Drug resistance in TB is a global problem. Multidrug-resistant TB (MDR-TB) is defined as bacilli resistant to at least two first-line agents, isoniazid (INH) and rifampin (RIF). Drug resistance has increased especially in regions where TB control programs are poorly enforced (http://www.who.int/mediacentre/ news/releases/2004/pr17/en/). According to WHO, every year 300,000 new cases of MDR-TB occur in the world. In 1994, the WHO, the International Union Against TB and Lung Diseases (IUATLD), and other partners conducted an anti-TB drug-resistance program and began to standardize the sampling techniques and laboratory methodologies used worldwide to measure and control drug-resistant TB. Surveillance by WHO/IUATLD reveals that Eastern Europe, Latin America, Africa, and Asia have more than 4% incidence of MDR-TB among new cases (WHO/74, 1997). According to the WHO report, in Eastern Europe and Central Asia, TB patients have 10 times more inclination to have MDR-TB than patients in other parts of the world. In Estonia, Kazakhstan, Latvia, Lithuania, Uzbekistan, and the Russia Federation the incidence rate of drug resistance is 14% (http://www.who.int/mediacentre/news/releases/2004/pr17/en/).
MDR-TB development not only hinders treatment but also increases the costs of treatment by 100-fold and lengthens the treatment time (WHO/74, 1997). The basic treatment of mycobacterial infection is chemotherapy. In TB treatment, because single drug therapy can cause an increase in drug resistance strains, a combined treatment should be applied. With a combined treatment, cure can be >95% (Geo. F. Brooks, 2001). INH, RIF, pyrazinamide (PZA), ethambutol (EMB), and streptomycin (SM) are the first-line agents. These drugs are used for drug-susceptible TB infections. The most important risk factor for MDR-TB is failure to complete treatment for tuberculosis. Six months short-course therapy, starting with treatment with INH, RIF, ETH, and PZA for 2 months, followed by 4 months treatment with INH and RIF, is still being used. The American Thoracic Society, the Centers for Diseases Control and Prevention (CDC), the Infectious Diseases Society of
America, WHO, and IUATLD advise slight modifications to this treatment protocol (Parsons et al., 2004).
In case of MDR-TB, unfortunately, second-line drugs are the choice for treatment of infection (Geo. F. Brooks, 2001). There are eight second-line drugs: kanamycin, capreomycin, ethionamide, cycloserine, ofloxacin, clofazamine, lev-ofloxacin, para-aminosalicylic acid, and ciprofloxacin (Starke, 2004). A TB cavity usually contains 107 to 109 bacilli. Between 1 in 106 and 1 in 108 replications of tubercle bacilli may result in spontaneous mutation that confers resistance to antituberculous therapy. When INH and RIF are used together, spontaneous mutations resulting in resistance would be extremely rare (1 in 1014). If the single drug or multidrug therapy is used episodically, resistant tubercle bacilli multiply under selective pressure and emerge rapidly (Geo. F. Brooks, 2001; Sharma and Mohan, 2004).
The genetic mutations responsible for resistance to tuberculosis therapy are myriad. The genes indan enoyl acp reductase (inhA), catalase-peroxidase (katG), alkyl hydroperoxide (ahpC), and oxidative stress regulator (oxyR) are responsible for INH resistance (Sharma and Mohan, 2004). RIF resistance is caused by mutations in RNA polymerase subunit 12 (rpsl) genes. Mutations in pncA gene lead to resistance against PZA. SM resistance is associated with mutations in ri-bosomal protein subunit 12 (rpsL), 16s ribosomal RNA (rrs), and aminoglycoside phosphotransferase gene (strA). Resistance to EMB and fluoroquinolones occurs secondary to mutations in arabinosyl transferase (emb A, B, and C) gene and DNA gyrase (gyr A and B) gene, respectively (Sharma and Mohan, 2004).
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