title: Evaluation of Mycobacterium tuberculosis cross-resistance to isoniazid, rifampicin and levofloxacin with their respective structural analogs.
abstract: 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.
authors.affiliation: Reference Laboratory of Tuberculosis Control Program of Buenos Aires Province, Dr Cetrángolo Hospital, Florida, Buenos Aires Province, Argentina.
authors.forename: Belén Rocío
authors.initials: BR
authors.lastname: Imperiale
authors.affiliation: Mycobacteria Laboratory, Petrona V de Cordero Hospital, San Fernando, Buenos Aires Province, Argentina.
authors.forename: Ángela Beatríz
authors.initials: ÁB
authors.lastname: Di Giulio
authors.affiliation: Biotechnology Institute, National Institute of Agricultural Technology (INTA), Los Reseros y Las Cabañas, Hurlingham, Buenos Aires Province, Argentina.
authors.forename: Angel
authors.initials: A
authors.lastname: Adrián Cataldi
authors.affiliation: Reference Laboratory of Tuberculosis Control Program of Buenos Aires Province, Dr Cetrángolo Hospital, Florida, Buenos Aires Province, Argentina.
authors.forename: Nora Susana
authors.initials: NS
authors.lastname: Morcillo
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001483:Base Sequence; D003124:Colorimetry; D024881:Drug Resistance, Bacterial / Q000235:genetics; D005000:Ethionamide / Q000494:pharmacology; D024841:Fluoroquinolones / Q000494:pharmacology; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D064704:Levofloxacin / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D016366:Open Reading Frames / Q000235:genetics; D017828:Rifabutin / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D017828:Rifabutin; D064704:Levofloxacin; D005000:Ethionamide; D000077266:Moxifloxacin; D007538:Isoniazid; D012293:Rifampin