Metronidazole, sold under the brand name Flagyl and Metrogyl among others, is an
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...
and
antiprotozoal medication.
[ It is used either alone or with other antibiotics to treat ]pelvic inflammatory disease
Pelvic inflammatory disease (PID), also known as pelvic inflammatory disorder, is an infection of the upper part of the female reproductive system, mainly the uterus, fallopian tubes, and ovaries, and inside of the pelvis. Often, there may be no ...
, endocarditis
Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves. Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, o ...
, and bacterial vaginosis
Bacterial vaginosis (BV) is an infection of the vagina caused by excessive growth of bacteria. Common symptoms include increased vaginal discharge that often smells like fish. The discharge is usually white or gray in color. Burning with urina ...
.[ It is effective for ]dracunculiasis
Dracunculiasis, also called Guinea-worm disease, is a parasitic infection by the Guinea worm ('' Dracunculus medinensis).'' A person becomes infected by drinking water contaminated with Guinea-worm larvae that reside inside copepods (a typ ...
, giardiasis
Giardiasis is a parasitic disease caused by the protist enteropathogen ''Giardia duodenalis'' (also known as ''G. lamblia'' and ''G. intestinalis''), especially common in children and travellers. Infected individuals experience steatorrhea, a typ ...
, trichomoniasis
Trichomoniasis (trich) is an infectious disease caused by the parasite ''Trichomonas vaginalis''. About 70% of affected people do not have symptoms when infected. When symptoms occur, they typically begin 5 to 28 days after exposure. Symptoms ca ...
, and amebiasis.[ It is an option for a first episode of mild-to-moderate ''Clostridioides difficile'' colitis if ]vancomycin
Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections. It is administered intravenously ( injection into a vein) to treat complicated skin infections, bloodstream infections, endocarditis, bone an ...
or fidaxomicin is unavailable. Metronidazole is available orally (by mouth), as a cream or gel, and by slow intravenous infusion
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
(injection into a vein).
Common side effects include nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat.
Over 30 d ...
, a metallic taste, loss of appetite
Anorexia is a medical term for a loss of appetite. While the term outside of the scientific literature is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while o ...
, and headaches.[ Occasionally ]seizure
A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
s or allergies to the medication may occur.[ Some state that metronidazole should not be used in early ]pregnancy
Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins.
Conception (biology), Conception usually occurs ...
, while others state doses for trichomoniasis are safe.[ Metronidazole is generally considered compatible with ]breastfeeding
Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...
.
Metronidazole began to be commercially used in 1960 in France. It is on the World Health Organization's List of Essential Medicines
The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
. It is available in most areas of the world. In 2022, it was the 133rd most commonly prescribed medication in the United States, with more than 4million prescriptions.
Medical uses
Metronidazole has activity against some protozoan
Protozoa (: protozoan or protozoon; alternative plural: protozoans) are a polyphyletic group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic debris. Historically ...
s and most anaerobic bacteria
An anaerobic organism or anaerobe is any organism that does not require molecular oxygen for growth. It may react negatively or even die if free oxygen is present. In contrast, an aerobic organism (aerobe) is an organism that requires an oxygenat ...
(both Gram-negative
Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is that their cell envelope consists ...
and Gram-positive
In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall.
The Gram stain is ...
classes) but not the aerobic bacteria
An aerobic organism or aerobe is an organism that can survive and grow in an oxygenated environment. The ability to exhibit aerobic respiration may yield benefits to the aerobic organism, as aerobic respiration yields more energy than anaerobic ...
.
Metronidazole is primarily used to treat: bacterial vaginosis
Bacterial vaginosis (BV) is an infection of the vagina caused by excessive growth of bacteria. Common symptoms include increased vaginal discharge that often smells like fish. The discharge is usually white or gray in color. Burning with urina ...
, pelvic inflammatory disease
Pelvic inflammatory disease (PID), also known as pelvic inflammatory disorder, is an infection of the upper part of the female reproductive system, mainly the uterus, fallopian tubes, and ovaries, and inside of the pelvis. Often, there may be no ...
(along with other antibacterials like ceftriaxone
Ceftriaxone, sold under the brand name Rocephin, is a third-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. These include middle ear infections, endocarditis, meningitis, pneumonia, bone and joi ...
), pseudomembranous colitis
Colitis is swelling or inflammation of the large intestine ( colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases.
In a medical context, the label ''colitis'' (without qualificati ...
, aspiration pneumonia
Aspiration pneumonia is a type of lung infection that is due to a relatively large amount of material from the stomach or mouth entering the lungs. Signs and symptoms often include fever and cough of relatively rapid onset. Complications may incl ...
, rosacea
Rosacea is a long-term skin condition that typically affects the face. It results in redness, pimples, swelling, and small and superficial dilated blood vessels. Often, the nose, cheeks, forehead, and chin are most involved. A red, en ...
(topical), fungating wounds (topical), intra-abdominal infections, lung abscess
Lung abscess is a type of liquefactive necrosis of the lung tissue and formation of cavities (more than 2 cm) containing necrotic debris or fluid caused by microbial infection.
This pus-filled cavity is often caused by aspiration, which m ...
, periodontal disease
Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main c ...
, amoebiasis
Amoebiasis, or amoebic dysentery, is an infection of the intestines caused by a parasitic amoeba '' Entamoeba histolytica''. Amoebiasis can be present with no, mild, or severe symptoms. Symptoms may include lethargy, loss of weight, colon ...
, oral infections, giardiasis
Giardiasis is a parasitic disease caused by the protist enteropathogen ''Giardia duodenalis'' (also known as ''G. lamblia'' and ''G. intestinalis''), especially common in children and travellers. Infected individuals experience steatorrhea, a typ ...
, trichomoniasis
Trichomoniasis (trich) is an infectious disease caused by the parasite ''Trichomonas vaginalis''. About 70% of affected people do not have symptoms when infected. When symptoms occur, they typically begin 5 to 28 days after exposure. Symptoms ca ...
, and infections caused by susceptible anaerobic organisms such as ''Bacteroides
''Bacteroides'' is a genus of Gram-negative, obligate anaerobic bacteria. ''Bacteroides'' species are non endospore–forming bacilli, and may be either motile or nonmotile, depending on the species. The DNA base composition is 40–48% GC. Un ...
, Fusobacterium
''Fusobacterium'' is a genus of obligate anaerobic, Gram-negative, non-sporeforming bacteria belonging to Gracilicutes. Individual cells are slender, rod-shaped bacilli with pointed ends. ''Fusobacterium'' was discovered in 1900 by Courmont an ...
, Clostridium
''Clostridium'' is a genus of anaerobic, Gram-positive bacteria. Species of ''Clostridium'' inhabit soils and the intestinal tracts of animals, including humans. This genus includes several significant human pathogens, including the causative ...
, Peptostreptococcus
''Peptostreptococcus'' is a genus of anaerobic, Gram-positive, non-spore forming bacteria. The cells are small, spherical, and can occur in short chains, in pairs or individually. They typically move using cilia. ''Peptostreptococcus'' are slow- ...
'', and '' Prevotella'' species.[ It is also often used to eradicate '']Helicobacter pylori
''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, Flagellum#bacterial, flagellated, Bacterial cellular morphologies#Helical, helical bacterium. Mutants can have a rod or curved rod shape that exhibits l ...
'' along with other drugs and to prevent infection in people recovering from surgery.[
Metronidazole is bitter and so the liquid suspension contains metronidazole benzoate. This may require ]hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
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
Clindamycin is a lincosamide antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media (mi ...
.
An effective treatment option for mixed infectious vaginitis is a combination of clotrimazole and metronidazole.
Trichomoniasis
The 5-nitroimidazole drugs (metronidazole and tinidazole
Tinidazole, sold under the brand name Tindamax among others, is a medication used against protozoan infections. It is widely known throughout Europe and the developing world as a treatment for a variety of anaerobic amoebic and bacterial infecti ...
) are the mainstay of treatment for infection with ''Trichomonas vaginalis
''Trichomonas vaginalis'' is an Anaerobic organism, anaerobic, flagellated protozoan parasite and the causative agent of a Sexually transmitted infection, sexually transmitted disease called trichomoniasis. It is the most common pathogenic protoz ...
''. 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
Giardiasis is a parasitic disease caused by the protist enteropathogen ''Giardia duodenalis'' (also known as ''G. lamblia'' and ''G. intestinalis''), especially common in children and travellers. Infected individuals experience steatorrhea, a typ ...
, however, the increasing incidence of nitroimidazole
Nitroimidazoles are the group of organic compound, organic compounds consisting of an imidazole ring with at least one nitro group substituent. The term also refers to the class of antibiotics that have nitroimidazole in their structures. These an ...
resistance is leading to the increased use of other compound classes.
Dracunculus
In the case of ''Dracunculus medinensis
''Dracunculus medinensis'' (Guinea worm, dragon worm, fiery serpent) is a nematode that causes dracunculiasis, also known as Guinea worm disease. The disease is caused by the female which, at around in length, is among the longest nematodes ...
'' (Guinea worm), metronidazole merely facilitates worm extraction rather than killing the worm.[
]
''C. difficile'' colitis
Initial antibiotic therapy for less-severe ''Clostridioides difficile infection
''Clostridioides difficile'' infection (CDI or C-diff), also known as ''Clostridium difficile'' infection, is a symptomatic infection due to the bacterial spores, spore-forming bacterium ''Clostridioides difficile''. Symptoms include watery di ...
'' colitis (pseudomembranous colitis
Colitis is swelling or inflammation of the large intestine ( colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases.
In a medical context, the label ''colitis'' (without qualificati ...
) consists of metronidazole, vancomycin
Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections. It is administered intravenously ( injection into a vein) to treat complicated skin infections, bloodstream infections, endocarditis, bone an ...
, or fidaxomicin by mouth. In 2017, the IDSA generally recommended vancomycin and fidaxomicin over metronidazole. Vancomycin by mouth
Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications.
Oral administ ...
has been shown to be more effective in treating people with severe ''C. difficile'' colitis.
''E. histolytica''
''Entamoeba histolytica
''Entamoeba histolytica'' is an anaerobic organism, anaerobic parasitic amoebozoan, part of the genus ''Entamoeba''. Predominantly infecting humans and other primates causing amoebiasis, ''E. histolytica'' is estimated to infect about 35-50 mil ...
'' invasive amebiasis is treated with metronidazole for eradication, in combination with diloxanide to prevent recurrence. Although it is generally a standard treatment it is associated with some side effects.
Preterm births
Metronidazole has also been used in women to prevent preterm birth
Preterm birth, also known as premature birth, is the Childbirth, birth of a baby at fewer than 37 weeks Gestational age (obstetrics), gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 ...
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 radiation-sensitizing effect of metronidazole in the context of radiation therapy against hypoxic tumors. However, the neurotoxic side effects occurring at the required dosages have prevented the widespread use of metronidazole as an adjuvant agent in radiation therapy. However, other nitroimidazole
Nitroimidazoles are the group of organic compound, organic compounds consisting of an imidazole ring with at least one nitro group substituent. The term also refers to the class of antibiotics that have nitroimidazole in their structures. These an ...
s 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.
Perioral dermatitis
'' Canadian Family Physician'' has recommended topical metronidazole as a third-line treatment for the perioral dermatitis
Perioral dermatitis, also known as periorificial dermatitis, is a common type of inflammatory skin rash. Symptoms include multiple small (1–2 mm) bumps and blisters sometimes with background redness and scale, localized to the skin aroun ...
either along with or without oral tetracycline
Tetracycline, sold under various brand names, is an antibiotic in the tetracyclines family of medications, used to treat a number of infections, including acne, cholera, brucellosis, plague, malaria, and syphilis. It is available in oral an ...
or oral erythromycin
Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used ...
as first and second line treatment respectively.
Adverse effects
Common adverse drug reaction
An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or may result from the combination of two or more drugs. The meaning of this ...
s (≥1% of those treated with the drug) associated with systemic metronidazole therapy include: nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat.
Over 30 d ...
, diarrhea
Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
, weight loss, abdominal pain, vomiting, headache, dizziness, and metallic taste in the mouth. Intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
administration is commonly associated with thrombophlebitis
Thrombophlebitis is a phlebitis (inflammation of a vein) related to a thrombus (blood clot). When it occurs repeatedly in different locations, it is known as thrombophlebitis migrans (migratory thrombophlebitis).
Signs and symptoms
The following ...
. Infrequent adverse effects include: hypersensitivity
Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes Imm ...
reactions (rash, itch, flushing, fever), headache, dizziness, vomiting
Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
, glossitis, stomatitis, dark urine, and paraesthesia
Paresthesia is a sensation of the skin that may feel like numbness (''hypoesthesia''), tingling, pricking, chilling, or burning. It can be temporary or chronic and has many possible underlying causes. Paresthesia is usually painless and can oc ...
. High doses and long-term systemic treatment with metronidazole are associated with the development of leucopenia
Leukopenia () is a decrease in the number of white blood cells (leukocytes). It places individuals at increased risk of infection as white blood cells are the body's primary defense against infections.
Signs and symptoms
Symptoms may include:
* sk ...
, neutropenia
Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
, increased risk of peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...
, and central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
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 has been associated with carcinogenic activity in animal studies. In rare cases, it can also cause temporary hearing loss
Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spo ...
that reverses after cessation of the treatment.
Some evidence from studies in rats indicates the possibility it may contribute to serotonin syndrome
Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...
, 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
The National Toxicology Program (NTP) is an inter-agency program run by the United States Department of Health and Human Services to coordinate, evaluate, and report on toxicology within public agencies.
The National Toxicology Program is head ...
(NTP) as reasonably anticipated to be a human carcinogen
A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and biologic agents such as viruse ...
. 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
In statistical hypothesis testing, a result has statistical significance when a result at least as "extreme" would be very infrequent if the null hypothesis were true. More precisely, a study's defined significance level, denoted by \alpha, is the ...
risk.
Metronidazole is listed as a possible carcinogen according to the World Health Organization
The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...
(WHO) International Agency for Research on Cancer
The International Agency for Research on Cancer (IARC; ) is an intergovernmental agency forming part of the World Health Organization of the United Nations.
Its role is to conduct and coordinate research into the causes of cancer. It also cance ...
(IARC). A study in those with Crohn's disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...
also found chromosomal abnormalities in circulating lymphocytes in people treated with metronidazole.
Stevens–Johnson syndrome
Metronidazole alone rarely causes Stevens–Johnson syndrome
Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and #Classification, Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN) overlap, they are considered febrile mucocutaneous d ...
, but is reported to occur at high rates when combined with mebendazole
Mebendazole (MBZ), sold under the brand name Vermox among others, is a medication used to treat a number of parasitic worm infestations. This includes ascariasis, pinworm infection, hookworm infections, guinea worm infections and hydatid di ...
.
Neurotoxicity
Several studies in the human and animal models have recorded the neurotoxicity
Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...
of metronidazole. One possible mechanism underlying this toxicity is that metronidazole may interference with postsynaptic central monoaminergic neurotransmission and immunomodulation. Additionally other research suggests that the role of nitric oxide
Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...
isoforms and inflammatory cytokine
An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include int ...
s may also play a role.
Drug interactions
Alcohol
Consuming alcohol
Alcohol may refer to:
Common uses
* Alcohol (chemistry), a class of compounds
* Ethanol, one of several alcohols, commonly known as alcohol in everyday life
** Alcohol (drug), intoxicant found in alcoholic beverages
** Alcoholic beverage, an alco ...
while taking metronidazole has been suspected in case reports
In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrence ...
to cause a disulfiram-like reaction
Disulfiram-alcohol reaction (DAR) is the effect of the interaction in the human body of alcohol drunk with disulfiram or some types of mushrooms. The DAR is key to disulfiram therapy that is widely used for alcohol-aversive treatment and managem ...
with effects that can include nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat.
Over 30 d ...
, vomiting
Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
, flushing of the skin, tachycardia
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...
, and shortness of breath
Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that con ...
. People are often advised not to drink alcohol 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
Propylene glycol ( IUPAC name: propane-1,2-diol) is a viscous, colorless liquid. It is almost odorless and has a faintly sweet taste. Its chemical formula is CH3CH(OH)CH2OH.
As it contains two alcohol groups, it is classified as a diol. An al ...
(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
Metronidazole is a moderate inhibitor of the enzyme CYP2C9
Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, t ...
belonging to the cytochrome P450
Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
family. As a result, metronidazole may interact with medications metabolized by this enzyme. Examples of such medications are lomitapide
Lomitapide , sold under the brand name Juxtapid in the US and Lojuxta in the EU, is a medication used as a lipid-lowering agent for the treatment of familial hypercholesterolemia, developed by Aegerion Pharmaceuticals. It has been tested in cli ...
and warfarin
Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...
, to name a few.[
]
Pharmacology

Mechanism of action
Metronidazole is of the nitroimidazole
Nitroimidazoles are the group of organic compound, organic compounds consisting of an imidazole ring with at least one nitro group substituent. The term also refers to the class of antibiotics that have nitroimidazole in their structures. These an ...
class. It is a prodrug that inhibits nucleic acid synthesis by forming nitroso radical
Radical (from Latin: ', root) may refer to:
Politics and ideology Politics
*Classical radicalism, the Radical Movement that began in late 18th century Britain and spread to continental Europe and Latin America in the 19th century
*Radical politics ...
s, which disrupt the DNA of microbial cells. Metronidazole activates by receiving an electron from the reduced ferredoxin
Ferredoxins (from Latin ''ferrum'': iron + redox, often abbreviated "fd") are iron–sulfur proteins that mediate electron transfer in a range of metabolic reactions. The term "ferredoxin" was coined by D.C. Wharton of the DuPont Co. and applied t ...
produced by pyruvate synthase (PFOR) in anaerobic organisms, equivalent to pyruvate dehydrogenase
Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate.
Pyruvate dehydrogenase is ...
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.
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
An aerobic organism or aerobe is an organism that can survive and grow in an oxygenated environment. The ability to exhibit aerobic respiration may yield benefits to the aerobic organism, as aerobic respiration yields more energy than anaerobic ...
.[
] 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
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
via the gut and peak blood plasma
Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...
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 protein
Plasma proteins, sometimes referred to as blood proteins, are proteins present in blood plasma. They perform many different functions, including transport of hormones, vitamins and minerals in activity and functioning of the immune system. Other b ...
s. It penetrates well into tissues, the cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
, the amniotic fluid
The amniotic fluid is the protective liquid contained by the amniotic sac of a gravid amniote. This fluid serves as a cushion for the growing fetus, but also serves to facilitate the exchange of nutrients, water, and biochemical products betwee ...
and breast milk, as well as into abscess
An abscess is a collection of pus that has built up within the tissue of the body, usually caused by bacterial infection. Signs and symptoms of abscesses include redness, pain, warmth, and swelling. The swelling may feel fluid-filled when pre ...
cavities.
About 60% of the metronidazole is metabolize
Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the ...
d by oxidation
Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
to the main metabolite hydroxymetronidazole and a carboxylic acid
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
derivative, and by glucuronidation
Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...
. The metabolites show antibiotic and antiprotozoal activity ''in vitro
''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
''. Metronidazole and its metabolites are mainly excreted via the kidneys (77%) and to a lesser extent via the faeces (14%).[ The ]biological half-life
Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a drug, biological substance (such as a medication) to decrease from its maximum concentration (chemistry), concentration (Cmax (pharm ...
of metronidazole in healthy adults is eight hours, in infants during the first two months of their lives about 23 hours, and in premature
Premature may refer to:
* ''Premature'' (2014 film), an American comedy film
* ''Premature'' (2019 film), an American romantic drama film
* '' PREMature'', a 2015 British television drama miniseries
See also
* Premature aging, of an organism
* ...
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. The serum half-life of hydroxymetronidazole after suppository
A suppository is a dosage form used to deliver pharmaceutical drug, medications by insertion into a body orifice (any opening in the body), where it dissolves or melts to exert local or systemic effects. There are three types of suppositories, eac ...
was 10 hours, 19 hours after intravenous infusion, and 11 hours after a tablet.
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 nitroimidazole
Nitroimidazoles are the group of organic compound, organic compounds consisting of an imidazole ring with at least one nitro group substituent. The term also refers to the class of antibiotics that have nitroimidazole in their structures. These an ...
s 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
An episome is a special type of plasmid, which remains as a part of the eukaryotic genome without integration. Episomes manage this by replicating together with the rest of the genome and subsequently associating with metaphase chromosomes during m ...
.
Other mechanisms may include reduced drug activation, efflux pump
An efflux pump is an active transporter in cells that moves out unwanted material. Efflux pumps are an important component in bacteria, particularly in their ability to remove antibiotics. The efflux process can also involve the movement of hea ...
s, 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
Rhône-Poulenc () was a French chemical and pharmaceutical company founded in 1928. In 1999, it merged with Hoechst AG to form Aventis. As of 2015, the pharmaceutical operations of Rhône-Poulenc are part of Sanofi and the chemicals divisions ...
in the 1950s and licensed to G.D. Searle. Searle was acquired by Pfizer in 2003. The original patent expired in 1982, but evergreening
Evergreening is any of various legal, business, and technological strategies by which producers (often pharmaceutical companies) extend the lifetime of their patents that are about to expire in order to retain revenues from them. Often the practice ...
reformulation occurred thereafter.
Brand name
In India, it is sold under the brand name Metrogyl and Flagyl. In Bangladesh, it is available as Amodis, Amotrex, Dirozyl, Filmet, Flagyl, Flamyd, Metra, Metrodol, Metryl, etc. 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.
Synthesis
2-Methylimidazole (1) may be prepared via the Debus-Radziszewski imidazole synthesis, or from ethylenediamine
Ethylenediamine (abbreviated as en when a ligand) is the organic compound with the formula C2H4(NH2)2. This colorless liquid with an ammonia-like odor is a basic amine. It is a widely used building block in chemical synthesis, with approximately ...
and acetic acid
Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main compone ...
, followed by treatment with lime, then Raney nickel
Raney nickel , also called spongy nickel, is a fine-grained solid composed mostly of nickel derived from a nickel–aluminium alloy. Several grades are known, of which most are gray solids. Some are pyrophoric, but most are used as air-stable s ...
. 2-Methylimidazole is nitrated to give 2-methyl-4(5)-nitroimidazole (2), which is in turn alkylated with ethylene oxide
Ethylene oxide is an organic compound with the chemical formula, formula . It is a cyclic ether and the simplest epoxide: a three-membered ring (chemistry), ring consisting of one oxygen atom and two carbon atoms. Ethylene oxide is a colorless ...
or 2-chloroethanol
2-Chloroethanol (also called ethylene chlorohydrin or glycol chlorohydrin) is an organic chemical compound with the chemical formula HOCH2CH2Cl and the ''simplest'' beta-halohydrin (chlorohydrin). This colorless liquid has a pleasant ether-like od ...
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
In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
(ROS) and nitric oxide
Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...
by activated immune cells, such as macrophage
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s and neutrophil
Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...
s. Metronidazole's immunomodulatory properties are thought to be related to its ability to decrease the activation of nuclear factor-kappa B
Nuclear may refer to:
Physics
Relating to the nucleus of the atom:
* Nuclear engineering
* Nuclear physics
* Nuclear power
*Nuclear reactor
*Nuclear weapon
* Nuclear medicine
*Radiation therapy
*Nuclear warfare
Mathematics
* Nuclear space
* Nu ...
(NF-κB), a transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
that regulates the expression of pro-inflammatory cytokine
Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling.
Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s, including chemokine
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addit ...
s, and adhesion molecules. Cytokines are small proteins that are secreted by immune cells and play a key role in the immune response. 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. 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. By inhibiting NF-κB activation, metronidazole can reduce the production of pro-inflammatory cytokines, such as TNF-alpha
Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
, IL-6, and IL-1β
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
.
Metronidazole has been studied in various immunological disorders, including inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine ...
, periodontitis
Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main c ...
, and rosacea
Rosacea is a long-term skin condition that typically affects the face. It results in redness, pimples, swelling, and small and superficial dilated blood vessels. Often, the nose, cheeks, forehead, and chin are most involved. A red, en ...
. In these conditions, metronidazole has been suspected to have anti-inflammatory and immunomodulatory effects that could be beneficial in the treatment of these conditions. Despite the success in treating rosacea with metronidazole, 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. 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.
Metronidazole is also researched as a potential anti-inflammatory agent in periodontitis
Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main c ...
treatment.
Veterinary use
Metronidazole is used to treat infections of ''Giardia
''Giardia'' ( or ) is a genus of anaerobic flagellated protozoan parasites of the phylum Metamonada that colonise and reproduce in the small intestines of several vertebrates, causing the disease giardiasis. Their life cycle alternates be ...
'' in dogs, cats, and other companion animals, but it does not reliably clear infection with this organism and is being supplanted by fenbendazole
Fenbendazole is a broad-spectrum benzimidazole anthelmintic used against gastrointestinal parasites including: roundworms, hookworms, whipworms, the tapeworm genus '' Taenia'' (but not effective against '' Dipylidium caninum'', a common dog ...
for this purpose in dogs and cats. It is also used for the management of chronic inflammatory bowel disease, gastrointestinal infections, periodontal disease, and systemic infections in cats and dogs. Another common usage is the treatment of systemic and/or gastrointestinal clostridia
The Clostridia are a highly polyphyletic class of Bacillota, including '' Clostridium'' and other similar genera. They are distinguished from the Bacilli by lacking aerobic respiration. They are obligate anaerobes and oxygen is toxic to them ...
l 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
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(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.
The appropriate dosage of metronidazole varies based on the animal species, the condition being treated and the specific formulation of the product.
References
External links
*
{{Authority control
Drugs developed by AbbVie
Antiprotozoal agents
Disulfiram-like drugs
Fishkeeping
French inventions
IARC Group 2B carcinogens
Nitroimidazole antibiotics
Drugs developed by Pfizer
Wikipedia medicine articles ready to translate
Sanofi
World Health Organization essential medicines
Hydroxyethyl compounds