Continuing Education Activity

Rifampin is a medication used in the management and treatment of various mycobacterial and gram-positive bacterial infections. It belongs to the antimicrobial class of drugs. This activity describes the indications, action, and contraindications for rifampin as a valuable agent in managing tuberculosis, leprosy, and serious gram-positive infections, including MRSA. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions) pertinent to members of the healthcare team in the management of patients with tuberculosis and related conditions.

Objectives:

• Identify the mechanism of action of rifampin.
• Describe the potential adverse effects of rifampin.
• Review the appropriate monitoring for patients receiving antimicrobial therapy with rifampin.
• Outline the interprofessional team strategies for improving care coordination and communication to advance rifampin and improve outcomes.

Indications

Rifampin is an antibacterial agent active against many gram-positive cocci, Mycobacteria, Clostridium difficle, and select gram-negative organisms, namely Neisseria meningitides, Neisseria gonorrhoeae, and Hemophilus influenzae. Clinically, rifampin is recommended for infections where the disease-causing organisms are identified and their drug susceptibility has been determined. To prevent drug resistance, rifampin is usually combined with other antimicrobial agents.[1] It is used for the treatment of active and latent tuberculosis (TB), leprosy, and, less commonly, for severe gram-positive bacterial infections like; osteomyelitis, endocarditis, brain abscess, meningitis, and implant infections. Prophylactically, it is used to prevent 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.[2][3] Rifampin is most known for being a pillar in the multi-drug treatment of drug-susceptible TB caused by Mycobacterium tuberculosis. Rifampin is administered alongside isoniazid, ethambutol, and pyrazinamide for the first two months, followed by four months of only rifampin and isoniazid.[4] This treatment regime has a total duration of 6 months and has 83% effectiveness in eradicating TB.[5]

Mechanism of Action

Rifampin produces bactericidal antimicrobial activity by inhibiting 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, halting further RNA synthesis. [6][7] Rifampin has no action on the mammalian RNAP enzyme, thereby decreasing the number of potential adverse effects in humans. Elevated levels of bile acids are primarily responsible for the pruritis seen with cholestatic diseases like primary biliary cirrhosis (PBC). The antipruritic effect of rifampin, which has been described to be of most benefit in cholestatic disorders, is mediated by the upregulation of the microsomal enzymes cytochrome P3A (CYP3A), which subsequently induces hydroxylation of bile acids. The hydroxylation of bile acids decreases their ileal reabsorption, which further alleviates the pruritic symptoms.[8]

Administration

Rifampin is a highly lipid-soluble drug, and it 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.[9] When meninges are inflamed, a significant amount of drugs can enter the cerebrospinal fluid, thereby making it useful clinically in the treatment of bacterial meningitis.[10] 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.

Adults

Tuberculosis

Rifampicin 10 mg/kg injected IV, in a single daily administration, not to exceed 600 mg/day. Rifampin is used in the treatment of all forms of tuberculosis. Usually, a three-drug regimen of rifampin, isoniazid, and pyrazinamide are given in the starting phase of short-course therapy, generally for two months.

The American Thoracic Society, the Centers for Disease Control and Prevention, and The Advisory Council for the Elimination of Tuberculosis recommend either ethambutol or streptomycin be added as a fourth drug in a regimen containing rifampin, isoniazid (INH), and pyrazinamide for TB treatment unless the likelihood of INH resistance is very low. The need to add the fourth medicine should be rechecked when the susceptibility testing results are obtained. If the community rates of INH resistance are less than 4%, an initial treatment regimen with less than four drugs can be considered. Following this initial phase, treatment should be continued with rifampin and isoniazid for at least four months. Maintenance therapy should be continued for an extended period if the patient is still culture or sputum positive, if the patient is HIV positive or if resistant organisms are present.

Patients with Renal Impairment: It does not require dosage adjustments in renal disorders.

Patients with Hepatic Impairment: It is usually avoided in patients with preexisting liver diseases since rifampin is associated with significant hepatotoxicity, but the dose can be adjusted if a potential benefit exists.

Pregnancy/Breastfeeding Considerations: It can be safely administered during pregnancy or breastfeeding and is not associated with any congenital malformations or neonatal complications.[11][12]

Geriatric Considerations: Cases of rifampin-induced esophagitis have also been documented, especially in the elderly population. This is why it is recommended that rifampin is taken with a full glass of water, 1 or 2 hours before meals.[13] 

Rifampin is a potent cytochrome P450 enzyme inducer. A careful review of the patient's medications should be performed in order to avoid any dampening effects of concomitant medications taken alongside rifampin.[14]

Adverse Effects

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 (which can stain the patient's contact lenses), sweat, saliva, urine, and feces due to its excretion in these fluids, and gastrointestinal symptoms including nausea, anorexia, and diarrhea.[15]

• Even though it is a rare presentation, in the case of diarrhea, testing for Clostridium difficile infection is indicated to rule out rifampin-induced pseudomembranous colitis. Adding metronidazole and discontinuing rifampin have been described to remarkably improve symptoms in these cases.[16]

• Constipation is the most common side effect when used for pruritus associated with PBC.[17] Asymptomatic hepatitis has also been reported in patients taking rifampin for pruritus.[18] 

• Hepatotoxicity can occur, 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. Many of the before-mentioned side effects tend to resolve after discontinuation of rifampin.[19][15]

Contraindications

Any previous history of allergy to rifampin or other rifamycins (rifabutin/ rifaximin/ rifapentine) is a significant contraindication to its use. In the management of drug-resistant TB, especially rifampin-resistant TB or polydrug-resistant TB, rifampin should be avoided. TB antibiotic susceptibility should be determined in order to implement proper treatment.[20]

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 CCBs, 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.[21]

Monitoring

Since rifampin can cause significant hepatoxicity, baseline liver function tests (LFTs) are recommended before starting the treatment. When symptoms of hepatotoxicity (nausea, vomiting, abdominal pain, worsening LFTs, pruritus) occur, the dose should be decreased, or rifampin should be stopped completely. Serial blood draws to monitor LFTs are recommended in these cases. With tuberculosis, guidelines establish that rifampin has to be stopped if alanine aminotransferase (ALT) increases three times the upper limit of normal (with hepatitis symptoms like jaundice, abdominal pain, nausea, anorexia) or five times (when asymptomatic).[22] 

The drug concentration levels of concomitantly administered medications are to be monitored regularly due to rifampin's ability to induce microsomal enzymes.[14] Special consideration in monitoring rifampin has to be made in certain conditions like; diabetes, malabsorption syndromes, HIV, or in the elderly population due to a higher rate of poor drug absorption and increased drug interactions caused by decreased metabolism or clearance.[23]

Toxicity

Rifampin is a well-tolerated drug, even in high concentrations, because of its rapid metabolization in the liver. Its toxicity has been determined as dose-related (hepato-toxic) or due to the duration of treatment (immuno-allergic toxicity).[15] Dose-related toxic effects start to appear with the ingestion of 9 to 15 g of rifampin.[24] A wide variety of symptoms can be seen like; 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, and active diuresis, and in severe cases, dialysis.[15][25]

Enhancing Healthcare Team Outcomes

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 interprofessional clinical team must 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's indications include diseases such as TB and leprosy, which require long-term treatment, the interprofessional team needs to educate the patient regarding the importance of administering the drug at the correct dosage and appropriate frequency. 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 the drug as per the recommended protocols. Complete utilization of the entire interprofessional healthcare team aims to ensure the patient is given the top priority with the best possible outcomes with minimum complications. [Level 5]