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Antimycobacterial Drugs

Learn about the challenges of treating mycobacterial infections and the first-line drugs used to combat them. Discover the mechanisms of action, toxic effects, and recommended treatment strategies.

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Antimycobacterial Drugs

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  1. Antimycobacterial Drugs September 2013

  2. Mycobacteria • Mycobacteria are intrinsically resistant to most antibiotics. • Because they grow slowly compared with other bacteria, antibiotics that are most active against growing cells are relatively ineffective. • Mycobacterial cells can also be dormant and thus completely resistant to many drugs or killed only very slowly. • The lipid-rich mycobacterial cell wall is impermeable to many agents. • Mycobacterial species are intracellular pathogens, and organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly.

  3. Mycobacteria (cont.) • Mycobacteria are notorious for their ability to develop resistance. • Combinations of two or more drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of therapy. • The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years, depending on which drugs are used.

  4. The first-line agents for treatment of tuberculosis: • Isoniazid (INH), • rifampin (or other rifamycin), • pyrazinamide, and • ethambutol,

  5. Isoniazid and rifampin are the two most active drugs. • An isoniazid-rifampin combination administered for 9 months will cure 95-98% of cases of tuberculosis caused by susceptible strains. • The addition of pyrazinamide to an isoniazid-rifampin combination for the first 2 months allows the total duration of therapy to be reduced to 6 months without loss of efficacy. • In practice, therapy is initiated with a four-drug regimen of isoniazid, rifampin, pyrazinamide, and ethambutol until susceptibility of the clinical isolate has been determined. • Ethambutol (and streptomycin) only provide additional coverage if the isolate proves to be resistant to isoniazid, rifampin, or both. • The prevalence of isoniazid resistance among US clinical isolates is approximately 10%. • Prevalence of resistance to both isoniazid and rifampin (ie, multiple drug resistance) is about 3%.

  6. Isoniazid • Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains. • It is small (MW 137) and freely soluble in water. • It has structural similarity to pyridoxine. • It is bactericidal for actively growing tuberculosis bacilli. • It is less effective against atypical mycobacterial species. • Isoniazid penetrates into macrophages and is active against both extracellular and intracellular organisms.

  7. Isoniazid • Isoniazid inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls. • Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase. • The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and a beta-ketoacyl carrier protein synthetase (KasA), which blocks mycolic acid synthesis and kills the cell.

  8. Isoniazid • Isoniazid-induced hepatitis is the most common major toxic effect. • Peripheral neuropathy is observed in 10-20% of patients given dosages greater than 5 mg/kg/d but is infrequently seen with the standard 300 mg adult dose. • Central nervous system toxicity, which is less common, includes memory loss, psychosis, and seizures. These may respond to pyridoxine.

  9. Rifampin • Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. • Rifampin binds to the beta subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis. • Rifampin is well absorbed after oral administration and excreted mainly through the liver into bile. • It then undergoes enterohepatic recirculation, with the bulk excreted as a deacylated metabolite in feces and a small amount in the urine. • Rifampin is distributed widely in body fluids and tissues.

  10. Ethambutol • Ethambutol is a synthetic, water-soluble, heat-stable compound. • Ethambutol inhibits mycobacterial arabinosyl transferases, which are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. • Ethambutol is well absorbed from the gut. • About 20% of the drug is excreted in feces and 50% in urine in unchanged form. • Ethambutol accumulates in renal failure, and the dose should be reduced by half if creatinine clearance is less than 10 mL/min. • As with all antituberculous drugs, resistance to ethambutol emerges rapidly when the drug is used alone. Therefore, ethambutol is always given in combination with other antituberculous drugs.

  11. Pyrazinamide • Pyrazinamide is a relative of nicotinamide, stable, and slightly soluble in water. • It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli and some other mycobacteria at concentrations of approximately 20 mcg/mL. • The drug is taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environment of lysosomes. • The drug target and mechanism of action are unknown. • Major adverse effects of pyrazinamide include hepatotoxicity (in 1-5% of patients), nausea, vomiting, drug fever, and hyperuricemia.

  12. (Rarely used in first line therapy today)

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