METRONIDAZOLE

Metronidazole is an antibiotic, amebicide, and antiprotozoal. It is the drug of choice for first episodes of mild-to-moderate Clostridium difficile infection. It is marketed in the U.S.A. by Pfizer and globally by Sanofi under the trade name Flagyl, in Bangladesh as "Filmet" by Beximco Pharmaceuticals Ltd, "Metrogyl" by Rephco Pharmaceuticals Limited, in Pakistan as Nidagyl by Star Laboratories also Marketed as Flagyl by Sanofi and in Thailand, as Mepagyl by Thai Nakhorn Patana. It is also marketed in UK by Milpharm Limited and Almus Pharmaceuticals. Metronidazole was developed in 1960. Metronidazole is used also as a gel preparation in the treatment of the dermatological conditions such as rosacea (Rozex and MetroGel by Galderma) and fungating tumours (Anabact, Cambridge Healthcare Supplies).

MEDICAL USES

Metronidazole is indicated for the treatment of:

BACTERIAL

Bacterial vaginosis, commonly associated with overgrowth of Gardnerella species and coinfective anaerobes (Mobiluncus, Bacteroides), in symptomatic patients Pelvic inflammatory disease in conjunction with other antibiotics such as ofloxacin, levofloxacin, or ceftriaxone Anaerobic infections such as Bacteroides fragilis, spp, Fusobacterium spp, Clostridium spp, Peptostreptococcus spp, Prevotella spp, or any other anaerobes in intra-abdominal abscess, peritonitis, diverticulitis, empyema, pneumonia, aspiration pneumonia, lung abscess, diabetic foot ulcer, meningitis and brain abscesses, bone and joint infections, septicemia, endometritis, or endocarditis Pseudomembranous colitis due to Clostridium difficile Helicobacter pylori eradication therapy, as part of a multi-drug regimen in peptic ulcer disease Dental infection of bacterial origin, such as periapical abscess, periodontal abscess, acute pericoronitis of impacted or partially erupted teeth; often used in conjunction with Amoxicillin.

PROTOZOAL

Amoebiasis: Infections caused by Entamoeba histolytica. Giardiasis: infection of the small intestine caused by the ingestion of infective cysts of protozoan Giardia lamblia. Trichomoniasis: infection caused by Trichomonas vaginalis, which is a common cause of vaginitis and is the most frequently presenting new infection of the common sexually transmitted diseases.

NONSPECIFIC

Prophylaxis for those undergoing potentially contaminated colorectal surgery or appendectomies and may be combined with neomycin[citation needed] Crohn's disease with colonic or perianal involvement (non-FDA approved) – believed to be more effective in combination with ciprofloxacin. Topical metronidazole is indicated for the treatment of rosacea, and in the treatment of malodorous fungating wounds.

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). A randomised controlled trial demonstrated that metronidazole was ineffective in preventing preterm delivery in high-risk pregnant women and, conversely, the incidence of preterm delivery was actually higher in women treated with metronidazole. In a study it has been found that metronidazole is not the right antibiotic to administer in these circumstances and that it was often administered too late to be of use. Clindamycin administered early in the second trimester to women who test positive for bacterial vaginosis seemed to be more effective.

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. Metronidazole 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 GI clostridial infections in horses. Metronidazole or simply "Metro" is used in the aquarium hobby to treat ornamental fish and as a wide spectrum treatment for bacterial and protozoan infections in reptiles and amphibians. It is also used to treat human enteric (gi) and systemic infections. In general, the veterinary community may use metronidazole for any potentially susceptible anaerobic infection. The U.S. Food and Drug Administration (FDA) prohibits the use of metronidazole in food animals.

ADVERSE EFFECTS

Common adverse drug reactions (=1% of patients) associated with systemic metronidazole therapy include: nausea, diarrhea, and/or 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/or paraesthesia. High doses and/or long-term systemic treatment with metronidazole is associated with the development of leukopenia, neutropenia, increased risk of peripheral neuropathy and/or CNS toxicity. 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[citation needed], oral exposure has been shown to cause cancer in experimental animals. The relationship between exposure to metronidazole and human cancer is unclear. One study (Beard et al. 1988) found an excess in lung cancer among women (even after adjusting for smoking), while other studies (IARC 1987; Thapa et al. 1998) 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 (IARC). Due to its potential carcinogenic properties, metronidazole is banned in the EU and the USA for veterinary use in the feed of animals and is banned for use in any food animals in the USA. In the USA, this type of restriction is covered under the Delaney clause. Earlier studies suggested a relation between metronidazole and various birth defects. Those studies are now considered flawed and more recent studies "do not support a significant increased risk for birth defects or other adverse effects on the fetus." Common adverse drug reactions associated with topical metronidazole therapy include local redness, dryness, and/or skin irritation; and eye watering (if applied near eyes).

METRONIDAZOLE TOXICITY OF THE BRAIN

Toxic levels of metronidazole can cause symmetrical lesions in the brain in the corpus callosum and dentate nuclei. Metronidazole toxicity is rare (though the actual incidence is not known with certainty). Patients present with nausea, vomiting, dysarthria, vertigo, and confusion. Other side effects of the metronidazole can include dry mouth, diarrhea, headache, dizziness, or peripheral neuropathy. An examination of a patient reveals that the patient is confused and has dysarthria (difficult or unclear articulation of speech that is otherwise linguistically normal), ataxia (loss of full control of bodily movements), abnormal eye movements including nystagmus and ophthalmoparesis. Magnetic resonance imaging (MRI) most often shows bilateral symmetric fluid-attenuated inversion recovery (FLAIR) hyperintense lesions of the dentate nuclei (which is one of the deep cerebellar nuclei), as well as symmetric lesions of the corpus callosum and basal ganglia. The brain lesions seen on the MRI rarely enhance and may be Diffusion-Weighted Imaging (DWI) hyperintense. It has a subacute to acute course. Most reports have been seen in patients who receive approximately one gram a day of metronidazole for over 30 days. Metronidazole can rarely cause central nervous system toxicity; it does not seem to be a dose- or duration-related phenomenon. Most patients will have MRI abnormalities. Prognosis is excellent with metronidazole cessation.

INTERACTION WITH ALCOHOL

Consuming ethanol (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 (accelerated heart rate), and shortness of breath. Typically a 2006 Medicines Handbook warns that consumption of alcohol should be avoided by patients during systemic metronidazole therapy and for at least 48 hours after completion of treatment. However there are studies calling into question the interaction of alcohol and metronidazole, and the mechanism of this reaction in the clinical setting has been questioned by some authors, and a possible central toxic serotonin reaction for the alcohol intolerance suggested.

STEVENS-JOHNSON SYNDROME WITH MEBENDAZOLE

Metronidazole alone rarely causes Stevens–Johnson syndrome but is reported to occur at high rates when combined with mebendazole.

POTENTIALLY FATAL SEROTONIN SYNDROME

It is important to note that serotonin syndrome is not fully understood. The complex drug interaction can happen after a couple days or take up to months. The exact mechanism is not known, a theory of serotonin dysfunction helps explain how the syndrome presents and how it is to be treated. Signs and symptoms are muscle rigidity, headache, elevated blood pressure, and changes in blood chemistry. The only direct treatment is to discontinue the offending drugs. Recently, there have been reported cases of SSRI/SNRI antidepressant drugs (e.g. paroxetine, citalopram, fluoxetine, sertraline, venlafaxine, duloxetine) and metronidazole induced serotonin syndrome, but this information is not included on the metronidazole patient information leaflet.

MECHANISMS OF ACTION

Metronidazole, taken up by diffusion, is selectively absorbed by anaerobic bacteria and sensitive protozoa. Once taken up by anaerobes, it is non-enzymatically reduced by reacting with reduced ferredoxin, which is generated by pyruvate oxido-reductase. Many of the reduced nitroso intermediates will form sulfinamides and thioether linkages with cysteine-bearing enzymes, thereby deactivating these critical enzymes. As many as 150 separate enzymes are affected. In addition or alternatively, the metronidazole metabolites are taken up into bacterial DNA, and form unstable molecules. 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.

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