Treatment of Invasive Candida Infections in the Neonatal Intensive Care Unit

PHARMACOLOGYAND PHARMACODYNAMICS OF ANTIFUNGAL AGENTS (P GUBBINS, SECTION EDITOR)

Treatment of Invasive Candida Infections in the NeonatalIntensive Care Unit

Megan G. Andrews & Roshni Patel & Jamie Miller

Published online: 5 April 2013# Springer Science+Business Media New York 2013

Abstract Invasive Candida infections are a leading cause ofmorbidity and mortality in the neonatal intensive care unit(NICU). Extremely preterm and very low birth weight infantsare at the highest risk of infection. There are currently noantifungal agents that have FDA-labeling for the treatment ofinvasive candidiasis in the neonatal population. Based on thecurrent IDSA guidelines, amphotericin and fluconazole areconsidered first-line options for neonatal candidiasis. Thenewer antifungal agents (i.e., echinocandins and voriconazole)are currently considered second-line or salvage therapy; how-ever, evidence supporting their use is emerging. This reviewfocuses on the supporting evidence for the selection of anti-fungal agents for treatment of invasive Candida infections inthe NICU.

Keywords Candida . Neonate . Infant . Antifungal

Introduction

The incidence of Candida central line–associated blood-stream infections (CLABSI) in U.S. neonatal intensive careunits (NICU) has been reported as 0.2 per 1000 central-line

days [1••]. Approximately 50 % of Candida CLABSI’s in theNICU are identified as C. albicans. The remaining 50 % areattributed to C. parapsilosis, C. tropicalis, C. lusitaniae, andC. glabrata, with C. parapsilosis occurring most frequently[1••]. Risk factors for invasive fungal infections in this popu-lation include prematurity, very low birth weight (VLBW),use of central lines, intubation, parenteral nutrition, broad-spectrum antibiotics, prolonged hospitalization, use of acid-suppressant agents, and colonization with Candida [2].

Antifungal agents used in the treatment of invasivecandidiasis in the NICU are broadly classified into fourgroups: polyenes (e.g., amphotericin), fluorinated pyrim-idines (i.e., flucytosine), triazoles (e.g., fluconazole), andechinocandins (e.g., caspofungin). No antifungal agentshave FDA-approved labeling for the management ofinvasive candidiasis in infants less than three monthsof age. Selection of the most appropriate agent shouldtake into consideration the institution’s susceptibilitypatterns, site of infection, and other patient specificfactors. This review will focus on the supporting evidencefor use of antifungal agents in the NICU.

Literature Search

A literature search was conducted utilizing MEDLINE(1946–December 2012), EMBASE (1980–December2012), International Pharmaceutical Abstracts (1970–December 2012), and the Cochrane Database of SystematicReviews (2005–December 2012) using the key wordsinfant, neonate, candida, amphotericin, fluconazole,voriconazole, caspofungin, micafungin, anidulafungin, andflucytosine. Results were limited to human studies pub-lished in English. Reference citations from relevant articleswere also reviewed. In an effort to capture the most currentevidence of antifungal use in the NICU, studies publishedsince 2000 were given priority. Older studies were includedif deemed relevant or if no current studies were identified.

M. G. Andrews : R. Patel : J. Miller (*)Department of Pharmacy: Clinical and Administrative Sciences,University of Oklahoma College of Pharmacy, P.O. Box 26901,1110 N. Stonewall Ave., CPB 206,Oklahoma City, OK 73117, USAe-mail: [email protected]

M. G. Andrewse-mail: [email protected]

R. Patele-mail: [email protected]

J. MillerDepartment of Pediatrics,University of Oklahoma College of Medicine,Oklahoma City, USA

Curr Fungal Infect Rep (2013) 7:96–109DOI 10.1007/s12281-013-0134-1

Antifungal Agents Used in the Treatment of Candidiasis

Amphotericin B

Amphotericin is a broad-spectrum agent with activityagainst many species including Aspergillus, Coccidioides,Histoplasma and Candida species. Amphotericin exhibitsfungicidal activity by binding to ergosterol and altering thepermeability of the cell membrane [3]. In addition toamphotericin dexoycholate [AmpD] (i.e., “conventional”amphotericin), three liposomal formulations [i.e.,amphotericin B lipid complex (ABLC, Abelcet®), liposomalamphotericin B (LAMB, AmBisome®), and amphotericin Bcolloidal dispersion (ABCD, Amphotec®)] were introducedin the 1990’s in an effort to limit renal toxicity and improvedelivery to the reticuloendothelial organs (e.g., lungs) [4].

Amphotericin B is one of the most commonly prescribedagents for treatment of invasive candidiasis in the neonatalpopulation [5]. The Infectious Disease Society of America(IDSA) recommends the use of AmpD 1 mg/kg/day as afirst-line treatment option for disseminated neonatal candidia-sis. Because liposomal amphotericin formulations (LipAF) donot concentrate in the urine, AmpD is recommended when theurine culture is positive [6••]. Lipid amphotericin B formula-tions at doses of 3–5 mg/kg/day are recommended as first-lineagents if the urine culture is negative [6••]. Prasad and col-leagues evaluated prescribing patterns of antifungals and founda significant shift in prescriptions from AmpD to LipAF due todecreased renal toxicity associated with LipAF [5].

Pharmacokinetics of Amphotericin B

There is limited pharmacokinetic (PK) data of AmpD in in-fants [7–9]. The PK studies conducted by Koren and col-leagues and Starke and colleagues both included neonatesand older children, with 18 neonates represented [8, 9]. Theseauthors report significant interpatient variability for half-life,volume of distribution (Vd), and clearance. The median half-life (hours), Vd (L/kg), and clearance (ml/min/1.73 m2) of theneonates in these studies were reported as 14.8, 1.5, and 19 byKoren and 22.1, 2.49, and 12 by Starke, respectively. The onlyAmpD PK study that focused specifically on neonates wasconducted by Baley and colleagues (Table 1) [7]. A notewor-thy finding of this study is that CSF concentrations were 40–60% of serum concentrations, exceeding the reported 5–10%in adults. This finding may explain why AmpD can be effec-tive for treatment of fungal meningitis in neonates.

Although LipAF use is increasing, only one PK study hasevaluated a lipid formulation. Wurthwein and colleaguesevaluated the PK of ABLC in 28 neonates and found thatdisposition is similar to other populations [10]. (Table 1)Urine concentrations were detectable; however, CSF con-centrations were minimal to undetectable.

Efficacy of Amphotericin B

Nine studies evaluating efficacy of amphotericin were iden-tified since 2000, representing 899 infants (Table 2). Thereare no randomized, comparison trials between agents. Thecomparison studies are nonrandomized prospective or retro-spective evaluations [11–13, 14••, 15] and the remainingstudies were descriptive evaluations [16–18]. Among theseevaluations, overall eradication rates with amphotericinranged from 53–100 %, with mortality rates between 5–18.2 % (Table 2).

A majority of the comparison trials found no differencein efficacy between AmpD and LipAF [11–13]. However,one study demonstrated decreased efficacy of LipAF [14••].This retrospective, database review included a large numberof infants (n=730) who received treatment for Candidapositive cultures. A majority of patients (68.0 %) receivedAmpD. Patients receiving any LipAF were included in onegroup. Two multivariable regressions were performed usingmortality and therapeutic failure as the dependent variables.These regressions were controlled for gestational age, age atinfection onset, delay in therapy, and infection site. Theauthors reported an increased failure rate (OR 1.62 [CI 1.00–2.64]) and mortality rate (OR 1.96 [CI 1.16–3.33]) inpatients receiving LipAF versus AmpD. Although variablesof acuity were included in the model, a limitation of thisstudy is the potential that LipAF were used in the moreacutely-ill patients because of decreased nephrotoxicity. Inaddition, extrapolation of these results to a specific lipidproduct is not feasible because patients were combined intoone treatment group.

To date, no study has demonstrated superiority of oneLipAF versus another. Two studies have compared the effi-cacy of LAMB and ABLC [12, 13]. Lopez-Sastre andcolleagues conducted an open-label, nonrandomized evalu-ation of antifungal therapy in 27 NICU’s [13]. A majority ofthese patients received either LAMB (n=81) or ABLC (n=29). No differences in mortality rate or mean time to clinicalrecovery were noted between these groups. These resultswere supported in a retrospective evaluation comparingLAMB (n=9) to ABLC (n=10) [12]. Only one study hascompared the efficacy of LAMB and ABCD in neonates[15]. In a prospective, open label study by Linder andcolleagues, neonates with a culture confirmed Candida in-fection were initiated on either AmpD, LAMB, or ABCD[15]. Patients with elevated serum creatinine were initiatedon either LAMB (n=6) or ABCD (n=14). No statisticallysignificant differences in mortality rate or eradication ratewere noted between patients treated with LAMB or ABCD.

The number of days until fungal eradication (i.e., nega-tive culture after a positive culture) was reported for sevenof the studies evaluating efficacy of amphotericin formula-tions [11–13, 14••, 15, 16, 18]. Fungal eradication in these

Curr Fungal Infect Rep (2013) 7:96–109 97

Tab

le1

Pharm

acok

inetic

Evaluations

ofAntifun

galAgentsin

Neonates/Infants

Reference

Descriptio

nof

studydesign

Study

populatio

nAge

atinitiation

Medicationanddose

Results

Amphotericin

Wurthwein

etal.[10]

Multicenter,open-label,

sequential-dose

escalatio

n(n=28)

GA:27

weeks

(range,24–41)

27days

(8–89)

ABLC

▪Dispositio

nnotdifferentfrom

otherage

groups

BW:0.91

kg(range,0.46–4.6)

2.5and5mg/kg/day

▪Term

inal

half-lifeof

395hours

▪CSFconcentrations

ranged

from

undetectable

to0.074mcg/m

L

▪Urine

concentrations

ranged

from

0.082±0.02

to0.205±0.04

mcg/m

L

Baley

etal.[7]

Open-label,dose

escalatio

n(n=13)

GA:Not

reported

Not

reported

AmpD

0.1-1mg/kg/day

▪CSFconcentrations

40–90

%of

serum

concentrations

BW:1.2±0.8kg

▪Interindividualvariability

forhalf-life,

Vd,

andCL

Fluconazole

Piper

etal.[22]

Prospectiv

e,open

label(n=10)

GA:37

weeks

(range,35–38)

16days

(range,13–32)

25mg/kg

loadingdose

follo

wed

by12

mg/kg/day

▪Fiveinfants(63%)achieved

the

therapeutic

target

of≥400mg*hr/L

onthefirstdayof

dosing

BW:2.8kg

(range,2.0–3.1)

▪MedianCLof

16mL/kg/hr

(range,13–21)

▪MedianVdof

1051

mL/kg

(range,858–1461)

▪Nodrug-related

adverseeffectsnoted

Wadeet

al.[21]

Doseexposure

Monte

Carlo

simulation

study(n=55)

GA:23

–40

weeks

Not

reported

3–12

mg/kg/day

▪Doses

of12

mg/kg/day

areneeded

toachieveAUCtarget

>400mcg*hr/L

BW:Not

reported

▪AUCtarget

canbe

achieved

byday2

with

loadingdose

of25

mg/kg

▪Doseadjustmentrequired

ifserum

creatin

ine≥1

.3mg/dL

for>96

hours

Wenzl

etal.[23]

Retrospectiv

ecase

series

(n=3)

Neonates:

Not

reported

4,4.5and5mg/kg/day

▪Doseof

4.5–6mg/kg/day

sufficient

tomaintainserum

concentrations

of5–15

mcg/m

LGA:24,28

and29

weeks

▪Vdincreasedin

neonates

comparedto

adults(1.21,

1.88,1.21

vs.0.65

L/kg,

respectiv

ely)

BW:Not

reported

▪Nodrug-related

adverseeffectsnoted

Caspofungin

Saez-Lorenset

al.[34•]

Multicenter,

noncom

parativ

eprospectivestudy

(Singledose,n=6;

multip

le-dose,n=12)

GA:24

–41

weeks

Not

reported

Panel

A:Singledose

of25

mg/m

2on

day1

▪Doses

of25

mg/m

2daily

resultin

similarexposure

toadultsreceiving

50mgdaily

BW:0.68-3.8

kg

Panel

B:25

mg/m

2perday

forat

least4days

▪Highertrough

concentrations

inneonates

vs.adults

▪Nodrug-related

adverseeventsnoted

98 Curr Fungal Infect Rep (2013) 7:96–109

Tab

le1

(con

tinued)

Reference

Descriptio

nof

studydesign

Study

populatio

nAge

atinitiation

Medicationanddose

Results

Micafungin

Hopeet

al.[46•]

PopulationPK,dose-range,

Monte

Carlo

simulation

(n=47)

GA:Not

provided

Not

reported

0.75

to15

mg/kg

▪PKslin

earfordosagesof

0.75

to15

mg/kg

Weighta:1.3±0.5kg

▪Suggested

infant

dose

of10

mg/kg/day

Benjamin

etal.[45]

Multicenter,open-label,

repeat

dose

(n=13)

7mg/kg

group:

7mg/kg

group:

44.1±37.4

days

7mg/kg/day

(if≥1000

gram

s)OR10

mg/kg/day

(if<1000

gram

s)

▪VdandCLhigher

ininfants<1kg

GA:29.6±5.5weeks

10mg/kg

group:

7.5±

5.5days

▪Drug-relatedadverseeffectsnoted:

increase

ALP,

phlebitis,hypokalemia,

temperature

elevation

Weighta:2.101±1.36

kg10

mg/kg

group:

GA:24.7±0.8weeks

Weighta:0.6877

±0.1067

kg

Smith

etal.[44]

Single-center,open-label,

repeated

dose

(n=12)

GA:27.0

weeks

(IQR,25.9–28.5)

4days

(range,2–

82)

15mg/kg

▪MeanCL34.5

mL/hr/kg

BW:0.775kg

(IQR,0.67–0.925)

▪CLmorerapidin

infants<1kg,butno

statistical

difference

(37.3vs

30.6

mL/hr/kg

▪Noadverseeventsreported

Heresiet

al.[43]

Phase

I,single-dose,

multicenter,open-label,

sequential-dose

(>1000

gram

weight

group,

n=18;

500–

1000

gram

weight

group,

n=5)

>1000

gram

group:

>1000

gram

group:

5.9±2.0weeks

>1000

gram

group:

0.75,1.5and3mg/kg

▪Shorter

meanhalf-life(8.3

hrs)

and

faster

CL(38.9mL/hr/kg)in

infants

vs.adults/older

child

ren

GA:26.4±2.4weeks

▪CLmorerapidin

infants<1kg

(79.3±12.5

ml/h

r/kg)vs.>1kg

BW:1.4974

±0.3033

kg500–1000

gram

group:

0.75

mg/kg

▪Hypokalem

iaidentifiedas

drug-related

adverseeffect

500–

1000

gram

group:

500–1000

gram

group:

GA:25.6±1.3weeks

Not

reported

BW:0.8476

±0.1738

kg

Anidulafungin

Cohen-W

olkowiez

etal.[51•]

Singlecenter,open-label

(n=15;8neonates,

7infants)

Neonates:

Neonates:

12days

(range,2–

28)

3mg/kg

loadingdose,

with

maintenance

dose

of1.5mg/kg/day

▪Doses

of1.5mg/kg/day

resultin

similar

exposure

tochild

renreceiving

1.5mg/kg/day

andadults100mg/day

GA:27

weeks

(range,26

–39)

Infants:

28days

(range,2–

451)

▪MedianCLof

0.017L/kg/hr

(range,0.005–0.049)

BW:1.12

kg(range,0.77–3.73)

▪MedianVdof

1.1L/kg(range,0.2–4.4)

Infants:

▪Nodrug-related

adverseeffectsnoted

GA:37

weeks

(range,24

–40)

BW:2.9kg

(range,0.66–3.969)

GA=gestationalage;

BW

=birthw

eight;ABLC=am

photericin

Blip

idcomplex;CSF=cerebrospinalfluid;

AmpD

=deoxycholate

amphotericin;Vd=volumeof

distributio

n;CL=clearance

aBirth

weightnotprovided


studies occurred at a mean of 5–10 days. However, thisoutcome cannot be compared across the studies because astandardized definition for fungal eradication was not used inall the studies. Juster-Reicher and colleagues evaluated LAMBat starting doses of 1 mg/kg/day with titration to a maximumdose of 5–7mg/kg/day [18]. These authors reported that fungaleradication was achieved more rapidly in patients who re-ceived aggressive titration of dose and suggested that LAMBtherapy should be initiated at 5–7 mg/kg/day. In studies com-paring agents, no statistically significant differences in time tofungal eradication were noted [11, 12, 14••, 15]. Linder andcolleagues reported no statistically significant differences ineradication days between AmpD, LAMB, and ABCD (8.4±5.8, 5.2±2.1, and 6.5±5.8, respectively), but these results doappear to be clinically significant considering a three daydifference [12]. These findings may be attributed to a type-2error due to small sample size.

Triazoles

The triazole class exhibits fungistatic activity by inhibitingthe fungal cytochrome P-450 (CYP) dependent enzyme,lanosterol-14-alpha-demethylase. Fluconazole andvoriconazole are the two triazole agents used in the neonatalpopulation and are available in enteral and intravenous (IV)formulations. In addition, both of these agents are inhibitorsand substrates of CYP2C19, 2C9, and 3A4. However,voriconazole has more drug-interactions because a greaterpercentage undergoes CYP450 metabolism when comparedto fluconazole [19].

Fluconazole

Fluconazole is commonly used in neonates. It has a broadspectrum of activity against many Candida species; al-though, some strains of C. glabrata have demonstratedincreased resistance to fluconazole, and all strains of C.kruseii are natively resistant [20]. Fluconazole’s PK profilemakes it attractive for treatment of invasive Candida. It hasgood oral bioavailability, excellent CSF penetration (70–80 %), and a long half-life [21]. The IDSA states thatfluconazole 12 mg/kg IV/PO every 24 hours is a suitablealternative to AmpD for the treatment of neonatal candidi-asis [6••]. Although the CSF penetration and adverse effectprofile favor fluconazole, it is considered an alternativebecause of the emergence of resistant Candida strains.

Pharmacokinetics of Fluconazole

Three PK studies were identified for fluconazole in infants[21–23]. Wade and colleagues conducted the largest PKstudy in 55 neonates [21]. The primary objective was todetermine the ideal fluconazole dose needed to achieve a

minimum area under the curve (AUC) of >400 mg*hr/L.Monte Carlo simulations were performed to predict flucon-azole exposure. It was demonstrated that traditional dosingof 6 mg/kg/day was insufficient to reach the AUC target.Doses of 12 mg/kg/day resulted in a median AUC of680 mg*hr/L for infants <30 weeks gestation and520 mg*hr/L for infants 30–40 weeks gestation. The authorsnoted that because of the long half-life in neonates, a25 mg/kg loading dose may be necessary to achieve theAUC target by day two versus day five with no loadingdose. Piper and colleagues also emphasized the need for aloading dose [22]. This study included late preterm and termneonates who received a 25-mg/kg loading dose. Sixty-threepercent of patients who received the loading dose achievedtherapeutic targets on day one, and all infants achieved theacceptable (>8 mg/dL) fluconazole concentration at24 hours. The authors highlight that no patient achieved anAUC >800 mg*hr/L, which is recommended in immuno-compromised adults with candidemia. Further research fo-cused on efficacy of loading doses is needed to determine ifthis practice results in a clinically significant difference, andmore data is needed for premature neonates due to differ-ences in PK parameters.

Efficacy of Fluconazole

Studies evaluating the efficacy of fluconazole for treatmentof neonatal candidemia were limited between the years of1994–2000. Six studies were identified, including four pro-spective and two retrospective evaluations [24–29]. Thesestudies represent 159 neonates who received either IVor POfluconazole. The overall eradication rates with fluconazolemonotherapy ranged from 63–97 %, and mortality ratesbetween 0–37 % (Table 2).

Only one prospective, randomized study has comparedthe use of fluconazole with the “gold standard”, AmpD [27].This open-label study was conducted in 23 infants withpositive fungal cultures and clinical and/or laboratory evi-dence of sepsis. Patients were randomized to fluconazole10-mg/kg IV/PO loading dose followed by 5 mg/kg IV/POevery 24 hours or AmpD 1 mg/kg every 24 hours (plus 5-flucytosine if CSF positive). The authors report no differ-ence in efficacy between agents. However, AmpD wasassociated with more adverse effects (i.e., hepatotoxicity,hyperbilirubinemia) and requirement of IV access for nearlythree times the duration. These findings were reaffirmed in aretrospective study by Ascher and colleagues who reportedno difference in mortality or efficacy in infants treated withfluconazole versus AmpD [14••]. However, a lower mortal-ity rate in infants treated with fluconazole versus LipAF(16 % versus 29 %, OR: 2.39 [1.18–4.83]) was noted. Thefluconazole failure rate was lower than AmpD (40 % versus47 %, OR 1.34 [0.73–2.46]), although not statistically


Tab

le2

Clin

ical

Evaluations

ofEfficacyof

Antifun

galAgentsin

theTreatmentof

NeonatalCandidiasis

Reference

Descriptio

nof

studydesign

Study

populatio

nAge

atinitiation

Dose

Durationof

treatm

ent

Primaryobjectiveof

study

Results

Amphotericin

Ascheret

al.[14••]

Retrospectiv

e,database

review

(n=497AmpD

;n=110fluconazole;

n=97

AmpL

;n=26

combo)

GA:27

weeks

23days

Not

reported

Not

reported

Overallmortalityand

therapeutic

failu

re▪Overallmortalityrate

19%

BW:1.035kg

▪Mortalitygreaterin

AmpL

group(29%)vs.AmpD

(18%)andfluconazole

(16%)

▪Higherrate

oftherapeutic

failu

rein

AmpL

group

(47%)vs.AmpD

(28%)

Jeon

etal.

[11]

Multi-center,prospective,

historical

control(n=26

LAMB;n=20

AmpD

matched

controls)

LAMB:

LAMB:23

±17

days

LAMB:

LAMB:

Fungaleradicationrate

andmortalityrate

▪Nodifference

ineradication

rate

(84vs

89%)or

days

toeradication(9±8vs

10±9days)

GA:26.1±3.0weeks

AmpD

:27

±16

days

Initial

dose

2.5±

2.1mg/kg/day

13±5days

▪Nodifference

inmortality

(12%

vs10

%)

BW:0.82

±0.24

kgMax

dose

5.2±

1.1mg/kg/day

AmpD

:

▪Low

erincidenceof

renaland

hepatic

toxicity

inLAMB

group

AmpD

:

AmpD

:

20±10

days

GA:26.9

Initial

dose

0.3±0.2mg/kg/day

±1.6weeks

Max

dose

1.5±0.6mg/kg/day

BW:0.901±0.218kg

Cetin

etal.[15]

Retrospectiv

ecomparison

(n=9LAMB;n=10

ABLC)

LAMB:

Not

reported

Initial

dose

1mg/kg/day,

with

daily

increase

by1mg/kg

tomax

of5mg/kg/day

a

LAMB:

Fungaleradication

▪Nodifference

ineradication

rate

(88.9%

vs80

%)

GA:33.0±3.6weeks

15.7±7.5days

▪Overallmortalityrate

15.8

%(LAMB=1;

ABLC=2)

BW:1.826±0.735kg

ABLC:

▪Nodifference

inadverse

effects

ABLC:

17.3±6.7days

GA:30.7±3.9weeks

BW:1.521±0.665kg

Juster-Reicher

etal.[16]

Prospectiv

e,descriptive

(n=37

LAMB)

GA:27

weeks

(range,25

–40)

7days

(range,8–

100)

6.5±0.8mg/kg/day

18(range,

7–35)

Describetheefficacy

ofhigh-dosetherapy

▪Fungaleradicationrate

of95

%

BW:1.017±0.57

kg▪Mortalityrate

of5%

▪Fungaleradicationmore

rapidwith

high

doses

Linderet

al.[12]

Prospectiv

e,non-

random

ized,comparison

(n=34

AmpD

;n=6

LAMB;n=14

ABCD)

AmpD

:AmpD

:AmpD

:AmpD

:Com

parisonof

effectiveness

andtolerability

▪Nostatistical

difference

ineradicationrate

(AmpD

67.6

%,LAMB83.3

%,

ABCD

57.1

%)

GA:29.3±4.2weeks

24.4±24.6

days

1mg/kg/day

19.3±13.4

days

▪Addition

of2n

dantifungal

increasederadicationratesto

100%

forAmpD

and

92.8

%forABCD

BW:1.197±0.623kg

LAMB:

LAMB:

LAMB:

▪Overallmortalitywas

14.8

%,no

differences

betweengroups

LAMB:

14.0±3.9days

5mg/kg/day

19.0±7.6days

GA:26.2

ABCD:

ABCD:

ABCD:

±2.1weeks

15.8±8.7days

3mg/kg/day

×1day,

then

5mg/kg/day

17.4±8.2days

BW:0.901±

0.273kg

ABCD:

GA:25.2±1.8weeks

BW:0.779±0.17

kg


Tab

le2

(con

tinued)

Reference

Descriptio

nof

studydesign

Study

populatio

nAge

atinitiation

Dose

Durationof

treatm

ent

Primaryobjectiveof

study

Results

Lopez

Sastre

etal.[13]

Prospectiv

e,multi-center,

non-random

ized,

descriptive(n=81

LAMB;n=29

ABLC;

n=4AmpD

)

LAMB:

LAMB:

LAMB:

LAMB:

Determineincidence,

etiology,andmortality

ofsystem

iccandidiasis

▪Candidiasisincidenceof

0.57

%GA:30.0±5.0weeks

25±20

days

Initial

2.1±1.7to

max

3.8±

1.1mg/kg/day

19±8days

▪Overallmortalityrate

of10.2

%BW:1.498±0.973kg

ABLC:

ABLC:

ABLC:

▪Nodifference

inefficacy

rate

betweenagents(LAMB

94%,ABLC86

%,100%

AmpD

)

ABLC:

31±26

days

Initial

2.6±1.5to

max

4.2±1.0mg/kg/day

15±6days

GA:30.0±4.7weeks

AmpD

:

AmpD

:BW:1.547±0.994kg

Initial

0.18

±0.3to

max

1.7±0.9mg/kg/day

16±5days

AmpD

:GA:34.2±5.4weeks

BW:2.092±1.091kg

Adler-Chohet

etal.[17]

Openlabel,descriptive

(n=11

ABLC)

Weight:1.4kg

(range,0.7–

5)b

7weeks

(range,3–

14)

4.9±1.0mg/kg/day

21.1±11.0

days

Describethesafety

and

efficacy

oftherapy

▪Clin

ical

successin

81.8

%of

patients

▪Mortalityrate

of18.2

%

▪Noappreciablechange

inrenalfunctio

n

Juster-Reicher

etal.[18]

Retrospectiv

e,descriptive

(n=24

LAMB)

GA:26

weeks

(range,24

–32)

17days

(range,7–

100)

5.1±1.5mg/kg/day

21days

(range,2–

31)

Describethesafety

and

efficacy

oftherapy

▪Eradicatio

nrate

of92

%

BW:0.847±0.244kg

▪Mortalityrate

of17

%

▪Noadverseeffectsreported

Fluconazole

Huang

etal.[29]

Retrospectiv

echart

review

(n=18)

GA:25

–36

weeks

46days

(range,

15–173)

3–15

mg/kg/day

Not

reported

Describethesafety

and

efficacy

▪Eradicatio

nrate

of68

%BW:0.756–

2.08

kg▪Mortalityrate

of0%

▪Noadverseeffectsreported

Schwarze

etal.[28]

Retrospectiv

ecase

review

(n=38)

GA:23

–38

weeks

Not

reported

5–6mg/kg/day

21days

Study

thetherapy,efficacy,

andsafety

▪Eradicatio

nrate

of81.6

%BW:1.120kg

▪Nosignificantadverseevents

reported

Huttova

etal.[24]

Multicenter,prospective

(n=32

fluconazole;

n=8fluconazole+LAMB)

GA:30.5

weeks

16.5

days

(range,10

–29)

6mg/kg/day

6–48

days

Assessefficacy

andsafety

▪Eradicatio

nrate

of80

%BW:1.290kg

(range,0.750–3.45)

▪Mortalityrate

of20

%▪Noseriousadverseeffects

reported

Waineret

al.[25]

Open,

non-comparativ

e,non-random

ized,

prospective(n=19)

GA:Not

reported

32.1

days

(range,16

–54)

Loading

dose

10mg/kg

PO/IV

3–57

days

Assesstheefficacy

and

safety

▪Eradicatio

nrate

of63

%BW:1.725kg

(range,0.85

–4.3)

Maintenance

dose:

5mg/kg/day

PO/IV

▪Mortalityrate

of37

%▪Nosignificantadverseeffects

noted

Driessenet

al.[27]

Propective,random

ized

trial

(n=12

fluconazole;

n=11

AmpD

)

GA:Not

reported

24±10.5

days

loadingdose:

10mg/kg

PO/IV

21days

(range,3–

39)

Com

pare

thesafety,

efficacy,andoverall

convenienceof

fluconazolevs.AmpD

▪Mortalityrate

of33

%for

fluconazoleand45

%for

AmpD

BW:1.392±0.561kg

Maintenance

dose:

5mg/kg/day

PO/IV

▪Few

eradverseeffectswith

fluconazole

Fasanoetal.[26]

Prospectiv

e,nonrandomized

(n=31)

GA:Not

reported

35days

(range,2–

103)

5.3mg/kg/day

(range,1–16)

26days

(2–80)

Assessefficacy

oftherapy

▪Eradicatio

nrate

of97

%BW:2.8kg

(range,0.5–

5.2)

▪Tw

o(5

%)infantshadadverse

events(anemia,elevated

transaminases)


Tab

le2

(con

tinued)

Reference

Descriptio

nof

studydesign

Study

populatio

nAge

atinitiation

Dose

Durationof

treatm

ent

Primaryobjectiveof

study

Results

Caspofungin

Moham

edet

al.

[42•]

Randomized,prospective,

double

blind(A

mpD

=17;

Caspofungin=15)

Caspofungin:

Caspofungin:

Caspofungin:

Not

reported

Assesstheefficacy,safety,

andtolerabilityof

caspofungincompared

toAmpD

▪Caspofungin

superior

toAmpD

,(efficacyrate

86.7

%vs

41.7

%)

GA:27.9±1.3weeks

21.1±3.1days

2mg/kg/day

▪Significantly

fewer

adverseeffects

incaspofungingroup(p=0.04)

BW:0.85

±0.14

kgAmpD

:AmpD

:AmpB

:22.3±2.4days

1mg/kg/day

GA:28.3±1.1weeks

BW:0.901±0.137kg

Natarajan

etal.[36]

Retrospectiv

echart

review

(n=13)

GA:27

weeks

(range,24

–41)

11–70

days

1mg/kg

once

daily

;loadingdose

of1.5mg/kg

(n=3)

7(2–43)days

Review

experience

with

caspofunginin

asadjunct

therapyto

AmpD

▪Eradicatio

nrate

of92

%

BW:0.8kg

(range,0.53

–5.6)

▪Mortalityrate

of54

%▪ADRs:thrombophlebitis

hypokalemia,andelevated

transaminases

Odioet

al.[35]

Prospectiv

e,nonrandomized

case

series

(n=10)

GA:33

weeks

(range,31

–37)

44days

(range,

13–105)

0.5–

1mg/kg/day

for

2–3days,then

1–2mg/kg/day

15–28

days

Evaluatethetolerability

andeffectiveness

▪Eradicatio

nrate

of80

%

BW:1.5kg

(range,1.15

–2.61)

▪Mortalityrate

of10

%

▪Nomedication-relatedadverse

effectsreported

Micafungin

Kaw

aguchi

etal.[48 ]

Retrospectiv

e,cohort

study(n=4)

GA:24.1±0.9weeks

16.5±10.0

days

0.5to

1mg/kg/day

9.8±3.1days

Toinvestigatetheefficacy

andtolerability

▪Eradicatio

nrate

of100%

BW:0.579±0.08

kg▪Mortalityrate

0%

▪Noside

effectsreported

Natarajan

etal.

(2009)

Retrospectiv

e,descriptive

study(“Respondersto

conventio

naltherapy”

n=10,“R

efractory”

n=15

micafungin;

n=4

caspofungin)

Responder

group:

Responder

group:

10mg/kg/day

15days

(range,2-51)

Toevaluate

theclinical

profile

andoutcom

esof

infants

refractory

toconventio

nal

therapyvs

thosewho

responded

▪Mortalityrateshigher

(53vs

20%)anderadicationrates

lower

(63.1vs

90%)in

refractory

group

GA:27.8±2.7weeks

23.1±24.6

days

▪Statistically

butnotclinically

significantincrease

inAST

BW:0.969±0.361kg

Refractorygroup:

Refractorygroup:

28.3±22.3

days

GA:27.0±3.1weeks

BW:0.931±0.642kg

AmpD

=Amph

otericin

deox

ycho

late;AmpL

=Amph

otericin

Blip

idprod

ucts

[specificprod

uctno

tidentified],GA

=Gestatio

nalAge;BW

=Birth

Weigh

t;ABLC

=Amph

otericin

BLipid

Com

plex;LAMB=Liposom

alAmph

otericin

B;ABCD

=Amph

otericin

BColloidal

Dispersion

aMeando

seno

trepo

rted

bBirth

weigh

tno

tprov

ided


significant. The authors of this study speculated that lowermortality with fluconazole may due to enhanced CNS pen-etration and increased urinary concentrations.

The remaining prospective studies in neonates wereopen-label use of fluconazole [24–26]. The primary focuswas to confirm that fluconazole was a safe and effectivetreatment for neonatal candidiasis. These studies report ef-ficacy rates ranging from 63–97 % and emphasize a favor-able safety profile at doses of 5–6 mg/kg/day. The findingswere corroborated in two retrospective evaluations whichreported that fluconazole was considered safe and effica-cious [28, 29].

Voriconazole

Voriconazole is a second-generation triazole and a syntheticderivative of fluconazole. Compared to fluconazole, it hasbroader activity including all Candida species, Cryptococ-cus neoformans, Trichosporan beigelii, and many species ofAspergillus [19]. As stated previously, an advantage withvoriconazole is the availability of both enteral and IV for-mulations. Intravenous voriconazole should be avoided inpatients with creatinine clearance <50 ml/min because ofaccumulation of the vehicle, sulfobutyl ether β-cyclodextrinsodium, which can cause renal and hepatic damage in highconcentrations [3].

Pharmacokinetics of Voriconazole

No studies have examined voriconazole PK parameters inneonates, and only one study examined PK parameters inchildren 2–11 years (n=28). This study is important becauseit demonstrates that voriconazole exhibits linear eliminationin children, which differs from the Michaelis-Menten typeelimination in adults [30]. The authors recommend using4 mg/kg every 12 hours to achieve similar exposure inadults at doses of 3 mg/kg every 12 hours.

Efficacy of Voriconazole

No prospective, randomized trials evaluating efficacy wereidentified. The available data is limited to one case-reportand two case-series. Muldrew and colleagues described theuse of IV voriconazole in a neonate receiving LAMB fortreatment of disseminated fluconazole-resistant C. albicans[31]. Voriconazole was initiated at 6 mg/kg/dose every12 hours, but was later increased to every 8 hour dosingdue to decreased voriconazole concentrations (i.e., 6-hrconcentration of 0.326 mcg/ml). The patient received a totalof 19 days of therapy and had complete fungal eradication.This patient required an increased dose of voriconazolebecause he was also receiving phenobarbital, which is astrong CYP inducer. This study highlights the need to

review the patient’s medications for possible interactionsthat could decrease the effectiveness of therapy.

Turan and colleagues described their experience with IVvoriconazole as adjunct therapy to LAMB in a case-seriesincluding six neonates [32]. Therapy was initiated at 6 mg/kgevery 8 hours and continued for 18–24 days. Fungal eradicationoccurred in 100 % of patients and no significant adverse effectswere reported. Likewise, oral voriconazole 4 mg/kg twice dailyhas been reported as safe and efficacious in two newborns inwhich IVaccess was discontinued [33]. An oral formulation ofvoriconazole is advantageous when IVaccess is lost or limited.

Echinocandins

The echinocandins are the newest class of antifungal agents.These agents exhibit fungicidal activity against most species ofCandida by inhibiting the production of beta (1,3)-D-glucan. Inthe current IDSA guidelines, echinocandins are recommendedif there is resistance to fluconazole/amphotericin or concern fortoxicity that would preclude these agents [6••]. Caspofungin isthe only echinocandin that has a FDA-labeled indication forchildren three months of age and older [3].

Caspofungin

Caspofungin is metabolized via hydrolysis and N-acetylation,as well as spontaneous degradation. Extensive metabolismoccurs, and metabolites are eliminated via the urine and feces.Patients with hepatic failure may require dose adjustment;however, no dose adjustment is required for renal failurebecause caspofungin is metabolized to inactive metabolites [3].

Pharmacokinetics of Caspofungin

Saez-Lorens and colleagues have published the onlycaspofungin PK study. This was a prospective, open-label,noncomparative study which included 18 patients less than3 months of age receiving caspofungin 25 mg/m2 as adjuncttherapy to amphotericin [34•]. This dose resulted in peakconcentrations similar to adult doses of 50 mg daily. Ele-vated trough concentrations were observed, likely due todecreased clearance of caspofungin in infants. The smallsample size limited the ability to calculate plasma exposure,clearance, and half-life. No medication-related adverseevents were noted. Pediatric dosing references recommenddosing of caspofungin based on body surface area (BSA) asa result of this PK study [3].

Efficacy of Caspofungin

Data supporting the efficacy of caspofungin is limited inneonates. Much of the literature is limited to case reports/seriesin which caspofungin was added after failure of first-line


agents. Odio and colleagues reported their experience withcaspofungin in ten patients with refractory candidiasis [35].Only one patient had relapse of the fungal infection, butresponded to a second course. No medication-related adverseeffects were reported. These findings are similar to those seenin other case reports [36–41]. In these reports, caspofungindosing was variable (0.5–6 mg/kg/day). Some authors utilizedloading doses, as is done in the adult population. Of thesereports, 62.5 % of patients (10/16) achieved cure, with theother six patients expiring due to unrelated conditions.

Caspofungin has mostly been studied as a “salvageagent” for those failing first-line therapies. Mohamed andcolleagues conducted the first prospective, randomized,comparison trial of caspofungin monotherapy versus AmpD[42•]. Thirty-two neonates received either caspofungin2 mg/kg/day (n=15) or AmpD 1 mg/kg/day (n=17). Unlikethe previous PK study, the authors chose to dosecaspofungin using mg/kg rather than BSA. Caspofunginwas significantly more efficacious versus AmpD (86.7 ver-sus 41.7 %, p=0.04). No caspofungin patients experienced arelapse, while two AmpD patients developed a subsequentfungal infection. Significantly fewer adverse effects werereported in the caspofungin group (4 % vs. 11 %; p=0.04).The authors propose that caspofungin should be consideredas an alternative first-line therapy.

Micafungin

Micafungin is hepatically metabolized primarily bynonoxidative metabolic pathways. These pathways includehydrolysis and N-acetylation, with elimination occurring pri-marily through the biliary tract. As a result, dose adjustmentsare not necessary in patients with renal or hepatic impairment.

Pharmacokinetics of Micafungin

Compared to the other echinocandins, the PK parameters ofmicafungin have been extensively evaluated in neonatesover a wide range of doses (i.e., 0.75–15 mg/kg/day)[43–45]. Heresi and colleagues were the first to conduct aPK study in preterm neonates (n=18) after a single dose of0.75, 1.5, or 3 mg/kg [43]. The authors reported an inverserelationship between clearance and age, with clearance ratesin neonates over twofold greater than adults. In addition, theVd in neonates is two times higher than adults. The authorssuggest that neonates require a dose of 5–7 mg/kg/day toapproximate the AUC exposure of adults receiving 100–150 mg/day for invasive candidiasis. However, it was spec-ulated that these doses may not produce sufficient concen-trations to effectively treat Candida meningitis.

Two studies expanded upon the work of Heresi andcolleagues in an effort to determine appropriate dosing forCandida meningitis. Smith and colleagues evaluated dosing at

15 mg/kg/day for five days in 12 premature infants [44]. Thisdose achieved a mean AUC of 437.5 mcg*hr/ml, which isbelow the values associated with safety in adult patients (i.e.,<600 mcg*hr/ml). No adverse effects were attributed tomicafungin therapy. Benjamin and colleagues evaluated dosesof 7 and 10 mg/kg/day in an effort to achieve an AUC ≥166.5 mcg*hr/ml [45]. Only one infant did not achieve the targetAUC. This study also confirmed the inverse relationship ofclearance and age and higher Vd, supporting the need forhigher mg/kg dosing in these patients.

Hope and colleagues used Monte Carlo simulations toevaluate the combined data of the 43 patients from the threeprevious PK studies [46•]. The authors reported linear PK fordosages ranging between 0.75–15 mg/kg. The authors reportthat a dose of 10 mg/kg would provide appropriate concen-trations to effectively treat Candida meningitis in 82.6 % ofinfants treated. Based on the current PK data, experts alsorecommend micafungin dosing at 10 mg/kg in preterm andterm infants [47].

Efficacy of Micafungin

There is limited data on the efficacy of micafungin in in-fants. Two retrospective studies have evaluated the efficacyof micafungin in refractory neonatal candidemia. Kawagu-chi and colleagues evaluated micafungin dosing at 0.5–1 mg/kg/day in four premature infants and reported thattherapy was effective for all patients and no adverse effectswere noted [48]. However, Natarjan and colleagues reporteda 63.1 % efficacy rate and survival rate <50 % with adjunctmicafungin therapy at 10 mg/kg/dose [49]. It is difficult tocompare the outcomes of these small retrospective studiesdue to differences in the patient populations and use ofmicafungin as a “salvage” treatment.

To date, there are no randomized, controlled studiesconducted specifically in the infant population. Queiroz-Telles and colleagues compared the use of micafungin2 mg/kg/day versus LAMB 3 mg/kg/day in 98 pediatricpatients ages 0–16 years [50]. All micafungin treated neo-nates (n=7) were considered to have treatment success,versus 57 % (4/7) of the LAMB treated neonates. Althoughsuccess rate was numerically greater, this finding should beviewed with caution due to the small sample size. In addi-tion, both medications were dosed at lower doses thancurrently recommended [6••, 47]. Micafungin treated pa-tients had a lower incidence of adverse effects (2.8 % versus16.7 %, p=0.05). The only micafungin-related adverse ef-fect reported was a moderate increase in serum creatinine.

Anidulafungin

Anidulafungin’s PK profile differs from that of caspofunginand micafungin. It undergoes slow chemical hydrolysis in


the blood and is primarily eliminated in the feces [3]. As aresult, this agent is an attractive choice in critically-ill pa-tients with hepatic and/or renal failure.

Pharmacokinetics of Anidulafungin

Cohen-Wolkowiez and colleagues conducted the only PKevaluation of anidulafungin in infants [51•]. (Table 1) Thisstudy demonstrated that infants had similar anidulafunginexposure compared to children 2–17 years, when given thesame weight-based dose of 1.5 mg/kg/day [52]. The medianhalf-life in neonates of 78 hours (range, 40–219) was longerthan in infants (median 33 hours, range 30–173), althoughnot statistically significant (p=0.13). These half-lives arelonger than previously reported in older children (20.8±6.2 hours) [52]. Of note, two neonates were on extracorporealmembrane oxygenation (ECMO) support. These patientshad the lowest AUC exposure, suggesting that the highlyprotein-bound anidulafungin was affected by the ECMOcircuit. The investigators suggest that patients on ECMOmay require two- to three-fold higher doses, although morestudy is needed.

Efficacy of Anidulafungin

There are no randomized, controlled trials to evaluate theefficacy of anidulafungin in the infant population. Only onecase-report describes the successful use of anidulafungin 1.5 mg/kg/day in a term neonate with peritoneal candidiasisand multi-system organ failure [53]. The patient was receiv-ing LAMB and continued to grow C. albicans from perito-neal cultures. Anidulafungin was selected because thepatient had renal and hepatic dysfunction. Cultures werenegative within four days of initiation and no adverse effectswere noted.

Flucytosine

Flucytosine differs from the other agents discussed because itexerts its effect intracellularly by altering RNA and DNAsynthesis [3]. Flucytosine is active against Candida, Aspergil-lus, and Cryptococcus species. It has excellent oral bioavail-ability and effectively penetrates the CSF. Unfortunately, thisagent has limited use in neonates because of lack of a paren-teral formulation, toxicity (e.g., hepatotoxicity, bone marrowsuppression), rapid development of resistance when used asmonotherapy, and limited efficacy data.

There are no clinical trials evaluating the efficacy offlucytosine in infants; however, this agent has been used incombination with AmpD for treatment of Candida menin-gitis and endocarditis [54–56]. Two case-reports have de-scribed successful use of combination therapy withfluconazole for Candida nephritis and peritonitis [57, 58].

Flucytosine was initiated at 100 mg/kg/day in all of thesepatients. Based on the IDSA guidelines, use of flucytosinein neonates with Candida meningitis is not routinelyrecommended [6••]. Some experts suggest that flucytosinebe reserved for those failing amphotericin monotherapy[59]. If used, therapeutic drug monitoring should beperformed, as emphasized by Pasqualotto and colleaguesin a retrospective evaluation of flucytosine concentrationsin 33 neonates [60]. One-third of the neonates had satisfac-tory concentrations (i.e., trough 20–40 mg/L; peak 50–80 mg/L) and nearly two-thirds had high concentrations.

Discussion

Invasive fungal infections continue to be a significant con-tributor to morbidity and mortality in premature neonates.However, PK and efficacy data for antifungal agents in thispopulation are generally lacking. Currently the IDSA guide-lines recommend amphotericin formulations and flucona-zole as first-line options for treatment of neonatalcandidiasis. Fluconazole and LipAF may be preferred be-cause they possess a better safety profile versus AmpD[14••]. Fluconazole may be preferred over LipAF for men-ingitis because of enhanced CNS penetration (i.e., 70–80 %of serum concentrations). Currently, the echinocandins areconsidered second-line; although, in limited reports theyappear to be at least as efficacious as the first-line agents,but possess a better safety profile. Micafungin andanidulafungin do not require dose adjustments for hepaticor renal impairment, making them ideal agents for critically-ill neonates. If the IV route is not available or access islimited (i.e., compatibility issues), fluconazole andvoriconazole can be administered enterally, as they haveexcellent oral bioavailability. Small case-series describe ef-ficacy of these agents when administered enterally.

The IDSA recommends the use of fungal prophylaxisin neonates <1 kg in NICUs with high rates of candidi-asis. Prophylaxis minimizes colonization, which in turndecreases the incidence of candidiasis. Fluconazole is themost commonly used; however, nystatin, LAMB, andmicafungin have also been evaluated for prophylaxis[61–68]. It seems prudent that if prophylaxis with aspecific agent is implemented, an alternative agent shouldbe used when candidiasis is suspected or identified. Thismay limit the utility of fluconazole as first-line, empirictreatment since it is the agent most commonly used forprophylaxis. Although most of the studies evaluated pro-phylaxis over a 4- to 6-week period, it could berecommended to discontinue therapy after the major riskfactors for candidiasis are removed (e.g., off parenteralnutrition, not receiving antibiotics, no IV access) in orderto reduce the promotion of resistance.


Conclusion

Overall, there is very limited data available for the PK andefficacy of antifungal agents in neonates. Amphotericin Bformulations and fluconazole are currently first-line agentsfor neonatal candidiasis; however, based on the review ofthe literature amphotericin B has been studied to a greaterextent in this population. However, these agents are associ-ated with adverse effects that may limit use. There is agrowing body of evidence demonstrating the safety andefficacy of echinocandins. A majority of studies evaluatedthe efficacy of echinocandins as adjunct therapy. Futurestudies are needed to evaluate echinocandin monotherapyand comparison of efficacy with first-line agents.

Conflict of Interest Megan G. Andrews declares that she has noconflict of interest.

Roshni Patel declares that she has no conflict of interest.Jamie Miller declares that she has no conflict of interest.

Support No financial support was provided for this study

References

Papers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. •• Chitnis AS, Magill SS, Edwards JR, et al. Trends in Candidacentral line-associated bloodstream infections among NICUs,1999–2009. Pediatr. 2012;130:e46–52. This study provides themost current trends of Candida spp. bloodstream infections inUS NICU’s from 1999–2009. The authors report a decline in theincidence of Candida infections among NICU patients. C. albicansand C. parapsilosis were the most common species identified.

2. Liebovitz E. Strategies for the prevention of neonatal candidiasis.Pediatr Neonatol. 2012;53:83–9.

3. Taketomo CK, Hodding JH, Kraus DM. Pediatric dosage hand-book. 19th ed. Hudson: Lexi-Comp, Inc; 2012.

4. Turkova A, Roilides E, Sharland M. Amphotericin B in neonates:deoxycholate or lipid formulation as first-line therapy – is there a‘right’ choice? Curr Opin Infect Dis 2011;24:163–71.

5. Prasad PA, Coffin SE, Leckerman KH, et al. Pediatric antifungalutilization: new drugs, new trends. Pediatr Infect Dis J.2008;27:1083–8.

6. •• Pappas PG, Kauffman CA, Benjamin DK, et al. Clinical practiceguidelines for the management of candidiasis: 2009 update by theInfectious Diseases Society of America. Clin Infect Dis.2009;48:503–35. These guidelines established by the InfectiousDiseases Society of America are the most current guidelines ad-dressing the management of invasive candidiasis in several patientpopulations. There is a section devoted specifically to the treat-ment of neonatal candidiasis.

7. Baley JE, Meyers C, Kliegman RM, et al. Pharmacokinetics,outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates. Pedaitr. 1990;116:791–7.

8. Koren G, Lau A, Klein J, et al. Pharmacokinetics and adverseeffects of amphotericin B in infants and children. J Pediatr.1988;113:559–63.

9. Starke JR, Mason Jr EO, Kramer WG, et al. Pharmacokinetics ofamphotericin B in infants and children. J Infect Dis.1987;155:766–74.

10. Wurthwein G, Groll AH, Hempel G, et al. Population pharmaco-kinetics of amphotericin B lipid complex in neontates. AntimicrobAgents Chemother. 2005;49:5092–8.

11. Jeon GW, Koo SH, Lee JH, et al. A comparison of Am Bisome toamphotericin B for treatment of systemic candidiasis in very lowbirth weight infants. Yonsei Med J. 2007;48:619–26.

12. Linder N, Klinger G, Shalit I, et al. Treatment of candidaemia inpremature infants: comparison of three amphotericin B prepara-tions. J Antimicrob Chemother. 2003;52:663–7.

13. Lopez Sastre JB, Coto Cotallo GD, Fernandez Colomer B, et al.Neonatal invasive candidiasis: a prospective multicenter study of118 cases. Am J Perinatol. 2003;20:153–63.

14. •• Ascher SB, Smith PB, Watt K, et al. Antifungal therapy andoutcomes in infants with invasive Candida infections. PediatrInfect Dis J. 2012;31:439–43. This recent retrospective, databasereview was the first to report an increased mortality rate inneonates treated with liposomal amphotericin formulations versusamphotericin dexoycholate or fluconazole.

15. Cetin H, Yalaz M, Akisu M, et al. The efficacy of two differentlipid-based amphotericin B in neonatal Candida septicemia.Pediatr Int. 2005;47:676–80.

16. Juster-Reicher A, Flidel-Rimon O, Amitay M, et al. High-doseliposomal amphotericin B in the therapy of systemic candidiasisin neonates. Eur J Clin Microbiol Infect Dis. 2003;22:603–7.

17. Adler-Chohet F, Waskin H, Lieberman JM. Amphotericin B lipidcomplex for neonatal candidiasis. Arch Dis Child Fetal NeonatalEd. 2001;84:F131–3.

18. Juster-Reicher A, Leibovitz E, Linder N, et al. Liposomalamphotericin B (AmBisome) in the treatment of neonatal candidi-asis in very low birth weight infants. Infection. 2000;28:223–6.

19. Johnson LB, Kauffman CA. Voriconazole: A new triazole antifun-gal agent. Clin Infect Dis. 2003;36:630–7.

20. Micromedex® Healthcare Series [Internet database]. GreenwoodVillage, Colo: Thomson Healthcare. Updated periodically.Accessed December 2012.

21. Wade KC, Benjamin Jr DK, Kaufman DA, et al. Fluconazoledosing for the prevention or treatment of invasive candidiasis inyoung infants. Pediatr Infect Dis J. 2009;28:717–23.

22. Piper L, Smith PB, Hornik CP, et al. Fluconazole loading dosepharmacokinetics and safety in infants. Pediatr Infect Dis J.2011;30(5):375–8.

23. Wenzl TG, Schefels J, Hornchen H, et al. Pharmacokinetics of oralfluconazole in premature infants. Eur J Pediatr. 1998;157(8):661–2.

24. Huttova M, Hartmanova I, Kralinsky K, et al. Candida fungemia inneonates treated with fluconazole: report of forty cases, includingeight with meningitis. Pediatr Infect Dis J. 1998;17(11):1012–5.

25. Wainer S, Cooper PA, Gouws H, et al. Prospective study offluconazole therapy in systemic neonatal fungal infection. PediatrInfect Dis J. 1997;16(8):763–7.

26. Fasano C, O'Keeffe J, Gibbs D. Fluconazole treatment of neonatesand infants with severe fungal infections not treatable with conven-tional agents. Eur J Clin Microbiol Infect Dis. 1994;13(4):351–4.

27. Driessen M, Ellis JB, Cooper PA, et al. Fluconazole vs.amphotericin B for the treatment of neonatal fungal septice-mia: a prospective randomized trial. Pediatr Infect Dis J.1996;15(12):1107–12.

28. Schwarze R, Penk A, Pittrow L. Treatment of candidal infectionswith fluconazole in neonates and infants. Eur J Med Res.2000;5(5):203–8.


29. Huang YC, Lin TY, Lien RI, et al. Fluconazole therapy in neonatalcandidemia. Am J Perinatol. 2000;17(8):411–5.

30. Walsh TJ, Karlsson MO, Driscoll T, et al. Pharmacokinetics andsafety of intravenous voriconazole in children after single- ormultiple-dose administration. Antimicrob Agents Chemother.2004;48:2166–72.

31. Muldrew KM, Maples HD, Stowe CD, Jacobs RF. Intravenousvoriconazole therapy in a preterm infant. Pharmacother.2005;25:893–8.

32. Turan O, Ergenekon E, Hirfanoglu IM, et al. Combination anti-fungal therapy with voriconazole for persistent candidemia in verylow birth weight neonates. Turk J Pediatr. 2011;53:19–26.

33. Kohli V, Taneja V, Sachdev P, Joshi R. Voriconazole in newborns.Ind Pediatr. 2008;45:236–8.

34. • Saez-Llorens X, Macias M, Maiya P, et al. Pharmacokinetics andsafety of caspofungin in neonates and infants less than 3 months ofage. Antimicrob Agents Chemother. 2009;53(3):869–75. This isthe first prospective PK study of caspofungin in neonates andinfants. Caspofungin dosed at 25 mg/m2 in infants provides asimilar plasma exposure to that of adults receiving 50 mg/day.Slight elevations in trough concentrations were noted in neonatesand infants, compared to the adult population.

35. Odio CM, Araya R, Pinto LE, et al. Caspofungin therapy ofneonates with invasive candidiasis. Pediatr Infect Dis J.2004;23(12):1093–7.

36. Natarajan G, Lulic-Botica M, Rongkavilit C, et al. Experience withcaspofungin in the treatment of persistent fungemia in neonates. JPerinatol. 2005;25(12):770–7.

37. Manzar S, Kamat M, Pyati S. Caspofungin for refractorycandidemia in neonates. Pediatr Infect Dis J. 2006;25(3):282–3.

38. Natale F, Castronovo A, Regoli D, et al. Successful treatment withcaspofungin of refractory Candida krusei candidemia in a very lowbirth weight preterm infant. Pediatr Infect Dis J. 2009;28(5):452.

39. Yalaz M, Akisu M, Hilmioglu S, et al. Successful caspofungintreatment of multidrug resistant Candida parapsilosis septicaemiain an extremely low birth weight neonate. Mycoses. 2006;49:242–5.

40. Haase R, Kreft B, Foell J, et al. Successful treatment of Candidaalbicans septicemia in a preterm infant with severe congenitalichthyosis (Harlequin baby). Pediatr Dermatol. 2009;26(5):575–8.

41. Smith PB, Steinbach WJ, Cotton CM, et al. Caspofungin for thetreatment of azole resistant candidemia in a premature infant. JPerinatol. 2007;27:127–9.

42. • Mohamed WA, Ismail M. A randomized, double-blind, prospec-tive study of caspofungin vs. amphotericin B for the treatment ofinvasive candidiasis in newborn infants. J Trop Pediatr.2012;58(1):25–30. This study randomized, double-blind trial tocompare use of caspofungin and amphotericin B in neonates withinvasive candidiasis. Caspofungin treated patients had a statisti-cally significant increase in efficacy rate and lower incidence ofadverse effects. Based on their results, the authors propose thatcaspofungin is an appropriate alternative to amphotericin for thetreatment of invasive candidiasis in neonates.

43. Heresi GP, Gerstmann DR, Reed MD, et al. The pharmacokineticsand safety of micafungin, a novel echinocandin, in prematureinfants. Pediatr Infect Dis J. 2006;25:1110–5.

44. Smith PB, Walsh TJ, Hope W, et al. Pharmacokinetics of anelevated dosage of micafungin in premature neonates. PediatrInfect Dis J. 2009;28:412–5.

45. Benjamin DK, Smith PB, Arrieta A, et al. Safety and pharmaco-kinetics of repeat-dose micafungin in young infants. ClinPharmacol Ther. 2010;87:93–9.

46. • Hope WW, Smith B, Arrieta A, et al. Population pharmacokinet-ics of micafungin in neonates and young infants. AntimicrobAgents Chemother. 2010;54:2633–7. This study is the largestmicafungin PK study in neonates. The authors combined the data

from three smaller PK studies with doses ranging from 0.75–15 mg/kg. Monte Carlo simulations were performed and the au-thors recommend dosing micafungin at 10 mg/kg/day to achieveadequate CNS concentrations in neonates.

47. Ascher S, Smith PB, Benjamin DK. Safety of micafungin in in-fants: insights into optimal dosing. Expert Opin Drug Saf.2011;10:281–6.

48. Kawaguchi C, Arai I, Yasuhara H, et al. Efficacy of micafungin intreating four premature infants with candidiasis. Pediatr Int.2009;51:220–4.

49. Natarjan G, Lulic-Botica M, Aranda JV. Refractory neonatalcandidemia and high-dose micafungin pharmacotherapy. JPerinatol. 2009;29:738–43.

50. Queiroz-Telles F, Berezin E, Leverger G, et al. Micafungin versusliposomal amphotericin B for pediatric patients with invasivecandidiasis: substudy of a randomized double-blind trial. PediatrInfect Dis J. 2008;27:820–6.

51. • Cohen-Wolkowiez M, Benjamin Jr DK, Piper L, et al. Safety andpharmacokinetics of multiple-dose anidulafungin in infants andneonates. Clin Pharmcol Ther. 2011;89:702–7. This is the firstPK study of anidulafungin in infants and neonates. This studydemonstrated that anidulafungin doses of 1.5 mg/kg/day achieveda similar area under the curve to children receiving the same dose.

52. Benjamin Jr DK, Discoll T, Seibel NL, et al. Safety and pharma-cokinetics of intravenous anidulafungin in children with neutrope-nia at high risk for invasive fungal infections. Antimicrob AgentsChemother. 2006;50:632–8.

53. Varisco BM, Benner KW, Prabhakaran P. Neonatal peritonealcandidiasis successfully treated with anidulafungin add-on therapy.Ann Pharmacother. 2009;43:1907–10.

54. Pahud BA, Greenhow TL, Piecuch B, et al. Preterm neonates withcandidal brain microabcesses: a case series. J Perinatol.2009;29:323–6.

55. Faix RG, Feick HJ, Frommelt P, et al. Successful medical treat-ment of Candida parapsilosis endocardidits in a premature infant.Am J Perinatol. 1990;7:272–5.

56. Zenker PN, Rosenberg EM, Van Dyke RB, et al. Successfulmedical treatment of presumed Candida endocarditis in criticallyill infants. J Pediatr. 1991;119:72–7.

57. Freydiere AM, Piens MA, Andre JM, et al. Successful treatment ofCandida glabrata peritonitis with fluconazole plus flucytosine in apremature infant following in vitro fertilization. Eur J ClinMicrobiol Infect Dis. 2005;24:704–5.

58. Wald M, Lawrenz K, Kretzer V, et al. A very low birth weightinfant with Candida nephritis with fungal balls. Full recovery afterpyletomy and antifungal combination therapy. Eur J Pediatr.2003;162:642–3.

59. Brecht M, Clerihew L, McGuire W. Prevention and treatment ofinvasive fungal infection in very low birthweight infants. Arch DisChild Fetal Neontal Ed. 2009;94:F65–9.

60. Pasqualotto AC, Howard SJ, Moore CB, et al. Flucytosine thera-peutic monitoring: 15 years experience from the UK. J AntimicrobChemother. 2007;59:791–3.

61. Kaufman D, Boyle R, Hazen KC, et al. Fluconazole prophylaxisagainst fungal colonization and infection in preterm infants. N EngJ Med. 2001;345:1660–6.

62. Kaufmann D, Boryle R, Hazen KC, et al. Twice weekly flucona-zole prophylaxis for prevention of invasive Candida infection inhigh-risk infants < 1000 grams birth weight. J Pediatr.2005;147:172–9.

63. Manzoni P, Stolfi I, Pugni L, et al. A multi-center, randomized trialof prophylactic fluconazole in preterm neonates. N Eng J Med.2007;256:2483–95.

64. Ozturk MA, Gunes T, Kokly E, et al. Oral nystatin prophylaxis toprevent invasive candidiasis in neonatal intensive care unit.Mycoses. 2006;49:484–92.


65. Howell A, Isaacs D, Halliday R. Oral nystatin prophylaxis andneonatal fungal infections. Arch Dis Child Fetal Neonatal Ed.2009;94:F429–33.

66. Ganesan K, Harigopal S, Neal T, et al. Prophylactic oral nystatinfor preterm babies under 33 weeks gestation decreases fungalcolonization and invasive fungaemia. Arch Dis Child FetalNeonatal Ed. 2009;94:F275–8.

67. Arrieta AC, Shea K, Dhar V, et al. Once-weekly liposomalamphotericin B as Candida prophylaxis in very low birth weightpremature infants: a prospective, randomized, open-label, placebo-controlled pilot study. Clin Ther. 2010;32:265–71.

68. Kawada M, Fukuoka N, Kondo M, et al. Pharmacokinetics ofprophylactic micafungin in very-low-birth-weight infants. PediatrInfect Dis J. 2009;28:840–3.


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Treatment of Invasive Candida Infections in the Neonatal Intensive Care Unit