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Rifampicin, also known as rifampin, is an ansamycin
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 ...
used to treat several types of bacterial infections, including
tuberculosis Tuberculosis (TB), also known colloquially as the "white death", or historically as consumption, is a contagious disease usually caused by ''Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can al ...
(TB), ''Mycobacterium avium'' complex,
leprosy Leprosy, also known as Hansen's disease (HD), is a Chronic condition, long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the Peripheral nervous system, nerves, respir ...
, 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, myalgia, muscle pains, and headach ...
. 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 is a serious infection caused by ''Neisseria meningitidis'', also known as meningococcus, a gram negative diplococcus. Meningococcal disease includes meningitis, meningococcal septicemia, or a combination of both, which c ...
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 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 ...
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 group of antibiotics. It works by decreasing the production of
RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...
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 s ...
. 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''.


Medical uses


Mycobacteria

Rifampicin is used for the treatment of
tuberculosis Tuberculosis (TB), also known colloquially as the "white death", or historically as consumption, is a contagious disease usually caused by ''Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can al ...
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. It 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. F ...
, 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), also known as Koch's bacillus, 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'' ha ...
'' 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 (TB). Active tuberculosis can be contagious while latent tubercul ...
infections to prevent or delay the development of active disease because only small numbers of bacteria are present. A
Cochrane review Cochrane is a British international charitable organisation formed to synthesize medical research findings to facilitate evidence-based choices about health interventions involving health professionals, patients and policy makers. It includes ...
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 (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdr ...
. 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'') an ...
infections including
leprosy Leprosy, also known as Hansen's disease (HD), is a Chronic condition, long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the Peripheral nervous system, nerves, respir ...
(Hansen's disease) and ''
Mycobacterium kansasii ''Mycobacterium kansasii'' is a Bacteria, bacterium in the ''Mycobacterium'' genus. It is an environmental bacteria that causes opportunistic infections in humans, and is one of the leading mycobacterial causes of human disease after tuberculosi ...
''. 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 an ...
and clofazimine to avoid causing drug resistance. It is also used in the treatment of '' Mycobacterium ulcerans'' infections as associated with Buruli ulcer, 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. Clari ...
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) 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 m ...
'' 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, an ...
'' when treatment with
doxycycline Doxycycline is a Broad-spectrum antibiotic, broad-spectrum antibiotic of the Tetracycline antibiotics, tetracycline class used in the treatment of infections caused by bacteria and certain parasites. It is used to treat pneumonia, bacterial p ...
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. As of 2024, 28 species have been identified. The genus is named in honour of the British pioneer of sterile surgery Joseph Lister. ''Listeria'' species ...
'' species, ''
Neisseria gonorrhoeae ''Neisseria gonorrhoeae'', also known as ''gonococcus'' (singular) or ''gonococci'' (plural), is a species of Gram-negative diplococci bacteria first isolated by Albert Ludwig Sigesmund Neisser, Albert Neisser in 1879. An obligate human pathog ...
'', ''
Haemophilus influenzae ''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, Motility, non-motile, Coccobacillus, coccobacillary, facultative anaerobic organism, facultatively anaerobic, Capnophile, capnophili ...
'', and ''
Legionella pneumophila ''Legionella pneumophila'', the primary causative agent for Legionnaires' disease, Legionnaire's disease, is an Aerobic organism, aerobic, pleomorphic, Flagellum, flagellated, non-spore-forming, Gram-negative bacteria, Gram-negative bacterium. ' ...
''. For these nonstandard indications, antimicrobial susceptibility testing should be done (if possible) before starting rifampicin therapy. The
Enterobacteriaceae Enterobacteriaceae is a large family (biology), family of Gram-negative bacteria. It includes over 30 genera and more than 100 species. Its classification above the level of Family (taxonomy), family is still a subject of debate, but one class ...
, '' Acinetobacter'' species, and ''
Pseudomonas ''Pseudomonas'' is a genus of Gram-negative bacteria belonging to the family Pseudomonadaceae in the class Gammaproteobacteria. The 348 members of the genus demonstrate a great deal of metabolic diversity and consequently are able to colonize a ...
'' species are intrinsically resistant to rifampicin. It has been used with
amphotericin B Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and cryptococ ...
in largely unsuccessful attempts to treat primary amoebic meningoencephalitis caused by '' Naegleria fowleri''. 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, 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 The 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 An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...
caused by primary biliary cholangitis. The treatment-related adverse effects include
hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdr ...
,
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 #Nomenclature, 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 ...
, 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 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 lesions, lumps. These are typically painful and break open, r ...
.


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 compli ...
is hepatotoxicity, and people receiving it often undergo baseline and frequent liver function tests 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 parenchyma, 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), Anorexia (symptom), poor appetite ...
, 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. 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, abdominal cramps,
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 ...
* Flu-like symptoms—chills, fever, headache,
arthralgia Arthralgia () literally means ' joint pain'. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication Medication (also called medicament, medicine, pharmaceuti ...
, and
malaise In medicine, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. It is considered a vague termdescribing the state of simply not feeling well. The word has exist ...
. 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 uneas ...
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 In organic chemistry, polyketides are a class of natural products derived from a Precursor (chemistry), precursor molecule consisting of a Polymer backbone, chain of alternating ketone (, or Carbonyl reduction, its reduced forms) and Methylene gro ...
belonging to the chemical class of compounds termed ansamycins, so named because of their heterocyclic structure containing a naphthoquinone core spanned by an aliphatic ansa chain. The naphthoquinonic
chromophore A chromophore is the part of a molecule responsible for its color. The word is derived . The color that is seen by our eyes is that of the light not Absorption (electromagnetic radiation), absorbed by the reflecting object within a certain wavele ...
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 (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...
s with amino acid residues on the protein. Rifampicin is the derivative of rifamycin SV.


Interactions

Rifampicin is the most powerful known inducer of the
hepatic The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
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 ...
enzyme system, including isoenzymes CYP2B6,
CYP2C8 Cytochrome P4502C8 (CYP2C8) is a member of the cytochrome P450 mixed-function oxidase system involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsat ...
,
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 ...
, CYP2C19,
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
,
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. It increases metabolism of many drugs and as a consequence, can make them less effective, or even ineffective, by decreasing their levels. For instance, patients undergoing long-term anticoagulation therapy with
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 ...
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 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 original ...
by its induction of the cytochrome P450 system, to the extent that unintended pregnancies 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,
atorvastatin Atorvastatin, sold under the brand name Lipitor among others, 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 ...
, rosiglitazone, pioglitazone, celecoxib,
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. Clari ...
,
caspofungin Caspofungin ( INN; brand name Cancidas) is a lipopeptide antifungal drug from Merck & Co., Inc. It is a member of a class of antifungals termed the echinocandins. It works by inhibiting the enzyme (1→3)-β-D-glucan synthase and thereby di ...
, voriconazole, and
lorazepam Lorazepam, sold under the brand name Ativan, Tavor among others, is a benzodiazepine medication. It is used to treat anxiety (including anxiety disorders), insomnia, severe agitation, active seizures including status epilepticus, alcoh ...
. 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 catalyzes the chemical reactions that synthesize RNA from a DNA template. Using the e ...
. 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 d ...
between the nucleotides in the RNA backbone, preventing elongation of the 5' end of the RNA transcript past more than two or three nucleotides. In a recent study rifampicin was shown to bind to cytochrome P450 reductase 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 ma ...
via
CYP21A2 Steroid 21-hydroxylase is a protein that in humans is encoded by the ''CYP21A2'' gene. The protein is an enzyme that Hydroxylation, hydroxylates steroids at the C21 position on the molecule. Naming conventions for enzymes are based on the subst ...
.


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'' 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 − ...
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-Car ...
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 amin ...
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 bacterium, bacterial species in the phylum ''Actinomycetota'' and the genus ''Mycobacterium''. It is 3.0 to 5.0 μm long with a bacillus (shape), bacillus shape and can be stained by Ziehl–Neels ...
,'' 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 is a British international charitable organisation formed to synthesize medical research findings to facilitate evidence-based choices about health interventions involving health professionals, patients and policy makers. It includes ...
updated in 2014 and 2021 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 tract is the largest of the body's systems, after the cardiovascular system. ...
(GI) tract; its
ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
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 hydrolysi ...
in
bile Bile (from Latin ''bilis''), also known as gall, is a yellow-green/misty green fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is primarily composed of water, is pro ...
, and it is catalyzed by a high pH and substrate-specific esterases. 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 is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...
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 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 ...
. 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.


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 ( , , ; ) is a city in northern Italy, regional capital of Lombardy, the largest city in Italy by urban area and the List of cities in Italy, second-most-populous city proper in Italy after Rome. The city proper has a population of nea ...
, Italy. There, a research group headed by Piero Sensi and Maria Teresa Timbal discovered a new bacterium, Nocardia mediterranei. Nocardia mediterranei produces a class of previously unknown molecules with antibiotic activity. Because Sensi, Timbal and the researchers were particularly fond of the French crime story ''
Rififi ''Rififi'' () is a 1955 French crime film adaptation of Auguste Le Breton's novel of the same name. Directed by American blacklisted filmmaker Jules Dassin, the film stars Jean Servais as the aging gangster Tony "le Stéphanois", Carl Möhn ...
'' (about a jewel heist and rival gangs), they decided to call these compounds rifamycins. Derivatives of one molecule, rifamycin B, which itself possess minimal antibiotic activity yielded several highly active antibiotics, one of the earliest which was used as a medicine being rifamycin SV, which was introduced in some countries for the parenteral and topical treatment of infections due to gram-positive bacteria and infections of the biliary tract. 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 respo ...
(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 and BAN, while rifampin is the USAN. 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

* {{Portal bar , Medicine Antileprotic drugs CYP1A2 inducers CYP3A4 inducers 4-Methylpiperazin-1-yl compounds Pregnane X receptor agonists Rifamycin antibiotics Wikipedia medicine articles ready to translate Anti-tuberculosis drugs World Health Organization essential medicines Nephrotoxins Orphan drugs Italian inventions Enol ethers