Neonatal fungal infections

Prematurity

The more premature the infant, the more underdeveloped the immune system and the barrier defenses and the greater the likelihood of procedures, antibiotic exposures, and use of other medications contributing to colonization and ICIs.

Colonization

Local colonization of the skin or mucosal surfaces can lead to ICIs, with Candida penetrating epidermal barriers to infect underlying tissue or directly invading the bloodstream and spreading hematogenously. Very-low-birth-weight (VLBW; <1500 g at birth) infants are more susceptible to colonization with Candida and are at a higher risk of progression to an invasive infection. Colonization is inversely correlated with gestational age and birth weight. In the first weeks after birth, >50% of extremely low-birth-weight (ELBW; <1000 g at birth) and 25% to 50% of VLBW infants are colonized, compared with 5% to 10% of full-term infants. Colonization during the first 2 weeks of life occurs primarily on the skin and in the gastrointestinal tract, including the rectum and oropharynx, followed a week or two later by respiratory tract colonization in high-risk infants. Progression to infection occurs in approximately one of four colonized infants, influenced by both the number and location of colonized sites in premature infants. Colonization of three or more sites or at a high-risk site (urine, catheter tips, drains, and surgical devices) is more likely to be associated with progression to an ICI.

Colonization can occur by way of vertical transmission from the mother or horizontal transmission from nosocomial sources. Early colonization (≤1 week of age) is more often attributed to maternal sources, with an increased risk for early Candida albicans colonization in premature infants born vaginally. Horizontal transmission occurs from healthcare workers, family, and medical interventions. In a prospective trial studying fungal colonization in six neonatal intensive care units (NICUs), 29% of healthcare workers had hand cultures positive for Candida species, with nearly the same percentage of infants (23%) having mucosal colonization. Although C. albicans was the more common fungal isolate in all NICU patients, C. parapsilosis was the most common species isolated from the hands of NICU staff. C. parapsilosis colonization is also associated with receiving parenteral nutrition.

Immune system

Immaturity of the immune system includes the physical barriers with regard to controlling colonization and preventing infection is evident in the underdeveloped skin, gut, and respiratory tract ( Figure 6.2 ). For example, at 26 weeks’ gestation, the stratum corneum is composed of only three cell layers and produces a thin keratin layer, compared with 15 layers with a thick keratin overlying layer in term infants ( Figure 6.2 A). Premature infants have a multitude of deficient immune cellular functions and reduced protein production. Neutrophils are one of the most important components in the initial response of the innate immune system to Candida infections, both through direct phagocytosis and through neutrophil extracellular trap formation. Premature infants have neutrophils with lower chemotaxis, fewer phagocytosing pathogens and producing NETs as compared to adults.

Gut microbiome

Like the immune system, the gut microbiota play an important role in suppressing Candida colonization and preventing invasive infection. The intestinal microbiota of premature infants are different and less diverse in composition than those of term infants. In one study, probiotics ( Lactobacillus reuteri and L. rhamnosus ) showed significantly lower Candida stool colonization compared with the control premature infants, whereas lactoferrin with and without L. rhamnosus decreased ICIs without changing Candida colonization, potentially preventing translocation. ^, Analysis of randomized controlled trials has been complex, with benefits found for infants 1000 to 1500 g but not for the highest risk infants (<1000 g). Specifically for preventing ICI, probiotics may alter colonization but not the incidence of ICI.

Medications

Certain medications, including antibiotics, histamine-2 antagonists, and postnatal corticosteroids, increase the risk of ICIs ( Figure 6.2 B). Longer antibiotic duration, administering two or more antibiotics, third- and fourth-generation cephalosporin, and carbapenem antibiotics are associated with increased risk of ICIs. Dexamethasone and high-dose hydrocortisone (>1 mg/kg/day) are associated with increased risk. Although ELBW infants are at high risk, exposure to hydrocortisone alone at 1 mg/kg/day with a weaning schedule did not further increase the high incidence of ICIs (9% in the hydrocortisone group vs. 10% in the control group).

Lines, tubes, and feedings

Use of central venous catheters ( Figure 6.2 A) and endotracheal tubes increases the risk of ICIs in infants. Infants who receive larger amounts of expressed milk from their mothers generally have fewer infections, but a decrease in ICIs has not been demonstrated. These studies have not controlled whether the milk was fresh or frozen. Freezing then thawing human milk is associated with a reduction of protective components such as maternal white blood cells, lactoferrin, immunoglobulin A, and lysozyme. Studies of pasteurized donor human milk have not demonstrated a decrease in infections of any type. Prospective epidemiologic studies have found that infants who are not able to or do not receive enteral feedings by 3 days after birth are more likely to develop an ICI.

Gastrointestinal pathology and abdominal surgery

GI pathology ( Figure 6.2 B) is associated with an increased risk for ICI in infants with tracheoesophageal fistula, gastroschisis, omphalocele, Hirschsprung disease, intestinal atresias, or necrotizing enterocolitis (NEC). ^,

Biofilm formation

C. albicans , C. parapsilosis , and other Candida species are able to form biofilms, which can promote invasion and resist killing by antifungal therapy (see Figure 6.3 A). These biofilms adhere to medical devices and prevent the penetration of antifungals. This trait explains in part the need to remove central venous catheters to clear candidemia and improve outcomes.