|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Bioavailability||90 to 95% (oral)|
|Metabolism||Hepatic and intestinal wall|
|Biological half-life||3–4 hours|
|Excretion||Urine (~30%), faeces (60–65%)|
|ATC code||J04 QJ54|
|PDB ligand ID||RFP (, )|
|Molar mass||822.94 g/mol|
|Melting point||183 to 188 °C (361 to 370 °F)|
|Boiling point||1,004.42 °C (1,839.96 °F) |
|(what is this?)|
Rifampicin, also known as rifampin, is an antibiotic used to treat a number of bacterial infections. This includes tuberculosis, leprosy, and legionella, among others. Often it is used along with other antibiotics. It is also used to prevent Haemophilus influenzae type b and meningococcal disease in those who have been exposed. Before treating someone for a long period of time testing the liver function and bloods counts are recommended. It is available by mouth and intravenously.
Common side effects include nausea, vomiting, diarrhea, and loss of appetite. It may also turn urine, sweat, and tears a red color. Liver problems or allergic reactions may occur. It is part of the recommended treatment of active tuberculosis during pregnancy even though safety is not clear in pregnancy. Rifampicin is of the rifamycin group of antibiotics. It works by stopping the making of RNA by the bacteria.
Rifampicin was first isolated in 1957 and first sold in 1971. It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system. It is available as a generic medication. The wholesale cost is about 3.90 USD a month. In the United States it is expensive with a month of treatment being about 120 USD. Rifampicin is made from Amycolatopsis rifamycinica.
Rifampicin is used in the treatment of tuberculosis in combination with other antibiotics such as pyrazinamide, isoniazid, ethambutol. For tuberculosis it is administered daily for 6 months or longer. Combination therapy is utilized to prevent the development of resistance and to shorten the length of treatment.
Rifampicin can also be used alone for latent tuberculosis infection to prevent progression to active disease. A Cochrane review found no difference between a three- to four-month regimen of rifampicin and a six month regimen of isoniazid for preventing active tuberculosis in those with HIV-negative latent tuberculosis, and rifampicin had a lower rate of hepatotoxicity. However, the quality of the evidence was judged to be low. A shorter two month course of rifampicin and pyrazinamide was previously recommended, but is no longer due to high rates of hepatotoxicity.
Rifampicin should be taken on an empty stomach with one glass of water. It is generally taken either one hour before meals or two hours after meals. However, it is important to discuss how to take any medicine with your doctor.
Other bacteria and protozoans
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. It is also used in prophylactic therapy against Neisseria meningitidis (meningococcal) infection. Rifampicin is also recommended as an alternative treatment for infections with the tick-borne disease pathogens, Borrelia burgdorferi and Anaplasma phagocytophilum when treatment with doxycycline is contraindicated, such as in pregnant women or in patients with a history of allergy to tetracycline antibiotics.
It is also used to treat infections 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.
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. Give 30 minute before meal or 2 hours after meal and antacids should be given at least one hour after meal.
The following represents minimum inhibitory concentration (MIC) data for a few medically significant pathogens:
- Mycobacterium tuberculosis — 0.002–64 µg/mL
- Mycobacterium bovis — 0.125 µg/mL
- Stapylococcus aureus (methicillin resistant) — ≤0.006–256 µg/mL
- Chlamydia pneumoniae — 0.005 µg/mL
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. For instance, patients undergoing long-term anticoagulation therapy with warfarin have to be especially cautious and increase their dosage of warfarin accordingly. Failure to do so could lead to undertreating 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:
- Liver toxicity — hepatitis, liver failure in severe cases
- Respiratory — breathlessness
- Cutaneous — flushing, pruritus, rash, hyperpigmentation, redness and watering of eyes
- Abdominal — nausea, vomiting, abdominal cramps with or without diarrhea
- Flu-like symptoms — chills, fever, headache, arthralgia, and malaise. Rifampicin has good penetration into the brain, and this may directly explain some malaise and dysphoria in a minority of users.
Allergic reactions may occur to rifampicin. Signs of these include rash, itching, swelling of the tongue or throat, severe dizziness, and trouble breathing.
Rifampicin is an inducer of many enzymes of the cytochrome P450 superfamily, including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, and CYP3A7. 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.
Rifampicin is antagonistic to the effect of gentamicin and amikacin.
Mechanism of action
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 blocking the formation of the phosphodiester bond in the RNA backbone, preventing extension of RNA products beyond a length of 2–3 nucleotides ("steric-occlusion" mechanism).
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. Resistant mutations map to the rpoB gene, encoding RNA polymerase beta subunit. In E. coli the majority of resistance mutations are found 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 found in other species the corresponding amino acid number in E. coli is usually used. In tuberculosis the majority of mutations leading to rifampicin resistance are in cluster I, most often a at amino acid 531. A change at that location of leucine to serine arising from a change in the genetic sequence of TCG to TTG is the most commonly seen in clinical isolates. Tuberculosis resistance has also been seen to arise from mutations in the N-terminal region of rpoB and cluster III.
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, and peak concentrations may be lower. 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 (GI) tract; its ester functional group is quickly hydrolyzed in the bile, and it is catalyzed by a high pH and substrate-specific 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, though, 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. 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 cerebrospinal fluid. 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, thus it is commonly used to inhibit the synthesis of host bacterial proteins during recombinant protein expression in bacteria. Since the RNA encoding for the recombinant gene is usually transcribed from DNA by a viral T7 RNA polymerase, its expression is not affected by the antibiotic.
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 Piero Sensi and Maria Teresa Timbal discovered a new bacterium. This new species appeared of 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), 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 was first sold in 1971.
Other names include
- 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
Rifampicin is available under many brand names worldwide.
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