Evaluation of genetic mutations associated with phenotypic resistance to Fluoroquinolones, Bedaquiline, and Linezolid in clinical Mycobacterium tuberculosis: A systematic review and meta-analysis.

The classification of drugs used in multidrug-resistant tuberculosis (MDR-TB) regimens was updated. Group A drugs (fluoroquinolones, bedaquiline (BDQ), and linezolid (LZD) are crucial drugs for the control of MDR-TB. Molecular drug resistance assays could facilitate the effective use of Group A drugs.We summarized the evidence implicating specific genetic mutations for Group A drugs. We searched PubMed, Embase, MEDLINE, and Cochrane library for studies published from the inception of each database until July 1, 2022. Using a random-effects model, we calculated the odds ratios (ORs) and 95% confidence intervals (CIs) as our measures of association.A total of 5,001 clinical isolates were included in 47 studies. The mutations of gyrA A90V, D94G, D94N, and D94Y were significantly associated with an increased risk of levofloxacin (LFX)-resistant isolates. In addition, the mutations of gyrA G88C, A90V, D94G, D94H, D94N, and D94Y were significantly associated with an increased risk of having moxifloxacin (MFX)-resistant isolates. Only in a single study, the majority of gene locus (n=126, 90.65%) observed to have unique mutations in atpE, Rv0678, mmpL5, pepQ, and Rv1979c in BDQ-resistant isolates. The most common mutations occurred at four sites in the rrl gene (g2061t, g2270c, g2270t, and g2814t) and one site in rplC (C154R) in LZD-resistant isolates. Our meta-analysis demonstrated no mutations associated with BDQ- or LZD-resistant phenotypes.The mutations detected by rapid molecular assay are correlated with phenotypic resistance to LFX and MFX. The absence of mutation-phenotype associations for BDQ and LZD hindered the development of a rapid molecular assay.