**3. Second-line antituberculosis drugs**

#### **3.1. Fluoroquinolones**

The fluoroquinolones (FQs) have broad-spectrum antimicrobial activity and so are widely used for the treatment of bacterial infections of the respiratory, gastrointestinal and urinary tracts, as well as sexually transmitted diseases and chronic osteomyelitis [63]. In contrast to many other antibiotics used to treat bacterial infections, the FQs have excellent in vitro and in vivo activity against *M. tuberculosis* [64, 65]. FQs include ciprofloxacin, ofloxacin, levofloxacin, and moxifloxacin. So, FQs are currently in use as second-line drugs in the treatment of TB. Adverse effects are relatively infrequent (0.5–10% of patients) and include gastrointestinal intolerance, rashes, dizziness, and headache. Most studies of fluoroquinolone side effects have been based on relatively short-term administration for bacterial infections, but trials have now shown the relative safety and tolerability of fluoroquinolones administered for months during TB treatment in adults.

The cellular target of FQs in *M. tuberculosis* is DNA gyrase, a type II topoisomerase consist‐ ing of two A and two B subunits encoded by *gyrA* and *gyrB* genes, respectively [66]. Muta‐ tions in a small region of *gyrA*, called quinolone resistance-determining region (QRDR) and, less frequently, in *gyrB* are the primary mechanism of FQ resistance in *M. tuberculosis* [66, 67]. Analysis of QRDR alone by genotypic tests has been suggested as sufficient for rapid identification of vast majority of FQ-resistant *M. tuberculosis* strains as additional targeting of *gyrB* did not enhance the sensitivity significantly [67, 68].

Mutations within the QRDR of *gyr*A have been identified in clinical and laboratory-selected isolates of *M. tuberculosis*, largely clustered at codons 90, 91 and 94 [69-73], with Asp94 being relatively frequent [71, 74]. Codon 95 (Ser95Thr) contains a naturally occurring polymor‐ phism that is not related to fluoroquinolone resistance, as it occurs in both fluoroquinolonesusceptible and fluoroquinolone-resistant strains [75]. A less common involvement is codon 88 [76]. For clinical isolates, *gyr*B mutations appear to be of much rarer occurrence [72, 73]. Generally, two mutations in *gyr*A or concomitant mutations in *gyr*A plus *gyr*B are required for the development of higher levels of resistance [69, 77].
