Neonates have underdeveloped immune systems and defects in structural defenses that result in increased susceptibility to infection. This is especially true in the neonate born prematurely. The skin, for example, normally provides a mechanical barrier between the host and the environment. In infants born before 32 weeks of gestation, the stratum corneum is poorly developed, and the skin is fragile, very permeable, and easily traumatized by routine procedures such as cleansing or removal of adhesive tape. Injured skin provides a portal of entry for infectious agents. Similar defects are seen in the alimentary tract, where low levels of mucosal immunoglobulin A, high gastric pH, and short gastric emptying times increase the susceptibility of the newborn to gastrointestinal infections. Macrophages and neutrophils have reduced numbers as well as impaired chemotaxis and activity. Neonates have functioning B cells and T cells, but they are immature, which results in diminished effectiveness of their response. For example, B cells make antibodies to protein antigens but respond poorly to polysaccharide antigens, including the bacterial capsular polysaccharides of group B Streptococcus (GBS) and Haemophilus influenzae. In addition, their immune systems lack the immunologic memory that results from prior exposure to pathogens and from immunization. Maturational defects in T-cell function enhance the susceptibility of the newborn to intracellular pathogens such as Listeria, Toxoplasma, and Salmonella. In the first weeks of life, the newborn depends on passively transferred maternal antibody and the repertoire of antibodies received depends on maternal exposure. Because placental transfer of antibody occurs in the third trimester, infants born at <34 weeks have low levels of immunoglobulin G antibodies. As a result of a reduced capacity to fight infection, even viral respiratory infections, such as rhinovirus, can result in substantial morbidity and mortality in hospitalized neonates.

The newborn may develop infection as a result of exposure to maternal flora during labor or delivery, or postpartum from maternal, hospital, or community sources. Postnatally, the hands of healthcare personnel (HCP) are the most common vehicles for transmission of potential pathogens in neonatal units.^8,9 Nursery outbreaks of Staphylococcus aureus, Enterococcus, a variety of Gram-negative bacilli, and viruses have been attributed to hand transmission.^{1,10,11,12,13,14,15,16,17} In one study, Gram-negative bacilli were found on the hands of 75% of NICU personnel.¹⁸ Usually, hands are transiently contaminated, and hand hygiene removes the microorganisms and interrupts transmission.¹⁹ Occasionally, personnel who are persistent carriers of potential pathogens such as S aureus or group A Streptococcus (GAS) have been implicated in nursery outbreaks.^20,21 Ophthalmologic exams for retinopathy of prematurity have been associated with the development of conjunctivitis, including outbreaks of adenoviral conjunctivitis.^22,23

Patient care equipment may also serve as a vehicle for transmission. Multiple outbreaks have been associated with contaminated respiratory care equipment including ventilator circuits,^24,25 laryngoscopes,²⁶ balloons used for manual ventilation,²⁷ and suction devices.^28,29,30 Inadequate disinfection of rectal thermometers contributed to nursery outbreaks of Salmonella eimsbuettel³¹ and Enterobacter cloacae.³² Infusion of contaminated intravenous fluids, including total parental nutrition solutions and lipid emulsions, may result in bacteremia or meningitis.^{33,34,35,36,37,38,39,40,41} Exposure to contaminated topical preparations and medications, including contaminated eyewash,⁴² umbilical cord wash,⁴³ and glycerin⁴⁴ may also result in invasive infections. Use of contaminated ultrasound gel resulted in an outbreak of pyoderma in hospitalized neonates,⁴⁵ while bathing practices have been linked in clusters of listeriosis⁴⁶ and Stenotrophomonas infections.⁴⁷

Hospitalized neonates are also at risk for food-borne infection. Powdered formula is not sterile, and feeding of reconstituted formula has been associated with Gram-negative bacteremia and meningitis.⁴⁸ Expressed breast milk may be contaminated during collection,^49,50,51 and both breast milk^52,53,54 and formula^55,56 may be contaminated during storage and handling. Feeding practices may also contribute to infection. A cluster of Elizabethkingia meningoseptica (formerly Flavobacterium meningosepticum) was linked to contamination of the formula preparation area and bottle stoppers.⁵⁷ Cases of Cronobacter sakazakii (formerly Enterobacter sakazakii) have been linked to contaminated powdered infant formula.⁵⁸

CVCs are frequently utilized in premature neonates to provide parenteral nutrition and medication administration with peripherally inserted central catheters (PICCs)
being the most commonly used CVCs in the NICU. Umbilical venous catheters and umbilical arterial lines, which are unique to the neonatal setting, are also utilized, especially in the first week of life to provide central access. The presence of a CVC is the most important risk factor associated with the development of a BSI in the NICU. Between 2011 and 2014 there were 15 538 central line-associated bloodstream infections (CLABSIs) reported to NHSN with 50.5% of these occurring in the NICU.⁶⁴ The pooled mean CLABSI rates are higher for lower birth weights (BWs), 2.1 CLAB-SIs/1000 CVC-days (BW 750 g or less) vs 0.7 CLABSIs/1000 CVC-days (BW >2500 g).⁸⁴ CoNS (28%), S aureus (25%), Enterococcus faecalis (8.4%), Escherichia coli (8.3%), and Klebsiella spp. (7%) are the most frequently identified pathogens causing CLABSIs in the NICU.⁶⁴ Candida spp. was the cause of 7% of CLABSIs in this population.⁶⁴

Although many of the risk factors associated with CLABSIs in neonates are similar to those in older children and adults, there are a few differences worth noting. The longer time that a CVC is in place increases the risk of a CLABSI. Unfortunately, neonates frequently require CVCs for prolonged periods of time.⁸⁵ Umbilical catheterization for more than 5 days is recognized as an independent risk factor for sepsis.⁸⁶ In one study, catheter duration of 10-21 days was associated with a 40-fold risk of Gram-negative BSIs in VLBW infants, while the risk was 90-fold with catheter duration of >21 days.⁸⁷ In a retrospective cohort study in a single NICU, the incidence rate of CLABSIs increased by 14% by day during the first 18 days after PICC insertion. The trend reversed from days 19 to 35 after insertion, but after day 36, the incidence rate of CLABSIs increased by 33% per day. While identifying and removing CVCs once they are no longer necessary reduces the risk of CLABSIs, the prolonged CVC dwell times required in the NICU highlight the importance of meticulous catheter care. In addition to low birth weight and GA, mechanical ventilation^86,88 and total parenteral nutrition⁸⁸ are risk factors for the development of CLABSIs. In one study involving 3470 catheter days, sampling of blood through the central line and disconnection of the catheter increased the risk of CLABSIs.⁸⁹ The importance of catheter location on the incidence of infection remains controversial. One study identified a higher rate of catheter-related sepsis in VLBW infants with femoral PICCs compared to those with nonfemoral PICCs (22.5% vs 12% or 10.9 vs 6.8 episodes/1000 catheter days).⁹⁰ Another study found no difference in infection rates when PICCs placed in an upper extremity were compared to those placed in a lower extremity, although the pathogens associated with infections did vary by site.^91,92 CoNS infections were more common in infants with upper extremity catheters, while more Gram-negative infections were diagnosed in children with lower extremity catheters. The skin of premature infants, which is more fragile and easily damaged, is another potential risk factor for CLABSIs in this population. Additionally, the immature gastrointestinal tract can result in translocation of pathogens into the bloodstream. Distortion of the premature neonatal microbiota has been associated with late-onset sepsis.⁹² The presence of an active intra-abdominal process has been identified as a significant risk factor resulting in a sixfold increase in CLABSIs in the NICU.⁹³ Premature neonates with intra-abdominal pathology may represent a distinct risk subset similar to oncology patients with mucosal barrier injury.

Over the past few years, there have been significant reductions in CLABSIs. Recent NHSN data show decreased CLABSIs across all birth weight categories.⁹⁴ Interventions to reduce CLABSIs have primarily focused on the insertion of the CVC and ongoing maintenance of the CVC. Organizations like the U.S. Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Society for Healthcare Epidemiology of America (SHEA) have developed evidence-based recommendations involving small groups of interventions designed to be implemented together (bundles) that focus on preventing infection before, during, and after insertion of the CVC.⁹⁵ Key bundle components are listed in Table 29-1. When performed consistently, these
bundles have been shown to reduce CLABSIs.^96,97 For the most part, these same bundles are applicable in the NICU. There are a few differences in CLABSI prevention in the NICU related to both insertion and maintenance practices that are worth noting.

Trained intravascular access teams are being increasingly utilized in NICUs to help standardize PICC placement as well as ongoing catheter care, such as dressing changes. In the NICU, the majority of these teams are nurse led. Implementation of dedicated teams focused on PICC insertion and maintenance have resulted in significant reductions in CLABSIs in the NICU.^98,99 The skin at the insertion site should be disinfected prior to insertion, typically with CHG. Currently, CHG is not approved by the U.S. Food and Drug Administration (FDA) for use in premature infants or infants under two months of age, but there is growing evidence that CHG can be used safely in this population.¹⁰⁰ This prompted the FDA to adjust the product label for CHG (2%) and isopropyl alcohol (70%), which now states “[u]se with care in premature infants or infants under two months of age. These products may cause irritation or chemical burns.”¹⁰⁰ CHG use in neonates is discussed in greater detail later in the chapter. Prior to CVC insertion, guidelines recommend scrubbing the site for 30 seconds or longer and then allowing the skin to dry completely. In premature neonates with fragile skin, this could result in skin injury; therefore, care should be used in disinfecting the insertion site.

Given the long duration that CVCs remain in place in neonates, special attention to maintenance bundles is required. Contamination of catheter hubs has been shown to play a role in the majority of CLABSIs in the NICU.¹⁰¹ Thus, disinfection of the catheter hubs and connectors must be performed consistently. Connection sites should be vigorously scrubbed for at least five seconds using an alcoholic CHG preparation, 70% alcohol or povidone-iodine, and allowed to dry prior to accessing.¹⁰² A recent multicenter quality improvement project performed in tertiary NICUs examined the impact of different maintenance bundle elements on CLABSI reduction.¹⁰³ The bundle elements significantly associated with reduced CLABSIs included hub-care compliance monitoring and sterile technique for tubing changes (hand hygiene, sterile gloves, mask, and sterile barrier under the catheter). The use of sterile tubing change decreased CLABSI rates by 0.51/1000 CVC days. Adding hub-care monitoring led to a decrease of 1.25 CLABSIs/1000 CVC days. An alternative to scrubbing the hub involves placing disinfectant caps containing 70% isopropyl alcohol on all unused hubs and connectors. At this time, there are no NICU-specific data, but their use in a trauma ICU resulted in a 40% decrease in CLABSIs.¹⁰⁴ Another study showed that for every 30% increase in utilization of the maintenance checklist, there was a 16.5% decrease in the CLABSI rate.⁹⁶ Skin protection is also a factor in CVC dressing changes for premature neonates. In general, guidelines recommend changing gauze dressings every two days and transparent dressing every seven days unless soiled, damp, or nonadherent.¹⁰² To reduce skin trauma or catheter dislodgement, some centers only change transparent dressings if they become soiled, damp, or nonadherent. Additional recommendations for the management of umbilical arterial and venous catheters, devices used exclusively in neonates, are listed in Table 29-2.

Antimicrobial lock therapy is a promising strategy for the prevention of CLABSIs. Filling the lumen of a catheter with a supraphysiologic concentration of an antibiotic or agent such as ethanol may prevent or eliminate the bacterial colonization that ultimately results in CLABSIs. Current guidelines suggest that lock therapy could be useful in certain high-risk patients or those with recurrent infections. However, few studies have evaluated lock therapy in neonates. Vancomycin-heparin locks were studied in a prospective randomized double-blind trial in NICU patients. When definite and probable BSIs were considered, there were significantly fewer infections in the lock group (2.3 vs 17.8/1000 catheter days; relative risk 0.13: 95% confidence interval: 0.01-0.57).¹⁰⁵ Similar results were observed in an Italian trial of a fusidic acid-heparin lock in neonates.¹⁰⁶ To date, however, few centers employ antibiotic lock therapy for primary prevention of CLABSIs in NICU patients.

CHG is a frequent component of CLABSI prevention protocols outside the NICU. CHG is used for skin disinfection at the CVC insertion site, for CHG bathing to decrease bacterial colonization on the skin, and in CHG-impregnated sponges (eg, Biopatch) that further protect the CVC insertion site. CHG bathing in adult ICUs was associated with a 50% reduction in CLABSI rates.^107,108,109 In a randomized trial in PICUs, there was a 48% decrease in CLABSI rates.¹¹⁰ In adults, the use of CHG-impregnated sponges at CVC insertion sites reduced CLABSI rates from 1.3 to 0.4/1000 CVC-days; however, a multicenter study in PICUs failed to demonstrate a significant reduction.^97,111 The primary
concerns with CHG use in the NICU are the potential for skin irritation or chemical burns and systemic absorption. Published data about CHG use for CVC care in neonates are limited. In one study, 48 infants ≥1500 g BW and at least 7 days of age were randomized to 2% CHG or 10% povidone-iodine for preparation of catheter insertion sites and for use with dressing changes.¹¹² Severe dermatitis did not occur in the CHG group. Cutaneous absorption of CHG was documented but was not associated with systemic toxicity. This small study was underpowered to show a difference in CLABSI or clinical sepsis. The enrolled infants were relatively mature (mean BW of 2000 g and 32-33 weeks of gestation). A study in less mature neonates did demonstrate CHG-related dermatitis. When an Australian NICU employed 2% aqueous CHG for central line insertion and maintenance, 4/26 infants <1000 g BW and <48 hours of age developed severe skin irritation (redness = 3; skin breakdown = 1).¹¹³ Nevertheless, a recent survey of neonatology training program directors confirms that off-label use of CHG is common in NICUs. Sixty-one percent of survey respondents reported using CHG in their NICUs.¹¹⁴ Despite this widespread use and evidence of systemic absorption, there have not been any documented neurologic adverse events. With the growing experience that suggests, with certain caveats, CHG can be used safely in infants under two months of age, the FDA revised its recommendations, stating CHG-impregnated cloths should be used with caution in this population.¹¹⁵ A recent Cochrane Database systematic review evaluated the effectiveness of CHG dressings compared to standard polyurethane dressings to prevent CLABSIs in the NICU. There was no significant difference in rates of sepsis or CLABSI.¹¹⁶ Use of a chlorhexidine-impregnated dressing has been associated with dermatitis in low birth weight neonates.¹¹⁷ Based on these data, in 2017, HICPAC updated its recommendations for use of CHG-impregnated dressings recommending against their use in premature neonates, although no recommendations were made for term neonates due to lack of sufficient evidence.¹¹⁸

Ventilator-associated pneumonia (VAP) is common in preterm infants, many of whom require prolonged ventilatory support. Recent NHSN data show that the majority of VAPs (63%) occur in the NICU.⁶⁴ VAP is the second most common HAI in the NICU with rates ranging from 0.2 to 1.8 infections per 1000 ventilator days.¹¹⁹ In a prospective study, nearly 30% of infants born at <28 weeks of gestation developed VAP; infection was significantly associated with mortality.¹²⁰ Not surprisingly, the rates of VAP reported through NHSN are consistently highest in infants of <1000 g birth weight.¹²¹ Pooled mean rates of VAP for level II/III NICUs reporting data to NHSN from 2006 to 2008 ranged from 0.6/1000 ventilator days in infants of >2500 g birth weight to 2.7/1000 ventilator days in infants of ≤ 750 g birth weight. More recently, the incidence of VAP in the NICU decreased. Between 2008 and 2012, the rate of VAP decreased from 1.6 to 0.6 per 1000 ventilator days.¹²² Risk factors for VAP in NICU patients include duration of mechanical ventilation, reintubation, treatment with opiates, and endotracheal suctioning.¹²³ Other modes of assisted ventilation, including nasal continuous positive airway pressure, have been associated with the development of healthcare-associated pneumonia, albeit at lower rates than those associated with mechanical ventilation.¹²⁴

The most common pathogen identified is S aureus (24.2%).⁶⁴ Gram-negative microorganisms are thought to cause at least 30% of VAP episodes, but a specific microbiologic diagnosis is often difficult unless there is secondary bacteremia.^65,125 Endotracheal cultures are rarely useful in the diagnosis of VAP because the respiratory tract of the intubated newborn rapidly becomes colonized with mixed Gram-positive flora by the second week of mechanical ventilation, and Gram-negative microorganisms after the fourth week.^126,127 The presence of purulence in a specimen suctioned from the endotracheal tube of a mechanically ventilated neonate has a poor positive predictive value for respiratory tract infection, including pneumonia and tracheitis.¹²⁷

The true burden of VAP remains unclear, because the diagnosis is difficult in NICU infants. Ultimately, many infants are treated empirically for presumed pulmonary infection. While NHSN surveillance definitions for VAP include criteria for infants <1 year of age, these definitions have not been validated in premature neonates. Premature neonates, especially those on prolonged ventilatory support, frequently have underlying chronic lung disease. Comorbid conditions such as bronchopulmonary dysplasia may mimic the clinical and radiographic features of VAP.¹²⁸ Detecting new persistent or progressive infiltrates overlaid upon underlying chronic lung changes is difficult. Developing accurate criteria for VAP in the NICU population remains a challenge. In attempt to improve the validity of VAP diagnosis, the CDC expanded the adult surveillance definition for VAP in 2013 to include other related complications and was termed ventilator-associated events (VAE).¹²⁹ The VAE criteria are discussed in more depth in Chapter 16 Healthcare-Associated Pneumonia and VAE.

Applying these definitions in children, especially neonates, presents a number of challenges. Positive end expiratory pressure (PEEP) changes, which is a criterion used in the adult definitions, may not reflect changes in ventilation and oxygenation in children as well as mean airway pressure (MAP).¹³⁰ In addition, the adult definition excludes high frequency ventilation, which is more commonly used in children. Temperature changes may be difficult to detect in neonates who are in temperature-regulated incubators. Finally, the white blood cell count definitions used in adults may not be appropriate in children and neonates. Recently, a pediatric VAE definition was developed.¹³¹ Similar to the adult definition, there are three nested categories. Pediatric ventilator-associated condition (VAC) includes at least two days of increased MAP by at least 4 cm H₂O or fraction of inspired oxygen (FiO₂) by at least 0.25 after a period of improvement or stability. Pediatric VAE with antimicrobial use (AVAC) removes the temperature and WBC criteria and is based on whether antibiotics are given for at least four calendar days. The addition of a positive diagnostic test for a respiratory infection to AVAC meets the criteria for a possible VAP (PVAP) in the pediatric definition. Comparing pediatric VAE definitions to NHSN VAP definitions shows poor correlation with only 6% overlap for VAC and 16% overlap for PVAP.¹³¹ In one study, children in the NICU and PICU with VACs were found to have higher mortality rates and longer durations of ventilation, ICU stays, and hospitalization.¹³⁰

At this time, there are no published guidelines for VAE prevention. Recommendations for the prevention of VAP in children and adults have been published, although not all of the recommended strategies are applicable for NICU patients.¹³² For example, elevation of the head of the bed to 30-45 degrees is not feasible in a 1000-g infant. Updated guidelines from SHEA and Infectious Diseases Society of America (IDSA) for the prevention of VAP in acute care hospitals include evidence-based recommendations for preterm neonates.¹³³ Basic practices encompass strategies with minimal associated risk that may potentially lower VAP rates. These include use of noninvasive methods of ventilation to avoid intubation; minimizing the duration of mechanical ventilation; when possible, managing patients without sedation, regularly assessing readiness to extubate; avoiding unplanned extubations; providing regular oral care with sterile water; and minimizing breaks in the ventilator circuit and only changing the ventilator circuit when soiled or malfunctioning. Additional strategies that may be implemented that have minimal risk but unknown benefit include positioning the patient in either the lateral recumbent position or reverse Trendelenburg position or using closed in-line suctioning (Table 29-3).

There are a number of strategies that are not recommended for preterm neonates for a variety of reasons. Use of antiseptics for oral care is not recommended as the impact on normal flora and the potential for systemic absorption is unknown. Use of histamine H2 receptor antagonists,^134,135 prophylactic antibiotics,^136,137 and spontaneous breathing trials^138,139 is not recommended due to the potential risk of harm. Finally, the use of probiotics in neonates is not FDA approved, and endotracheal tubes with subglottic suction drains or silver-coated endotracheal tubes are not commercially available in appropriate sizes for neonates.