Review of Fluconazole Treatment and Prophylaxis for Invasive Candidiasis in Neonates

Abstract

Invasive candidiasis accounts for approximately 10% of nosocomial infections in preterm infants, with an incidence of 1% to 4% among neonatal intensive care unit (NICU) admissions and a mortality as high as 20% to 30%. These outcomes warrant improved treatment and prevention strategies for infants at highest risk. The Infectious Diseases Society of America provides guidelines on antifungal medications for the prophylaxis and treatment of candidiasis in NICUs; however, there are still variations in practice on the use of fluconazole for prophylaxis and treatment of invasive candidiasis. This review provides specific information regarding fluconazole activity, pharmacokinetics, and a literature evaluation of dosing strategies and comparisons to other treatments in the neonatal population.

Introduction

Invasive candidiasis accounts for approximately 10% of nosocomial infections in preterm infants, with an incidence of 1% to 4% among NICU admissions.¹ With advances in treatment and improved understanding of modifiable risk factors, infections by Candida species have been on the decline. However, mortality is still as high as 20% to 30%, and rates of morbidity are estimated at 59% to 73%.^2,3 Owing to the complications and risks associated with infections caused by Candida spp, the Infectious Diseases Society of America (IDSA) has provided guidance on the use of antifungal medications within this population.⁴

The IDSA guidelines are endorsed by the American Academy of Pediatrics and the Pediatric Infectious Disease Society and address the prophylaxis and treatment of Candida spp infections for patients with varying ages. Fluconazole, a triazole antifungal with activity against many Candida spp, is recommended as an option for treatment and prophylaxis of candidiasis when warranted by institution-specific data.

Diagnosis of Invasive Candidiasis in Neonates

Preterm infants are primarily at risk of invasive fungal infections owing to an underdeveloped immune system. The underdevelopment of the epidermis layer of the preterm infant's skin and the permeable nature of the gastrointestinal tract both increase the risk of translocation of Candida spp.⁵ Besides their immature immunologic status, preterm infants are at increased risk for invasive candidiasis (IC) due to the use of parenteral nutrition, mechanical ventilation, central venous access, postnatal corticosteroids, and broad-spectrum antibiotics, particularly third-generation cephalosporins and carbapenems. In addition, abdominal surgery and intestinal infections place preterm infants at greater risk.^6,7

The common presentation of an invasive fungal infection in preterm infants typically occurs around the third week of life, is similar in nature to signs and symptoms of generalized late-onset sepsis (respiratory distress, feeding intolerance, lethargy, and hypotension), and is the result of a predominately Candida spp infection.⁸ Organ systems impacted by candidiasis in preterm infants, particularly with persistent infection, include the CNS (25%), kidney (5%), eye (3%), and heart (5%).^9–11 This is the reason IDSA recommends that infants treated for a CNS infection should have a lumbar puncture and dilated retinal examination if blood and/or urine cultures are positive for Candida spp. IDSA also recommends imaging using either CT or ultrasonography of the genitourinary tract, liver, and spleen with persistently positive blood cultures for Candida spp.⁴ Further laboratory parameters indicative of Candida infection in preterm infants include hyperglycemia and prolonged thrombocytopenia with a lower nadir than seen with bacterial infection.^6,12

Fluconazole

Spectrum of Activity. Fluconazole inhibits fungal cytochrome P450 activity, decreasing ergosterol synthesis, and inhibiting cell membrane formation. Its activity against various Candida spp includes the 2 most common causative fungi of invasive fungal infections in infants: C albicans and C parapsilosis.⁴ Additionally, fluconazole is active against various other less common Candida spp, including C dubliniensis, C lusitaniae, and C tropicalis, while having minimal activity against C glabrata and no activity against C krusei. The MIC breakpoints for these organisms are provided in Table 1. Activity against less common causative agents is not well described, but few reports have described the successful use of fluconazole in cases against C lusitaniae and C dubliniensis. Table 2 describes the MIC cutoffs for selected wild-type Candida spp and suggested epidemiologic thresholds, which may help clinicians understand fluconazole's role in treatment against infections caused by these organisms.¹³

Table 1.

Minimum Inhibitory Concentration (mg/L) Breakpoints for Fluconazole Against Common Candida Species⁴

Candida Species	Minimum Inhibitory Concentration, mg/L
	Susceptible	Intermediate*	Resistant
C albicans	≤2	4	≥8
C glabrata†		≤32	≥64
C krusei	—	—	—
C parapsilosis	≤2	4	≥8
C tropicalis	≤2	4	≥8

^* Susceptibility depends on achieving the maximum serum drug concentration.

^† If fluconazole is appropriate to use, then maximum dosage should be used.

Table 2.

Minimum Inhibitory Concentration (mg/L) Distributions for Wild-Type Candida Species¹³

Candida Species	Minimum Inhibitory Concentration, mg/L														ECV*(%)
	<0.008	0.015	0.03	0.06	0.12	0.25	0.5	1	2	4	8	16	32	64
C dubliniensis					20	24	23		1	1			1		0.5 (95.7)
C guilliermondii							8	32	88	52	6	5	3	2	8 (95)
C lusitaniae					47	81	99	34	9				1	1	2 (98)

^* Epidemiologic cutoff value.

Pharmacokinetics. From data extrapolated from adult studies, fluconazole is one of the first-line therapies for IC and one of the most common antifungals used in neonatal patients.¹⁴ It is excreted nearly unchanged in the urine and has excellent penetration into the cerebral spinal fluid.¹⁵ In addition, studies have shown that IV and enteral fluconazole achieve comparable serum concentrations in preterm infants.^16,17

For treatment doses, the target area under the concentration curve at 24 hours (AUC₂₄) is ≥400 mg^*hr/L if the MIC breakpoint is ≤8 mg/L. The ratio of AUC₂₄/MIC >50 mg^*hr/L is associated with clinical efficacy in adult patients. Contrasting with adult data, pharmacokinetic (PK) studies in infants have demonstrated that higher doses of 12 mg/kg/day are required to reach these target concentrations.^18–20 The model from one study predicted a daily dose of 6 mg/kg/day would not reach this therapeutic target.¹⁹ While several studies have demonstrated higher dosing requirements than had been previously used, additional clinical outcomes data need to be studied in infants.

Additionally, the larger volume of distribution and prolonged half-life of fluconazole in infants compared with adults led investigators to study a more rapid attainment of therapeutic targets. This was achieved by providing loading doses of 25 mg/kg to infants for treatment of IC.^20–22 In 2011, Piper et al²⁰ conducted a single-center, open-label trial to evaluate the PK and safety of a 1-time fluconazole 25-mg/kg loading dose in infants younger than 60 days old. Patients had a median postnatal age of 16 days and median gestational age (GA) of 37 weeks. Drug concentrations from 8 infants were obtained, and 5 infants achieved the therapeutic target of an AUC₂₄ ≥400 mg^*hr/L after a single loading dose. The median AUC₂₄ of all 8 infants was 479 mg^*hr/L (IQR, 347–496) with no adverse events thought to be related to fluconazole.²⁰

Leroux et al²² conducted a prospective, randomized, open-label, PK and safety study of fluconazole and micafungin in NICUs in Spain and France. Eighteen infants received a fluconazole 25-mg/kg loading dose followed by 12 mg/kg/day or 20 mg/kg/day for infants <30 weeks' GA or ≥30 weeks' GA, respectively. All patients reached the target systemic exposure of AUC₂₄ ≥400 mg^*hr/L. A Monte Carlo simulation showed that this target attainment at 24 hours of therapy increases from 30% to 93% when a loading dose is used. No adverse effects due to fluconazole therapy were reported.²² Although these studies were included in its report, the IDSA guidelines highlight the need for further studies before a loading dose can be formally recommended. While there is variability in practice among institutions regarding the use of a loading dose of fluconazole, the opinions of the authors of this review favor use of a loading dose in clinical practice for neonates with concern for invasive candidiasis.

Monitoring. The most common adverse effects associated with fluconazole include gastrointestinal irritation and elevations in liver function tests.²³ Weekly monitoring of aspartate transaminase, alanine amino-transferase, and alkaline phosphatase is a reasonable approach owing to data suggesting elevations in liver functions tests are comparable to placebo.²⁴ However, hepatotoxicity is not related to the amount or duration of exposure to therapy.²⁵ Because its elimination is dependent on renal function, fluconazole dosing is adjusted on serum creatinine values and GA of the patient.¹⁹ With similar PK parameters of either IV or enteral administration route, clinicians may use either formulation of fluconazole to produce similar response rates.¹⁶

The greatest long-term concern for the use of fluconazole prophylaxis in all extremely preterm infants is the risk of emergence of organisms with increasing antifungal resistance. A study by Lee and colleagues²⁶ reported an increase in the incidence of invasive infections with fluconazole-resistant C parapilosis in the patients receiving fluconazole prophylaxis of 3 mg/kg/dose twice weekly. This highlights the need to consider restrictions for use of fluconazole prophylaxis to infants at highest risk for infection. Additionally, studies are also needed to determine any potential impact on neurological development, as long-term data are currently not available.²⁷

Fluconazole for Prophylaxis Against Invasive Candidiasis

A recent meta-analysis evaluating various dosing regimens for the use of prophylactic fluconazole in NICUs recommended that only if fluconazole prophylaxis is warranted, should the lowest dose of fluconazole at 3 mg/kg be used in units in order to decrease the potential for adverse effects and increased cost while maintaining a high rate of efficacy in units with lower resistance rate.²⁸ Similar to treatment dosing, fluconazole prophylaxis dosing strategies in extremely preterm infants have been based on PK data with consideration for the MIC of colonizing Candida spp. These dosing strategies are summarized in Table 3. To prevent the emergence of more resistant Candida isolates, the target AUC₂₄ of 50 to 100 mg^*hr/L should be maintained. In NICUs with surveillance and in vitro susceptibility testing of fungal isolates of Candida spp with MIC ≤ 2 mg/L, fluconazole 3 mg/kg every 72 hours has been shown to prevent the growth of Candida spp for the first 42 days of life in infants born <30 weeks' GA. However, for MIC > 2 to 4 mg/L, fluconazole dosing must be higher at 6 mg/kg every 72 hours for the first 42 days followed by 6 mg/kg every 48 hours to achieve the target time above the MIC.^19,29

Table 3.

Fluconazole Prophylaxis Dosing Studies in Premature Infants

	Type of Study	Population	Number of Infants	Fluconazole Dose
Saxen50	Pharmacokinetic	750–1100 g	12	6 mg/kg every 72 hr
Kicklighter31	Single-center RCT	<1500 g	103	6 mg/kg every 72 hr first wk of life, then daily until 28 days
Kaufman32	Single-center RCT	<1000 g	100	3 mg/kg every 24–72 hr first 6 wk
Kaufman51	Single-center RT	<1000 g	81	3 mg/kg every 72 hr vs 3 mg/kg every 24–48 hr
Manzoni30	Multicenter RCT	<1500 g	322	3 mg/kg or 6 mg/kg for 30 days in 1000–1500 g, for 45 days in <1000 g
Parikh52	Single-center RCT	<1500 g	120	6 mg/kg every 72 hr for first 7 days, then daily until 28 days
Wade19	Population pharmacokinetics	23–40 wk GA	55	For <30 weeks’ GA: 3 mg/kg or 6 mg/kg twice weekly for 42 days
Benjamin33	Multicenter RCT	<750 g	361	6 mg/kg twice weekly for 42 days
Momper29	Population pharmacokinetics	<750 g	141	6 mg/kg twice weekly

GA, gestational age; RCT, randomized, blinded, placebo-controlled trial; RT, randomized trial

Several trials have also evaluated the safety and efficacy of fluconazole prophylaxis for IC in preterm infants.^30–33 A meta-analysis of randomized, placebo-controlled trials of preterm infants conducted in the United States showed that fluconazole prophylaxis was safe compared with placebo, with similar reported incidence of adverse effects and no difference in the proportion of resistant isolates to fluconazole between groups.³⁴ In addition, fluconazole prophylaxis reduced the odds of IC or death as well as colonization of Candida spp.³⁴ Despite demonstrating both safety and efficacy in reducing rates of IC, investigators have concluded that fluconazole prophylaxis should be limited only to preterm infants at high risk. The authors of this review do not routinely use fluconazole prophylaxis owing to low rates of IC in their respective NICUs; however, when prophylaxis is considered for high-risk infants, the authors' use of 3-mg/kg vs 6-mg/kg dosing strategies varies as based on local MIC data. Institutions should evaluate their concern for resistant Candida spp and weigh this with the potential for adverse effects from fluconazole.

IDSA recommends that centers with high rates of IC, defined as an incidence >10%, should use either IV or enteral fluconazole prophylaxis for 6 weeks in extremely low birth weight (ELBW) infants. These recommendations are consistent with significant relative reduction (RR) in IC incidences seen in the fluconazole prophylaxis trials. The RR is approximately 80% in most trials; therefore, it is likely that the highest-risk NICUs would see the most meaningful reduction with fluconazole prophylaxis.³⁵ For instance, if the baseline IC incidence is 20%, an 80% RR would decrease the rate to 4% with the use of fluconazole prophylaxis. The number needed to treat would be 6 patients in order to prevent 1 additional case of IC. However, for centers with lower overall rates, it is not clear if routine prophylaxis would provide significant benefit because the number needed to treat would be significantly higher.

Many centers still use prophylaxis in a select number of high-risk infants even if their NICU has a low incidence of IC.^36,37 An association of IC and treatment with third-generation cephalosporins and other broad-spectrum antibiotics in ELBW infants has been observed. In more than 3700 ELBW infants across similar NICUs, the incidence of IC ranged from 2.4% to 20.2%. Centers with higher incidences of IC had higher average number of days of broad-spectrum antibiotics (like cefotaxime) administration with negative cultures per patient.^2,38 Potentially modifiable risk factors, such as prolonged use of central venous access and broad-spectrum antibiotics, should be evaluated and minimized.^6,39 If avoidance of broad-spectrum antibiotics is not possible for high-risk ELBW infants, selective use of fluconazole prophylaxis may reduce the risk of IC for those individual patients.

Similar to IDSA guidelines for prophylaxis, guidelines from the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) recommend fluconazole prophylaxis in ELBW infants in NICUs with a high frequency of IC.^40,41 Both also suggest the use of nystatin 100,000 units (1 mL) orally every 8 hours, but this is moderately supported by ESCMID and weakly recommended by IDSA when fluconazole is not available or if triazole resistance is suspected. Experts from ESCMID also suggest that the use of lactoferrin 100 mg/day alone or in combination with lactobacillus should be instituted in very low birth weight infants to reduce late-onset sepsis.

Recommendations for the Treatment of Invasive Candidiasis

The clinical practice guideline for the management of candidiasis, previously published in 2009 by IDSA,⁴⁰ was updated in 2016.⁴ The main treatment recommendations for disseminated candidiasis in infants did not change, with the guidelines making a strong recommendation of amphotericin B deoxycholate 1 mg/kg IV daily as first-line treatment, based on moderate quality evidence. The guidelines continue to strongly recommend fluconazole 12 mg/kg IV or enterally daily as a reasonable alternative for patients who have not previously received fluconazole prophylaxis, also based on moderate quality evidence. The liposomal formulation of amphotericin B 3 to 5 mg/kg IV daily is an alternative, but it should be used with caution in the presence of urinary tract involvement and concern for renal fungal balls. Echinocandins should be reserved for salvage therapy in the setting of toxicity from or resistance to first-line agents. The recommended duration of therapy for candidemia for localized infections is 2 weeks after documented clearance of Candida spp from the bloodstream and resolution of signs attributable to candidemia.^4,40

The 2016 IDSA guidelines also elaborate on the management of CNS candidiasis treatment.^4,40 Based on low-quality evidence, the guidelines strongly recommend amphotericin B deoxycholate 1 mg/kg IV daily as the preferred initial treatment, and liposomal amphotericin B 5 mg/kg IV daily may be used as an alternative. The addition of enteral flucytosine is recommended for use only in infants who have not responded to amphotericin monotherapy, because it is poorly tolerated. Step-down therapy from amphotericin to fluconazole 12 mg/kg daily is recommended in patients following clinical response to initial regimen and determination of in vitro susceptibility. Optimal duration of treatment for CNS candidiasis is unclear but should be continued until clinical, microbiologic, and radiographic resolution is achieved.^4,40

In contrast to the IDSA treatment guidelines, the ESCMID recommends different dosing for liposomal amphotericin B of 2.5 to 7 mg/kg/day, based on pre-clinical data that demonstrated antifungal activity in the brain.⁴¹ In addition, the fluconazole dosing differs in that the ESCMID recommends a loading dose of 25 mg/kg, followed by 12 mg/kg in neonates who have not received fluconazole. Despite receiving both FDA and European Medicines Agency approval for use in neonates, micafungin at a dose of 4 to 10 mg/kg/day is recommended for treatment of neonatal IC in the ESCMID guidelines. The guidelines further outline that higher doses of micafungin 10 mg/kg/day should be used for CNS disease. The combination of amphotericin and flucytosine is not defined in the ESCMID guidelines.

Comparative Evaluation of Fluconazole to Other Antifungals for the Treatment of Invasive Candidiasis

Amphotericin B deoxycholate has historically been the mainstay agent for the treatment of neonatal candidiasis. The first study of fluconazole in neonates was published in 1994.²³ Patients received fluconazole only if antifungal therapy with amphotericin B was ineffective or contraindicated. Mycologic eradication with fluconazole was reported in 30 of 31 subjects (97%), including 10 of 10 subjects with confirmed meningitis (100%). Since this original study was published more than 2 decades ago, few comparison studies have been published to help guide empiric selection of antifungal agents in the neonatal population.

The moderate quality evidence cited for amphotericin B deoxycholate and fluconazole for neonatal candidiasis at the time of the most recent IDSA publication in 2016 included only 4 studies.^2,42–44 Similarly, the 2012 Cochrane review evaluating antifungal therapy for invasive fungal infections in newborn infants concluded that insufficient data exist to guide practice.⁴⁵ The final analysis only included 1 study that was cited in the IDSA guideline.⁴² Only 2 of these studies provide comparative data between amphotericin B and fluconazole: one was a small prospective study and the other was a larger multicenter retrospective study.^42,44 A summary of these 2 studies can be found in Table 4. Based on the need for more robust data to recommend one empiric agent, there continues to be variability among NICUs regarding the preferred first-line antifungal choice for neonatal candidiasis.

Table 4.

Summary of Studies Comparing Fluconazole and Amphotericin B Products in Neonates

Study	Study Population	Methods	Results
Driessen42	23 infants <3-mo-old with fungal septicemia; Mean BW, 1300–1400 g; Mean PNA, 27–30 days; C albicans only (n = 14); Other Candida (n = 5); C albicans with other fungus (n = 2); other (n = 2)	Prospective, randomized Groups: AMB-D IV 1 mg/kg/day (n = 11) FLC IV/PO 10 mg/kg LD then 5 mg/kg/day (n = 12)	Mortality was 33% in the FLC group compared with 45% in the AMB-D group; Significant increase in DBili with AMB-D compared with FLC; Overall increase in liver enzymes with AMB-D compared with overall decrease with FLC; No difference in renal or hematologic toxicities; higher incidence of thrombophlebitis with AMB-D (n = 5) than with FLC (n = 1); Number of days central line needed for treatment higher with AMB-D (27 days) than with FLC (0 days)
Ascher44	730 infants <120-days-old with positive Candida cultures and received an antifungal agent for at least 1 day; Mean GA, 27 wk; Mean BW, 1035 g; PNA at start of therapy, 23 days	Retrospective; database of 192 NICUs Groups: AMB-D ABLC products FLC	Higher mortality with ABLC than FLC (29% vs 16%; OR 2.39 [1.18, 3.33]) No difference in mortality with AMB-D and FLC (18% vs 16%); Therapeutic failure was highest with ABLC products than with AMB-D and FLC (47% vs 38% vs 40%; NS for comparisons to FLC); no difference in duration of treatment between agents

ABLC, amphotericin B lipid complex; AMB-D, amphotericin B deoxycholate; BW, birth weight; Dbili, direct bilirubin; FLC, fluconazole; GA, gestational age; LD, loading dose; NS, non-significant; PNA, postnatal age; PO, enterally

Based on existing data, fluconazole seems to be a reasonable alternative to amphotericin B deoxycholate for the empiric management of candidiasis and a preferred agent over liposomal amphotericin B. Potential mechanisms for the decreased efficacy of liposomal amphotericin B for neonatal candidiasis include inadequate penetration to the kidneys and understudied dosing strategies for preterm infants. Some additional practical reasons fluconazole may be preferred over amphotericin products include its availability as an oral suspension as well as its improved IV compatibility profile, compared with amphotericin B products. Infants are often limited by their IV access, and those with candidiasis are often critically ill and receiving multiple continuous infusions and parenteral nutrition. Incompatibilities may limit the ability to administer amphotericin B products to these patients. A comparison of compatibility data between fluconazole and amphotericin B with frequently used continuous IV medications in the neonatal population is presented in Table 5.

Table 5.

Intravenous Compatibility of Commonly Used Neonatal Medications and Fluconazole Vs Amphotericin B Deoxycholate^46,47

Medication	Fluconazole	Amphotericin B Deoxycholate
Cisatracurium	C	Variable†
Dexmedetomidine	C	I
Dobutamine	C	I
Dopamine	C	I
Epinephrine	C	I
Fentanyl	C	Variable‡
Furosemide	Variable*	Variable§
Insulin regular	C	Variable¶
Midazolam	C	I
Morphine	C	I
Parenteral nutrition (2-in-1)	C	I
Parenteral nutrition (3-in-1)	C	I
Rocuronium	C	I
Vasopressin	C	I
Vecuronium	C	I

AMB-D, amphotericin B deoxycholate; C, compatible; FLC, fluconazole; I, incompatible

^* FLC 2 mg/mL was found to be compatible in 4 studies using furosemide 5 mg/mL and incompatible in 1 study using furosemide 10 mg/mL.

^† AMB-D 0.6 mg/mL in Dextrose 5% was found to be compatible in 1 study using cisatracurium 0.1 mg/mL in Dextrose 5% but incompatible in 2 studies using cisatracurium 2 mg/mL and 5 mg/mL.

^‡ AMB-D 0.4 mg/mL was found to be compatible in 1 study using fentanyl 25 mcg/mL in Dextrose 5% and incompatible in 3 studies using fentanyl 25 mcg/mL in Dextrose with sodium-containing solutions. Incompatibility was also noted with diluents alone due to the sodium-containing solutions. Likely compatible in dextrose only containing solutions.

^§ AMB-D 0.4 mg/mL was found to be compatible in 1 study using furosemide 5 mg/mL in Dextrose 5% and incompatible in 3 studies using furosemide 5 mg/mL in Dextrose with sodium-containing solutions. Incompatibility was also noted with diluents alone due to the sodium-containing solutions. Likely compatible in dextrose-only–containing solutions.

^¶ AMB-D 0.4 mg/mL was found to be compatible in 1 study using insulin regular 50 units/mL and incompatible in 3 studies using insulin 50 units/L in sodium-containing solutions. Likely compatible in dextrose-only–containing solutions.

To date, no comparative studies for fluconazole to other agents such as echinocandins or other triazole antifungal agents for the treatment of neonatal candidiasis are available. Pharmacokinetic data of echinocandins in neonates are still limited. A recent study evaluated the PK of micafungin and compared the outcomes to treatment with amphotericin B deoxycholate in a small cohort of patients.⁴⁶ Fungal-free survival was noted in 12 of 20 (60%) micafungin subjects compared with 7 of 10 (70%) amphotericin B deoxycholate subjects. Further research comparing antifungal agents to help guide practice, including empiric medication selection and dose optimization, is needed.

Conclusion

Despite the decline in the incidence of IC in the United States over the past decade, a high morbidity and mortality continues in infants, especially the ELBW population.⁴⁹ In those who survive, a high rate of neurodevelopmental impairment is observed. These outcomes warrant improved treatment and prevention strategies for infants at highest risk. Randomized controlled trials have demonstrated both safety and efficacy of fluconazole prophylaxis for the prevention of IC in these infants, and NICUs with high rates of IC may benefit from this strategy. Prophylactic fluconazole dosing of 3 or 6 mg/kg every 72 hours should be considered. In addition, empiric treatment with fluconazole 25-mg/kg loading dose followed by 12 mg/kg/day is being used more commonly in NICUs because of several safety and feasibility advantages over amphotericin B and echinocandins. On the basis of the available literature, the authors of this article use fluconazole loading doses when clinical scenarios warrant their use, such as concern for disseminated candidiasis, septic shock, or confirmed fungemia with neutropenia. However, more PK, safety, and efficacy studies are needed to support current antifungal guidelines for neonatal patients.

ABBREVIATIONS

ABLC

amphotericin B lipid complex

AMB

amphotericin B

AMB-D

amphotericin B deoxycholate

AUC₂₄

area under the concentration curve

BW

birth weight

C

compatible

CNS

central nervous system

CT

computed tomography

Dbili

direct bilirubin

ELBW

extremely low birth weight

ESCMID

European Society for Clinical Microbiology and Infectious Diseases

FDA

US Food and Drug Administration

GA

gestational age

I

incompatible

IC

invasive candidiasis

IDSA

Infectious Diseases Society of America

IQR

interquartile range

IV

intravenous

LD

loading dose

MIC

minimum inhibitory concentration

NI

no information

NICU

neonatal intensive care unit

NS

non-significant

PK

pharmacokinetic

PNA

postnatal age

PO

enterally

RR

relative reduction

RCT

randomized, blinded, placebo-controlled trial