Improvements in survival of very-low-birth-weight infants have been made possible, in part, as a result of advances in neonatal intensive care. However, this high-risk population of neonates is also at risk of nosocomial or health care-associated infections (HAIs). Risk for acquiring HAIs is high, due to intrinsic risk factors of the extreme preterm infant, fragility of the skin resulting in its readiness to breakdown, use of invasive monitoring, and need for ventilator support, all in the setting of a poorly developed immune system.

Neonates and young children rank among hospitalized patients at highest risk for acquiring HAIs. For the purposes of HAI tracking, positive cultures obtained greater than 3 days after birth are considered late onset disease. Clinical manifestations of infection in neonates often are delayed, and determining whether an infection was acquired from the mother or from transmission within the nursery is difficult. National Healthcare Safety Network (NHSN) reports all infections except those that are transmitted transplacentally as HAIs. HAIs present as late-onset sepsis, and occur in inverse proportion to birth weight. Birth weight-specific rates of bloodstream infection are calculated per 1,000 devicedays, and are stratified by birth weight (five categories: ≤750 g, 751 to 1,000 g, 1,001 to 1,500 g, 1,501 to 2,500 g, and >2,500 g) (Table 45.1) (1). According to data from the NHSN in 2012, extremely low birth weight (<750 g, 751 to 1,000 g) infants have the highest rates of central line-associated bloodstream infections (CLABSIs) compared with all other birth weight categories among infants in level III neonatal intensive care units (NICUs) (1). Device utilization (DU) is used in calculating risk-adjusted infection rates in the NICU. DU is one measure of the use of invasive devices and constitutes an extrinsic risk factor for HAI. It may serve as a marker for severity of illness, as severely ill patients require more devices. DU is calculated as a ratio of device days to patient-days. The clinical manifestations of sepsis are most often nonspecific and most frequently are temperature instability, apnea and bradycardia, feeding intolerance, and lethargy. Infants less than 1,500 g experience a disproportionate share of HAIs (approximately 75%) compared to other newborns in the NICU (2). The skin of the premature neonate can be easily damaged and serve as a portal of entry of pathogens into the bloodstream.

Coagulase-negative staphylococci (CONS) are the most common pathogens responsible for late-onset sepsis in the NICU. CONS are part of the patient’s endogenous flora, colonizing the oral mucosa and/or skin. The National Institute of Child Health and Development (NICHD) Neonatal Research Network reports that gram-positive organisms, specifically CONS, were the most common pathogens causing late-onset (>3 days) bloodstream infections in neonates. CONS were isolated from 43.4% of cases with late-onset sepsis in very-low-birth-weight infants in the NICHD Neonatal Research Network and 31.6% in the Pediatric Prevention Network (3). Infants with late-onset sepsis have significantly increased length of stay in hospital and higher mortality.

Persistent infections with CONS occur in significantly smaller and less mature infants than do infections with non-CONS, but generally mortality is not higher. Infants with persistent infection should undergo aggressive evaluation for a focus of infection. Most CONS isolates causing sepsis are methicillin (oxacillin) resistant.

The role of CONS as causative pathogens or contaminants in blood cultures is difficult to determine. Procedures to help differentiate CONS-positive blood cultures from CONS contaminants include drawing of at least two blood cultures from separate sites, each 0.5 to 2 mL in volume, following serial laboratory studies compatible with sepsis (elevated absolute total neutrophils, ratio of absolute total immature neutrophils to total neutrophils [I:T] >0.2, C-reactive protein [CRP], etc.), and monitoring response to antibiotic therapy (4,5).

A study by NICHD Neonatal Research Network revealed that one-third of patients with late-onset meningitis had meningitis in the absence of sepsis. Cerebrospinal fluid cultures were performed only half as often as were blood cultures, suggesting that meningitis may be underdiagnosed among very-low-birth-weight infants. CONS were recovered from 29% of cases when meningitis occurred (6).

In studies from the Neonatal Research Network, S. aureus was the second most common pathogen isolated. In the point-prevalence study of the pediatric prevention network, however, S. aureus was only isolated from 3.4% of bloodstream infections (2,3). The principle mode of transmission of S. aureus is via the hands of the health care worker. Recently, outbreaks of methicillin-resistant Staphylococcus aureus (MRSA) have surpassed outbreaks of methicillinsensitive S. aureus.

Enterococci have also been recognized as clinically important pathogens in high-risk, hospitalized children and are being diagnosed with increasing frequency. The Pediatric Prevention Network’s point prevalence study of NICUs reports enterococci as the second most frequent (15%) nosocomial pathogen among neonates admitted to the NICU in 1999 and third most common (7.8%) in NICHD Neonatal Research Network studies (2,3). Enterococci are indigenous to the normal flora in humans and are known to colonize the intestines, gastrointestinal tract, and female genital tract. Outbreaks of vancomycin-resistant enterococci (VRE) have been associated with environmental contamination and horizontal transmission among health care workers. Two major species of enterococci infect humans, Enterococcus faecalis (E. faecalis) and Enterococcus faecium (E. faecium).

Although gram-positive organisms cause the majority of late-onset (>3 days) sepsis in very-low-birth-weight neonates (<1,500 g), mortality is highest with gram-negative sepsis. Environmental sources, such as cribs, incubators, and various equipment, yield growth of several pathogens, bacteria, and fungi. The presence of gram-negative pathogens, such as Pseudomonas aeruginosa and Serratia marcescens, varies in different environments and poses a potential threat for infection.

Cronobacter sakazakii has also been reported as a rare cause of invasive infection with high mortality rates in neonates. These
neonates can present with intestinal colonization or more invasive disease such as sepsis and meningitis with cerebral infarction. C. sakazakii has neurotropic qualities and should be considered as a part of differential diagnosis of central nervous system abscess and/or infarction along with Citrobacter diversus. Outbreaks of C. sakazakii necrotizing enterocolitis (NEC) have been seen in premature infants. This infection has been reported with ingestion of contaminated powdered formula in health care settings. Infection with C. sakazakii has also been reported with the use of contaminated spoons or blenders and with ready-made formula kept warm in bottle heaters. Powdered milk is not sterile and can contain low numbers of C. sakazakii. Formula made from powder should be prepared daily and may be kept in the refrigerator up to 24 hours.

In an era of increasing incidence of antimicrobial resistance, the empiric treatment of clinical sepsis in high-risk neonates should include adequate antimicrobial coverage for resistant gram-negative bacilli.

Candida species are a common cause of late-onset sepsis in NICU patients, particularly those receiving broad-spectrum antibiotic therapy. Recently, there has been a 24% reduction in the number of Candida infections per 1,000 patient days among neonates less than 1,000 g, with a stable rate in larger neonates (7). The case mortality for candidemia has been reported at 54% (8). Although gram-positive organisms caused the majority of late-onset sepsis (>3 days) in very-low-birth-weight neonates (<1,500 g), mortality was highest with gram-negative and fungal sepsis.

Prior colonization of body sites (gastrointestinal tract, skin, respiratory tract) is an important risk factor for invasive disease. The gastrointestinal tract appears to be the earliest, most common site of colonization. Approximately one-half of very-low-birthweight infants colonized with less than 8 × 106 colony-forming units of Candida species in their gastrointestinal tract developed feeding intolerance and/or bloody stools; 29% of these infants developed candidemia (9). Colonization of the gastrointestinal tract in NICU patients has been associated with the use of antibiotics, particularly third-generation cephalosporins, central catheters, intravenous lipids, and H₂ blockers. NEC and gastrointestinal tract, respiratory tract, or skin colonization of neonates with Candida species have also been associated with invasive disease. Loss of normal gastrointestinal tract flora secondary to antimicrobial treatment and delayed enteral feedings may facilitate Candida species colonization, while skin colonization may occur through horizontal transmission from the hands of health care workers (Candida parapsilosis).

Malassezia furfur is a lipid-dependent yeast that can colonize and also cause systemic infections in neonates. It is usually seen in neonates receiving intravenous lipid emulsions. Extremely low birth weight infants, when compared to low-birth-weight infants, are at significantly increased risk for skin colonization with M. furfur. Colonization, however, does not predict infection, and the predictive value of surveillance cultures is poor. Consideration should be given to detection of this lipophilic yeast when neonates receiving intralipids develop signs of catheter-related sepsis.

Multidrug-resistant organisms such as MRSA, VRE, and antimicrobial-resistant Enterobacteriaceae have emerged as major causes of HAIs. According to the CDC-NNIS, recent analysis shows a continuing increase in the incidence of multidrug-resistant organisms in intensive care units in hospitals in the United States. Clinical manifestations of HAIs with multidrug-resistant organisms or susceptible organisms are indistinguishable, which makes it necessary to diagnose these infections and treat them promptly.

Due to the subjectivity and complexity of the surveillance definition of ventilator-associated pneumonia in the NICU, the Centers for Disease Control have adopted the term “ventilator-associated condition” to allow greater flexibility in diagnosis of acute illness associated with ventilator use. Critically ill, premature neonates in NICUs require ventilator support. The care of these hospitalized neonates contributes to increased rates of ventilator-associated events.

Airway colonization of in-patients begins within 3 days to 2 weeks of the start of mechanical ventilation and may be due to either endogenous or exogenous organisms. In young children, bacterial colonization and infection occur more frequently in patients ventilated through a tracheotomy. During endotracheal ventilation, lower airway colonization occurs after 2 weeks of mechanical ventilation. Very-low-birth-weight infants are at risk of airway colonization with gram-negative bacilli and also secondary bloodstream infections. Systemic antimicrobial treatment does not eradicate airway colonization with gram-negative bacilli. This may be in part due to the presence of foreign bodies (tracheal or endotracheal tube), low levels of antimicrobial concentration in respiratory secretions, or translocation of bacteria from the gastrointestinal tract. High case fatality rates (30% to 50%) with P. aeruginosa invasive infections have been seen in patients with compromised host defenses and in very-lowbirth-weight infants (14). Of note, tracheal culture can be negative preceding invasive infections. Therefore, if P. aeruginosa ventilator-acquired pneumonia (VAP) is suspected, presence of a negative tracheal culture should not preclude treatment for pseudomonas infection.

Pseudomonas aeruginosa is ubiquitous in the hospital environment and is found on moist surfaces such as sinks, toilets, floor mops, and respiratory equipment. Environmental reservoirs have been implicated as sources of transmission of P. aeruginosa to patients in NICUs.

Health care-associated urinary tract infection (UTI) in the neonate continues to be a source of morbidity and prolonged hospital stay. Prevalence of UTI in the hospitalized neonate ranges from 4% to 25%, but few data are available on UTI prevalence in NICUs. (15). Prematurity, low birth weight, and male gender contribute to increased risk for UTI in the hospitalized neonate. The exact mechanism of UTI in the very low birth weight is unknown, as they usually do not have indwelling catheters.