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Growth Units in the MGIT below the instrument threshold to call resistance may be predictive of Rv0678 conferring resistance mutations

E Ardizzoni(1) J Vereecken(1) J Keysers(1) C Hewison(2) A Dippenaar(3) B de Jong(1) L Rigouts(1,4)

1:Institute of Tropical Medicine of Antwerp; 2:Médecins sans Frontières; 3:Faculty of Medicine and Health Sciences, University of Antwerp; 4:Department of Biomedical Sciences, University of Anwterp

For drug-susceptibility testing (DST), MGIT™960 interprets mycobacterial growth units (GU) in drug-containing tubes as resistant (R) when ≥100 GUs are detected (commonly reaching 400), and susceptible (S) when <100 (typically 0), without differentiating GUs between 0-100 or 101-400.

At ITM, Mycobacterium tuberculosis isolates from MSF projects are tested for bedaquiline (Bdq) susceptibility with MGIT-DST, minimal-inhibitory concentration (MIC) determination, and Rv0678 sequencing by Deeplex® Myc-TB or whole genome sequencing, subsequently analysed by the MAGMA pipeline. Bdq-resistance-associated variants with ≥95% allele frequency are considered fixed.

Of 100 isolates with Bdq-MGIT, MIC and Rv0678 sequencing results available, 50 showed Rv0678 variants. Of these, 30 were MGIT-R: 21 with GU=400 and 9 with GU between 111-337. For both groups, Bdq-MIC ranged between 0.25µg/ml and 0.5µg/ml, with unfixed variants equally represented (n=9 and n=4). The remaining 20 isolates with variants were MGIT-S: 12 with GU=0 and 8 with GU between 4-84. In both groups, Bdq-MIC ranged between ≥0.125 and ≤0.5µg/ml, and 4 unfixed variants in each group.

All 50 WT isolates were MGIT-S, 48 showed GU=0 and Bdq-MIC ≥0.0155 and ≤0.25µg/ml, and two GU=13 and GU=100, with MIC=0.06µg/ml. MIC sensitivity to detect variants was 39% and specificity 100%. If MGIT GUs between 1 and 100 were classified as MGIT-R, sensitivity would increase from 58% to 74%, decreasing specificity from 100% to 96%.

Currently applied critical concentrations do not detect all Rv0678 mutants. While unfixed- variants do not affect MGIT sensitivity, GU between 1-100 in MGIT-S results may indicate the presence of variants associated with Bdq-resistance.

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