitude; peak values are reached 6 to 8 hours after delivery. A recent study suggested that the lower limits of normal WBCs at that time should be 7500/mm³ for infants born at more than 36 weeks’ gestation, 3500/mm³ for those between 28 and 36 weeks’ gestation, and 1500/mm³ for less than 28 weeks’ gestation.

The sensitivity of CRP at birth is low because it requires an inflammatory response to increase (with the release of IL-6). Its sensitivity improves dramatically if the determination is made 6 to 12 hours later. Two normal CRP determinations (8 to 24 hours after birth and 24 hours later) have a negative predictive accuracy of 99.7% for proven neonatal sepsis.

A number of inflammatory mediators have been investigated as possible diagnostic tests for neonatal sepsis. IL-6, IL-8, and IL-10 have been found to have a critical role in the inflammatory response during neonatal sepsis; however, none of these mediators has sufficient sensitivity or specificity for the diagnosis of infection in this population. These mediators are currently not available for routine clinical purposes. ⁴¹

Antibiotic Treatment

Once sepsis is suspected in a neonate, antimicrobial treatment should be promptly begun after cultures have been obtained, even when there are no obvious risk factors for sepsis. Because GBS and E. coli are the most common pathogens of early-onset sepsis in the United States, a synergistic combination of ampicillin and an aminoglycoside (usually gentamicin) is suitable for the initial treatment of early-onset sepsis. Ampicillin is the antimicrobial of choice for treatment of GBS, Listeria monocytogenes, and most enterococci. Once the pathogen is identified, antimicrobial therapy should be narrowed (unless synergism is needed). ⁴²

Third-generation cephalosporins such as cefotaxime are associated with rapid development of drug-resistant bacteria in nurseries, and extensive use has been reported to be a risk factor for invasive candidiasis. Furthermore, the third-generation cephalosporins are not active against Listeria and Enterococcus species. Because of its excellent CSF penetration, the use of cefotaxime should be restricted for infants with meningitis attributable to gram-negative organisms. ⁴³

Ceftriaxone can displace bilirubin from albumin and may increase the risk of kernicterus in a jaundiced infant.

Stopping treatment for bacteremia without an identifiable focus of infection remains controversial, and the final decision requires consideration of antibiotic use during labor and the infant’s clinical course. Three recent observational studies have demonstrated an association between antibiotic use for longer than 5 days in infants with suspected early-onset sepsis (and negative blood cultures) with death and necrotizing enterocolitis. Therefore in a well-appearing infant antibiotics should not be continued for more than 48 hours (72 hours in certain cases).

A recent double-blind control trial of adjunctive therapy with intravenous Ig showed no effect on the outcomes (death and major disability at 2 years) of suspected or proven neonatal sepsis. ⁴⁴

Because Staphylococcus epidermidis is the most common cause of nosocomial sepsis in neonates, empiric therapy should include vancomycin. This antibiotic is generally paired with an aminoglycoside antibiotic to cover gram-negative organisms.

See Table 13-5.

Some studies have shown a higher risk for contracting ascending intrauterine infection in the first twin born, but this risk is modified by delivery mode and other obstetric variables. More intriguing is the observation of simultaneous occurrence of late-onset sepsis among twins, which warrants close observation and consideration of cultures in the asymptomatic twin.

Neonatal Meningitis

See Table 13-6.

A regimen of ampicillin and cefotaxime is recommended for initial empiric therapy. Treatment should be modified according to microbiology results. Meropenem or ceftazidime should be reserved for infections caused by resistant microorganisms.

Two viral infections must be considered. The first is disseminated HSV with CNS involvement. One helpful diagnostic clue is the development of skin vesicles, which can also be used as a source from which to isolate virus for diagnosis. However, about 20% of infants with this form of HSV never develop skin vesicles. Other sources for detection of the virus include respiratory secretions, blood, and CSF. If infection with HSV is strongly suspected, therapy with acyclovir should begin while viral polymerase chain reaction (PCR) and cultures remain pending. The other viral infections associated with a severe neonatal sepsis syndrome are enteroviral infections (especially Coxsackievirus).

Group B Streptococcal (GBS) Infections

Between 10% and 30% of women are colonized with GBS in their birth canal. Chronic, intermittent, or transient patterns of GBS colonization have been described. Pregnant woman with GBS colonization are 25 times more likely to deliver an infant with early-onset GBS sepsis than women whose cultures are negative (though infants with early-onset GBS have been born to women with negative antenatal cultures). Affected infants became infected during labor and delivery. In the absence of intrapartum prophylaxis, 2% of infants will develop early-onset GBS sepsis. ⁴⁶

Universal screening of all pregnant women at 35 to 37 weeks’ gestation has been recommended since 2002. Specimens should be obtained from the lower rectum and vagina and placed in a selective broth media. This enrichment step significantly increases the sensitivity of the test with at least a twofold greater yield of positive culture results than nonselective methods. On the other hand, standard laboratory methods for the isolation of GBS from blood and spinal fluid are fully adequate.

Nucleic acid amplification tests (NAATs), including PCR, for GBS can be used to screen women at term with no other risk factors but should not replace traditional antenatal cultures because they have lower sensitivity. Chromogenic media can facilitate the detection of beta-hemolytic GBS, but may not detect nonhemolytic strains. ⁴⁷⁴⁸⁴⁹

Ten serotypes have been identified on the basis of capsular polysaccharide antigens. Early studies of GBS disease in North America demonstrated a predominance of the type III serotype, thought also to be the most virulent serotype. Currently, type III accounts for approximately 70% of isolates from infants with meningitis and is isolated in almost two thirds of infants with late-onset diseases. Since the 1970s there has been a progressive change in the predominant serotypes, with type Ia now the leading cause of early-onset infection. Types VI, VII, VIII, and IX rarely cause human diseases in the United Kingdom or the United States, but worldwide its distribution varies (e.g., types VI and VIII are the most common isolates from healthy Japanese women). From an immunologic and public health perspective, the recognition of multiple new serotypes has confounded the efforts of investigators to develop an effective multivalent vaccine to prevent this disease in newborns. ⁵⁰

Penicillin (3 g [5 million units] intravenously followed by 1.5 to 1.8 g [2.5 to 3 million units] every 4 hours administered at least 4 hours before delivery) is the first-line agent for prevention of early onset GBS disease. Ampicillin is an effective alternative. Cefazolin (first-generation cephalosporin) is preferred for penicillin-allergic women at low risk for anaphylaxis. ⁵¹

The mother’s strain should be tested for sensitivity to clindamycin and inducible resistance (D-zone test) because 25% of GBS strains are resistant to clindamycin. If the test is not available, clindamycin should not be used. Erythromycin should also not be used for IAP. Vancomycin is the recommended drug for women with severe allergic reactions if the strain has not been tested for susceptibility to clindamycin. IAP with vancomycin is probably effective but is considered inadequate (in terms of neonatal management) because of the lack of efficacy data.

According to the American College of Obstetrics and Gynecology (ACOG) the following women should receive antibiotic prophylaxis:

Pros: IAP has resulted in a dramatic reduction in incidence of early-onset disease. Figure 13-4 illustrates the decline in incidence of early-onset GBS disease over the past decade as IAP programs were implemented. The graph is based on composite data from surveillance centers of the Centers for Disease Control and Prevention (CDC), a National Institute of Child Health and Development multicenter study reviewing disease rates from 1992 to 1997, and ongoing surveillance at the author’s center. The incidences of disease from 1990 to 1993 represent the pre-IAP era, whereas data from 1993 to 1996 followed the ACOG and American Academy of Pediatrics (AAP) recommendations published in 1993. The third data set reflects the impact of the CDC recommendations published in 1996.

Cons:

In 2010 the CDC published new guidelines for prevention of early-onset GBS sepsis ( http://www.cdc.gov/groupbstrep/guidelines/index.html). These are summarized in Figure 13-5.

A recent retrospective analysis revealed that women undergoing GBS screening at the time of labor were as likely to have false-negative cultures as those undergoing screening between 35 and 37 weeks’ gestation. This study claimed that the majority of false-negative screens result from inappropriate collection or processing of specimens. Another ongoing challenge is clinical adherence to current guidelines; missed opportunities for GBS prevention happen frequently, particularly among women delivering preterm infants.

Most infants who contract late-onset disease acquire the organism outside the hospital. Mothers of these infants may have no history of genital colonization with GBS during pregnancy. ⁵⁵

Staphylococcus Epidermidis

CoNS are commensal skin and mucosal flora. Nearly 99% of healthy neonates will have positive nose or umbilicus swabs for CoNS by day 4 of life. However, these organisms also account for up to one half of reported bloodstream infections in VLBW (<1500 g) infants. ⁵⁶

Improved survival rates of VLBW infants have resulted in an increased risk for sepsis because of the many invasive therapies required for management, such as central venous catheters. Central lines are associated with an increased risk of CoNS bacteremia. Colonization precedes infection with this species. Therefore CoNS infections present a particular dilemma because their isolation from a single blood culture in a neonate can either reflect contamination or true bacteremia. A suggested algorithm for interpreting blood cultures caused by CoNS is shown in Figure 13-6. ⁵⁷

Umbilical vessels and intravascular catheters are essential in the NICU, and results of blood cultures can yield ambiguous interpretations (e.g., contamination versus catheter colonization versus systemic infection). Some microbiological features can be useful assisting this decision, such as time to growth (the longer the time elapsed between obtaining the blood culture and its growth, the more likely it is it represents a contaminant), number of positive cultures (especially if obtained from different sources; peripheral and central), the organisms’ isolates (contamination is more likely when multiple specimens grow), and clinical signs. ⁵⁸⁵⁹

The initial recommended therapy is vancomycin, which may be modified once the isolate susceptibility is known. In cases of persistent bacteremia, a combination of vancomycin and rifampin may increase efficacy.

When an indwelling catheter must be left in place, antibiotic therapy should be administered through the catheter. Removal of the catheter may be necessary if the culture remains positive. The same applies for other medical devices, such as meningitis resulting from an infected ventriculoperitoneal shunt.

Because of concerns regarding the emergence of vancomycin-resistant organisms, routine use of prophylactic vancomycin for all neonates at risk of CoNS bacteremia is not currently recommended. ⁶¹⁶²

Candida

Approximately 1.4% of early-onset neonatal infections result from Candida species (mainly Candida albicans but increasingly from other species, such as Candida parapsilosis and Candida glabrata). For late-onset sepsis the incidence varies from 2.6% to 16.7% among VLBW infants and up to 20% for extremely-low-birth-weight infants. There is a marked inverse correlation between mortality caused by Candida species and neonatal weight; a recent analysis reported an all-cause mortality rate of 26% in infants weighing less than 1000 g with candidiasis compared with 13% in infants without candidiasis. ⁶⁶⁶⁷

Early-onset candidal disease, or congenital candidiasis, arises from exposure of the infant to organisms colonizing the maternal genital tract. Cutaneous findings are the hallmark of the disease, but the association with pulmonary disease conveys a poor prognosis despite systemic antifungal therapy. On the other hand, catheter-associated fungemia generally arises from organisms on the skin or within the gastrointestinal tract.

Candida infections acquired after the first week of life might be limited to the bloodstream, urine, or CSF or may disseminate to involve one or many organ systems. Fungal abscesses may be found in the heart, bones, kidneys, bladder, eyes, or brain. The medical literature concerning end-organ evaluation after neonatal candidemia is heterogeneous; however, a retrospective study suggested potential damage from the following sources: endophthalmitis (median, 3%), meningitis (15%), brain abscess or ventriculitis (4%), endocarditis (5%), positive renal ultrasound (5%), and positive urine culture (61%). ⁶⁸⁶⁹

The highest risk period for ICIs in preterm neonates occurs during the first 4 to 8 weeks of life. Several studies have shown that fluconazole prophylaxis can reduce those infections among preterm infants, with highest efficacy among VLBW infants and those weighing 750 g or less. The pros and cons of antifungal prophylaxis are summarized in Table 13-7. ⁷⁰