Annals of Laboratory Medicine

Korean Society for Laboratory Medicine (대한진단검사의학회)
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Delamanid, Bedaquiline, and Linezolid Minimum Inhibitory Concentration Distributions and Resistance-related Gene Mutations in Multidrug-resistant and Extensively Drug-resistant Tuberculosis in Korea

  • Received : 2017.09.22
  • Accepted : 2018.06.27
  • Published : 2018.11.01
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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 ${\leq}0.025$ to >1.6 mg/L, ${\leq}0.0312$ to >4 mg/L, and ${\leq}0.125$ 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.

Keywords

Acknowledgement

Supported by : Ministry of Health & Welfare

References

  1. Blair HA and Scott LJ. Delamanid: a review of its use in patients with multidrug-resistant tuberculosis. Drugs 2015;75:91-100. https://doi.org/10.1007/s40265-014-0331-4
  2. World Health Organization. Global tuberculosis report 2016. http://www.who.int/tb/publications/global_report/en (Updated on Jun 2016).
  3. Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med 2012;366:2151-60. https://doi.org/10.1056/NEJMoa1112433
  4. Matsumoto M, Hashizume H, Tomishige T, Kawasaki M, Tsubouchi H, Sasaki H, et al. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med 2006;3:e466. https://doi.org/10.1371/journal.pmed.0030466
  5. Haver HL, Chua A, Ghode P, Lakshminarayana SB, Singhal A, Mathema B, et al. Mutations in genes for the F420 biosynthetic pathway and a nitroreductase enzyme are the primary resistance determinants in spontaneous in vitro-selected PA-824-resistant mutants of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2015;59:5316-23. https://doi.org/10.1128/AAC.00308-15
  6. Feuerriegel S, Koser CU, Bau D, Rusch-Gerdes S, Summers DK, Archer JA, et al. Impact of fgd1 and ddn diversity in Mycobacterium tuberculosis complex on in vitro susceptibility to PA-824. Antimicrob Agents Chemother 2011;55:5718-22. https://doi.org/10.1128/AAC.05500-11
  7. Andries K, Verhasselt P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005;307:223-7. https://doi.org/10.1126/science.1106753
  8. Huitric E, Verhasselt P, Andries K, Hoffner SE. In vitro antimycobacterial spectrum of a diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother 2007;51:4202-4. https://doi.org/10.1128/AAC.00181-07
  9. Andries K, Villellas C, Coeck N, Thys K, Gevers T, Vranckx L, et al. Acquired resistance of Mycobacterium tuberculosis to bedaquiline. PLoS One 2014;9:e102135. https://doi.org/10.1371/journal.pone.0102135
  10. Huitric E, Verhasselt P, Koul A, Andries K, Hoffner S, Andersson DI. Rates and mechanisms of resistance development in Mycobacterium tuberculosis to a novel diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother 2010;54:1022-8. https://doi.org/10.1128/AAC.01611-09
  11. Gu B, Kelesidis T, Tsiodras S, Hindler J, Humphries RM. The emerging problem of linezolid-resistant Staphylococcus. J Antimicrob Chemother 2013;68:4-11. https://doi.org/10.1093/jac/dks354
  12. Birmingham MC, Rayner CR, Meagher AK, Flavin SM, Batts DH, Schentag JJ. Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-use program. Clin Infect Dis 2003;36:159-68. https://doi.org/10.1086/345744
  13. Hillemann D, Rusch-Gerdes S, Richter E. In vitro-selected linezolid-resistant Mycobacterium tuberculosis mutants. Antimicrob Agents Chemother 2008;52:800-1. https://doi.org/10.1128/AAC.01189-07
  14. Beckert P, Hillemann D, Kohl TA, Kalinowski J, Richter E, Niemann S, et al. rplC T460C identified as a dominant mutation in linezolid-resistant Mycobacterium tuberculosis strains. Antimicrob Agents Chemother 2012;56:2743-5. https://doi.org/10.1128/AAC.06227-11
  15. Schena E, Nedialkova L, Borroni E, Battaglia S, Cabibbe AM, Niemann S, et al. Delamanid susceptibility testing of Mycobacterium tuberculosis using the resazurin microtiter assay and the BACTECTM MGITTM 960 system. J Antimicrob Chemother 2016;71:1532-9. https://doi.org/10.1093/jac/dkw044
  16. Kaniga K, Cirillo DM, Hoffner S, Ismail NA, Kaur D, Lounis N, et al. A multilaboratory, multicountry study to determine bedaquiline minimal inhibitory concentration quality control ranges for phenotypic drug-susceptibility testing. J Clin Microbiol 2016;54:2956-62. https://doi.org/10.1128/JCM.01123-16
  17. Keller PM, Homke R, Ritter C, Valsesia G, Bloemberg GV, Botteger EC. Determination of MIC distribution and epidemiological cutoff values for bedaquiline and delamanid in Mycobacterium tuberculosis using the MGIT 960 system equipped with TB eXiST. Antimicrob Agents Chemother 2015;59:4352-5. https://doi.org/10.1128/AAC.00614-15
  18. Bloemberg GV, Keller PM, Stucki D, Trauner A, Borrell S, Latshang T, et al. Acquired resistance to bedaquiline and delamanid in therapy for tuberculosis. N Engl J Med 2015;373:1986-8. https://doi.org/10.1056/NEJMc1505196
  19. Huang TS, Liu YC, Sy CL, Chen YS, Tu HZ, Chen BC. In vitro activities of linezolid against clinical isolates of Mycobacterium tuberculosis complex isolated in Taiwan over 10 years. Antimicrob Agents Chemother 2008;52:2226-7. https://doi.org/10.1128/AAC.00414-07
  20. Lee SH, Choi HB, Yu SY, Chang UJ, Kim CK, Kim HJ. Detection of first-line anti-tuberculosis drug resistance mutations by allele-specific primer extension on a microsphere-based platform. Ann Lab Med 2015;35: 487-93. https://doi.org/10.3343/alm.2015.35.5.487
  21. Stinson K, Kurepina N, Venter A, Fujiwara M, Kawasaki M, Timm J, et al. MIC of delamanid (OPC-67683) against Mycobacterium tuberculosis clinical isolates and a proposed critical concentration. Antimicrob Agents Chemother 2016;60:3316-22. https://doi.org/10.1128/AAC.03014-15
  22. European Committee on Antimicrobial Susceptibility Testing. Definitions of clinical breakpoints and epidemiological cut-off values. Clinical Breakpoints Table V.7.1. Valid From 2017-03-10. http://www.eucast.org/clinical_breakpoints/ (Updated on Mar 2017).
  23. CLSI. Susceptibility testing of mycobacteria, nocardiae, and other aerobic actinomycetes. 2nd edition. CLSI M24-A2. Wayne, PA: Clinical Laboratory Standards Institute. 2011.
  24. Segala E, Sougakoff W, Chauffour AN, Jarller V, Petrella S. New mutations in the mycobacterial ATP synthase: new insights into the binding of the diarylquinoline TMC207 to the ATP synthase C-ring structure. Antimicrob Agents Chemother 2012;56:2326-34. https://doi.org/10.1128/AAC.06154-11
  25. Zhang S, Chen J, Cui P, Shi W, Shi X, Niu H, et al. Mycobacterium tuberculosis mutations associated with reduced susceptibility to linezolid. Antimicrob Agents Chemother 2016;60:2542-4. https://doi.org/10.1128/AAC.02941-15

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