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Original Articleped_3574 341..

349
Neonatal candidiasis: Results of an 8 year study
Solmaz Celebi,
1
Mustafa Hacimustafaoglu,
1
Nilgun Koksal,
2
Hilal Ozkan,
2
Merih Cetinkaya
2
and Beyza Ener
3
1
Department of Pediatrics, Division of Pediatric Infectious Diseases,
2
Department of Pediatrics, Division of Neonatology and
3
Department of Microbiology, Uludag University Medical Faculty, Gorukle, Bursa, Turkey
Abstract Background: The aim of the present study was to evaluate the risk factors, demographic features, treatment and clinical
outcome associated with candidemia in a neonatal intensive care unit (NICU) within an 8 year period.
Methods: The data of infants who were diagnosed as having candidemia, were evaluated.
Results: Between January 2000 and December 2007, a total of 28 candidemia episodes were identied in 28 infants. A
1.1% candidemia incidence was documented in the neonatal intensive care unit (NICU). The species most frequently
causing candidemia were Candida parapsilosis (57.1%), followed by C. albicans (42.9%). The main predisposing
factors for candidemia with C. parapsilosis included presence of maternal pre-eclampsia, prematurity, prolonged
mechanical ventilation, prolonged total parenteral nutrition and presence of jaundice. Retinopathy of prematurity and
bronchopulmonary dysplasia were the most frequently seen underlying illnesses in infants with C. parapsilosis. In the
present study, 13 infants (46.4%) had evidence of organ dissemination. The mortality rate was 42.8% in infants with
candidemia. Mean leukocyte counts and mean C-reactive protein were signicantly higher in neonates who died
compared with those who survived.
Conclusion: Candida parapsilosis (57.1%) was the leading causative organism, followed by C. albicans (42.9%) in
infants. The rate of organ dissemination in the present cases was high. The mortality rate was 42.8% in infants with
candidemia.
Key words candidemia, infants, neonatal intensive care unit, risk factors for candidemia.
Candida species are recognized as leading pathogens in the neo-
natal intensive care unit (NICU) for infections occurring after the
third day of life. The incidence has been observed to range from
2.2% to 12.9% among very low-birthweight infants (VLBW;
birthweight <1500 g) and from 5.5% to 16.5% among extremely
low-birthweight infants (ELBW; birthweight <1000 g).
16
It was
reported that Candida was responsible for 9% of all episodes of
late-onset (>3 days of life) bloodstream infections among VLBW
infants.
1
Candida infections are a signicant cause of mortality
(1054%) and morbidity (25%) in the NICU.
7,8
Acquired late-
onset systemic fungal infections occur in neonates who have risk
factors such as prematurity, use of broad spectrum antibiotics,
prolonged endotracheal intubation, total parenteral nutrition
(TPN), presence of central venous catheters, prior colonization
with Candida species, and concomitant drug use such as H2
blockers and steroids.
813
Candida albicans is the most common pathogen associated
with neonatal infections, and C. parapsilosis is the second
common yeast species isolated from bloodstream infections in
several surveys.
14,15
In some NICUs, C. parapsilosis is the most
commonly identied species of Candida.
1618
Preterm and low-
birthweight infants are more vulnerable to acute fungal sepsis,
because of an immature immune system and invasive interven-
tions; and, in addition, prolonged use of antimicrobials that serve
as risk factors for fungal colonization.
19,20
Candida species can
spread through vertical transmission from maternal ora or via
horizontal transmission from the hands of health-care workers or
contaminated sources.
The aim of the present study was to evaluate the incidence,
risk factors, demographic features, causative pathogens, treat-
ment and clinical outcome associated with candidemia in neo-
nates, and to dene parameters associated with candidemia due
to C. albicans and non-albicans species.
Methods
Subjects and denitions
The Pediatric Clinic at Uludag University Hospital in Bursa,
Turkey is a tertiary care pediatric referral unit in the South
Marmara region that includes a 15-bed neonatal NICU. Atotal of
28 infants who were diagnosed with candidemia according to
clinical ndings and positive blood cultures between January
2000 and December 2007 were included in this study. Detailed
demographic, microbiological and clinical data were prospec-
tively collected for each patient. Gestational age, birthweight,
gender, mode of delivery, Apgar scores at 1 and 5 min, prenatal
Correspondence: Solmaz Celebi, MD, Department of Pediatrics and
Pediatric Infectious Diseases, Uludag University Medical Faculty,
16059, Gorukle, Bursa, Turkey. Email: solmaz@uludag.edu.tr
Received 12 September 2011; revised 9 January 2012; accepted 10
January 2012.
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Pediatrics International (2012) 54, 341349 doi: 10.1111/j.1442-200X.2012.03574.x
2012 The Authors
Pediatrics International 2012 Japan Pediatric Society
demographics, premature rupture of membrane (PROM) and
history of chorioamnionitis, TPN, umbilical catheterization,
presence of urinary catheter and/or nasogastric tube, mechanical
ventilation, previous hospitalization were all recorded. Patients
were monitored for nosocomial infections at all body sites and
data were collected prospectively according to standard surveil-
lance protocols, and Centers for Disease Control and Prevention
criteria were used as standard denitions for nosocomial infec-
tions.
21
We dened nosocomial candidemia as the occurrence of
at least one positive blood culture yielding Candida spp. plus
signs and symptoms of infection after at least 72 h of hospital-
ization.
21
The study protocol was approved by the Ethics Com-
mittee of Uludag University, Faculty of Medicine. Informed
consent was obtained from the legal guardians of all infants.
This study included two casecontrol studies. The rst study
was performed to assess the risk factors for candidiasis (compar-
ing C. albicans and C. parapsilosis) in infants with candidemia.
The second study was an assessment of the parameters associated
with mortality in patients with candidemia. Cases were dened as
patients who died from candidemia, controls were dened as
patients who survived candidemia.
Temperature instability (fever or hypothermia), apnea, need
for supplemental oxygen, need for ventilation, tachycardia/
bradycardia, hypotension, feeding intolerance, abdominal disten-
sion, and necrotizing enterocolitis were considered to be clinical
signs of sepsis. Prematurity was dened as gestational age 237
weeks. Prolonged hospitalization was dened as >14 days. Pro-
longed antibiotics use was dened as >14 days.
The changes in the hematologic parameters were analyzed
using the Manroe and Rodwell scoring systems.
22,23
Leukopenia
was dened as leukocyte counts 25000/mm
3
; leukocytosis was
dened as leukocyte counts 325 000/mm
3
at birth, 330 000/mm
3
at 1224 h and 321 000/mm
3
after the second day of life. Throm-
bocytopenia was dened as platelet counts 2150 000/mm
3
.
Before initiating antimicrobial therapy, blood samples for whole
blood count, C-reactive protein (CRP), culture were obtained.
Meningitis was diagnosed according to the cell count, glucose
and protein levels of cerebrospinal uid (CSF) and the CSF
culture. Whole blood count was performed using an automatic
counter, Cell Dyn 3700 (Abbott Diagnostics Division, Abbott
Park, IL, USA). CRP was determined on immunonephelometry
using a BN II device (Dade Behring Marburg, Marburg,
Germany). Detection limits were 0.5 mg/dL for CRP.
Patients were considered to have organ dissemination if, in
addition to a positive blood culture to candidemia, one or more of
the following were present: (i) chorioretinitis or endophthalmitis
on ophthalmologic examination; (ii) endocarditis, with echocar-
diographic evidence of a valvular vegetation; or (iii) solid organ
involvement with focal, discrete or nodular lesions on computed
tomography, magnetic resonance imaging or ultrasound.
The empiric antibiotic therapy protocols in the NICU were
ampicillin plus gentamicin for early onset sepsis. Ceftazidime (or
cefotaxime) plus amikacin with or without vancomycin were
used for late-onset sepsis. Amphotericin B deoxycholate
(D-AmB) or uconazole was initiated for fungal sepsis at NICU.
Liposomal amphotericin B (L-AmB) was used as second-line
therapy if the patient had failed to respond to previous antifungal
therapy and/or there was toxicity due to antifungal therapy.
Patients who had pre-existing renal or hepatic dysfunction
received L-AmB as rst-line therapy. Flucytosine was used only
in combination with other agents. Doses of the antifungal drugs
were as follows: uconazole, 12 mg/kg i.v. (infused in 2 h) as an
initial dose, then 12 mg/kg once daily i.v. (infused in 1 h) in term
neonates; and 12 mg/kg per day once every 72 h during the rst
week of life in preterm neonates <1500 g; D-AmB, 0.5 mg/kg per
day i.v. dissolved in 5% dextrose water (at a concentration of
0.1 mg/mL) infused in 46 h and protected from light as an initial
dose, then 1 mg/kg once daily i.v.; L-AmB, 3 mg/kg per day i.v.
infused in 1 h; ucytosine, 100 mg/kg per day orally in four
divided doses. In the NICU at Uludag University Medical
Faculty, none of the infants received antifungal prophylaxis.
Microbiology
Blood cultures were obtained from peripheral veins by sterile
technique. Other cultures such as urine, CSF and peritoneal uid
were obtained from other sterile sites when clinically indicated.
Blood, CSF, and peritoneal uid specimens were inoculated into
BACTEC Peds Plus/F (Becton-Dickinson, Sparks, MD, USA)
culture bottles. Urine specimens were inoculated into a 5% de-
brinated sheep blood agar and an eosin-methylene blue (EMB)
agar plate. Urinary tract infection was dened as growth of a
single organism at 310
4
c.f.u./mL in urine collected by catheter-
ization. All cultures were monitored using an automated culture
system. Passages to blood agar and Sabouraud dextrose agar
were performed. The isolated yeasts (C. albicans and non-
albicans species) were presumptively identied as C. albicans
using morphological criteria (germ tube and chlamydospore for-
mation) and denitive identication was made using the API ID
32 C system (BioMerieux Diagnostic System, Grenoble, France).
Because C. parapsilosis was isolated from 10 neonates in
NICU between October 2005 and December 2005, we investi-
gated the source of the infection. During investigation into the
possible source of the infection, samples for cultures were taken
from: the TPN solutions, segments of intravascular lines used for
TPN, surfaces of vacuum pump devices, other surfaces exposed
to hand contact and hands of health-care workers in the NICU.
Also, surveillance cultures (oropharyngeal and skin swabs) were
taken from patients with candidemia.
Statistical analysis
Statistical analysis was performed using SPSS (version 13.0;
SPSS, Chicago, IL, USA). Descriptive statistics are given as a
mean 1 SD, and a percentage. The ShapiroWilk test was used to
test the normal distribution of data. The categorical data were
analyzed using a chi-square test and Pearson test. Continuous
variables (birthweight, gestational age and total hospitalization
duration) were compared between groups with MannWhitney
test. P < 0.05 was considered statistically signicant.
Results
A total of 2420 infants were admitted to NICU between January
2000 and December 2007. In the study period, we identied 28
342 S Celebi et al.
2012 The Authors
Pediatrics International 2012 Japan Pediatric Society
infants with candidemia, the overall incidence of candidemia was
11.5 per 1000 NICU admissions. Annual rates of nosocomial
candidemia cases per 1000 admissions are given in Figure 1. In
Turkey no data are collected on vaginal fungal colonization in
pregnancy. The mean number of positive blood cultures per
patient was 4 (range, 122). All of the Candida species were
classied as nosocomial isolates, Forty-six percent of patients
had more than one positive culture. Eighty-six percent of infants
were premature newborns. Mean gestational age and mean birth-
weight of infants with candidemia were 31.4 1 4 weeks (range,
2640 weeks) and 1417.1 1 252.6 g (range, 5902400 g), respec-
tively. C. parapsilosis and C. albicans accounted for 16 (57.1%)
and 12 (42.9%) of the isolates respectively. Demographic and
clinical characteristics and outcome of the patients with candi-
demia are listed in Table 1. Although all of the infants required
nasogastric catheterization, only 24 infants required mechanical
ventilation. Also, 23 infants required both TPN and umbilical
vein catheterization. There were no statistically signicant dif-
ferences between the candidemia caused by C. albicans and
C. parapsilosis with regard to gender, gestational age, birth-
weight, cesarean delivery, maternal age, frequency of organ dis-
semination or mortality rate. Apgar scores at 1 and 5 min were
lower in patients with C. parapsilosis compared with that in
those with C. albicans (P = 0.017). Maternal pre-eclampsia was
more frequent in patients with C. parapsilosis than in those with
C. albicans (P < 0.001). When we compared the candidemia with
regard to most commonly seen underlying illness, prematurity
(P = 0.024), retinopathy of prematurity (P = 0.007) and bron-
chopulmonary dysplasia (P = 0.0003) were more common in
patients with C. parapsilosis than in those with C. albicans.
Patients with C. parapsilosis were more likely to receive ucy-
tosine and L-AmB treatment (P = 0.024). Patients with C. albi-
cans were more likely to receive uconazole treatment (P =
0.024). Fifteen infants (53.7%) had candidemia alone, whereas
13 infants (46.4%) had evidence of organ dissemination. Organ
involvement was most commonly identied in the brain (25%),
followed by kidney (10.7%), and peritoneal cavity (10.7%). Six
patients with meningitis (85.7%) had positive CSF cultures.
None had ndings of endophthalmitis on eye examination. All
Fig. 1 Annual rates of candidemia cases per 1000 admissions.
Table 1 Subject characteristics and candidemia outcome vs species
C. albicans C. parapsilosis P
(n = 12) (n = 16)
Mean 1 SD (range) Mean 1 SD (range)
Male, n (%) 9 (75) 8 (50) 0.253
Gestational age (weeks) 33.5 1 5 (2640) 29.9 1 2.2 (2734) 0.059
Birthweight (g) 1673 1 592 (8702400) 1224 1 384 (5902050) 0.082
Cesarean delivery, n (%) 7 (58.3) 12 (75) 0.432
Apgar at 1 min 6.6 1 2.4 (49) 4.5 1 2.3 (19) 0.017
Apgar at 5 min 8.3 1 1.6 (610) 7 1 1.6 (510) 0.017
Maternal pre-eclampsia, n (%) 0 (0) 9 (56.2) <0.001
Underlying illness, n (%)
RDS

9 (75) 16 (100) 0.06


ROP

1 (8.3) 10 (62.5) 0.007


NEC

5 (41.6) 9 (56.2) 0.445


IVH

3 (25) 8 (50) 0.253


BPD

3 (25) 14 (87.5) 0.003


PDA

1 (8.3) 3 (18.8) 0.613


Treatment, n (%)
Fluconazole 4 (33) 0 (0) 0.024
D-AmB 5 (42) 7 (43.8) 1
L-AmB 3 (25) 5 (31.2) 1
Flucytosine and L-AmB 0 (0) 4 (25) 0.024
Organ dissemination, n (%) 7 (58.3) 6 (37.5) 0.274
Mortality, n (%) 6 (50) 6 (37.5) 0.508

At birth;

during the complete hospitalization. BPD, bronchopulmonary dysplasia; D-AmB, amphotericin B deoxycholate; IVH, intraventricular
hemorrhage; L-AmB, liposomal amphotericin B; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; PROM, premature rupture of
membranes; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity.
Neonatal candidiasis 343
2012 The Authors
Pediatrics International 2012 Japan Pediatric Society
of the patients received previous antibiotic treatment in different
combinations of ampicillin, gentamicin, cefotaxime, amikacin,
ceftazidime, vancomycin and carbapenem. Prior to candidemia,
all of the infants received systemic antibiotic treatment, 10 of
whom had documented bacteremia (methicillin-resistant Staphy-
lococcus epidermidis in six, Pseudomonas aeruginosa in two,
Klebsiella pneumoniae in two). Ampicillin plus gentamicin or
cefotaxime plus amikacin were the empiric antibiotics used in the
NICU while awaiting cultures, to which all 28 infants had been
exposed for at least 48 h.
Empiric antifungal therapy was initiated in 16 patients
(57.1%) before a positive blood culture was reported, because of
clinical suspicion of fungal sepsis. The mean length of antifungal
therapy was 28.5 1 18.8 days (range, 585 days). Ten patients
(35.7%) were initially treated with uconazole. No uconazole-
related toxicity was observed. D-AmB was used in 14 patients
(64.2%) as initial therapy. In eight patients (66.6%), however,
D-AmB was changed to L-AmB, because hypokalemia
(<3 meq/dL) attributed to D-AmB was seen in three patients, and
persistently positive cultures and/or persistence of the clinical
signs and symptoms of the candidal infection occurred in ve
patients. L-AmB was given to four patients (14.2%) as initial
therapy. Flucytosine was added to L-AmB in four patients
(14.2%), because of persistence of the clinical signs and symp-
toms of the candidal meningitis. No ucytosine-related toxicity
was observed. Death occurred in one of the patients (25%)
treated with uconazole. Among the patients treated with
D-AmB, L-AmB and L-AmB plus ucytosine, ve, four, and two
patients died, respectively.
Predisposing factors associated with C. albicans and
C. parapsilosis are listed in Table 2. There were signicant dif-
ferences in the mean duration of mechanical ventilation (5.5 1 6.6
days vs 35 1 38.2 days), and TPN (8 1 6.5 days vs 31.5 1 30 days)
before a diagnosis of systemic infection with C. albicans and C.
Parapsilosis, respectively. Also, the duration of total hospitaliza-
tion of patients with C. parapsilosis (93.5 days) was signicantly
longer than in those with C. albicans (43 days; P = 0.037).
Clinical characteristics of the patients with candidemia by
species are given in Table 3. Presence of jaundice was associated
with candidemia caused by C. parapsilosis. The most common
manifestations were jaundice (75%); tachypnea (71.4%); worsen-
ing in general condition (67.9%); low activity (46.4%); and
fever (32.1%). Laboratory ndings of the candidemia patients by
species are presented in Table 4. No statistically signicant dif-
ferences were found in laboratory ndings in candidemia caused
by C. albicans and C. parapsilosis. Demographic and clinical
characteristics associated with mortality are presented in Table 5.
There were also no statistically signicant differences in gender,
gestational age, birthweight, cesarean delivery, apgar scores at
1 and 5 min, or frequency of organ dissemination between
the patients who died from candidemia and those who survived
candidemia.
Predisposing factors associated with mortality are presented
in Table 6. No statistically signicant differences were found in
predisposing factors between the patients who died from candi-
demia and those who survived candidemia.
Clinical ndings associated with mortality are given in
Table 7. There were no signicant differences in clinical ndings
between the patients who died from candidemia and those who
survived. Laboratory ndings associated with mortality are listed
in Table 8. Mean leukocyte count and CRP were higher in
patients who died from candidemia than in those who survived
candidemia (P = 0.01 vs P = 0.03, respectively).
Of the samples taken from the environment, hands of health-
care workers, and the oropharyngeal and skin swabs, none was
positive. Of the 30 segments of intravascular lines used for TPN
cultures, two were positive for C. parapsilosis. Active surveil-
lance for hospital-associated bloodstream infection is conducted
by the infection prevention and control team for all patients
hospitalized at Uludag University Medical Faculty. In the present
Table 2 Predisposing factors
C. albicans (cases) C. parapsilosis (controls) P
(n = 12) (n = 16)
Mean 1 SD (range) Mean 1 SD (range)
Prematurity (<37 week), n (%) 8 (66.6) 16 (100) 0.024
Duration of hospitalization (days)

16.6 1 10.5 (536) 40.2 1 38.6 (7125) 0.280


Duration of antibiotics use (days)

16.6 1 10.5 (536) 40.2 1 38.6 (7125) 0.280


Neutropenia, n (%) 2 (16.7) 5 (31.3) 0.662
Mechanical ventilation (days)

5.5 1 6.6 (117) 35 1 38.2 (1118) 0.004


Total parenteral nutrition (days)

8 1 6.5 (117) 31.5 1 30 (1102) 0.037


Total hospitalization (days) 43 1 34 (12132) 93.5 1 41.5 (7155) 0.003
Nasogastric catheter (days)

14.4 1 8.9 (136) 37.7 1 39.4 (1125) 0.205


Umbilical catheter (days)

4 1 4.6 (114) 6.4 1 2.4 (110) 0.059

From admission to candidemia.


Table 3 Clinical characteristics of candidemia patients vs species
Clinical ndings C. albicans C. parapsilosis P
(n = 12), n (%) (n = 16), n (%)
Tachypnea 8 (66.7) 12 (75) 0.691
Low activity 7 (58.3) 6 (37.5) 0.274
Worsening in general
condition
7 (58.3) 12 (75) 0.432
Fever 6 (50) 3 (18.7) 0.114
Jaundice 6 (50) 15 (93.7) 0.022
Gastric distention 3 (25) 6 (37.5) 0.687
Apnea 1 (8.3) 4 (25) 0.355
344 S Celebi et al.
2012 The Authors
Pediatrics International 2012 Japan Pediatric Society
Table 4 Laboratory ndings of candidemia patients vs species
Laboratory ndings C. albicans C. parapsilosis P
(n = 12) (n = 16)
Mean 1 SD (range) Mean 1 SD (range)
WBC (mm
3
) 12 424 1 4 800 (4 35015 300) 10 467 1 6 236 (3 21025 400) 0.280
Leukocytosis (>20 000/mm
3
), n (%) 0 (0) 2 (12.5) 0.492
Leukopenia (<5 000/mm
3
), n (%) 1 (8.3) 4 (25) 0.355
Thrombocytopenia (<150 000/mm
3
), n (%) 6 (50) 10 (62.5) 0.702
CRP (mg/dL) 5.6 1 6 (012) 6.74 1 4.7 (117.2) 0.223
CRP positivity (>0.5 mg/dL), n (%) 11 (91.6) 16 (100) 0.429
CRP, C-reactive protein; WBC, white blood cells.
Table 5 Factors associated with mortality
Died Survived P
(n = 12) (n = 16)
Mean 1 SD (range) Mean 1 SD (range)
Male, n (%) 8 (66.6) 9 (56.2) 0.705
Gestational age (weeks) 30.2 1 3.6 (2640) 32.3 1 4.2 (2740) 0.174
Birthweight (g) 1232 1 525.1 (5902300) 1555 1 497 (9002400) 0.053
Apgar at 1 min 4.9 1 2.5 (29) 5.8 1 2.6 (19) 0.423
Apgar at 5 min 7.5 1 1.5 (610) 7.6 1 1.8 (510) 0.945
Pre-eclampsia, n (%) 4 (33.3) 5 (31.2) 1
Maternal age (years) 26.1 1 4.3 (2133) 28.6 1 5.4 (2239) 0.260
Underlying illness, n (%)
RDS

11 (91.6) 14 (87.5) 1
ROP

4 (33.3) 8 (50) 0.377


NEC

8 (66.6) 6 (37.5) 0.126


IVH

5 (41.6) 6 (37.5) 1
BPD

7 (58.3) 10 (62.5) 0.637


PDA

2 (16.6) 2 (12.5) 1
Organ dissemination, n (%) 7 (58.3) 6 (37.5) 0.274
Treatment, n (%)
Fluconazole therapy 1 (8.3) 3 (18.7) 0.281
D-AmB therapy 5 (41.6) 7 (43.7) 1
L-AmB therapy 4 (33.3) 4 (25) 1
Flucytosine and L-AmB therapy 2 (16.6) 2 (12.6) 1

At birth;

during the complete hospitalization. BPD, bronchopulmonary dysplasia; D-AmB, amphotericin B deoxycholate; IVH, intraventricular
hemorrhage; L-AmB, liposomal amphotericin B; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; RDS, respiratory distress
syndrome; ROP, retinopathy of prematurity.
Table 6 Predisposing factors associated with mortality
Died Survived P
(n = 12) (n = 16)
Mean 1 SD (range) Mean 1 SD (range)
Prematurity (<37 weeks), n (%) 11 (91.6) 13 (81.2) 0.613
Duration of hospitalization (days)

28.5 1 34.6 (7117) 31.3 1 30.6 (1125) 0.537


Duration of antibiotics use (days)

28.5 1 34.6 (7117) 31.3 1 30.6 (1125) 0.537


Duration of antifungal therapy (days)

26.3 1 25.3 (585) 31.2 1 16.3 (1478) 0.108


Neutropenia, n (%) 4 (33.3) 3 (18.7) 0.418
Mechanical ventilation (days)

0.1 1 0.3 4.8 1 7.1 0.82


Total parenteral nutrition (days)

24.3 1 32 (1102) 28.5 1 34.6 (7117) 0.568


Total hospitalization (days) 49.6 1 40.7 (7125) 88.6 1 42.7 (17155) 0.17
Nasogastric catheter (days)

0.4 1 0.7 6.7 1 8.1 0.599


Umbilical catheter (days)

0.1 1 0.3 2.5 1 3.2 0.982

From admission to candidemia.


Neonatal candidiasis 345
2012 The Authors
Pediatrics International 2012 Japan Pediatric Society
study, the possible cause of the outbreak of C. parapsilosis can-
didemia in NICU was contamination of intravascular catheters.
Infection control measures such as skin antisepsis at catheter
insertion sites and strict handwashing practice, helped us to
control this outbreak.
Discussion
Neonatal candidiasis is an important cause of morbidity and
mortality in premature infants.
24
In recent years, candidemia has
emerged as a leading cause of late-onset infection in premature
infants.
25,26
Kossoff et al. reported that 1% of all NICU infants
developed candidemia, and the rate of candidemia had increased
11-fold during the 15-year study period.
3
Arecent study involving
a prospective observational cohort of infants with birthweight
21000 g by Benjamin et al. found that invasive candidiasis
occurred in 137 of 1515 infants (9%).
27
In the present study, we
found that overall incidence of candidemia was 1.1%. This was
lower than the incidence reported from the NICUs in other devel-
oped countries of 1.65%.
4,13,28
The demographic and clinical characteristics of neonates with
candidemia in the present study paralleled previous studies in
some respects: prematurity, use of central venous catheterization,
use of prolonged antibiotic treatment, prolonged mechanical ven-
tilation, prolonged parenteral nutrition, and prolonged hospital-
ization.
29,30
Eighty-six of the present cases involved premature
infants, and all of the present patients had received previous
antibiotic treatment in different combinations of cefotaxime,
amikacin, vancomycin and carbapenem.
Neonatal candidemia presents with manifestations similar to
bacterial sepsis. The signs and symptoms are non-specic and
include temperature instability, refusal of feeds, respiratory
distress, abdominal distension, apnea, lethargy, bradycardia,
decreased perfusion or seizures.
31
As in that previous report, we
found jaundice (75%), tachypnea (71.4%), worsening in general
condition (67.9%), low activity (46.4%), and fever (32.1) in the
present candidemia patients.
Previous studies reported that C. albicans was the most com-
monly isolated Candida species, followed by C. parapsilosis in
the cases of candidal bloodstream infections in infants.
14,15,28
Other Candida species included C. tropicalis, lusitaniae, gla-
brata, and krusei at 4%, 2%, 2%, and <1% of cases, respec-
tively.
28
In the present study, in contrast to previous studies,
14,15,28
C. parapsilosis (57.1%) was the most frequent cause of candi-
demia, followed by C. albicans (42.9%). A change in the distri-
bution of Candida species causing candidemia has been noted in
several institutions, with increasing isolation of non-albicans
species in neonates.
3,18,32
Neonatal infections caused by non-
albicans species occur at a later age and are more likely to be
acquired from the hospital environment than is C. albicans. A
recent study by Al-Sweih et al. reported that C. parapsilosis
accounted for 57% of candidemia cases.
16
The role of C. parap-
silosis as an exogenous acquired pathogen is well known and has
been associated with parenteral alimentation, intravascular
devices, contamination from hands of health-care workers, and
contaminated solutions.
33,34
In the present study, two intravascular
line cultures were also positive for C. parapsilosis. We consid-
ered that the possible cause of outbreak of C. parapsilosis can-
didemia in NICU was contamination of intravascular catheters.
C. parapsilosis nosocomial outbreaks have been described pre-
viously, in which the hands of health-care workers, infusates,
biomaterials, and the inanimate environment were found to be the
predominant infection source.
24,35,36
In agreement with other studies,
37,38
candidemia due to
C. parapsilosis was associated with prolonged length of
mechanical ventilation, prolonged TPN and prolonged total hos-
pitalization in the present study. Also, we found that candidemia
due to C. parapsilosis was associated with lower Apgar scores at
1 and 5 min, prematurity, maternal pre-eclampsia, retinopathy of
prematurity and bronchopulmonary dysplasia. Mittal et al. per-
formed a prospective analysis of 253 infants and found that
Candida sepsis developed in 22 infants.
39
A signicantly
increased incidence of retinopathy of prematurity was seen
among the infants with Candida sepsis (95%) compared to those
without sepsis (69%).
Table 7 Clinical ndings associated with mortality
Clinical ndings Died Survived P
(n = 12) (n = 16)
n (%) n (%)
Tachypnea 9 (75) 11 (68.7) 1
Low activity 5 (41.6) 8 (50) 0.662
Worsening in general condition 10 (83.3) 9 (56.2) 0.223
Fever 3 (25) 6 (37.5) 0.687
Gastric distention 5 (41.6) 4 (25) 0.432
Apnea 1 (8.3) 4 (25) 0.355
Table 8 Laboratory ndings associated with mortality at onset of candidemia
Laboratory ndings Died Survived P
(n = 12) (n = 16)
Mean 1 SD (range) Mean 1 SD (range)
WBC (mm
3
) 15 025 1 10 041 (5 35025 400) 12 153 1 5 688 (3 21015 300) 0.01
Leukocytosis (>20 000/mm
3
), n(%) 1 (8.3) 1 (6.2) 1
Leukopenia (<5 000/mm
3
), n (%) 2 (16.6) 3 (18.7) 1
Platelets (<150 000/mm
3
), n (%) 7 (58.3) 9 (56.2) 1
CRP (mg/dL) 10.4 1 5.5 (117.2) 4.1 1 4.4 (012) 0.03
CRP positivity (>0.5 mg/dL), n (%) 12 (100) 15 (93.7) 1
CRP, C-reactive protein; WBC, white blood cells.
346 S Celebi et al.
2012 The Authors
Pediatrics International 2012 Japan Pediatric Society
Candida species invade virtually all tissues, including the
retina, brain, heart, lung, liver, spleen, and joints.
40
The changing
epidemiology of candidemia in many NICUs may explain some
of the heterogeneity in the proportion of infants who experienced
end-organ damage. In a recent study of neonatal candidemia, the
authors reported the following median end-organ invasion rates
for candidemia: meningitis (15%), central nervous abscesses and
ventriculitis (4%), endophthalmitis (3%), endocarditis (4%),
renal abscess (3%), and liver/spleen abscess (1%).
41
Makhoul
et al. reported that fungal dissemination in infants was rare (2.5
7.1%).
5
In the present study, 13 infants (46.4%) had evidence of
organ dissemination. Meningitis (25%) was most common, fol-
lowed by renal involvement (10.7%), and peritonitis (10.7%).
The rate of organ dissemination in the present patients was very
high compared with previous studies. Although C. parapsilosis
probably causes less mortality than C. albicans,
6
there are not
sufcient data to support different end-organ damage evaluations
on the basis of species in infants. In our previous study, we found
that C. albicans had a higher rate of organ dissemination com-
pared with non-albicans species in children.
42
In the present
study, no statistically signicant difference was found in organ
dissemination in candidemia caused by C. albicans and
C. parapsilosis.
Amphotericin B continues to be the mainstay of therapy for
systemic fungal infections. In a prospective study of 67 infants
with systemic candidiasis, cure rates were 67.6% and 83.3% for
D-AmB and L-AmB, respectively.
43
In another study, 24 infants
with culture-proven candidiasis were treated with uconazole,
and both clinical and microbiological cure was achieved in 96%
of neonates.
26
Although a previous study showed that uconazole
and D-AmB were equally effective in the treatment of dissemi-
nated neonatal fungal infections; uconazole produced fewer
toxic manifestations than D-AmB and was more convenient to
use.
44
In that study, most of the infants (71.4%) were treated with
amphotericin B monotherapy. Fluconazole was used as a single
agent in four infants (14.3%). Patients with C. albicans were
more likely to receive uconazole treatment. Combinations of
amphotericin B, uconazole and ucytosine have been reported
to be successful in circumstances in which one or two agents
were unsuccessful at controlling infection.
45
In the present study,
ucytosine was added to L-AmB in four patients (14.3%),
because of persistence of the clinical signs and symptoms of the
candidal meningitis. In these patients, ucytosine was added to
L-AmB because ucytosine penetrates the CSF well and is syn-
ergistic to amphotericin B.
45
In the present study, mean leukocyte count and mean CRP
were signicantly higher in neonates who died compared with
the infants who survived. These ndings suggest that infants who
died were severely ill. Many studies have reported high rates of
mortality among infants with candidemia: there is a wide varia-
tion in crude mortality associated with candidemia in infants,
ranging from 10% to 54%.
7,8
In a recent review article, Chapman
reported that candidemia in infants had a crude mortality of
30%.
46
In previous studies, the rate of mortality due to C. albi-
cans infection was signicantly higher than that due to C. parap-
silosis infection (36% vs 7%
6
and 26% vs 4%
3
). In the present
study, the mortality rate was 42.8%. Because this mortality rate
was high, we suggest some precautions for treating Candida
infections in preterm infants. As stated in recent reviews, empiric
antifungal treatment for suspected invasive Candida infections
(ICI) and standardization of treatment regimens including appro-
priate dosing with prompt central catheter removal for docu-
mented candidal bloodstream infections have been shown to
decrease ICI mortality. Also, the infection control practices stated
here were likely to contribute to reduce the rate of ICI. Just as
antibiotic prophylaxis has been implemented for prevention of
early-onset group B streptococcal infections, development of
local, national, and international guidelines to prevent invasive,
life-threatening candidal infections in the highest-risk NICU
patients should also be developed. Antifungal prophylaxis given
to infants with birthweight <1000 g and/or 227 weeks gestational
age can reduce and potentially eliminate ICI and Candida-related
mortality.
47
Anumber of randomized trials has been conducted to evaluate
the benets of uconazole for 46 weeks in ELBWinfants (birth-
weight <1000 g). These studies showed a reduction in the preva-
lence of invasive candidiasis.
4850
They were all performed,
however, in the setting of increased baseline prevalence rates.
Investigators have suggested that antifungal prophylaxis should
be targeted at populations with a baseline rate of candidiasis
>10%.
51
A previous study reported that uconazole-resistant
C. parapsilosis emerged in an NICU after 10 years of using
prophylactic uconazole.
52
In the present study, based upon the
previous literature, our approach is not to give antifungal prophy-
laxis to infants because of the concern of promoting resistant
Candida species within the NICU. Recent reviews, however,
suggest antifungal prophylaxis in extremely preterm neonates
(<1000 g and <27 gestational weeks) who also had other risk
factors such as central line and use of broad spectrum antibiot-
ics.
47
Therefore, in the presence of these factors, prophylaxis
should be started.
The present study had several limitations. We were not able to
obtain data on specic characteristics of non-infected patients in
the NICU. The number of cases of candidemia was not sufcient
to use multivariate logistic regression analysis. Susceptibility
testing was also not performed.
In conclusion, the present data demonstrate that the incidence
of candidemia was low in the NICU at Uludag University
Medical Faculty, but it was associated with a high mortality rate
in infants. Also, we found that the rate of organ dissemination
was high. Continued surveillance is necessary to estimate the real
incidence and impact of this infection. Further candidemia
studies in the NICU should focus on efforts to prevent, or early
empiric therapy for, this infection.
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Neonatal candidiasis 349
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