International Journal of Medical and Pharmaceutical

Case Reports
7(1): 1-5, 2016; Article no.IJMPCR.24618
ISSN: 2394-109X, NLM ID: 101648033

SCIENCEDOMAIN international
www.sciencedomain.org

Meropenem Associated Prolonged Cholestasis in

the Newborn: A Report of Two Cases
Adaobi U. Solarin1* and Olufunke M. Olugbade1
1

Department of Paediatrics and Child Health, Babcock University Teaching Hospital, Ilisan Remo,
Ogun State, Nigeria.
Authors contributions

This work was carried out in collaboration between both authors. Author AUS wrote the draft of the
manuscript and managed the literature searches. Author OMO wrote the cases and contributed to the
correction of the draft. Both authors read and approved the final manuscript.
Article Information
DOI: 10.9734/IJMPCR/2016/24618
Editor(s):
(1) Rakesh Kumar Tiwari, Chapman University School of Pharmacy, Chapman University Harry and Diane Rinker Health
Sciences Campus, Irvine, CA, USA.
Reviewers:
(1) Cucunawangsih, University of Pelita Harapan, Indonesia.
(2) Shalini Malhotra, Delhi University, India.
Complete Peer review History: http://sciencedomain.org/review-history/13736

Case Study

Received 27th January 2016

th
Accepted 7 March 2016
Published 16th March 2016

ABSTRACT
Meropenem is one of the new carbapenem antibacterial agent with wide spectrum of activity
against Gram-negative, Gram-positive and anerobic organisms. It has greatest utility in the
treatment of children hospitalized with serious bacterial infections. Despite its usefulness and
relative safety, adverse events have been documented with an overall incidence of 1%. We report
two cases of cholestasis in neonates of gestational ages 36 weeks and 32 weeks respectively who
had septicaemia and received meropenem for 14 days. These infants developed cholestasis and
deranged liver transaminases several days after the discontinuation of therapy with meropenem.
Meropenem has also been linked to rare cases of cholestatic jaundice that usually arises after 1 to
3 weeks of therapy. Most cases are mild and self-limited, but at least one instance of vanishing bile
duct syndrome related to meropenem therapy has been published.
Aims/Objectives: This report is to create awareness about this uncommon adverse effect of
meropenem. This is also important because of the increasing use of drugs such as meropenem as
a result of the problem of increasing resistance of microorganisms to commonly used antibiotics.
Methods: A descriptive report of the cases.
_____________________________________________________________________________________________________
*Corresponding author: E-mail: asolar234@gmail.com;

Solarin and Olugbade; IJMPCR, 7(1): 1-5, 2016; Article no.IJMPCR.24618

Results: Both neonates developed cholestasis with deranged liver enzymes. Resolution occurred
gradually over six weeks.
Conclusion: Meropenem remains a useful antimicrobial agent in the treatment of severe infections
with a good safety profile. However, it must be noted that although the liver injury due to this drug
may be mild and self-limiting, it may also cause a clinically apparent and protracted cholestatic
hepatitis that is self-limiting but may lead to vanishing bile duct syndrome.

Keywords: Meropenem; cholestasis; vanishing bile duct syndrome.

when given for up to 14 days [5]. These
elevations are usually transient, mild and
asymptomatic;
and rarely require dose
adjustment. Meropenem has also been linked to
rare cases of cholestatic jaundice that usually
arises after 1 to 3 weeks of therapy [5].
Immunoallergic features may be present, but are
rarely prominent. Autoantibodies are rare. Most
cases are mild and self-limited, but at least one
instance of vanishing bile duct syndrome related
to meropenem therapy has been published
[6]. Meropenem has not been reported to cause
acute liver failure. This report is to create
awareness about this uncommon adverse effect
of meropenem. This is also important because of
the increasing use of drugs such as meropenem
as a result of the problem of increasing
resistance of microorganisms to commonly used
antibiotics.

1. INTRODUCTION
Meropenem, a beta lactam drug belonging to the
carbapenem subgroup is stable against most
beta-lactamases produced by Gram-negative
bacteria and has greatest utility in treating severe
infections among hospitalized children [1].
Meropenem has a broad spectrum of activity
against many aerobic and anaerobic grampositive and gram-negative organisms, including
Staphylococcus
aureus,
Streptococcus
pyogenes, Streptococcus agalactiae, viridans
group streptococci, Enterococcus faecalis,
Pseudomonas aeruginosa, Escherichia coli,
Proteus mirabilis, Bacteroides fragilis and
Peptostreptococcus species [1].
Meropenem acts by binding to the penicillin
binding proteins and disrupting bacterial cell wall
integrity and synthesis. It penetrates well into
many body fluids including the cerebrospinal
fluids. This is the reason it has been found useful
in treatment of childhood meningitis and
infections in neutropenic children [1]. Meropenem
is primarily excreted by the kidney with about half
to three-fourths of dose excreted unchanged in
the urine and a further one-fourth excreted as a
-lactam
microbiologically
inactive
open
metabolite [2]. Meropenem is stable against
hydrolysis by human renal dehydropeptidase
(DHP-1) and concomitant administration of
cilastatin (DHP inhibitor) is not required [3].
Meropenem was approved for use in the United
States in 1996 and is currently indicated for the
treatment of severe or complicated skin, tissue,
intra-abdominal and urogenital infections as well
as sepsis due to susceptible organisms. Its use
is generally reserved for severe infections in
hospitalized children. The most commonly
reported adverse effects of meropenem from
previously published paediatric studies include
diarrhoea (3.3%4.7%), nausea and vomiting
(0.4%1%), skin rash (0.8%), glossitis (1%), and
oral thrush (1.9%) [4]. Serum aminotransferase
elevations have also been reported in 1% to
6% of recipients of intravenous meropenem

2. CASE 1
Baby A was a near-term male (Gestational Age
36 weeks) delivered by emergency Caesarean
section on account of persistent breach
presentation in a primiparous woman. Apgar
scores were 4 in 1 minute and 9 in 5 minutes and
the birth weight was 2.67 kg. The mother was
Hepatitis B surface antigen positive but
seronegative for syphilis (Venereal Disease
Research Laboratory-VDRL negative) and
Human Immunodeficiency Virus (HIV). The baby
received both hepatitis B vaccine and
immunoglobulin within 6 hours of life.
The baby was treated for hyperbilirubinemia with
exchange blood transfusion on the fifth day of life
when the Total Serum Bilirubin and Conjugated
Serum Bilirubin recorded were 21.9 mg/dl and
3.7 mg/dl respectively. Although the intial
haemograms were insignificant, the baby
developed fever (peak of 38.7C) on the fourth
day,
necessitating
blood
culture
and
commencement of empirical antibiotic treatment
with intravenous ceftazidime and amikacin. Blood
culture yielded significant growth of Klebsiella

Solarin and Olugbade; IJMPCR, 7(1): 1-5, 2016; Article no.IJMPCR.24618

Table 1. Serial results of liver function tests for baby A

Laboratory
parameters

Day 5 on
Meropenem

Day 6 on
Meropenem

Day 10 on
Meropenem
18
10
410
11.0
3.2

Day 13 after
discontinuing
Meropenem
118
170
852
10.9
6.0

Day 24 after
discontinuing
Meropenem
153
131
968
6.3
5.0

Day 33 after
discontinuing
Meropenem
45
89
163
5.7
4.5

ALT (u/L)
AST (u/L)
ALP (u/L)
TSB (mg/dl)
Conj.bil.
(mg/dl)
Unconj.
bil(mg/dl)
Tot.protein
(g/dl)
Albumin
(g/dl)
Globulin
(g/dl)

21
24
276
10.1
3.8

20
16
765
14.8
6.5

6.3

8.3

7.8

4.9

1.3

1.2

5.9

7.5

6.1

6.4

6.8

7.7

3.1

3.8

3.0

4.1

4.4

3.4

2.8

3.1

2.3

2.4

ALT- Alanine transaminase, AST- Aspartate transaminase, ALP- Alkaline Phosphatase, TSB- Total Serum Bilirubin, Conj.bilConjugated bilirubin, Unconj.bil- Unconjugated bilirubin

species with sensitivity to meropenem, amikacin,

and ciprofloxacin but resistant to ceftazidime.
Subsequently, the antibiotic therapy was
th
changed to meropenem on the 6 day of life.
Gavage feeding was commenced on the 9th day
and at this point, the initial jaundice had cleared.
The clinical state gradually improved until the
17th day of life when the baby was noticed to be
deeply jaundiced with passage of clay coloured
stools and deranged liver transaminases. With
reassuring normal findings on abdominal
ultrasound, the baby was discharged home for
furthter follow-up on out-patient basis. The
jaundice resolved after about six weeks after
discharge.

cefotaxime and amikacin on the 9th day.

Eventually, the blood culture yielded heavy
growth of Pseudomonas spp sensitive to
imipenem, levofloxacin and ceftazidime but
resistant to cefotaxime and amikacin. There was
no improvement in the clinical state of the baby
and based on the cuture and sensitivity report,
meropenem, which is more readily available
compared to iminepem, was commenced on the
17th day. Meropenem was administered for 14
days. On the 32nd day, the baby was noticed to
be icteric with the passage of pale stools. The
liver transaminases were deranged and
abdominal ultrasound showed gall bladder wall
thickening with pericholecystic halo suggestive of
cholecystitis. There was gradual resolution of
jaundice
and
normalization
of
liver
transaminases over three months. Abdominal
ultrasound repeated at a follow up visit also
showed resolution of the pericholecystic halo.

3. CASE 2
Baby OA was a preterm, very low birth weight
male
neonate
delivered
by emergency
caesarean section on account of severe
intrauterine growth restriction in a primiparous
woman with poorly controlled pregnancy-induced
hypertension at gestational age of 34 weeks. The
mother was seronegative for HIV, Hepatitis B
and VDRL. The baby was vigorous at birth with
a birth weight of 1.35 kg (less than the 10th
centile). He remained clinically stable until the 6th
day of life (post-conceptional age 34 weeks plus
6 days) when he had two documented episodes
of hyperpyrexia. He was investigated for sepsis
and empirical treatment with intravenous
cefuroxime was commenced. There was
progressive deterioration in the babys clinical
state
with
worsening
thrombocytopenia,
persistent fever and abdominal distension. The
antibiotics were empirically switched to

4. DISCUSSION
Several studies have demonstrated that
meropenem is an effective and safe treatment for
infants and children with serious infections such
as urinary tract infections, pneumonia, sepsis,
intra-abdominal infections, and skin and softtissue infections) including nosocomial infections.
[1,7,8] Meropenem is currently approved by the
Food and Drug Administration (FDA) for use in
children 3 months of age with bacterial
meningitis and/or complicated intra-abdominal
infections; however, there is substantial off-label
use of meropenem in infants <3 months of age
[9] despite the lack of adequate dosing, safety,
and efficacy data in this vulnerable group.
3

Solarin and Olugbade; IJMPCR, 7(1): 1-5, 2016; Article no.IJMPCR.24618

Table 2. Serial liver function test results for baby OA

Laboratory parameters

ALT (u/L)
AST (u/L)
ALP (u/L)
TSB (mg/dl)
Conj.bil (mg/dl)
Unconj. bil(mg/dl)
Tot.protein (g/dl)
Albumin (g/dl)
Globulin (g/dl)

Day 12 of life,
following paralytic
ileus (before
Meropenem)
38
19
110
9.9
4.0
5.9
4.0
1.9
2.1

Day 9 on
Meropenem

Day 6 after
discontinuing
Meropenem

Day 26 after
discontinuing
Meropenem

146
49
166
5.9
3.6
2.3

84
39
283
16.8
12.2
4.6
6.0
2.0
4.0

67
132
767
11.9
9.3
2.6
4.8
3.5
-

ALT- Alanine transaminase, AST- Aspartate transaminase, ALP- Alkaline Phosphatase, TSB- Total Serum Bilirubin, Conj.bilConjugated bilirubin, Unconj.bil- Unconjugated bilirubin

The experience with the use of Meropenem in

neonates is limited and its safety not fully
established. In most of the studies in neonates, a
dose similar to that recommended for children
over 3 months has been successfully used.

transaminase (AST), alkaline phosphatase (ALP)

and bilirubin were observed in 5.2%, 4.3%, 2.2%
and 0.7% respectively [12].
A large multicentre retrospective study on infants
less than 3 months old comparing safety profile
of meropenem and imipenem/cilastatin observed
fewer adverse effects in terms of seizures and
deaths in infants exposed to meropenem.
However, laboratory adverse effects were
commoner with meropenem- 6.9% had elevated
AST or ALT [13]. Another retrospective study of
53 patients aged 4 days to 20 years noted low
platelet count in 3.8% and elevated liver function
test in 7.5% [8]. The specific mechanism of
meropenem associated hepatotoxicity is unclear,
although rare cases of vanishing bile duct
syndrome in adults have been attributed to
meropenem and reversed with discontinuation of
the drug [6].

In paediatric patients, diarrhoea and rash are

among the most common clinical AEs and
elevation in hepatic transaminases among the
most common laboratory AEs reported with use
of meropenem [10]. Serum aminotransferase
elevations have been reported in 1% to 6% of
recipients of intravenous meropenem when given
for up to 14 days. These elevations are usually
transient, mild and asymptomatic; and rarely
require dose adjustment. Meropenem has also
been linked to rare cases of cholestatic jaundice
that usually arises after 1 to 3 weeks of therapy
[4].
In a study [11], most commonly reported adverse
effect included sepsis (6%), seizures (5%), and
elevated conjugated bilirubin (5%). In the same
study, an increasing trend in the alkaline
phosphatase and direct bilirubin were noted;
however, the transaminases remained within
normal values.

The rare case study [6] noted the deranged liver

function persisted over months before returning
to baseline values. Our reports presented a
similar pattern of deranged liver transaminases
persisting over several weeks to months despite
discontinuing therapy with meropenem. We did
not perform a liver biopsy on these neonates for
logistic reasons but the neonates conservatively
followed up on out-patient basis.

Most commonly reported adverse effects of

meropenem from previous published studies [4]
included diarrhoea (3.3-4.7%), nausea and
vomiting (0.4-1%), rash (0.8%), glossitis (1%)
and oral thrush (1.9%). The two cases we
presented did not have any of these findings. In a
review of 6154 patients that received
meropenem in 54 clinical trials involving more
than 900 children, although meropenem
demonstrated a favourable safety profile,
elevated alanine transaminase (ALT), aspartate

In summary, Meropenem remains a useful

antimicrobial agent in the treatment of severe
infections with a good safety profile. However, it
must be noted that although the liver injury due
to this drug may be mild and self-limiting, it may
also cause a clinically apparent and protracted
cholestatic hepatitis that is self-limiting but may
lead to vanishing bile duct syndrome.

Solarin and Olugbade; IJMPCR, 7(1): 1-5, 2016; Article no.IJMPCR.24618

Available:http://livertox.nih.gov/Meropene
m.htm
(Accessed on December 10th 2015)
It is not applicable.
6.
Schmaker AL, Okulicz JF. Meropeneminduced vanishing bile duct syndrome.
ETHICAL APPROVAL
Pharmacotherapy. 2010;30:335e-338e.
7.
Arrieta
A. Use of meropenem in the
It is not applicable.
treatment of serious infections in children:
Review of the current literature. Clin Infect
ACKNOWLEDGEMENTS
Dis. 1997;24(Suppl 2):S207-S212.
8.
Hsu HL, Lu CY, Tseng HY, Lee PI, Lai HP,
Dr. T.A. Ogunlesi is acknowledged for his useful
Lin WC, et al. Empirical monotherapy with
comments.
meropenem in serious bacterial infections
in children. Microbiol Immunol Infect.
COMPETING INTERESTS
2001;34:275-280.
9.
Clark RH, Bloom BT, Spitzer AR,
Authors have declared that no competing
Gerstmann DR. Reported medication use
interests exist.
in the neonatal intensive care unit: Data
from a large national data set. Pediatrics.
REFERENCES
2006;117:197987.
10. MERREM IV. (meropenem for injection)
[package
insert].
Wilmington,
DE:
1.
Shah D, Narang M. Meropenem (Drug
AstraZeneca
pharmaceuticals;
2007.
therapy). Indian Pediatrics. 2005;42:44311. Cohen-Wolkowiez M, Poindexter B,
450.
Bidegain M, Weitkamp J, Schelonka RL,
2.
Smith PB, Cohen-Wolkowiez M, Castro
Randolph DA, et al. Safety and
LM, Poindexter B, Bidegain M, Weitkamp
effectiveness of meropenem in infants with
J, et al. Population pharmacokinetics of
suspected or complicated intra-abdominal
meropenem in plasma and cerebrospinal
infections. Clin Infect Dis. 2012;55:1495
fluid of infants with suspected or
1502.
complicated intra-abdominal infection.
Available:http://cid.oxfordjournals.org
Pediatr Infect Dis J. 2011;30:844-849.
12. Linden P. Safety profile of meropenem: An
3.
Cojocel C. Beta lactam antibiotics. In: de
updated review of over 6000 patients
Broe ME, Porter GA, Editors. Clinical
treated with meropenem. Drug Saf.
nephrotoxin: Renal injury from drugs and
2007;30:657-68.
rd
chemicals. 3 Ed. New York: Springer 13. Hornik CP, Herring AH, Benjamin Jr DK,
science +Business Media; 2008.
Capparelli EV, Kearns GL, van den Anker
4.
Bradley JS, Faulkner KL, Klaugman KP.
J et al. On behalf of Best pharmaceuticals
Effectiveness, safety and tolerability of
for children act-pediatric trials network.
meropenem as empiric antibiotics therapy
Adverse
events
associated
with
in hospitalised pediatric patients. Pediatr
meropenem versus imipenem/cilastatin
Infect Dis J. 1996;15:749-57.
therapy in a large retrospective cohort of
hospitalized infants. Pediatr Infect Dis J.
5.
Clinical and Research information on drug
induced injury. United States Library of
2013;32:748753.
Medicine.
DOI: 10.1097/INF.0b013e31828be70b
_________________________________________________________________________________

CONSENT

2016 Solarin and Olugbade; This is an Open Access article distributed under the terms of the Creative Commons Attribution
License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.

Peer-review history:
The peer review history for this paper can be accessed here:
http://sciencedomain.org/review-history/13736