Late-Onset Sepsis

KEY POINTS

• 1.

  Late-onset sepsis in the neonatal intensive care unit is defined by culture-confirmed infection ≥72 hours after birth.

• 2.

  Incidence is highest among preterm infants.

• 3.

  The pathophysiology involves colonization with perinatally and/or hospital-acquired organisms, with transition to invasive infection promoted by hospital devices and immature mucosa.

• 4.

  Risk factors include prematurity, presence of a central venous catheter, prolonged parenteral nutrition, and lack of breast milk feeding.

• 5.

  The most common causative organisms are coagulase-negative Staphylococci and Staphlycoccus aureus.

• 6.

  Clinical manifestations are nonspecific and often difficult to distinguish from instability characteristic of prematurity.

• 7.

  Identification of a pathogenic organism by culture of a normally sterile bodily fluid, primarily blood or cerebrospinal fluid, is currently the gold standard for diagnosis.

• 8.

  The choice of empiric antimicrobial therapy should be based on local microbiology and antibiotic susceptibility patterns, and targeted therapy should be narrowed based upon the isolate susceptibility profile and clinical response.

Introduction

Late-onset sepsis (LOS) is an important contributor to morbidity and mortality among both term (≥37 weeks’ gestational age [GA]) and preterm (<37 weeks’ GA) newborn infants. LOS is defined by isolation of a pathogenic species from a normally sterile body fluid. Among preterm infants, LOS is most commonly defined by isolation from blood or cerebrospinal fluid (CSF) culture. Infection confined to the urinary tract, joints, or bones may also occur as part of LOS with specific organisms. Bacteria, fungi (primarily Candida species), and viruses (herpes simplex virus, cytomegalovirus) may cause LOS. A consensus, physiology-based definition for neonatal sepsis does not currently exist. LOS is also defined based on the timing of the infection relative to birth. Among continuously hospitalized infants cared for in the neonatal intensive care unit (NICU), LOS is defined as occurring in infants ≥72 hours or 3 days after birth. Risk factors for infection and organisms causing infection rapidly change from those reflecting perinatal risk and perinatally acquired flora to those reflecting nosocomial risk factors and hospital-­acquired flora. In contrast, among infants discharged home from the birth hospital in the first week after birth, LOS is defined as occurring in infants 7 to 90 days of age. This chapter will focus on bacterial and fungal LOS among primarily preterm infants cared for in the NICU.

Epidemiology

The incidence of LOS is inversely related to the degree of maturity (GA and birth weight [BW]) and varies across populations. Up to 40% of very preterm infants (<28 weeks’ GA) admitted to the NICU have at least one episode of LOS, compared with 30% of moderately preterm infants (28–32 weeks’ GA) and 17% of late preterm and term infants (≥33 weeks GA). The peak incidence of LOS is between the 10th and 22nd postnatal day. ^, The incidence of LOS has increased over time, likely related to improved survival of extremely preterm infants with prolonged hospitalization and intensive care.

Pathophysiology

The pathogenesis of gram-positive LOS, particularly that due to coagulase-negative Staphylococci (CONS) and Staphylococcus aureus , is often related to adherence and proliferation of bacteria on indwelling plastic medical devices, whereas gram-negative LOS often occurs by transmission from healthcare workers and contamination of catheters, parenteral solutions, or enteral formulas. ^, Intestinal, nasal mucosal, and skin colonization with invasive pathogens may also promote LOS both in the presence and absence of invasive medical devices. ^,

Risk Factors

Multiple studies provide evidence for both nonmodifiable and modifiable risk factors for LOS. Nonmodifiable risk factors include lower GA and lower BW. ^{, ,} Among preterm infants, some studies suggest small-for-GA infants may be at increased risk for LOS, particularly CONS infection. ^, Potentially modifiable risk factors for LOS include prolonged parenteral nutrition, presence of a central venous catheter (CVC), and breast milk feeding. ^{, , ,} The decreased risk of LOS with breast milk is likely attributable to the complex immunomodulatory and antiinfective components of breast milk; more rapid achievement of full enteral feeds and decreased exposure to parenteral nutrition time and CVCs; and potentially to differences in constitution of the infant gut microbiome. Multiple studies identify presence and duration of a CVC as a risk factor for LOS. This may be due to entrance of commensal skin organisms into the catheter track or contamination of the catheter hub. ^, Mechanical ventilation and bladder catheterization also increase the risk of LOS. There is conflicting evidence for the role of early antibiotic administration on subsequent risk of all-cause LOS, fungal LOS, and comorbidities associated with LOS, such as necrotizing enterocolitis (NEC). ^{, ,} Racial disparity has been observed in LOS caused by group B Streptococcus (GBS), with maternal black race a significant risk factor. Additional specific risk factors for fungal LOS due to Candida albicans include treatment with cephalosporin antibiotics, steroids, intralipids, and gastric acid suppressing medications.