Acute pancreatitis following doxycycline and ornidazole coadministration.

Abstract

Drugs are related to the etiology of acute pancreatitis in approximately 1.4-2.0% of cases. Although antibiotics constitute a small number of the drugs suspected, tetracycline is the most encountered antibiotic among those drugs.
A 33-year-old woman was admitted to the emergency room complaining of nausea and abdominal pain after the use of doxycycline 500 mg and ornidazole 500 mg twice daily for three days for a vaginal infection. She experienced epigastric pain, which worsened over time and radiated to her back. After a detailed evaluation, she was diagnosed as having mild acute pancreatitis which improved with medical treatment. All other possible causes of pancreatitis were eliminated.
Antibiotic-associated pancreatitis usually has a silent and mild course. To the best of our knowledge the literature reports only two cases of doxycycline-induced acute pancreatitis reported and there are no reports of pancreatitis associated with ornidazole. Our case is the first case reported in which doxycycline and ornidazole coadministration induced acute pancreatitis.

Full text

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JOP. J Pancreas (Online) 2010 Nov 9; 11(6):614-616.
JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 11, No. 6 - November 2010. [ISSN 1590-8577]
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CASE REPORT


Acute Pancreatitis Following Doxycycline and
Ornidazole Coadministration


Serkan Ocal1, Haldun Selçuk1, Murat Korkmaz1, Hakan Unal2, Uğur Yilmaz1


1Department of Gastroenterology, Baskent University. Ankara, Turkey.
2Department of Gastroenterology, Baskent University. Istanbul, Turkey


ABSTRACT
Context Drugs are related to the etiology of acute pancreatitis in approximately 1.4-2.0% of cases. Although antibiotics constitute a
small number of the drugs suspected, tetracycline is the most encountered antibiotic among those drugs. Case report A 33-year-old
woman was admitted to the emergency room complaining of nausea and abdominal pain after the use of doxycycline 500 mg and
ornidazole 500 mg twice daily for three days for a vaginal infection. She experienced epigastric pain, which worsened over time and
radiated to her back. After a detailed evaluation, she was diagnosed as having mild acute pancreatitis which improved with medical
treatment. All other possible causes of pancreatitis were eliminated. Conclusions Antibiotic-associated pancreatitis usually has a
silent and mild course. To the best of our knowledge the literature reports only two cases of doxycycline-induced acute pancreatitis
reported and there are no reports of pancreatitis associated with ornidazole. Our case is the first case reported in which doxycycline
and ornidazole coadministration induced acute pancreatitis.

INTRODUCTION

The frequent use of multiple drugs increases the risk of
drug-induced pancreatitis [1, 2, 3, 4]. Detailed
information regarding antibacterial drug-induced acute
pancreatitis published in 2005 reported that 34 cases of
them were related to tetracycline, 24 cases to
trimethoprim/sulfamethoxazole, 25 cases to rifampin ,
11 cases to erythromycin and sporadic cases were
induced by metronidazole, isoniazid and amoxicillin-
clavulanic acid [4]. There were two cases of
doxycycline-induced acute pancreatitis [3, 5]. We do
not have additional information about the course of the
disease and the final status of the patient. We could not
find any cases of ornidazole-induced pancreatitis in
literature. Our case is the first with detailed patient
information regarding doxycycline- and/or ornidazole-
induced acute pancreatitis.

CASE REPORT

A 33-year-old female patient was admitted to the
emergency room complaining of nausea and abdominal
pain after the use of doxycycline 500 mg and
ornidazole 500 mg twice daily for three days for a
vaginal infection. She experienced abdominal pain in
the epigastric region which radiated to her back and
worsened with time.
Upon admittance to the emergency room, she had
stable vital signs. Her body temperature was 36.7°C,
blood pressure 120/80 mmHg and pulse rate was 88
min-1. She experienced pain during epigastric palpation
and had slightly diminished bowel sounds. Her
physical examination was otherwise normal.
Her laboratory values are shown in detail in Table 1.
Serum liver and renal function values were all in the
normal range with elevated serum amylase and lipase
levels: 220 U/L (reference range: 30-110 U/L) and 595
U/L (reference range: 13-60 U/L), respectively. Serum
total cholesterol and triglyceride levels were 128
mg/dL (reference range: 130-200 mg/dL) and 130
mg/dL (reference range: 50-160 mg/dL), respectively.
She had normal levels of serum calcium (8.8 mg/dL;
reference range: 8.5-10.5 mg/dL) and total bilirubin
(0.3 mg/dL; reference range: 0.2-1.2 mg/dL) with a
slightly elevated CRP level (11.5 mg/L; reference
range: 0-10 mg/L). She had no signs of viral infection,
no history of trauma or alcohol use and no family
history of pancreatic diseases.
Upper abdominal ultrasonography revealed normal
images of the pancreas, liver, gallbladder and intra-
extrahepatic bile ducts. The pancreas was also assessed
as normal by abdominal-computed tomography.
The ornidazole and doxycycline were discontinued and
supportive medical treatment was begun. Her
Received July 11th, 2010 - Accepted August 9th, 2010
Key words Drug toxicity; Pancreatitis /etiology
Correspondence Hakan Unal
Kisikli Caddesi, Oymaci sokak No: 7, Altunizade-Uskudar-
İstanbul, Turkey
Phone: +90-216.554.1500; Fax: +90-216.651.9858
E-mail: hakan75unal@yahoo.com
Document URL http://www.joplink.net/prev/201011/02.html

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symptoms decreased after the first day and were
completely resolved after two days. Her serum
amylase, lipase and CRP levels returned to normal after
three days.

DISCUSSION

Drug-induced pancreatitis constitutes 1.4% of all
causes of acute pancreatitis. Mallory and Kern [6]
developed diagnostic criteria for evaluating drug-
induced pancreatitis in 1980. These criteria can be
summarized as: 1) the pancreatitis develops during
drug therapy; 2) all other possible causes of
pancreatitis should be eliminated; 3) the pancreatitis
should resolve after discontinuing the suspected drug;
and 4) the re-appearance of pancreatitis after using the
same drug. Drug induced pancreatitis can be classified
as definite, highly probable or weakly probable in
accordance with those criteria.
In our patient, the acute pancreatitis developed three
days after the administration of doxycycline and
ornidazole and was resolved three days after
discontinuation of the drugs. All other possible factors,
such as alcohol use, gallstones, hypercalcemia,
hyperlipidemia, family history and malignancy were
eliminated by means of physical examination, blood
chemistry tests and radiodiagnostic imaging modalities.
The period between the start of the antibiotic therapy
and the development of acute pancreatitis is variable
and has been reported as 1-37 days for metronidazole
[7], the 5th day of clarithromycin use [8] and
immediately after isoniazid use [9]. Drug-induced
pancreatitis developed on the third day of antibiotic use
in our patient. As reported previously, our patient
experienced a mild course of acute pancreatitis, which
was resolved spontaneously with supportive care in a
few days.
Other predictable adverse effects of doxycycline are
the elevation of liver and renal function tests, diarrhea,
nausea, vomiting and dysphagia while ornidazole has
prominent neurologic side effects. Doxycycline is part
of the tetracycline group of antibiotics. One case of
demeclocycline [10] and four cases of minocycline [11,
12], also members of the tetracycline group, have been
linked to acute pancreatitis cases. More interestingly,
Papaioannides et al. reported a case of brucellosis-
induced acute pancreatitis which was resolved after
doxycycline treatment [13]. It is well known that
pancreatic phospholipase A2 contributes to the tissue
damage associated with acute pancreatitis. Since, in
experimental models, lipophilic tetracyclines, such as
minocycline and doxycycline, are anti-inflammatory,
Pruzanski et al. examined their effects on pancreatic
phospholipase A2 activity using two assay systems in
vitro [14]. They found that minocycline and, to a lesser
degree, doxycycline were markedly inhibitory to both
pancreatic and non-pancreatic phospholipase A2. The
possible protective mechanism of doxycycline in acute
pancreatitis may be elucidated by inhibiting pancreatic
phospholipase A2.
We did not recognize any abnormalities related to
acute pancreatitis, such as pancreatic edema or
peripancreatic fluid, during radiologic investigations.
The only reported doxycycline-induced
pancreatitis case did not have any data regarding
laboratory or radiologic imaging while two of the
seven metronidazole-induced acute pancreatitis cases
revealed radiologic abnormalities [7].
Steinberg and Tenner initially classified drug-induced
pancreatitis as associated with intrinsic toxins versus
idiosyncratic reactions following the well-known
classification of drug-induced liver diseases [1]. The
authors hypothesized that the direct toxic effect of free
oxygen radicals on pancreatic beta cells, and
immunologic and metabolic injury of the pancreatic
duct could be the possible
metronidazole-induced acute pancreatitis [7]. We did
not recognize any data in the literature regarding the
mechanisms of how doxycycline and ornidazole cause
acute pancreatitis.
In conclusion, we think that our case is unique and
interesting because it is probably the first case of
doxycycline- and/or ornidazole-induced
pancreatitis. Although it is likely that this patient
suffered from acute pancreatitis due to doxycycline and
ornidazole since other causes of pancreatitis were
eliminated, it is difficult to conclude which drug was
the main culprit since re-challenge is not ethical and
might harm the patient. Although the precise incidence
of this adverse effect is not well known, it is probably
quite rare. Physicians should consider checking serum
amylase and lipase levels for patients who develop
nausea, vomiting and epigastric pain when taking
doxycycline and/or ornidazole. It is important to
consider doxycycline and/or ornidazole as a possible
acute
mechanisms of
acute
Table 1. Patient laboratory values.
Parameters On admission Day 2 Day 4 Reference range
CRP (mg/L) 11.5 19.8 5.1 0-10
Amylase (U/L) 232 144 78 30-110
Lipase (U/L) 595 215 73 13-60
ALT (U/L) 10 15 10 0-40
AST (U/L) 13 30 14 0-41
BUN (mg/dL) 10 12 - 6-21
Creatinine (mg/dL) 0.55 0.62 - 0.5-1.4
Hemoglobin (g/dL)
WBC (mm-3)
Platelets (mm-3)
11.4 11.5 11.3 13.5-18.0
10,100 9,800 7,980 4,500-11,000
255,000 256,000 255,000 150,000-400,000

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etiology for acute pancreatitis in patients presenting
with gastrointestinal symptoms, even after a few days
of doxycycline and/or ornidazole exposure. If
doxycycline and/or ornidazole are suspected as the
causative agent, they should then be discontinued and
rechallenge should be avoided.

Conflict of interest The authors have no potential
conflict of interest

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