Antimycobacterial Drugs PDF

Antimycobacterial Drugs Asist. Prof. Zülfiye GÜL Mycobacteria Mycobacteria are intrinsically resistant to most antibiotics. 1. They grow slowly 2. dormant and thus completely resistant 3. The lipid-rich mycobacterial cell wall is impermeable to many agents. 4. Residing within mac...

Antimycobacterial Drugs Asist. Prof. Zülfiye GÜL Mycobacteria Mycobacteria are intrinsically resistant to most antibiotics. 1. They grow slowly 2. dormant and thus completely resistant 3. The lipid-rich mycobacterial cell wall is impermeable to many agents. 4. Residing within macrophages are inaccessible to drugs that penetrate these cells poorly. 5. Notorious for their ability to develop resistance. Combination therapy Combinations of two or more drugs are required to The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years The first-line agents for treatment of tuberculosis: Isoniazid (INH) Ethambutol Rifampin (or other rifamycin) Pyrazinamide Streptomisin Isoniazid  Resistance can emerge rapidly if the drug is used alone High-level resistance is associated with deletion in the katG gene that codes for a catalase-peroxidase involved in the bioactivation of INH INH is bactericidal for actively growing tubercle bacilli, but is less effective against dormant organisms. 2. Pharmacokinetics INH is well absorbed orally and penetrates cells to act on intracellular mycobacteria The liver metabolism of INH is by acetylation and is under genetic control – The proportion of fast acetylators is higher among people of Asian origin (and Native Americans) than those of European or African origin. – Fast acetylators may require higher dosage than slow acetylators for equivalent therapeutic effects. 3. Clinical use INH is the single most important drug used in tuberculosis and is a component of most drug combination regimens In the treatment of latent infection (formerly known as prophylaxis) including skin test converters and for close contacts of patients with active disease, INH is given as the sole drug. 4. Toxicity and interactions Neurotoxic effects are common and include peripheral neuritis, restlessness, muscle twitching, and insomnia. INH is hepatotoxic and may cause abnormal liver function tests, jaundice, and hepatitis. Fortunately, hepatotoxicity is rare in children. INH may inhibit the hepatic metabolism of drugs (eg, carbamazepine, phenytoin, warfarin). Ethambutol 2. Pharmacokinetics The drug is well absorbed orally and distributed to most tissues, including the CNS. A large fraction is eliminated unchanged in the urine. Dose reduction is necessary in renal impairment. 3. Clinical uses The main use of ethambutol is in tuberculosis, and it is always given in combination with other drugs. 4. Toxicity and interactions The most common adverse effects are dose-dependent visual disturbances, including decreased visual acuity, red- green color blindness , optic neuritis, and possible retinal damage Contraindicated in children!!! too young to permit of visual acuity and red green colour discrimination Pyrazinamide 1. Mechanisms The mechanism of action of pyrazinamide is not known; but pyrazinoic acid disrupts mycobacterial cell membrane and transport function its bacteriostatic action appears to require metabolic conversion via pyrazinamidases (encoded by the pncA gene) present in M tuberculosis. İmportant front-line drug used in conjunction with INH and Rifampin in short-course (6 month) regimens as a sterilizing agent active against residual intracelular organism that may cause relapse Resistance occurs via mutations in the gene that encodes enzymes involved in the bioactivation of pyrazinamide and by increased expression of drug efflux systems. 2. Pharmacokinetics Pyrazinamide is well absorbed orally and penetrates most body tissues, including the CNS. The drug is partly metabolized to pyrazinoic acid, and both parent molecule and metabolite are excreted in the urine. The plasma half-life of pyrazinamide is increased in hepatic or renal failure. 3. Clinical uses The combined use of pyrazinamide with other antituberculous drugs is an important factor in the success of short course treatment regimens. 4. Toxicity and interactions Approximately 40% of patients develop nongouty polyarthralgia. Hyperuricemia occurs commonly but is usually asymptomatic. Other adverse effects are myalgia, gastrointestinal irritation, maculopapular rash, hepatic dysfunction, porphyria, and photosensitivity reactions. Pyrazinamide should be avoided in pregnancy.  Rifampin 1. Mechanisms Bactericidal against M tuberculosis. The drug inhibits DNA- dependent RNA polymerase (encoded by the rpo gene) Resistance via changes in drug sensitivity of the polymerase 2. Pharmacokinetics Rifampin is well absorbed and is distributed to most body tissues and central nervous system (CNS). Both free drug and metabolites, which are orange- colored, are eliminated mainly in the feces. 3. Clinical uses In the treatment of tuberculosis, rifampin is almost always used in combination with other drugs. Rifampin can be used as the sole drug in treatment of latent tuberculosis in INH-intolerant patients or in close contacts of patients with INH-resistant strains of the organism. 4. Toxicity and interactions Rifampin commonly causes light- chain proteinuria and may impair antibody responses. If given less often than twice weekly, rifampin may cause a flu- like syndrome and anemia. Rifampin strongly induces liver drug-metabolizing enzymes and enhances the elimination rate of many drugs, including anticonvulsants, contraceptive steroids,cyclosporine,ketoconazole, methadone, terbinafine, and warfarin. 5. Other rifamycins Rifabutin effective as an antimycobacterial agent less likely to cause drug interactions than rifampin preferred over rifampin in the treatment of tuberculosis or other mycobacterial infections in AIDS patients Rifaximin, a rifampin derivative that is not absorbed from the gastrointestinal tract, has been used in traveler’s diarrhea. Streptomycin This aminoglycoside is now used more frequently than before because of the growing prevalence of strains of M tuberculosis resistant to other drugs. Streptomycin penetrates into cells poorly and is active mainly against extracellular tubercle bacilli. Streptomycin is used principally in drug combinations for the treatment of life-threatening tuberculous disease, including meningitis, miliary dissemination, and severe organ tuberculosis. Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing loss are the most common adverse effects and may be permanent. Alternative Drugs Amikacin is indicated for the treatment of tuberculosis suspected to be caused by streptomycin-resistant or multidrug resistant mycobacterial strains. Ciprofloxacin and ofloxacin are often active against strains of M tuberculosis resistant to first-line agents.  Ethionamide is a congener of INH, but cross-resistance does not occur. The major disadvantage of ethionamide is severe gastrointestinal irritation and adverse neurologic effects at doses needed to achieve effective plasma levels. p-Aminosalicylic acid (PAS) is rarely used because primary resistance is common. In addition, its toxicity includes gastrointestinal irritation, peptic ulceration, hypersensitivity reactions, and effects on kidney, liver, and thyroid function. Other drugs of limited use because of their toxicity include capreomycin (ototoxicity, renal dysfunction) and cycloserine (peripheral neuropathy, CNS dysfunction). Antitubercular Drug Regimens Standard regimens For empiric treatment of pulmonary TB (in most areas of