Rifampicin

Systematic (IUPAC) name
(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-{(E)-[(4-methylpiperazin-1-yl)imino]methyl}-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(28),2,4,9,19,21,25(29),26-octaen-13-yl acetate
Clinical data
Trade names	Rifadin
AHFS/Drugs.com	International Drug Names
MedlinePlus	a682403
Pregnancy cat.	C (AU)
Legal status	Prescription Only (S4) (AU) POM (UK)
Routes	Oral, IV
Pharmacokinetic data
Bioavailability	90 to 95%
Metabolism	Hepatic and intestinal wall
Half-life	1.5 to 5 hours
Excretion	15 to 30% renal 60% faecal
Identifiers
CAS number	13292-46-1 Y
ATC code	J04AB02 QJ54AB02
PubChem	CID 5360416
IUPHAR ligand	2765
DrugBank	DB01045
ChemSpider	4529237 N
UNII	VJT6J7R4TR Y
KEGG	D00211 Y
ChEBI	CHEBI:28077 Y
ChEMBL	CHEMBL180 N
NIAID ChemDB	007228
Synonyms	5,6,9,17,19,21-Hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-(4-methyl-1-piperazinyl)formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)-naphtho[2,1-b]furan-1,11(2H)-dione 21-acetate
Chemical data
Formula	C43H58N4O12
Mol. mass	822.94 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C43H58N4O12/c1-21-12-11-13-22(2)42(55)45-33-28(20-44-47-17-15-46(9)16-18-47)37(52)30-31(38(33)53)36(51)26(6)40-32(30)41(54)43(8,59-40)57-19-14-29(56-10)23(3)39(58-27(7)48)25(5)35(50)24(4)34(21)49/h11-14,19-21,23-25,29,34-35,39,44,49-51,53H,15-18H2,1-10H3,(H,45,55)/b12-11-,19-14+,22-13+,28-20+/t21-,23-,24-,25-,29-,34+,35+,39-,43-/m0/s1 N Key:FZYOVNIOYYPUPY-KMBRGFCMSA-N N
Physical data
Melt. point	183–188 °C (361–370 °F)
N (what is this?)  (verify)

Rifampicin (INN) ( /rɪˈfæmpəsɪn/) or rifampin (USAN) is a bactericidal antibiotic drug of the rifamycin group.^[1] It is a semisynthetic compound derived from Amycolatopsis rifamycinica (formerly known as Amycolatopsis mediterranei and Streptomyces mediterranei).^[2] Rifampicin may be abbreviated R, RMP, RA, RF, or RIF (US).

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, Italy. There, a research group headed by Prof. Piero Sensi (1920-) and Dr. Maria Teresa Timbal (1925 - 1969) discovered a new bacterium. This new species appeared immediately of great scientific interest since it was producing a new class of molecules with antibiotic activity. Because Sensi, Timbal and the researchers were particularly fond of the French crime story Rififi (about a jewel heist and rival gangs),^[3] 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 1959 and was named "rifampicin".

Rifampicin is also known as rifaldazine, R/AMP, rofact (in Canada), and rifampin in the United States. There are various types of rifamycins from which this is derived, but the rifampicin form, with a 4-methyl-1-piperazinaminyl group, is by far the most clinically effective.

Rifampicin is an intensely red solid, and the small fraction which reaches body fluids is known for imparting a harmless red-orange color to the urine (and to a lesser extent, also sweat and tears) of users, for a few hours after a dose. Maximal concentrations in the blood are decreased by about a third when the antibiotic is taken with food.^[4]

Indications[link]

Rifampicin was introduced in 1967,^[5] as a major addition to the cocktail-drug treatment of tuberculosis and inactive meningitis, along with isoniazid, ethambutol, pyrazinamide and streptomycin. It requires a prescription in North America. It must be administered regularly daily for several months without break; otherwise, the risk of drug-resistant tuberculosis is greatly increased.^[5] In fact, this is the primary reason it is used in tandem with the three aforementioned drugs, particularly isoniazid.^[6] This is also the primary motivation behind directly observed therapy for tuberculosis.

Rifampicin resistance develops quickly during treatment, so monotherapy should not be used to treat these infections — it should be used in combination with other antibiotics.

Rifampicin is also used in the treatment of cholestatic pruritus.^[7]

Mycobacteria[link]

Rifampicin is typically used to treat Mycobacterium infections, including tuberculosis and Hansen's disease. It can be used to treat BCG-oma, which follows as an uncommon complication of BCG vaccination for tuberculosis.

With multidrug therapy used as the standard treatment of Hansen's disease, rifampicin is always used in combination with dapsone and clofazimine to avoid eliciting drug resistance.

Other bacteria[link]

Rifampicin is used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in combination with fusidic acid, including in difficult to treat infections such as osteomyelitis and prosthetic joint infections.^[8] It is also used in prophylactic therapy against Neisseria meningitidis (meningococcal) infection.

It is also used to treat infection by Listeria species, Neisseria gonorrhoeae, Haemophilus influenzae and Legionella pneumophila. For these nonstandard indications, sensitivity testing should be done (if possible) before starting rifampicin therapy.

The Enterobacteriaceae, and Acinetobacter and Pseudomonas species are intrinsically resistant to rifampicin.

Further, it has been used with amphotericin B 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 treatment of active infections, so the drug is always used against active infections in combination with other antibiotics.

Viruses[link]

Rifampicin has some effectiveness against vaccinia virus.^[9][10]

Mechanism of action[link]

Rifampicin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.^[11]

Crystal structure data and biochemical data indicate that rifampicin binds to RNA polymerase at a site adjacent to the RNA polymerase active center and blocks RNA synthesis by physically preventing extension of RNA products beyond a length of 2-3 nucleotides ("steric-occlusion" mechanism).^[12][13]

Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin.^[13] Resistant mutations map to the rpoB gene, encoding RNA polymerase beta subunit.

Adverse effects[link]

The most serious adverse effect is related to rifampicin's hepatotoxicity, and patients receiving it often undergo baseline and frequent liver function tests to detect liver damage.

Rifampicin is an effective liver enzyme-inducer, promoting the upregulation of hepatic cytochrome P450 enzymes (such as CYP2C9 and CYP3A4), increasing the rate of metabolism of many other drugs that are cleared by the liver through these enzymes. As a consequence, rifampicin can cause a range of adverse reactions when taken concurrently with other drugs.^[14] For instance, patients undergoing long term anticoagulation therapy with warfarin have to be especially cautious and increase their dosage of warfarin accordingly.^[15] Failure to do so could lead to under-treating with anticoagulation, resulting in serious consequences of thromboembolism.

Upregulation of hepatic metabolism of hormones decreases their levels, and rifampicin can also in similar fashion reduce the efficacy of hormonal contraception, to the extent the unintended pregnancies have been reported among users of oral contraceptives taking rifampicin in even short courses (for example, as prophylaxis against exposure to bacterial meningitis).

The more common unwanted effects include fever, gastrointestinal disturbances, rashes, and immunological reactions.

Taking rifampicin can cause certain bodily fluids, such as urine and tears, to become orange-red in color, a benign side effect which can be frightening if it is not expected and prepared for. This effect 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 discolorizion 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, breast feeding should be avoided while it is being taken.

Adverse effects include:

• Hepatotoxic - hepatitis, jaundice, liver failure in severe cases
• Respiratory - breathlessness
• Cutaneous - flushing, pruritus, rash, redness and watering of eyes
• Abdominal - nausea, vomiting, abdominal cramps with or without diarrhea
• Flu-like symptoms - with chills, fever, headache, arthralgia, and malaise, rifampin has good penetration into the brain, and this may directly explain some malaise and dysphoria in a minority of users.

Pharmacokinetics[link]

Orally administered rifampicin results in peak plasma concentrations in about two to four hours. 4-Aminosalicylic acid (another antituberculosis drug) significantly reduces absorption of rifampicin,^[16] and peak concentrations may not be reached. If these two drugs must be used concurrently (which happens often in treatment of TB), they must be given separately with an interval of eight to 12 hours between administrations.

Rifampicin is easily absorbed from the gastrointestinal tract; its ester functional group is quickly hydrolyzed in the bile; and it is catalyzed by a high pH and substrate-specific enzymes called esterases. After about six hours, almost all of the drug is deacetylated. Even in this deacetylated form, rifampin is still a potent antibiotic; however, it can no longer be reabsorbed by the intestines and it is subsequently eliminated from the body. Only about 7% of the administered drug will be excreted unchanged through the urine, though urinary elimination accounts for only about 30% of the drug excretion. About 60% to 65% is excreted through the feces.

The half-life of rifampicin ranges from 1.5 to 5.0 hours, though hepatic impairment will significantly increase it. Food consumption, on the other hand, inhibits absorption from the GI tract, and the drug is more quickly eliminated. When rifampicin is taken with a meal, peak blood concentration falls by 36%. Antacids do not affect absorption, however.^[4] The decrease in rifampin 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 CSF. 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.^[17]

Interactions[link]

Rifampicin is an inducer of many enzymes of the cytochrome P450 superfamily, including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, and CYP3A7.^[18] Thus it will speed up the metabolism of any drug metabolized by any of these enzymes in the body. Other possible interactions which may not be listed include antiretroviral agents, everolimus, atorvastatin, rosiglitazone/pioglitazone, celecoxib, clarithromycin, caspofungin, and lorazepam.^[19]

Preparations[link]

Rifampicin is available in:

• Bulgaria as Tubocin (by Actavis/Balkanpharma)
• Romania as Sinerdol (Sicomed)
• UK as Rifadin (Aventis), Rimactan (Sandoz), Rifater (a combination with isoniazid and pyrazinamide) (Aventis), Rifinah (a combination with isoniazid) (Aventis), and Rimactazid (a combination with isoniazid) (Sandoz)
• U.S. as Rifadin (Aventis), Rifater (combination with isoniazid and pyrazinamide) (Aventis), Rimactane (Novartis)
• France as Rifadine (Aventis)
• India R-Cinex 600 (Lupin Ltd)/Micox (a combination of rifampicin and isoniazid)
• Australia as Rimycin (Alphapharm)
• Egypt as Rimactan (Sandoz)
• Germany as Eremfat (Riemser)

References[link]

External links[link]

• Rifampicin bound to proteins in the PDB
• PubPK - Rifampicin pharmacokinetics
• Prescribing Information for RIFADIN by Sanofi-Aventis
• U.S. National Library of Medicine: Drug Information Portal - Rifampicin
• PDR.net Concise Monograph - Rifadin