Acquisition of bedaquiline and clofazimine resistance in association with a novel loss-of-function mutation in the <i>pepQ</i> gene during treatment of multidrug-resistant tuberculosis
Bibliographic record
Abstract
ABSTRACT Background Bedaquiline (BDQ) has transformed the management of multidrug-resistant (MDR) and rifampin-resistant tuberculosis (TB). Unfortunately, the expanded use of BDQ in these regimens has been accompanied by resistance, which is steadily increasing in certain regions of the world. Nonetheless, our understanding of the mechanisms behind BDQ resistance remains poor, limiting the utility of more rapid molecular or genomic-based diagnostics for the detection of BDQ-resistant isolates. Case Summary We describe an unusual case of a rapid, 2-year evolution of a fully susceptible Mycobacterium tuberculosis strain to extensively drug-resistant TB in a 44-year-old Canadian-born woman with Crohn’s disease. Comparative whole-genome sequencing captured the progressive development of resistance mutations and identified a novel loss-of-function mutation (Glu-177-STOP) in the M. tuberculosis pepQ gene that was associated with treatment failure while on BDQ and phenotypic BDQ/clofazimine (CFZ) cross-resistance. Therapeutic drug monitoring while on MDR therapy (daily ethambutol, pyrazinamide, linezolid, CFZ, and intravenous amikacin) detected low serum levels of CFZ, which was not addressed prior to the addition of BDQ to her 5-drug regimen and may have selected for BDQ/CFZ cross-resistance. Conclusion This case contributes to the limited clinical data implicating pepQ in BDQ/CFZ cross-resistance and describes a novel loss-of-function mutation associated with resistance. As our understanding of genotypic BDQ resistance remains elementary, when novel drug mutations arise, practitioners should consider their significance in the context of phenotypic drug susceptibility test results and the patient’s clinical response.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".