Lomefloxacin + Pyrazinamide + Prothionamide + Etambutol + Pyridoxine - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Other synthetic antibacterial agents

Included in the formulation

Prothiocomb®

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AKRIKHIN HFK, JSC Russia

Protub-5

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FARMASINTEZ, JSC (Irkutsk) Russia

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

АТХ:

J.04.A.M Combinations of antituberculous drugs

Pharmacodynamics:

Antimicrobial agent of the group of fluoroquinolones. Has a bactericidal effect. Inhibits the activity of DNA-gyrase, an enzyme involved in the transcription and replication of bacterial DNA.

Highly active against aerobic gram-negative bacteria: Escherichia coli, Salmonella spp., Citrobacter diversus, Enterobacter cloacae, Haemophilus influenzae, Klebsiella pneumoniae, Proteus vulgaris, Morganella morganii, Legionella pneumophila, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella catarrhalis.

Lomefloxacin is moderately sensitive Proteus mirabilis, Proteus stuartii, Providencia rettgeri, Pseudomonas aeruginosa, Serratia liquefaciens, Serratia agglomerans, Haemophilus parainfluenzae, Providencia alcalifaciens, Aeromonas hydrophila, Hafnia alvei, Mycobacterium tuberculosis, Chlamydia trachomatis, as well as some Gram-positive aerobic bacteria (Staphylococcus aureus, Staphylococcus epidermidis).

Lomefloxacin is stable Streptococcus spp., Pseudomonas cepacia, Ureaplasma urealyticum, Mycoplasma hominis and anaerobic bacteria.

Lomefloxacin has anti-tuberculosis activity, acting both on the outside and intracellularly located Mycobacterium tuberculosis.

Prothionamide, an analog of ethionamide, is used more widely due to lower toxicity and somewhat greater antimicrobial activity.The mechanism of action is the blockade of the synthesis of mycolic acids, which are an important structural component of the cell wall Mycobacterium tuberculosis, a nicotinic acid antagonist. In high concentrations, it acts bactericidal, disrupting the synthesis of the microbial cell. Effective in relation to Mycobacterium tuberculosis, resistant to anti-TB drugs. Affects both extracellular and intracellularly located mycobacteria. Little active in relation to Mycobacterium tuberculosis bovine type, atypical mycobacteria and acid-resistant saprophytes. Does not affect the pathogenic nonspecific flora.

Pyrazinamide has a bactericidal action at acidic values pH. Well penetrates into the tuberculosis foci. Its activity is high in caseous-necrotic processes, caseous lymphadenitis, tuberculomas. To manifest the bactericidal activity of pyrazinamide, the preparation is subjected to enzymatic conversion into the active form - pyrazinic acid. On non-tuberculosis pathogens does not work.

Etambutol is a bacteriostatic drug that is effective against typical and atypical mycobacteria tuberculosis.The mechanism of action of the drug associated with the violation of RNA synthesis in bacterial cells, inhibits cell wall synthesis by blocking the insertion mikolievyh acids. Ethambutol Active against rapidly and slowly growing atypical mycobacteria. On non-tubercular pathogens ethambutol It does not work.

Pyridoxine hydrochloride is a vitamin remedy. Participates in the metabolism. It is necessary for the normal functioning of the central and peripheral nervous system. In the treatment of anti-tuberculosis drugs, a pyridoxine deficiency may occur. In this regard, the daily dose of vitamin increases. If simultaneous reception of pyridoxine inwardly with isoniazid, rifampicin, pyrazinamide there is no interaction of these drugs on the pharmacokinetic and microbiological levels.

Pharmacokinetics:

Lomefloxacin

Lamefloxacin intake in conjunction with other drugs from the combination does not affect the rate of its absorption from the gastrointestinal tract. Bioavailability of Lomefloxacin is more than 90%. The time to reach the maximum concentration is 1-1.5 hours. The half-life is 8-9 hours.Communication with blood proteins is negligible 10%. In small amounts, biotransformation is carried out in the liver with the formation of metabolites that have little antimicrobial activity. In 80% it is excreted by kidneys, feces, then and saliva. Hepatic failure does not affect the biotransformation of lomefloxacin. The average renal clearance is 145 ml / min.

Prothionamide

Quickly absorbed in the digestive tract. The maximum concentration is reached in 2-3 hours after its reception. Well absorbed in an acidic environment. Penetrates into all tissues and body fluids, including spinal fluid, tuberculosis foci, cavities and encapsulated formations. Biotransformiruetsya in the liver, partially turning into an active metabolite - sulfoxide. It is excreted partially by the kidneys - up to 18.5%. The rest of the medicinal part is excreted with bile.

Pyrazinamide

The maximum concentration is achieved 2 hours after taking the drug and averages 10-12 hours. Pyrazinamide well penetrates into the organs, tissues and body fluids, including the lymph nodes and cerebrospinal fluid. Metabolized in the liver, the main metabolite of pyrazinamide - pyrazinic acid has anti-tuberculosis activity, about 10-20% of the drug binds to plasma proteins.Up to 70% are excreted in urine.

Ethambutol

The maximum concentration is achieved 2 hours after application. The half-life is 5-6 hours. On average, 25% of the drug binds to plasma proteins. Well penetrates into various organs and biological fluids except ascites, pleural fluid and liquor. Undergoes biotransformation in the liver with the formation of inactive metabolites. Excreted in urine in 70% in unchanged form and in 30% in the form of aldehyde and carboxyl inactive metabolites.

Pyridoxine hydrochloride

Absorbed rapidly throughout the small intestine, a larger amount is absorbed in the jejunum. Metabolized in the liver with the formation of pharmacologically active metabolites (pyridoxalphosphate and pyridoxamine phosphate). Pyridoxalphosphate with plasma proteins binds to 90%. Metabolites penetrate well into all tissues: they accumulate mainly in the liver, less in the muscles, in the central nervous system. Penetrates through the placenta, secreted with breast milk 15-20 days. It is excreted by the kidneys.

Indications:

- drug-resistant tuberculosis with moderate resistance of mycobacterium tuberculosis (isoniazid - to 10, rifampicin - up to 40, ethambutol - up to 2 μg / ml);

- acutely progressive course of tuberculosis;

- tuberculosis with concomitant inflammatory diseases caused by non-specific pathogenic flora, sensitive to lomefloxacin.

ICD-10

I.A15-A19.A16 Tuberculosis of respiratory organs, not confirmed bacteriologically or histologically

I.A15-A19.A17 Tuberculosis of the nervous system

I.A15-A19.A18 Tuberculosis of other organs

Contraindications:

Hypersensitivity to pyrazinamide, isoniazid, ethionamide, nicotinic acid or other chemical related facilities, lomefloxacin, other chemically similar or fluoroquinolones means (cinoxacin, nalidixic acid), prothionamide, ethambutol, pyridoxine.

Gastric ulcer and duodenal ulcer, ulcerative colitis, acute hepatitis, liver cirrhosis, children's age (18 years), pregnancy, breast-feeding.

Carefully:

Gout is a history of liver dysfunction, central nervous system diseases, including cerebral atherosclerosis, mental illness, epilepsy, stroke, convulsive conditions, diarrhea, renal failure, combined hepatic or renal failure, deficiency glucose-6-phosphate dehydrogenase, myasthenia gravis, diabetes mellitus, porphyria, optic neuritis, cataract, diabetic retinopathy, inflammatory eye diseases, thrombophlebitis.

Pregnancy and lactation:

Contraindicated in pregnancy. For all fluoroquinolones: adequate and well-controlled studies in humans have not been conducted. Since the use of fluoroquinolones in studies on immature animals has led to the development of arthropathy, the use of drugs of this group is not recommended during pregnancy. For Lomefloxacin: Reproduction studies in rats receiving oral doses 34 times higher than the recommended dose for humans did not report any harm to the fetus. An increase in embryonic loss in monkeys was observed with doses 6-12 times higher than the recommended doses for humans (calculated as mg / kg). No teratogenic effects were observed in rats or monkeys using doses 16 times the recommended doses for humans. Studies in rabbits: maternal toxicity and related fetal toxicity, a decrease in the weight of the placenta and changes in the coccyx spine occurred when doses were used that were 2 times higher than those recommended for humans (when calculating mg / m²).There is no information on the penetration into breast milk. If the appointment of alternative antibacterial drugs is not possible and the use of fluoroquinolones is necessary, breast-feeding is not recommended.

The category of FDA recommendations is not defined.

Dosing and Administration:

Inside. The drug is taken 1 time per day after meals, preferably in the morning. The drug is dosed according to lomefloxacin at the rate of 13.2 mg / kg body weight, but not more than 5 tablets. Duration of treatment - 3 months.

With indications the drug is combined with streptomycin or kanamycin (intramuscularly at a dose of 16 mg / kg once a day for 3 months).

Side effects:

Lomefloxacin

From the digestive system: nausea, vomiting, dry mouth, gastralgia, abdominal pain, diarrhea, constipation, flatulence, pseudomembranous enterocolitis, dysphagia, discoloration of the tongue, decreased appetite, bulimia, taste distortion, dysbiosis, increased hepatic transaminase activity, bleeding from the digestive tract.

From the central nervous system and peripheral nervous system: fatigue, malaise, asthenia, headache, dizziness, fainting, insomnia, hallucinations, convulsions, hyperkinesia, tremor, paresthesia, nervousness, anxiety, depression, arousal.

On the part of the genitourinary system: glomerulonephritis, dysuria, polyuria, anuria, albuminuria, bleeding from the urethra, crystalluria, hematuria, urinary retention, edema; in women - vaginitis, leukorrhea, intermenstrual bleeding, pain in the perineum, vaginal candidiasis; in men - orchitis, epididymitis.

From the side of metabolism: hypoglycemia, gout.

From the musculoskeletal system: arthralgia, spasms of the calf muscles, pain in the back and chest area.

On the part of the organs of hematopoiesis: thrombocytopenic purpura, increased fibrinolysis.

On the part of the respiratory system: dyspnoea, respiratory infections, bronchospasm, cough, hypersecretion of phlegm, flu-like syndrome, epistaxis.

From the senses: visual impairment, pain and noise in the ears, pain in the eyes.

From the cardiovascular system: lowering blood pressure, tachycardia, bradycardia, extrasystole, arrhythmias, progression of heart failure and angina, pulmonary embolism, myocardiopathy, phlebitis.

Allergic reactions: itching, hives, malignant exudative erythema (Stevens-Johnson syndrome).

Influence on the fetus: fetotoxic action (arthropathy).

Other: candidiasis, increased sweating, chills, thirst, reinfection, lymphadenopathy, photosensitivity.

Prothionamide

On the part of the digestive system: nausea, vomiting, diarrhea, hypersalivation, "metallic" taste in the mouth, impaired liver function.

From the central nervous system and peripheral nervous system: insomnia, agitation, depression, anxiety, dizziness, drowsiness, headache, asthenia, paresthesia, peripheral neuropathy, optic neuritis.

From the cardiovascular system: tachycardia, weakness, orthostatic hypotension.

Allergic reactions: skin rash.

Other: hypoglycemia (in patients with diabetes mellitus), gynecomastia, dysmenorrhea, hypothyroidism, decreased potency.

Pyrazinamide

On the part of the digestive system: nausea, vomiting, diarrhea, a "metallic" taste in the mouth, a decrease in appetite, a violation of liver function, liver tenderness, hepatomegaly, jaundice, yellow liver atrophy, exacerbation of peptic ulcer.

From the central nervous system and peripheral nervous system: dizziness, headache, sleep disturbances, increased excitability, depression; hallucinations, convulsions, confusion.

From the hematopoiesis: thrombocytopenia, sideroblastic anemia, erythrocyte vacuolization, porphyria, hypercoagulation, splenomegaly.

From the musculoskeletal system: arthralgia, myalgia.

From the side of the urinary system: dysuria, interstitial nephritis.

Allergic reactions: skin rash, hives.

Other: hyperthermia, acne, hyperuricemia, exacerbation of gout, photosensitivity, increased serum iron concentration.

Ethambutol

From the side of the central nervous system and peripheral nervous system: weakness, headache, dizziness, impaired consciousness, disorientation, hallucinations, depression, peripheral neuritis (paresthesia in the extremities, numbness, paresis, itching), optic neuritis (decreased visual acuity), impaired color perception (green and red colors), color blindness, scotoma.

On the part of the digestive system: decreased appetite, nausea, vomiting, gastralgia, impaired liver function, increased activity of hepatic transaminases.

Allergic reactions: dermatitis, skin rash, itching, arthralgia, fever, anaphylaxis.

Other: photosensitization, hyperuricemia, exacerbation of gout.

Pyridoxine hydrochloride

Allergic reactions, hypersecretion of hydrochloric acid, numbness, the appearance of a feeling of compression in the limbs - a symptom of "stocking" and "gloves", rarely - a skin rash, itching of the skin.

Overdose:

Symptoms: nausea, vomiting, impaired liver function, peripheral neuropathy, slurred speech, confusion, visual and hearing impairment, convulsions, respiratory depression, pulmonary edema, stupor, coma.

Treatment: gastric lavage, the appointment of activated charcoal, forced diuresis, artificial ventilation, intravenous short-acting barbiturates, pyridoxine, osmotic diuretics, sodium hydrogen carbonate (with metabolic acidosis).

Interaction:

The use of lomefloxacin together with isoniazid, ethambutol and, especially, pyrazinamide significantly increases antimicrobial activity against sensitive and particularly resistant Mycobacterium tuberculosis. The combined use of the drug with probenecid slows the excretion of lomefloxacin. Sucralfate and antacid agents containing magnesium or aluminum form chelate-forming complexes with lomefloxacin.The use of these drugs should be performed 2 hours before or 2 hours after taking lomefloxacin.

Taking the drug with rifampicin leads to a decrease in the antimicrobial activity of this combination in relation to Mycobacterium tuberculosis because of the antagonism existing between lomefloxacin and rifampicin at the microbial level.

Prothionamide in combination with lomefloxacin significantly increases antimicrobial activity against Mycobacterium tuberculosis. Antacids reduce the absorption of protionamide. Prothionamide reduces the effectiveness of antihypertensive drugs.

Pyrazinamide increases the concentration of isoniazid in the serum, slowing its excretion. When taking rifampicin together with pyrazinamide, the risk of developing hepatotoxic reactions increases.

Aluminum hydroxide reduces the absorption of ethambutol. Admission ethambutol with aminoglycosides. imipenem, carbamazepine, lithium salts, quinine increases the risk of neurotoxic action of the drug. Ethambutol enhances the antimicrobial activity of other antituberculosis drugs.

Pyridoxine weakens the action of levodopa when combined. Pyridoxine reduces the risk of toxic effects of antituberculosis drugs on the central and peripheral nervous system. Pyridoxine in the composition of the drug does not affect the antimicrobial activity of the drugs included in its composition.

Special instructions:

There are no studies confirming the effectiveness of the combination.

Monitoring: liver function (hepatic transaminases: before treatment and every 2-4 weeks during treatment, but an increase in the activity of enzymes in the blood plasma may not be a harbinger of hepatitis and may return to normal with continued therapy), the concentration of uric acid in the blood plasma (in time of therapy, since it is possible to increase with the development of an acute attack of gout), prothrombin time (when combined with warfarin), ophthalmological examination (fields, visual acuity and differences of red and green colors, especially during long-term therapy or a dose of more than 15 mg / kg), blood glucose, thyroid function and vision (periodically), peripheral blood patterns, and the functional state of the liver and kidneys (with prolonged therapy).

In patients with diabetes, the risk of hypoglycemia increases.

Features of combining with diagnostic studies

Determination of ketones in urine - pyrazinamide can react with sodium nitroprusside to form colored rosy-brown products.

When determining urobilinogen using Ehrlich's reagent, the results may be distorted.

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

It is not represented in US and UK Pharmacopoeias.

Instructions

Lomefloxacin + Pyrazinamide + Prothionamide + Etambutol + Pyridoxine (Lomefloxacinum + Pyrazinamidum + Prothionamidum + Aethambutolum + Pyridoxinum)