Metronidazole

Metronidazole (AAN, BAN, INN, USAN) /mɛtrəˈnaɪdəzoʊl/ (Flagyl and others) is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. It is antibacterial against anaerobic organisms, an amoebicide, and an antiprotozoal. It is the drug of choice for first episodes of mild-to-moderate Clostridium difficile infection. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.

Medical uses

Metronidazole is primarily used to treat: bacterial vaginosis, pelvic inflammatory disease (along with other antibacterials like ceftriaxone), pseudomembranous colitis, aspiration pneumonia, rosacea (topical), fungating wounds (topical), intra-abdominal infections, lung abscess, gingivitis, amoebiasis, giardiasis, trichomoniasis, and infections caused by susceptible anaerobic organisms such as Bacteroides, Fusobacterium, Clostridium, Peptostreptococcus, and Prevotella species. It is also often used to eradicate Helicobacter pylori along with other drugs and to prevent infection in people recovering from surgery.

Bacterial vaginosis

Drugs of choice for the treatment of bacterial vaginosis include metronidazole and clindamycin. The treatment of choice for bacterial vaginosis in nonpregnant women include metronidazole oral twice daily for seven days, or metronidazole gel intravaginally once daily for five days, or clindamycin intravaginally at bedtime for seven days. For pregnant women, the treatment of choice is metronidazole oral three times a day for seven days. Data do not report routine treatment of male sexual partners.

Trichomoniasis

The 5-nitroimidazole drugs (metronidazole and tinidazole) are the mainstay of treatment for infection with Trichomonas vaginalis. Treatment for both the infected patient and the patient's sexual partner is recommended, even if asymptomatic. Therapy other than 5-nitroimidazole drugs is also an option, but cure rates are much lower.

C. difficile colitis

Initial antibiotic therapy for less-severe Clostridium difficile colitis (pseudomembranous colitis) consists of oral metronidazole or oral vancomycin. Several randomized controlled trials have demonstrated equivalent efficacy of oral metronidazole and oral vancomycin in treating this colitis. However, oral vancomycin is shown to be more effective in treating patients with severe C. difficile colitis.

E. histolytica

Invasive colitis and extraintestinal disease including liver abscesses, pleuropulmonary infections, and brain abscesses can result from infection with Entamoeba histolytica. Metronidazole is widely used in patients with these infections.

Preterm births

Metronidazole has also been used in women to prevent preterm birth associated with bacterial vaginosis, amongst other risk factors including the presence of cervicovaginal fetal fibronectin (fFN). Metronidazole was ineffective in preventing preterm delivery in high-risk pregnant women (selected by history and a positive fFN test) and, conversely, the incidence of preterm delivery was found to be higher in women treated with metronidazole.

Adverse effects

Common adverse drug reactions (≥1% of those treated with the drug) associated with systemic metronidazole therapy include: nausea, diarrhoea, weight loss, abdominal pain, vomiting, headache, dizziness, and metallic taste in the mouth. Intravenous administration is commonly associated with thrombophlebitis. Infrequent adverse effects include: hypersensitivity reactions (rash, itch, flushing, fever), headache, dizziness, vomiting, glossitis, stomatitis, dark urine, and paraesthesia. High doses and long-term systemic treatment with metronidazole are associated with the development of leucopenia, neutropenia, increased risk of peripheral neuropathy, and central nervous system toxicity. Common adverse drug reaction associated with topical metronidazole therapy include local redness, dryness and skin irritation; and eye watering (if applied near eyes).

Metronidazole may cause mood swings. Some evidence from studies in rats indicates the possibility it may contribute to serotonin syndrome, although no case reports documenting this have been published to date.

Mutagenesis and carcinogenesis

Metronidazole is listed by the US National Toxicology Program (NTP) as reasonably anticipated to be a human carcinogen. Although some of the testing methods have been questioned, oral exposure has been shown to cause cancer in experimental animals and has also demonstrated some mutagenic effects in bacterial cultures. The relationship between exposure to metronidazole and human cancer is unclear. One study found an excess in lung cancer among women (even after adjusting for smoking), while other studies found either no increased risk, or a statistically insignificant risk. Metronidazole is listed as a possible carcinogen according to the WHO International Agency for Research on Cancer. A study in those with Crohn's disease also found chromosomal abnormalities in circulating lymphocytes in people treated with metronidazole.

Due to its potential carcinogenic properties, metronidazole is banned in the European Union and the USA for veterinary use in the feed of animals and is banned for use in any food animals in the USA.

Interaction with alcohol

Consuming alcohol while taking metronidazole has long been thought to have a disulfiram-like reaction with effects that can include nausea, vomiting, flushing of the skin, tachycardia, and shortness of breath. Consumption of alcohol is typically advised against by patients during systemic metronidazole therapy and for at least 48 hours after completion of treatment. However, some studies call into question the mechanism of the interaction of alcohol and metronidazole, and a possible central toxic serotonin reaction for the alcohol intolerance is suggested. Metronidazole is also generally thought to inhibit the liver metabolism of propylene glycol (found in some foods, medicines, and in many electronic cigarette e-liquids), thus propylene glycol may potentially have similar interaction effects with metronidazole.

Other drug interactions

It also inhibits CYP2C9 and CYP3A4, so may interact with medications metabolised by these enzymes (e.g. lomitapide, warfarin).

Stevensâ€"Johnson syndrome

Metronidazole alone rarely causes Stevensâ€"Johnson syndrome, but is reported to occur at high rates when combined with mebendazole.

Mechanism of action

It inhibits nucleic acid synthesis by disrupting the DNA of microbial cells. This function only occurs when metronidazole is partially reduced, and because this reduction usually happens only in anaerobic cells, it has relatively little effect upon human cells or aerobic bacteria.

Synthesis

2-Methylimidazole (1) may be prepared via the Debus-Radziszewski imidazole synthesis, or from ethylenediamine and acetic acid, followed by treatment with lime, then Raney nickel. 2-Methylimidazole is nitrated to give 2-methyl-4(5)-nitroimidazole (2), which is in turn alkylated with ethylene oxide or 2-chloroethanol to give metronidazole (3):

Veterinary use

Metronidazole is not labeled for animal use, but is widely used to treat infections of Giardia in dogs, cats, and other companion animals, although it does not reliably clear infection with this organism and is being supplanted by fenbendazole for this purpose in dogs and cats. It is also used for the management of chronic inflammatory bowel disease in cats and dogs. Another common usage is the treatment of systemic and/or gastrointestinal clostridial infections in horses. Metronidazole is used in the aquarium hobby to treat ornamental fish and as a broad-spectrum treatment for bacterial and protozoan infections in reptiles and amphibians. In general, the veterinary community may use metronidazole for any potentially susceptible anaerobic infection. The U.S. Food and Drug Administration suggests it only be used when necessary because it has been shown to be carcinogenic in mice and rats, as well as the microbes for which it is prescribed, and resistance can develop.

References

External links

• "Metronidazole for veterinary use". Wedgewood pharmacy. 

• "Metronidazole". Merck manuals. 

• "Metronidazole". patient.co.uk. 

• "Metronidazole". Drug Information Portal. U.S. National Library of Medicine. 

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