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Metronidazole
Antibiotic and antiprotozoal medication

Metronidazole, marketed as Flagyl among others, is an antibiotic and antiprotozoal medication used to treat infections such as pelvic inflammatory disease, endocarditis, and bacterial vaginosis. It is effective against giardiasis, trichomoniasis, and amebiasis, and can be administered orally, topically, or by intravenous infusion. Common side effects include nausea and metallic taste. Although some caution its use during pregnancy, it’s generally safe during breastfeeding. Introduced in 1960, metronidazole is listed on the WHO Model List of Essential Medicines and remains widely prescribed globally.

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Medical uses

Metronidazole has activity against some protozoans and most anaerobic bacteria (both Gram-negative and Gram-positive classes) but not the aerobic bacteria.1819

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.20 It is also often used to eradicate Helicobacter pylori along with other drugs and to prevent infection in people recovering from surgery.21

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.2223

Bacterial vaginosis

Drugs of choice for the treatment of bacterial vaginosis include metronidazole and clindamycin.24

An effective treatment option for mixed infectious vaginitis is a combination of clotrimazole and metronidazole.25

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.26

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.27

Dracunculus

In the case of Dracunculus medinensis (Guinea worm), metronidazole merely facilitates worm extraction rather than killing the worm.28

C. difficile colitis

Initial antibiotic therapy for less-severe Clostridioides difficile infection colitis (pseudomembranous colitis) consists of metronidazole, vancomycin, or fidaxomicin by mouth.29 In 2017, the IDSA generally recommended vancomycin and fidaxomicin over metronidazole.30 Vancomycin by mouth has been shown to be more effective in treating people with severe C. difficile colitis.31

E. histolytica

Entamoeba histolytica invasive amebiasis is treated with metronidazole for eradication, in combination with diloxanide to prevent recurrence.32 Although it is generally a standard treatment it is associated with some side effects.33

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.34

Hypoxic radiosensitizer

In addition to its anti-biotic properties, attempts were also made to use a possible radiation-sensitizing effect of metronidazole in the context of radiation therapy against hypoxic tumors.35 However, the neurotoxic side effects occurring at the required dosages have prevented the widespread use of metronidazole as an adjuvant agent in radiation therapy.36 However, other nitroimidazoles derived from metronidazole such as nimorazole with reduced electron affinity showed less serious neuronal side effects and have found their way into radio-onological practice for head and neck tumors in some countries.37

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.38

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.39 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.40 Common adverse drug reaction associated with topical metronidazole therapy include local redness, dryness and skin irritation; and eye watering (if applied near eyes).4142 Metronidazole has been associated with cancer in animal studies.43 In rare cases, it can also cause temporary hearing loss that reverses after cessation of the treatment.4445

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.4647

Mutagenesis and carcinogenesis

In 2016 metronidazole was listed by the U.S. National Toxicology Program (NTP) as reasonably anticipated to be a human carcinogen.48 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.4950 The relationship between exposure to metronidazole and human cancer is unclear.5152 One study 53 found an excess in lung cancer among women (even after adjusting for smoking), while other studies 545556 found either no increased risk, or a statistically insignificant risk.5758 Metronidazole is listed as a possible carcinogen according to the World Health Organization (WHO) International Agency for Research on Cancer (IARC).59 A study in those with Crohn's disease also found chromosomal abnormalities in circulating lymphocytes in people treated with metronidazole.60

Stevens–Johnson syndrome

Metronidazole alone rarely causes Stevens–Johnson syndrome, but is reported to occur at high rates when combined with mebendazole.61

Neurotoxicity

Several studies in the human62 and animal models have recorded the neurotoxicity of metronidazole. One possible mechanism underlying this toxicity is that metronidazole may interference with postsynaptic central monoaminergic neurotransmission and immunomodulation.63 Additionally other research suggests that the role of nitric oxide isoforms and inflammatory cytokines may also play a role.64

Drug interactions

Alcohol

See also: Disulfiram-like drug

Consuming alcohol 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.65 People are often advised not to drink alcohol during systemic metronidazole therapy and for at least 48 hours after completion of treatment.66 However, some studies call into question the mechanism of the interaction of alcohol and metronidazole,676869 and a possible central toxic serotonin reaction for the alcohol intolerance is suggested.70 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.[medical citation needed]

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.717273 Examples of such medications are lomitapide and warfarin, to name a few.74

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.7576 Metronidazole activates by receiving an electron from the reduced ferredoxin produced by pyruvate synthase (PFOR) in anaerobic organisms, equivalent to pyruvate dehydrogenase in aerobic organisms, thus turning into a highly reactive radical anion. After the radical loses the electron to its target, it recycles back to the unactivated form of metronidazole, ready to be activated again.77

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.78 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.79

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 plasma proteins. It penetrates well into tissues, the cerebrospinal fluid, the amniotic fluid and breast milk, as well as into abscess cavities.80

About 60% of the metronidazole is metabolized by oxidation to the main metabolite hydroxymetronidazole and a carboxylic acid derivative, and by glucuronidation. The metabolites show antibiotic and antiprotozoal activity in vitro.81 Metronidazole and its metabolites are mainly excreted via the kidneys (77%) and to a lesser extent via the faeces (14%).8283 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 premature babies up to 100 hours.84

The biological activity of hydroxymetronidazole is 30% to 65%, and the elimination half-life is longer than that of the parent compound.85 The serum half-life of hydroxymetronidazole after suppository was 10 hours, 19 hours after intravenous infusion, and 11 hours after a tablet.86

Resistance

See also: Antibiotic abuse and Antibiotic 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.87

Resistance in bacteria is documented in Bacteriodes spp. that resistant to nitroimidazoles 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.888990

Other mechanisms may include reduced drug activation, efflux pumps, 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.919293

History

The drug was initially developed by Rhône-Poulenc in the 1950s94 and licensed to G.D. Searle.95 Searle was acquired by Pfizer in 2003.96 The original patent expired in 1982, but evergreening reformulation occurred thereafter.97

Brand name

In India, it is sold under the brand name Metrogyl and Flagyl.98 In Bangladesh, it is available as Amodis, Amotrex, Dirozyl, Filmet, Flagyl, Flamyd, Metra, Metrodol, Metryl, etc.99 In Pakistan, it is sold under the brand name of Flagyl and Metrozine. In the United States it is sold under the brand name Noritate.100

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):101102103

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 macrophages and neutrophils. 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 cytokines, including chemokines, and adhesion molecules. Cytokines are small proteins that are secreted by immune cells and play a key role in the immune response.104 Chemokines are a type of cytokines that act as chemoattractants, meaning they attract and guide immune cells to specific sites in the body where they are needed.105 Cell adhesion molecules play an important role in the immune response by facilitating the interaction between immune cells and other cells in the body, such as endothelial cells, which form the lining of blood vessels.106 By inhibiting NF-κB activation, metronidazole can reduce the production of pro-inflammatory cytokines, such as TNF-alpha, IL-6, and IL-1β.107

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.108 Despite the success in treating rosacea with metronidazole,109110111112113 the exact mechanism of why metronidazole in rosacea is efficient is not precisely known, i.e., which properties of metronidazole help treat rosacea: antibacterial or immunomodulatory or both, or other mechanism is involved.114115 Increased ROS production in rosacea is thought to contribute to the inflammatory process and skin damage, so metronidazole's ability to decrease ROS may explain the mechanism of action in this disease, but this remains speculation.116117

Metronidazole is also researched as a potential anti-inflammatory agent in periodontitis treatment.118

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.119 It is also used for the management of chronic inflammatory bowel disease, gastrointestinal infections, periodontal disease, and systemic infections in cats and dogs.120121 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 (FDA) suggests it only be used when necessary because it has been shown to be carcinogenic in mice and rats, as well as to prevent antimicrobial resistance.122123

The appropriate dosage of metronidazole varies based on the animal species, the condition being treated and the specific formulation of the product.124

References

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