Ann Lab Med.  2018 Nov;38(6):563-568. 10.3343/alm.2018.38.6.563.

Delamanid, Bedaquiline, and Linezolid Minimum Inhibitory Concentration Distributions and Resistance-related Gene Mutations in Multidrug-resistant and Extensively Drug-resistant Tuberculosis in Korea

• Yang JS
• Kim KJ
• Choi H
• Lee SH

• KMID: 2429122
• DOI: http://doi.org/10.3343/alm.2018.38.6.563

Abstract

BACKGROUND
Delamanid, bedaquiline, and linezolid have recently been approved for the treatment of multidrug- and extensively drug-resistant (MDR and XDR, respectively) tuberculosis (TB). To use these drugs effectively, drug susceptibility tests, including rapid molecular techniques, are required for accurate diagnosis and treatment. Furthermore, mutation analyses are needed to assess the potential for resistance. We evaluated the minimum inhibitory concentrations (MICs) of these three anti-TB drugs for Korean MDR and XDR clinical strains and mutations in genes related to resistance to these drugs.
METHODS
MICs were determined for delamanid, bedaquiline, and linezolid using a microdilution method. The PCR products of drug resistance-related genes from 420 clinical Mycobacterium tuberculosis strains were sequenced and aligned to those of M. tuberculosis H37Rv.
RESULTS
The overall MICs for delamanid, bedaquiline, and linezolid ranged from ≤0.025 to >1.6 mg/L, ≤0.0312 to >4 mg/L, and ≤0.125 to 1 mg/L, respectively. Numerous mutations were found in drug-susceptible and -resistant strains. We did not detect specific mutations associated with resistance to bedaquiline and linezolid. However, the Gly81Ser and Gly81Asp mutations were associated with resistance to delamanid.
CONCLUSIONS
We determined the MICs of three anti-TB drugs for Korean MDR and XDR strains and identified various mutations in resistance-related genes. Further studies are needed to determine the genetic mechanisms underlying resistance to these drugs.

Keyword

Mycobacterium tuberculosis; Delamanid; Bedaquiline; Linezolid; Mutation; Minimum inhibitory concentration

MeSH Terms

Diagnosis
Extensively Drug-Resistant Tuberculosis*
Korea*
Linezolid*
Methods
Microbial Sensitivity Tests*
Mycobacterium tuberculosis
Polymerase Chain Reaction
Tuberculosis
Linezolid

Figure

• 

  Fig. 1 Drug resistance patterns of the clinical strains used in this study, as assessed by phenotypic drug susceptibility testing.*Failed test isolates (N=26) and contaminated isolates (N=11).Abbreviations: MIC, minimum inhibitory concentration; MDR TB, multidrug-resistant tuberculosis; XDR TB, extensively drug-resistant tuberculosis; Pre-XDR, pre-extensively drug-resistant tuberculosis (MDR TB with resistant to either a fluoroquinolone and second-line injectable drug but not both).

• 

  Fig. 2 Overall MIC distribution for 420 clinical strains: (A) Delamanid, (B) bedaquiline, and (C) linezolid MICs. The number above each bar indicates the number of strains.Abbreviations: MIC, minimum inhibitory concentration; MDR, multidrug-resistant tuberculosis; XDR, extensively drug-resistant tuberculosis; Pre-XDR, pre-extensively drug-resistant tuberculosis.

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