DRUGS USED IN TUBERCULOSIS

TB History: Streptomycin , in the late (1940s) followed by Isoniazide Rifampicin & ethambutol (1960s)

WHO, estimates that one- third of the word’s population(2billion people) are currently infected with the bacillus. Infection rates are falling very slowly, but in 2008 there were over 9 million new cases and the disease killed about 1.8 million people.

TB continue…………………… Africa and Asia bears the brunt of the disease, partly because of an ominous synergy between mycobacteria (e.g.M. tuberculosis, M. Avium, intercellulare ) and HIV. About one-third of HIV-associated deaths in the continent are causes by tuberculosis. The disease is out of control in many countries.

IDENTIFICATION Mycobacteria are very slowly growing organism. They are relatively resistant to antibiotics. Mycobacteria cells can also be dormant and thus completely resistant to many drugs- or killed only very slowly by the few drugs that are active. The lipid- rich mycobacteria cell wall is impermeable to many agents.

Id contiue………………………. A substantial proportion of mycobacterial organisms are intracellular, residing within macrophages, and inaccessible to drugs that penetrate poorly. A particular problem with this organism is that they can survive inside macrophages after phagocytosis, unless these cells are ‘activated’ by cytokines produced by T-helper 1 lymphocytes.

Id continue………………………. Finally, mycobacteria are notorious for their ability to develop resistance to any single drug. Combination of 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.

First-line agents Drug Typical Adult Dosage Isoniazid Rifampin Pyrazinamide Ethambutol Streptomycin 300 mg/d 600 mg/d 25 mg/kg/d 15–25 mg/kg/d 15 mg/kg/d

Alternative Second-Line Drugs for Tuberculosis The alternative drugs are usually considered only (1) in case of resistance to first-line agents; (2) in case of failure of clinical response to conventional therapy; (3) in case of serious treatment-limiting adverse drug reactions; (4) when expert guidance is available to deal with the toxic effects.

Multidrug-Resistant Tuberculosis (MDR TB) and Possible Effective Treatments

Extensively Drug-Resistant Tuberculosis (XDR TB) Diminishing Options for Treatment

Second-line agent 600mg (Adult) Drug Typical Adult Dosage Amikacin  Aminosalicylic acid Capreomycin Ciprofloxacin Levofloxacin Cycloserine Ethionamide Linezolid   15 mg/kg/d 8-12g/d 15mg/kg/d 1500mg/d divided 500mg/d 500-1000mg/d divided 500-750mg/d 600mg (Adult)  

To decrease the probability of the emergence of resistant organisms, compound drug therapy is frequent strategy,This commonly involves: An initial phase of treatment (about 2 months ) with a combination of isoniazid , rifampicin and pyrazinamide ( plus ethambutol if the organism is suspected to be resistant)

Continu…….. A second, continuation phase (about 4 months ) of therapy with isoniazid and rifampicin ; long – term treatment is needed for patients with meningitis, bone/joint involvement or drug-resistant infection.

DURATION OF THERAPY An isoniazid rifampin combination administered for 9 months will cure 95-98% of cases of tuberculosis caused by susceptible strains.

DURATION continue………… The addition of pyrazinamide to an isoniazid-rifampin combination for the first two months allows the total duration of therapy to be reduced to 6 months without loss of efficacy.

Recommended Duration of Therapy for Tuberculosis Regimen (in Approximate Order of Preference) Duration in Months Isoniazid, rifampin, pyrazinamide 6 Isoniazid, rifampin 9 Rifampin, ethambutol, pyrazinamide Rifampin, ethambutol 12 Isoniazid, ethambutol 18 All others 24

DURATION continue………….. In practice , therapy is initiated with a four – drug regimen of isoniazid, rifampin, pyrazinamide,and either ethambutol or sterptomycin until susceptibility of the clinical isolate has been determined.

ISONIAZID(INH) Isoniazid is a most active drug for the treatment of tuberculosis caused susceptible strain. The antibacterial activity of isoniazid is limited to mycobacteria. It halts the growth of resting organism(e.g. is bacteriostatic) but can kill dividing bacteria.

MECHANISM OF ACTION (INH) Isoniazid inhibits synthesis of mycolic acids, important constituent of the cell wall peculiar to mycobacteria. It is also reported to combine with an enzyme that is uniquely found in isoniazid – sensitive strains of mycobacteria , disrupting cellular metabolism. Isoniazid is a prodrug,it must be activated in the body.

RESISTANCE Resistance to the drug , caused by reduced penetration into the bacterium, may be encountered. Resistance mutants occur in susceptible mycobacterial populations with a frequency of about 1 bacillus in 106 .

PARMACOKINETIC It is readily absorbed from GI It is widely distributed throughout the tissue, body fluids and CSF An important point is that it penetrates well into ‘caseous’ tuberculous lesions. Metabolism, which involves largely acetylation. Half-life in slow inactivators is 3h and rapid one is 1h

CLINICAL USES ISONIAZID It is usually given by mouth but can be given parenterally. As a single agent is also indicated for treatment of latent TB by a positive tuberculin skin test. It is routinely recommended for very young children. Persons who test positive within 2 years after a documented negative skin test(ie, recent converters) And immunocompromised individual (HIV).

ADVERSE REACTIONS Unwanted effects depend on dosage and occur in about 5% of individual. A. Allergic: Fever, skin rashes, Drug induce systemic lupus erythematous has been reported. B.Hepatitis(increases aminotransferase) loss of appetite,nausea,vomating,jaundice and pain can be fatal.

HEPATITIS continue……………… The risk of hepatitis depended on ages: Under age 20 rarely Age 21 – 35 0.3% Age 36- 50 1.2% Age up to50 2.3%

HEPATITIS continue…………. The risk of hepatitis is greater in: Alcoholics During pregnancy and postpartum period. Development of isoniazid hepatitis contraindication further use of drug.

ADVERSE REACTION continue………. Peripheral neuropathy is observed in 10-20% It is more likely to occur in slow acetylation Malnutrition Alcoholism Diabetes AIDS Uremia

ADVERSE REACTION continue…………. Neuropathy is due to a relative pyridoxine deficiency . Isoniazid can reduced the metabolism of the antiepileptic agents phenytoin, ethosuximide, and carbamazepine,

RIFAMPIN It is one of the most active antituberculosis agents know. It enters phagocytic cells and can therefore kill intracellular micro-organisms including the tubercle bacillus. It inhibits RNA synthesis. Resistance result from mutation the gene for the RNA polymerase. These mutation prevent binding of rifampin to RAN polymerase

PARMACOKINETIC Rifampin is given orally and is widely distributed in the tissues and body fluid . Giving an orange tinge to saliva, sputum , tears and sweat. It is excreted mainly through the liver into bile. It then undergoing enterohepatic recirculation, excreted as a deacylated metabolite in feces and a small amount in urine. In the CSF, it reaches 10-40% of serum concetration.

ADVERSE REACTION The commonest side effects are skin eruption, fever, GI disturbance, liver damage with jaundic, Liver function should be assessd before treatment is started. Rifampin causes induction of hepatic metabolising enzymes.

Rifabutin (Ansamycin) Rifapentine

ETHAMBUTOL It is given orally and is well absorbed . It can also reach therapeutic concentration in the CSF in tuberculous meningitis. Resistance emerges rapidly if the drug used alone. Ethambutol is partly metabolised and is excreted in the urine.

Ethambutol Mechanism Ethambutol inhibits mycobacterial arabinosyl transferases. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. Resistance to ethambutol is due to mutations resulting in over expression of  gene products.

ADVERSE REACTION Optic neuritis, which is does-related and is more likely to occur if renal function is decreased. Visual disturbances ( red - green colour blindness ).

PYRAZINAMIDE The drug is well absorbed after oral administration and is widely distributed, penetrating well in meninges. It is effective against the intracellular organisms in macrophages with acidic environment.

ADVERSE REACTION Gout , which is associated with high concentration of plasma urates. GI upsets Malaise & fever With high doses of drug serious hepatic damage.

DRUGS ACTIVE AGAINST ATYPICAL MYCOBACTERIA M Kansasii is susceptible to rifampin and ethambutol but not isoniazid. M avium complex Azitromycin, or Clarithromycin , plus Ethambutol is an effective and well tolerated regimen. A third agent is Ciprofloxacin

Species Clinical Features Treatment Options M kansasii Resembles tuberculosis Ciprofloxacin, clarithromycin, ethambutol, isoniazid, rifampin, trimethoprim-sulfamethoxazole M marinum Granulomatous cutaneous disease Amikacin, clarithromycin, ethambutol, doxycycline, minocycline, rifampin, trimethoprim-sulfamethoxazole

M scrofulaceum Cervical adenitis in children Amikacin, erythromycin (or other macrolide), rifampin, streptomycin (Surgical excision is often curative and the treatment of choice.) M avium complex Pulmonary disease in patients with chronic lung disease; disseminated infection in AIDS Amikacin, azithromycin, clarithromycin, ciprofloxacin, ethambutol, rifabutin M chelonae Abscess, sinus tract, ulcer; bone, joint, tendon infection Amikacin, doxycycline, imipenem, macrolides, tobramycin M fortuitum Amikacin, cefoxitin, ciprofloxacin, doxycycline, ofloxacin, trimethoprimsulfamethoxazole M ulcerans Skin ulcers Isoniazid, streptomycin, rifampin, minocycline (Surgical excision may be effective.)