Tuberculosis (TB)

Tuberculosis (TB) 

Tuberculosis (TB) is a deadly disease pandemic caused by Mycobacterium tubercle bacillus Gram positive bacteria that most often affect the lungs.

• Mycobacterium tuberculosis has an unusual, high lipid content cell wall (mycolic acid), which makes the cells impermeable to Gram staining, hence Ziehl-Neelsen stain/acid-fast detection techniques are used instead. 

• Mycobacterium tubercle needs high levels of oxygen in order to survive, so it primarily takes shelter in mammalian respiratory system and infects the lungs. 

• The incidence of this disease directly related to dense population, poverty, malnutrition and poor hygienic conditions.  

• Recently increasing emergence of drug-resistant TB, especially multidrug-resistant (at least two of first line drugs such as isoniazid and rifampin) is particularly alarming due to impermeability of the highly hydrophobic cell envelope to many drugs, as well as development of bacterial efflux pump system and production of certain enzymes to inactivate the drugs (β-lactamases, amino glycoside acyl transferase). 

• The lethal combination of drug-resistant TB and HIV co-infection is a growing problem in TB control. 

• Multidrug-resistant tuberculosis leads to extensively drug-resistant TB (XDR TB) due to irregular medication and mismanagement of all prescribed medicines. XDR TB is resistant to isoniazid and rifampin, plus at least one of the three injectable second-line drugs (amikacin, kanamycin, or capreomycin). 

TB therapy

• Single drug treatment in tuberculosis resulted in the rapid development of resistance and treatment failure. 

• According to various experimental and clinical studies by WHO recommended standard TB chemotherapy, called DOTS (directly observed treatment, short course), is a combination six months therapy comprising of an initial two-month phase of treatment with four drugs such as isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB), followed by a continuation phase of treatment with INH and RIF for another four months.

• It has a cure rate up to 95%. However, DOTS alone may not work in areas, where there is a high prevalence of MDR-TB. In such situations, WHO recommends the use of DOTS-Plus.

•  The current TB drugs categorized as first-line drugs (ethambutol, isoniazid, pyrazinamide, and rifampicin), second-line drugs (amino glycosides, polypeptides, fluoroquinolones, thioamides, cycloserine, terizidone) and third-line drugs (rifabutin, macrolides, linezolid, thioacetazone, thioridazine, arginine, vitamin D, R207910). 

Classification of TB drugs based on mechanism of action

TB drugs are classified into four groups based on mechanism of action. 

a) cell wall synthesis inhibitors (INH)

 b) nucleic acid synthesis inhibitors (RIF, FQ)

c) protein synthesis inhibitors (SM)

d) Membrane energy inhibitors (PZA)