Rifampicin
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|---|---|
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| 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  |
| ATC code | J04AB02 QJ54AB02 |
| PubChem | CID 5360416 |
| IUPHAR ligand | 2765 |
| DrugBank | DB01045 |
| ChemSpider | 10468813 |
| UNII | VJT6J7R4TR |
| KEGG | D00211 |
| ChEBI | CHEBI:28077 |
| ChEMBL | CHEMBL180  |
| 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
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| Physical data | |
| Melt. point | 183–188 °C (361–370 °F) |
| (what is this?) (verify) | |
Rifampicin (INN) /rɪˈfæmpəsɪn/ or rifampin (USAN) is a bactericidal antibiotic drug of the rifamycin group.[1]
Rifampicin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.<ref name="Calvori"
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 (1920-2013[3]) 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),[4] 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.[5]
Medical uses
Rifampicin was introduced in 1967,[6] as a major addition to the cocktail-drug treatment of tuberculosis and inactive meningitis, along with pyrazinamide, isoniazid, ethambutol, and streptomycin ("PIERS"). 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.[6] In fact, this is the primary reason it is used in tandem with the three aforementioned drugs, particularly isoniazid.[7] 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.[8]
Mycobacteria
Rifampicin is typically used to treat Mycobacterium infections, including tuberculosis and leprosy (Hansen's disease). It can be used to treat abscesses, as an uncommon complication of BCG vaccination for tuberculosis. [citation needed]
There is no difference between a three to four month regimen of rifampicin and a six to nine month regimen for preventing active tuberculosis in those with HIV-negative latent tuberculosis.[9] The quality of the evidence was however low.[9]
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
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.[10] 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.[11][12]
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.
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
Rifampicin has some effectiveness against vaccinia virus.[13][14]
Mechanism of action
Rifampicin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.[15]
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).[16][17]
Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin.[17] Resistant mutations map to the rpoB gene, encoding RNA polymerase beta subunit.
Adverse effects
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.[18] For instance, patients undergoing long term anticoagulation therapy with warfarin have to be especially cautious and increase their dosage of warfarin accordingly.[19] 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, 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
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,[20] 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.[5] 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.[21]
Interactions
Rifampicin is an inducer of many enzymes of the cytochrome P450 superfamily, including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, and CYP3A7.[22] 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.[23]
Rifampicin is antagonistic to the effect of gentamycin and amikacin.
Preparations
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 Limited)/Micox (a combination of rifampicin and isoniazid)
- Australia as Rimycin (Alphapharm)
- Egypt as Rimactan (Sandoz)
- Germany as Eremfat (Riemser)
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.
References
- ↑ Masters, Susan B.; Trevor, Anthony J.; Katzung, Bertram G. (2005). Katzung & Trevor's pharmacology. New York: Lange Medical Books/McGraw Hill, Medical Pub. Division. ISBN 0-07-142290-0.
- ↑ Sensi P, Margalith P, Timbal MT (1959). "Rifomycin, a new antibiotic—preliminary report". Farmaco Ed Sci 14: 146–147.
- ↑ http://archiviostorico.corriere.it/2013/agosto/10/chimico_che_salvo_molte_vite_co_0_20130810_63918b4e-017d-11e3-ae0c-005a4b618eb7.shtml
- ↑ "When I Use a Word . . .I Mean It". British Medical Journal 1999;319(7215):972 (9 October). Retrieved 2009-07-10.
- ↑ 5.0 5.1 "Kinetics of Rifampin taken with food and with antacids" (PDF). Retrieved 2011-11-07.
- ↑ 6.0 6.1 Long, James W. (1991). Essential Guide to Prescription Drugs 1992. New York: HarperCollins Publishers. pp. 925–929. ISBN 0-06-273090-8.
- ↑ Erlich, Henry, W Ford Doolittle, Volker Neuhoff, and et al. . Molecular Biology of Rifomycin. New York, NY: MSS Information Corporation, 1973. pp. 44-45, 66-75, 124-130.
- ↑ Hofmann, AF (2002). "Rifampicin and treatment of cholestatic pruritus". Gut 51 (5): 756–757. doi:10.1136/gut.51.5.756. PMC 1773428. PMID 12377823. More than one of
|work=and|journal=specified (help) - ↑ 9.0 9.1 Sharma, SK; Sharma, A; Kadhiravan, T; Tharyan, P (Jul 5, 2013). "Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB.". The Cochrane database of systematic reviews 7: CD007545. PMID 23828580.
- ↑ Aboltins CA, Page MA, Buising KL, et al. (June 2007). "Treatment of staphylococcal prosthetic joint infections with debridement, prosthesis retention and oral rifampicin and fusidic acid". Clinical Microbiology and Infection 13 (6): 586–591. doi:10.1111/j.1469-0691.2007.01691.x. PMID 17331125.
- ↑ Wormser, Gary P.; Dattwyler, Raymond J.; Shapiro, Eugene D.; Halperin, John J.; Steere, Allen C.; Klempner, Mark S.; Krause, Peter J.; Bakken, Johan S.; Strle, Franc; Stanek, Gerold; Bockenstedt, Linda; Fish, Durland; Stephen Dumler, J.; Nadelman, Robert B. (1 November 2006). "The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America". Clinical Infectious Diseases 43 (9): 1089–1134. doi:10.1086/508667. PMID 17029130.
- ↑ Thomas RG, Dumler SJ, Carlyon JA (August 2009). "Current management of human granulocytic anaplasmosis, human monocytic ehrlichiosis and Ehrlichia ewingii ehrlichiosis". Expert Reviews in Anti-Infection Therapies 7 (6): 709–722. doi:10.1586/eri.09.44. PMC 2739015. PMID 19681699.
- ↑ Charity JC, Katz E, Moss B (March 2007). "Amino acid substitutions at multiple sites within the vaccinia virus D13 scaffold protein confer resistance to rifampicin". Virology 359 (1): 227–32. doi:10.1016/j.virol.2006.09.031. PMC 1817899. PMID 17055024.
- ↑ Sodeik B, Griffiths G, Ericsson M, Moss B, Doms RW (February 1994). "Assembly of vaccinia virus: effects of rifampin on the intracellular distribution of viral protein p65". J. Virol. 68 (2): 1103–14. PMC 236549. PMID 8289340.
- ↑ Calvori, C.; Frontali, L.; Leoni, L.; Tecce, G. (1965). "Effect of rifamycin on protein synthesis". Nature 207 (995): 417–8. doi:10.1038/207417a0. PMID 4957347.
- ↑ Campbell, E.A., Korzheva, N., Mustaev, A., Murakami, K., Nair, S., Goldfarb, A., Darst, S.A. (2001). "Structural mechanism for rifampicin inhibition of bacterial RNA polymerase". Cell 104 (6): 901–12. doi:10.1016/S0092-8674(01)00286-0. PMID 11290327.
- ↑ 17.0 17.1 Feklistov, A., Mekler, V., Jiang, Q., Westblade, L.F., Irschik, H., Jansen, R., Mustaev, A., Darst, S.A., Ebright, R.H. (2008). "Rifamycins do not function by allosteric modulation of binding of Mg2+ to the RNA polymerase active center". Proc Natl Acad Sci USA 105 (39): 14820–5. doi:10.1073/pnas.0802822105. PMC 2567451. PMID 18787125.
- ↑ Collins, R Douglas. Atlas of Drug Reactions. New York, NY: ChurchillLivingstone, 1985. pp. 123.
- ↑ Stockley, Ivan H. "Anticoagulant Drug Interactions." Drug Interactions. 3rd ed. Boston: Blackwell Scientific Publications, 1994. pp. 274-275.
- ↑ G Curci, A Ninni, A.D'Aleccio (1969) Atti Tavola Rotonda Rifampicina, Taormina, page 19. Edizioni Rassegna Medica, Lepetit, Milano
- ↑ Hardman, Joel G., Lee E. Limbird, 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.
- ↑ "Division of Clinical Pharmacology | Indiana University Department of Medicine". Medicine.iupui.edu. 2011-09-27. Retrieved 2011-11-07.
- ↑ Riss, J.; Cloyd, J.; Gates, J.; Collins, S. (Aug 2008). "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics". Acta Neurol Scand 118 (2): 69–86. doi:10.1111/j.1600-0404.2008.01004.x. PMID 18384456.
External links
- 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
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