Tuberculosis - I.T. Pyatnochka 2005

Treatment of tuberculosis
Antimycobacterial agents

Antimycobacterial therapy is the cornerstone of Treatment for patients with tuberculosis affecting various Organs and systems. Based on their efficacy, antimycobacterial drugs are divided into three groups. Group I (A), comprising the most potent agents, includes isoniazid and rifampicin. Group II (B), consisting of moderately effective drugs, includes streptomycin, pyrazinamide, amikacin, kanamycin, florimycin, ethambutol, ethionamide, prothionamide, cycloserine, ofloxacin, ciprofloxacin, and capreomycin. Group III (C) comprises the least effective chemotherapeutic agents, namely PAS and thioacetazone.

Isoniazid and rifampicin are considered the most potent antimycobacterial drugs, followed by streptomycin and pyrazinamide. The efficacy of these agents is evaluated based on their bacteriostatic or bactericidal activity, their ability to cross cellular and tissue membranes, and their effect on extracellular, intracellular, rapidly multiplying, and persistent forms of M. tuberculosis. Bactericidal activity at therapeutic doses is characteristic only of rifampicin.

In general, antituberculosis drugs are classified into lines, with each drug corresponding to an international symbol (Table 5).

Isoniazid (Isoniazidum) is the primary representative of the isonicotinic acid hydrazide (INAH) group. It is the most potent of all antimycobacterial agents, exhibits strict Specificity exclusively against M. tuberculosis, and readily crosses cellular, tissue, and Blood-Brain barriers. Isoniazid acts on both extracellular and intracellular mycobacteria, predominantly targeting rapidly multiplying organisms and, to a lesser extent, slow-growing ones. The MECHANISM OF ACTION involves the blockade or inactivation of microbial Enzymes and Coenzymes, disrupting Protein METABOLISM, DNA, RNA, and phospholipid synthesis, as well as the redox processes of M. tuberculosis. Isoniazid is rapidly absorbed after oral administration, reaching peak blood concentrations within 1.5–3 hours. It is excreted in the urine over 12 hours.

Class="center">Table 5. Names of antituberculosis drugs and their Abbreviations

Isoniazid is available in 0.1 g, 0.2 g, and 0.3 g tablets, as well as in 5 ml ampoules of a 10% solution. The daily dose is 8–10 mg/kg (0.3–0.6 g for adults), administered orally after meals either once daily or divided into two doses. Isoniazid can also be administered intravenously, intramuscularly, and via inhalation (aerosols).

Adverse effects and complications of isoniazid include headache, dizziness, Sleep disturbances, euphoria, memory impairment, cardialgia, arthralgia, hepatitis, peripheral neuritis, hypersensitivity, psychosis, convulsions, allergic rashes, gynecomastia, and menometrorrhagia. Prevention of neurotoxic complications involves The Use of Vitamins B₁ and B₆.

Isoniazid derivatives include phthivazide (Phthivazidum), prescribed at 0.5 g three times daily (30–40 mg/kg); methazide (Methazidum) at 0.3 g three times daily (20 mg/kg); larusan (Larusanum) at 0.5 g 2–3 times daily; and saluzid (Saluzidum) at 0.5 g 2–3 times daily (20 mg/kg). Saluzid is available in ampoules as a 10% or 5% solution for endobronchial and intrapleural administration.

Rifampicin (Rifampicinum) is a semi-synthetic broad-spectrum antibiotic. The drug exhibits marked bacteriostatic activity against extracellular and intracellular M. tuberculosis, affecting both rapidly and slowly multiplying populations. It readily crosses the blood-brain barrier and penetrates various body Tissues, specific lesion sites, and caseous masses. Peak blood concentrations of rifampicin are reached 1.5–4 hours after administration, and bacteriostatic levels persist in the blood for over 12 hours. The Mechanism of the tuberculostatic action of rifampicin involves the inhibition of ribonucleic acid synthesis in mycobacteria via the blockade of RNA polymerase.

Rifampicin is available in 0.15 g and 0.3 g capsules and ampoules. The daily dose is 8–10 mg/kg, averaging 0.45–0.6 g for adults, taken orally as a single dose 30 minutes before meals. Rifampicin can also be administered via intravenous infusion and endobronchially.

Adverse effects and complications include hyperthermia, rhinitis, myalgia, arthralgia, dyspeptic disorders, obstructive respiratory symptoms, Skin rashes, hematological complications (erythrocyte hemolysis), hemorrhages, hepatitis, hepatorenal syndrome, and anaphylactic reactions.

Hepatotoxic reactions may occur during treatment with isoniazid and rifampicin. For preventive purposes, hepatoprotectors (vitamins, Carsil, Essentiale, Legalon, thiotriazoline), antioxidants (tocopherol acetate, galascorbic acid), Hypoxia suppressants (calcium pangamate, piracetam), and vitamins B₁, B₆, and C are prescribed.

Irregular intake of rifampicin can lead to The formation of drug-induced Antibodies, resulting in red blood Cell hemolysis or acute renal or hepatorenal failure. In such cases, rifampicin must be discontinued immediately, corticosteroid therapy initiated, and hemodialysis performed. Rifampicin is contraindicated in patients with hepatitis or Kidney disease.

Rp.: Rifampicini 0,15

D. t. d. № 30 in caps.gelat.

S. Take 4 capsules as a single dose

half an hour before meals

Streptomycin group: streptomycin sulfate (Streptomycini sulfas), dihydrostreptomycin sulfate (Dihydrostreptomycini sulfas), and streptomycin calcium chloride complex (Streptomycini et calcii chloridum). All are Antibiotics, with streptomycin sulfate being the most widely used. At therapeutic doses, it exerts a bacteriostatic effect exclusively on rapidly multiplying extracellular M. tuberculosis. Streptomycin inhibits oxidative processes and Protein Synthesis in the bacterial cell by binding to Transfer RNA. During streptomycin therapy, phagocytosis and granulation tissue formation are enhanced, while the healing process is dominated by fibrosis and encapsulation of specific lesions.

Peak blood concentrations of streptomycin following intramuscular injection are reached within 2 hours. The daily dose of streptomycin is 15–20 mg/kg (averaging 0.75–1.0 g for adults). In addition to the intramuscular route, the drug can be administered intrapleurally, endobronchially, or via aerosols. For endlumbar (intrathecal) administration, only the streptomycin calcium chloride complex is used at a dose of 0.1–0.2 g.

Adverse effects and complications include local analgesic effects accompanied by hyperemia and rashes on the skin and mucous membranes, angioedema, bronchospasm, anaphylactic Shock, neurotoxicity, ototoxicity, nephrotoxicity, and cardiotoxic effects.

In cases of anaphylactic shock, norepinephrine and prednisolone are administered by intravenous drip; for bronchospasm, aminophylline is used. To prevent ototoxic complications, calcium pantothenate is prescribed at 0.4 g twice daily or administered as 2 ml of a 20% solution intramuscularly twice a day.

Rp.: Streptomycini sulfatis 1,0

D.t.d. № 30

S. For intramuscular administration, dissolve the Contents of the vial in 3 ml of 0.25% novocaine solution.

Kanamycin sulfate (Kanamycini sulfas) belongs to the aminoglycoside antibiotics. Its bacteriostatic effect on MTB is lower compared to streptomycin, while its toxicity is higher. The mechanism of the tuberculostatic action on MTB is similar to that of streptomycin, as are the doses, routes of administration, side effects, and complications (ototoxicity and nephrotoxicity).

Rp.: Kanamycini sulfatis 1,0

D.t.d. № 30

S. For intramuscular administration, dissolve the contents of the vial in 3 ml of 0.25%> novocaine solution.

Florimycin sulfate (Florimycini sulfas) or viomycin (Viomicyni sulfas) is an antibiotic with properties similar to those of streptomycin and kanamycin; however, its bacteriostatic activity against MTB is lower and its toxicity is greater. Florimycin is effective against MTB strains resistant to streptomycin and kanamycin; however, Bacteria resistant to florimycin are simultaneously non-susceptible to both antibiotics. Therefore, these antibiotics are prescribed in a specific sequence: streptomycin, kanamycin, florimycin.

Rp.: Florimycini sulfatis 1,0

D.t.d. № 30.

S. Dissolve the contents of the vial in 3 ml of 0.25% novocaine solution and administer intramuscularly once daily.

Capreomycin (Capreomycinum) is an antibiotic produced by the fungus Streptomyces capreolus. Available forms: 0.5 g and 1 g vials. Pharmacological properties: Capreomycin acts against Mycobacterium tuberculosis, particularly strains resistant to other antibacterial drugs, while showing little activity against other microorganisms. Following intramuscular administration, peak blood concentrations are reached within 1 h, maintained for 2–3 h, and the drug is completely eliminated after 24 hours.

It is prescribed for all clinical forms and localizations of tuberculosis. It is administered intramuscularly at a dose of 0.015–0.02 g/kg (approximately 1 g per day) daily for 2 months, and then twice a week until the completion of treatment. For children, it is administered at a dosage of 0.015 g/kg.

Contraindications, precautions, side effects, and complications are similar to those of streptomycin.

Ofloxacin (Ofloxacin). Synonyms: tarivid, ofloxin, ciprofloxacin, zanocin. Available forms: 0.2 g tablets, 100 ml vials (0.2 g per vial). Pharmacological properties: Ofloxacin is a broad-spectrum antibiotic, effective inter alia against Mycobacterium tuberculosis. The elimination half-life is 6 hours. It is prescribed for all clinical forms and localizations of tuberculosis at a dose of 0.008–0.015 g/kg per day. Average doses: single dose – 0.5–1 g, daily dose – 0.5–1 g.

Contraindications: hypersensitivity to ofloxacin, Epilepsy; pregnant and breastfeeding women, children, and adolescents with incomplete skeletal maturation.

Precautions: It is not recommended to take ofloxacin concomitantly with medications that reduce Gastric Acidity (antacids).

Side effects and complications: Allergic reactions such as skin rash, facial edema, edema of the vocal cords; shock is possible. In some cases, the following may occur: abdominal pain, nausea, vomiting, diarrhea, headache, dizziness, sleep disturbances, and elevated serum bilirubin levels.

Ethambutol (Ethambutolum) is a synthetic antituberculosis drug that selectively inhibits rapidly multiplying extracellular and intracellular MTB. The mechanism of action of ethambutol on MTB involves blocking and sequestering magnesium ions from metabolic processes and inhibiting nucleic acid synthesis. The drug is well absorbed from the gastrointestinal tract into the bloodstream, where peak concentrations are achieved in 3–4 hours, and bacteriostatic activity is sustained for 6 hours.

Ethambutol is available in tablets of 0.1 g, 0.2 g, and 0.4 g. The daily dose is 20–25 mg/kg; the average dose for adults ranges from 0.8 to 1.6 g, taken as a single dose after breakfast.

Side effects and complications: retrobulbar neuritis accompanied by decreased visual acuity and constriction of visual fields for green and red light, eye pain and cutting sensation, paresthesias, dizziness, epileptiform manifestations, hepatitis, and rash.

Before prescribing ethambutol and throughout the course of treatment, visual function must be systematically monitored. If necessary, tocopherol acetate is prescribed at 1 capsule (0.05–0.1) 1–2 times a day. The drug is contraindicated in eye diseases, primarily neuritis and retinitis.

Rp.: Tab. Ethambutoli 0,4 № 100

 D. S. Take 3 tablets once daily after meals.

Pyrazinamide (Pyrazinamidum) is a specific synthetic anti-tuberculosis drug that acts exclusively on MTB, specifically functioning even in an acidic environment, i.e., within caseous necrosis. Pyrazinamide is more active against phagocytosed MTB compared to extracellular ones. When used in combination Chemotherapy regimens, the risk of relapse is significantly reduced because it targets slowly multiplying MTB residing within macrophages. The mechanism of the tuberculostatic action of pyrazinamide consists in inhibiting oxygen consumption by MTB.

The drug is well absorbed in the gastrointestinal tract, with peak blood concentrations reached 3 hours after administration; it exhibits good diffusion properties and crosses the blood-brain barrier. Available in 0.5 g tablets. The daily dose is 25–30 mg/kg (for adults – 1.5 g once daily or 1 g twice daily) taken after meals.

Side effects and complications: dyspeptic disorders, arthralgia, blood hemostatic dysfunction, allergic dermatitis, hyperthermia, and hepatotoxic action. To prevent toxic Liver damage, hepatoprotectors and vitamins B₆ and B₁₂ are prescribed.

Pyrazinamide is contraindicated in severe Diabetes Mellitus, liver diseases, and Gout.

Rp.: Tab. Pyrazinamidi 0,5 № 100

D. S. 3 tablets once daily, after meals.

Morphazinamide (Morphazinamidum). An antimycobacterial drug closely related to pyrazinamide, yet superior in its potency. It is administered in a daily dose of 2-3 g in combination with other antimycobacterial agents.

Its pharmacological properties, clinical uses, indications, contraindications, precautions, side effects, and complications are identical to those of pyrazinamide.

Ethionamide (Ethionamidum) and prothionamide (Protionamidum) are chemosynthetic agents with similar chemical structures and Mechanisms of action, which are exerted exclusively against MTB. The bacteriostatic activity of ethionamide is 10 times lower than that of isoniazid.

The mechanism of action of ethionamide involves inhibiting the uptake of sulfur, phosphorus, and carbon into the protein and DNA of the microbial cell, disrupting PROTEIN SYNTHESIS AND thereby delaying MTB Replication. The drug works effectively in an acidic environment, suppressing rapidly multiplying extracellular and intracellular MTB. Peak blood concentrations are reached 3-6 hours after oral administration. It is available in 0.25 g tablets. The daily dose is 10-12 mg/kg (for adults, 0.75 g as a single daily dose) taken after meals. Ethionamide hydrochloride is also available in 0.5 g vials for intravenous drip infusion.

Side effects: dyspeptic symptoms, headache, sleep disorders, neuritis, depression, mental disorders, cardialgia, hepatitis, endocrine disorders (gynecomastia, impotence, uterine bleeding), pellagra-like symptoms, skin pigmentation and desquamation, Hair loss, and allergic reactions. To prevent the Adverse effects of ethionamide, nicotinamide, B-group vitamins, and demulcents are co-prescribed.

Ethionamide is contraindicated in hepatitis, gastrointestinal diseases, and during Pregnancy (due to its teratogenic effect).

Cycloserine (Cycloserinum) is a broad-spectrum synthetic antibiotic that inhibits the growth of most Gram-positive and Gram-negative bacteria, rickettsiae, and spirochetes. The bacteriostatic activity of cycloserine against MTB is 10 times lower than that of streptomycin. Its mechanism of action involves disrupting mycobacterial protein metabolism by blocking Pyridoxal phosphate. In addition, it binds A number of Trace Elements that play a crucial role as catalysts in oxidation processes. Cycloserine acts on rapidly multiplying MTB as well as on intracellularly and extracellullarly located bacilli.

The drug is rapidly absorbed, reaching peak blood concentrations within 3-4 hours, and readily penetrates various organs and tissues. Cycloserine is available in 0.25 g tablets. The daily dose is 10-20 mg/kg (for adults, 0.25 g three times a day), taken before meals.

Side effects: functional Disorders of the Central Nervous system, neuropsychiatric disorders, headache, sleep disturbances, depression, hallucinations, psychoses, convulsions, peripheral neuritis, cardialgia, and dyspeptic disorders.

To prevent and eliminate the adverse effects of cycloserine, glutamic acid, vitamins B₁, B₆, and ATP are administered.

Rp.: Tab. Cycloserini 0,25 №30

S. 1 tablet 3 times a day before meals.

Sodium para-aminosalicylate (Natrii paraaminosalicylas), or PAS-sodium, is a specific antituberculosis drug.

Availability: powder and 0.5 g tablets; 3% solution in 250-500 ml vials. Sodium PAS inhibits the growth of Mycobacterium tuberculosis. Following oral administration, peak blood levels are reached in 2 hours, with only trace amounts remaining after 8 hours. It is prescribed for all clinical forms and localizations of the process at a dosage of 0.15-0.2 g/kg body weight per day. Average doses: single dose 4-12 g, daily dose 9-12 g. Intravenously, 300-500 ml of a 3% sodium PAS solution is administered.

Contraindications: renal, hepatic, and blood disorders, thyroid hypofunction, grade III cardiovascular failure, gastric and duodenal ulcer, and hypersensitivity to PAS.

Side effects and complications. Dyspeptic disorders, allergy, anemia, hepatitis, agranulocytosis, hypothyroidism, and precordial pain.

BEPASAS (Bepasum) is calcium para-benzoylaminosalicylate.

Availability: tablets and 0.5 g powder. Pharmacological properties, clinical uses, contraindications, side effects, and complications are similar to those of PAS.

Currently, the drug is very rarely used due to its low bacteriostatic activity against MTB and frequent adverse reactions.

Thioacetazone (Thioacethazonum) is a chemosynthetic drug with weak bacteriostatic activity and relatively high toxicity. Its mechanism of action involves inhibiting amine oxidase activity and disrupting microbial metabolic processes; the drug acts exclusively on rapidly multiplying Mtb.

Following oral administration, the drug is rapidly absorbed, reaching peak concentration in 2 hours. Thioacetazone is most effective in Tuberculosis of the mucous membranes, Lymph Nodes, and skin. It is available in 0.025 g and 0.05 g tablets. The daily dose is 2-2.5 mg/kg for adults, administered as 0.05 g two to three times daily. For endobronchial and aerosol administration, soluble thioacetazone (soluthizone) is used in 2 ml ampoules of a 2% solution.

Adverse effects: hepatotoxicity and neurotoxicity, dyspeptic symptoms, allergic reactions, dizziness; it frequently suppresses hematopoiesis, which may manifest as leukopenia, thrombocytopenia, and agranulocytosis.

Thioacetazone is contraindicated in Diseases of the liver, Kidneys, Hematopoietic organs, and in diabetes mellitus.

Currently, the Treatment of tuberculosis patients includes: flurenizide, rifabutin, rifapentine, as well as pefloxacin and lomefloxacin (fluoroquinolones), roxithromycin, azithromycin, and clarithromycin (macrolides), and amikacin (Aminoglycosides). Combined antimycobacterial agents include Macox and Myrin.

Rp.: Rifabutini 0,15

D. t.d. № 50 in caps. gelat.

S. Take 4 capsules as a single dose half an hour before meals.

Rp.: Tab. «Rifapentini» № 50

D. S. Take 1 tablet 2 times a week (half an hour before meals).

Rp.: Tab. Flurenizidi 0,15 № 50

D. S. Take 4 tablets as a single daily dose.

Rp.: Tab. Lomefloxacini 0,5 № 50

D. S. Take 1 tablet twice a day.

Rp.: Tab. Roxitromycini 0,15 № 50

D. S. Take 1 tablet twice a day.

Rp.: Tab. Azithromycini 0,25 № 50

D. S. 2 tablets on the first day, followed by 1 tablet daily for the next 3-4 days.

Rp.: Amicacini sulfatis 0,5

D.t.d. № 30

S. Dissolve the contents of the vial in 200 ml of a 5% glucose solution or isotonic solution and administer intravenously twice daily.

Rp.: Amicacini sulfatis 0,5 D.t.d. № 30

S. Dissolve the contents of the vial in 2 ml of sterile water for injection and administer intramuscularly twice daily.

Myrin is available in tablets, each containing ethambutol 225 mg, rifampicin 120 mg, isoniazid 60 mg, and pyrazinamide 300 mg. The average daily dose is 5 tablets.

Rp.: Tab. "Mayrini-P" №40

S. Take 5 tablets as a single dose 1-2 hours before meals.

Macox is available in tablets, each containing 225 mg of rifampicin, 750 mg of pyrazinamide, and 150 mg of isoniazid. The average daily dose for adults is 2 tablets.

Rp.: Tab. "Makokc ZH" №30

S. Take 2 tablets once daily 1-2 hours before meals.

Ofloxacin, ciprofloxacin, pefloxacin, lomefloxacin, roxithromycin, azithromycin, and clarithromycin are successfully used in combination with anti-tuberculosis drugs, primarily rifampicin and isoniazid. If the tuberculosis process progresses during anti-mycobacterial treatment, amoxicillin-clavulanic acid or tienam is prescribed.

Rp.: Timern 0.5 g D. t. d № 20

S. Dissolve the contents of the vial in 2-3 ml of solvent, add 1 ml of 2% lidocaine, and administer intramuscularly twice a day.

Rp.: Tienam 120 ml D.t.d. № 20

S. Dissolve in 200 ml of isotonic solution and administer intravenously twice a day.

Rp.: Tab. Amoxiclavi 625mg № 40

S. Take 1 tablet 3 times a day after meals.

In recent years, the effectiveness of Tuberculosis Treatment has been declining. There is a decrease in the frequency of cessation of bacterial excretion and the healing of cavity lesions. One of the reasons for this is drug-resistant forms of tuberculosis. It has been proven that the treatment regimens proposed by the WHO are the most optimal and effective for treating various categories of patients, including those with resistant tuberculosis. However, these regimens for various Clinical forms of tuberculosis, including drug-resistant TB, require substantial modification; physicians may adjust them depending on the susceptibility of mycobacterium tuberculosis to anti-mycobacterial drugs and previous treatment regimens.

Tables 6-8 present the daily doses of first-line and second-line anti-tuberculosis drugs used in the treatment of tuberculosis patients.

Table 6 First-line anti-tuberculosis drugs used to treat newly diagnosed Pulmonary Tuberculosis and relapses of the disease

Note. * Recommended doses are prescribed per single administration.

Table 7 Second-line anti-tuberculosis drugs used to treat all categories of patients with documented resistance to first-line anti-tuberculosis drugs or poor tolerability

Table 8 Other anti-tuberculosis drugs that can be used as reserve agents in patients of all categories in case of resistance to first- and second-line drugs or their intolerance