Rifampin - About an Essential Antimycobacterial

Overview

Rifampin is an antibacterial prescription medicine for treating tuberculosis (TB). It was approved by the U.S. Food and Drug Administration (FDA) on 29th October 1999. Rifampin has been enlisted in The WHO Model Lists of Essential Medicines, which contains the names of the safest and most effective medications formulated for the essential needs of the healthcare system. Rifampin is a semisynthetic antibiotic derivative of Rifamycin, obtained from Amycolatopsis rifamycinica. It is a macrocyclic antibiotic that is highly active against mycobacteria and is commonly used in combination therapy of tuberculosis to prevent the emergence of drug-resistant tuberculosis. It is a structural tautomer of Rifampicin zwitterion.

What Are the Indications of Rifampin?

Rifampin is indicated in treating several mycobacterial and bacterial (gram-positive) infections. Its use is recommended for the following infectious diseases:

• Primary tuberculosis and tuberculosis-related infections.

• Pulmonary tuberculosis.

• Extrapulmonary tuberculosis.

• Tuberculosis meningitis.

• Latent TB infection.

• Reactivated tuberculosis.

• Secondary tuberculosis infection in HIV individuals.

• Leprosy.

• Gram-positive infections such as MRSA (Methicillin Resistant Staphylococcus Aureus).

• Prophylactic use for prevention of tuberculosis.

• Eradication of Neisseria meningococci in the carrier state.

• Hemophilus influenzae type B infections.

What Are the Contraindications of Rifampin?

Rifampin is recommended only for infections where the causative organisms have been detected and their drug susceptibility is confirmed. It is not used as a broad-spectrum antibiotic. Some of the contraindications for using Rifampin are as follows:

• Known case of drug hypersensitivity to Rifampin.

• Patients with jaundice and impaired liver function.

• Alcoholics with severe hepatic dysfunction.

• In Pregnancy - Though no reported drug effects on the fetus (teratogenic effect observed in animal models), its use is recommended only in severe forms of tuberculosis.

Dosage and Administration

• Oral Route - Suspension and syrup (20 mg per mL).

• Oral Route - Capsules and tablets (150 mg and 300 mg).

• Parenteral Administration (General Injections or IV) - 600 mg (vial powder for injection).

• DOT (Directly Observed Therapy) - Oral dose of 10 mg per kg (body weight) daily or weekly twice.

Oral Administration

• When a single oral dose of 600 mg Rifampin is administered in healthy adults, the peak serum concentration reaches 7 mcg/mL with a range from 4 to 32 mcg/mL.

• Pediatrics Oral Dose - For six to 58-month-old neonates, Rifampin suspension syrup at a dosage of 10 mg/kg body weight is recommended.

Intravenous Administration

• Intravenous Dose - 300 or 600 mg Rifampin is infused over 30 minutes to three hours.

• Rifampin dosage (600mg) is repeated as once-a-day infusions for three hours in patients for seven successive days.

• Pediatric Dosage - For 0.25 to 12.8-year-old children, 300mg/mL as a 30-minute infusion is recommended.

Precautions

• The prescribed dose must not exceed 600 mg in a single day.

• In patients with renal diseases, no change in the Rifampin dose is recommended.

• It is usually avoided in patients with hepatic dysfunction because Rifampin has hepatotoxic side effects. However, the dose is adjusted if there is potential demand.

• It is safe to administer Rifampin during pregnancy and breastfeeding since there is no evidence of any congenital anomaly or neonatal complications.

• In geriatric cases, Rifampin-induced esophagitis is reported.

• It is advised to take Rifampin and a full glass of water, particularly one to two hours before meals, to avoid gastric side effects in elderly people.

Storage and Disposal

• Rifampin is unstable in light, heat, moisture, and air.

• Rifampin capsules are stored in light-resistant, airtight containers at room temperature (30 °C or less).

• The capsules must not be exposed to excess heat or in direct sunlight.

• It should be kept out of reach of children in a cool, dry place and should not be frozen.

• Disposal of unused Rifampin must follow safe disposal methods and not be thrown in drains or open spaces.

For Patients

What Is Tuberculosis?

Tuberculosis is the most common bacterial infectious disease caused by Mycobacterium tuberculosis. It is a major public health threat worldwide. Tuberculosis is spread by infectious droplets present in the air. Infection is spread by aerosol transmission from the infected individuals. Children and young adults are affected in the majority by this infection. More tuberculosis-related deaths are reported in developing countries.

Mycobacterium tuberculosis is a slow-growing bacteria, and it primarily infects the lungs. The infection affects the lower lobes of the lungs and slowly spreads to other parts. Lymph nodes are enlarged, indicating active infection. Mycobacterium tuberculosis also infects extrapulmonary sites such as the spinal cord, bone, joints, urogenital system, and kidneys. The clinical symptoms include low-grade fever with a persistent cough. A sudden decrease in body weight and night sweats indicate tuberculosis infection. Blood culture and chest examination help to detect Mycobacterium tuberculosis. Advanced techniques like immunoassay and molecular diagnostics are also employed to identify tuberculosis in susceptible cases.

BCG vaccination is given to prevent tuberculosis. Antituberculosis agents and antimicrobial drugs are used to treat tuberculosis. Extreme caution and a strict regime are followed in these antimicrobial medications to prevent drug resistance. Latent tuberculosis, recurrent infections, secondary TB to HIV infections, and extrapulmonary tuberculosis are challenging both in terms of diagnosis as well as treatment interventions.

What Is Rifampin?

Rifampin is an antituberculosis agent. It is highly effective against Mycobacterium tuberculosis. Rifampin has both bactericidal and bacteriostatic activity, depending on the dosage given. It is not only given to treat infections but also prophylactically to prevent the recurrence of TB infections. Rifampin is also used to manage other bacterial infections because of its bactericidal effects. It is a safe and effective drug whose usage is well monitored to improve its efficacy and prevent adverse effects. Improper use of Rifampin causes liver toxicity and drug resistance (bacteria become resistant to drug usage and do not respond to treatment).

What Are the Side Effects of Rifampin?

Rifampicin is generally well tolerated during regular therapy. However, adverse reactions and side effects are reported in the irregular intake of Rifampin. Dose-dependent adverse reactions are also reported. The most commonly occurring side effects are as follows:

• Febrile illness.

• Urticaria.

• Eosinophilia.

• Pruritus.

• Leukopenia.

• Thrombocytopenia.

• Purpura.

• Hemolysis and shock.

• Hepatotoxicity.

• Nephrotoxicity.

• Gastrointestinal disturbances.

• Abdominal pain.

• Nausea.

• Anorexia.

• Diarrhea.

• Pseudomembranous colitis.

• Neurotoxic effects such as confusion, ataxia, and blurring of vision.

• Dizziness.

• Peripheral neuritis.

• Reddish discoloration of the skin.

• Orange discoloration of body fluids.

• Fatal hemolytic reactions.

What Are the Precautions to Be Followed While Using Rifampin?

Generally, Rifampin is well-tolerated even in high doses. However, individuals under Rifampin therapy must be aware of the common side effects. Some of the essential precautionary measures to be taken in Rifampin therapy are as follows:

• Any pre-existing allergic conditions or hypersensitivity should be reported before starting the therapy.

• Individuals with liver problems should consult the doctor before taking Rifampin.

• Alcohol intake is to be avoided along with Rifampin intake.

• High blood sugar levels and high blood pressure levels are to be regulated before medication.

• Rifampin enters all body fluids and can stain contact lenses.

• Symptoms like fever, nausea, rashes, and abdominal pain should be reported to the doctor immediately.

• Use of contraceptive pills becomes ineffective when taken along with Rifampin.

• Liver toxicity is a common side effect of Rifampin therapy. Regular monitoring and periodic liver function tests are to be done to assess the normal functioning of the liver.

• Rifampin could cause absorption problems in elderly people.

• Conditions like pregnancy and lactation must be informed to the doctor before starting the therapy.

• Self-medication is strictly prohibited. Dosage and frequency of usage must be taken only under prescription.

• Irregular use or inappropriate discontinuation of the therapy makes the drug ineffective and also worsens the existing disease.

For Doctors

Therapeutic Uses of Rifampin

Rifampin is a potent antimicrobial agent used against several microorganisms. Its therapeutic uses include:

• Antitubercular agent.

• It is a potent inhibitor of bacterial enzymes (RNA polymerase and DNA synthetase) essential for microbial DNA replication.

• A leprostatic drug that inhibits the growth of Mycobacterium leprae.

• An Escherichia coli (E coli) metabolite shows antiamoebic effects.

• Protein synthesis inhibitor.

• It acts as a neuroprotective agent.

• It inhibits angiogenesis and exhibits antineoplastic properties.

• It has no therapeutic effects and acts as a geroprotector.

Pharmacodynamics

Rifampicin, a semisynthetic derivative that belongs to a group of Rifamycins, is highly active against mycobacterium species such as Mycobacterium tuberculosis and Mycobacterium leprae. It exhibits bactericidal activity against Staphylococcus aureus, Neisseria meningitidis, coagulase-negative staphylococci, Haemophilus influenzae, Listeria monocytogenes, Clostridium species, Bacteroides, and some strains of E coli.

The bactericidal and bacteriostatic property of Rifampin is determined by its bioavailability and its peak concentration at the infection site. It enhances the upregulation of bile acids in their metabolism and thus prevents pruritus in cholestatic diseases. Rifampicin also exhibits immunosuppressive effects.

Chemical Taxonomy of Rifampin

• Kingdom - Organic compounds.

• Super Class - Phenylpropanoids and polyketides.

• Class - Macrolactams.

• Sub Class - Data not available.

• Direct Parent Compound - Macrolactams.

• Alternative Parent Compound - Naphthofurans, benzofurans, aryl alkyl ketones, hydroquinones, amino acids, and their derivatives.

• Substituents - 1,4-diazinane, acetal, amine, aromatic hetero polycyclic compound, azacycle.

• Molecular Framework - Aromatic hetero polycyclic compounds.

• External Descriptors - N-methyl piperazine, Rifamycin (CHEBI:28077).

Mechanism of Action

• Its bactericidal activity is by interfering with nucleic acids (DNA and RNA) synthesis and inhibiting bacterial DNA-dependent RNA polymerase (RNAP) enzymes.

• This prevents RNA transcription and subsequent DNA chain elongation.

• Rifampin blocks the path of RNA elongation by inhibiting RNA polymerase enzymes.

• It also decreases the affinity of these polymerases (RNAP) for the transcription of RNA.

• Rifampin does not affect mammalian RNA enzymes (no potential adverse effects on humans).

• Rifampin selectively inhibits only microbial RNAP and halts the progression of RNA synthesis, thus preventing microbial replication and growth.

Pharmacokinetics

Bioavailability and Plasma Concentrations

• When administered orally, 90 percent of Rifampin is immediately absorbed into the gastrointestinal tract.

• Peak concentrations in plasma reach within one to four hours after oral administration. However, the presence of food materials delays and reduces absorption.

• Rifampin administered intravenously also follows the same distribution pattern as in oral exposure.

• Plasma proteins restrain eighty-nine percent of circulating Rifampin.

• Due to its lipid solubility, Rifampin is broadly distributed in most body fluids and tissues.

• Therapeutic levels are reached in the bronchial secretions, lungs, pleural fluid, bile, liver, urine, and other body cavity fluids.

• Rifampin also enters cerebrospinal fluid (CSF) during inflammation of the meninges.

• An increased degree of placental transfer occurs, where the fetal to maternal serum Rifampin level ratio is 0.3. It is also distributed in lactating milk.

• The bioavailability and half-life of Rifampin range from two to five hours. A single high-loading dose or liver disease increases its half-life.

• Rifampin induces its metabolism; 40 percent of the half-life decreases within the initial two weeks of therapy. Increased biliary excretion and repeated administration also favor this reduction in half-life.

• The plasma half-life of Rifampin reaches a constant threshold after one to two weeks of daily administration. The presence of anemia further reduces its half-life.

Metabolism

• The site of metabolism is the liver, which includes hepatocytes and canaliculi of the hepatic system.

• In hepatocytes, 85 percent of Rifampin uptake occurs and is metabolized by microsomal enzymes in the liver.

• Diacetyl Rifampin is the active and prime metabolite of Rifampin. This metabolite does not undergo recirculation, unlike Rifampin, which enters enterohepatic recirculation.

• Rifampin regulates its metabolism by increasing its metabolic rate. In other parts of the body, Rifampin gets deactivated.

Drug Clearance and Elimination

• Rifampin and its metabolites, such as deacetyl Rifampin, are excreted in the bile and urine.

• About 65 percent gets eliminated through feces and 30 percent in urine.

• Within 24 hours, 50 percent of the dosage is eliminated.

• A small fraction of 6 to 30 percent of the unaltered drug also gets excreted.

• Its renal clearance rate is 8.7 mL/min/Kg, which is reduced during renal failure.

• Its intrinsic body clearance is 3.5 (+/- 1.5) mL/min/Kg.

• 1 to 3 ug/ml is also excreted in breast milk.

• Peritoneal dialysis and hemodialysis do not significantly affect plasma Rifampin levels.

Drug Interactions

• The bioavailability of Rifampin is reduced by antacids containing aluminum hydroxide.

• Alcohol intake with Rifampin results in hepatotoxicity.

• Combined interactions of Rifampin with Isoniazid cause hepatic injury.

• Rifampin enhances the metabolism of certain drugs such as beta-blockers, Cyclosporin, Diazepam, oral hypoglycemic drugs, Calciferol, and oral contraceptive pills by inducing liver microsomal enzymes.

• Rifampin reduces chloramphenicol levels in serum.

• Corticosteroid levels are reduced as Rifampin decreases plasma half-life and increases urinary excretion.

• Rifampin rapidly destroys estrogen in contraceptive pills and decreases its effectiveness.

• Rifampin increases the antifungal activity of Amphotericin B.

Toxicity

Clinically, Rifampin is a well-tolerated drug. Its high tolerance is attributed to its rapid metabolization by the hepatic system. Its toxicity is due to dose-related hepatotoxic effects or due to immune-allergic toxicity (prolonged duration of treatment). Ingestion of 9 to 15 g of Rifampin results in dose-related toxicity.

Hepatotoxicity

• Rifampin causes transient elevations of serum aminotransferase and bilirubin levels, resulting in acute liver disease.

• Defect in hepatic uptake and biliary excretion results in cholestasis in both hepatic canaliculi and sinusoids.

Nephrotoxicity

• Due to hypersensitive reactions.

• Irregular or interrupted Rifampin therapy.

A wide range of clinical symptoms that occur due to Rifampin toxicity is as follows:

• Metabolic acidosis.

• Nausea.

• Vomiting.

• Abdominal pain.

• Hyperventilation.

• Fatigue.

• Thrombocytopenia.

• Skin and mucosal bleeding.

• Oliguric renal failure.

• Convulsions.

• Cholestatic jaundice.

• Red man syndrome (glowing red skin discoloration of the skin with periorbital and facial edema).

• Hepatitis (in pre-existing liver diseases).

• Flu-like symptoms in case of hypersensitivity.

Management of Toxicity

No specific antidote or neutralizing agent is available to control Rifampin toxicity. The treatment for Rifampin toxicity includes supportive care and symptomatic management.

• Airway maintenance.

• Antiemetic medications.

• Gastric lavage by using activated charcoal.

• Correction and stabilization of electrolytes and acid-base balances.

• Active diuresis.

• Dialysis.

Steps to Enhance the Outcome of the Healthcare Faculty

• Regular monitoring is to be followed to prevent hepatotoxicity.

• Baseline liver function tests (LFT) should be done before the commencement of the therapy and should be used as a reference to detect progressive liver changes. Subsequent LFTs are also recommended.

• If symptoms of hepatotoxicity (nausea, abnormal LFT, abdominal pain) occur, the dosage of Rifampin is to be adjusted or stopped for a short duration.

• In the case of certain clinical conditions associated with poor drug absorption and drug interaction (diabetes, HIV, malabsorption syndrome, and elderly people), special monitoring is needed.

• Drug resistance in bacteria commonly occurs in any antimicrobial regime. Rifampin, being an antimicrobial agent, should be cautiously administered in combination with other antimicrobial agents to prevent drug resistance.

• Drug susceptibility tests are mandatory before using Rifampin in tuberculosis.

• Previous drug history is essential to prevent adverse drug interactions.

• Patients are to be educated on adverse side effects and instructed to report in cases of symptoms of side effects.

• Rifampin therapy is a long-duration regime. Care and monitoring are needed in evaluating dose adjustments and frequency of usage.

• Patients should be given precautions about the relapse of tuberculosis or the development of drug resistance due to irregular or improper discontinuation of therapy.

• Effective coordination between multi-professional health care faculty and the patient population is essential to achieve complete utilization and efficacy of Rifampin.