Metronidazole Toxicity in Cockayne
Syndrome: A Case Series
Brian T. Wilson, MBBS, PhD, MRCPCHa,b, Andrew Strong, BScb, Sean O’Kelly, BScb, Jennifer Munkley, PhDb,
Zornitza Stark, BM, BCh, FRACPc
abstract
a
Northern Genetics Service, Newcastle Upon Tyne NHS
Foundation Trust, and bInstitute of Genetic Medicine,
Newcastle University, International Centre for Life,
Newcastle Upon Tyne, United Kingdom; and cVictorian
Clinical Genetics Services, Murdoch Childrens Research
Institute, Melbourne, Australia
Dr Wilson designed the study, collected and analyzed
clinical data, and drafted the initial manuscript;
Mr Strong and Mr O’Kelly carried out laboratory
analyses and critically reviewed the manuscript;
Dr Munkley supervised laboratory experiments and
critically reviewed the manuscript; Dr Stark
identified patients, collected clinical data, and
reviewed and revised the manuscript; and all
authors approved the final manuscript as
submitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2015-0531
DOI: 10.1542/peds.2015-0531
Accepted for publication May 11, 2015
Address correspondence to Brian T. Wilson, MBBS,
PhD, Northern Genetics Service & Institute of
Genetic Medicine, Newcastle University, International
Centre for Life, Newcastle upon Tyne, NE1 3BZ, UK.
E-mail: brian.wilson@ncl.ac.uk
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
Copyright © 2015 by the American Academy of
Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated
they have no financial relationships relevant to this
article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have
indicated they have no potential conflicts of interest
to disclose.
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CASE REPORT
Cockayne syndrome (CS) is a rare genetic disorder characterized by small
stature, intellectual disability, and accelerated pathologic aging. Through the
Cockayne Syndrome Natural History Study, we have identified 8 cases of acute
hepatic failure after metronidazole administration (8% of our cohort), 3 of
which were fatal. The interval between initial administration and death was 6
to 11 days. Two of these patients also experienced acute neurologic deficit.
Both hepatotoxicity and acute neurologic deficit have been reported
previously as extremely rare adverse events after metronidazole
administration. However, we have not identified any patients with CS who
have received metronidazole without serious adverse effects. We recommend
that a diagnosis of CS be considered an absolute contraindication to the use of
metronidazole.
Cockayne syndrome (CS) is a rare, Clostridium difficile toxin assay was
autosomal recessive disorder negative, that is, there was no evidence
characterized by small stature, of infection. He received empirical
intellectual disability, and features intravenous metronidazole, 10 mg/kg
representing accelerated pathologic every 6 hours for 2.5 days, then 7.5
aging.1 The mean age at death is 8.4 mg/kg every 6 hours for an additional
years (B.T.W., unpublished data); 3.5 days. No other systemic medication
rarely, patients survive .30 years. was given. His diarrheal symptoms
Through the Cockayne Syndrome resolved, and he was discharged. He
Natural History Study, we have presented the next day generally
identified 8 cases of acute hepatic unwell, with jaundice and steatorrhea.
failure after metronidazole Liver function tests were markedly
administration (representing 8% of our deranged (Table 1). Coagulation was
cohort), 3 of which were fatal. Detailed also grossly abnormal. Serology for
information was available for 4 hepatitis B surface antigen, hepatitis C,
patients. Metronidazole-induced enterovirus, and adenovirus were
hepatotoxicity is extremely rare. Our
negative. Urine, blood, endotracheal,
series more than doubles the number and ascitic cultures were negative.
of cases reported. We have not Methicillin-resistant Staphylococcus
identified any patients with CS who aureus screen was normal. He
have received metronidazole without developed shock and was intubated,
adverse effects. but intensive therapy proved futile. He
Patient 1 was a 19-month-old boy with died 11 days after initial metronidazole
CS who underwent elective Nissen administration. Postmortem
fundoplication with gastrostomy for examination identified extensive
gastroesophageal reflux. After hepatic necrosis to be the cause of
discharge, he developed diarrhea. Stool death. There was no suggestion of liver
culture was negative, and although an sepsis. Variable loss of hepatocytes was
antigen test was positive, the seen throughout the liver, with
PEDIATRICS Volume 136, number 3, September 2015
 extensive fibrosis in severely affected bacterial overgrowth (ie, loose stools
International Normalized areas and lobular fibrosis between with no objective evidence of

[0.8–1.2]
[0.8–1.2]
[0.8–1.2]
[0.8–1.2]
Ratio remaining hepatocytes. infection). Hepatic function was
6·24
Patients 2 and 3 were twin women, deranged, with bilirubin and alanine

1.4
.10
.10 aged 18 years, who had insulin- aminotransferase improving,
dependent diabetes as part of their although g-glutamyl transferase and
CS. They were treated with empirical activated partial thromboplastin time
oral metronidazole every 8 hours in peaked 2 weeks after admission
Activated Partial Thromboplastin

the community for loose stools, (Fig 1A). During admission, she had
pending results of investigations for a neurometabolic stroke, with
hemiparesis and acute on chronic
[24–36]
[27–39]
[27–39]
[24–34]

gastrointestinal infection. These were

Time (s)

negative. After 2 days, blood glucose swallowing difficulties, resulting in

measurements became elevated and likely aspiration pneumonia. MRI
55
53
50
43

difficult to control, leading to could not be performed; head

admission on day 4 of metronidazole computed tomography scan showed
therapy. On admission, both patients no acute changes. This patient
were given a loading dose of 15 mg/ survived.
Alkaline phosphatase

kg intravenous metronidazole, An additional 4 patients received

[85–360]
[30–120]
[30–120]
[35–104]

followed by 7.5 mg/kg every 8 hours. empirical metronidazole for

(U/L)

Liver enzymes were elevated on presumed gastrointestinal infection

admission (Table 1) but were thought and became systemically unwell, with
848
300
273
309

to be secondary to ischemic damage liver signs. One patient also became

in the context of metabolic acidosis acutely nonambulant; this condition
g-Glutamyl Transferase

and shock. Both patients deteriorated gradually resolved over the next year.
rapidly. Again, intensive therapy Liver function gradually recovered
188 [0–40]
159 [0–40]
388 [5–40]

proved futile. The sisters died within after early cessation of metronidazole
(U/L)
ND

4 hours of each other, 6 days after therapy.

initial administration of Given this unprecedented adverse
metronidazole. drug reaction to metronidazole
Patient 4 is a 21-year-old woman who among patients with CS, we evaluated
Aspartate Aminotransferase

developed jaundice 2 weeks after the effect of this medication on

becoming generally unwell after 3 patient and control fibroblasts. Using
3561 [5–105]

days of 400 mg twice-daily oral trypan blue, we found a significant

(U/L)

ND
ND
ND

metronidazole for gastrointestinal decrease in the proportion of viable

TABLE 1 Liver Function and Coagulation Profiles, Patients 1–4
Alanine Aminotransferase

Laboratory reference ranges appear in brackets, [n]. ND, not done.

[7–110]
[5–30]
[5–30]
[0–40]
(U/L)
3004
6206
.2000
544
[0.1–1 (,0.6)]a
Total (direct) Bilirubin

[0–15 (,5)]b
[0–15 (,5)]b
[1–17]b

FIGURE 1
A, Close monitoring of liver function tests in patient 4 after admission (ie, 2 weeks after oral
7.5 (6.7)
37 (34)
33 (28)
121

metronidazole). Normal ranges appear in Table 1. B, Viability of fibroblasts grown in the presence of
5 mg/mL metronidazole: normal controls (NHDFs and 1BR.3, open symbols) and patients with CS
(ENG027 and ENG028, closed symbols). Topical metronidazole preparations are typically 7.5 mg/mL.
b In mmol/L.

Values represent mean 6 SEM for 3 repeats. *Significantly different from controls at day 4 (P , .005
a In U/L.
Patient

using a 2-tailed Student’s t test). ALT, alanine aminotransferase; APTT, activated partial thrombo-
plastin time; GGT, g-glutamyl transferase.
1
2
3
4

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PEDIATRICS Volume 136, number 3, September 2015 e707
CS versus control cells after 4 days of
treatment with 5 mg/mL
metronidazole (Fig 1B), consistent
with the time frame of deterioration
in our patients.
Loose stools, with or without
coexisting constipation, are common
in CS (B.T.W., unpublished data),
affecting ∼30% of patients and
occurring independently of
gastrointestinal infection. Given the
lack of comprehensive information on
the natural history and management
of CS, it is not surprising that in some
cases new-onset diarrhea has been
managed preemptively, to prevent
clinical deterioration while laboratory
investigations seeking objective
evidence of infection are carried out.
For most patient groups, this course
of action would be considered the
most prudent, with minimal risk to
the patient. Metronidazole is
a synthetic nitroimidazole, widely
used to treat anaerobic gut infections.
It has an excellent safety profile. A
handful of cases of metronidazole-
induced hepatotoxicity have been
reported previously, usually
associated with ethanol intake.2
Hepatotoxicity has been reported for
the related drug ornidazole, in the
absence of ethanol, suggesting that in
some patients an alternative
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e708
mechanism may be responsible.
Neurotoxicity is more widely
recognized after metronidazole
administration, and onset may be
delayed by several weeks.3,4 This
neurotoxicity produces acute changes
on T2-weighted MRI of the brain,
particularly in cerebellum and basal
ganglia. Interestingly, patients with CS
commonly experience hepatic and
cerebellar decline (B.T.W.,
unpublished data). This is the first
disorder-specific adverse drug
reaction reported in this class of
drugs and therefore probably is
a consequence of the underlying
pathology of CS. Our experimental
data indicate that this is a generalized
rather than tissue-specific
phenomenon. Additional
investigation may lead to an
improved understanding of the
biology of this class of drugs.
CONCLUSIONS
Metronidazole is contraindicated in
CS, and intravenous administration
may be fatal. Drugs in the same class
should be avoided or used only with
extreme caution and close monitoring
of liver function and coagulation. This
monitoring should continue 2 to 4
weeks after last administration.
ACKNOWLEDGMENTS
We thank all affected families for
supporting publication. Ethical
approval for the Cockayne Syndrome
Natural History study was granted by
the NRES Committee North East,
Newcastle and North Tyneside 2.
Written consent was obtained from
all families for participation and
publication of clinical information.
ABBREVIATION
CS: Cockayne syndrome
REFERENCES
1. Nance MA, Berry SA. Cockayne syndrome:
review of 140 cases. Am J Med Genet.
1992;42(1):68–84
2. Tabak F, Ozaras R, Erzin Y, Celik AF, Ozbay G,
Senturk H. Ornidazole-induced liver
damage: report of three cases and review
of the literature. Liver Int. 2003;23(5):
351–354
3. Kuriyama A, Jackson JL, Doi A, Kamiya T.
Metronidazole-induced central nervous
system toxicity: a systematic review. Clin
Neuropharmacol. 2011;34(6):241–247
4. Woodruff BK, Wijdicks EF, Marshall WF.
Reversible metronidazole-induced lesions
of the cerebellar dentate nuclei. N Engl
J Med. 2002;346(1):68–69
WILSON et al
 Metronidazole Toxicity in Cockayne Syndrome: A Case Series
Brian T. Wilson, Andrew Strong, Sean O'Kelly, Jennifer Munkley and Zornitza Stark
Pediatrics 2015;136;e706
DOI: 10.1542/peds.2015-0531 originally published online August 24, 2015;

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 Metronidazole Toxicity in Cockayne Syndrome: A Case Series
Brian T. Wilson, Andrew Strong, Sean O'Kelly, Jennifer Munkley and Zornitza Stark
Pediatrics 2015;136;e706
DOI: 10.1542/peds.2015-0531 originally published online August 24, 2015;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/136/3/e706

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