**1. Introduction**

Tuberculosis (TB) is caused by infection with *Mycobacterium tuberculosis*, which is transmitted through inhalation of aerosolized droplets. TB mainly attacks the lungs, but can also affect other parts of the body. TB is highly contagious during the active stage of the disease and can infect an individual through inhalation of as few as 10 *Mycobacterium tuberculosis* (MTB) bacteria. After inhalation, these bacteria are mainly captured by the alveolar macrophages, but they can evade the host immune system and remain in the dormant stage for a long period of time, at which point they can reactivate to a virulent form under immune-compromised conditions of the host. This is possible because *M. tuberculosis* can persist in slow growing as well as in fast growing stages which makes treatment challenging. Almost all of the antibiotics that can be used to treat TB work when the bacteria are actively dividing. In the intensive phase of TB treatment, the antibiotics mainly kill rapidly growing bacteria, which causes rapid sputum conversion, and the eradication of clinical symptoms. However, in order to kill the persistent or slow growing strains of MTB, the continuation phase of the treatment is essential. TB can be treated effectively by using first line drugs (FLD) isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), ethambutol (EMB) and streptomycin (SM). However, this first line therapy often fails to cure TB for several reasons. Relapse and the spread of the disease contribute to the emergence of drug resistant bacteria. The emergence of multidrug resistant TB (MDR-TB), i.e. which is resistant to at least isoniazid (INH) and rifampicin (RIF), is of great concern, because it requires the use of second-line drugs that are difficult to procure and are much more toxic and expensive than FLDs [1]. Therefore, the detection and treatment of drug susceptible or single drug resistant TB is an important strategy for preventing the emergence of MDR-TB [2]. *M. tuberculosis* strains with extensively drug resistant-TB (XDR-TB), that is resistant to either isoniazid or rifampicin (like MDR tuberculosis), any fluoroquinolone, and at least one of three second-line antituberculosis injectable drugs—*i.e*., capreomycin, kanamy‐ cin, and amikacin have also been reported [3].

© 2013 Jnawali and Ryoo; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

First- and second-line drugs, minimum inhibitory concentrations (MICs) and mechanisms of drug resistance are presented in Table 1 [4]. Antituberculosis drugs are mainly divided into two parts.

**2. First-line antituberculosis drugs**

administration are hepatotoxicity and neurotoxicity.

peroxidase, with MICs ranging from 0.2 to 256 mg/L.

Isoniazid (INH) is one of the most effective and specific antituberculosis drugs, which has been a key to treatment since its introduction in 1952 [5]. *M. tuberculosis* is highly susceptible to INH (MIC 0.02–0.2 μg/ml). INH is only active against growing tubercle bacilli, and is not active against non-replicating bacilli or under anaerobic conditions. INH enters the mycobacterial cell by passive diffusion [6]. The most significant adverse reactions associated with isoniazid

First– and Second–Line Drugs and Drug Resistance

http://dx.doi.org/10.5772/54960

165

Resistance to isoniazid is a complex process. Mutations in several genes, including *katG*, *ahpC*, and *inhA*, have all been associated with isoniazid resistance. INH is a prodrug that is activated by the mycobacterial enzyme KatG [7]. INH-resistant clinical isolates of *M. tubercu‐ losis* often lose catalase and peroxidase enzyme encoded by *kat*G [8], especially in high-level resistant strains (MIC > 5 μg/ml) [9]. Low-level resistant strains (MIC < 1 μg/ml) often still possess catalase activity [9]. Although mutations in *katG* have been shown to be responsible for INH resistance [10], it is not clear whether the regulation of *katG* expression plays a role in INH resistance. The *katG* gene encodes a bifunctional catalase-peroxidase that converts INH to its active form [7]. Activated INH inhibits the synthesis of essential mycolic acids by inactivating the NADH-dependent enoyl-acyl carrier protein reductase encoded by *inhA* [11].

A study by Hazbo´n et al. [12] analysed 240 alleles and found that mutations in *katG*, *inhA* and *ahpC* were most strongly associated with isoniazid resistance. A decrease in or total loss of catalase/peroxidase activity as a result of *katG* mutations are the most common genetic alterations associated with isoniazid resistance [7]. Ser315Thr is the most widespread *katG* mutation in clinical isolates, but there are many mutations that result in inactivation of catalase-

Mutations in *inh*A or its promoter region are usually associated with low-level resistance (MICs = 0.2 −1 μg/ml) and are less frequent than *kat*G mutations [10, 12]. INH-resistant *M. tuberculo‐ sis* harboring *inh*A mutations could have additional mutations in *kat*G, conferring higher levels of INH resistance [13]. The most common *inhA* mutation occurs in its promoter region (-15C → T) and it has been found more frequently associated with mono-resistant strains [14].

In *M. tuberculosis*, *ahpC* codes for an alkyl hydroperoxidase reductase that is implicated in resistance to reactive oxygen and reactive nitrogen intermediates. It was initially proposed that mutations in the promoter of *ahpC* could be used as surrogate markers for the detection of isoniazid resistance [15]. However, several other studies have found that an increase in the expression of *ahpC* seems to be more a compensatory mutation for the loss of catalase/

Rifampicin (RIF) was introduced in 1972 as an antituberculosis drug and has excellent steriliz‐ ing activity. Rifampicin acts by binding to the β-subunit of RNA polymerase (*rpoB*) [17], the en‐

peroxidase activity rather than the basis for isoniazid resistance [4, 16].

**2.1. Isoniazid**

**2.2. Rifampicin**

	- **i.** Fluoroquinolones- Ofloxacin (OFX), levofloxacin (LEV), moxifloxacin (MOX) and ciprofloxacin (CIP).
	- **ii.** Injectable antituberculosis drugs- Kanamycin (KAN), amikacin (AMK) and capreomycin (CAP).
	- **iii.** Less-effective second-line antituberculosis drugs- Ethionamide (ETH)/Prothio‐ namide (PTH), Cycloserine (CS)/Terizidone, P-aminosalicylic acid (PAS).


**Table 1.** First- and second-line drugs, MICs and mechanisms of drug resistance
