Metronidazole, sold under the brand name Flagyl and Metrogyl among others, is an antibiotic and antiprotozoal medication.[ It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis.][ It is effective for dracunculiasis, giardiasis, trichomoniasis, and amebiasis.][ It is an option for a first episode of mild-to-moderate Clostridioides difficile colitis if vancomycin or fidaxomicin is unavailable.]
Common side effects include nausea, Dysgeusia, loss of appetite, and headaches.[ Occasionally or allergies to the medication may occur.][ Some state that metronidazole should not be used in early pregnancy, while others state doses for trichomoniasis are safe.][ Metronidazole is generally considered compatible with breastfeeding.]
Metronidazole began to be commercially used in 1960 in France.
Medical uses
Metronidazole has activity against some and most anaerobic bacteria (both Gram-negative and Gram-positive classes) but not the aerobic bacteria.
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, periodontal disease, amoebiasis, oral infections, 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.][
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Metronidazole is bitter and so the liquid suspension contains metronidazole benzoate. This may require hydrolysis in the gastrointestinal tract and some sources speculate that it may be unsuitable in people with diarrhea or feeding-tubes in the duodenum or jejunum.
Bacterial vaginosis
Drugs of choice for the treatment of bacterial vaginosis include metronidazole and clindamycin.
An effective treatment option for mixed infectious vaginitis is a combination of clotrimazole and metronidazole.
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.
Giardiasis
Oral metronidazole is a treatment option for giardiasis, however, the increasing incidence of nitroimidazole resistance is leading to the increased use of other compound classes.
Dracunculus
In the case of Dracunculus medinensis (Guinea worm), metronidazole merely facilitates worm extraction rather than killing the worm.[
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C. difficile colitis
Initial antibiotic therapy for less-severe Clostridioides difficile infection colitis (pseudomembranous colitis) consists of metronidazole, vancomycin, or fidaxomicin by mouth.
E. histolytica
Entamoeba histolytica invasive Amoebiasis is treated with metronidazole for eradication, in combination with diloxanide to prevent recurrence.
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.
Hypoxic radiosensitizer
In addition to its anti-biotic properties, attempts were also made to use a possible Radiosensitizer of metronidazole in the context of radiation therapy against hypoxic tumors.
Perioral dermatitis
Canadian Family Physician has recommended topical metronidazole as a third-line treatment for the perioral dermatitis either along with or without oral tetracycline or oral erythromycin as first and second line treatment respectively.
Adverse effects
Common adverse drug reactions (≥1% of those treated with the drug) associated with systemic metronidazole therapy include: nausea, diarrhea, 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.[ Common adverse drug reaction associated with topical metronidazole therapy include local redness, dryness and skin irritation; and eye watering (if applied near eyes).]
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
In 2016 metronidazole was listed by the U.S. National Toxicology Program (NTP) as reasonably anticipated to be a human carcinogen.[ The relationship between exposure to metronidazole and human cancer is unclear.]
Stevens–Johnson syndrome
Metronidazole alone rarely causes Stevens–Johnson syndrome, but is reported to occur at high rates when combined with mebendazole.
Neurotoxicity
Several studies in the human
Drug interactions
Alcohol
Consuming ethanol while taking metronidazole has been suspected in case reports to cause a disulfiram-like reaction with effects that can include nausea, vomiting, flushing of the skin, tachycardia, and shortness of breath.[
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Other drug interactions
Metronidazole is a moderate inhibitor of the enzyme CYP2C9 belonging to the cytochrome P450 family. As a result, metronidazole may interact with medications metabolized by this enzyme.[
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Pharmacology
Mechanism of action
Metronidazole is of the nitroimidazole class. It is a prodrug that inhibits nucleic acid synthesis by forming nitroso radicals, which disrupt the DNA of microbial cells.
This function only occurs when metronidazole is partially reduced, and because oxygen competes with metronidazole for the electron, this reduction requires a local environment with low oxygen concentration that usually happens only in anaerobic bacteria and protozoans. Therefore, it has relatively little effect upon human cells or aerobic bacteria.[
] Elevation of oxygen level in the organism will decrease its rate of generating the activated metronidazole, but also increase the rate of recycling back to the unactivated metronidazole.
Pharmacokinetics
Oral metronidazole is approximately 80% bioavailable via the gut and peak blood plasma concentrations occur after one to two hours. Food may slow down absorption but does not diminish it. Of the circulating substance, about 20% is bound to . It penetrates well into tissues, the cerebrospinal fluid, the amniotic fluid and breast milk, as well as into abscess cavities.
About 60% of the metronidazole is by oxidation to the main metabolite hydroxymetronidazole and a carboxylic acid derivative, and by glucuronidation. The metabolites show antibiotic and antiprotozoal activity in vitro.[ The biological half-life of metronidazole in healthy adults is eight hours, in infants during the first two months of their lives about 23 hours, and in Preterm birth babies up to 100 hours.]
The biological activity of hydroxymetronidazole is 30% to 65%, and the elimination half-life is longer than that of the parent compound.
Resistance
Resistance in parasites is found in T. vaginilis, and G. lamblia, but not E. histolytica, and two major methods are observed. The first method involves an impaired oxygen scavenging capability that increase the local concentration of oxygen, leading to the decreased activation and increased recycling of metronidazole. The second method is associated with lowered levels of pyruvate synthase and ferredoxin, the latter due to the lowered transcription of the ferredoxin gene. Strains employing the second method will still respond to a higher dosage of metronidazole.
Resistance in bacteria is documented in Bacteriodes spp. that resistant to including metronidazole. In the resistant strains, 5-nitroimidazole reductase is identified as the culprit that actively reduces metronidazole to inactive forms. Currently eleven types are identified which are encoded by nimA through nimK respectively. The gene is encoded either in the chromosome or the episome.
Other mechanisms may include reduced drug activation, , altered redox potential and biofilm formation. In the recent years it is observed that the resistance to metronidazole is increasingly common, complicating its clinical effectiveness.
History
The drug was initially developed by Rhône-Poulenc in the 1950s
Brand name
In India, it is sold under the brand name Metrogyl and Flagyl.
Synthesis
2-Methylimidazole ( 1) may be prepared via the Debus-Radziszewski imidazole synthesis, or from ethylenediamine and acetic acid, followed by treatment with calcium oxide, then Raney nickel. 2-Methylimidazole is nitrated to give 2-methyl-4(5)-nitroimidazole ( 2), which is in turn alkylation with ethylene oxide or 2-chloroethanol to give metronidazole ( 3):
Research
Metronidazole is researched for its anti-inflammatory and immunomodulatory properties. Studies have shown that metronidazole can decrease the production of reactive oxygen species (ROS) and nitric oxide by activated immune cells, such as and . Metronidazole's immunomodulatory properties are thought to be related to its ability to decrease the activation of nuclear factor-kappa B (NF-κB), a transcription factor that regulates the expression of pro-inflammatory , including , and adhesion molecules. Cytokines are small proteins that are secreted by immune cells and play a key role in the immune response.
Metronidazole has been studied in various immunological disorders, including inflammatory bowel disease, periodontitis, and rosacea. In these conditions, metronidazole has been suspected to have anti-inflammatory and immunomodulatory effects that could be beneficial in the treatment of these conditions.
Metronidazole is also researched as a potential anti-inflammatory agent in periodontitis treatment.
Veterinary use
Metronidazole is used to treat infections of Giardia in dogs, cats, and other companion animals, but it does not reliably clear infection with this organism and is being supplanted by fenbendazole for this purpose in dogs and cats.
The appropriate dosage of metronidazole varies based on the animal species, the condition being treated and the specific formulation of the product.
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