Managing Invasive Fungal Infections in Newborns

Pathogenesis

The most common neonatal presentation of Candida infections is invasive bloodstream infection and may be viewed as primary or secondary to other sites of primary infection. Infection can originate from the urinary tract, GI tract, skin and soft tissue, lung, CNS or the cardiovascular systems. Pathogenesis is influenced by transmission of the organism from a source, colonization and penetration of the organism through the host epithelial barriers resulting in dissemination.

Transmission

Candida infections are transmitted vertically from the mother or via horizontal transmission from healthcare workers or the hospital environment.^[34,35] Heavy maternal Candida colonization or vaginitis increases risk of neonatal colonization.^[36] In a study by Ali et al. vaginal delivery and prolonged duration of premature rupture of membranes were significantly positively correlated to neonatal colonization.^[37] Breastfeeding can result in transmission of Candida from the maternal skin to the oral mucosa of the infant, especially in mothers with Candida mastitis. Several outbreaks of C. albicans,^[38–40]C. parapsilosis,^[8]C. tropicalis^[41] and C. lusitaniae^[42] infection have been reported due to horizontal transmission from healthcare staff. In particular, the primary mode of transmission for C. parapsilosis is horizontal from healthcare workers.^[43,44] Both C. albicans and C. parapsilosis can survive on glass (3 days), stainless steel (14 days) and fabrics (14 days), for significant time periods.^[45] Contamination of medications,^[46] retrograde medication administration using multiple-use syringes^[47] and glycerin suppository use^[46] have been reported as sources of Candida infection outbreaks.

Colonization

Candida species colonize the skin, GI tract, lower female genital tract, intertriginous areas and the foreskin of the uncircumcised male. Colonization precedes invasive fungal infection and neonates are generally infected with the colonized strain.^[47,48] Colonization occurs in 30–60% of infants admitted to the NICU.^[49] The rate of colonization increases with decreasing birth weight with almost two-thirds of ELBW infants being colonized by 6 weeks of age. The greater the density of organisms, the more likely it is that the organism will penetrate the host epithelial barriers, spread to the underlying tissue and disseminate to the bloodstream.^[50] In a study of 40 VLBW infants, those with heavy Candida colonization (defined as a colony count of 8 × 10⁶Candida colony-forming unit [CFU]/g of stool) were more likely to have feeding intolerance, bloody stools and candidemia compared with those with lower counts.^[51] Patients who are intubated can have colonization of their upper respiratory tract and are at an increased risk of invasive candidiasis.^[52] The balance between benign colonization and invasive infection may depend on host risk factors.

Risk Factors

Premature infants in the NICU are at particularly increased risk of invasive fungal infection due to increased Candida colonization, deficient immunity and underdeveloped or breached anatomic barriers (catheters and intubation).^[13,53] Preterm infants have low levels of circulating maternal IgG due to the loss of transplacental transfer that occurs during the third trimester of pregnancy.^[54] Even in the presence of adequate IgG concentrations, opsonization and complement functions are reduced, especially in preterm infants.^[55] Neutropenia is also a common finding in premature infants with Candida infections.^[50] Factors that promote Candida overgrowth, such as the use of broad-spectrum antimicrobial agents and the presence of a central catheter or endotracheal tube, increase the risk of candidiasis.^[6,53] Risk assessment is better than clinical judgment when based on predictors of invasive candidiasis which were presence of Candida-like dermatitis on examination, vaginal delivery, presence of a central catheter, enteral feeding, increasing blood glucose level in preceding 24 h, antibiotic days in week before culture, decreasing platelet count and lower gestational age.^[1]

Table 1. Invasive fungal infections in the newborn.
Fungal organism	Species	Risk factors	Clinical manifestations	Management	Ref.
Candida	C. albicans C. parapsilosis C. tropicalis C. lusitaniae ^† C. glabrata ^‡ C. krusei ^‡	CVC Vaginal delivery Hyperglycemia Broad-spectrum antibiotics Thrombocytopenia Lower gestational age H2 receptor blockers	Sepsis UTI Meningitis Peritonitis Endopthalmitis Endocarditis Osteoarticular infections	Remove CVC Amphotericin B deoxycholate Fluconazole Caspofungin	[1,12–14]
Aspergillosis	A. fumigatus A. flavus A. niger	CVC Adhesive tape	Skin Pulmonary (hemorrhagic necrosis) Systemic dissemination	Local debridement Amphotericin B deoxycholate HEPA filters in the ventilation system	[11,15–18]
Cryptococcoses	C. neoformans C. laurenti	CVC	Sepsis Pneumonia Meningitis	Remove CVC Amphotericin B deoxycholate with flucytosine	[19–21]
Malessezia	M. furfur M. globus M. sympodialis M. pachydermatis (nonlipophilic)	Intralipid emulsions CVC Contact transmission Hands of medical personnel	Sepsis Pneumonia	Stop intralipids Remove CVC Amphotericin B deoxycholate	[22–24]
Zygomycoses	Z. rhizopus Z. mucor Z. absidia	Contact transmission	Skin: vascular thrombosis and tissue necrosis NEC-like illness without radiographic signs	Local debridement/resection Amphotericin B deoxycholate	[25–27]
Pichia	P. anomala P. fabianii Kodea (Pichia) ohmeri	Contact Hands of medical personnel	Sepsis	Amphotericin B deoxycholate	[28–31]
Blastomycoses	B. dermatitidis	Vertical and intrapartum transmission from infected mother	Pulmonary	Amphotericin B deoxycholate	[11,32]
Coccidiodomycoses	C. immitis	Vertical and intrapartum transmission from mothers	Pulmonary with systemic dissemination	Amphotericin B deoxycholate	[11,33]

†Resistant to amphotericin B deoxycholate.
‡Resistant to fluconazole.
CVC: Central venous catheter; HEPA: High efficiency particulate air; NEC: Necrotizing enterocolitis; UTI: Urinary tract infection.

Table 2. Systemic antifungal agents for neonates.
Drug	Mechanism of action	Side effects	Daily dose (mg/kg per 24 h)	Susceptible organisms	Ref.
*Polyenes*
Amphotericin B deoxycholate (iv.)	Binds to ergosterol in the fungal cell membrane leading to cell leakage	Nephrotoxicity Hypokalemia Hypomagnesemia Bone marrow suppression Infusion reactions	0.5–1.5	Candida spp., except C. lusitaniae	[87–91,111]
Lipid formulations AmB lipid complex AmB colloidal dispersion Liposomal AmB (iv.)		Less nephrotoxic	3–5		[92–94,119]
*Triazoles*
Fluconazole (iv.; p.o.)	Inhibits 14-α-sterol demethylase essential for ergosterol synthesis	Hepatotoxicity	6–12	Candida spp., (except C. krusei and C. glabrata) Cryptococcus neoformans	[95–101]
Voriconazole (iv.; p.o.)		Disturbance in vision, torsades de pointes	8–12	Increased efficacy against non-Albicans spp., including C. krusei and Aspergillus spp.	[102–104]
*Echinocandins*
Caspofungin (iv.)	Inhibits 1,3-β-d-glucan synthase enzyme complex → inhibit formation of glycan polymers of the fungal cell wall		1–2.5	Candida spp. and Aspergillus spp.	[105,106,111–114,121]
Micafungin (iv.)		Need more studies, RCT currently in progress	7–10; 10–15 if CNS involvement		[108–110,122]
Anidulafungin		Need more studies	1.5		[123]
*Nucleoside analogues*
Flucytosine	Inhibits fungal nucleic acid synthesis	Bone marrow suppression	50–200	Candida meningitis	[88,90,105]