33 Candidiasis
CATHERINE M. BENDEL
CHAPTER OUTLINE Epidemiology and Transmission
Microbiology
Pathogenesis
Pathology
Clinical Manifestations
Oropharyngeal Candidiasis
Diaper Dermatitis
Congenital Candidiasis
Invasive Fungal Dermatitis
Candida species are important pathogens in the neonate.
After a significant increase in the incidence of systemic
candidiasis in neonatal intensive care (NICU) patients in
the late 1990s, since 2000 the incidence has remained
stable or even decreased slightly.1-4 However, this has
clearly become a disease of the extremely-low-birth-weight
(ELBW; birth weight ≤ 1000 g) or medically complex larger
infant.5-8 Infections range from superficial colonization
to widely disseminated, life-threatening disease. Unfortu-
nately, the most dramatic rise has been in the incidence
of invasive or systemic candidiasis. With improvements in
technology, more aggressive approaches to the treatment
of very-low-birth-weight (VLBW; ≤1500 g) infants have
become the standard of care. Concomitantly, there has been
an increase in risk factors for neonates to develop candi-
demia, most notably the prolonged use of indwelling intra-
vascular catheters and multiple courses of broad-spectrum
antimicrobial agents.6,9
Candida albicans remains the most frequently isolated
yeast species among infected neonates; however, the inci-
dence of infection with other species, particularly Candida
parapsilosis and Candida glabrata, has increased exponen-
tially over the past 10 years.4,10,11 The importance of Can-
dida as a pathogen in VLBW infants is reflected by a mortality
rate approaching 30% in this fragile group of immunocom-
promised patients, even among those who receive appro-
priate antifungal therapy, and a significant accompanying
morbidity among survivors.11-13
Epidemiology and Transmission
Infections with Candida spp. afflict neonates, immunocom-
promised hosts, diabetics, trauma patients, postoperative
patients (particularly after gastrointestinal procedures),
and are most often nosocomially acquired.1,7,13,14 The
SENTRY Antimicrobial Surveillance Program, monitor-
ing bloodstream infections caused by both Candida spp.
and bacteria among all patients in participating hospitals,
1058
Catheter-Related Candidal Infections
Candidemia and Disseminated
Candidiasis
Diagnosis
Treatment
Antifungal Agents
Prevention
Fluconazole Prophylaxis
reports Candida spp. as the fourth most common noso-
comial bloodstream infection overall, with C. albicans
the most common single pathogen.13,15 In neonates, the
numbers are equally striking. Approximately 1% of early-
onset neonatal infections result from Candida spp.; for late-
onset sepsis, center-specific incidence reports vary from
2% to 28%, with combined study averages of 5% to 10%
among the VLBW infants and 8% to 15% for the ELBW
infants .7,9,16-19 Among hospitals participating in the Neo-
natal Institute of Child Health and Human Development
(NICHD) National Research Network, C. albicans was the
third most frequent single organism isolated among all
pathogens responsible for late-onset sepsis.5
Although C. albicans remains the leading cause of dis-
seminated fungal infection among hospitalized patients,
the isolation of other yeast species, including C. glabrata,
C. parapsilosis, Candida tropicalis, Candida krusei, Candida lusita-
niae, Candida dubliniensis, and even Saccharomyces cerevisiae,
is occurring more frequently.3,4,11,15,20 Table 33-1 displays
the relative distribution of Candida spp. recovered from the
bloodstream of all NICU patients in the National Nosoco-
mial Infection Surveillance (NNIS) system compared with
the overall population reported in the SENTRY program.4,15
Among neonates, C. albicans and C. parapsilosis remain the
predominant species compared with adults, in whom the
predominant species isolated is C. albicans—responsible for
approximately 50% of infections—followed by C. parapsilosis
and C. glabrata, each of which accounts for approximately
15% of yeast infections.11,15 Historically, C. albicans has been
considered the most virulent species. A retrospective study
of neonatal candidiasis before 2000 revealed a 24% mortal-
ity rate among infants infected with C. albicans but no deaths
among those infected with C. parapsilosis.21 However, more
recent reports dispute this assumption: Overall, mortality
rates have increased to 25% to 40% with C. albicans infec-
tions, and there has been an overall increase in infections
with non–Candida albicans Candida (NCAC) spp., with mortal-
ity for neonates infected with C. glabrata and C. parapsilosis
equivalent to that for C. albicans infections.7,11,22,23 Although

Table 33-1 Frequency of Isolation of Candida Species
Causing Candidemia Sepsis
PERCENT OF BLOOD CULTURE ISOLATES
Candida Species Neonates* All Patients†
C. albicans 58 50
C. parapsilosis 34 15
C. glabrata 2 18
C. tropicalis 4 10
Other species 2 7
*Data from Fridkin SK, Kaufman D, Edwards JR, et al: Changing incidence
of Candida bloodstream infections among NICU patients in the United
States: 1995-2004, Pediatrics 117:1680-1687, 2006.
†Data from Pfaller MA, Messer SA, Moet GJ, et al: Candida bloodstream infec-
tions: comparison of species distribution and resistance to echinocandin
and azole antifungal agents in intensive care unit (ICU) and non-ICU
­settings in the SENTRY Antimicrobial Surveillance Program (2008-2009),
Int J Antimicrob Agents 38:65-69, 2011.
C. albicans may be responsible for more infections than NCAC
species, almost all Candida spp. have been implicated in dis-
ease, and any candidal infection in the neonate can be life
threatening.
Candida spp. are commensal organisms, colonizing the
human skin, gastrointestinal tract, and female genitouri-
nary tract.15,24,25 Studies evaluating gastrointestinal tract
colonization document approximately 5% of neonates are
colonized with Candida on admission to the NICU; up to
50% are colonized by the end of the first week and almost
three fourths by the end of the first month of life.26,27 A
variety of Candida spp. colonize the human gastrointesti-
nal tract, including C. albicans, C. tropicalis, C. glabrata, and
C. parapsilosis in neonates.27,28 More than one species may be
recovered from a single host, but there is usually a predomi-
nant colonizing species.29 The Candida strain colonizing the
infant most often is acquired by vertical transmission from
the maternal vaginal mucosa after passage through the
birth canal.29-31 Using molecular typing techniques, verti-
cal transmission of C. albicans, C. parapsilosis, and C. glabrata
has been documented in term and preterm infants.29,30
Heavy maternal colonization or maternal Candida vaginitis
is an important risk factor for efficient transmission, result-
ing in increased neonatal colonization and the potential for
disease.30-33 Intrauterine fetal infections occur rarely, but
they have been attributed to ascending infection from the
vagina of the mother and transplacental transmission.34
Breastfeeding can result in transmission of yeast present
on the maternal skin to the infant’s oral mucosa, and Can-
dida spp. have been recovered from expressed breast milk,
although lactoferrin present in human milk can inhibit
the growth of C. albicans.35 Candidal mastitis increases the
risk of transmission. Perinatal transmission can result in
colonization, congenital candidiasis, or mucocutaneous
infections in the term infant, whereas the result can be dis-
seminated or systemic candidiasis in the preterm infant.36
Although maternal vertical transmission is more com-
mon, acquisition of Candida from care providers may occur
and historically was considered the primary mode of trans-
mission for C. parapsilosis.26,29,30 In one study evaluating
19 mother-infant pairs, no maternal reservoir could be
demonstrated among infants colonized with C. parapsilo-
sis.29 More recent studies have demonstrated maternal
33 • Candidiasis 1059
gastrointestinal colonization, highlighting the changing
epidemiology as colonization rates alter with antimicrobial
pressure.33,37 After birth, NICU personnel, rather than the
mother, may have the greatest contact with the preterm or
sick infant. Because C. parapsilosis is the most common Can-
dida spp. recovered from the hands of health care providers,
transmission can be expected and may be a contributing
factor to the increased incidence of C. parapsilosis catheter-
associated infections in high-risk neonates.38-41
Colonization is important in the development of disease
because the Candida strain recovered in infection usually is
identical to the colonizing strain.42,43 Disseminated infec-
tions result from translocation across the gastrointestinal
tract epithelium of commensal Candida spp.14,18,42 However,
colonization does not inevitably lead to disease, and infec-
tion does occur in the absence of apparent colonization.44
Direct transmission of Candida to NICU infants has been
documented from exogenous yeast carried by hands of hos-
pital personnel or found on equipment.41,45,46 This empha-
sizes the need for proper hand hygiene among health care
workers in the NICU. It is primarily the mechanical action
of hand washing that decreases the burden of Candida spp.
present because most of the antimicrobial soaps available
are not fungicidal.47 Vaudry and colleagues48 described
an outbreak of candidemia in seven infants without cen-
tral intravascular catheters, and molecular typing of the C.
albicans strains grouped the isolates into two cohorts corre-
sponding with the timing of infections and the geographic
location of babies in the nursery. The use of intravascular
pressure-monitoring devices has been associated with C.
parapsilosis fungemia in a NICU.49 Candida infections have
resulted from retrograde administration of medications by
multiple-use syringes in infants receiving total parenteral
nutrition; in these cases, the responsible organisms, C. albi-
cans, C. tropicalis, and C. parapsilosis, were isolated from
the blood of the infants and the medication syringe.41 The
outbreak subsided with a change to single-use syringes. A
nursery outbreak of Candida guilliermondii, a typically non-
pathogenic NCAC, was traced to contaminated heparin
vials used for flushing needles for blood drawing.49 All of
these examples point to the ubiquitous nature of Candida
spp. and the need for stringent infection control practices
on the NICU to decrease the acquisition of nosocomial
infections.50,51
Microbiology
The name Candida comes from the Latin term candidus,
meaning “glowing white,” which refers to the smooth, glis-
tening white colonies formed by these yeasts when grown
on culture media. The taxonomy of the genus Candida
is somewhat challenging and incomplete because of the
reclassification of certain species (e.g., Torulopsis glabrata
has been correctly identified as C. glabrata) and the discov-
ery of new species, such as C. dubliniensis, Candida orthop-
silosis, and Candida matepsilosis (the last two previously
classified as part of the C. parapsilosis complex).52-54 Pre-
viously used terms, such as Fungi Imperfecti, Oidium, and
Monilia, are no longer used in classifying the genus Candida.
Fungi Imperfecti, or Deuteromycetes, refers to the class of
fungi that reproduce asexually. This was the prevailing
1060 SECTION IV • Protozoan, Helminth, and Fungal Infections

theory regarding Candida; however, a teleomorph, or sexual

stage, has been described for certain Candida spp. (e.g., C.
krusei, C. guilliermondii), eliminating this characteristic as a
useful tool in classification.55 Oidium and Monilia were 19th
century terms that are no longer used to refer to the genus
Candida, although the term monilial is still commonly used
to describe the characteristic rash observed in cutaneous
Candida infections.55,56
Although more than 150 species of Candida have been
described, relatively few species infect humans. Most exist as
environmental saprophytes, and more than one half the Can-
dida spp. described cannot even grow at 37° C, making them
unlikely candidates to be successful human pathogens.55,56
C. albicans is the most prevalent species causing human dis-
ease, but other pathogenic species include C. parapsilosis,
C. glabrata, C. tropicalis, Candida pseudotropicalis, Candida para-
tropicalis, C. krusei, Candida lusitaniae, C. guilliermondii, C. dub- A
liniensis, and C. orthopsilosis. The primary pathogens among
neonates are C. albicans and C. parapsilosis (see Table 33-1).
Members of the genus Candida are ubiquitous and form a
heterogeneous group of eukaryotic, dimorphic, or polymor-
phic organisms. All Candida spp. grow as yeast cells or blas-
toconidia under general culture conditions between 25° C
and 35° C, and growth is augmented by increased sugar or
fat content in the media. Yeast cells are approximately 2 to B C
10 μm in the largest dimension, round to oval, and repro-
duce by budding. C. albicans is among the larger yeast at 4 Figure 33-1 Light microscopy photographs of Candida albicans blas-
to 6 × 6 to 10 μm, whereas C. glabrata and C. parapsilosis are toconidia or yeast cells (A), pseudohyphae (B), and true hyphae (C).
among the smallest at 1 to 4 μm × 2 to 9 μm and 2 to 4 × 2 (Courtesy Cheryl A. Gale, MD, University of Minnesota Medical School,
­Minneapolis.)
to 9 μm, respectively.55 Figure 33-1A shows C. albicans sin-
gle blastoconidia and budding yeast cells. Most members of
the genus also produce a filamentous form: pseudohyphae Ligands include sugar residues on human buccal epi-
(Fig. 33-1B) or true hyphae (Fig. 33-1C). C. glabrata is the thelial cells and a wide variety of extracellular matrix
only pathogenic species that does not produce filamentous proteins, such as fibronectin, fibrinogen, types I and IV
forms, existing exclusively as blastoconidia.55 C. parapsilosis collagen, laminin, and the complement components iC3b
forms pseudohyphae but not true hyphae. Only C. dublini- and C3d.68 Reciprocally, human cells recognize yeast cell
ensis and C. albicans form true hyphae (see Fig. 33-1C), dis- ligands via pattern recognition receptors, such as Toll-like
tinguishing these two species as polymorphic rather than receptors (TLR) or the β-glucan receptor (βGR) dectin-1.69
dimorphic. Formation of a germ tube precedes the develop- In tissue culture assays, C. albicans is more adherent than
ment of true hyphae, and this change in morphology can other Candida spp. to every form of human epithelium and
be induced by growth in serum or other specialized media endothelium available, including cultured buccal epithe-
or by incubation at 37° C. The clinical diagnostic microbiol- lium, enterocytes (adult and fetal), cervical epithelium,
ogy laboratory has exploited this distinction by use of the and human umbilical vein endothelial cells.32,70-72 The
germ tube formation test to rapidly identify C. albicans or adhesive molecules responsible for epithelial and endo-
C. dubliniensis over other Candida spp.57 thelial adhesion may also facilitate binding between indi-
The ability to form true hyphae is considered one of vidual Candida cells and the subsequent development of
the prime virulence factors for C. albicans.58 Microscopic “fungus balls” found in infected organs.68 No single adhe-
examination of infected human and animal tissue usually sin molecule is completely responsible for the adherence
demonstrates the presence of C. albicans hyphae.59-62 Con- of C. albicans to human epithelium, and multiple methods
versely, nonfilamentous yeast, such as S. cerevisiae, rarely of interacting with the host surface are postulated for this
cause human disease, and genetically altered strains of commensal organism.68 C. albicans and C. parapsilosis both
C. albicans, which cannot filament normally, are gener- adhere well to the surface of catheters and, in the process,
ally less virulent in animal models of fungemia.63-65 Other form a biofilm, although the biofilms formed by C. albicans
commonly recognized virulence factors for C. albicans are more dense and complex than those formed by other
include the production of proteinases and phospholipases, Candida spp.73,74 The biofilm microenvironment promotes
hydrophobicity, the presence of various surface molecules fungal growth with hyphal transformation and may con-
(e.g., receptors, adhesions), and the production of biofilm, fer relative drug resistance because of poor penetration
which may be particularly important in catheter-associated of antimicrobial agents into this mass of extracellular
infections.59,62,64,66,67 matrix, yeast cells, and hyphae.67,73,75 In vitro studies of
A variety of surface molecules of C. albicans are responsi- C. albicans biofilms document the development of fluco-
ble for modulating epithelial adhesion by interacting with nazole resistance within 6 hours of formation.73 Biofilm
host ligands on the epithelial or endothelial surface.63,66 formation is associated with persistent fungemia and with

coinfection by nosocomial bacterial pathogens, such as
Staphylococcus spp.73,76,77 Candida spp. induce a strong
TLR-mediated proinflammatory response in cultured oral
epithelial cells, resulting in profound interleukin-8 secre-
tion.78,79 In addition, the βGR dectin-1 and Toll-like recep-
tors TLR2 and TLR4 (thought to be the main receptors
for the innate immune system recognition of C. albicans)
appear to work synergistically, with dectin-1 amplifying
tumor necrosis factor-α (TNF-α) production via the TLR
pathway.69 The ability to adhere to human epithelium
and endothelium (and to itself and catheters), resulting
in microenvironmental changes, is a significant virulence
factor setting C. albicans apart from other Candida spp. and
may be a prominent reason for the increased frequency
with which C. albicans is found colonizing the host and
causing disease at epithelial and endothelial sites.
Virulence factors of other Candida spp. have not been well
studied. A fibronectin receptor that facilitates epithelial
adhesion has been described in C. tropicalis.66,80 C. glabrata
colonizes the gastrointestinal tract, and this nonfilamen-
tous Candida spp. can form biofilms.75 C. parapsilosis has
been recovered from the alimentary tract of neonates, but
no work has been done to implicate or exclude the gastro-
intestinal tract as a possible source of infection among neo-
nates, and no specific virulence factors have been identified
in this Candida spp.23,29,74 C. glabrata and C. parapsilosis pro-
duce biofilms; however, this area has not been well inves-
tigated for either of these pathogenic NCAC species.67,74,81
Overall, Candida spp. exhibit relatively low-level virulence
factors compared with organisms that typically cause dis-
ease in an immunocompetent host. Candidal virulence fac-
tors serve to differentiate the more virulent from the less
virulent Candida spp., rather than to distinguish Candida
from other more pathogenic microbes.
Pathogenesis
The pathogenesis of invasive candidiasis involves a com-
mon sequence of events in all at-risk hosts: colonization,
resulting from adhesion of the yeast to the skin or mucosal
epithelium (particularly the gastrointestinal tract); penetra-
tion of the epithelial barriers; and locally invasive or widely
disseminated disease. Dissemination to deep visceral organs
results from hematogenous spread.14 However, not every
colonized patient develops a Candida infection. The unique
combination of host factors and yeast virulence mecha-
nisms results in the persistence of benign colonization or the
progression to infection among high-risk neonatal patients,
as outlined in Figure 33-2. Yeast virulence factors were
described in the preceding section. Host risk factors, listed
in Box 33-1, are potentially more important in the devel-
opment of neonatal candidal infections.6,51,82 Limitation of
exposure to all predisposing conditions for candidal infec-
tion is highly desirable but rarely feasible, especially in the
VLBW infant. However, we should consider limiting any of
these risk factors, if possible, in the ELBW infant. Benjamin
and colleagues7 have reported that the most significant
“potentially modifiable” risk factors for invasive candidia-
sis are broad-spectrum antibiotic exposure (adjusted odds
ratio [aOR], 1.98), central catheter in place (aOR, 1.94),
intravenous lipid emulsion (aOR, 1.66), endotracheal tube
33 • Candidiasis 1061
Colonization/exposure
Yeast
Invasion/translocation
Host
virulence factors risk factors
Localized Disseminated
disease candidiasis
Figure 33-2 The pathogenesis of neonatal candidiasis follows a path-
way from colonization to infection, modified by multiple host factors
and yeast virulence factors.
Box 33-1 Host Factors Enhancing Risk for
Candidiasis in Neonates
High burden of colonization with Candida species
Prematurity, especially gestational age < 28 weeks
Very low birth weight (<1500 g)
Apgar score < 5 at 5 minutes
Prolonged broad-spectrum antimicrobial therapy
Third-generation cephalosporin exposure
Indwelling catheters, especially central intravascular catheters
Total parenteral hyperalimentation > 5 days
Intravenous lipid emulsion > 7 days
Intubation
Exposure to an H2 blocker
Abdominal surgery
Necrotizing enterocolitis
Spontaneous intestinal perforation
Cardiac surgery
Prolonged hospitalization > 7 days
Steroid therapy
Neutropenia
Hyperglycemia
in place (aOR, 1.58), and exposure to antenatal antibiotics
(aOR, 1.40)]. They also reported the following “predictors”
of invasive candidiasis: Candida-like dermatitis (aOR, 3.22),
central catheter in place (aOR, 1.85), vaginal versus cesar-
ean delivery (aOR, 1.84), enteral feeding (aOR, 1.52), lower
gestational age (aOR, 1.29), hyperglycemia (aOR, 1.22),
thrombocytopenia (aOR, 1.17), and antibiotic exposure in
the week before infection (aOR, 1.13).7
Indiscriminate, frequent, or prolonged use of broad-
spectrum antimicrobial agents, resulting in alterations of
the normal skin and intestinal microbial flora, allows over-
growth of the colonizing strain of Candida and a concomi-
tant increased risk for translocation and hematogenous
spread.18 The greater the density of organisms in the neo-
natal gastrointestinal tract, the greater is the chance of dis-
semination.83 High levels of Candida colonization found in
certain nurseries are linked to patterns of antibiotic usage,
including a particularly strong association with third-­
generation cephalosporin use.26,43,84
The immunocompromised state predisposes an infant to
candidal infection, whether caused by the developmentally
immature immune system of the newborn, a congenital
1062 SECTION IV • Protozoan, Helminth, and Fungal Infections
immunodeficiency, or the immunosuppression accompany-
ing steroid therapy. No single defect in the immune system
appears to be solely responsible for an increased suscepti-
bility of premature neonates to candidal infections. Healthy
adults have circulating immunoglobulin G (IgG) antibodies
to Candida antigens, which effectively opsonize the organ-
ism and activate the alternative complement pathway.85
Neonatal IgG levels depend on maternal exposure to the
yeast, accompanied by transplacental transmission of can-
didal antibodies, and the ability for the infant to respond to a
new challenge with a Candida spp., which may be slow and
inadequate.86 Polymorphonuclear leukocytes ingest and
kill Candida; therefore neutropenia is an important risk fac-
tor.6,18 Disseminated candidiasis in neonates is associated
with the intravenous administration of dexamethasone
and hydrocortisone.87,88 Steroid therapy results in immu-
nosuppression and may have direct effects on colonization
and translocation from the gastrointestinal tract. In vitro
studies have shown that C. albicans is more adherent to
monolayers of cultured enterocytes treated with dexa-
methasone than to untreated control monolayers, whereas
mice injected with dexamethasone demonstrate higher
levels of gastrointestinal tract colonization with C. albicans
and increased rates of dissemination to the kidney.61 Ste-
roids may have a direct effect on the yeast by regulation of
gene expression, including multidrug-resistance genes and
other modulators of virulence.89 The presence of indwelling
catheters is a significant predisposing risk factor for neo-
natal candidiasis. Endotracheal tubes, urinary catheters,
peritoneal catheters, chest tubes, mediastinal tubes, and
ventriculoperitoneal shunts can all become infected, but
the greatest risk lies with intravascular catheters, particu-
larly central venous catheters (CVCs).7,51,82 All catheters
in the vascular space for more than a day begin to develop
a thrombin sheath with a matrix-like substance providing
an optimal site for accumulation of microorganisms.73 Can-
dida spp. adhere extremely well to the inert surface of the
catheter, and electron microscopy studies have shown that
Candida spp. are able to burrow into the catheter and form a
surrounding biofilm.73,90 This sequence results in a unique
microenvironment, providing a barrier to host defenses
and offering optimal conditions for growth and prolifera-
tion of the Candida organism, often resulting in the devel-
opment of an infected mural thrombus extending from the
tip of the catheter.91-93 The “fungal mass” adherent to the
catheter can then serve as a source for persistent fungemia
or embolic spread of Candida spp. to distant organs.1,18 The
original source of the yeast that “sticks” to the line may be
from hematogenous spread of endogenous gastrointesti-
nal tract Candida strains or from nosocomial transmission
through placement or handling of the catheter itself.41,48
Use of the catheter for hyperalimentation is an addi-
tional risk, especially with the infusion of high-dextrose–­
containing total parenteral solutions and intralipids.6,7,18
Any compromise of epithelial barriers can predispose the
neonate to candidal infections. Abdominal surgery and car-
diac surgery are associated with an increased risk for dis-
seminated candidiasis, especially among term infants.18,76
Necrotizing enterocolitis (NEC) is strongly associated with
Candida fungemia.6,7,14 The loss of mucosal integrity after
mesenteric ischemia and NEC provides a portal of entry for
the dissemination of endogenous gastrointestinal flora.14
Spontaneous intestinal perforation, occurring most often in
the extremely preterm infant, is highly associated with can-
didemia.19,94 As with any nosocomially acquired organism,
prolonged hospitalization is a significant risk factor for the
development of candidiasis.6,7,14,18
Prematurity is a key risk factor for candidiasis, especially
infants born at less than 28 weeks of gestation or VLBW
neonates.3,7,18 With improvements in technology, the cur-
rent standard of care in the NICU includes an aggressive
approach to the treatment of VLBW infants such that life
for an extremely premature infant combines nearly all the
risk factors for candidiasis in one patient.7,18 The prema-
ture infant is born with immature epithelial barriers and
an immature immune system. The skin and mucosal epi-
thelium of these very tiny infants are minimally protective,
readily breaking down with exposure to air and routine
nursing procedures.19,95,96 Preterm infants have the lowest
levels of circulating maternal IgG of all neonates, having
lost the opportunity for transplacental transfer that occurs
during the third trimester of pregnancy.97 Even if specific
anti-Candida IgG is present, opsonization and comple-
ment activation are diminished.85 Complement levels are
low in preterm infants (see Chapter 4), with biochemical
abnormalities of C3 resulting in inadequate activation of
this pathway for fighting infections.98 Neutropenia is com-
mon among infants born at less than 28 weeks of gesta-
tion.99,100 Virtually every premature infant begins life with
a course of empirical broad-spectrum antibiotics, leading to
an interruption in the process of establishing the normal
gastrointestinal microflora and the potential for unchecked
proliferation of Candida.36,100 Endotracheal and intravas-
cular catheters are true lifelines for the VLBW premature
infant needing respiratory, inotropic agent, and nutritional
support. Because venous access is often difficult to obtain
and maintain in these infants, intravascular access lines
are not automatically rotated and frequently remain in
place for weeks. Even the fairly healthy VLBW infant often
displays feeding intolerance that can require prolonged
central total parenteral nutrition (TPN) rather than enteral
feeds.6,7 As reported by the NICHD Neonatal Research Net-
work, the aOR for any episode of late-onset sepsis is 3.1
in VLBW infants receiving TPN for 8 to14 days, rising to
4.0 for an infant receiving TPN for more than 22 days.5
Saiman and colleagues18 reported odds ratios for develop-
ing candidemia of 2.93 for infants less than 1000 g receiv-
ing TPN for more than 5 days and 2.91 for intravenous
(IV) intralipid use for more than 7 days. Unfortunately,
NEC may also accompany feeding intolerance, leading to
an additional risk for disseminated candidiasis.101,102 Cor-
ticosteroid use is also common in these patients.87,88 Mul-
tiple reviews report that almost one half of the infants with
a birth weight of less than 750 g are postnatally exposed to
corticosteroids: hydrocortisone used to treat hypotension;
dexamethasone, methylprednisolone, or hydrocortisone
used for severe lung disease.87,88,102 Hyperglycemia and
hyperlipidemia are common in these immature patients
receiving TPN, steroids, or both.88 Prolonged length of stay
is the rule rather than the exception for the NICU infant,
with or without a nosocomially acquired infection. The
average corrected gestational age at discharge from the
NICU is between 35 and 37 weeks, and the average NICU
hospitalization is approximately 62 days; however, the

length of stay to achieve 36 weeks of gestational age is even
longer for the infant born at less than 28 weeks of gesta-
tion.5,18 Each of these factors, especially in combination,
makes the VLBW preterm infant an extremely high-risk
candidate for the development of candidiasis.
Pathology
The tissue pathology observed in Candida spp. infections
depends on the site of involvement and the extent of inva-
sion or dissemination. Histologic evaluation of mucosal or
epithelial lesions reveals superficial ulcerations with the
presence of yeast and filamentous forms of Candida spp.,
including a prominent polymorphonuclear (PMN) leuko-
cyte infiltration.96 ELBW infants can develop invasive fun-
gal dermatitis with erosive lesions; biopsy of these lesions
reveals invasion of fungal elements through the epidermis
into the dermis.19,96 In disseminated neonatal infections,
Candida spp. can invade virtually any tissue. Microabscesses
are commonly found in the kidney, retina, and brain, but
they also have been described in the liver, spleen, perito-
neum, heart, lungs, and joints.96,103-105 When C. albicans is
the infecting organism, abscesses contain a predominance
of hyphal elements with a significant accompanying infil-
tration of PMNs and prominent tissue necrosis, especially
in the kidney.59,91,104 Mycelia are frequently found invad-
ing the walls of blood vessels within infected tissues.13,60,104
Retinal lesions, vitreal fungal lesions, and even lens
abscesses with cataract formation have been described in
neonates.106,107 Evaluation of brain material shows signifi-
cant inflammation with seeding of the meninges and may
include parenchymal lesions, ventriculitis, perivasculitis,
and ependymal inflammation.105,108-110 Macroscopic fun-
gus balls can form in fluid-filled spaces lined with epithelial
or endothelial cells, such as the urinary tract, the central
nervous system (CNS), and the intravascular space (partic-
ularly the right atrium).92,111 Fungus balls are large collec-
tions of intertwined hyphae, pseudohyphae, and yeast cells
that presumably grow from Candida spp. initially adher-
ent to the epithelial or endothelial surface of the involved
organ.104,112,113 Foreign bodies present in these fluid-filled
spaces, such as urinary catheters, ventricular shunts, or
CVCs, can also serve as the nidus for infection and precipi-
tate the formation of a fungus ball.92,103,104,112,113
In intrauterine candidal infections, macroscopic cho-
rioamnionitis is evident, and histologic examination of
the fetal membranes and the chorionic plate often reveals
fungal elements with an extensive PMN infiltration.114
Along with diffuse placental inflammation, focal granulo-
matous lesions can be present in the chorioamniotic mem-
branes and umbilical cord.114-116 The detection of placental
pathology consistent with candidal chorioamnionitis can
lead to the early detection of congenital candidiasis in the
infant.114
Clinical Manifestations
Candida spp. are responsible for a variety of infections in
neonates with a broad spectrum of clinical presentations,
ranging from mild, irritating thrush and diaper dermatitis
33 • Candidiasis 1063
in the healthy term infant to life-threatening systemic dis-
ease in the extremely premature infant. The primary forms
of candidiasis among infants are mucocutaneous infec-
tions, congenital candidiasis, catheter-related candidemia,
and systemic or disseminated candidiasis. Individual organ
system involvement (e.g., urinary tract infection, isolated
meningitis, endophthalmitis) can occur, but infection
occurs much more often as a component of disseminated
infection, especially in the premature infant. Table 33-2
lists features of the various presentations of neonatal
candidiasis.
OROPHARYNGEAL CANDIDIASIS
Oropharyngeal candidiasis (i.e., thrush) can occur at any
time during infancy. Among hospitalized infants, the over-
all incidence is reported as 3%, with a median age of onset
of 9 to 10 days in NICU patients.19,117,118 Specific risk fac-
tors include vaginal delivery, maternal vaginal Candida spp.
infection, and birth asphyxia.118,119 In a study of more than
500 mother-infant pairs, an eightfold increase was observed
in the incidence of thrush among infants born to moth-
ers with symptomatic candidal vaginitis compared with
infants born to asymptomatic mothers.119 A multivariate
analysis of factors among NICU infants reported that birth
asphyxia was the only event significantly associated with
the development of thrush.118 Although Candida spp. can
be transmitted from mother to infant during breastfeeding,
thrush occurs more often among formula-fed infants.120
C. albicans is the most common species isolated from infants
with thrush, but other NCAC species, such as C. parapsilosis
and C. glabrata, increasingly are found as commensals and
infecting agents.120,121
Thrush manifests as irregular white plaques on the oral
mucosa, including the buccal and lingual surfaces and the
palate. The underlying mucosa may appear normal or ery-
thematous and may have an ulcerative base to the white
lesion. Physical removal of the plaques usually is difficult
and often results in mucosal damage. Infected infants can
be healthy or quite irritable, with disinterest in oral feedings
and obvious discomfort with any care involving contact
with the oral lesions.
DIAPER DERMATITIS
Diaper dermatitis can occur any time during infancy, with
a peak incidence at age 7 to 9 months in term infants (10%
incidence) and approximately 10 to 11 weeks among
VLBW infants (28% incidence).28,36,122 Most infants with
candidal diaper dermatitis have gastrointestinal coloniza-
tion, with stool cultures positive for a Candida spp.122 Some
infants also have oropharyngeal candidiasis. C. albicans
is the most common species isolated, but there has been
an increase in the recovery of other NCAC species, par-
ticularly C. glabrata and C. parapsilosis, when cultures are
obtained.19
The characteristic rash of candidal diaper dermatitis is
confluent and intensely erythematous with satellite lesions
and pustules.19,122 As with oral thrush, the lesions can be
very irritating to the infant, especially during normal peri-
neal care. In the term infant, the rash resolves rapidly after
treatment with an appropriate topical antifungal agent.120
 1064
Table 33-2 Features of Neonatal Candidiasis

SECTION IV • Protozoan, Helminth, and Fungal Infections

Multiorgan Involve-
Clinical ­Syndrome Age at Onset Host Risk F
­ actors* Presentation Diagnosis Treatment ment Prognosis
MUCOCUTANEOUS INFECTIONS
Thrush Throughout infancy Birth asphyxia White plaques on oral Physical examination Topical or oral antifungal None Excellent
mucosa therapy
Diaper ­dermatitis Throughout infancy; Gastrointestinal Intense erythema of Physical examination Topical antifungal None in term infants Excellent
peak at 7-9 mo ­colonization perineal area with therapy
(term) and 10-11 satellite lesions
wk (preterm)
Congenital Birth Premature rupture Widespread erythem- Physical examination Topical antifungal Uncommon Excellent in term infants;
­candidiasis of membranes or atous maculopapu- Culture of lesions for therapy ­Dissemination can excellent in preterm
uterine foreign body lar rash ± vesicles Candida spp. Systemic antifungal occur in preterm infants without dis-
Pneumonia in preterm therapy for pneumonia infants semination
infants
Invasive fungal <2 weeks <1000 g Erosive, crusting Physical examination Systemic antifungal Common Good if localized without
­dermatitis Vaginal delivery lesions in depen- Biopsy and culture of therapy dissemination
Postnatal steroids— dent areas lesions
hyperglycemia
SYSTEMIC INFECTIONS
Catheter-related >7 days Intravascular catheters Sepsis Blood culture by cath- Catheter removal and Rare endocarditis or Good without dissemina-
infections eter grows Candida systemic antifungal right atrial mass or tion or complication
spp. but peripheral therapy thrombus
blood cultures sterile
Candidemia >7 days Sepsis Only blood cultures Systemic antifungal Common in VLBW Good to fair
grow Candida spp. therapy infants Risk of ROP in VLBW
infants
Disseminated >7 days Severe sepsis Blood and urine, CSF Systemic antifungal Always (sites most Fair to poor
­candidiasis Multiorgan or other sites grow therapy often involved are
­involvement Candida spp. kidneys, CNS, eyes,
Clinical and/or radio- heart)
graphic evidence for
multiorgan involve-
ment
Renal candidiasis >7 days Congenital urinary tract Sepsis Urine culture grows Systemic antifungal Uncommon with Good
anomalies Urinary tract Candida spp. therapy isolated UTI
Neurogenic bladder ­obstruction Ultrasound evidence of
renal fungal lesions
CNS candidiasis >7 days Neural tube defects Indwelling CSF shunt CSF culture grows Systemic antifungal Common Poor
or catheter Candida spp. therapy
Sepsis CSF culture grows Can-
None to focal dida spp. ± signs of
­neurologic signs inflammation; lesions
by cranial imaging

CNS, Central nervous system; CSF, cerebrospinal fluid; ROP, retinopathy of prematurity; UTI, urinary tract infection; VLBW, very low birth weight.
*Factors, in addition to those listed in Box 33-1, pertaining to the specific clinical syndrome listed.

The preterm infant has a greater risk for spread beyond the
diaper area. In a prospective study, Faix and colleagues117
found mucocutaneous disease in 7.8% of all preterm
infants, and most had diaper dermatitis. Among preterm
infants with dermatitis and an associated change in clini-
cal status, 32% developed systemic disease compared with
2.1% of healthy preterm infants without dermatitis.117
Therefore it is prudent to monitor the preterm infants with
candidal diaper dermatitis for signs of systemic infection.
CONGENITAL CANDIDIASIS
Congenital candidiasis typically presents at birth or within
the first 24 hours of life, resulting from a maternal intrauter-
ine infection or from massive exposure to maternal vaginal
colonization with Candida during labor and delivery.114,115
Candida chorioamnionitis has been associated with intra-
uterine fetal death and preterm delivery.115,123 Hematog-
enous dissemination from mother to fetus, direct invasion
of intact membranes, and ascending infection after ruptured
membranes have been postulated as mechanisms for intra-
uterine infection.19,123 Recognized risk factors for congenital
candidiasis differ from those associated with postnatal infec-
tion and include prolonged rupture of membranes and the
presence of an intrauterine foreign body, most commonly
a cerclage suture.123,124 Infants with the latter risk factor
are more likely to be born prematurely and to have more
severe skin involvement with disseminated disease.115,123
Although C. albicans is the predominant species responsible
for congenital candidiasis, cases of congenital infections with
C. glabrata and C. parapsilosis have been described.19,124,125
Although there are rare case reports of infants with con-
genital candidiasis without skin involvement, the classic
presentation is one of diffuse cutaneous disease.34,126 Der-
matologic findings include a widespread erythematous
maculopapular rash, often with well-demarcated borders,
that evolves into vesicles or pustules with eventual desqua-
mation.124,126 Any part of the skin may be involved, includ-
ing the palms and soles, but the lesions typically are more
prominent in the skin folds or intertriginous areas.19,127
Preterm infants can have a diffuse, widespread, intensely
erythematous dermatitis that resembles a mild burn or the
early stages of staphylococcal scalded skin syndrome.19,96
This form of congenital candidiasis often leads to massive
desquamation, often accompanied by a prominent leukocy-
tosis.34 Extensive desquamation can lead to severe fluid and
electrolyte imbalances in the extremely premature infant.34
In term infants, clinical findings usually are limited to
the skin, and recovery is uneventful after topical antifun-
gal therapy. However, meningitis has been reported in the
term infant with congenital candidiasis, and some infants
may have nonspecific clinical signs of sepsis, such as poor
perfusion, hypotonia, and temperature instability, sug-
gesting systemic disease.126,128 In preterm infants, cutane-
ous findings can be coupled with pulmonary invasion and
early respiratory distress. In this circumstance, the chest
radiograph is atypical for surfactant deficiency, and the
expected ground-glass appearance is replaced by a nodu-
lar or alveolar infiltrate.127 Hematogenous dissemination
is uncommon, but it can occur more frequently among
preterm neonates and infants with widespread cutaneous
involvement, pulmonary disease, and central intravascular
33 • Candidiasis 1065
catheters.124,126 Every attempt should be made to avoid
placing central intravascular catheters through the infected
skin of patients with congenital cutaneous candidiasis.
INVASIVE FUNGAL DERMATITIS
Invasive fungal dermatitis is a unique clinical entity
described in the ELBW infant occurring during the first 2
weeks of life.96,129 Candida spp. are frequently isolated, but
infection with other filamentous non-Candida fungi, includ-
ing species of Aspergillus, Trichosporon, Curvularia, and Bipo-
laris, can result in this clinical presentation.96,130,131 Specific
risk factors for invasive fungal dermatitis include a gesta-
tional age less than 26 weeks, vaginal birth, postnatal ste-
roid administration, and hyperglycemia.96 The immature
skin of the extremely preterm infant is not an efficient bar-
rier to the external invasion of Candida, making these neo-
nates more susceptible to invasive cutaneous disease. The
stratum corneum of the preterm infant is extremely thin,
and keratinization with maturation of the barrier properties
typically occurs beyond the second week of life.124
Neonates with invasive fungal dermatitis have charac-
teristic skin lesions with severe erosions, serous drainage,
and crusting, often occurring on dependent surfaces such
as the back or abdomen.96 Biopsy of the affected area shows
invasion of fungal elements through the epidermis into the
dermis.96 Without prompt and appropriate therapy, dis-
semination with resulting widespread systemic disease is
a frequent complication. As with congenital candidiasis,
infants with extensive erosive lesions are at risk for the
development of fluid and electrolyte abnormalities and sec-
ondary infections with other skin microorganisms.
CATHETER-RELATED CANDIDAL INFECTIONS
Catheter-related candidal infections are disease processes
of the sick, hospitalized preterm or term infant requiring
prolonged use of intravascular catheters or other invasive
means of support.7,18,51 Almost any type of indwelling for-
eign body can become infected, but vascular catheter-related
candidemia is the most frequent and serious infection. The
incidence increases after a central vascular catheter has
been in place for more than 7 days. These infections have
been associated with umbilical venous and arterial catheters
and with percutaneously placed arterial or CVCs (i.e., femo-
ral venous, subclavian, Broviac, or Silastic lines).6,50 Periph-
eral venous catheters have the same potential for fungemia
in the premature infant, especially when used for the delivery
of hyperalimentation fluid, and have been associated with
the development of skin abscesses at the insertion site.132,133
Catheter-related Candida infection can occur in the absence
of cutaneous infection in neonates with one or more of the
predisposing conditions listed in Box 33-1, and the infec-
tion can arise from endogenous gastrointestinal organisms
or from nosocomial transmission. Infected neonates exhibit
nonspecific signs of sepsis, including feeding intolerance,
apnea, hyperglycemia, and temperature instability, but no
evidence of multiorgan involvement. Preterm infants also
may exhibit hemodynamic instability or respiratory distress.
Thrombocytopenia is a common presenting feature.3,134 The
vascular catheter tip provides an excellent nidus for growth
of Candida and affords a source of ongoing fungemia. An
1066 SECTION IV • Protozoan, Helminth, and Fungal Infections
infected thrombus or fungus ball can form on the catheter
tip, serving as a source of platelet consumption or embolic
dissemination.104 By definition, catheter-related candidemia
is infection of the catheter only; there is no dissemination or
multiorgan involvement. Prompt catheter removal at the
earliest sign of infection, although often impractical in the
management of many of the highest-risk neonates, is nec-
essary to contain the infection and prevent persistent can-
didemia with the attendant risk of developing disseminated
infection or other complications.135,136 Candidal infections
of right atrial catheters are associated with endocarditis and
intracardiac fungal masses; the latter may result in cardiac
dysfunction because of the enlarging right atrial mass.92,137
Although infected intravascular catheters provide the
greatest concern for dissemination, infection can occur
with almost any type of catheter used in the treatment of
the VLBW infant. Prolonged endotracheal intubation for
mechanical ventilation can be required in the extremely pre-
mature infant with respiratory distress and in the sick term
infant after cardiac or other extensive surgery. The concur-
rent ongoing presence of the endotracheal tube can lead to
candidal colonization with the potential for development
of pneumonia, although invasive lung infection is uncom-
mon.7,9,76 Candidal cystitis can accompany the prolonged
use of indwelling bladder catheters by facilitating ascending
infection, and cystic fungal masses can form, resulting in
urethral obstruction.50,51,111-113,138 Infants with vesicoure-
teral reflux and a candidal bladder infection are at increased
risk for renal parenchymal infection.112,138 Candidal perito-
nitis can develop with the prolonged use of peritoneal cath-
eters placed intraoperatively for drainage or, more often,
placed for peritoneal dialysis.103 Peritoneal dialysis cath-
eters are at extremely high risk for infection because of the
frequent handling required and the high dextrose concen-
tration of the indwelling dialysis fluid.103 Candida spp. have
been recovered from the pleural fluid draining from thoracic
tubes and from the fluid draining through surgically placed
mediastinal tubes.127 With cystitis, dissemination and wide-
spread disease can be complications, but Candida peritonitis
or pleuritis rarely leads to fungemia.112,138
Candidemia and Disseminated
Candidiasis
Candidemia and disseminated or systemic candidiasis usu-
ally are associated with multiple invasive infection enhanc-
ing factors and are infections of the sick preterm or term
infant who is in the NICU more than 7 days.7,8,104 How-
ever, most cases occur among ELBW infants, who have an
incidence of candidemia ranging from 5.5% to 20%.7,18,51
The source of the infecting Candida spp. can be the infant’s
endogenous flora or from nosocomial transmission, and all
the Candida spp. listed in Table 33-1 have been implicated in
systemic disease.5,18 Although candidemia without organ
involvement can occur, Candida spp. have such high affin-
ity for certain organs (e.g., kidney, eye, heart, CNS) that
dissemination appears to be the rule rather than the excep-
tion, particularly in the neonate with persistent funge-
mia.2,51,104,105 The clinical presentation of the infant with
candidemia can vary greatly depending upon the extent
of systemic disease. The most common presentation is one
with clinical features typical of generalized sepsis, includ-
ing lethargy, feeding intolerance, hyperbilirubinemia,
apnea, cardiovascular instability, and the development or
worsening of respiratory distress. The preterm infant can
become critically ill, requiring a significant escalation in
cardiorespiratory support. Fever rarely occurs, even with
widespread disease. New-onset glucose intolerance and
thrombocytopenia are common presenting findings that
can persist until adequate therapy has been instituted and
the infection contained.18,50,88,134 This association is so
strong that the presence of persistent hyperglycemia with
thrombocytopenia in a neonate cared for in the NICU is
almost diagnostic for untreated candidemia.134 Leukocy-
tosis with either a neutrophil predominance or neutrope-
nia can be seen.100 Neutropenia is more often associated
with overwhelming systemic disease. Skin abscesses have
been described with systemic disease and are attributed to
the deposition of septic emboli in end vessels of the skin.139
Infants also can have specific organ involvement, such as
renal insufficiency, meningitis, endophthalmitis, endocar-
ditis, or osteomyelitis, confirming dissemination. Complex
multiorgan involvement is the hallmark of disseminated
candidiasis, especially among VLBW premature infants, and
results from diffuse hematogenous spread.50,140 The suspi-
cion or diagnosis of candidemia or the diagnosis of candidal
infection of any single organ system should prompt a thor-
ough examination and survey of the infant for additional
organ involvement.2,50,140 Almost any organ can become
infected, but the most common sites for candidal dissemi-
nation are the urinary tract, the CNS, and the eye.2,50,140
The specific clinical presentation for each of these systems is
described separately in the following sections. For the infant
with disseminated candidiasis, complications can be exten-
sive, multiorgan system failure common, and the need for
escalated intensive support frequent and prolonged.50,104
Renal Candidiasis
Renal involvement occurs in most infants with candi-
demia because each of the risk factors that predispose
to disseminated disease specifically increases the risk for
renal disease.112,138 Every infant with candidemia should
have an evaluation of the urinary tract for candidal infec-
tion. Infants with congenital urinary tract anomalies and
those requiring frequent catheterization for neurologic rea-
sons are at increased risk for an isolated Candida spp. uri-
nary tract infection (UTI).111,112 Congenital urinary tract
anomalies, such as cloacal exstrophy, can provide a portal
of entry for Candida spp. present on the skin. Urinary stasis,
whether caused by a congenital anatomic obstruction or a
functional obstruction (e.g., in the neurogenic bladder with
myelomeningocele), increases the risk of candidal bladder
infections.112 Regardless of the underlying cause, candidal
UTIs generally manifest with the same nonspecific systemic
signs as with candidemia, whereas specific renal findings
can be silent or manifest as urinary tract obstruction, hyper-
tension, or renal failure.111,112,141-144 Acute renal insuffi-
ciency or failure is a common clinical presentation and may
be nonoliguric, oliguric, or anuric. In the nonoliguric form,
urine output remains normal or near normal, but eleva-
tion of the serum creatinine level may be quite dramatic.111
Renal ultrasonography often reveals parenchymal abnor-
malities suggestive of single or multiple abscesses; however,

lesions may not be obvious at initial presentation, becoming
evident only later in the disease process.112,141 With oligu-
ria, obstruction of the urinary tract by a discrete fungus ball
or balls must be considered.142 These fungal masses com-
monly are found in the ureteropelvic junction and usually
are diagnosed by ultrasonography but are found rarely by
physical examination as a palpable flank mass.59,144 Hyper-
tension may be the only initial clinical feature in neonatal
renal candidiasis.143
Central Nervous System Candidiasis
Central nervous system candidiasis most often accompanies
disseminated candidiasis, with up to 50% of VLBW infants
having some form of CNS infection.6,18,50,145 Neonates with
neural tube defects and those requiring indwelling cerebro-
spinal fluid (CSF) shunts are at increased risk for isolated
candidal infections of the CNS. Meningitis is the most fre-
quently reported form of CNS infection, but parenchymal
abscesses, ventriculitis, vasculitis and perivasculitis, epen-
dymal inflammation, osteomyelitis of the skull or vertebral
bodies, and even fungus balls within the subarachnoid space
have been described, although rarely.2,105,113,141,146 The
specific clinical presentation is extremely variable but typi-
cally occurs when infants are older than 1 week.6,147 The
initial presentation is similar to that of disseminated candidi-
asis, subtle or quite severe, with cardiorespiratory instability
and rapid overall deterioration.105 Less frequently, an infant
may have only neurologic signs, such as seizures, focal neu-
rologic changes, an increase in head circumference, or a
change in fontanelle quality.105,145,147 Because clinical find-
ings may be limited or nonexistent, the possibility of CNS
involvement with Candida must always be considered in
neonates with candidemia or evidence for invasive candidal
disease at other sites. A high index of suspicion is required;
in one reported series, blood cultures were negative in up to
half the ELBW infants with Candida meningitis.6
Candidal Ophthalmologic Infections
Endophthalmitis results from hematogenous spread of Can-
dida spp. to the eye of the infant and is a diagnosed com-
plication in approximately 6% of infants with systemic
candidiasis.106 Overall risk factors for ophthalmologic infec-
tion are the same as factors predisposing to disseminated
disease. Infants with prolonged candidemia (i.e., blood cul-
tures positive for more than 4 days) are significantly more
likely to develop end-organ involvement of the eye, kidney,
or heart.140 Ophthalmic infections have been reported with
all Candida spp. listed in Table 33-1.106,140 Because the clini-
cal presentation of candidal chorioretinitis is frequently
silent, an indirect ophthalmoscopic examination should
be performed on all infants diagnosed with or suspected of
having candidemia or systemic candidiasis. Lesions can be
unilateral or bilateral, and these appear as individual yel-
low-white, elevated lesions with indistinct borders in the
posterior fundus.106 Vitreous lesions occasionally occur,
and some infants show vitreal inflammation or a nonspe-
cific choroidal lesion with hemorrhage or Roth spots in the
posterior retina.50,108 Infection of the lens occurs rarely; five
case reports of lens abscesses in preterm infants exist, and
each infant presented with a unilateral cataract.108,148-150
In addition to the ophthalmologic infections caused
by Candida spp., an association between candidemia and
33 • Candidiasis 1067
retinopathy of prematurity (ROP) has been described in
neonates with no previous evidence for chorioretinitis or
endophthalmitis.151-156 Early reports suggested a significant
increase in the incidence of any stage ROP among infants
with Candida sepsis compared with those without candidi-
asis (95% vs. 69%) and an increased probability of severe
ROP requiring laser surgery (41% vs. 9%).151 Subsequent
retrospective studies have demonstrated a greater incidence
of threshold ROP and need for laser surgery among infants
with Candida sepsis but no greater overall incidence of ROP
of any severity.153,155,156 Data are inconclusive as to cause
and effect, but an association clearly is documented.151,155
Premature infants of any gestational age who develop can-
didal sepsis should be followed closely by an ophthalmolo-
gist for the late development of severe ROP.
Spontaneous Intestinal Perforation
Invasive disseminated candidiasis is associated with the
occurrence of spontaneous intestinal perforation in preterm
infants.96,103,157,158 This syndrome is distinct from NEC,
occurring predominantly during the first 2 to 3 weeks of life
among the smallest, most premature infants on the NICU
(median gestational age, 24 weeks; median birth weight,
634 g).94 Specific predisposing factors identified for spon-
taneous intestinal perforation include umbilical arterial
catheterization, hypothermia, indomethacin therapy (pro-
phylactic or treatment), and cyanotic congenital heart dis-
ease.96,103,159 Neonates typically have bluish discoloration
of the abdomen and a gasless pattern on abdominal radio-
graphs, without pneumatosis intestinalis, often accompa-
nied by systemic signs such as hypotension.94 Disseminated
candidiasis frequently is diagnosed in association with
this syndrome; one series reported up to 33% of affected
infants with cultures of blood, peritoneal fluid, CSF, or urine
positive for Candida spp.94 Pathologic examination of the
involved intestinal area demonstrates mucosal invasion
by yeast and filamentous forms of Candida spp.96,157,159 It
is not clear from these specimens, nor from the clinical pic-
ture, whether the perforation is a result of primary candidal
invasion of the intestinal mucosa or the colonizing Candida
strain merely invades bowel damaged by another insult.
Whatever the cause, the association exists, suggesting that
clinicians should consider extensive evaluation for dissemi-
nated candidiasis with the diagnosis of a spontaneous intes-
tinal perforation in the extremely premature infant.
Diagnosis
The diagnosis of most mucocutaneous disease is based on
the characteristic clinical findings described earlier. Culture
of the lesions of oral thrush or diaper dermatitis usually is
not indicated. However, in an infant refractory to therapy,
culture with susceptibility determination of the recovered
organism may identify a NCAC species with a susceptibility
pattern requiring modification of specific therapy.121,124 In
congenital candidiasis, a presumptive diagnosis can be made
by Gram stain of vesicular contents of an individual lesion
or by potassium hydroxide preparations of skin scrapings,
with confirmation by culture of discrete lesions or swabs of
skin folds or intertriginous areas. Cultures of blood, urine,
and CSF are indicated for term infants with systemic signs
1068 SECTION IV • Protozoan, Helminth, and Fungal Infections
of infection and for all affected preterm infants, healthy or
ill appearing.34 In the infant with change in respiratory or
radiographic status, endotracheal aspirate cultures that
grow Candida spp. are difficult to interpret because most
often this represents colonization rather than pulmonary
invasion.24 The characteristic skin lesions of invasive fun-
gal dermatitis often are diagnostic, but a skin biopsy pro-
vides a definitive diagnosis and tissue for culture and species
determination. Biopsy is more sensitive than skin swabs in
identifying other non-Candida filamentous fungi included in
the differential diagnosis for this disease process.96
Given the increasing incidence of invasive candidiasis
among premature infants, clinicians caring for these infants
must be alert to the possibility of Candida in any infant who
develops signs of systemic infection, especially neonates
with predisposing conditions (see Box 33-1). The differ-
ential diagnosis includes primarily other microorganisms
responsible for nosocomial sepsis.5,6 At a minimum, any
infant with systemic signs of infection should have blood
cultures obtained from a peripheral venipuncture and from
all indwelling intravascular catheters. Most Candida spp. are
identified by growth on standard bacteriologic culture media
with aerobic processing, and requesting separate fungal cul-
tures does not increase the yield of Candida spp.57 Previous
recommendations were to monitor such cultures for up to
10 days to ensure adequate growth of the slower-growing
Candida spp.57,127 However, in one report, 90% of cultures
for Candida spp. were positive by 72 hours, before and imme-
diately after the initiation of antifungal therapy.160 Multiple
or repeat blood cultures increase the likelihood of obtaining
a positive result.161,162 For infants with an indwelling intra-
vascular catheter or catheters, samples obtained through
each catheter and from a peripheral vessel are recommended
for culture. Recovery of a Candida spp. from the culture sam-
ple obtained from an intravascular catheter and not from the
peripheral blood supports the diagnosis of catheter-related
candidemia without dissemination. However, caution
should be used in making this distinction in neonates. First,
the sensitivity of a single blood culture in diagnosing candi-
diasis is low; a single sterile peripheral blood culture does not
exclude disseminated candidiasis.51,161 Second, by the time
the culture results are known (usually 24-48 hours after
collection), dissemination might have occurred, especially
in the preterm infant. Disparate results do indicate that the
catheter tip is infected, and prompt removal of the catheter is
indicated to prevent dissemination and other complications.
If disseminated candidiasis is suspected based on the
clinical picture or a positive blood culture is obtained from a
peripheral vessel, additional studies are indicated. Even after
the initiation of appropriate antifungal therapy, daily blood
samples should be collected until culture results are negative
because the risk for multiorgan involvement increases the
longer fungemia persists.140 Because renal and CNS candi-
diasis can be clinically silent at presentation, urine and CSF
should be obtained for analyses and culture. The presence of
budding yeast or filamentous fungal forms by microscopic
examination of the urine or CSF suggests invasive disease.
Because Candida spp. are frequent contaminants of nonster-
ilely collected urine samples, urine should be obtained by ster-
ile urethral catheterization or suprapubic aspiration.51,112 In
clinical practice, suprapubic aspiration is infrequently per-
formed in many NICUs, and sterile urethral catheterization
is reported to be an efficient method for obtaining urine cul-
tures from infants younger than 6 months.163 The current
consensus is that a Candida spp. UTI in neonates be defined
as 104 or more colony-forming units of Candida spp. per mil-
liliter in a culture obtained by sterile urethral catheteriza-
tion.112 Cultures of the CSF are more likely to be positive if
the volume of CSF obtained is at least 1 mL.105 Even when an
optimal volume of CSF is cultured, a negative result does not
eliminate the possibility of CNS disease because infection can
occur in areas of the brain not in communication with the
CSF.105,110 Analysis of the CSF for abnormalities suggestive
of inflammation, including an elevated white blood cell count
or protein level or a decreased glucose level, suggests menin-
gitis, but normal values do not exclude CNS infection.147,164
Interpretation of CSF values can be complicated by the pres-
ence of blood resulting from a traumatic lumbar puncture or
preexisting intracranial hemorrhage in the preterm infant.
Cultures of other clinically suspicious sites, such as peritoneal
fluid or a skin abscess or vesicle, can help to confirm the diag-
nosis in an ill infant. However, cultures of healthy-appearing
skin and mucous membranes or cultures of endotracheal
secretions without the presence of pulmonary symptoms are
not helpful in diagnosing systemic infections. Endotracheal
tube secretion cultures may not be helpful in the infant with
respiratory symptoms because Candida pneumonia is more
often a result of hematogenous spread.26,50,82 If any other
catheters are present, such as chest or mediastinal tubes, cul-
tures of the fluid drainage also should be obtained.
A culture from a usually sterile body site that grows
Candida spp. confirms the diagnosis of candidiasis. Deter-
mination of the Candida spp. involved is equally impor-
tant. Historically, because most infections were caused by
C. albicans, many laboratories did not go beyond the ini-
tial identification of a yeast in culture as Candida.13,57,165
Today, the incidence of infections with the NCAC species
has increased dramatically, and identification of the species
involved is important for epidemiologic and therapeutic
reasons.127,166,167 Knowledge of the infecting Candida spp.
can help to determine whether the source of the infection
is endogenous or from nosocomial transmission. This can
be especially important in determining whether an appar-
ent outbreak of candidiasis in a particular NICU is a coinci-
dence or caused by a common source.45,48,49,165,167 From
the therapeutic perspective, when comparing the various
pathogenic Candida spp., variations exist in susceptibility
to the common antifungal agents (Table 33-3), and defin-
ing the infecting Candida spp. is important in determining
appropriate antifungal therapy.51,82
To determine the extent and severity of candidiasis, addi-
tional laboratory tests are indicated when evaluating the
infant with suspected disseminated candidiasis, including a
complete blood count with differential and platelet counts
and determinations of the levels of serum glucose, creati-
nine, blood urea nitrogen, bilirubin, liver aminotransferases,
and C-reactive protein. The white blood cell count may be
normal, high, or low; however, in the neonate, neutropenia
may suggest a severe, overwhelming infection.99 Thrombo-
cytopenia is strongly associated with systemic candidiasis
and may be an early indicator of this disease.125,134 Eleva-
tions in the blood urea nitrogen and serum creatinine levels
may indicate renal infection. Mild elevations in the serum
bilirubin levels may be a part of the sepsis syndrome, but

Table 33-3 General Patterns of Susceptibility of Candida Species to Antifungal Agents
Candida Species Amphotericin B Fluconazole
C. albicans S S
C. parapsilosis S S
C. glabrata S to I† I to R‡
C. tropicalis S S
C. krusei S to I† R∥
C. lusitaniae I to R S S
Data from references 18, 135, 176-178, 187, 216, and 220.
I, Intermediately resistant; R, resistant; S, susceptible.
*Isolates of C. parapsilosis have slightly higher minimal inhibitory concentrations.
†A significant proportion of clinical isolates of C. glabrata and C. krusei have reduced susceptibility to amphotericin B.
‡Between 30% and 65% of clinical isolates of C. glabrata are resistant to fluconazole.
§Susceptibility is dose dependent.
∥C. krusei is intrinsically resistant to fluconazole.
marked elevations in the serum bilirubin concentration or
liver enzymes indicate extensive liver involvement.6 Eleva-
tion of the C-reactive protein level is a nonspecific indicator
of systemic infection.50,51 Unfortunately, obtaining normal
values for any or all of these ancillary laboratory tests does
not completely exclude the possibility of candidiasis, espe-
cially CNS disease, in the high-risk neonate.105
Because of the predilection of Candida for certain organs,
specific imaging studies are indicated to diagnose the
extent of dissemination. Renal ultrasonography, echocar-
diography, and cranial imaging are recommended for all
infants with candidemia or systemic candidiasis.140 Renal
and bladder ultrasonography are extremely sensitive, but
nonspecific, in their ability to define abnormalities result-
ing from Candida infections. The ultrasonographic appear-
ance of a nonshadowing echogenic focus strongly suggests
a renal fungus ball, particularly when the infant has a urine
culture that grows Candida.168 However, blood clots, fibrin-
ous deposits, and nephrocalcinosis may have the same
ultrasound appearance, confounding interpretation.168
Another common ultrasonographic finding is renal paren-
chymal infiltration characterized by enlarged kidneys with
diffusely increased echogenicity. In any given infant with
renal candidiasis, one or both of these ultrasound findings
can be seen. Limited information exists about the accu-
racy of computed tomography (CT) or magnetic resonance
imaging (MRI) in diagnosing renal candidiasis.168,169 Echo-
cardiography is useful in neonates with CVCs when the pri-
mary concern is for endocarditis with an infected thrombus
at the catheter tip site or a right atrial mass.92,137 Cranial
ultrasonography easily can reveal enlarged ventricles, cal-
cifications, cystic changes, and intraventricular fungus
balls in infants with CNS candidiasis.109,141 Ventriculitis
can be diagnosed by the appearance of intraventricular
septations or debris.105 Interpretation of the cranial ultra-
sonography can be difficult in the preterm neonate who has
experienced an intraventricular hemorrhage in the past
or has developed periventricular leukomalacia. Cranial
CT and MRI offer certain advantages over ultrasonogra-
phy, including superior imaging of the posterior fossa and
infratentorial and nonmidline structures.169 Calcifications
are seen best with CT, and the addition of intravenous con-
trast can aid in the identification of intracranial abscesses.
However, as a practical matter, cranial ultrasonography
33 • Candidiasis 1069
Voriconazole Echinocandins
S S
S S to I*
S to I§ S
S S
S S
S
is more frequently used because it can be performed at the
bedside of a critically ill infant. In addition to these imag-
ing studies, all neonates with confirmed or suspected candi-
demia should have a dilated ophthalmologic examination,
preferably by a pediatric ophthalmologist.106 The infant
who has characteristic lesions of Candida endophthalmitis
has a confirmed diagnosis of disseminated disease.
Despite heightened awareness of the more subtle presen-
tations of disseminated candidiasis and improvements in
the ancillary and imaging studies available to clinicians,
an accurate and timely diagnosis of candidal infections in
the neonate remains a challenge. This largely reflects con-
tinued reliance on a positive culture for Candida spp. from
a normally sterile body fluid (e.g., blood, urine, CSF, peri-
toneal fluid) or a potentially infected site to confirm the
diagnosis and guide therapy. Autopsy studies suggest that
the specificity of blood cultures for candidiasis approaches
100%; however, the sensitivity in the diagnosis of dissemi-
nated candidiasis is low, ranging from 30% with single-
organ involvement up to 80% with four or more organs
involved.161 The situation in the neonate is further compli-
cated by the fact that fluid volumes as low as 1 mL may be
obtained for culture, additionally diminishing the sensitiv-
ity, especially if the total burden of organisms in the fluid is
low.161 The development of techniques for more sensitive,
reliable, and rapid diagnosis of candidal infections is a prior-
ity and is an active area of investigation.161,170 A number
of molecular diagnostic assays that exploit recognition of
small amounts of Candida spp. proteins or DNA, including
the β-glucan antigen assay, scanning electron microscopy
of fluid containing yeast, and polymerase chain reaction
(PCR) testing, are being evaluated in adults and older chil-
dren.170-172 None of these assays has been rigorously evalu-
ated in a population of neonates.173-176 β-1,3-d-Glucan is a
major component of the fungal cell wall found in all clini-
cally relevant Candida spp. Various assays are reported to
have 85% sensitivity and 95% specificity for candidemia by
detecting very small amounts of this fungal cell wall anti-
gen.173 PCR amplification of an area of the genome com-
mon to C. albicans and other pathogenic Candida spp. can be
successfully performed, again using very small volumes of
blood, urine, or CSF; this assay appears to be the best hope
for rapid diagnosis.171 Extensive use of PCR assays has pre-
viously been limited by unacceptably high rates of fungal
1070 SECTION IV • Protozoan, Helminth, and Fungal Infections

Table 33-4 Systemic Antifungal Agents for the Treatment of Invasive Candidiasis in Neonates
Toxicity
Drug Dose Interval Route Indications Toxicities ­Monitoring Comments
Amphotericin B 0.5-1.0 mg/kg/day q24h IV Candidemia, inva- Renal, hemato- Urine output, Not indicated to
sive candidiasis logic, hepatic creatinine, treat C. lusitaniae
potassium, Dose adjustments
magnesium, may be required
liver enzymes for renal failure
Lipid-associated 1-5 mg/kg/day q24h IV Invasive candi- Similar to Urine output, May be indicated in
amphotericin B diasis with severe amphotericin B; creatinine, patients failing
preparations preexisting renal decreased renal potassium, therapy or requir-
insufficiencies toxicities magnesium, ing higher doses
liver enzymes
Fluconazole 6-12 mg/kg/day ≤14 days,* PO, IV Alternative therapy Hepatic, gastroin- Liver enzymes Excellent CSF
(consideration may be q72h; to amphotericin testinal penetration; oral
given to 25 mg/kg 15-27 days, B for localized formulation well
loading dose) q48h; urinary tract absorbed; not
≥28 days, infection, indicated to treat
q24h mucocutaneous Candida krusei or
disease Candida glabrata
Micafungin† 4-10 mg/kg/day q24h IV Severe and/or Minimal, potential Creatinine, urine CSF penetration
(as high as 15 mg/kg/ refractory sys- output, liver variable
day has been well temic infections; enzymes
tolerated and may hepatic and renal
be indicated for CNS infections
disease)

Data from references 82, 135, 176, 179, 186, 187, and 210.
CNS, Central nervous system; CSF, cerebrospinal fluid; IV, intravenous; PO, oral.
*Age in days.
†Published reports on echinocandin use in neonates include small studies of patients with caspofungin and micafungin, neither of which is currently licensed

for use in neonates. However, the data suggest safety and efficacy (see text for further details). We recommend verifying dosage and indications based on
most current publications.
Note: Recommendations are not included for the use of 5-fluorocytosine because of potential toxicities, nor voriconazole and caspofungin because of potential
toxicities and lack of adequate published data in neonates (see text for further details and Chapter 37).

contamination resulting in false-positive tests, but newer
assays are more specific and sensitive.171,174,175 Each of
these assays holds promise for the rapid detection of fun-
gus in small volumes of body fluids and does not require
the presence of live Candida spp. One major drawback to
many early PCR assays, compared with culture, was the
lack of differentiation between pathogenic Candida spp.; the
diagnosis they provided was simply candidiasis. However,
newer PCR assays are able to distinguish between various
yeast species.175 With specific culture or PCR results, the
clinician knows which Candida spp. is causing the infection
and can tailor the therapeutic plan accordingly. Without
specific results, more generic management plans must be
used. However, because the institution of therapy often
is delayed because of the lack of a positive culture when
clinical deterioration begins, which may lead to systemic
complications from persistent fungemia, knowing the neo-
nate has a Candida spp. may lead to improved therapeutic
management.
Treatment
Therapy and management of candidiasis in the neonate
require an effective antifungal agent coupled with appro-
priate supportive care and measures to eliminate factors
favoring ongoing infection. In the NICU, the first two objec-
tives are easier to achieve than the last. Multiple antifungal
therapies are available, but few have been studied for deter-
mination of appropriate dose and interval, safety, and effi-
cacy in neonates, especially VLBW infants. Amphotericin B
has been the mainstay of antifungal therapy for more than
40 years, but newer agents may be indicated in certain set-
tings.82,135,136,176-179 Table 33-3 summarizes the antimi-
crobial susceptibility pattern of pathogenic Candida spp. to
the most common antifungal agents, and Table 33-4 and
the following discussion outline important features regard-
ing use of each agent in the neonate with candidiasis.
Because candidiasis often is a nosocomially acquired infec-
tion, most infected infants are already in the NICU, where
appropriate intensive care to support these critically ill
infants is readily available. If the hospital nursery is unable
to address the needs of a critically ill neonate, transfer to a
higher-level NICU should be considered. Unfortunately, the
elimination of all risk factors for ongoing candidemia often
is an unattainable goal, and the clinician frequently must
settle for a less than optimal reduction of risk factors (see
Table 33-2 and preceding section on pathogenesis regard-
ing reduction of risk factors).7
With the diagnosis of candidemia or disseminated can-
didiasis, immediate consideration should be given to the
removal of all potentially contaminated medical hardware,
especially central intravascular catheters.180 For ongoing
fungemia, successful medical treatment of Candida spp. infec-
tions while the catheters remain in place is rare.51,82,91,104
The risk of dissemination also increases with every day the

infant remains fungemic, as does the rate of infection of
previously uninfected intravascular lines.104,181 The clini-
cian must face the reality that most preterm infants with
systemic candidiasis require central access because of the
clinical instability directly attributable to the ongoing can-
didemia, which in large part is caused by the ongoing pres-
ence of the infected catheter. If all lines cannot be removed,
removal of a potentially infected catheter with insertion of
a new line at a different site or a sequential reduction in the
number of catheters is preferable to inaction. Infants with
more than one catheter may not have all lines infected at
the time of diagnosis, and removal of the catheter known
or most likely to be infected may resolve the problem and
allow continued therapy through the remaining line.93
Antifungal therapy should be administered through the
remaining central catheter to maximize drug delivery to
a potential site of ongoing infection. Daily blood cultures
to determine whether fungemia is persistent and whether
additional infected catheters should be removed are neces-
sary. Consideration should be given to surgical resection of
infected tissue if antifungal therapy does not achieve steril-
ization (e.g., urine) or if mechanical complications caused
by the presence of a fungus ball arise (e.g., right atrial
mass). Although successful medical therapy for endocar-
ditis caused by Candida spp. can often be achieved, large
right atrial masses are almost impossible to sterilize and
may also compromise hemodynamic function, necessitat-
ing surgical removal.92,93,137,169,182 Surgical removal of an
enlarging right atrial candidal mass in the face of ongoing
fungemia and hemodynamic instability may be lifesaving
for the premature infant.137 Most renal fungal balls can be
treated medically because of the high levels of most anti-
fungal agents attained in the urine.112,138 However, in an
infant with complete obstruction of urinary flow caused by
the presence of one or more fungal balls, surgical removal
is indicated.142,143 Hyperglycemia can be avoided by judi-
cious administration of dextrose and insulin therapy if glu-
cose intolerance persists. Corticosteroid therapy should be
avoided or tapered as tolerated.
ANTIFUNGAL AGENTS
Topical Antifungal Therapy
Topical antifungal agents are indicated for thrush, dia-
per dermatitis, and uncomplicated congenital candidiasis
in the term infant.19 Nystatin, the most commonly used
topical therapy, is a polyene drug that is not absorbed
by the gastrointestinal tract, making it a topical agent in
any of the three common formulations: oral suspension,
ointment, or powder. The oral suspension is indicated for
the treatment of thrush in patients of all ages. However,
because of the high osmolality of the oral suspension
(caused by the added sucrose excipient), care should be
taken and use limited in the very premature infant or the
neonate with compromise of the gastrointestinal tract.120
Reports of clinical cure vary widely, from as low as 30%
to as high as 85%.120,121 Nystatin should be applied
directly to the lesions of oral thrush. If swallowed rapidly,
there is minimal contact with the lesions and little effi-
cacy. Nystatin ointment or powder, when applied to dia-
per dermatitis, has an 85% cure rate.120 Because thrush
33 • Candidiasis 1071
often accompanies diaper dermatitis, many clinicians add
oral Nystatin when prescribing perineal therapy, even if
no oral lesions exist. Data suggest no added efficacy with
this practice, which should be discouraged.120,183 If oral
lesions are present, treatment is indicated. However, if oral
lesions are not present, the source of the Candida spp. prob-
ably is the lower gastrointestinal tract, in which Nystatin
is not an optimal agent.
Miconazole gel is a nonabsorbable formulation of this
azole, developed particularly for treatment of thrush, which
is not available in the United States.120,184 The gel formu-
lation is said to offer more prolonged contact with the oral
lesions and has a reported efficacy of greater than 90%.120
Side effects predominantly are gastrointestinal, similar to
Nystatin, but use of this agent has been evaluated only in
a limited number of preterm infants.154 Miconazole creams
and ointments and other topical azole formulations fre-
quently are prescribed for diaper dermatitis with excellent
results.120,185
Gentian violet, the first topical therapy for oral thrush,
has become the treatment of last resort. Although effective,
the liquid treatment must be applied directly to the lesions,
and it causes unsightly dark purple stains on the infant’s
mouth, clothes, bedclothes, and often on the hands and
clothes of the care provider. Complications include local
irritation and ulceration from the direct application of
the treatment to adjacent normal mucosa.120 Given these
inconveniences, most clinicians avoid gentian violet in
favor of administering systemic therapy when topical treat-
ments fail.121
Systemic Antifungal Therapy
For all the drugs discussed in this section, see Chapter 37 for
complete details on antimicrobial activity, pharmacokinet-
ics, safety, and alternative dosing.
Amphotericin B. Amphotericin B deoxycholate is an anti-
fungal agent available since 1958. The American Academy
of Pediatrics Committee on Infectious Diseases, the Pedi-
atric Infectious Disease Society, and the Infectious Disease
Society of America (IDSA) recommend amphotericin B as
the primary antifungal agent for the treatment of candi-
demia, disseminated candidiasis, and any form of invasive
candidiasis in the neonate.* Most pathogenic Candida spp.
are susceptible to amphotericin B (see Table 33-3). How-
ever, reports suggest a proportion of C. glabrata and C. krusei
isolates have a somewhat reduced susceptibility to ampho-
tericin B, which can be overcome by using higher-dose
therapy, and resistance has been described for isolates of
C. lusitaniae.15,177-179,188 Very occasional resistance with
C. parapsilosis has been reported.189
Toxicities reported in neonates receiving amphoteri-
cin B include renal insufficiency with occasional renal
failure, hypokalemia, and hypomagnesemia caused by
excessive renal losses; bone marrow suppression with
anemia and thrombocytopenia; and abnormalities in
hepatic enzymes.82,164 Most toxicities are dose dependent
and reversible on cessation of therapy.82 Nephrotoxicity is
the most common and worrisome toxic effect. A substan-
tial rise in creatinine and decrease in urine output can be
* References 82, 135, 136, 179, 186, 187.
1072 SECTION IV • Protozoan, Helminth, and Fungal Infections
observed; however, it is frequently difficult to differenti-
ate between renal insufficiency caused by inadequately
treated systemic renal candidiasis and that caused by
amphotericin B. Although there is a potential for renal
failure, most infants display no or mild nephrotoxicity that
resolves with decreasing the dose of amphotericin B or
after completion of therapy. A common and very uncom-
fortable side effect in adults and older children receiving
amphotericin B is an infusion-related reaction consist-
ing of fever, chills, nausea, headache, and occasionally
hypotension.190 No such toxicity has been described in
neonates, and test doses are not indicated.190 The risk
for dissemination is so high among infants that no delay
should occur in delivering treatment doses. Any neonate
receiving amphotericin B should have serial monitoring
of serum potassium and magnesium levels and of renal,
liver, and bone marrow function.
The recommended treatment dose is 1 mg/kg given
every 24 hours, intravenously.82 Reports suggest variable
CSF concentrations, ranging from 40% to 90% of plasma
levels in one study of preterm infants.191 CSF and brain
tissue penetration is generally better in neonates than
adults, so a change in dosing is not necessarily indicated
with concerns for CNS disease.82 Successful treatment of
CNS disease with amphotericin monotherapy has been
reported.82,164
Amphotericin B Lipid Formulations. As an alternative
to standard amphotericin B, three lipid-associated formula-
tions are approved for use in adults: liposomal amphotericin
B (L-amphotericin B), amphotericin B lipid complex (ABLC),
and amphotericin B cholesterol sulfate complex (ABCD).
Fungal susceptibility patterns for these lipid-associated for-
mulations are the same as for conventional amphotericin
B deoxycholate.192,193 Each is significantly more expensive
than conventional amphotericin B.176 The main purported
advantage to these amphotericin B preparations is the abil-
ity to deliver a higher dose of medication with lower levels
of toxicity. In adults and older children receiving a lipid-for-
mulation of amphotericin B, significantly lower rates of infu-
sion-related reactions and serum creatinine elevations are
reported, compared with conventional amphotericin B.194
Several case reports of successful use of these preparations
in neonates have been published, demonstrating no major
adverse events, diminished toxicities associated with con-
ventional amphotericin (i.e., hypokalemia and hyperbiliru-
binemia), and treatment success rates of 70% to 100%, but
no controlled trials have been performed.82,193,195 Studies
of ABLC in pediatric patients have included small numbers
of neonates and demonstrated efficacy rates of 75% to 85%,
with no significant toxicities.82,193 Renal penetration of the
lipid-associated formulations is poor compared with con-
ventional amphotericin, and treatment failure at this site of
infection has been reported.194
Although randomized, controlled trials of the lipid-
associated preparations in neonates are lacking, available
information suggests that they may be safe and effective,
although not superior to conventional amphotericin B.
Treatment with amphotericin B deoxycholate remains the
most appropriate therapy for infants with invasive infec-
tions with Candida spp., especially for those with renal infec-
tion.82,135,136,179 The amphotericin B lipid formulations
may have a role in the treatment of invasive candidiasis in
neonates with preexisting severe renal disease or in infants
who fail to respond to conventional amphotericin B after
removal of all intravascular catheters, but more data are
needed. Current dosing recommendations suggest 1-5 mg/
kg/day.82,135
5-Fluorocytosine. 5-Fluorocytosine (5-FC) is a fluorinated
analogue of cytosine. All pathogenic Candida spp. are sus-
ceptible to this agent, but resistance develops rapidly when
used as monotherapy (see Table 33-3).177 5-FC has excel-
lent CNS penetration and historically was used in combi-
nation with amphotericin B in the treatment of neonatal
CNS candidiasis because early studies demonstrated syn-
ergy with these two agents.177,196 However, more recent
reports suggest no added therapeutic benefit when 5-FC is
combined with amphotericin B.6,179 The potential benefit
of 5-FC added to amphotericin B must be carefully weighed
against common significant toxicities, including azotemia,
renal tubular acidosis, and myelosuppression.82 Serum lev-
els must be followed closely.82 5-Fluorocytosine is available
only in an enteral preparation, significantly limiting its use
in most critically ill neonates with systemic candidiasis,
who are also at risk for necrotizing enterocolitis.
Azoles. The azoles are a class of synthetic fungistatic
agents that inhibit fungal growth. The most common
side effects are alterations in the pharmacokinetics of
concomitant medications the infant is receiving and mild
hepatotoxicity.197 Clinically significant hepatotoxicity is
rare with use of the newer azoles, such as fluconazole and
voriconazole, in adults and older children, and their over-
all safety profile is favorable.198 However, monitoring of
aminotransferases and serum bilirubin levels in neonates
receiving azoles is recommended.198 In addition, not all
Candida spp. are sensitive to all members of this class of
antifungal agents (see Table 33-3), limiting use in empiri-
cal therapy.13,15
Fluconazole, the azole used most frequently in neonates,
is water soluble, available in oral or intravenous prepara-
tions, and highly bioavailable in the neonate.198,199 Flu-
conazole has a long plasma half-life, with excellent levels
achieved in the blood, CSF, brain, liver, spleen, and espe-
cially the kidneys, where it is excreted unchanged in the
urine.176,179,199 The pharmacokinetics of fluconazole in
neonates change dramatically over the first weeks of life,
presumably because of increased renal clearance with
maturity; therefore the dosing interval is based on both
postnatal and postconceptual age (see Table 33-4 and
Chapter 37).82,199 Transient thrombocytopenia, eleva-
tions in creatinine, mild hyperbilirubinemia, and transient
increases in liver aminotransferases have been documented
in neonates.28,176,179,200
Several studies have shown fluconazole to be efficacious
in the treatment of invasive candidiasis in the neonate. In
one prospective, randomized trial versus amphotericin B,
rates of survival and clearance of the organism were equiv-
alent for both treatment groups.201 Infants treated with
fluconazole had less renal and hepatic toxicity and had a
shorter time to the complete removal of central intravascu-
lar catheters, which was attributed to the ability to convert
to oral therapy for completion of the treatment course.201

Although these features make the use of fluconazole appear
quite attractive, the primary concern with fluconazole is
fungal resistance, limiting its use as a first-line therapeu-
tic medication.13,15,202 Although most pathogenic Candida
spp. are susceptible to fluconazole, C. krusei is intrinsically
resistant to this azole, as are up to 65% of C. glabrata iso-
lates (see Table 33-3).176-178 Both of these NCAC species
can cause neonatal disease; therefore the use of fluconazole
as empirical single therapy is not recommended. The IDSA
guidelines recommend the administration of fluconazole as
an alternative therapy to amphotericin B for disseminated,
invasive neonatal candidiasis or congenital candidiasis with
systemic signs after the pathogenic Candida spp. is identified
and susceptibility determination completed.135 Because of
its unaltered renal clearance, fluconazole is an excellent
choice for the treatment of isolated urinary tract infections
resulting from susceptible Candida spp., and oral fluconazole
is an alternative therapy in refractory mucocutaneous dis-
ease.121,199 Combination therapy with amphotericin B was
evaluated in a multicellular trial of nonneutropenic adults
with candidemia with excellent results.181
Voriconazole is a second-generation azole, derived from
fluconazole, with increased potency and a broader spec-
trum of activity (see Table 33-3 and Chapter 37).203,204
Voriconazole is active in vitro against all clinically rele-
vant Candida spp., including C. krusei and C. glabrata, and
no resistance by fluconazole-resistant strains has been
reported.176,179,203 Voriconazole is metabolized by the liver,
and the only clinically significant adverse event reported in
adults is the occurrence of visual disturbances.203 For this
reason, concerns have been raised about the possibility of
unknown interactions with the developing retina, discour-
aging therapeutic trials in neonates.186 The neonatal litera-
ture is limited, but one case report does describe successful
combination therapy with voriconazole and liposomal
amphotericin B in a premature infant with disseminated
fluconazole-resistant C. albicans infection.205 A more recent
report showed safety and efficacy in a very small group of
neonates treated with voriconazole.206 Although this agent
appears to be safe and effective in children, further trials
in neonates are indicated before a routine recommenda-
tion can be established.207 There is genetic variation in the
metabolism of voriconazole, and slow metabolizers may
accumulate concentrations up to four times greater than
others, which along with the paucity of data regarding
pharmacokinetics in neonates suggest caution in the use of
this agent at this age and, if used, that drug concentrations
be monitored (see Chapter 37).
Echinocandins. Echinocandins are a novel class of anti-
fungal drugs that act by a unique and completely fun-
gal-specific mechanism—inhibition of the synthesis of
β-1,3-d-glucan, an essential component of the fungal cell
wall.207 Because there is no mammalian equivalent to the
fungal cell wall, the safety profile for the echinocandins,
in adults and older children, is excellent and significantly
better than the polyenes or azoles.207 Three drugs in this
class—anidulafungin, caspofungin, and micafungin—are
currently licensed for use in the United States for adults; use
in neonates is considered off-label by the U.S. Food and Drug
Administration,176,179,186 whereas micafungin is approved
for use in neonates by the European Medicines Agency.
33 • Candidiasis 1073
Echinocandins are fungicidal against all pathogenic Candida
spp.203,208 Because the mechanism of action is completely
different from the other antifungal agents currently in use,
the echinocandins are excellent candidates for use in com-
bined therapy, especially for refractory infections. Pharma-
cokinetic studies in the neonatal population are limited,
but those completed show caspofungin and micafungin are
well tolerated but have a shorter serum half-life and more
rapid clearance, emphasizing the importance of evaluating
the neonatal population separate from older children and
adults.179,186,209 Recommendations for optimal dosage in
the neonate, especially a preterm one, for either of these
agents remain unclear (see Chapter 37).82,179 Multiple case
reports suggest safety and efficacy.179,186,210 The most cur-
rent guidelines from the IDSA recommend caspofungin
as a second-line agent for neonatal candidemia without
dissemination.135 Development of this novel class of truly
fungicidal agents against Candida spp. has greatly expanded
our options for treating invasive candidiasis in adults. If
the echinocandins prove to be as safe and effective for neo-
nates, clinicians could have the ability to combine antifun-
gal agents with different general mechanisms of action (i.e.,
amphotericin B plus an echinocandin, or an azole plus an
echinocandin) to optimize therapeutic efficacy.
Length of Therapy
No matter which antifungal therapy is chosen, the length
of therapy to adequately treat invasive neonatal candidiasis
is prolonged (see Table 33-2). There are no controlled clini-
cal trials to provide the optimal length of therapy for any of
the antifungal agents and no consensus among neonatolo-
gists and pediatric infectious disease specialists.50,82,176,179
The IDSA recommends a minimum of 14 to 21 days of sys-
temic therapy after negative blood, urine, and CSF culture
results have been obtained, along with the resolution of
clinical findings.135 Therapy for endocarditis typically lasts
6 weeks.135,136 In neonates with isolated Candida cystitis,
treatment for 7 days appears to be adequate. Therapy must
be administered intravenously initially, but in an infant
who responds to fluconazole, completion of the course
with oral therapy is acceptable.112,199 Infants with fungal
abscesses, renal lesions, intracranial lesions, or right atrial
fungal masses should have sonographic or radiographic
evidence of resolution before completing therapy.51,111
Close monitoring for relapse after the cessation of therapy
is necessary given the high rate of recurrence, especially in
infants with CNS disease.2,105,148
Prognosis
Despite the current advances in neonatal care and anti-
fungal therapy, the prognosis for the infant who develops
an invasive fungal infection is still quite variable but gen-
erally poor. Mortality rates range from 20% to 50%, with
significant accompanying morbidity and length of stay on
the NICU.6,51,117,211 Factors determining the final prognosis
include the degree of prematurity, extent of dissemination,
severity of illness, and the rapidity of institution of appropri-
ate antifungal and supportive therapy.7,211,212 Infants with
isolated catheter-related candidal infections, uncomplicated
urinary tract infections, or candidemia without dissemina-
tion tend to have a good outcome with the potential for
complete recovery without sequelae. Infants with extreme
1074 SECTION IV • Protozoan, Helminth, and Fungal Infections
prematurity, widely disseminated disease, multiorgan
involvement, renal or hepatic failure, and ophthalmologic
or CNS infection have a much worse prognosis. In stud-
ies of VLBW infants surviving candidemia, disseminated
candidiasis, or candidal meningitis, candidiasis survivors
were significantly more likely to have a major neurologic
abnormality (40%-60% vs. 11%-25%) and a subnormal
(<70) Mental Developmental Index (40% vs. 14%) than
noninfected infants of the same gestational age and birth
weight.108,211 In a series of ELBW neonates with dissemi-
nated candidiasis, including meningitis, Friedman and col-
leagues212 found a higher incidence of chronic lung disease
(100% vs. 33%), periventricular leukomalacia (26% vs.
12%), severe ROP (22% vs. 9%), and adverse neurologic
outcomes at 2 years of corrected age (60% vs. 35%) for
infected infants than for gestational age- and birth weight–
matched, noninfected controls. Among the infected neo-
nates with adverse neurologic outcomes, 41% had severe
disabilities compared with 12% of the control infants, and
all infants with parenchymal brain lesions diagnosed by
cranial ultrasonography at the time of candidiasis had poor
neurologic outcomes.11,50 The visual outcome after endo-
phthalmitis is generally good after provision of appropriate
systemic antifungal therapy. Only a small percentage of
infants have significant visual impairment, although most
have some decrease in visual acuity.106 Severe ROP has
developed in preterm infants who recovered from candi-
diasis but never had endophthalmitis.152,154 These infants
may require laser surgery and may be at significant risk
for vision loss.154 Great strides have been made in our abil-
ity to diagnose and treat invasive candidiasis, but we must
strive to continue to improve therapeutic management and
address the issues of morbidity.
Prevention
The old adage that “an ounce of prevention is worth a
pound of cure” could never be truer than when considering
neonatal candidiasis. Treatment is difficult, prolonged, and
prevents mortality and morbidity little more than one half
of the time. In addition, as outlined in the preceding section
on prognosis, neonatal systemic candidal infections lead
to an increase in both risk of neurodevelopmental impair-
ment and length of stay.211 The development of strategies
to prevent neonatal candidal infections should be a pri-
ority on the NICU. Many of the factors listed in Box 33-1
that enhance the risk for candidiasis are unavoidable, such
as prematurity and low birth weight, but every attempt
should be made to address conditions that can be reduced,
starting with exposure to the yeast itself (see Table 33-2
and preceding section on pathogenesis regarding reduction
of host risk factors).7 Appropriate diagnosis and treatment
of maternal candidal vaginosis and urinary tract infections
during pregnancy may decrease vertical transmission.135
Prevention of horizontal transmission from caregivers by
the use of good hand hygiene and gloves should always be
encouraged but has resulted in limited success.44,45,180 In
studies of health care workers, appropriate hand hygiene is
helpful in reducing superficial and transient flora, and the
mechanical action of scrubbing does reduce the fungal bur-
den on the hands of providers.47 However, antimicrobial
or alcohol washes do not alter the deep or permanent
yeast flora, with no significant reduction in the recovery of
C. albicans detected on the hands of providers.47,213 Elimi-
nation of artificial fingernails among care providers has
been shown to drastically reduce exposure and transmis-
sion.45 The meticulous care of long-term indwelling cath-
eters is recommended, including standard procedures for
insertion and maintenance, especially if used to administer
hyperalimentation136 The use of topical petrolatum oint-
ment in skin care of the ELBW infant is associated with a
significantly increased incidence of invasive candidal infec-
tions.214 Although attempts at providing good skin care to
prevent epidermal breakdown in the ELBW infant are laud-
able, the use of petrolatum ointment does not appear to be
the best choice, and the increased risk of infection appears
to outweigh any potential benefits.
Reduction in exposures to medications associated with
neonatal candidiasis is likely the most important part of
prevention. Broad-spectrum antibiotic therapy (especially
third-generation cephalosporins) and the postnatal use
of H2 antagonists, hydrocortisone, and dexamethasone
are each associated with a higher incidence of fungal sep-
sis.18,87,61,151,180 These medications alter the enteric micro-
environment, favoring increased candidal colonization and
potential dissemination. Reviews of these risk factors sug-
gest that judicious use of antimicrobial agents may be the
most important step in preventing systemic candidiasis.7,10
Optimization of all the strategies described above should
precede implementation of any protocol for widespread
chemoprophylaxis.
FLUCONAZOLE PROPHYLAXIS
Chemoprophylaxis with antifungal agents such as oral
Nystatin and especially fluconazole has been a major area
for investigation in recent years, with the goal of reducing
candidal colonization and the accompanying potential for
invasive disseminated disease. The cardinal rule of anti-
microbial prophylaxis is to use one agent with minimal
toxicities for prophylaxis and others for therapy. The use
of oral Nystatin to prevent systemic candidiasis has been
practiced in many NICUs for decades, is tolerated well by
neonates, with no fungal resistance documented, but effi-
cacy in preventing invasive infection is not consistently
achieved.132,215,216 Based on studies demonstrating safety
and efficacy, fluconazole is currently recommended for
targeted anticandidal prophylaxis among ELBW infants in
NICUs with moderate (5%-10%) or high (>10%) rates of
invasive candidiasis.47,216,217 The recommended regimen
is to provide 3 mg/kg/dose, twice weekly, starting at 48 to
72 hours and continuing for 4 to 6 weeks or until IV access
is no longer present.47,216,218 No increase in fungal resis-
tance to fluconazole has been noted.216,219 Efficacy is less
conclusive among NICUs with low rates of systemic infec-
tion (<5%), and there is no consensus as to the appropriate
recommendation for these patients.82,220,221
Although multiple randomized controlled trials have sug-
gested that fluconazole prophylaxis will reduce invasive can-
didiasis in ELBW infants in high-risk NICUs, none has looked
at the combined outcome of infection or death.82 A meta-­
analysis of prophylactic fluconazole versus death before
discharge showed no difference between the groups.22 In

addition, little is known about long-term outcomes and poten-
tial effects of early fluconazole exposure in ELBW infants.
One study of 38 ELBW infants suggested no differences in
neurodevelopmental outcomes at 8 to 10 years of age, com-
paring those who received fluconazole prophylaxis versus
placebo.222 This small study suggests no adverse neurode-
velopmental outcomes after early exposure to fluconazole on
a prophylaxis regimen, but as we have learned over time in
neonatology, caution must be exercised until more informa-
tion is known. Additional studies are indicated to look at the
long-term outcomes of additional ELBW infants, as well as to
explore the use of additional novel therapies for the preven-
tion of Candida spp. colonization and systemic disease. Vigi-
lance in our monitoring and adherence to the reduction of all
risk factors for invasive candidiasis in the care of the ELBW
infant is still the best approach and may preclude the need for
chemoprophylaxis in a low-incidence NICU.
Thus the role for fluconazole prophylaxis, targeted or not,
requires further clarification.
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