AKURIT 3

Indications

• Tuberculosis, in combination with other drugs (standard treatment)
• Multiple-drug resistant pulmonary tuberculosis, in combination with other drugs

Dosage

Children: Child: 20 mg/kg once daily for 2 months (initial phase) or 30 mg/kg 3 times a week for 2 months (initial phase).

Adults: Adult: 15 mg/kg once daily for 2 months (initial phase) or 100 mg twice daily for 24 weeks, continue appropriate combination therapy after delamanid.

Mechanism of action

Ethambutol inhibits the enzyme arabinosyl transferase, which is involved in the biosynthesis of the mycobacterial cell wall component, arabinogalactan. This inhibition disrupts the integrity of the bacterial cell wall, leading to bacterial cell death.

Pharmacodynamics

Ethambutol exhibits bacteriostatic activity against M. tuberculosis. Its action is concentration-dependent, and effectiveness can be enhanced when used in combination with other antitubercular agents. Resistance can develop through mutations in the gene encoding arabinosyl transferase, leading to decreased drug efficacy.

Pharmacokinetics

Ethambutol is well absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 2 to 4 hours post-administration. The drug has a half-life of approximately 3 to 5 hours and is primarily excreted unchanged in urine. Dose adjustments may be necessary in patients with renal impairment, as the drug's clearance is significantly affected by renal function.

Contra-indications

• Optic neuritis
• Poor vision

Adverse effects

• Anxiety
• Appetite decreased
• Asthenia
• Chest pain
• Cough
• Depression
• Dyslipidaemia
• Dyspnoea
• Ear pain
• Electrolyte imbalance
• Gastrointestinal discomfort
• Haemoptysis
• Headache
• Hyperhidrosis
• Hypertension
• Hypotension
• Malaise
• Muscle weakness
• Nausea
• Oropharyngeal pain

Interactions

• Cycloserine
• Deltyba (Delamanid)

Precautions

• Monitor serum albumin and electrolytes before and during treatment
• Monitor blood-cycloserine concentration if creatinine clearance is less than 50 mL/min
• Use with caution in elderly and young children
• Patients should be able to report symptomatic visual changes accurately

Pregnancy

Manufacturer advises use only if potential benefit outweighs risk, as it crosses the placenta.

Breast-feeding

Present in milk, but amount is too small to be harmful.

Storage

Dispense in original container (contains desiccant).

Formulations

• Capsule
• Tablet

Indications

• Treatment of active tuberculosis
• Prevention of tuberculosis in susceptible individuals, especially close contacts of infected persons

Dosage

Adults: 10 mg/kg daily (maximum per dose 300 mg) for 3 months, to be taken by mouth or via intramuscular or intravenous

Mechanism of action

Isoniazid is activated by the bacterial catalase-peroxidase KatG, which reduces the ferric form of the enzyme and enables it to react with oxygen to form an oxyferrous enzyme complex. The active form of isoniazid then inhibits the synthesis of mycolic acids by forming a covalent adduct with NAD, inhibiting the enoyl reductase InhA. This inhibition is crucial for the integrity of the mycobacterial cell wall, leading to the bactericidal activity of isoniazid against actively growing Mycobacterium tuberculosis.

Pharmacodynamics

Isoniazid is a bactericidal agent particularly effective against the Mycobacterium genus, including M. tuberculosis, M. bovis, and M. kansasii. It exhibits bactericidal properties during periods of rapid mycobacterial growth and becomes bacteriostatic when the bacteria are in a dormant state. Given its mechanism of action, isoniazid is highly selective, targeting mycobacteria without significant effects on other types of bacteria.

Pharmacokinetics

Isoniazid is well-absorbed following oral administration, with peak plasma concentrations occurring within 1 to 2 hours. It is widely distributed in body tissues and crosses the blood-brain barrier. The drug is metabolized in the liver primarily through acetylation, with variable metabolism rates observed in different populations due to genetic polymorphisms in acetylation. The elimination half-life ranges from 1 to 4 hours, and the drug is excreted in the urine, predominantly as metabolites.

Contra-indications

• History of hypersensitivity to isoniazid
• Acute liver disease
• Severe hepatic impairment
• Previous history of isoniazid-induced liver injury

Adverse effects

• Hepatitis
• Peripheral neuropathy
• Optic neuritis
• Gastrointestinal disturbances
• Rash
• Fever
• Agranulocytosis
• Hematological disorders
• Lupus-like syndrome

Interactions

• Carbamazepine: Increased risk of hepatotoxicity
• Cycloserine: Increased risk of CNS toxicity
• Phenytoin: Increased concentration of phenytoin
• Levodopa: Decreased effects of levodopa
• Lomitapide: Increased exposure
• Antiepileptics: Unknown interactions leading to increased concentrations

Precautions

• Monitor liver function during treatment
• Use with caution in patients with renal impairment
• Patients with diabetes or a history of peripheral neuropathy should be monitored closely
• Ocular monitoring for young children on treatment

Pregnancy

Not known to be harmful; however, prophylactic pyridoxine is recommended.

Breast-feeding

Amount too small to be harmful; monitor infant for possible toxicity.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Oral tablets
• Oral suspension
• Intramuscular injection
• Intravenous injection

Indications

• Pulmonary tuberculosis
• Tuberculosis in combination therapy

Dosage

Children: For children, refer to the BNF for Children for appropriate dosing guidance.

Adults: The usual adult dose is 15 mg/kg daily, up to a maximum of 1.6 g per day, in combination with other anti-tuberculosis agents.

Mechanism of action

Ethambutol diffuses into Mycobacterium cells and inhibits the arabinosyltransferases (embA, embB, and embC). This inhibition prevents the formation of arabinogalactan and lipoarabinomannan, which are essential for the integrity of the bacterial cell wall. The resultant decrease in arabinogalactan reduces binding sites for mycolic acid, leading to its accumulation and consequently impairing cell division. Additionally, reduced levels of lipoarabinomannan interfere with the interaction of mycobacteria with host cells. Ethambutol's bacteriostatic action is effective only when the bacteria are actively dividing.

Pharmacodynamics

Ethambutol is indicated for use in combination with other anti-tuberculosis drugs for the treatment of pulmonary tuberculosis. Its long duration of action allows for daily administration, which is beneficial for patient adherence. However, it is important for patients to be informed about potential side effects, including the risk of optic neuritis and hepatic toxicity, which are associated with its use.

Pharmacokinetics

Ethambutol is well absorbed from the gastrointestinal tract, with a peak plasma concentration occurring approximately 2 to 4 hours after administration. It has a volume of distribution that suggests good tissue penetration. The drug is primarily excreted unchanged in the urine, with a half-life of about 3 to 4 hours in individuals with normal renal function. Dosage adjustments may be necessary in patients with renal impairment.

Contra-indications

• Optic neuritis
• Severe renal impairment

Adverse effects

• Optic neuritis
• Visual disturbances
• Nausea
• Vomiting
• Loss of appetite
• Rash
• Hepatic toxicity

Interactions

• Antacids may reduce absorption
• Aluminium-containing antacids may decrease ethambutol serum concentration

Precautions

• Regular monitoring of visual acuity is recommended
• Use with caution in patients with renal impairment
• Periodic liver function tests may be necessary

Pregnancy

Ethambutol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Ethambutol is excreted in breast milk; caution should be exercised when administered to a nursing mother.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets
• Oral suspension

Indications

• Tuberculosis (TB)
• Leprosy
• Other infections caused by susceptible strains of bacteria

Dosage

Children: Refer to the BNF for Children for appropriate dosing recommendations based on the child's age and weight.

Adults: Refer to the BNF for specific dosing guidelines based on the condition being treated.

Mechanism of action

Rifampin works by binding to the beta-subunit of microbial DNA-dependent RNA polymerase (RNAP), inhibiting the enzyme and thus impeding RNA synthesis. It reduces the affinity of RNAP for short RNA transcripts and forms a stable drug-enzyme complex, suppressing the initiation of RNA chain formation. Notably, rifampin has no activity against mammalian RNAP, making it selective for bacterial processes.

Pharmacodynamics

Rifampin is characterized by its broad-spectrum antimicrobial activity and is particularly effective against _Mycobacterium tuberculosis_. It demonstrates bactericidal effects, which means it kills bacteria instead of merely inhibiting their growth. This makes it a critical component in the treatment regimen for tuberculosis and other bacterial infections.

Pharmacokinetics

Rifampin is absorbed well from the gastrointestinal tract, with peak plasma concentrations typically reached within a few hours after oral administration. It is extensively metabolized in the liver, primarily via cytochrome P450 enzymes, and has a relatively long half-life. The drug is excreted mainly in bile, with a small percentage eliminated in urine. Its pharmacokinetic profile allows for once-daily dosing in many cases, aiding patient compliance.

Contra-indications

• Hypersensitivity to rifampicin or any of its components
• Concurrent use with protease inhibitors such as darunavir, indinavir, or nelfinavir
• Severe hepatic impairment

Adverse effects

• Hepatotoxicity
• Gastrointestinal disturbances (nausea, vomiting, diarrhea)
• Rash and other allergic reactions
• Discoloration of body fluids (e.g., urine, sweat, tears)
• Flu-like syndrome
• Thrombocytopenia
• Leukopenia

Interactions

• May reduce the effectiveness of oral contraceptives
• Increases metabolism of drugs metabolized by CYP450 enzymes
• May interact with anticoagulants, antiepileptics, and certain antiretrovirals
• Concomitant use with drugs such as ketoconazole and erythromycin may increase risk of liver toxicity

Precautions

• Monitor liver function tests regularly
• Use with caution in patients with a history of liver disease
• Assess for signs of hypersensitivity reactions
• Consider potential interactions with other medications

Pregnancy

Rifampin is categorized as a pregnancy category C drug. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Rifampin is excreted in breast milk; caution should be exercised when administering to nursing mothers.

Storage

Store in a cool, dry place, away from direct sunlight and moisture. Keep out of reach of children.

Formulations

• Oral capsules (150 mg, 300 mg)
• Oral suspension (10 mg/mL)
• Injectable solution (rifampicin for injection)

Mechanism of action

Isoniazid is a prodrug and must be activated by bacterial catalase. Specficially, activation is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex. Once activated, isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular <i>Mycobacterium tuberculosis</i> organisms. Specifically isoniazid inhibits InhA, the enoyl reductase from <i>Mycobacterium tuberculosis</i>, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA. Although the mechanism of action of isoniazid is unknown, several hypotheses have been proposed. These include effects on lipids, nucleic acid biosynthesis, and glycolysis. ... /It has been suggested that/ a primary action of isoniazid /is/ to inhibit the biosynthesis of mycolic acids, important constituents of the mycobacterial cell wall. Because mycolic acids are unique to mycobacteria, this action would explain the high degree of selectivity of the antimicrobial activity of isoniazid. Exposure to isoniazid leads to a loss of acid fastness and a decrease in the quantity of methanol-extractable lipid of the microorganisms. Isoniazid is bacteriostatic for "resting" bacilli but is bactericidal for rapidly dividing microorganisms. The minimal tuberculostatic concentration is 0.025 to 0.05 ug/ml.

Pharmacodynamics

Isoniazid is a bactericidal agent active against organisms of the genus Mycobacterium, specifically <i>M. tuberculosis</i>, <i>M. bovis</i> and <i>M. kansasii</i>. It is a highly specific agent, ineffective against other microorganisms. Isoniazid is bactericidal when mycobacteria grow rapidly and bacteriostatic when they grow slowly.

Mechanism of action

Ethambutol diffuses into _Mycobacterium_ cells. Once inside the cell, ethambutol inhibits the arabinosyltransferases (embA, embB, and embC), preventing formation of the cell wall components arabinogalactan and lipoarabinomannan, and preventing cell division. Decreased concentrations of arabinogalactan in the cell wall reduces the number of binding sites for mycolic acid, leading to the accumulation of mycolic acid, trehalose monomycolate, and trehalose dimycolate. Lipoarabinomannan is a component of a cell surface molecule involved in the interaction with host cells. Reduced levels of lipoarabinomannan may interfere with mycobacterial interaction with host cells. Ethambutol is bacteriostatic in action. Although the exact mechanism of action has not been fully elucidated, the drug appears to inhibit the synthesis of one or more metabolites in susceptible bacteria resulting in impairment of cellular metabolism, arrest of multiplication, and cell death. Ethambutol is active against susceptible bacteria only when they are undergoing cell division.

Pharmacodynamics

Ethambutol is indicated in combination with other anti-tuberculosis drugs in the treatment of pulmonary tuberculosis. It has a long duration of action as it is administered daily, and a moderate therapeutic window. Patients should be counselled regarding the risk of optic neuritis and hepatic toxicity.

Mechanism of action

Rifampin works by binding to the beta-subunit of microbial DNA-dependent RNA polymerase (RNAP), thereby inhibiting the enzyme and impeding RNA synthesis. It reduces the affinity of RNAP for short RNA transcripts. It has no activity against the mammalian RNAP enzyme. Although rifampin is most active during cell multiplication ... /it/ appears to have some effect on resting cells. Electron microscopy has revealed changes in cytoplasm and disappearance of ribosomes in tubercle bacilli exposed to rifampin, indicating inhibition of DNA-dependent RNA polymerase. Rifampin inhibits DNA-dependent RNA polymerase of mycobacteria and other microorganisms by forming a stable drug-enzyme complex, leading to suppression of initiation of chain formation (but not chain elongation) in RNA synthesis. More specifically, the beta subunit of this complex enzyme is the site of action of the drug, although rifampin binds only to the holoenzyme. Nuclear RNA polymerase from a variety of eukaryotic cells does not bind rifampin, and RNA synthesis is correspondingly unaffected. While rifampin can inhibit RNA synthesis in mammalian mitochondria, considerably higher concentrations of the drug are required than for the inhibition of the bacterial enzyme. High concentrations of rifamycin antibiotics also inhibit viral DNA-dependent RNA polymerases and reverse transcriptases. Rifampin is bactericidal for both intracellular and extracellular microorganisms. Developmental expression of CYPlAl, CYPlA2 and CYP3A6 in the rabbit have been studied. Cytochromes P450IAl, P450IA2 and P450IIIA6 exhibited comparable patterns of developmental expression. Present at low level (less than 0.05 mnol/ng) in the new born animal up to week 3, these proteins sharply accumulated between weeks 3 and 4 to reach a maximum by week 4 (P450IAl, 0.2 nmol/mg; P450IA2, 0.8 nmol/ng; P450IIIA6, 0.12 nmol/mg) and decr in the adult (P450IAl, 0.2 nmol/mg; P450IA2, 0.4 mnol/mg; P450IIIA6, 0.09 nmol/mg). Cytochromes P450IAl and P450IA2 were not expressed in the untreated fetus. Onset of CYP3A6 gene expression occurred at day 30 of gestation and both transcription and mRNA accumulation were transplacentally inducible by rifampicin only shortly before birth, i.e. after treatment of the females between days 28 and 30 of gestation. Both long (1.85 kb) and short (1.7 kb) mRNA transcripts were expressed in untreated or rifampicin treated fetuses. CYP3A6 gene expression was also induced by rifampicin in l week old and 2 week old animals. Developmental expression of CYPlAl and CYPlA2 genes was shown to be closely related to the diet change accompanying weaning which occurs at weeks 3-4. In animals subjected to either delayed (week 6) or early (week 2) weaning, sharp accumulation of messages, proteins and related activities were delayed or anticipated accordingly with respect to normal weaning. Artificially scheduled weaning gave similar results when repeated with biological grade lucern (grown in the absence of chemical fertilizers, pesticides) ... the main constituent of commercial rabbit chow. While CYP3A6 gene expression could be brought forward by early weaning at week 2, both message and protein did not exhibit incr accumulation after delayed weaning at week 6, and remained at the low level of the new born animal. Treatment of l week old and 2 week old animals with triiodothyronine or of 3 week old animals with propylthiouracil, an antithyroid factor, did not modify the normal pattern of developmental expression of genes CYPlAl, CYPlA2 and CYP3A6. ...

Pharmacodynamics

Rifampin is an antimicrobial agent with bactericidal effects and a broad-spectrum activity. It is active against intracellular and extracellular _Mycobacterium tuberculosis_.