Updated Perspectives on the Diagnosis and Management of Neonatal Invasive Candidiasis

Figures & data

Table 1 Risk Factors for Neonatal Invasive Candidiasis

	Non-Modifiable	Potentially Modifiable
Prenatal	Prematurity Low birth weight Vaginal delivery
Postnatal	Skin or GI colonization at delivery Low Apgar scores Hospitalization >7 days GI or mucosal compromise Sepsis or shock Disseminated intravascular coagulation Thrombocytopenia	Central venous catheters Groin catheters Mechanical ventilation Broad-spectrum antibiotics H2 blockers Systemic steroids Parenteral nutrition Intravenous lipid emulsion use

Abbreviations: GI, gastrointestinal; H2, histamine-2.

Table 2 Tools for Diagnosis of Neonatal Invasive Candidiasis: Strengths and Limitations

Test	Benefits	Limitations
Microbiologic culture	Species identification Antibiotic susceptibility testing	Long mean time to positivity (36–42 hours)^Citation39 Low sensitivity (~50%)^Citation40 High rate of intermittently or falsely negative cultures (21%)^Citation12 Requires a relatively large volume blood sample
Hyperglycemia, thrombocytopenia, leukocytosis	Rapid results	Conflicting data on significance
1,3-β-D-glucan	Sensitive (89%)^Citation31 Can be used to monitor response to treatment	Not specific (60%)^Citation31
Serum mannan/anti-mannan	Rapid results Sensitive (94.4%)^Citation41 Specific (94.2%)^Citation41 High negative predictive value (98%)^Citation41	Minimal sensitivity for C. parapsilosis and C. krusei infection
Blood T2Candida	Rapid results Sensitive (100%)^Citation42 Specific (94.1%)^Citation42	Only identifies 5 species – C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei High percentage (~10%) of invalid results^Citation43 Limited availability
Panfungal PCR	Available 2.2 days before culture on average Sensitive (87.5%)^Citation44 Specific (81.6%)^Citation44 High NPV in low prevalence settings (99%)^Citation37	Lack of standardization Limited studies in neonates Low PPV in low-prevalence cohort (16.7%)^Citation44

Abbreviations: PCR, polymerase chain reaction; NPV, negative predictive value; PPV, positive predictive value.

Table 3 Overview of Antifungal Therapy Used in the Treatment of Neonatal Invasive Candidiasis

Drug Class	Mechanism of Action	Drug	Important Properties	Notable Side Effects
Polyene	Interacts with ergosterol, leading to formation of pores in cell membrane	Amphotericin B deoxycholate	Highly protein-bound Excreted in urine and feces Variable volume of distribution and clearance in neonates Good CSF penetration	Infusion-related reactions Hypokalemia Questionable renal toxicity
Triazoles	Inhibit CYP450 enzyme that synthesizes ergosterol	Fluconazole	1st generation triazole Concentration-dependent activity Fungistatic activity Low protein binding High tissue, urine, and CSF penetration Renal elimination Requires dose adjustment based on gestational and postnatal age Strong CYP2C9 and CYP3A4 inhibitor	Gastrointestinal symptoms Rash Hepatotoxicity QT prolongation
		Itraconazole	1st generation triazole Concentration-dependent activity Fungistatic activity Variable, dose-dependent oral bioavailability Highly protein bound Extensive hepatic metabolism Excreted by liver and kidneys CYP3A4 inhibitor	Gastrointestinal symptoms
		Voriconazole	2nd generation triazole Concentration-dependent fungistatic activity Moderate protein binding Good tissue, CSF penetration Extensive CYP2C19 metabolism FDA approved for ages 2 and older Need for drug monitoring	Elevated transaminases Skin photosensitization
		Posaconazole	2nd generation triazole Concentration-dependent activity Fungistatic activity Highly protein bound Eliminated mostly in feces but also by kidneys Not FDA approved for infants Need for drug monitoring	Gastrointestinal symptoms
Echinocandins	Inhibit 1,3-β-D-glucan synthase	Micafungin	Concentration-dependent fungicidal activity Highly protein bound Inverse relationship between weight and clearance Dose-dependent CNS penetration Elimination via biliary system	Transaminitis Hypokalemia
		Caspofungin	Concentration-dependent activity Hepatic metabolism Dosing based on body surface area FDA approved for ages 3 months and older	Fever Rash Transaminitis Hypokalemia

Abbreviations: CSF, cerebrospinal fluid; CYP, cytochrome P; FDA, US Food and Drug Administration; CNS, central nervous system.

Table 4 Guidelines for the Treatment of Invasive Candidiasis in Neonates by Infectious Disease Society

IDSA		ESCMID		DMYG/PEG
Medication	Dosage	Medication	Dosage	Medication	Dosage
Amphotericin B deoxycholate	1 mg/kg daily	Amphotericin B deoxycholate	1 mg/kg daily
Fluconazole	12 mg/kg daily	Fluconazole	25 mg/kg loading dose followed by 12 mg/kg daily	Fluconazole	12 mg/kg daily divided over 4 doses
Amphotericin B lipid formulation	3–5 mg/kg daily	Liposomal amphotericin B	2.5–7 mg/kg daily	Liposomal amphotericin B	5 mg/kg daily divided over 4 doses
		Micafungin	4–10 mg/kg daily	Micafungin	2 mg/kg daily divided over 4 doses
				Caspofungin	25 mg/m^2 daily

Abbreviations: IDSA, Infectious Diseases Society of America; ESCMID, European Society for Clinical Microbiology and Infectious Diseases; DMYG, German Speaking Mycological Society (DMYG); PEG, Paul Ehrlich Society for Chemotherapy.

Table 5 Prevention of Invasive Candidiasis in Neonates as Recommended by the IDSA and ESCMID

Medication	Dosage
Fluconazole	3–6 mg/kg twice weekly
Nystatin	100,000 units three times daily for six weeks
Oral bovine lactoferrin	100 mg daily

Abbreviations: IDSA, Infectious Diseases Society of America; ESCMID, European Society for Clinical Microbiology and Infectious Diseases.

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