Fungal Infections in the Neonatal Intensive Care Unit

Key Points

Fungal infections account for approximately 12% of neonatal late-onset sepsis, with a mortality rate of approximately 32%, and the most important risk factor remains the gestational age at birth.
When a lumbar puncture is performed, 10% to 50% of candidemic infants have associated meningitis and a significant percentage of extremely low birth weight (ELBW, BW<1000 g) infants with Candida meningitis have negative blood cultures.
Candida species isolated from a blood culture should be considered as an infection, not a contaminant.
Rapid institution of parenteral amphotericin B deoxycholate is the therapy of choice for systemic fungal infection; if there is also meningitis, 5-flucytosine or fluconazole should be added.
Central venous catheters should be removed within 24 hours after the identification of yeasts in the blood culture, if possible.
The finding that prophylactic fluconazole reduces the incidence of invasive neonatal fungal infections should be interpreted with caution; nevertheless, recent guidelines recommend fluconazole prophylaxis in ELBW infants in nurseries with high rates (>10%) of invasive candidiasis.

Epidemiology

Invasive fungal infection accounts for approximately 10% of healthcare associated infections in very low birth weight infants and occurs in approximately 1% to 2% of all infants admitted to US neonatal intensive care units (NICUs). The incidence rises dramatically with decreasing gestational age and birth weight. Fungal infections are associated with high mortality and morbidity, including poor neurodevelopmental outcomes in extremely low and very low birth weight infants. Among the fungi, Candida species (spp.) are the dominant pathogens. There are over 200 identified species of Candida , but fewer than 12 appear to cause disease in neonates. These infections are evenly distributed among C. albicans and non– C. albicans spp. ( C. parapsilosis, C. orthopsilosis/C. metapsilosis, C. glabrata, C. guilliermondii, C. krusei , and C. lusitaniae ). Candida spp. are the third most common pathogen in neonatal nosocomial bloodstream infections and carry a fatality rate more than sevenfold greater than that of Staphylococcus epidermidis , the most common pathogen found in the NICU. In late-onset sepsis, fungi account for approximately 12% of cases, with a mortality rate of 32%. Other fungi encountered include Aspergillus (fumigatus and flavus) and Malassezia (furfur and pachydermatis) . The yeast Cryptococcus neoformans and the fungi Histoplasma capsulatum, Blastomyces dermatitidis , and Coccidioides immitis are rarely seen in the NICU.

Pathophysiology

The most important risk factor for fungal infection is gestational age. In a survey of 2847 infants from six different nurseries, the incidence of candidemia in infants weighing less than 800 g (7.55%) was 25 times that of the infants weighing more than 1500 g ( Fig. 36.1 ). This latter group acquires bloodborne candidal infection in association with congenital anomalies, especially those of the gastrointestinal tract. Candidemia carries a mortality rate exceeding 25% in most studies.

Fig. 36.1, Incidence of Candidemia related to birthweight in grams.

Colonization with ubiquitous fungal spp. occurs in at least 25% of very low birth weight (VLBW) infants, and both the amount of Candida in the gastrointestinal tract and colonization at sites such as endotracheal tubes have been correlated with increased risk of invasive disease caused by Candida spp. Prospective studies correlating colonization by other fungal genera (e.g., Aspergillus, Malassezia ) with risk of invasive disease have not been done.

Apart from colonization and gestational age, other host factors that contribute to the susceptibility of the NICU neonate to fungal infection include a 5-minute Apgar score of less than five and an age-dependent immunocompromised state ascribable to reduced numbers of T cells, impaired phagocyte number and function, and reduced levels of complement. Other factors thought to increase the risk of fungal infections include length of NICU stay greater than 1 week, indwelling central venous catheters (CVCs), abdominal surgery, parenteral nutrition, intralipids, H ₂ blockers, endotracheal intubation, and prolonged use of broad-spectrum antimicrobials, especially third-generation cephalosporins. Some studies have identified associations with systemic steroids and catecholamine infusions and with topical petrolatum.

A number of variables appear to not be associated with candidal colonization, including use of antibiotics in the mother, premature rupture of the membranes, the infant’s gender, use of antimicrobial agents other than third-generation cephalosporins in the infant, surgical procedures, or frequency of intubation. Although approximately 5% of NICU staff carry C. albicans on their hands and 19% carry C. parapsilosis , there is no correlation with site-specific rates of neonate colonization.

This chapter will place its major emphasis on infections caused by Candida spp. and will also discuss infections caused by other fungi, as well as the approach to diagnosis, treatment, and management of infants with fungal infection.

Infections Caused by Candida Species

Congenital Candidiasis

Congenital candidiasis typically presents within the first 24 hours of life in both full-term and premature neonates. The infection manifests as a deeply erythematous skin rash in the setting of pronounced neutrophilia, with white blood cell counts often rising to 50,000 mm ³ or more. Candida funisitis (discussed later in the chapter) can be an infrequent accompaniment. In the full-term neonate, there are usually no invasive consequences, and desquamation typically ensues within 2 to 3 days. In contrast, the condition is life-threatening in the premature neonate and is distinguished by a pustular rash, hazy infiltrates reminiscent of respiratory distress syndrome on chest radiograph, and frequently positive blood cultures. The premature neonate is thought to acquire the organism from inhalation of infected amniotic fluid.

The diagnosis of congenital candidiasis in both premature and full-term neonates requires visualization of the organism on Gram stain from a bullous lesion or an opened pustule. On rare occasions, placental culture can yield the diagnosis. Treatment for the full-term neonate requires only the full-body application of topical antifungal creams containing either nystatin or azoles such as miconazole or clotrimazole. In the premature neonate, the initiation of parenteral amphotericin B deoxycholate at a dose of 1 to 1.5 mg/kg is mandatory (this dose may be reduced to 1.0 mg/kg), but respiratory involvement typically heralds death despite antifungal therapy. (Except where noted, all dosages come from Nelson’s Pediatric Antimicrobial Therapy , 2017 edition, AAP Press.)

Local Infections With Candida Species

Diaper Dermatitis

This entity presents as an erythematous, erosive dermatitis of the perineal region, typically with pustular “satellite lesions” beyond the borders of the rash. Predisposing factors include systemic antibiotics, glucosuria, and wet diapers. Care must be taken to differentiate this tractable condition from invasive fungal dermatitis (discussed later in the chapter). Candida diaper dermatitis responds well to topical antifungal ointments.

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