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Metronidazole is an antiprotozoal and antibacterial medication used mainly in the treatment of infections caused by susceptible organisms, particularly anaerobic bacteria (organism which does not require oxygen for growth) and protozoa. It is marketed by Pfizer under the trade name Flagyl in the US, while Sanofi-Aventis markets metronidazole globally under the same tradename, Flagyl, and also by various generic manufacturers, who sell it at a cheaper price.

Metronidazole was synthesized by France's Rhone-Poulenc laboratories and introduced in the mid-1950s under the brand name Flagyl. It was the first of the group of drugs that are now called nitroimidazoles. In the US it was licensed to Searle.

Metronidazole is one of the rare examples of a drug developed against a parasite which has since gained broad use as an antibacterial agent. Briefly, at Rhone-Poulenc labs, extracts of Streptomyces spp. were screened for activity against Trichomonas vaginalis, a cause of vaginal itching. Azomycin, a nitroimidazole, was identified, and metronidazole, a synthetic derivative, was used to treat chronic trichomonad infections, beginning in 1959.

The antibacterial activity of metronidazole was discovered by accident in 1962 when metronidazole cured a patient of both trichomonad vaginitis and bacterial gingivitis. However, it was not until the 1970s that metronidazole was popularized for treatment of infections caused by gram-negative anaerobes such as bacteroides or gram-positive anaerobes such as clostridia.

Presently, metronidazole, which is inexpensive, has good tissue penetration, and produces relatively mild side effects, is on the formulary at most hospitals for prophylaxis against anaerobic infection after bowel surgery, for treatment of wound abscess, and for treatment of antibiotic-associated colitis caused by Clostridium difficile. Metronidazole is an important part of combination therapy against Helicobacter pylori, a major cause of gastritis and a risk factor for stomach cancer.

The nitroimidazole antibiotic metronidazole has a limited spectrum of activity that encompasses various protozoans and most Gram-negative and Gram-positive anaerobic bacteria. Metronidazole has activity against protozoans like Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis, for which the drug was first approved as an effective treatment.

Metronidazole is indicated for the treatment of the following infections due to susceptible strains of sensitive organisms:

• Trichomoniasis: symptomatic, asymptomatic, asymptomatic consorts
• Amebiasis: acute intestinal amebiasis (amebic dysentery) and amebic liver abscess
• Anaerobic Bacterial Infections
• Intra-abdominal infections, including peritonitis, intra-abdominal abscess, and liver abscess
• Skin and skin structure infections
• Gynecologic infections, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection
• Bacterial Septicemia
• Bone and joint infections, as adjunctive therapy
• Central Nervous System infections, including meningitis and brain abscess
• Lower Respiratory Tract infections, including pneumonia, empyema, and lung abscess
• Endocarditis

Off-label and investigational uses of Metronidazole include:

• Crohn's disease
  Metronidazole3-4 is one of the most commonly used antibiotic for Crohn's disease. Metronidazole may be used to treat infections that develop because of Crohn's disease, especially when abscesses, abnormal connections (fistulas) between two parts of the intestines; treat active disease and may help with symptoms when aminosalicylates do not; keep symptoms of Crohn's disease from coming back after surgery.
• Giardiasis
  Giardiasis is an intestinal infection caused by a parasitic organism called Giardia lamblia. Metronidazole is the antimicrobial agent most commonly used in the treatment of giardiasis in the United States. It has a cure rate of 85-90%. The recommended adult dose is 250 mg tid (three times a day) for 5-7 days7.
• Antibiotic-associated colitis caused by the bacterium.
  Antibiotics are known to disrupt the colonic microflora, facilitating C. difficile colonization and growth. C difficile infection has been reported with use of virtually all antibiotics and some antiviral and antifungal agents. It most commonly occurs with use of the penicillins ampicillin and amoxicillin (Amoxil, Trimox), the cephalosporins, and clindamycin (Cleocin).
  Metronidazole is first-line therapy for reasons of cost as well as concern about antibiotic resistance. It has high in vivo activity against C difficile.
  
• Helicobacter pylori infections.
  Infection with Helicobacter pylori can cause chronic gastritis and lead to peptic ulcer disease. The infection is usually acquired during childhood and, if eradicated, is believed to rarely recur during adult life. The two main antibiotics used are metronidazole and clarithromycin. Metronidazole is active against H. pylori8, and its bioavailability is not influenced by acid suppression. However, H.pylori easily becomes resistant to metronidazole.
• Hepatic encephalopathy
  Hepatic encephalopathy is brain and nervous system damage that occurs as a complication of liver disorders. Metronidazole5 and neomycin (Neo-Fradin) are most commonly used antibiotics. Metronidazole is generally administered at 250 mg every 8 to 12 hours (500 to 750 mg daily). Dose and duration of metronidazole should be minimized as much as possible to avoid peripheral neuropathy, serious side effect associated with its long-term use.

Advantages:

• Inexpensive. Different generic formulations are available.
• Good tissue penetration.
• Does not induce antibiotic-associated diarrhea (pseudomembranous colitis).

Disadvantages:

• Carcinogenic potential. Metronidazole hydroxy metabolite is potentially a carcinogen1. Also, metronidazole is a proven carcinogenic to animals. It has shown to have tumorigenic activity in mice and rats, the most prominent being pulmonary lesions in the mouse. Unnecessary use of the drug should be avoided.
• Mutagenicity. Metronidazole is a proven mutagen in rodents in high doses for prolonged periods. It is also mutagenic in bacteria. Mutagenic activity associated with metronidazole has been reported in the urine of patients receiving therapeutic doses.
• Alcohol interaction.
  Consuming alcohol while taking metronidazole causes a disulfiram-like reaction with effects that can include nausea, vomiting, flushing of the skin, tachycardia (accelerated heart rate), shortness of breath, and even death. Consumption of alcohol should be avoided by patients during systemic metronidazole therapy and for at least 24 hours after completion of treatment. However, the mechanism of this reaction has recently been questioned by some researches, and a possible central toxic seratonin reaction for the alcohol intolerance suggested.
• Gastrointestinal tract and nervous system toxicity. Acute toxicity causes gastrointestinal tract symptoms. Chronic toxicity causes neurological damage. There is the risk of convulsive seizures and peripheral neuropathy.

Metronidazole is bactericidal. The activity of metronidazole against Trichomonas, amoebae and Giardia is also likely to be attributable to disruption of existing DNA and inhibition of its synthesis in those organisms.

Metronidazole is selectively taken up by anaerobic bacteria and sensitive protozoal organisms because of the ability of these organisms to reduce metronidazole to its active form intracellularly.

The half-life of Metronidazole is about 8 hours. So it takes about 1-2 days to clear out of the system.

• Metronidazole (Flagyl) versus Other Medications

• 1. Mene'ndez D, Bendesky A, Rojas E, Salamanca F, Ostrosky-Wegman P. Role of P53 functionality in the genotoxicity of metronidazole and its hydroxy metabolite. Mutat Res. 2002 Apr 25;501(1-2):57-67. PubMed
• 2. Wenisch C, Parschalk B, Hasenhu"ndl M, Hirschl AM, Graninger W. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis. 1996 May;22(5):813-8. PubMed
• 3. Prantera C, Zannoni F, Scribano ML, Berto E, Andreoli A, Kohn A, Luzi C.An antibiotic regimen for the treatment of active Crohn's disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin. Am J Gastroenterol. 1996 Feb;91(2):328-32. PubMed
• 4. Froehlich F, Juillerat P, Felley C, Mottet C, Vader JP, Burnand B, Michetti P, Gonvers JJ. Treatment of postoperative Crohn's disease. Digestion. 2005;71(1):49-53. Epub 2005 Feb 4. PubMed
• 5. Morgan MH, Read AE, Speller DC. Treatment of hepatic encephalopathy with metronidazole. Gut. 1982 Jan;23(1):1-7. PubMed
• 6. Karabay O, Tamer A, Gunduz H, Kayas D, Arinc H, Celebi H. Albendazole versus metronidazole treatment of adult giardiasis: An open randomized clinical study. World J Gastroenterol. 2004 Apr 15;10(8):1215-7. PubMed
• 7. Alizadeh A, Ranjbar M, Kashani KM, Taheri MM, Bodaghi M. Albendazole versus metronidazole in the treatment of patients with giardiasis in the Islamic Republic of Iran. East Mediterr Health J. 2006 Sep;12(5):548-54. PubMed
• 8. Murakami K, Okimoto T, Kodama M, Sato R, Watanabe K, Fujioka T. Evaluation of three different proton pump inhibitors with amoxicillin and metronidazole in retreatment for Helicobacter pylori infection. J Clin Gastroenterol. 2008 Feb;42(2):139-42. PubMed

Published: March 31, 2008
Last updated: January 07, 2010