Invasive Fungal Infections in Newborns and Current Management Strategies

Shilpa Hundalani; Mohan Pammi

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

Diagnosis

Systemic Disease or Invasive Focal Infection

Cultures of the Blood, Urine & CSF Multiple or repeat blood cultures should be performed to increase the likelihood of detecting candidemia as the sensitivity of a single blood culture is low in detecting disseminated candidiasis. Blood cultures can be negative in up to 50% of autopsy-proven cases of deep-seated candidiasis or may only become positive late in the infection.^[66,83,84] If a central venous catheter is present, cultures should be obtained through the catheter and a peripheral vessel to distinguish between disseminated infection and catheter-related candidiasis. A drawback of all blood culture systems as the primary means of establishing the diagnosis of candidemia is that 1–4 days are required for growth of the organism. Molecular diagnostic methods based on amplification of fungal ribosomal DNA in blood samples are under evaluation.^[85] The diagnosis of a Candida infection of any one organ system should prompt a thorough examination and evaluation to detect candidemia and other organ involvement. Other options are as follows:

Cranial imaging by head ultrasound, CT or MRI is recommended in systemic candidiasis;
Dilated eye examination;
Echocardiogram to determine whether there are any cardiac thrombi or vegetations;
Diagnostic imaging of the liver, spleen and kidney;
Skin biopsy to confirm invasive fungal dermatitis.

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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]