Fluoroquinolone resistance and mutational profile of gyrA gene in pulmonary MDR tuberculosis patients

Abstract

Background Flouroquinolones (FQs) are the potential drugs that inhibit DNA synthesis and used in the treatment of MDR-TB and anti-TB short term regimens. In recent year’s high proportion of flouroquinolone (FQs) resistance in Mycobacterium tuberculosis isolates has been observed. The development of FQs resistance among multidrug resistant TB (Pre-XDR TB) negatively impact patient treatment outcome and is a serious threat to control TB. Methods A total of 562 samples were included in the study from patients with pulmonary TB which had been on anti-tuberculosis therapy. MTBDRsl assay was performed for molecular detection of mutations. Sequence analysis was performed for characterization and mutational profiling of FQ resistant isolates. Results FQs resistance was observed in 104 (18.5%) samples and most of them were previously treated and treatment failure cases. A total of 102 isolates had mutations in gyrA gene while gyrB gene mutations were observed in only two isolates. Mutational analysis showed that the mutations mostly alter protein at codon 94 (D94G) (represents the replacement of aspartic acid with glycine) and 90 (A90V) (substitution of alanine with valine). In MDR and treatment failure cases, the FQs-R was most commonly associated with D94G mutation. Whereas, a high proportion of A90V mutation was observed in MTB isolates which were newly diagnosed. Conclusion The findings suggest that the genotypic studies for FQs resistance should be carried out at the time of initial diagnosis, before starting treatment, to rule out all type of mutations for its potential use in treatment to control the resistance.

MTBDRplus and MTBDRsl for simultaneous diagnosis of gastrointestinal tuberculosis and detection of first‐line and second‐line drug resistance

“…18,19 There were four cases of FqR in the present study that produced positive bands against mutation probe MUT3C on MTBDRsl, which corresponds to D94G mutation in gyrA. 35 These four isolates were found to be resistant to both Ofx and concentrations of Mox on pDST and had the D94G mutation on gyrA sequencing. The D94G mutation confers high-level resistance to fluoroquinolones, making even the higher generations of this class of drugs ineffective.…”

“…The D94G mutation confers high-level resistance to fluoroquinolones, making even the higher generations of this class of drugs ineffective. 35 This is in contrast to another mutation, A90V, wherein resistance develops to levofloxacin but higher Fq like Mox is still effective at higher concentrations. 35 The D94G mutation in gyrA gene, found in 13.33% cases of the current study, was also the most prevalent form of mutation conferring FqR in 44% pulmonary isolates from Pakistan, 35 whereas both D94G and A90V were equally prevalent (36% each) in FqR-pulmonary isolates of China.…”

“…35 This is in contrast to another mutation, A90V, wherein resistance develops to levofloxacin but higher Fq like Mox is still effective at higher concentrations. 35 The D94G mutation in gyrA gene, found in 13.33% cases of the current study, was also the most prevalent form of mutation conferring FqR in 44% pulmonary isolates from Pakistan, 35 whereas both D94G and A90V were equally prevalent (36% each) in FqR-pulmonary isolates of China. 36 Pre-XDR GITB was reported for the first time in the world in the current study.…”