Evaluation of Mycobacterium tuberculosis cross-resistance to isoniazid, rifampicin and levofloxacin with their respective structural analogs

The emergence of drug-resistant, multidrug-resistant and extensively drug-resistant tuberculosis (TB) is of major public health concern in several countries. In this study, the pharmacodynamic relationships among the structural analogs of antibiotics belonging to the same family were taken into consideration. The aim of this study was to compare the susceptibility of Mycobacterium tuberculosis to isoniazid (INH), rifampicin and levofloxacin (LX) to their respective structural analogs, which are frequently used as second-line agents. The microplate colorimetric method was used to determine the MIC to INH, ethionamide (ETH), rifampicin, rifabutin, LX and moxifloxacin (MOX) in clinical isolates previously shown to be drug resistant. Mutations conferring drug resistance were detected by GenoType MTBDR plus and DNA sequencing. INH and ETH cross-resistance was found in 95.12% (39/41) of the INH-resistant isolates harboring a mutation in inhAP or inhA open reading frame, but rifabutin cross-resistance was observed in 90.0% (63/70) of the clinical isolates originally shown to be resistant to rifampicin. Isolates with high LX-resistance levels also showed high MIC to MOX. Fluoroquinolone cross-resistance was verified in isolates containing the gyrA94 and the gyrA90 mutation. In general, isolates with high INH, rifampicin and LX-resistance levels also displayed high MIC values for their structural analogs. These findings suggest the need to test in vitro the second-line drugs before their incorporation in the therapeutic schemes.