Managing Invasive Fungal Infections in Newborns

Combination Therapy

There is a paucity of data in neonates examining combination therapy. In a study by Linder et al., a second antifungal agent (fluconazole) was used in combination with amphotericin B in patients with fungal sepsis if one of the following was present: positive urine culture; development of an abscess and/or 10 days of persistently positive cultures. Patients were treated for 14 days or more after negative culture or until radiographic resolution of abscess, if present.^[119] Overall mortality was 15%. Sterilization occurred in 36 patients (67%) with monotherapy and increased to 52 patients (96%) with polytherapy. Amphotericin B with the addition of flucytosine has been used to treat meningitis in infants who can tolerate the oral formulation of flucytosine. However, efficacy of this regimen has not been shown to be superior to that of amphotericin B alone. Flucytosine monotherapy rapidly leads to resistance, so flucytosine cannot be used alone. For meningitis in patients with CNS abscess or persistent CSF cultures, the addition of fluconazole (because of its excellent CSF penetration) is a therapeutic option.

Reduction of horizontal transmission in the NICU by hand washing, glove use and avoidance of artificial fingernails may help reduce transmission of Candida from healthcare workers to neonates. H2-receptor antagonists, proton pump inhibitors, broad-spectrum antibiotics (third-generation cephalosporins and imipenems) and glucocorticoids predispose to invasive Candida infection and should be avoided.^[13,53,124] In addition, the use of topical petrolatum is associated with an increase in invasive fungal infection and its use should be avoided.^[125] Medical hardware such as central venous catheters predispose neonates to biofilm formation and bloodstream infections. Efforts focussed on collaborative prevention bundles that focus on sterile catheter practices, hub and dressing care, and a dedicated team to place lines have shown to decrease central line-associated bloodstream infections.^[126–130] Measures to reduce reliance on catheters such as initiation of early feeding, feeding protocols and promoting breast milk may prevent invasive fungal infections by 16.5%.^[62,137]Aspergillus air spores should be prevented by filtration of NICU ventilation systems and containment of dust, especially during hospital renovation and construction. High-efficiency particulate air filters are excellent in clearing almost all of these fungi. NICUs should have continuous surveillance programs for mold, especially in and around windows. There is no evidence that single room isolation or cohorting infants who are colonized or infected with Candida decreases Candida colonization or invasive fungal infection.^[131]

The use of probiotics to reduce gastrointestinal Candida colonization has been suggested. In a prospective study of preterm infants, gastrointestinal Candida colonization rates were lower in patients who received either Lactobacillus reuteri or Lactobacillus rhamnosus compared with patients who received no probiotic therapy.^[132] In a large multicenter randomized controlled study, the use of bovine lactoferrin (with or without L. rhamnosus) was not associated with a decrease in fungal colonization rate compared with placebo, but the risk of invasive fungal infections was lower in preterm VLBW infants.^[133]

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]