Metronidazole in Brief
- Generic name : Metronidazole
- Brand names: Flagyl
- Therapeutic class: Antibiotic; Antiprotozoal; Anaerobic antibacterial;
- Pharmacologic class: Nitroimidazole
- Chemical Formula: C6H9N3O3
- Pregnancy Category: B (however, it is recommended to avoid metronidazole use during the first trimester)
- Originally discovered: 1950s, France
Metronidazole is an antiprotozoal and antibacterial medication used
mainly in the treatment of 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 trade name, Flagyl, and also by various generic manufacturers.
Metronidazole was synthesized by France's Rhone-Poulenc laboratories
and introduced in the mid-1950s under the brand name Flagyl. It was the first member 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 as antiparasitic 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.
Currently, metronidazole 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 in combination with other agents is widely used against Helicobacter pylori, a
major cause of gastritis and a risk factor for stomach cancer.
FDA approved uses
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
Metronidazole is NOT effective for infections caused by aerobic bacteria that can survive in the presence of oxygen. Metronidazole is only effective against anaerobic bacterial infections because the presence of oxygen will inhibit the nitrogen-reduction process that is crucial to the drug's mechanism of action.
Off-label & Investigational uses
is often used for Crohn's disease, a chronic inflammatory disease of the digestive system. 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. It is used to treat active disease and may help with
symptoms when aminosalicylates do not work; keep symptoms of Crohn's disease from coming back after surgery.
Giardiasis is an intestinal infection caused by a parasitic microscopic parasite
Giardia lamblia. Metronidazole is an effective antimicrobial agent for treatment of giardiasis.
It provides a a cure rate of about 85-90% 6. Metronidazole dosage regimen for the treatment of giardiasis is 250 mg 3 times a day for 5-7 days.
Clostridium Difficile Colitis
Antibiotics are known to disrupt the colonic microflora, facilitating C. difficile colonization and growth. C. difficile,
a spore-forming gram-positive rod, produces toxins that inflame the colon. Rarely, the toxins destroy the tissue of the
inner lining of the colon.
Virtually any antibiotic may induce C. difficile colitis, but broad-spectrum antibiotics with activity against
enteric bacteria are the most frequent culprits. According to the Infectious Diseases Society of America guidelines11 metronidazole is the first-line therapy for the initial episode of mild-to-moderate disease. The recommendation is based on metronidazole's high in vivo activity against C. difficile, its low cost as well
as a growing concern of emerging resistance to other important antibiotics 9.
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. pylori 7, and its bioavailability is not influenced by acid suppression (active at low pH). However, H.pylori easily becomes resistant to metronidazole.
Hepatic encephalopathy is a brain disorder due to liver failure. It occurs when toxins such as ammonia and mercaptans accumulate in the blood and reach the brain. Metronidazole 5 works by decreasing intestinal ammonia production by colon bacteria.
Ulcerative gingivitis. Metronidazole (alone or in combination with other antibacterials) provides an effective therapy for gum disease 10.
Metronidazole may facilitate removal of adult guinea worms in dracunculiasis.
Metronidazole "pros" and "cons"
- Variety of available formulations -- oral, intravenous, intravaginal, and topical.
- Oral metronidazole is extremely well absorbed.
- Bactericidal activity against obligate anaerobes.
- Excellent activity against anaerobic gram-negative bacilli, including B. fragilis that are frequently resistant to other antibiotics 8.
- Excellent penetration into almost all body tissue and fluids, including saliva, vaginal seminal fluids, and cerebrospinal fluid.
- Minimal suppression of normal gut flora. Does not induce antibiotic-associated diarrhea (pseudomembranous colitis).
- Very low cost.
- Relatively mild side effects.
- 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 metronidazole should be avoided.
- Mutagenicity. Metronidazole is mutagenic in rodents and bacteria. However, teratogenicity in humans has not been demonstrated.
- 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 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 with long-term use.
- Frequently causes unpleasant, metallic taste in the mouth.
- Metronidazole is active only against anaerobes and cannot used as a single agent in mixed infections.
- Undergoes extensive hepatic metabolism.
- Metronidazole may potentiate the anticoagulant effect of warfarin and other coumarin anticoagulants.
- Sensory neuropathies12 (numbness, paresthesias) have been reported. The reversal of severe neuropathies may be slow or incomplete.
Mode of action
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.
Time to clear out of the system
The half-life of Metronidazole is about 8 hours. So it takes about 1-2 days to clear out of the system.
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F, Ostrosky-Wegman P. Role of P53 functionality in the genotoxicity
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AM, Graninger W. Treatment of Clostridium difficile-associated
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of hepatic encephalopathy with metronidazole. Gut. 1982 Jan;23(1):1-7.
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- 11. Clinical practice guidelines for Clostridium difficile infection IDSA PDF
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Published: March 31, 2008
Last updated: September 28, 2015