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NafE Metronidazole-Induced Acute Pancreatitis Woodrow A. Corey, Bradley N. Doebbeling, Kurtis J. Dejong, and Bradley E. Britigan

From the Department of Internal Medicine and Research Service, Veterans Administration Medical Center, and The University of Iowa College of Medicine, Iowa City, Iowa

Metronidazole was introduced in 1959 as an antiprotozoal and antibacterial agent. It has been utilized successfully in the treatment of infections caused by Trichomonasvaginalis, Giardia lamblia, Entamoebahistolytica,Bacteroides fragilis, Clostridium difficile, and other obligate anaerobic bacteria [1]. More recently, metronidazole has demonstrated efficacy in the treatment of perineal Crohn's disease [2, 3]. Adverse effects of metronidazole that havebeenreported include reversible neutropenia, mild gastrointestinal upset, metallic taste, vaginal and urethral burning, urticaria, headache, vertigo, ataxia, peripheral neuropathy, and a disulfiram-like reaction [1]. Data on metronidazolefrom studiesof animals haveraised concerns about potential mutagenicity and carcinogenicity [1, 4]. Three case reports published since 1985 describe the development of acute pancreatitis during therapy with metronidazole [5-7]. Recently, we encountered a patient who developed acute, reversible pancreatitis following metronidazole therapy for a relapse of Crohn's disease.

Case Report A 63-year-oldwoman who had a 44-year history of Crohn's disease was admitted to the hospital on 22 March 1989 because of abdominal pain. Her Crohn's disease had been relatively well controlled over the previous 9 years with use of sulfasalazine. Complications included arthritis, a rectovaginal fistula, and three previous partial small bowel resections.

Received 2 October 1990; revised 27 December 1990. Reprints and correspondence: Dr. Bradley E. Britigan, Department ofInternal Medicine, The University of Iowa, Iowa City, Iowa 52242. Reviews of Infectious Diseases 1991;13:1213-5 © 1991 by The University of Chicago. All rights reserved. 0162-0886/9111306-0047$02.00

Twelvedays before admission, the rectovaginal fistula recurred. Five days later, metronidazole (250 mg four times daily) was added to her medical regimen, which consisted of sulfasalazine, sucralfate, theophylline, naproxen, folic acid, nifedipine, isosorbide dinitrate, and salsalate. Therapy with sulfasalazine had been started 9 years earlier. All the other medications were begun at least 36 months previously. One week after initiation of metronidazole therapy, the patient developed loose watery stools and progressively severe, sharp, unremitting midepigastric abdominal pain that radiated to the back. The pain was not associated with nausea, vomiting, hematemesis, hematochezia, melena, dysuria, fever, or recent abdominaltraumaand wasnot temporallyrelatedto meals or specific foods. There was no history of pancreatic disease, hyperparathyroidism, cholecystitis, cholelithiasis, or hypertriglyceridemia. The patient denied the use of alcohol, illicit drugs, or any new medications other than metronidazole during the prior 18 months. Metronidazole had not been used previously. The physical examination revealed a thin woman in mild discomfort who had a blood pressure of 150/92 mm Hg, a pulse rate of 90, a respiratory rate of28, and an oral temperature of 36.8°C. The sclerae were not icteric. The lungs were clear, and the cardiac examination was unremarkable. The abdomen was soft and not distended, and no organomegaly or masses were detected. Bowelsounds were normal. There was diffuse abdominal tenderness, especially on deep palpation over the epigastrium, but no rebound tenderness or abdominalguardingwasnoted. Neither Cullen's signnor Turner's sign waspresent. On pelvic examinationa large rectocele with trabeculation posteriorly near the introitus was evident, althougha specificrectovaginal fistula was not identified. Results of a guaiac test of stool for occult blood were negative. Examination revealed no other abnormalities. Laboratory studiesdisclosedthe following values: amylase, 906 U/L (normal, 0-170 U/L); lipase, 2,148 U/L (normal,

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Three cases of metronidazole-induced acute pancreatitis have been reported recently in three women who were being treated for nonspecific vaginitis. We report the fourth such case in a 63-year-old woman with long-standing Crohn's disease who developed acute pancreatitis that was temporally associated with the initiation of metronidazole therapy for a rectovaginal fistula. No other risk factors for pancreatitis were identified except for possibly Crohn's disease itself. We review the literature with regard to metronidazole-induced acute pancreatitis and suggest a possible mechanism. Metronidazole should be considered as a possible cause of acute pancreatitis, and its use should be discontinued if no other risk factor is found.

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Discussion The patient's clinical presentation and hospital course are typical for acute pancreatitis. Given the lack of other described risk factors for pancreatitis and the temporal relationship between the onset of symptoms and the initiation of metronidazole therapy, it seems likely that metronidazole caused her pancreatitis. The prompt resolution of symptoms and the normalization of elevated enzyme levels following discontinuation of the drug's use provide additional support. Although sulfasalazine has also been associated with pancreatitis, its contribution to our patient's pancreatitis is very unlikely for two reasons. First, sulfasalazine had been administered for the prior 9 years and is still being administered

without any complications. Second, the use of sulfasalazine was continued throughout the entire hospitalization, during which time the pancreatitis resolved. Pancreatitis has been reported to be an independent complication of Crohn's disease [8], and the contribution of this disease as a precipitating factor cannot be entirely ruled out. The etiology of acute pancreatitis is frequently classified as idiopathic in the absence of other obvious causes; however, the failure of pancreatitis to recur over the ensuing 18 months argues against an idiopathic etiology. Endoscopic retrograde cholangiopancreatography was not performed; therefore, a structural lesion cannot be definitively ruled out, although an abdominal ultrasonogram and an abdominal CT scan did not reveal any evidence of this type of lesion. A congenital pancreatic anomaly is a potential explanation but is extremely unlikely because of the patient's age. Rechallenge with metronidazole would have provided more conclusive evidence, but it was not considered to be in the patient's best interests. In contrast to many other antibiotics, metronidazole sufficiently penetrates pancreatic tissue to reach therapeutic levels [9]. Metronidazole has not been generally recognized as a cause of drug-induced pancreatitis [10]. To the best of our knowledge, this case represents the fourth reported occurrence of metronidazole-induced pancreatitis [5-7] and is the first in a patient with Crohn's disease. All three previously reported cases of metronidazoleinduced acute pancreatitis occurred in young women who were being treated for vaginal discharge [5-7]. Two to four episodes of acute pancreatitis occurred in each patient before the possibility of drug-induced pancreatitis was considered (table 1). The duration of therapy prior to the onset of symptoms ranged from 12 hours to 37 days; the mean was 7 days, which was the duration observed in our patient. All patients reported midepigastric or right-upper-quadrant pain that frequently radiated to the back and was associated with anorexia, nausea, and vomiting. Eosinophilia was uniformly absent. An abdominal ultrasonogram and a CT scan of the abdomen typically revealed no abnormalities or demonstrated evidence of slight pancreatic edema, although endoscopic retrograde cholangiopancreatography demonstrated dilatation of the pancreatic duct in one of two patients. No long-term sequelae were noted. The authors of these case reports uniformly recommended that metronidazole should not be reused therapeutically for patients whose acute pancreatitis recurs after rechallenge. Friedman and Selby [11] retrospectively reviewed the hospitalization records of patients who received metronidazole for diagnoses of acute pancreatitis. None of the 6,485 patients who received metronidazole required hospitalization for acute pancreatitis. The upper 95 % confidence limit for metronidazole-induced pancreatitis requiring hospitalization was estimated at 4.6/10,000 metronidazole recipients and 3.9/10,000 metronidazole prescriptions. The study was therefore limited

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0-190 U/L); alkaline phosphatase, 105 lUlL (normal, 30-115 lUlL); total bilirubin, 0.3 mgldL (normal, 0.2-1.0 mg/dL); aspartate aminotransferase, 18 lUlL (normal, 0-131 lUlL); lactate dehydrogenase, 164 lUlL (normal, 100-210 lUlL); triglycerides, 89 mgldL (normal, 55-210 mgldL); and cholesterol, 142 mg/dL (normal, 140-240 mg/dL). The results of the remainder of the chemistry tests on serum including the serum calcium concentration were normal. The hemoglobin level was 12.8 gldL (normal, 11.9-15.4 g/dL); the hematocrit was 40% (normal, 35%-46%); the platelet count was 405,000/mm3 (normal, 151,000-400,000/mm3) ; and the leukocyte count was 14,600/mm3 (normal, 3,700-10,4001 mm'), with 85% neutrophils, 7% lymphocytes, 6% monocytes, 1% eosinophils, and 1% basophils. Results of urinalysis were normal. Examination and cultures of stool were negative for enteric pathogens, C. difficile toxin, and ova and parasites. Chest and abdominal roentgenograms revealed no abnormalities. Ultrasonography of the right upper quadrant demonstrated a normal gallbladder and pancreas; no biliary dilatation or cholelithiasis was detected. Computed tomography (CT) of the abdomen revealed a healthy gallbladder, a normal-sized pancreas, and no evidence of pancreatic cysts or abscesses. The use of metronidazole was discontinued upon hospitalization. Oral intake was limited to all other preadmission medications including sulfasalazine. Therapy with intravenous fluids was started, and meperidine hydrochloride and hydroxyzine were administered parenterally for pain. Within 2 days the diarrhea and abdominal pain resolved; serum levels of amylase and lipase decreased to 133 U/L and 708 U/L, respectively. By hospital day 10, amylase and lipase levels returned to baseline, and when these levels were rechecked 1 month later they were normal. In the subsequent 18months, two flares of the patient's Crohn's disease occurred; in both instances, the patient was treated with prednisone and an increased dose of sulfasalazine. Therapy with all other medications was continued at their previous dosages. The patient was not rechallenged with metronidazole, and no additional episodes of pancreatitis occurred.

RID 1991;13 (November-December)

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RID 1991;13 (November-December)

Table 1. Characteristics of patients with metronidazole-induced acute pancreatitis. [Reference]! episode [5] 1 2 [6] I 2,3,4 [7] 1 2,3 PR 1 NS

Dose interval (h)

29!F

250 NS

8 NS

23!F

250 500

8 12

8 3-7

Bacterial vaginosis Bacterial vaginosis

22!F

250 NS

8 NS

0.5 1

Unspecified vaginitis Unspecified vaginitis

63!F

250

6

7

Crohn's disease

Onset (no. of days after initiation) 1 37

Underlying disease Postpartum unspecified vaginitis Unspecified vaginitis

= not specified; and PR = present report.

to the approximately one-third to one-half of individuals who required hospitalization for severe pancreatitis. Similarly, the study did not attempt to verify the absence of pancreatitis in patients or admission to nonaffiliated hospitals. Nevertheless, evidence to date suggests that the risk of metronidazoleinduced acute pancreatitis is likely very low. No information regarding a mechanism whereby metronidazole could cause pancreatic injury is available. It is of interest that under aerobic conditions nitro heterocyclic compounds, such as metronidazole, have the potential to undergo redox cycling and yield superoxide, hydrogen peroxide, and possibly other free radicals [12]. Streptozotocin and alloxan, both redox-active compounds, are toxic to pancreatic B cells [13], and oxygen-centered free radicals have been implicated in some animal models of pancreatitis [14, 15]. However, any link between metronidazole-induced generation of free radicals and pancreatitis remains only speculative. In conclusion, metronidazole is a generally well-tolerated antimicrobial agent. Although rare, acute pancreatitis may be one of the more serious adverse effects associated with the use of metronidazole. Metronidazole should be considered as a potential cause of acute pancreatitis, and its use should be discontinued once other causes of this disease are excluded. References 1. Finegold SM. Metronidazole. Ann Intern Med 1980;93:686-7 2. Brandt U, Bernstein LH, Boley SI, Frank MS. Metronidazole therapy for perineal Crohn's disease: a follow-up study. Gastroenterology 1982;83:383-7

3. Ursing B, AIm T, Barany F, Bergelin I, Ganrot-Norlin K, Hoevels 1, Huitfeldt B, Jarnerot G, Krause U, Krook A, Lindstrom B, Nordle 0, Rosen A. A comparative study of metronidazole and sulfasalazine for active Crohn's disease: the cooperative Crohn's disease study in Sweden. n. Result. Gastroenterology 1982;83:550-62 4. Rustia M, Shubik P. Experimental induction of hepatomas, mammary tumors, and other tumors with metronidazole in noninbred Sas: MRC(W1)BR rats. 1 Natl Cancer Inst 1979;63:663-7 5. Plotnick BH, Cohen I, Tsang T, Cullinane T. Metronidazole-induced pancreatitis. Ann Intern Med 1985;103:891-2 6. Sanford KA, Mayle IE, Dean HA, Greenbaum DS. Metronidazoleassociated pancreatitis. Ann Intern Med 1988;109:756-7 7. Celifarco A, Warschauer C, Burakoff R. Metronidazole-induced pancreatitis. Am 1 GastroenteroI1989;84:958-60 8. Matsumoto T, Matsui T, Iida M, Nunoi K, Fujishima M. Acute pancreatitis as a complication of Crohn's disease. Am 1 Gastroenterol 1989;84: 804-7 9. Wallace IR, Cushing RD, Bawdon RE, Sugawa C, Lucas CE, Ledgerwood AM. Assessment of antimicrobial penetrance into the pancreatic juice in humans. Surg Gynecol Obstet 1986;162:313-6 10. Mallory A, Kern F. Drug-induced pancreatitis: a critical review. Gastroenterology 1980;78:813-20 11. Friedman GD, SelbyIV. How oftendoes metronidazole induce pancreatitis? Gastroenterology 1990;98:1702-3 12. Rao DNR, Harman L, Motten A, Schreiber 1, Mason RP. Generation of radical anions of nitrofurantoin, misonidazole, and metronidazole by ascorbate. Arch Biochem Biophys 1987;255:419-27 13. Oberley LW. Free radicals and diabetes. Free Radic BioI Med 1988; 5:113-24 14. Rutledge PL, Saluja AK, PowersRE, Steer ML. Role of oxygen-derived free radicals in diet-induced hemorrhagic pancreatitis in mice. Gastroenterology 1987;93:41-7 15. Blind PI, Marklund SL, Sterling R, Dahlgren ST. Parenteral superoxide dismutase plus catalase diminishes pancreatic edema in sodium taurocholate-induced pancreatitis in the rat. Pancreas 1988;3:563-7

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NOTE.

Individual dose (mg)

Age (y)!sex

Metronidazole-induced acute pancreatitis.

Three cases of metronidazole-induced acute pancreatitis have been reported recently in three women who were being treated for nonspecific vaginitis. W...
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