Rifampin is an antibacterial agent active against many gram-positive cocci, Mycobacteria, Clostridium difficle, and select gram-negative organisms, namely Neisseria meningitides, N. gonorrhoeae, and Hemophilus influenzae. Clinically, rifampin is recommended for infections where the disease-causing organisms are identified, their drug susceptibility determined, and it is used in combination with other antimicrobial agents to prevent the drug resistance. It is used for the treatment of active/latent tuberculosis (TB), leprosy, and severe gram-positive bacterial infections like osteomyelitis, endocarditis, brain abscess, meningitis, and implant infections in combinations with other antimicrobial agents. Prophylactically, it is used for the prevention of TB, Meningococcal infections in high-risk groups like close contacts, history of travel to endemic areas, and Hemophilus influenzae carriers who can transmit the infection to children less than four years. It is also beneficial as a second-line agent for the treatment of cholestatic pruritis.
Rifampin produces the antimicrobial activity by inhibition of DNA dependent RNA polymerase (RNAP) either by sterically blocking the path of the elongating RNA at the 5′ end or by decreasing the affinity of the RNAP for short RNA transcripts. It specifically inhibits the microbial RNAP and has no action on the mammalian enzyme, thereby decreasing the number of adverse effects it can cause in humans.
Elevated levels of bile acids are primarily responsible for the pruritis seen with cholestatic diseases like primary biliary cirrhosis. Its antipruritic effect in these cholestatic disorders is by the upregulation of microsomal enzymes CYP3A, which in turn induces hydroxylation of bile acids. The hydroxylation of bile acids makes them incapable of inducing pruritis or decreases their ileal reabsorption or both, thus alleviating the pruritic symptoms.
Rifampin is a highly lipid-soluble drug and is available in oral or intravenous formulations. When given orally, it is rapidly absorbed and distributed throughout the body. It is excreted equally in bile and urine and has a half-life of 2.5 hours. When meninges are inflamed, a significant amount of drug can enter the cerebrospinal fluid, thereby making it useful clinically in the treatment of bacterial meningitis. It is available for intravenous use in critically ill patients with life-threatening infections caused by gram-positive organisms when oral formulations are not as effective.
It does not require dosage adjustments in renal disorders, but it is required in patients with preexisting liver diseases since rifampin is associated with significant hepatotoxicity. It can be safely administered during pregnancy and breastfeeding and is not associated with any congenital malformations or neonatal complications.
Rifampin is generally a well-tolerated drug but is associated with both dose-dependent and dose-independent adverse effects. Dose-dependent side effects include orange discoloration of body fluids like tears (can stain the contact lenses), sweat, saliva, urine, and also feces due to its excretion in them and gastrointestinal symptoms like nausea, anorexia, and diarrhea. If it causes diarrhea, testing for Clostridium difficile infection is indicated to rule out antibiotic-induced pseudomembranous colitis. Hepatotoxicity is also a well-documented side effect, especially in those with preexisting liver disease. Dose-independent adverse effects include hypersensitive reactions like urticaria, flu-like symptoms, thrombocytopenia, hemolysis, and renal failure. These hypersensitivity reactions are common when used intermittently or for a prolonged duration. They generally resolve with the discontinuation of rifampin.
Any previous history of allergy to rifampin or other rifamycin's (rifabutin/ rifaximin/ rifapentine) is a significant contraindication to its use. It is also a potent inducer of many drug-metabolizing enzymes, notably cytochrome P450 (CYP) 3A4 and drug transporter proteins, such as hepatic P-glycoprotein. This property of rifampin reduces the efficacy of concomitantly administered drugs and thus can limit its administration. Commonly involved drugs include HIV protease inhibitors, antimycotics (itraconazole and ketoconazole), cyclosporine (can cause graft rejections), DHP CCB's, sulfonylureas, oral contraceptives, and warfarin. After starting rifampin, it takes around a week to induce drug-metabolizing enzymes and produce clinically significant interactions. Furthermore, it takes almost two weeks for this effect to wear-off after stopping rifampin.
Since rifampin can cause significant hepatoxicity, liver function tests (LFT's) are recommended before starting the treatment with it or when symptoms of hepatotoxicity (nausea, vomiting, abdominal pain, worsening LFTs, pruritus) occur. With tuberculosis, rifampin has to be stopped if ALT increases three times the upper limit of normal (with hepatitis symptoms like jaundice, abdominal pain, nausea, anorexia) or five times (when asymptomatic). The drug concentration levels of concomitantly administered medications are to be monitored regularly due to its ability to induce microsomal enzymes.
Rifampin is a well-tolerated drug even in high concentrations because of its rapid metabolization in the liver. The toxic effects have appeared with the ingestion of 9 to 15 g of rifampin. It can produce symptoms of metabolic acidosis (nausea, vomiting, abdominal pain, hyperventilation, and fatigue), thrombocytopenia (skin and mucosal bleeding), oliguric renal failure, convulsions, cholestatic jaundice, and red man syndrome (glowing red discoloration of the skin, facial, and periorbital edema). There is no specific antidote for its toxicity, and treatment is mostly supportive, including airway maintenance, antiemetic medications, gastric lavage with activated charcoal, correction of electrolytes and acid-base balances, active diuresis and in severe cases, may require dialysis.
Rifampin is a commonly administered antimicrobial agent, and drug-resistance in bacteria to it is quite common. Hence, it should be administered along with other antimicrobial agents only in specific infections like tuberculosis or when the drug susceptibility of the organism to rifampin is determined. The clinical team needs to obtain a systematic drug history to prevent significant drug interactions. The patients should be made aware of the common and significant adverse effects and advised to visit the hospital if they notice any such symptoms. Since rifampin indications for diseases like TB and leprosy, which require long term treatment, the patient requires education about the importance of administration of the correct dosage and frequency of the drug. Pharmacists are involved in patient education, and social workers can help determine compliance. In an inpatient setting, proper communication between doctor, pharmacist, and nurse ensures dispensing of the drug as per the recommended protocols. Complete utilization of the health care resources aims to ensure the patient is given the top priority with the best possible outcomes with minimum complications.
|||Rothstein DM, Rifamycins, Alone and in Combination. Cold Spring Harbor perspectives in medicine. 2016 Jul 1; [PubMed PMID: 27270559]|
|||Howard P,Twycross R,Grove G,Charlesworth S,Mihalyo M,Wilcock A, Rifampin (INN Rifampicin). Journal of pain and symptom management. 2015 Dec; [PubMed PMID: 26432572]|
|||Mieras LF,Taal AT,van Brakel WH,Cambau E,Saunderson PR,Smith WCS,Prakoeswa CRS,Astari L,Scollard DM,do Nascimento DC,Grosset J,Kar HK,Izumi S,Gillini L,Virmond MCL,Sturkenboom MGG, An enhanced regimen as post-exposure chemoprophylaxis for leprosy: PEP . BMC infectious diseases. 2018 Oct 5; [PubMed PMID: 30290790]|
|||Campbell EA,Korzheva N,Mustaev A,Murakami K,Nair S,Goldfarb A,Darst SA, Structural mechanism for rifampicin inhibition of bacterial rna polymerase. Cell. 2001 Mar 23; [PubMed PMID: 11290327]|
|||McClure WR,Cech CL, On the mechanism of rifampicin inhibition of RNA synthesis. The Journal of biological chemistry. 1978 Dec 25; [PubMed PMID: 363713]|
|||Schulz W,Zillig W, Rifampicin inhibition of RNA synthesis by destabilisation of DNA-RNA polymerase-oligonucleotide-complexes. Nucleic acids research. 1981 Dec 21; [PubMed PMID: 6174947]|
|||Wietholtz H,Marschall HU,Sjövall J,Matern S, Stimulation of bile acid 6 alpha-hydroxylation by rifampin. Journal of hepatology. 1996 Jun; [PubMed PMID: 8835747]|
|||Hofmann AF, Rifampicin and treatment of cholestatic pruritus. Gut. 2002 Nov; [PubMed PMID: 12377823]|
|||Acocella G, Clinical pharmacokinetics of rifampicin. Clinical pharmacokinetics. 1978 Mar-Apr; [PubMed PMID: 346286]|
|||Treatment of tuberculosis. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports. 2003 Jun 20; [PubMed PMID: 12836625]|
|||Bothamley G, Drug treatment for tuberculosis during pregnancy: safety considerations. Drug safety. 2001; [PubMed PMID: 11444726]|
|||Tran JH,Montakantikul P, The safety of antituberculosis medications during breastfeeding. Journal of human lactation : official journal of International Lactation Consultant Association. 1998 Dec; [PubMed PMID: 10205455]|
|||Khurana S,Singh P, Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials. Liver international : official journal of the International Association for the Study of the Liver. 2006 Oct; [PubMed PMID: 16953834]|
|||Grosset J,Leventis S, Adverse effects of rifampin. Reviews of infectious diseases. 1983 Jul-Aug; [PubMed PMID: 6356277]|
|||Niemi M,Backman JT,Fromm MF,Neuvonen PJ,Kivistö KT, Pharmacokinetic interactions with rifampicin : clinical relevance. Clinical pharmacokinetics. 2003; [PubMed PMID: 12882588]|
|||Saukkonen JJ,Cohn DL,Jasmer RM,Schenker S,Jereb JA,Nolan CM,Peloquin CA,Gordin FM,Nunes D,Strader DB,Bernardo J,Venkataramanan R,Sterling TR, An official ATS statement: hepatotoxicity of antituberculosis therapy. American journal of respiratory and critical care medicine. 2006 Oct 15; [PubMed PMID: 17021358]|
|||Sridhar A,Sandeep Y,Krishnakishore C,Sriramnaveen P,Manjusha Y,Sivakumar V, Fatal poisoning by isoniazid and rifampicin. Indian journal of nephrology. 2012 Sep; [PubMed PMID: 23326053]|