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Genotypic and phenotypic drug susceptibility testing (DST) for Bedaquiline, Delamanid and Pretomanid in South-East Asian multi-drug resistant TB (MDR-TB) isolates

T L Kee(1) N B Mohd Ya'akob(1) J F Wee(1) C S Gan(1) B X Tan(1) L H Sng(1)

1:Singapore General Hospital

Conventional treatment of MDR-TB is lengthy, costly and associated with drug toxicity. WHO recommends using a new 6-month oral regimen of bedaquiline (BDQ), pretomanid (Pa), linezolid and moxifloxacin in people infected with MDR/RR-TB or MDR/RR-TB with additional resistance to fluoroquinolones. With increased demand for both phenotypic and genotypic DST for the newer drugs, we surveyed for resistance in high-risk cases while validating the DST methods in our laboratory.

Thirty-nine MDR-TB and 2 pan-susceptible isolates from treatment-naive patients between 2022-2023 were tested against BDQ, Pa and delamanid using the BACTEC MGIT 960 with critical concentrations of 1.0, 1.0 and 0.06 µg/ml respectively. Whole genome sequencing (WGS) was performed (n=32) and the results interpreted using the WHO Catalogue of Mutations (Second Edition). All isolates were susceptible to the drugs, except for 2 isolates that had invalid results for Pa due to poor growth.

No mutations associated with resistance were found in all isolates. For BDQ, there were 2 isolates with Rv0678 mutations: “Uncertain significance” mutation Rv0678_p.Arg96Trp and unclassified mutation Rv0678_p.Ala99Thr; both isolates were resistant to clofazimine at 0.5 µg/ml. “Uncertain significance” mutations in mmpL5, Rv1979c and lpqB also occurred less frequently and were found in both MDR and susceptible isolates. Majority of isolates (>86%) contained mtrB mutations that were not associated with resistance.

Polymorphisms detected for delamanid included one of “Uncertain significance”:  fbiA_p.Arg175His. The most frequently encountered polymorphism was fgd1_c.960T>C (76.9% of isolates).

In our study, resistance to the new drugs was absent and the phenotypic and genotypic DST results were concordant.

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