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Limited phenotypic resistance for African clinical Mycobacterium tuberculosis isolates harboring variants in genes relevant for bedaquiline and delamanid resistance

J Van Puyvelde(1,2) F I Massou(2,3) W Mulders(1) R Balde(1) R Reenaers(1) C Vuchas(4) J C Ngabonziza(5,15) S C Agbla(6) O El Tayeb(7) M K Kaswa(8,13,14) G Abebe(9) L Camara(10) B Diarra(11,16) B C de Jong(1) C Merle(12) D Affolabi(3) L Rigouts(1,2)

1:Institute of Tropical Medicine; 2:University of Antwerp; 3:Laboratoire de Référence de Mycobactéries; 4:Bamenda Center for Health Promotion and Research; 5:Rwanda Biomedical Center; 6:London School of Hygene and Tropical Medicine; 7:Damien Foundation; 8:Institut National de Recherche Biomédical; 9:University of Jimma; 10:Service de Pneumophtisiologie; 11:Université des Sciences, Techniques et Technologies de Bamako; 12:World Health Organization; 13:University of Kinshasa; 14:National TB Program DRC; 15:University of Rwanda; 16:University Clinical Research Unit Bamako

We determined minimal inhibitory concentrations (MICs) by the broth microdilution method (BMD) for bedaquiline, clofazimine, delamanid and pretomanid for Mycobacterium tuberculosis complex isolates (DIAMA project; nine African countries; 2017-2021; baseline isolates from rifampicin-resistant and -susceptible TB, BDQ/DLM-inexperienced patients;, NCT03303963). All isolates underwent whole genome sequencing. Thirteen percent (213/1586) of isolates harbored genetic variants in genes potentially implicated in resistance to these drugs. We prioritized variants that were not mono-phyletic, had uncertain significance or not classified in the WHO Mutation Catalogue V2, and were available at ITM: 5 atpE, 10 mppR5/L5, 16 pepQ, 3 Rv1979c, 13 ddn, 22 fibA, 24 fbiB, 63 fbiC, 5 fbiD and 43 fgd1.

Valid BMD results for 49 isolates with potential delamanid-resistance associated mutations showed a mode of 0.008 µg/ml. Seven (14%) showed an MIC above the cut-off (0.125 µg/ml), and had a mutation in fbiB/C/D or fgd1. The same seven and two additional isolates had pretomanid-MICs ranging from 0.5 to 2 µg/ml (mode 0.06 µg/ml). Twenty-seven isolates with potential bedaquiline-resistance associated mutations had a mode of 0.06 µg/ml. Four (14%) showed a MIC above the cut-off (0.25 µg/ml): three having a mmpR5 (1 µg/ml) and one a pepQ variant (0.5 µg/ml). The three mmpR5 variants had a clofazimine MIC of 2 µg/ml, and the pepQ variant 0.125 µg/ml. No other isolates were clofazimine resistant.

These preliminary MIC results for mutants of unknown significance reveal resistance to new anti-TB drugs among drug-naïve patients, albeit for only a minority (~14%) of isolates with genetic variants.


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