Managing Invasive Fungal Infections in Newborns

Epidemiology

The incidence of Candida infections is greatest in ELBW infants and is well demonstrated by a study from the National Nosocomial Infections Surveillance system that evaluated 130,523 patients admitted to 128 neonatal intensive care units (NICUs) between 1995 and 2004.^[3] The annual incidence of candidemia per 1000 patient-days for infants increased with decreasing gestational age and birth weight as follows: 0.5 in infants >2500 g, 0.42 in infants 1501–2500 g, 0.9 in infants between 1001 and 1500 g and 3.51 in infants <1000 g. In this study, the overall incidence of Candida bloodstream infections was 1.53 per 1000 patient-days among infants admitted to the NICU.^[3]Candida albicans and Candida parapsilosis were the causative agents in 6 and 4% of first episodes of late-onset sepsis, following coagulase negative Staphylococcus (48%) and Staphylococcus aureus (8%) in frequency.^[3]C. albicans was the most commonly isolated Candida species (60%) followed by C. parapsilosis (34%) in the 1997 identified cases of Candida bloodstream infections. Other Candida species included Candida tropicalis, Candida lusitaniae, Candida glabrata and Candida krusei isolated in 4, 2, 2 and <1% of cases, respectively.^[3] In another prospective study of 19 NICUs, invasive candidiasis (defined as a positive culture from a normally sterile fluid, such as blood, urine and cerebrospinal fluid [CSF]) occurred in 9% of 1515 ELBW infants (birth weight <1000 g).^[1] The rates of candidemia vary tenfold among tertiary care NICUs across the world, and it is possible that differences in clinical practice such as use of third-generation cephalosporins, steroids and gastric acid reducing agents, and feeding practices contribute to this wide range of incidence.^[4,5]

A change in the distribution of Candida species causing candidemia has been noted in several institutions with increasing isolation of non-Albicans species in neonates.^[6]C. parapsilosis is the second most commonly isolated Candida species, accounting for a quarter to a third of systemic neonatal Candida infections.^[3,7] In a review of neonatal C. parapsilosis infections, it comprised a third of all Candida infections with an associated mortality of approximately 10%.^[8]C. parapsilosis predominantly presents as a bloodstream infection, mostly in association with a central venous catheter. Although the use of prophylactic fluconazole has not resulted in an increase in the incidence of C. glabrata in neonates, it is important to monitor the relative incidences of the different Candida species as fluconazole use increases in NICU patients.^[9] Increased caspofungin use has also been associated with increased incidence of C. parapsilosis fungemia.^[10]

Fungal infections other than those caused by Candida species, are uncommon in neonates. Nonetheless, non-Candida fungal infections occur in neonates resulting in significant mortality and morbidity. Similar to Candida infections, the incidence of non-Candida fungal infections in neonates appears to be increasing, particularly in premature infants.^[11] Table 1 reviews invasive fungal infections in neonates including the uncommon fungal infections.^[1,11–33]

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]