Rifampicin, also known as rifampin, is an
ansamycin
Ansamycins is a family of bacterial secondary metabolites that show antimicrobial activity against many Gram-positive and some Gram-negative bacteria, and includes various compounds, including streptovaricins and rifamycins. In addition, these ...
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
used to treat several types of
bacterial infections
Pathogenic bacteria are bacteria that can cause disease. This article focuses on the bacteria that are pathogenic to humans. Most species of bacteria are harmless and are often beneficial but others can cause infectious diseases. The number of t ...
, including
tuberculosis
Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...
(TB),
''Mycobacterium avium'' complex,
leprosy
Leprosy, also known as Hansen's disease (HD), is a long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the nerves, respiratory tract, skin, and eyes. This nerve damag ...
, and
Legionnaires’ disease
Legionnaires' disease is a form of atypical pneumonia caused by any species of ''Legionella'' bacteria, quite often '' Legionella pneumophila''. Signs and symptoms include cough, shortness of breath, high fever, muscle pains, and headaches. Naus ...
.
It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended"
for latent TB infection; and when used as post-exposure prophylaxis to prevent
''Haemophilus influenzae'' type b and
meningococcal disease
Meningococcal disease describes infections caused by the bacterium ''Neisseria meningitidis'' (also termed meningococcus). It has a high mortality rate if untreated but is vaccine-preventable. While best known as a cause of meningitis, it can al ...
in people who have been exposed to those bacteria.
Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended.
Rifampicin may be given either
by mouth
Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...
or intravenously.
Common side effects include nausea, vomiting, diarrhea, and loss of appetite.
It often turns urine, sweat, and tears a red or orange color.
Liver problems or allergic reactions may occur.
It is part of the recommended treatment of active tuberculosis during pregnancy, though its safety in pregnancy is not known.
Rifampicin is of the
rifamycin
The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium ''Amycolatopsis rifamycinica'' or artificially. They are a subclass of the larger family of ansamycins. Rifamycins are particularly effective again ...
group of antibiotics.
It works by decreasing the production of
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
by bacteria.
Rifampicin was discovered in 1965, marketed in Italy in 1968, and approved in the United States in 1971.
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 ...
.
The World Health Organization classifies rifampicin as critically important for human medicine. It is available as a
generic medication
A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
.
Rifampicin is made by the soil bacterium ''
Amycolatopsis rifamycinica
''Amycolatopsis rifamycinica'' is a species of Gram-positive bacteria in the genus '' Amycolatopsis''. It produces the rifamycin antibiotics (''e.g.'', rifamycin SV), which are used to treat mycobacterial diseases such as tuberculosis and lep ...
''.
Medical uses
Mycobacteria
Rifampicin is used for the treatment of
tuberculosis
Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...
in combination with other antibiotics, such as
pyrazinamide
Pyrazinamide is a medication used to treat tuberculosis. For active tuberculosis, it is often used with rifampicin, isoniazid, and either streptomycin or ethambutol. It is not generally recommended for the treatment of latent tuberculosis. I ...
,
isoniazid
Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. For la ...
, and
ethambutol
Ethambutol (EMB, E) is a medication primarily used to treat tuberculosis. It is usually given in combination with other tuberculosis medications, such as isoniazid, rifampicin and pyrazinamide. It may also be used to treat ''Mycobacterium avi ...
. For the treatment of tuberculosis, it is administered daily for at least six months.
Combination therapy is used to prevent the development of resistance and to shorten the length of treatment.
Resistance of ''
Mycobacterium tuberculosis
''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on its c ...
'' to rifampicin develops quickly when it is used without another antibiotic, with laboratory estimates of resistance rates from 10
−7 to 10
−10 per tuberculosis bacterium per generation.
Rifampicin can be used alone in patients with latent tuberculosis
Latent tuberculosis (LTB), also called latent tuberculosis infection (LTBI) is when a person is infected with ''Mycobacterium tuberculosis'', but does not have active tuberculosis. Active tuberculosis can be contagious while latent tuberculosis is ...
infections to prevent or delay the development of active disease because only small numbers of bacteria are present. A Cochrane review found no difference in efficacy between a 3- to 4-month regimen of rifampicin and a 6-month regimen of isoniazid for preventing active tuberculosis in patients not infected with HIV, and patients who received rifampicin had a lower rate of hepatotoxicity
Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fro ...
.[ However, the quality of the evidence was judged to be low.] A shorter 2-month course of rifampicin and pyrazinamide had previously been recommended but is no longer recommended due to high rates of hepatotoxicity.
Rifampicin should be taken on an empty stomach with a glass of water. It is generally taken either at least one hour before meals or two hours after meals.
Rifampicin is also used to treat nontuberculous mycobacterial
''Mycobacterium'' is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis ('' M. tuberculosis'') and ...
infections including leprosy
Leprosy, also known as Hansen's disease (HD), is a long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the nerves, respiratory tract, skin, and eyes. This nerve damag ...
(Hansen's disease) and ''Mycobacterium kansasii
''Mycobacterium kansasii'' is a bacterium in the ''Mycobacterium'' genus. It is an environmental bacteria that causes opportunistic infections in humans, and is the one of the leading mycobacterial causes of human disease after tuberculosis and ...
''.
With multidrug therapy used as the standard treatment of Hansen's disease, rifampicin is always used in combination with dapsone
Dapsone, also known as 4,4'-sulfonyldianiline (SDA) or diaminodiphenyl sulfone (DDS), is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is a second-line medication for the treatment a ...
and clofazimine
Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to sup ...
to avoid causing drug resistance.
It is also used in the treatment of ''Mycobacterium ulcerans
''Mycobacterium ulcerans'' is a species of bacteria found in various aquatic environments. The bacteria can infect humans and some other animals, causing persistent open wounds called Buruli ulcer. ''M. ulcerans'' is closely related to '' Mycob ...
'' infections as associated with Buruli ulcer
Buruli ulcer () is an infectious disease characterized by the development of painless open wounds. The disease is limited to certain areas of the world, most cases occurring in Sub-Saharan Africa and Australia. The first sign of infection is a s ...
, usually in combination with clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, ''H. pylori'' infection, and Lyme disease, among others. Clarith ...
or other antibiotics.
Other bacteria and protozoans
In 2008, tentative evidence showed rifampicin may be useful in the treatment of methicillin-resistant ''Staphylococcus aureus'' (MRSA
Methicillin-resistant ''Staphylococcus aureus'' (MRSA) is a group of Gram-positive bacteria that are genetically distinct from other strains of ''Staphylococcus aureus''. MRSA is responsible for several difficult-to-treat infections in humans. ...
) in combination with other antibiotics, including in difficult-to-treat infections such as osteomyelitis and prosthetic joint infections. As of 2012, if rifampicin combination therapy was useful for pyogenic vertebral osteomyelitis was unclear. A meta-analysis concluded that adding adjunctive rifampicin to a β-lactam or vancomycin may improve outcomes in staphylococcus aureus bacteremia. However, a more recent trial found no benefit from adjunctive rifampicin.
It is also used as preventive treatment against ''Neisseria meningitidis'' (meningococcal
''Neisseria meningitidis'', often referred to as meningococcus, is a Gram-negative bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life-threatening sepsis. The bacterium is referred to as a ...
) infections. Rifampicin is also recommended as an alternative treatment for infections by the tick-borne pathogens ''Borrelia burgdorferi
''Borrelia burgdorferi'' is a bacterial species of the spirochete class in the genus ''Borrelia'', and is one of the causative agents of Lyme disease in humans. Along with a few similar genospecies, some of which also cause Lyme disease, it make ...
'' and ''Anaplasma phagocytophilum
''Anaplasma phagocytophilum'' (formerly ''Ehrlichia phagocytophilum'') is a Gram-negative bacterium that is unusual in its tropism to neutrophils. It causes anaplasmosis in sheep and cattle, also known as tick-borne fever and pasture fever, and ...
'' when treatment with doxycycline
Doxycycline is a broad-spectrum tetracycline class antibiotic used in the treatment of infections caused by bacteria and certain parasites. It is used to treat bacterial pneumonia, acne, chlamydia infections, Lyme disease, cholera, typhus, an ...
is contraindicated, such as in pregnant women or in patients with a history of allergy to tetracycline antibiotics.
It is also sometimes used to treat infections by ''Listeria
''Listeria'' is a genus of bacteria that acts as an intracellular parasite in mammals. Until 1992, 17 species were known, each containing two subspecies. By 2020, 21 species had been identified. The genus is named in honour of the British pi ...
'' species, ''Neisseria gonorrhoeae
''Neisseria gonorrhoeae'', also known as ''gonococcus'' (singular), or ''gonococci'' (plural), is a species of Gram-negative diplococci bacteria isolated by Albert Ludwig Sigesmund Neisser, Albert Neisser in 1879. It causes the sexually transmit ...
'', ''Haemophilus influenzae
''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, non-motile, coccobacillary, facultatively anaerobic, capnophilic pathogenic bacterium of the family Pasteurellaceae. The bacteria ...
'', and ''Legionella pneumophila
''Legionella pneumophila'' is a thin, aerobic, pleomorphic, flagellated, non-spore-forming, Gram-negative bacterium of the genus ''Legionella''. ''L. pneumophila'' is the primary human pathogenic bacterium in this group and is the causative age ...
''. For these nonstandard indications, antimicrobial susceptibility testing should be done (if possible) before starting rifampicin therapy.
The Enterobacteriaceae, ''Acinetobacter
''Acinetobacter'' is a genus of gram-negative bacteria belonging to the wider class of Gammaproteobacteria. ''Acinetobacter'' species are oxidase-negative, exhibit twitching motility, and occur in pairs under magnification.
They are important ...
'' species, and ''Pseudomonas
''Pseudomonas'' is a genus of Gram-negative, Gammaproteobacteria, belonging to the family Pseudomonadaceae and containing 191 described species. The members of the genus demonstrate a great deal of metabolic diversity and consequently are able ...
'' species are intrinsically resistant to rifampicin.
It has been used with amphotericin B
Amphotericin B is an antifungal medication used for serious mycosis, fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candida infections, candidiasis, coccidioidomy ...
in largely unsuccessful attempts to treat primary amoebic meningoencephalitis
Naegleriasis (also known as primary amoebic meningoencephalitis; PAM) is an almost invariably fatal infection of the brain by the free-living unicellular eukaryote ''Naegleria fowleri''. Symptoms are meningitis-like and include headache, fever, ...
caused by ''Naegleria fowleri
''Naegleria fowleri'', colloquially known as a "brain-eating amoeba", is a species of the genus ''Naegleria'', belonging to the phylum Percolozoa, which is technically not classified as true amoeba, but a shapeshifting amoeboflagellate excava ...
''.
Rifampicin can be used as monotherapy for a few days as prophylaxis against meningitis, but resistance develops quickly during long-term treatment of active infections, so the drug is always used against active infections in combination with other antibiotics.
Rifampicin is relatively ineffective against spirochetes
A spirochaete () or spirochete is a member of the phylum Spirochaetota (), (synonym Spirochaetes) which contains distinctive diderm (double-membrane) gram-negative bacteria, most of which have long, helically coiled (corkscrew-shaped or ...
, which has led to its use as a selective agent capable of isolating them in materials being cultured in laboratories.
Viruses
Rifampicin has some effectiveness against vaccinia
''Vaccinia virus'' (VACV or VV) is a large, complex, enveloped virus belonging to the poxvirus family. It has a linear, double-stranded DNA genome approximately 190 kbp in length, which encodes approximately 250 genes. The dimensions of the ...
virus.
Pathogen susceptibility
The minimum inhibitory concentrations of rifampicin for several medically significant pathogens are:
* ''Mycobacterium tuberculosis'' — 0.002 – 64 µg/ml
* ''Mycobacterium bovis'' — 0.125 µg/ml
* ''Staphylococcus aureus'' (methicillin resistant) — ≤ 0.006–256 µg/ml
* ''Chlamydia pneumoniae'' — 0.005 µg/ml
Primary biliary cholangitis
Rifampicin is used to treat itchiness
Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...
caused by primary biliary cholangitis
Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build ...
. The treatment-related adverse effects include hepatotoxicity
Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fro ...
, nephrotoxicity Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxin ...
, hemolysis
Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...
, and interactions with other drugs. For those reasons as well as some ethical concerns regarding off-label use of antibiotics, rifampin as a very effective preventive antibiotic for meningitis, is not considered appropriate for itchiness.
Hidradenitis suppurativa
Rifampicin with clindamycin
Clindamycin is an 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 (middle ear infec ...
has been used to treat the skin disease hidradenitis suppurativa
Hidradenitis suppurativa (HS), sometimes known as acne inversa or Verneuil's disease, is a long-term dermatological condition characterized by the occurrence of inflamed and swollen lumps. These are typically painful and break open, releasing ...
.
Adverse effects
The most serious adverse effect
An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...
is hepatotoxicity, and people receiving it often undergo baseline and frequent liver function tests
Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin ti ...
to detect early liver damage.
The more common side effects include fever, gastrointestinal disturbances, rashes, and immunological reactions. Taking rifampicin usually causes certain bodily fluids, such as urine, sweat, and tears, to become orange-red in color, a benign side effect that nonetheless can be frightening if it is not expected. This may also be used to monitor effective absorption of the drug (if drug color is not seen in the urine, the patient may wish to move the drug dose farther in time from food or milk intake). The discolorization of sweat and tears is not directly noticeable, but sweat may stain light clothing orange, and tears may permanently stain soft contact lenses. Since rifampicin may be excreted in breast milk, breastfeeding should be avoided while it is being taken.
Other adverse effects include:
* Liver toxicity—hepatitis
Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pa ...
, liver failure in severe cases
* Respiratory—breathlessness
* Cutaneous—flushing, pruritus, rash, hyperpigmentation, redness and watering of eyes
* Abdominal — nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
, vomiting, abdominal cramps, diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
* Flu-like symptoms
Influenza-like illness (ILI), also known as flu-like syndrome or flu-like symptoms, is a medical diagnosis of possible influenza or other illness causing a set of common symptoms. These include fever, shivering, chills, malaise, dry cough, loss ...
—chills, fever, headache, arthralgia
Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication.
According to MeSH, ...
, and malaise
As a medical term, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. The word has existed in French since at least the 12th century.
The term is often used ...
. Rifampicin has good penetration into the brain, and this may directly explain some malaise and dysphoria
Dysphoria (; ) is a profound state of unease or dissatisfaction. It is the semantic opposite of euphoria. In a psychiatric context, dysphoria may accompany depression, anxiety, or agitation.
In psychiatry
Intense states of distress and unea ...
in a minority of users.
* Allergic reaction—rashes, itching, swelling of the tongue or throat, severe dizziness, and trouble breathing
Chemical structure
Rifampicin is a polyketide
Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
belonging to the chemical class of compounds termed ansamycin
Ansamycins is a family of bacterial secondary metabolites that show antimicrobial activity against many Gram-positive and some Gram-negative bacteria, and includes various compounds, including streptovaricins and rifamycins. In addition, these ...
s, so named because of their heterocyclic structure containing a naphthoquinone
Naphthoquinones constitute a class of organic compounds structurally related to naphthalene. Two isomers are common for the parent naphthoquinones:
* 1,2-Naphthoquinone
* 1,4-Naphthoquinone
Natural products
* Alkannin
* Hexahydroxy-1,4-napht ...
core spanned by an aliphatic ansa chain. The naphthoquinonic chromophore gives rifampicin its characteristic red-orange crystalline color.
The critical functional groups of rifampicin in its inhibitory binding of bacterial RNA polymerase are the four critical hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
groups of the ansa bridge and the naphthol ring, which form hydrogen bond
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
s with amino acid residues on the protein.
Rifampicin is the derivative of rifamycin SV.
Interactions
Rifampicin is the most powerful known inducer
In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely:
*By disabling repressors. The gene is expressed because an inducer binds to the repressor. The binding of the inducer to the r ...
of the hepatic
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
enzyme system, including isoenzymes CYP2B6
Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.
Funct ...
, CYP2C8
Cytochrome P4502C8 (abbreviated CYP2C8), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-cha ...
, CYP2C9
Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...
, CYP2C19
Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...
, CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
, CYP3A5
Cytochrome P450 3A5 is a protein that in humans is encoded by the ''CYP3A5'' gene.
Tissue distribution
''CYP3A5'' encodes a member of the cytochrome P450 superfamily of enzymes. Like most of the cytochrome P450, the CYP3A5 is expressed in the ...
, and CYP3A7
CYP3A7 is an enzyme belonging to the cytochrome P450 family. It is 503 amino acids in size and shares 87% of its sequence with CYP3A4. It carries out a similar role in fetuses that CYP3A4 serves in adults. The gene location is 7q22.1.
The CYP3 ...
. It increases metabolism of many drugs and as a consequence, can make them less effective, or even ineffective, by decreasing their levels.[Collins, R Douglas. Atlas of Drug Reactions. New York, NY: ChurchillLivingstone, 1985. p. 123.] For instance, patients undergoing long-term anticoagulation therapy with warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent strok ...
have to increase their dosage of warfarin and have their clotting time checked frequently because failure to do so could lead to inadequate anticoagulation, resulting in serious consequences of thromboembolism.
Rifampicin can reduce the efficacy of birth control pills Oral contraceptives, abbreviated OCPs, also known as birth control pills, are medications taken by mouth for the purpose of birth control.
Female
Two types of female oral contraceptive pill, taken once per day, are widely available:
* The combin ...
or other hormonal contraception
Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The origin ...
by its induction of the cytochrome P450 system, to the extent that unintended pregnancies
Unintended pregnancies are pregnancies that are mistimed, unplanned or unwanted at the time of conception.
Sexual activity without the use of effective contraception through choice or coercion is the predominant cause of unintended pregnancy. W ...
have occurred in women who use oral contraceptives and took rifampicin even for very short courses (for example, as prophylaxis against exposure to bacterial meningitis).
Other interactions include decreased levels and less effectiveness of antiretroviral agents, everolimus
Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours.
It is the 40 ...
, atorvastatin
Atorvastatin is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.
Common ...
, rosiglitazone
Rosiglitazone (trade name Avandia) is an antidiabetic drug in the thiazolidinedione class. It works as an insulin sensitizer, by binding to the PPAR in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutica ...
, pioglitazone
Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes. It may be used with metformin, a sulfonylurea, or insulin. Use is recommended together with exercise and diet. It is not re ...
, celecoxib
Celecoxib, sold under the brand name Celebrex among others, is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, ankyl ...
, clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, ''H. pylori'' infection, and Lyme disease, among others. Clarith ...
, caspofungin
Caspofungin (INN) (brand name Cancidas) is a lipopeptide antifungal drug from Merck & Co., Inc. discovered by James Balkovec, Regina Black and Frances A. Bouffard. It is a member of a new class of antifungals termed the echinocandins. It wor ...
, voriconazole
Voriconazole, sold under the brand name Vfend among others, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, candidiasis, coccidioidomycosis, histoplasmosis, penicilliosis, and infections by '' ...
, and lorazepam
Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety disorders, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and c ...
.
Rifampicin is antagonistic to the microbiologic effects of the antibiotics gentamicin and amikacin. The activity of rifampicin against some species of mycobacteria can be potentiated by isoniazid (through inhibiting mycolate synthesis) and ambroxol (through host directed effects in autophagy and pharmacokinetics).
Pharmacology
Mechanism of action
Rifampicin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase
In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template.
Using the enzyme helicase, RNAP locally opens the ...
.
Crystal structure data and biochemical data suggest that rifampicin binds to the pocket of the RNA polymerase β subunit within the DNA/RNA channel, but away from the active site.[ The inhibitor prevents RNA synthesis by physically blocking elongation, and thus preventing synthesis of host bacterial proteins. By this "steric-occlusion" mechanism, rifampicin blocks synthesis of the second or third ]phosphodiester bond
In chemistry, a phosphodiester bond occurs when exactly two of the hydroxyl groups () in phosphoric acid react with hydroxyl groups on other molecules to form two ester bonds. The "bond" involves this linkage . Discussion of phosphodiesters is ...
between the nucleotides in the RNA backbone, preventing elongation of the 5' end of the RNA transcript past more than 2 or 3 nucleotides.
In a recent study Rifampicin was shown to bind to cytochrome P450 reductase
Cytochrome P450 reductase (; also known as NADPH:ferrihemoprotein oxidoreductase, NADPH:hemoprotein oxidoreductase, NADPH:P450 oxidoreductase, P450 reductase, POR, CPR, CYPOR) is a membrane-bound enzyme required for electron transfer from NADP ...
and alter its conformation as well as activity towards supporting metabolism of progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
via CYP21A2
Steroid 21-hydroxylase (also known as steroid 21-monooxygenase, cytochrome P450C21, 21α-hydroxylase and less commonly 21β-hydroxylase) is an enzyme that hydroxylates steroids at the C21 position and is involved in biosynthesis of aldosteron ...
.
Mechanism of resistance
Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin.[ Resistance mutations map to the '']rpoB
The ''rpoB'' gene encodes the β subunit of bacterial RNA polymerase and the homologous plastid-encoded RNA polymerase (PEP). It codes for 1342 amino acids in ''E. coli'', making it the second-largest polypeptide in the bacterial cell. It is targe ...
'' gene, encoding the beta subunit of RNA polymerase. The majority of resistance mutations in ''E. coli'' are in 3 clusters on ''rpoB''. Cluster I is amino acids 509 to 533, cluster II is amino acids 563 to 572, and cluster III is amino acid 687.
When describing mutations in ''rpoB'' in other species, the corresponding amino acid number in ''E. coli'' is usually used. In ''Mycobacterium tuberculosis'', the majority of mutations leading to rifampicin resistance are in cluster I, in a 81bp hotspot core region called RRDR for "rifampcin resistance determining region". A change in amino acid 531 from serine
Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
to leucine
Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- ca ...
arising from a change in the DNA sequence of TCG to TTG is the most common mutation.[ Tuberculosis resistance has also occurred due to mutations in the ]N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
region of ''rpoB'' and cluster III.[
An alternative mechanism of resistance is through Arr-catalyzed ADP-ribosylation of rifampicin. With the assistance of the enzyme Arr produced by the pathogen '']Mycobacterium smegmatis
''Mycobacterium smegmatis'' is an acid-fast bacterial species in the phylum ''Actinomycetota'' and the genus ''Mycobacterium''. It is 3.0 to 5.0 µm long with a bacillus shape and can be stained by Ziehl–Neelsen method and the auramine-rh ...
,'' ADP-ribose is added to rifampicin at one of its ansa chain hydroxy groups, thereby inactivating the drug.
Resistance in tuberculosis
Mycobacterial resistance to rifampicin may occur alone or along with resistance to other first-line antitubercular drugs. Early detection of such multidrug or extensively drug-resistant tuberculosis is critical in improving patient outcomes by instituting appropriate second-line treatments, and in decreasing transmission of drug-resistant TB. Traditional methods of detecting resistance involve mycobacterial culture and drug susceptibility testing, results of which could take up to 6 weeks. Xpert MTB/RIF assay is an automated test that can detect rifampicin resistance, and also diagnose tuberculosis. A Cochrane review
Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health professi ...
updated in 2014 concluded that for rifampicin resistance detection, Xpert MTB/RIF was accurate, that is (95%) sensitive and (98%) specific.
Pharmacokinetics
Orally administered rifampicin results in peak plasma concentrations in about 2–4 hours. 4-Aminosalicylic acid (another antituberculosis drug) significantly reduces absorption of rifampicin, and peak concentrations may be lower. If these two drugs must be used concurrently, they must be given separately, with an interval of 8 to 12 hours between administrations.
Rifampicin is easily absorbed from the gastrointestinal
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
(GI) tract; its ester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
functional group is quickly hydrolyzed
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysis ...
in bile
Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...
, and it is catalyzed by a high pH and substrate-specific esterases
An esterase is a hydrolase enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis.
A wide range of different esterases exist that differ in their substrate specificity, their protein structur ...
. After about 6 hours, almost all of the drug is deacetylated. Even in this deacetylated form, rifampicin is still a potent antibiotic; however, it can no longer be reabsorbed by the intestines and is eliminated from the body. Only about 7% of the administered drug is excreted unchanged in urine, though urinary elimination accounts for only about 30% of the drug excretion. About 60% to 65% is excreted through feces.
The half-life
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...
of rifampicin ranges from 1.5 to 5.0 hours, though hepatic impairment significantly increases it. Food consumption inhibits its absorption from the GI tract, and the drug is more quickly eliminated. When rifampicin is taken with a meal, its peak blood concentration falls by 36%. Antacids do not affect its absorption. The decrease in rifampicin absorption with food is sometimes enough to noticeably affect urine color, which can be used as a marker for whether or not a dose of the drug has been effectively absorbed.
Distribution of the drug is high throughout the body, and reaches effective concentrations in many organs and body fluids, including the cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.
CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
. Since the substance itself is red, this high distribution is the reason for the orange-red color of the saliva, tears, sweat, urine, and feces. About 60% to 90% of the drug is bound to plasma proteins.[Hardman, Joel G., ]Lee E. Limbird
Lee Limbird (born November 27, 1948 in Philadelphia, Pennsylvania) is a pharmacologist, Dean of the School of Natural Science, Mathematics and Business & Professor in the
Department of Life and Physical Sciences at Fisk University, Nashville ...
, and Alfred G. Gilman, eds. "Rifampin." The Pharmacological Basis of Therapeutics. 10th ed. United States of America: The McGraw-Hill Companies, 2001. pp. 1277–1279.
Use in biotechnology
Rifampicin inhibits bacterial RNA polymerase, and is commonly used to inhibit the synthesis of host bacterial proteins during recombinant protein expression in bacteria. RNA encoding for the recombinant gene is usually transcribed from DNA by a viral T7 RNA polymerase
T7 RNA Polymerase is an RNA polymerase from the T7 bacteriophage that catalyzes the formation of RNA from DNA in the 5'→ 3' direction.
Activity
T7 polymerase is extremely promoter-specific and transcribes only DNA downstream of a T7 promo ...
, which is not affected by rifampicin.
History
In 1957, a soil sample from a pine forest on the French Riviera was brought for analysis to the Lepetit Pharmaceuticals research lab in Milan
Milan ( , , Lombard: ; it, Milano ) is a city in northern Italy, capital of Lombardy, and the second-most populous city proper in Italy after Rome. The city proper has a population of about 1.4 million, while its metropolitan city h ...
, Italy. There, a research group headed by Piero Sensi and Maria Teresa Timbal discovered a new bacterium. This new species produced a new class of molecules with antibiotic activity. Because Sensi, Timbal and the researchers were particularly fond of the French crime story ''Rififi
''Rififi'' (french: Du rififi chez les hommes) is a 1955 French crime film adaptation of Auguste Le Breton's novel of the same name. Directed by American Hollywood blacklist, blacklisted filmmaker Jules Dassin, the film stars Jean Servais as the ...
'' (about a jewel heist and rival gangs), they decided to call these compounds ''rifamycins''. After two years of attempts to obtain more stable semisynthetic products, a new molecule with high efficacy and good tolerability was produced in 1965 and was named rifampicin.[
Rifampicin was first sold in Italy in 1968 and was approved by the FDA in 1971.][
]
Society and culture
Cancer-causing impurities
In August 2020, 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 respon ...
(FDA) became aware of nitrosamine impurities in certain samples of rifampin.[ ] The FDA and manufacturers are investigating the origin of these impurities in rifampin, and the agency is developing testing methods for regulators and industry to detect the (MNP). MNP belongs to the nitrosamine class of compounds, some of which are classified as probable or possible human carcinogens (substances that could cause cancer), based on laboratory tests such as rodent carcinogenicity studies. Although there are no data available to directly evaluate the carcinogenic potential of MNP, information available on closely related nitrosamine compounds was used to calculate lifetime exposure limits for MNP.
As of January 2021, the FDA continues to investigate the presence of (MNP) in rifampin or (CPNP) in rifapentine approved for sale in the US.
Names
Rifampicin is the INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
and BAN, while rifampin is the USAN
280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk(于山國)was Ulleungdo(鬱陵島)
Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to th ...
. Rifampicin may be abbreviated R, RMP, RA, RF, or RIF (US).
Rifampicin is also known as rifaldazine, rofact, and rifampin in the United States, also as rifamycin SV.
Its chemical name is .
Rifampicin is available under many brand names worldwide.
References
External links
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