Bacterial Infections in the Neonate

Description of Pathogens

Neonatal sepsis accounts globally for approximately 3 million cases annually with a mortality of between 11% and 19%. These figures are derived from several high-income and a few low-income countries, thus, the true impact is significantly higher. The mortality rate in resource-rich countries also is substantial, estimated at 5%–10%. Neonatal sepsis is characterized by systemic signs and bloodstream infections (BSIs) occurring in the first month of life. The survival of very low birth weight (VLBW; <1500 g) and extremely low birth weight (ELBW; <1000 g) infants in the US and other resource-rich countries has expanded use of the term, neonate, to infants requiring prolonged hospitalization for complications of prematurity.

Over past decades, the incidence of early-onset sepsis has declined in resource-rich countries, and that of later-onset sepsis either increased or remained the same. The incidence of early-onset group B streptococcal (GBS) infection has declined by 85% to about 0.25 cases per 1000 live births, in association with maternal intrapartum antibiotic prophylaxis. The predominant pathogens causing early-onset (age 0–6 days) bacterial infections continue to be GBS and Escherichia coli, which together account for approximately 70% of infections ( Table 92.1 ). ^{, ,} Most infants with early-onset sepsis due to GBS are term (∼60%), and most with E. coli are preterm (∼70%). The remaining early-onset infections are caused by other streptococci, including viridans streptococci and Enterococcus; Haemophilus species; enteric gram-negative bacilli; and Listeria monocytogenes or other maternal genital flora. Maternal vaginal colonization with methicillin-susceptible Staphylococcus aureus (MSSA) or methicillin-resistant S. aureus (MRSA), although uncommon, poses potential for vertical transmission and resultant neonatal infection.

In late preterm infants (34–36 weeks’ gestation), gram-positive organisms are the main causes of early-onset sepsis, but among VLBW infants, the relative importance of E. coli has increased. ^, More than half of early-onset infections in preterm infants at Centers of the National Institute for Child Health and Human Development Neonatal Research Network (NICHD NRN) were caused by gram-negative enteric organisms, especially E. coli . Escherichia coli disease occurred primarily among preterm VLBW infants. Approximately 67% of E. coli isolates causing early-onset sepsis were ampicillin-resistant. Each of the bacteria causing early-onset sepsis can cause late-onset disease ( Table 92.1 ).

The predominant organism among VLBW neonates is coagulase-negative staphylococci (CoNS), which can occur in association with a medical device (e.g., intravascular catheter), result from a gastrointestinal disorder (e.g., necrotizing enterocolitis), or occur de novo. Among VLBW infants, later-onset infections are caused predominantly by gram-positive organisms (70%). True infection, based on isolation of CoNS from two or more blood cultures or one blood culture and a sterile site, is unlikely in infants with birth weight exceeding 2000 g or gestation exceeding 34 weeks. Infection rates due to CoNS can be reduced with implementation of infection-prevention initiatives.

Gram-negative enteric bacilli, such as Enterobacter and Klebsiella spp., and nosocomial gram-negative pathogens, such as Pseudomonas aeruginosa and Serratia marcescens, also are encountered. Streptococcus pneumoniae and Haemophilus influenzae are uncommon causal organisms. Infants with late-onset sepsis due to S. pneumoniae are usually at term and have infection at 3 weeks of life or later.

S. aureus is the cause of healthcare-associated infection, accounting for 8% of late-onset infections in the NICHD NRN. The incidence of late-onset MRSA infections increased by >300% among all birth categories between 1995 and 2004 according to data reported by the National Nosocomial Infections Surveillance (NNIS) system but the prevalence of this organism diminished after 2010. MRSA emerged as a cause of late-onset sepsis in neonates hospitalized in the neonatal intensive care unit (NICU) since birth. Although the mortality rate is high among VLBW infants with invasive staphylococcal infections, BSIs due to MRSA and MSSA have equivalent morbidity and mortality rates. Enterococci and Candida must be considered in infections that arise from the intestine or with use of intravascular devices.

Anaerobes and several unusual bacteria have caused infections in neonates. Any bacterial isolate from blood or a normally sterile body site of a clinically ill neonate should be considered a true pathogen unless there is sufficient evidence to conclude that it is a contaminant.

Epidemiology

Systemic bacterial infections affect approximately 1 per 1000 liveborn neonates, with incidence inversely related to gestation. Characterized by age at onset, infections are called early or late ( Table 92.2 ). The age at onset for early-onset bacterial infection is defined as 72 hours or less, usually with reference to neonates hospitalized in an intensive care unit compared with <7 days, often with reference to illness in term infants. The burden of early-onset sepsis in the US is about 3300 cases annually; preterm and Black infants are disproportionately afflicted.

Most infants with early-onset infection are ill at or within 36–48 hours of birth (see Chapter 90 ). Maternal obstetric complications are common and the source of pathogens is the maternal genital tract. The typical clinical presentation is respiratory distress or non-specific signs, often indistinguishable from non-infectious disorders, but without evidence of focal infection other than pneumonia. Among VLBW infants, early-onset sepsis does not increase the risk for late-onset sepsis.

For infants with late-onset infection, maternal obstetric complications other than preterm delivery are uncommon. The incidence of infection is similar for singleton and multiple birth infants. The source can be the maternal genital tract, the hospital environment if duration of hospitalization exceeds a few days, or the community. The usual clinical presentation is one of nonspecific signs but focal manifestations, such as skin or soft tissue infection, or meningitis are more frequent than with early-onset infection.

The survival of VLBW or ELBW neonates has prompted the use of a third category: late or very late onset. Although these infants are strictly speaking no longer neonates, their median gestational age of <28 weeks at birth and their recurrent hospitalizations for postnatal complications accord them an extended interval as “newborns” on the basis of postmenstrual age and immune competence. These infants often have devices (catheters) that can lead to infection by commensal species such as CoNS. The mortality rate ranges from 5% to 60%, depending on the infectious agent.

Pathogenesis

Infants who experience early-onset sepsis, especially preterm infants, often have one or more risk factors associated with their mother’s labor and delivery ( Table 92.3 ). Although term infants with early-onset sepsis can have associated maternal intrapartum complications, 50%–70% of those with early-onset GBS sepsis have no identifiable maternal factors. Maternal factors enhancing risk for early-onset sepsis include preterm delivery, premature rupture of membranes (rupture of membranes before onset of labor at any gestation), prolonged rupture of membranes (≥18 hours), chorioamnionitis (intraamniotic infection), GBS bacteriuria during pregnancy, early postpartum febrile conditions (including maternal bacteremia, endometritis, and caesarian wound infection), and complications of delivery causing or associated with fetal hypoxia.

The pathogenesis of neonatal septicemia is multifactorial and encompasses microbial, host, metabolic, and environmental factors. Infants with exposure to a high maternal genital inoculum (≥10 ⁵ colony-forming units/mL) of GBS, for example, are at a greater risk for septicemia than those exposed to a maternal carrier who has low-density colonization. Compared with term infants, premature neonates are at increased risk of septicemia because of passive acquisition of lower levels of maternally derived total immunoglobulin G (IgG) and specific antibodies to bacterial pathogens. Immature function of neutrophils, decreased neutrophil storage pools, decreased expression of lectin family proteins and immature immune responses to pulmonary invasion and bacteremia each enhance neonatal susceptibility to invasive infection. In addition, intestinal dysbiosis marked by a decelerated phylogenetic diversity with overrepresentation of aerobic bacteria and lack of anaerobic bacterial populations has been noted in preterm infants who develop late-onset sepsis when compared to those who remain well. Damage to the intestinal barrier by fermentation products as ethanol and formic acid by aerobic bacteria is proposed as a mechanism by which translocation of luminal contents may occur.

Metabolic factors such as hypoxia, acidosis, and hyperbilirubinemia further compromise host response. Interruption of mucosal or skin barriers by endotracheal or nasogastric tubes, intravascular access devices, blood sampling, and monitoring equipment promote bacterial invasion, particularly for late or late-onset infection. Prior therapy with broad-spectrum antimicrobial agents increases the likelihood that bacteria resistant to routinely employed antimicrobial regimens will cause late-onset infection.

Clinical Manifestations