Effect of amphotericin B lipid complex (ABLC) in very low birth weight infants.

ORIGINAL ARTICLE
Effect of amphotericin B lipid complex (ABLC)
in very low birth weight infants
Ari Auron & Moises Auron-Gomez & Rupesh Raina &
Sreekanth Viswanathan & Maroun J. Mhanna
Received: 9 June 2008 /Revised: 11 September 2008 /Accepted: 12 September 2008
# IPNA 2008
Abstract The aim of this retrospective, case–control study
was to determine the effect of the amphotericin B lipid
complex (ABLC) on serum creatinine (SCr), blood urea
nitrogen (BUN), sodium (Na), and potassium (K) in very
low birth weight (VLBW) infants. Medical records of all
VLBW infants who were admitted to our Neonatal
Intensive Care Unit between May 1998 and May 2006
and had received ABLC for at least 2 weeks were reviewed
for patient demographics, use of medications (ABLC,
diuretics, xanthines, indomethacin, vancomycin, gentami-
cin, pressors, and inotropes), fluid intake, urinary output,
and serum electrolytes. Thirty-five patients who received
ABLC were identified and matched by gestational age
(GA) to 35 patients who served as controls. Infants who
received ABLC had an average GA of 25.7±2.1 weeks and
a birth weight of 764±196 g. Between day 1 and 14 of
ABLC treatment, the BUN decreased from 17.5±11.5 to
10.5±6.8 mg/dl (p=0.01), the SCr varied between 0.78±
0.32 and 0.69±0.32 mg/dl, Na varied between 136.6±5.8
and 137.8±3.6 mEq/l, and K varied between 4.8±0.9 and
4.9±0.6 mEq/l, respectively. Based on these results, we
conclude that treatment with ABLC for 2 weeks did not
increase BUN or SCr, nor decrease Na or K in VLBW
infants.
Keywords Amphotericin B lipid complex .
Blood urea nitrogen . Potassium . Serum creatinine .
Sodium . Very low birth weight infants
Introduction
Renal function is immature in very low birth weight
(VLBW) premature infants as compared to adults [1–4].
The amphotericin B lipid complex (ABLC; Abelcet;
Enzon Pharmaceuticals, Bridgewater, NJ) has been ap-
proved in patients with renal failure or patients with side
effects related to amphotericin B deoxycolate (Fungizone).
The structure of ABLC consists of non-liposomal lipid
bilayers, or “ribbons”, complexed with amphotericin B; as
such, it has a selective affinity to fungal (ergo-based)
rather than mammalian (cholesterol-based) cellular mem-
branes and, therefore, is less nephrotoxic than amphoter-
icin B [5–7]. However, ABLC may also induce azotemia,
a decreased glomerular filtration rate, and severe hypoka-
lemia [8, 9]. The ABLC and other lipid formulations of
amphotericin B, such liposomal amphotericin B, have
been used in preterm infants, term infants, children, and
adults [7, 8, 10–17]. Although a number of studies have
compared the different types of lipid formulations of
amphotericin B or compared a lipid formulation and
regular amphotericin B in infants and adults [7, 9], the
effect of ABLC (Abelcet) on renal function and serum
electrolytes in VLBW infants has not been fully investi-
gated. Consequently, the aim of the study reported here
was to determine the effect of ABLC on serum creatinine
Pediatr Nephrol
DOI 10.1007/s00467-008-1017-5
A. Auron
Section of Pediatric Nephrology, Blank Children’s Hospital,
Iowa Health System,
Des Moines, IA, USA
M. Auron-Gomez
Department of Hospital Medicine, Cleveland Clinic Foundation,
Cleveland, OH, USA
R. Raina : S. Viswanathan : M. J. Mhanna (*)
Department of Pediatrics, MetroHealth Medical Center,
Case Western Reserve University,
2500 MetroHealth Drive,
Cleveland, OH 44109, USA
e-mail: mmhanna@metrohealth.org

(SCr), blood urea nitrogen (BUN), sodium (Na), and
potassium (K) in VLBW infants.
Patients and methods
Patients
The medical records of all VLBW infants (≤1500 g at birth)
admitted to our Neonatal Intensive Care Unit between 1
May 1998 and 1 May 2006 were reviewed. All VLBW
infants who received ABLC for at least 2 weeks were
included in the study. Each patient who received ABLC
was matched for gestational age (GA) and birth weight
(BW) (within 10%) with a previously or consecutively
admitted VLBW infant who was not treated with antifungal
therapy.
Patients were excluded from the study if they had a
severe congenital abnormality or were oligo-anuric (defined
as an average daily urinary output < 1 ml/kg per hour
during the study period for the control group or prior to the
administration of ABLC in the ABLC group). Hemolyzed
samples, as identified by the laboratory technicians, were
also excluded. Medical records were reviewed for GA, BW,
gender, race, Apgar scores at 1 and 5 min, daily fluid
intake, and daily urinary output. The medical records were
also reviewed for morning laboratory values for BUN, SCr,
serum Na, and serum K during the study period. The study
period was defined as the first 2 weeks of treatment with
ABLC in the ABLC group or the corresponding matched
2 weeks in the control group. For example, if an infant was
started on ABLC on his 5th day of life, his medical record
was reviewed and data recorded for the next consecutive
14 days (from day 5 to day 19 of life). The matched control
infant’s medical record was reviewed for the same period
(day 5 to day 19 of life).
The use of medications during the study period that
would interfere with renal function, such as indomethacin,
vancomycin, gentamicin, xanthines (aminophylline and
caffeine), pressors (dopamine), inotropes (dobutamine)
and diuretics (furosemide, hydrochlorothiazide and bume-
tanide), were also reviewed. Medical records were also
reviewed for days of mechanical ventilation during the
study period.
An increase in SCr or in BUN was defined as an increase
in SCr or BUN by 50% from baseline on any day during
the study period. Hyponatremia was defined as a serum
Na < 125 mEq/l, and hypokalemia was defined as a serum
K < 4.2 mEq/l on any day during the study period.
During the study period, it was the treating physician’s
preference to use Abelcet whenever a fungal infection was
suspected (given the lipid formulation’s lower side effects
in older patients). Abelcet was always mixed in dextrose–
water and administered over a 2-h period intravenously. In
accordance with our unit’s policy, infants were not routinely
pretreated with an intravenous saline infusion prior to the
Abelcet infusion.
The study was approved by our Institutional Review
Board at MetroHealth Medical Center.
Statistical analysis
A t test was used to compare continuous variables, and a
chi-square test was used to compare nominal variables. All
data were expressed as means ± standard deviations or as
medians with interquartile ranges. Statistical significance
was set at p<0.5. A logistic regression analysis was used to
adjust for possible confounding. Variables known to affect
SCr and serum electrolytes were entered in a logistic
regression model using the presence or absence of an
increase in SCr > 50% from baseline during the study
period as a classifying and dependent variable. Similar
logistic regression analyses were also conducted, whereas
the classifying and dependent variables were either an
increase in BUN > 50% from baseline or hyponatremia
(Na < 125 mEq/l) or hypokalemia (K < 4.2 mEq/l) during
the study period.
Results
During the study period, 1143 VLBW infants were
admitted to our NICU. However, only 35 VLBW infants
received ABLC for at least 2 weeks and met our inclusion
criteria. Thirty-five infants, matched for GA and BW,
served as controls.
The patients’ demographics and baseline characteristics
are summarized in Table 1. There were no differences
between the ABLC group and the control group in terms of
GA, BW, gender, or race. However, patients on ABLC had
a lower Apgar score at 1 min but a similar Apgar score at
5 min of age. The daily fluid intake, urine output, and
Table 1 Patients demographics and baseline characteristics
Demographics and
baseline characteristics
ABLC
(n=35)
Control
(n=35)
p value
GA (weeks) 25.7±2.1 26.0±2.1 0.57
BW (g) 764±196 819±222 0.27
Male (%) 19/35 (54%) 18/35 (51%) 0.81
Caucasian (%) 17/35 (49%) 13/35 (37%) 0.33
Apgar at 1 min (median) 3 6 0.002
Apgar at 5 min (median) 6 8 0.11
ABLC Amphotericin B lipid complex; GA gestational age; BW birth
weight
Values are given as means ± standard deviations
Pediatr Nephrol

morning serum electrolytes at different times during the
study period are summarized in Table 2. In patients treated
with ABLC, the baseline values for fluid intake, urine
output, SCr, or serum K did not differ from those at 1 and
2 weeks of treatment; however, there was a decrease in
BUN values between the baseline and 2-week measure-
ments. When the ABLC group was compared to the control
group, the ABLC group had a higher BUN at baseline and
also a higher Na after 2 weeks of ABLC treatment.
There were no differences between the ABLC and the
control groups regarding the concomitant use of other
medications that can affect renal function during the study
period (such as diuretics, indomethacin, gentamicin, and
dopamine/dobutamine). However, the ABLC group re-
ceived more vancomycin and less xanthines than the
control group [26/35 (74%) vs. 15/35 (42%), p=0.007;
14/35 (40%) vs. 24/35 (68%), p=0.01, respectively]. To
adjust for risk factors associated with an elevated SCr, we
conducted a logistic regression analysis. Variables known to
affect SCr were entered in a logistic regression model using
the presence or absence of SCr > 50% of baseline during
the study period as a classifying and dependent variable.
Among all of the variables that might have affected SCr,
ABLC was not found to be associated with an increase in
SCr, whereas gentamicin, dopamine, and dobutamine were
found to be associated with increased SCr levels (Table 3).
During the study period, 20% (7/35) of the patients in
the ABLC group and 20% (7/35) of those in the control
group showed a >50% increase in SCr.
To adjust for the higher BUN level at baseline in the
ABLC group, another logistic regression analysis was
conducted in which >50% increase in serum BUN was set
as the dependent variable. The ABLC was also not found to
be among the variables that might have affected serum
BUN, although xanthines were found to be protective
against azotemia (Table 4). During the study period, 26%
(9/35) of the patients in the ABLC group and 26% (9/35) of
the patients in the control group had a >50% increase in
BUN.
To adjust for risk factors associated with hypokalemia or
hyponatremia, we also conducted two logistic regression
analyses in which the classifying and dependent variables
were either hyponatremia (Na < 125 mEq/l) or hypokalemia
(K < 4.2 mEq/l) during the study period, and the risk
factors were the same as the factors used in the two
previous analyses. None of the aforementioned risk factors
or ABLC was associated with hyponatremia or hypokale-
mia: 66% (23/35) of patients in the ABLC group had
hypokalemia versus 46% (16/35) in the control group (p=
0.09), and 14% (5/35) of the patients in the ABLC group
had hyponatremia versus 6% (2/35) in the control group
(p=0.42).
During the study period, 83% (29/35) of ABLC patients
were on mechanical ventilation versus 66% (23/35) of
control patients (p=0.10). Control patients were admitted
during the same period (within days, weeks or months) as
ABLC patients. On average, control patients were admitted
to the NICU within 110±102 days of the admissions of the
ABLC patients.
Among the 35 patients who were treated with ABLC, 15
patients had Candida albicans, 14 patients had C. para-
psilosis (one patient had both C. albicans and C. para-
psilosis), and seven patients did not have an identified
organism. Twenty-two patients had a positive fungal blood
culture, 13 had a positive fungal urine culture, seven had a
positive fungal sputum culture, one patient had a positive
fungal cerebral spinal fluid culture, and five patients had
other sites that were positive for fungal infections. On
average, ABLC therapy was started on 21.46±24.64 days
of life at a dose of 5.0±0.1 mg/kg per day, and the duration
of therapy was, on average, 25.11±8.15 days (range 14–
49 days). Infants who were treated with ABLC had a
Table 2 Daily fluid intake, urine output, and serum electrolytes at baseline and at 1 week and 2 weeks in patients treated with ABLC and the
control group
Clinical parameters ABLC Control
Baseline 1 week 2 weeks Baseline 1 week 2 weeks
Total fluid (ml/kg) 141 (132–166) 150 (130–166) 141 (129–153) 148 (135–161) 150 (142–157) 148 (140–157)
Urine (ml/kg) 3.9 (3.1–4.5) 3.8 (3.0–5.2) 3.9 (3.4–5.3) 4.0 (3.0–4.7) 4.3 (3.3–5.1) 3.7 (3.2–4.5)
Blood urea nitrogen (mg/dl)a 16.0 (10–22) 17.0 (10–21) 9.0 (5.0–14.7) 10.5 (4.0–15.7) 7.5 (5.0–18.5) 8.0 (4.0–14.5)
Creatinine (mg/dl) 0.7 (0.5–1.0) 0.8 (0.5–1.0) 0.6 (0.4–0.9) 0.7 (0.5–1.0) 0.7 (0.5–1.0) 0.6 (0.4–0.8)
Na (mEq/l)b 137 (133–139) 137 (135–140) 138 (135–140) 136 (134–138) 135 (133–139) 134 (132–136)
K (mEq/l) 5.1 (4.2–5.4) 5.3 (4.2–5.5) 4.9 (4.5–5.4) 4.8 (3.9–5.5) 4.7 (4.1–5.0) 4.8 (4.4–5.5)
All values are expressed as medians and interquartile ranges
a There is a statistically significant difference in blood urea nitrogen (BUN) between ABLC patients at baseline and control patients at baseline
(p=0.03) as well as a difference within the ABLC patients between baseline and 2 weeks of treatment (p=0.01)
b There is a statistically significant difference in Na (p≤0.01) between ABLC patients at 2 weeks and control patients at 2 weeks
Pediatr Nephrol

repeated negative fungal culture 6.6±4.6 days (average)
following the initiation of the ABLC therapy (median 6
days, interquartile range 3–8 days). All patients treated with
ABLC had clearance of their fungal infections.
Discussion
We have shown that following 2 weeks of treatment with
ABLC there was no significant alteration in SCr or
electrolytes in VLBW infants. This finding is consistent
with previous reports in children and infants [6, 11, 12, 17].
Walsh et al. [6], in a study evaluating the safety and
efficacy of ABLC in pediatric patients between the age
of 21 days and 16 years, found no significant change in
the mean SCr levels, BUN, or K during 6 weeks of
treatment. Their patients included 11 infants < 6 months
of age (age 3–13 weeks, weight 0.8–5 kg) who received
ABLC, and their findings are consistent with ours. We
did not find any significant differences in SCr or K
following 2 weeks of ABLC therapy. Our patients treated
with ABLC had an elevated BUN at baseline; however,
their BUN decreased over the 2-week period of antifun-
gal therapy. In another study of six children (age
4–17 years) with hepatosplenic candidiasis and malig-
nancies, ABLC did not induce a significant change in
mean SCr throughout the 6-week course of therapy, but
one patient developed hypokalemia during the adminis-
tration of ABLC that resolved after the discontinuation of
therapy [12]. In our VLBW infants, we found no
significant differences in serum K or SCr between the
ABLC and the control group during the 2-week study
period. If we were to have followed our patients for a
longer period we may have found more patients with
significant hypokalemia. Our findings are also consistent
with those of Adler-Shohet et al., who reported an
improvement or no change in the renal function of eight
8 of 11 infants who received ABLC [17].
Different forms of amphotericin B with less nephrotox-
icity have been used in infants. Liposomal amphotericin B
(AmBisome), another lipid formulation of amphotericin B,
has been used in premature infants. Scarcella et al. [10]
reported that absence of side effects in 40 preterm infants
treated with AmBisome (mean GA age 28 weeks). Juster-
Reicher el al. [13] also found no major adverse effects in 24
VLBW infants treated with AmBisome (mean GA of
26 weeks), and Weitkamp et al. [14] reported the absence
of nephrotoxicity related to AmBisome therapy in 21
VLBW infants (GA age 23–31 weeks). In another study
of 52 preterm infants, Linder et al. showed an improvement
in renal function during treatment with three amphotericin
B preparations. They also found that K supplementation
during treatment was required in 47% of infants who were
treated with amphotericin B and in none of the VLBW
infants who were treated with liposomal amphotericin B
(n=6) and amphotericin B colloidal dispersion (n=14) [16].
To our knowledge, we are the first to report a large series of
35 VLBW infants treated with ABLC (Abelcet, a lipid
formulation of amphotericin B).
In newborn and premature infants, amphotericin B
deoxycolate has a narrow therapeutic index and can induce
nephrotoxicity that is characterized by azotemia and renal
tubular toxicity, such as renal concentrating defects,
hypomagnesemia, and increased urinary losses of K and
other elements [18–21]. Therefore, ABLC can be an
alternative to amphotericin B deoxycolate in these infants
[22].
We have previously shown that SCr decreases with
advancing GA and BW [23]. Therefore, to be able to study
the effect of ABLC on SCr that usually decreases with
advancing GA, we added a matched control group of
patients to our analysis in order to adjust for the factor of
time on SCr. However, our study has several limitations. A
significant number of our patients were also on other
medications that could have affected SCr, BUN, Na, and K
levels (such as antibiotics, diuretics, pressors, inotorops,
indomethacin, and xanthines). To adjust for the concurrent
Table 3 Adjusted odds ratio of risk factors associated with an
elevation in serum creatinine (>50% from baseline) during the study
period
Risk factors Adjusted OR 95% CI p values
ABLC 1.32 0.26–6.70 0.73
Diureticsa 2.86 0.49–16.45 0.23
Indomethacin 2.58 0.30–21.87 0.38
Gentamicin 10.85 1.12–104.91 0.03
Vancomycin 0.18 0.01–1.97 0.16
Xanthines 0.58 0.11–2.8 0.50
Dopamine/Dobutamine 7.64 1.34–43.47 0.02
OR Odds ratio; 95% CI 95% confidence interval
a Including furosemide, hydrochlorothiazide and or bumetanide
Table 4 Adjusted odds ratio of risk factors associated with serum
BUN elevation (>50% from baseline) during the study period
Risk factors Adjusted OR 95% CI p values
ABLC 1.02 0.26–4.01 0.97
Diureticsa 1.41 0.37–5.38 0.61
Indomethacin 5.69 0.83–39.00 0.07
Gentamicin 5.39 0.73–39.89 0.09
Vancomycin 0.17 0.02–1.37 0.09
Xanthines 0.23 0.05–0.96 0.04
Dopamine/dobutamine 1.04 0.18–6.01 0.96
a Including furosemide, hydrochlorothiazide and or bumetanide
Pediatr Nephrol

use of such medications during the study period, we entered
variables known to affect SCr and serum electrolytes in a
logistic regression model using the presence or absence of
an increase in SCr > 50% from baseline during the study
period as a classifying and dependent variable. Similar
logistic regression analyses were also conducted in which
the classifying and dependent variables were either an
increase in BUN > 50% from baseline or hyponatremia
(Na < 125 mEq/l) or hypokalemia (K < 4.2 mEq/l) during
the study period.
The ABLC was not found to be associated with an
increase in SCr or BUN or a decrease in Na or K. However,
xanthines were found to have a protective effect against an
elevation in BUN, a finding that could be consistent with
previous reports, whereas theophylline was found to
improve renal function in preterm infants with respiratory
distress syndrome [24], and in term infants with asphyxia
[25].
We conclude that 2 weeks of ABLC (Abelcet) does not
significantly change SCr, Na, or K levels in VLBW infants.
Treatment with ABLC also does not increase serum BUN.
Future larger studies with longer follow-ups (>2 weeks) are
needed to establish prospectively the safety of ABLC and
to compare its use to amphotericin B deoxycolate in VLBW
infants.
Financial support: None.
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