High fluoroquinolone resistance proportions among multidrug-resistant tuberculosis driven by dominant L2 Mycobacterium tuberculosis clones in the Mumbai Metropolitan Region

Abstract

Background Multidrug-resistant (MDR) Mycobacterium tuberculosis complex (MTBC) strains are a serious health problem in India, also contributing to one-fourth of the global MDR tuberculosis (TB) burden. About 36% of the MDR MTBC strains are reported fluoroquinolone (FQ) resistant leading to high pre-extensively drug-resistant (pre-XDR) and XDR-TB (further resistance against bedaquiline and/or linezolid) rates. Still, factors driving the MDR/pre-XDR epidemic in India are not well defined. Methods In a retrospective study, we analyzed 1852 consecutive MTBC strains obtained from patients from a tertiary care hospital laboratory in Mumbai by whole genome sequencing (WGS). Univariate and multivariate statistics was used to investigate factors associated with pre-XDR. Core genome multi locus sequence typing, time scaled haplotypic density (THD) method and homoplasy analysis were used to analyze epidemiological success, and positive selection in different strain groups, respectively. Results In total, 1016 MTBC strains were MDR, out of which 703 (69.2%) were pre-XDR and 45 (4.4%) were XDR. Cluster rates were high among MDR (57.8%) and pre-XDR/XDR (79%) strains with three dominant L2 (Beijing) strain clusters (Cl 1–3) representing half of the pre-XDR and 40% of the XDR-TB cases. L2 strains were associated with pre-XDR/XDR-TB (P < 0.001) and, particularly Cl 1–3 strains, had high first-line and FQ resistance rates (81.6–90.6%). Epidemic success analysis using THD showed that L2 strains outperformed L1, L3, and L4 strains in short- and long-term time scales. More importantly, L2 MDR and MDR + strains had higher THD success indices than their not-MDR counterparts. Overall, compensatory mutation rates were highest in L2 strains and positive selection was detected in genes of L2 strains associated with drug tolerance (prpB and ppsA) and virulence (Rv2828c). Compensatory mutations in L2 strains were associated with a threefold increase of THD indices, suggesting improved transmissibility. Conclusions Our data indicate a drastic increase of FQ resistance, as well as emerging bedaquiline resistance which endangers the success of newly endorsed MDR-TB treatment regimens. Rapid changes in treatment and control strategies are required to contain transmission of highly successful pre-XDR L2 strains in the Mumbai Metropolitan region but presumably also India-wide.

Access the Diagnostic Accuracy of GeneXpert to Detect <em>Mycobacterium tuberculosis</em> and Rifampicin-Resistance Tuberculosis among Presumptive Tuberculosis and Presumptive Drug Resistant Tuberculosis Patients

“…In this study, 16.56% (26/157) of Multidrug-resistant tuberculosis isolates and 4.02% (20/498) isoniazid-resistant are fluoroquinolone-resistant, a characteristic distribution leading to about 17.2% of fluoroquinolone resistance events and relevant marker gyr-A mutations in MDR tuberculosis isolates. Dreyer et al [40] reported 69.2% (703/1016) fluoroquinolone resistance among 1016 Multidrug-resistant tuberculosis isolates tested for resistance. In India, 36% of the Multidrugresistant tuberculosis isolates are browned to have additional resistance to fluoroquinolone [41,42], and about 3% of MDR-TB isolates are estimated to have extensively drug-resistant (XDR-TB).…”

Assess the Diagnostic Accuracy of GeneXpert to Detect Mycobacterium tuberculosis and Rifampicin-Resistant Tuberculosis among Presumptive Tuberculosis and Presumptive Drug Resistant Tuberculosis Patients

“…In this study, 16.56% (26/157) of multidrug-resistant tuberculosis isolates and 4.02% (20/498) isoniazid-resistant are fluoroquinolone-resistant, a characteristic distribution leading to about 17.2% of fluoroquinolone resistance events and relevant marker gyr-A mutations in MDR tuberculosis isolates. Dreyer et al [44] reported 69.2% (703/1016) fluoroquinolone resistance among 1016 multidrug-resistant tuberculosis isolates tested for resistance. In India, 36% of the multidrug-resistant tuberculosis isolates are browned to have additional resistance to fluoroquinolone [45,46], and about 3% of MDR-TB isolates are estimated to be extensively drug-resistant (XDR-TB).…”

OASIS: An interpretable, finite-sample valid alternative to Pearson’sX2for scientific discovery

“…M. Tuberculosis data is publicly available under Accession ID PRJEB41116 (18). SARS-CoV-2 data is publicly available under Accession ID PRJNA817806 (6).…”

“…We tested the generality of OASIS-opt's inferential power to classify microbial variants in a different microorganism, the bacterium M. Tuberculosis. We processed data from 25 isolates from two subsublineages known to derive from the sublineage 3.1: 3.1.1 and 3.1.2 (Accession ID PRJEB41116 (19)). Currently, bacterial typing is based on manual curation and SNPs, is highly manually intensive, and requires mapping to a reference genome.…”