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DRUG RECORD

 

METRONIDAZOLE

OVERVIEW
Metronidazole

 

Metronidazole is a nitroimidazole derivative bactericidal agent widely used in the treatment of many anaerobic and certain protozoan and parasitic infections.  Metronidazole has been linked to rare instances of acute, clinically apparent liver injury.

 

Background

Metronidazole (met" roe nid' a zole) is a nitroimidazole antibiotic that is activated by reduction of its nitro group by susceptible organisms.  The activated form of metronidazole is a highly reactive radical anion which targets and damages large protein molecules and DNA.  Metronidazole was approved for use in the United States in 1963 and currently several million prescriptions are filled yearly.  Metronidazole is indicated for treatment and prophylaxis of infections with susceptible anaerobic bacteria and protozoa.  The recommended dosage is 500 to 750 mg taken orally three times daily for 5 to 10 days.  Metronidazole is available alone in tablets of 250, 375, 500 and 750 mg as well as in combination with other medications, in multiple generic formulations and under several brand names including Flagyl, Metryl, Noritate, Pylera and Helida.  Other formulations include injectable solutions, extended release tablets, suppositories, and topical creams.  The most common side effects include metallic taste, nausea, vomiting, abdominal discomfort and diarrhea.

 

Hepatotoxicity

Despite the wide use of metronidazole, only rare cases of hepatotoxicity have been reported, and metronidazole is not listed among causes of drug induced liver injury and acute liver failure in large case series.  High doses of metronidazole given parenterally or in an overdose can cause elevations in serum aminotransferase levels, but these are usually self-limited and minimally symptomatic (Case 1).  Acute, clinically apparent liver injury from metronidazole is rare.  Ornidazole, another synthetic nitroimidazole that was available in Europe, was implicated in several cases of drug induced liver injury, with a latency of a few days or weeks and a hepatocellular pattern of injury.  Metronidazole has been associated with a similar acute hepatitis-like syndrome with a short incubation period, but much more rarely.  Fever, rash and eosinophilia are uncommon as are autoimmune features.  A fatal recurrence of acute liver injury after reexposure to metronidazole has been published (Case 2).

 

Mechanism of Injury

The cause of acute liver injury due to metronidazole is probably immunoallergic, given the short latency period and recurrence with rechallenge.

 

Outcome and Management

The liver injury from metronidazole is rare, but can result in liver failure and death.  In typical cases, recovery is expected in 1 to 3 months.  Rechallenge results in prompt recurrence and should be avoided.

 

Drug Class:  Antiinfective Agents

 

Other Drugs in the Subclass, Nitroimidazoles:  Tinidazole

 

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CASE REPORTS
Metronidazole

 

Case 1.  Elevations in serum aminotransferase levels during intravenous metronidazole therapy.

[Modified from:  Appleby DH, Vogtland HD. Suspected metronidazole hepatotoxicity. Clin Pharm 1983; 2: 373-4. PubMed Citation]

A 58 year old man underwent prostate biopsy and cystoscopy and 32 hours later developed fever and was admitted for treatment of suspected urosepsis.  After a combination of cephalosporin and tobramycin failed to affect his course, intravenous metronidazole (500 mg every 6 hours) was added.  He had rapid clinical improvement, but then complained of abdominal pain, nausea, headache, and a metallic taste.  Metronidazole was stopped after 5 days, and he was switched on oral cefaclor.  At the same time, serum ALT and alkaline phosphatase levels were found to be elevated.  Physical exam showed slight hepatomegaly without jaundice.  Hepatitis B serology was negative.  Over the following week, the patient recovered symptomatically and was discharged home.  All laboratory tests were normal 4 weeks after stopping metronidazole.

 

Key Points

Medication: Metronidazole, 500 mg iv every 6 hours for 5 days
Pattern: Hepatocellular (R=10)
Severity: 1+ (ALT elevations without jaundice)
Latency: 5 days
Recovery: 24 days after stopping
Other medications: Cefaclor, tobramycin

Laboratory Values

Time After Starting Time After Stopping ALT (U/L) Alk P (U/L) Bilirubin (mg/dL) Other
Pre Pre 65 Prostate biopsy, cystoscopy
Fever 104 oF: cefapirin, tobramycin
0 Start iv metronidazole Continued fever
5 days 0 Stop metronidazole Started cefaclor
6 days 1 day 720 200 0.4 GGT 459
7 days 2 days 238 0.5
9 days 4 days 464 191 0.9
10 days 5 days 319
2 weeks 9 days 167 71 Discharged
4 weeks 24 days 42 80 0.3
Normal Values <42 <115 <1.2

Comment

The serum enzyme elevations were compatible with mild metronidazole hepatotoxicity, given the short latency period and rapid recovery after stopping.  The rapid onset and rapid recovery after high doses of intravenous metronidazole suggest direct hepatic injury.  However, idiosyncratic cases are also marked by short latency period and rechallenge, even with oral metronidazole should be avoided.

 

Case 2.  Acute hepatocellular injury due to metronidazole with fatal recurrence on re-exposure.

[Modified from:  Björnsson E, Nordlinder H, Olsson R. Metronidazol as a probable cause of severe liver injury. Hepatogastroenterology 2002; 49: 252-4. PubMed Citation]

A 24 year old woman was treated with metronidazole for Clostridium difficile infection after a course of penicillin for a tooth abscess.  Her diarrhea improved, but a few days later she developed nausea and vomiting followed by jaundice.  Her past medical history included asthma and frequent upper respiratory infections.  Laboratory tests showed total bilirubin of 7.9 mg/dL with marked elevations in serum aminotransferase levels, but modest increase in alkaline phosphatase (Table).  Tests for hepatitis A, B ad C and for autoantibodies were negative.  An ultrasound showed no evidence of biliary obstruction.  Metronidazole was discontinued and she began to improve, but her recovery was slow and symptoms persisted for at least two months and laboratory tests did not return to normal for at least nine months.  Two years later, she was treated for bacterial vaginitis with metronidazole and tetracycline and one week later developed nausea, vomiting and jaundice.  Serum bilirubin was 12.2 mg/dL, ALT and AST were more than 100 fold elevated, and prothrombin index was <9%.  She was transferred to a liver transplant center where she developed progressive hepatic coma.  Tests for hepatitis A, B and C were again negative.  She underwent liver transplantation, but died in the perioperative period.  Explant showed massive hepatic necrosis and cholestasis.

 

Key Points

Medication: Metronidazole (dose and duration not given)
Pattern: Hepatocellular (R=62)
Severity: 3+ initially (jaundice and hospitalization)
5+ on reexposure (liver transplantation, death)
Latency: ~5-10 days
Recovery: 10 months after initial exposure
Other medications: Oral tetracycline

Laboratory Values

Time After Starting Time After Stopping ALT* (U/L) Alk P* (U/L) Bilirubin *(mg/dL) Other
0 Metronidazole given for C difficile
~10 days 0 5282 606 7.9
15 days 5 days 3000 500 20.1
1 mo 1 mo 104 450 10.5
2.5 mos 2.5 mos 102 492 1.0
9 mos 9 mos 84 <300 1.0
26 mos Metronidazole given for bacterial vaginitis
~7 days 0 11104 810 12.2 Protime index < 9%
~10 days ~3 days 20.5 Liver transplant, post-operative death
Normal Values <42 <300 <1.2

*Values estimated from Figure 1. Bilirubin results converted from mol to mg/dL (17.1) and enzyme results converted from kat to U/L (0.01667).

 

Comment

Severe acute hepatocellular injury from a short course of metronidazole with slow recovery, followed by tragic rapid and fatal recurrence on reexposure.

 

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PRODUCT INFORMATION
Metronidazole

 

REPRESENTATIVE TRADE NAMES
Metronidazole – Generic, Flagyl®

 

DRUG CLASS
Antiinfective Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH


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DRUG CAS REGISTRY NO MOLECULAR FORMULA STRUCTURE
Metronidazole
443-48-1
C6-H9-N3-O3 Metronidazole  chemical structure

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REFERENCES
Metronidazole

 

References Last Updated:  14 February 2014

  1. Zimmerman HJ. Amebicides.  Hepatic injury from antimicrobial agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, p. 592.  (Expert review of liver injury published in 1999 mentions that metronidazole has only rarely been incriminated in causing liver injury).

  2. Moseley RH. Hepatotoxicity of antimicrobials and antifungal agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 463-82.  (Review of hepatotoxicity of antibiotics does not discuss metronidazole).

  3. Phillips MA, Stanley SL Jr.  Chemotherapy of protozoal infections.  In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1423-41.  (Textbook of pharmacology and therapeutics).

  4. Fagin ID. Jaundice associated with metronidazole. JAMA 1965; 193: 1128. Not in PubMed  (46 year old man developed fever after 4 days of metronidazole [250 mg/day] and he was given an injection of penicillin; 6 days later, he developed jaundice [bilirubin 5.4 mg/dL, AST 143 U/L, Alk P 1.5 times ULN], resolving in 2 months).

  5. Bonfiglio G, Donadio G. Results of the clinical testing of a new drug metronidazole in the treatment of chronic alcoholism. Br J Addict 1967; 62: 249-55.  (Open label trial of metronidazole [750 mg daily] in 60 patients with alcoholism for up to 45 days, most patients had flushing response to alcohol; no mention of hepatotoxicity or ALT elevations).

  6. Prospective, randomized comparison of metronidazole and clindamycin, each with gentamicin, for the treatment of serious intra-abdominal infection. Surgery 1983; 93 (1 Pt 2): 221-9. PubMed Citation  (Multicenter study comparing clindamycin to metronidazole in 186 patients with severe infections; similar efficacy, AST elevations in 18% on metronidazole vs 10% on clindamycin, but no frank hepatitis or discontinuation for liver injury).

  7. Appleby DH, Vogtland HD. Suspected metronidazole hepatotoxicity. Clin Pharm 1983; 2: 373-4. PubMed Citation  (58 year old man with urosepsis developed ALT [735 U/L] and Alk P [238 U/L] elevations without jaundice after 4 days of iv metronidazole, resolving in 1 week; also received tobramycin and cefapirin: Case 1).

  8. Uchihara M, Maeda M, Koyama W, Sakamoto S, Kanayama M. A case of metronidazole-induced liver injury. Acta Hepatol Jpn 1984; 25: 1612-5.  (35 year old man developed fever, abdominal discomfort, eosinophilia and enzymes elevations [bilirubin 1.6 mg/dL, ALT 478 U/L, Alk P 469 U/L] after 2 weeks of oral metronidazole, with positive lymphocyte stimulation test, recovery in 4 weeks).

  9. Smilack JD, Wilson WR, Cockerill FR 3rd. Tetracyclines, chloramphenicol, erythromycin, clindamycin, and metronidazole. Mayo Clin Proc 1991; 66: 1270-80. PubMed Citation (Review of uses and toxicities of antibiotics; no mention of hepatotoxicity of metronidazole).

  10. Hestin D, Hanesse B, Frimat L, Trechot P, Netter P, Kessler M. Metronidazole-associated hepatotoxicity in a hemodialyzed patient. Nephron 1994; 68: 286. PubMed Citation  (68 year old woman developed nausea and right upper quadrant pain after 1 week of oral metronidazole therapy; ALT 650 U/L but no jaundice, resolved within 15 days of stopping).

  11. Lam S, Bank S. Hepatotoxicity caused by metronidazole overdose. Ann Intern Med 1995; 122: 803. PubMed Citation  (58 year old woman took an overdose of metronidazole ~12.5 g and developed asymptomatic rise in ALT [to 2570 U/L], AST [6120 U/L], but minimal increase in Alk P [95 U/L] and bilirubin [2.1 mg/dL], levels peaking 2-3 days after overdose and resolving to normal within 4 weeks).

  12. Kosar Y, Sasmaz N, Oguz P, Kacar S, Erden E, Parlak E, Akdogan M. Ornidazole-induced autoimmune hepatitis. Eur J Gastroenterol Hepatol 2001; 13: 737-9. PubMed Citation  (35 year old woman developed jaundice within a few days of starting oral ornidazole [bilirubin 17 mg/dL, ALT 1140 U/L, Alk P 145 U/L, SMA 1:1280], responding to corticosteroids and no relapse when stopped, but retreated with ornidazole and promptly redeveloped similar clinical picture with rise in SMA from 1:80 to 1:1280).

  13. Björnsson E, Nordlinder H, Olsson R. Metronidazol as a probable cause of severe liver injury. Hepatogastroenterology 2002; 49: 252-4. PubMed Citation  (24 year old woman treated with metronidazole for pseudomembraneous colitis developed symptoms and jaundice a few days later with progression to acute hepatitis [bilirubin 7.9 mg/dL, ALT 100 times ULN, Alk P 2 times ULN], with slow and incomplete recovery, and relapse and acute liver failure with retreatment with metronidazole 2 years later, the explant showing massive necrosis: Case 2).

  14. 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: 351-4. PubMed Citation  (Ornidazole, a nitroimidazole derivative similar to metronidazole, was linked to 3 cases of acute hepatitis, in women, ages 25-50 years, arising after 3-4 days of therapy with ALT 977, 3042 and 1160 U/L; Alk P 1062, 422 and 431 U/L; bilirubin 32, 48 and 10 mg/dL, resolving in 1-2 months, no autoantibodies or allergic findings; 6 cases in literature, 4 icteric, 1 fatal).

  15. Orion E, Matz H, Wolf R. The life-threatening complications of dermatologic therapies. Clin Dermatol 2005; 23: 182-92. PubMed Citation  (Review of serious complications of medications of skin disorders, mentions hepatotoxicity of metronidazole briefly).

  16. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of druginduced liver disease in the US collected from 2004 to 2008, no case was attributed to metronidazole).

  17. Hussein R, El-Halabi M, Ghaith O, Jurdi N, Azar C, Mansour N, Sharara AI. Severe hepatotoxicity associated with the combination of spiramycin plus metronidazole. Arab J Gastroenterol 2011; 12: 44-7. PubMed Citation  (Three men, ages 22 to 41 years, developed jaundice “a few weeks” to 2 months after treatment with a fixed combination of spiramycin and metronidazole [Rodogyl] for dental infections [bilirubin 28, 8.0 and 11.3 rising to 24 mg/dL, ALT 210, 1900 and 188 U/L, Alk P 109 and 344 U/L], one recovering spontaneously, one treated with prednisone and one undergoing emergency liver transplantation).

  18. Kancherla D, Gajendran M, Vallabhaneni P, Vipperla K. Metronidazole induced liver injury: a rare immune mediated drug reaction. Case Rep Gastrointest Med 2013; 2013: 568193. PubMed Citation  (54 year old man developed jaundice a few weeks after a 2 week course of metronidazole for Clostridium difficile associated diarrhea [bilirubin 7.2 mg/dL, ALT 973 U/L, Alk P 96 U/L, INR 1.9], with a severe and prolonged course, corticosteroid therapy, but eventual recovery).

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OTHER REFERENCE LINKS
Metronidazole
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