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| Pronunciation | /rɪˈfæmpəsɪn/ |
| Trade names | Rifadin, others |
| Other names | Rifampin (USANUS) |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682403 |
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| Routes of administration | By mouth,Intravenous therapy |
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| Bioavailability | 90 to 95% (by mouth) |
| Protein binding | 80% |
| Metabolism | Liver and intestinal wall |
| Eliminationhalf-life | 3–4 hours |
| Excretion | Urine (~30%), faeces (60–65%) |
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| ECHA InfoCard | 100.032.997 |
| Chemical and physical data | |
| Formula | C43H58N4O12 |
| Molar mass | 822.953 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 183 to 188 °C (361 to 370 °F) |
| Boiling point | 937 °C (1,719 °F)[2] |
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Rifampicin, also known asrifampin, is anansamycinantibiotic used to treat several types ofbacterial infections, includingtuberculosis (TB),Mycobacterium avium complex,leprosy, andLegionnaires' disease.[3] It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended"[4] for latent TB infection; and when used as post-exposure prophylaxis to preventHaemophilus influenzae type b andmeningococcal disease in people who have been exposed to those bacteria.[3] Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended.[3] Rifampicin may be given eitherby mouth or intravenously.[3]
Common side effects include nausea, vomiting, diarrhea, and loss of appetite.[3] It often turns urine, sweat, and tears a red or orange color.[3] Liver problems or allergic reactions may occur.[3] It is part of the recommended treatment of active tuberculosis during pregnancy, though its safety in pregnancy is not known.[3] Rifampicin is of therifamycin group of antibiotics.[3] It works by decreasing the production ofRNA by bacteria.[3]
Rifampicin was discovered in 1965, marketed in Italy in 1968, and approved in the United States in 1971.[5][6][7] It is on theWorld Health Organization's List of Essential Medicines.[8] The World Health Organization classifies rifampicin as critically important for human medicine.[9] It is available as ageneric medication.[3] Rifampicin is made by the soil bacteriumAmycolatopsis rifamycinica.[7]
Rifampicin is used for the treatment oftuberculosis in combination with other antibiotics, such aspyrazinamide,isoniazid, andethambutol.[10] For the treatment of tuberculosis, it is administered daily for at least six months.[11] Combination therapy is used to prevent the development of resistance and to shorten the length of treatment.[12]Resistance ofMycobacterium tuberculosis 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.[13][14]
Rifampicin can be used alone in patients withlatent tuberculosis infections to prevent or delay the development of active disease because only small numbers of bacteria are present. ACochrane 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 ofhepatotoxicity.[15] However, the quality of the evidence was judged to be low.[15] A shorter 2-month course of rifampicin and pyrazinamide had previously been recommended but is no longer recommended due to high rates of hepatotoxicity.[16]
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.[17]
Rifampicin is also used to treat nontuberculousmycobacterial infections includingleprosy (Hansen's disease) andMycobacterium kansasii.[18]
With multidrug therapy used as the standard treatment of Hansen's disease, rifampicin is always used in combination withdapsone andclofazimine to avoid causing drug resistance.[citation needed]
It is also used in the treatment ofMycobacterium ulcerans infections as associated withBuruli ulcer, usually in combination withclarithromycin or other antibiotics.[19]
In 2008, tentative evidence showed rifampicin may be useful in the treatment of methicillin-resistantStaphylococcus aureus (MRSA) in combination with other antibiotics, including in difficult-to-treat infections such as osteomyelitis and prosthetic joint infections.[20] As of 2012, if rifampicin combination therapy was useful for pyogenic vertebral osteomyelitis was unclear.[21] A meta-analysis concluded that adding adjunctive rifampicin to a β-lactam or vancomycin may improve outcomes in staphylococcus aureus bacteremia.[22] However, a more recent trial found no benefit from adjunctive rifampicin.[23]
It is also used as preventive treatment againstNeisseria meningitidis (meningococcal) infections. Rifampicin is also recommended as an alternative treatment for infections by the tick-borne pathogensBorrelia burgdorferi andAnaplasma phagocytophilum when treatment withdoxycycline is contraindicated, such as in pregnant women or in patients with a history of allergy to tetracycline antibiotics.[24][25]
It is also sometimes used to treat infections byListeria species,Neisseria gonorrhoeae,Haemophilus influenzae, andLegionella pneumophila. For these nonstandard indications, antimicrobial susceptibility testing should be done (if possible) before starting rifampicin therapy.[citation needed]
TheEnterobacteriaceae,Acinetobacter species, andPseudomonas species are intrinsically resistant to rifampicin.[citation needed]
It has been used withamphotericin B in largely unsuccessful attempts to treatprimary amoebic meningoencephalitis caused byNaegleria fowleri.[citation needed]
Rifampicin can be used as monotherapy for a few days as prophylaxis against meningitis, butresistance develops quickly during long-term treatment of active infections, so the drug is always used against active infections in combination with other antibiotics.[26]
Rifampicin is relatively ineffective againstspirochetes, which has led to its use as a selective agent capable of isolating them in materials being cultured in laboratories.[27]
Rifampicin has some effectiveness againstvaccinia virus.[28][29]
The minimum inhibitory concentrations of rifampicin for several medically significant pathogens are:
Rifampicin is used to treatitchiness caused byprimary biliary cholangitis. The treatment-related adverse effects includehepatotoxicity,nephrotoxicity,hemolysis, and interactions with other drugs.[32] 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.[33][34][35]
Rifampicin withclindamycin has been used to treat the skin diseasehidradenitis suppurativa.[36]
The most seriousadverse effect is hepatotoxicity, and people receiving it often undergo baseline and frequentliver function tests to detect early liver damage.[37]
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.[citation needed]
Other adverse effects include:
Rifampicin is apolyketide belonging to the chemical class of compounds termedansamycins, so named because of their heterocyclic structure containing anaphthoquinone core spanned by an aliphatic ansa chain. The naphthoquinonicchromophore gives rifampicin its characteristic red-orange crystalline color.[citation needed]
The critical functional groups of rifampicin in its inhibitory binding of bacterial RNA polymerase are the four criticalhydroxyl groups of the ansa bridge and the naphthol ring, which formhydrogen bonds with amino acid residues on the protein.[40]
Rifampicin is the 3-(4-methyl-1-piperazinyl)-iminomethyl derivative ofrifamycin SV.[41]
Rifampicin is the most powerful knowninducer of thehepaticcytochrome P450 enzyme system, including isoenzymesCYP2B6,CYP2C8,CYP2C9,CYP2C19,CYP3A4,CYP3A5, andCYP3A7.[42] It increases metabolism of many drugs[43] and as a consequence, can make them less effective, or even ineffective, by decreasing their levels.[44] For instance, patients undergoing long-term anticoagulation therapy withwarfarin 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.[45]
Rifampicin can reduce the efficacy ofbirth control pills or otherhormonal contraception by its induction of the cytochrome P450 system, to the extent thatunintended 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).[citation needed]
Other interactions include decreased levels and less effectiveness ofantiretroviral agents,everolimus,atorvastatin,rosiglitazone,pioglitazone,celecoxib,clarithromycin,caspofungin,voriconazole, andlorazepam.[46]
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)[47] and ambroxol (through host directed effects in autophagy and pharmacokinetics).[48]
Rifampicin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependentRNA polymerase.[49]
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.[40] 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 thirdphosphodiester bond between the nucleotides in the RNA backbone, preventing elongation of the 5' end of the RNA transcript past more than two or three nucleotides.[40][50]
In a recent study rifampicin was shown to bind tocytochrome P450 reductase and alter its conformation as well as activity towards supporting metabolism ofprogesterone viaCYP21A2.[51]
Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin.[50] Resistance mutations map to therpoB gene, encoding the beta subunit of RNA polymerase. The majority of resistance mutations inE. coli are in 3 clusters onrpoB.[13] Cluster I is amino acids 509 to 533, cluster II is amino acids 563 to 572, and cluster III is amino acid 687.[citation needed]
When describing mutations inrpoB in other species, the corresponding amino acid number inE. coli is usually used. InMycobacterium 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".[52] A change in amino acid 531 fromserine toleucine arising from a change in the DNA sequence of TCG to TTG is the most common mutation.[13] Tuberculosis resistance has also occurred due to mutations in theN-terminal region ofrpoB and cluster III.[13]
An alternative mechanism of resistance is through Arr-catalyzedADP-ribosylation of rifampicin. With the assistance of the enzyme Arr produced by the non-pathogenic Mycobacterium smegmatis, ADP-ribose is added to rifampicin at one of its ansa chain hydroxy groups, thereby inactivating the drug.[53]
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.[54] 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. ACochrane review updated in 2014 and 2021 concluded that for rifampicin resistance detection, Xpert MTB/RIF was accurate, that is (95%) sensitive and (98%) specific.[55]
Orally administered rifampicin results in peak plasma concentrations in about 2–4 hours.4-Aminosalicylic acid (another antituberculosis drug) significantly reduces absorption of rifampicin,[56] 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.[citation needed]
Rifampicin is easily absorbed from thegastrointestinal (GI) tract; itsester functional group is quicklyhydrolyzed inbile, and it is catalyzed by a high pH and substrate-specificesterases. 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.[citation needed]
Thehalf-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.[57] 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.[citation needed]
Distribution of the drug is high throughout the body, and reaches effective concentrations in many organs and body fluids, including thecerebrospinal 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.[58]
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 viralT7 RNA polymerase, which is not affected by rifampicin.[citation needed]
In 1957, a soil sample from a pine forest on the French Riviera was brought for analysis to the Lepetit Pharmaceuticals research lab inMilan, Italy. There, a research group headed by Piero Sensi[59] 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 storyRififi (about a jewel heist and rival gangs),[60] 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.[61] 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.[5]
Rifampicin was first sold in Italy in 1968 and was approved by the FDA in 1971.[5]
In August 2020, the U.S.Food and Drug Administration (FDA) became aware of nitrosamine impurities in certain samples of rifampin.[62] 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 1-methyl-4-nitrosopiperazine (MNP).[62] 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.[62] 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.[62]
As of January 2021, the FDA continues to investigate the presence of 1-methyl-4-nitrosopiperazine (MNP) in rifampin or 1-cyclopentyl-4-nitrosopiperazine (CPNP) in rifapentine approved for sale in the US.[63]
Rifampicin is theINN andBAN, while rifampin is theUSAN. Rifampicin may be abbreviated R, RMP, RA, RF, or RIF (US).[citation needed]
Rifampicin is also known as rifaldazine,[64][65] rofact, and rifampin in the United States, also as rifamycin SV.[66]
Its chemical name is 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.[citation needed]
Rifampicin is available under many brand names worldwide.[67]
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