Rifampicin

Pharmacodynamics and pharmacokinetics

Low concentrations of the drug have a bactericidal effect on chlamydia, mycobacterium tuberculosis, rickettsia, legionella, and mycobacterium leprosy. High concentrations of the drug are active against gram-negative flora.

Rifampicin is a first-line anti-tuberculosis drug. High activity is observed when exposed to staphylococci, clostridia, gonococci, meningococci. The drug acts on extracellular as well as intracellular bacteria.

The mechanism of action is based on the inhibition of RNA polymerase of microorganisms. Cross-resistance with other antibacterial agents has not been recorded. With drug monotherapy, rapid development of selection of microorganisms to the antibiotic is observed.

Rifampicin[edit | edit code]

Rifamycins are a group of related, structurally complex macrocyclic antibiotics produced by Streptomyces mediterranei (Farr, 2000), and the semisynthetic compounds fampicin, rifabutin, rifapentine derived from them). Rifampicin is a derivative of rifamycin B.

Chemical properties[edit | edit code]

Rifampicin is soluble in organic solvents and aqueous acid solutions. Its structure formula is as follows:

Structural formula of rifampicin

Antimicrobial activity[edit | edit code]

Rifampin inhibits the growth of many gram-negative (Escherichia coli, Pseudomonas spp., Klebsiella spp., indole-positive and indole-negative Proteus spp.) and most gram-positive bacteria. It is very active against staphylococci, including Staphylococcus aureus (MIC ranges from 0.003 to 0.012 μg/ml), works well against Neisseria meningitidis and Haemophilus influenzae (MIC ranges from 0.1 to 0.8 μg/ml), and also has pronounced bacteriostatic effect against Legionella spp. (both in cell culture and in animal experiments).

The MIC for Mycobacterium tuberculosis is 0.005-0.2 μg/ml; for Mycobacterium kansasii it is 0.25-1 μg/ml. The growth of most strains of Mycobacterium scrofulaceum and Mycobacterium avium-intracellulare is inhibited at a rifampicin concentration of 4 µg/ml, although some strains can grow even at a rifampicin concentration of 16 µg/ml. Mycobacterium fortuitum is extremely resistant to the drug. In vitro, rifampicin enhances the antituberculosis activity of streptomycin and isoniazid, but not ethambutol (Hobby and Lenert, 1972).

Stability[edit | edit code]

In vitro, microorganisms can quickly acquire resistance to rifampicin. The probability of the emergence of resistant strains of Mycobacterium tuberculosis is 1 in 107-108. Typically, resistance is caused by a mutation between codons 507 and 533 of the rB gene, which encodes bacterial RNA polymerase (Blanchard, 1996). The same thing apparently happens in vivo, which is why rifampicin is always prescribed to patients with tuberculosis in combination with other anti-tuberculosis drugs. The failure of attempts to eliminate the carriage of meningococci using rifampicin was also due to drug resistance: resistant strains appeared within 2 days. after starting treatment. Some rifampicin-resistant strains have reduced virulence. In patients who have not previously taken anti-tuberculosis drugs, rifampicin-resistant strains of Mycobacterium tuberculosis are isolated extremely rarely, in less than 1% of cases (Cauthen et al., 1988).

Mechanism of action[edit | edit code]

Rifampicin inhibits bacterial RNA polymerase, forming a stable complex with it and preventing the initiation (but not elongation) of transcription. The target of rifampicin is the β-subunit of RNA polymerase; although it only binds to the holoenzyme. Nuclear RNA polymerase of eukaryotic cells is insensitive to rifampicin, but at concentrations significantly higher than bactericidal levels, rifampicin inhibits the synthesis of mitochondrial RNA. At high concentrations, rifampicin also inhibits the activity of viral PH K-polymerases and reverse transcriptases. Rifampicin has a bactericidal effect on both extracellular and intracellular microorganisms.

Side effects of Rifampicin

Digestive tract: pseudomembranous enterocolitis , vomiting, loss of appetite, nausea, increased levels of liver enzymes, hepatitis , hyperbilirubinemia , diarrhea , erosive gastritis .

Nervous system: disorientation , decreased visual acuity, headache, ataxia .

Genitourinary system: interstitial nephritis , nephronecrosis .

hyperuricemia , myasthenia , leukopenia , allergies , exacerbation of gout , dysmenorrhea is possible .

If the drug is not used regularly, it is possible to develop a flu-like condition and the following side effects: myalgia , chills , fever , dizziness , headaches .

Instructions for use of Rifampicin (Method and dosage)

The drug is taken orally and administered intravenously.

Rifampicin tablets, instructions for use

Take half an hour before meals, on an empty stomach.

In the treatment of tuberculosis, this medicine must be combined with other anti-tuberculosis medications ( Ethambutol , Pyrazinamide , Isoniazid ). Adults are prescribed 10 mg/kg once every 24 hours. No more than 1200 mg per day, for children - no more than 600 mg.

Combination of tuberculosis with HIV , tuberculosis damage to the spinal column with neurological symptoms, disseminated tuberculosis, tuberculous meningitis: 2 months Rifampicin is used with Pyrazinamide , Isoniazid , Ethambutol , Streptomycin , the next 7 months the antibiotic is combined with Isoniazid .

If mycobacteria are detected in sputum or pulmonary tuberculosis, the patient is prescribed one of three antimicrobial therapy regimens, used in combination with other drugs.

Multibacillary types of leprosy (borderline, lepromatous, mixed): 600 mg once a month along with Dapsone 100 mg once a day and clofazimine (300 mg once a month, 50 mg daily).

Pausibacillary types of leprosy (borderline tuberculoid, simple tuberculoid): once a month 600 mg together with Dapsone 100 mg daily, the course of therapy is designed for six months.

Therapy for brucellosis : a single dose of 900 mg on an empty stomach in the morning along with Doxycycline , the course is designed for 45 days.

Prevention of meningococcal meningitis : every 12 hours - 600 mg, course for 2 days.

Using the solution

IV adults are prescribed 600 mg per day, children 10 mg per kg once a day. The maximum dose for intravenous administration is 600 mg.

Rifampicin

Manufacturer: BINERGIA CJSC (Russia)

lyophilisate for preparation. solution for infusion 150 mg: amp. 5, 10, 100, 125, 250, 500 or 1000 pcs. Reg. No.: LP-001911

Clinical and pharmacological group:

Antibiotic of the rifamycin group. Anti-tuberculosis drug

Release form, composition and packaging

Lyophilisate for the preparation of solution for infusion

in the form of a porous mass or a mixture of porous mass and powder of brick or brown-red color, marbling of color is allowed.

Excipients:

sodium ascorbate 17.1 mg, sodium sulfite 3 mg.

150 mg - glass ampoules (5) - plastic contour packages (1) - cardboard packs. 150 mg - glass ampoules (5) - plastic contour packages (2) - cardboard packs. 150 mg - glass ampoules (5) - contour plastic packaging (20) - cardboard boxes. 150 mg - glass ampoules (5) - contour plastic packaging (25) - cardboard boxes. 150 mg - glass ampoules (5) - contour plastic packaging (50) - cardboard boxes. 150 mg - glass ampoules (5) - contour plastic packaging (100) - cardboard boxes. 150 mg - glass ampoules (5) - contour plastic packaging (200) - cardboard boxes. 150 mg - glass ampoules (5) - contour blister packs (1) - cardboard packs. 150 mg - glass ampoules (5) - contour blister packs (2) - cardboard packs. 150 mg - glass ampoules (5) - contour blister packaging (20) - cardboard boxes. 150 mg - glass ampoules (5) - contour blister packaging (25) - cardboard boxes. 150 mg - glass ampoules (5) - contour blister packaging (50) - cardboard boxes. 150 mg - glass ampoules (5) - contour blister packaging (100) - cardboard boxes. 150 mg - glass ampoules (5) - contour blister packs (200) - cardboard packs.

Description of the active components of the drug "Rifampicin"

pharmachologic effect

Semi-synthetic broad-spectrum antibiotic of the rifamycin group. Has a bactericidal effect. Suppresses bacterial RNA synthesis by inhibiting the DNA-dependent RNA polymerase of the pathogen.

Highly active against Mycobacterium tuberculosis, it is a first-line anti-tuberculosis drug.

Active against gram-positive bacteria: Staphylococcus spp. (including multidrug-resistant), Streptococcus spp., Bacillus anthracis, Clostridium spp., as well as against some gram-negative bacteria: Neisseria meningitidis, Haemophilus influenzae, Brucella spp., Legionella pneumophila.

Active against Rickettsia prowazekii, Mycobacterium leprae, Chlamydia trachomatis.

Resistance to rifampicin develops rapidly. Cross-resistance to other anti-tuberculosis drugs (with the exception of other rifamycins) was not observed.

Indications

Tuberculosis (including tuberculous meningitis) as part of combination therapy. MAS infection. Infectious and inflammatory diseases caused by pathogens sensitive to rifampicin (including osteomyelitis, pneumonia, pyelonephritis, leprosy; meningococcal carriage).

Dosage regimen

When taken orally for adults and children - 10 mg/kg 1 time/day or 15 mg/kg 2-3 times a week. Take on an empty stomach, the duration of treatment is determined individually.

IV for adults - 600 mg 1 time/day or 10 mg/kg 2-3 times a week, for children - 10-20 mg/kg 1 time/day or 2-3 times a week.

It is possible to administer 125-250 mg to the pathological focus (by inhalation, intracavitary administration, as well as injection into the focus of the skin lesion).

Maximum doses:

when taken orally for adults, the daily dose is 1.2 g, for children 600 mg, when administered intravenously for adults and children - 600 mg.

Side effect

From the digestive system:

nausea, vomiting, diarrhea, loss of appetite; increased levels of liver transaminases, bilirubin in the blood plasma, pseudomembranous colitis, hepatitis.

Allergic reactions:

urticaria, Quincke's edema, bronchospasm, influenza-like syndrome.

From the hematopoietic system:

rarely - thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, hemolytic anemia.

From the side of the central nervous system:

headache, ataxia, visual impairment.

From the urinary system:

necrosis of kidney tubules, interstitial nephritis, acute renal failure.

From the endocrine system:

menstrual irregularities.

Other:

red-brown coloring of urine, feces, saliva, sputum, sweat, tears.

Contraindications

Jaundice, recent (less than 1 year) infectious hepatitis, severe renal dysfunction, hypersensitivity to rifampicin or other rifamycins.

Pregnancy and lactation

If it is necessary to use rifampicin during pregnancy, the expected benefit of therapy for the mother and the potential risk to the fetus should be assessed.

It should be borne in mind that the use of rifampicin in the last weeks of pregnancy increases the risk of bleeding in newborns and mothers in the postpartum period.

Rifampin is excreted in breast milk. If necessary, use during lactation should stop breastfeeding.

Use for liver dysfunction

Contraindicated in case of jaundice, recent (less than 1 year) infectious hepatitis.

Use for renal impairment

Contraindicated in cases of severe renal impairment.

Application for children

In newborns and premature infants, rifampicin is used only when absolutely necessary.

special instructions

Use with caution for liver diseases and exhaustion. When treating non-tuberculosis infections, rapid development of microbial resistance is possible; this process can be prevented by combining rifampicin with other chemotherapeutic agents. Rifampicin is better tolerated when taken daily than when taken intermittently. If it is necessary to resume treatment with rifampicin after a break, then you should start with a dose of 75 mg/day, gradually increasing it by 75 mg/day until the desired dose is reached. In this case, renal function should be monitored; additional administration of GCS is possible.

With long-term use of rifampicin, systematic monitoring of blood counts and liver function is indicated; You cannot use a test with a load of bromsulfalein, since rifampicin competitively inhibits its excretion.

PAS preparations containing bentonite (hydrosilicate of aluminum) should be prescribed no earlier than 4 hours after taking rifampicin.

In newborns and premature infants, rifampicin is used only when absolutely necessary.

Drug interactions

Due to the induction of microsomal liver enzymes (CYP2C9, CYP3A4 isoenzymes), rifampicin accelerates the metabolism of theophylline, oral anticoagulants, oral hypoglycemic drugs, hormonal contraceptives, digitalis drugs, verapamil, phenytoin, quinidine, corticosteroids, chloramphenicol, antifungal drugs, which leads to a decrease in their plasma concentrations blood and, accordingly, to a decrease in their effect.

Drug interactions

Due to the induction of microsomal liver enzymes (CYP2C9, CYP3A4 isoenzymes), rifampicin accelerates the metabolism of theophylline, oral anticoagulants, oral hypoglycemic drugs, hormonal contraceptives, digitalis drugs, verapamil, phenytoin, quinidine, corticosteroids, chloramphenicol, antifungal drugs, which leads to a decrease in their plasma concentrations blood and, accordingly, to a decrease in their effect.

Interaction

Rifampicin reduces the activity of digitalis drugs, oral hypoglycemic medications, anticoagulants, contraceptives, antiarrhythmic drugs ( tocainide , pyrmenol , disopyramide , mexiletine , quinidine ), phenytoin , dapsone , glucocorticosteroids, ketoconazole , chloramphenicol , sex hormones, benzodiazepines, nor triptyline , , cyclosporine , cimetidine , Enalapril , BMCC, beta-blockers, Azathioprine (rifampicin can accelerate metabolism due to the induced induction of certain enzymes of the liver system).

Ketoconazole , anticholinergics, opiates and antacids reduce the bioavailability of the antibiotic.

When taking Pyrazinamide or Isoniazid , the hepatotoxic effect increases.

The drug Pask can be prescribed 4 hours after using Rifampicin to prevent absorption.

special instructions

Antibacterial therapy can lead to a reddish coloration of urine, tears, feces, sweat, skin and sputum. Permanent staining of contact lenses is possible.

Intravenous infusions of Rifampicin are carried out under blood pressure monitoring. Long-term therapy leads to the formation of phlebitis . To prevent resistance, the drug is used in combination with other antibiotics and antimicrobial agents.

When registering a flu-like syndrome (without bronchospasm , hemolytic anemia , shortness of breath, renal failure , shock, thrombocytopenia ) in patients who are taking medication on an intermittent regimen, the attending physician should consider switching to daily use of an antibiotic. In this case, the dose increase occurs slowly, titration takes 3-4 days. Regular monitoring of the state of the renal system is required, and the use of glucocorticosteroids is possible.

Rifampin during pregnancy is used exclusively for health reasons. Prescribing an antibiotic in the last days of pregnancy can cause bleeding in the newborn, as well as postpartum bleeding in the mother. , vitamin K is recommended . Women during the period of antibacterial therapy should be reliably protected from pregnancy.

When carrying out prophylaxis against meningococcal bacilli, strict control over the group is required for timely detection of symptoms in the development of resistance to the antibacterial drug.

Long-term therapy requires regular monitoring of the state of the hepatic system and peripheral blood.

The medication affects the level of vitamin B12 and folic acid in the blood serum.

Pharmacokinetics[edit | edit code]

The maximum serum concentration of rifampicin is achieved 2-4 hours after oral administration and varies widely. When taken at a dose of 600 mg, it is about 7 mcg/ml. Food and aminosalicylic acid slow the absorption of rifampicin, reducing its serum concentration.

When administered simultaneously, the interval between taking rifampicin and aminosalicylic acid should be 8-12 hours (Radner, 1973).

After absorption from the gastrointestinal tract, rifampicin quickly enters the bile and participates in the enterohepatic circulation. At the same time, it is gradually deacetylated, and after 6 hours only the deacetylated derivative of rifampicin is detected in the bile. The latter almost completely retains its antimicrobial activity, but is poorly reabsorbed in the intestine and excreted in the feces. The half-life (T1/2) of rifampicin ranges from 1.5 to 5 hours. In liver diseases, this figure increases, and in individuals with low activity of acetylating enzymes who are simultaneously receiving isoniazid, it decreases.

During treatment, the elimination of rifampicin is accelerated (by approximately 40% for the first 14 days) due to the induction of liver microsomal enzymes that deacetylate the drug. Up to 30% of rifampicin is excreted in the urine, 60-65% in feces, and the unchanged drug accounts for less than half of this amount. In case of renal failure, the dose of rifampicin is not reduced.

Rifampicin is distributed throughout the body, reaching therapeutic concentrations in many tissues and body fluids, including the CSF (Sippel et al., 1974). Patients should be warned that the drug turns urine, feces, saliva, sputum, tears and sweat orange. The metabolism of rifampicin is described in more detail, for example, in Furesz (1970), Farr (2000).