Invasive Fungal Infections in Newborns and Current Management Strategies

Shilpa Hundalani; Mohan Pammi

Expert Rev Anti Infect Ther. 2013;11(7):709-721.

Expert Commentary & Five-year Review

The emphasis in the next 5 years will be on the prevention of invasive fungal infection by targeting risk factors for colonization and invasive infection. Simple but significant measures for prevention of fungal infection should include early enteral feeding with human milk, avoidance of formula feeds, decreasing dependence on catheters and parenteral nutrition. Avoidance of broad-spectrum antibiotics, steroids, gastric acid reducing agents (e.g., H₂ blockers and proton pump inhibitors) is strongly recommended. Careful prevention of horizontal transmission in the NICU is paramount for C. parapsilosis infections. In addition, better molecular diagnostic techniques such as PCR, DNA sequencing and hybridization techniques will allow rapid detection even after antimicrobial treatment is started.^[148] Investigators are examining the role of biomarkers to diagnose and evaluate responses to antifungal therapy. These markers include β-glucan of the cell wall, anti-Candida antibodies, D-arabinitol (candidal metabolite) and fungal chitin synthase (assessed with PCR).^[149–151] Microarray technology and gene chips are being studied to rapidly determine susceptibility and resistance patterns at the time of diagnosis which will facilitate early initiation of therapy with the appropriate antifungal agent.^[152,153] Empiric antifungal therapy in the presence of risk factors and clinical illness has been debated, but careful modeling may indicate high-risk patients that may benefit before fungal cultures become positive. Use of prebiotics such as lactoferrin and probiotics optimized for the type of organisms and dosage have a great potential in altering the gastrointestinal microbiome of neonates, decreasing fungal colonization and hence invasive fungal infections. Antifungal prophylaxis with fluconazole or other agents such as nystatin or miconazole would be beneficial in high-risk patients such as ELBW infants or in units with high baseline fungal infection rates.

1 2 3 4 5 6 7 8 9

Next Section

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]