Table 2.
Overview of M. tuberculosis isolates selected from either preclinical or clinical settings for which susceptibility to both delamanid (DLM) and pretomanid (PMD) was determined, together with an investigation of coinciding gene mutations
| Author/setting of isolation | Resistance type | Resistant toa | MIC (mg/L) | Gene | Mutation | |
|---|---|---|---|---|---|---|
| Delamanid | Pretomanid | |||||
| Rifat et al. (2020)36 | ||||||
| Preclinical | DLM; PMD | >16 | >32 | fbiA | Q27* | |
| Preclinical | DLM; PMD | >16 | >32 | fbiA | D49G | |
| Preclinical | DLM; PMD | >16 | >32 | fbiA | −G in aa 47 | |
| Preclinical | DLM; PMD | >16 | >32 | fbiA | L308P | |
| Preclinical | DLM; PMD | >16 | 32 | fbiA | Q120P | |
| Preclinical | DLM; PMD | >16 | 32 | fbiA | D286A | |
| Preclinical | DLM; PMD | 0.06–0.125 | 8–32 | fbiB | L15P | |
| Preclinical | DLM; PMD | 0.125 | 32 | fbiB | L173P | |
| Preclinical | DLM; PMD | 0.06–0.125 | 32 | fbiB | −T in aa 684 | |
| Preclinical | DLM; PMD | >16 | >32 | fbiC | C562W | |
| Preclinical | DLM; PMD | 1 | >32 | fbiC | G194D | |
| Preclinical | DLM; PMD | 2 | >32 | fbiC | −C in aa 20 | |
| Preclinical | DLM; PMD | >16 | >32 | fbiC | K684T | |
| Preclinical | DLM; PMD | >16 | >32 | fbiC | IS6110 ins. 85 bp upstream of fbiC | |
| Preclinical | DLM; PMD | >16 | >32 | fbiC | L377P | |
| Preclinical | DLM; PMD | >16 | >32 | fbiC | A827G | |
| Preclinical | DLM; PMD | 0.5 | 32 | fgd1 | K9N | |
| Preclinical | DLM; PMD | >16 | >32 | fgd1 | G191D | |
| Preclinical | DLM; PMD | >16 | ≥32 | ddn | R112W | |
| Preclinical | DLM; PMD | >16 | ≥32 | ddn | IS6110 ins. in D108 | |
| Preclinical | DLM; PMD | >16 | >32 | ddn | −G in aa 39 | |
| Preclinical | PMD | 0.03 | 32 | fbiA | S219G | |
| Preclinical | PMD | 0.03 | 16 | fbiB | W397R | |
| Preclinical | PMD | 0.03 | 16–32 | fbiC | R25G | |
| Preclinical | PMD | 0.03 | 16–32 | fbiC | M776R | |
| Preclinical | PMD | 0.06 | >32 | fbiD | G147C | |
| Preclinical | PMD | 0.06 | >32 | fbiD | A132V | |
| Preclinical | PMD | 0.06 | >32 | fbiD | −ATC in aa 129 | |
| Preclinical | PMD | 0.03–0.06 | >32 | fbiD | R25S | |
| Preclinical | PMD | 0.06 | >32 | fbiD | A198P | |
| Preclinical | PMD | 0.06 | >32 | fbiD | C152R | |
| Preclinical | PMD | <0.03 | >32 | fbiD | A68E | |
| Wen et al. (2019)49 | ||||||
| Clinical | XDR | DLM; PMD | >16 | 8 | b | b |
| Clinical | XDR | DLM; PMD | >16 | >16 | fgd1 | F320F |
| fbiA | E249K | |||||
| Clinical | MDR | DLM | 16 | 0.063 | fgd1 | F320F |
| Clinical | MDR | DLM | >16 | 0.031 | b | b |
| Clinical | MDR | DLM | 0.5 | 0.063 | fgd1 | F320F |
| Clinical | MDR | DLM | >16 | 0.063 | fgd1 | F320F |
| Clinical | XDR | DLM | >16 | ≤0.016 | fgd1 | F320F |
| Clinical | XDR | PMD | ≤0.016 | >16 | b | b |
| Clinical | MDR | None | ≤0.016 | 0.13 | fgd1 | F320F |
| Clinical | MDR | None | ≤0.016 | 0.25 | fgd1 | F320F |
| Clinical | MDR | None | ≤0.016 | 0.5 | fgd1 | F320F |
| Clinical | XDR | None | ≤0.016 | 0.25 | fgd1 | F320F |
| Lee et al. (2020)29 | ||||||
| Clinical | DLM; PMD | 32 | 256 | ddn | S78Y | |
Rifat et al.36 determined the MIC by broth macrodilution assay, Wen et al.49 by microplate Alamar blue assay (MABA) and Lee et al.29 by resazurin assay.
a
The clinical breakpoint for susceptibility to delamanid is ≤0.06 mg/L, as set by the EUCAST73; EUCAST clinical breakpoints for pretomanid are awaited. In this Table, 1 mg/L is used as the cut-off value for susceptibility to pretomanid.70
b
No mutations were found in ddn, fgd1, fbiA, fbiB, or fbiC.