Genotype-Phenotype Characterization of Serial Mycobacterium tuberculosis Isolates in Bedaquiline-Resistant Tuberculosis
© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com..
BACKGROUND: Emerging resistance to bedaquiline (BDQ) threatens to undermine advances in the treatment of drug-resistant tuberculosis (DRTB). Characterizing serial Mycobacterium tuberculosis (Mtb) isolates collected during BDQ-based treatment can provide insights into the etiologies of BDQ resistance in this important group of DRTB patients.
METHODS: We measured mycobacteria growth indicator tube (MGIT)-based BDQ minimum inhibitory concentrations (MICs) of Mtb isolates collected from 195 individuals with no prior BDQ exposure who were receiving BDQ-based treatment for DRTB. We conducted whole-genome sequencing on serial Mtb isolates from all participants who had any isolate with a BDQ MIC >1 collected before or after starting treatment (95 total Mtb isolates from 24 participants).
RESULTS: Sixteen of 24 participants had BDQ-resistant TB (MGIT MIC ≥4 µg/mL) and 8 had BDQ-intermediate infections (MGIT MIC = 2 µg/mL). Participants with pre-existing resistance outnumbered those with resistance acquired during treatment, and 8 of 24 participants had polyclonal infections. BDQ resistance was observed across multiple Mtb strain types and involved a diverse catalog of mmpR5 (Rv0678) mutations, but no mutations in atpE or pepQ. Nine pairs of participants shared genetically similar isolates separated by <5 single nucleotide polymorphisms, concerning for potential transmitted BDQ resistance.
CONCLUSIONS: BDQ-resistant TB can arise via multiple, overlapping processes, including transmission of strains with pre-existing resistance. Capturing the within-host diversity of these infections could potentially improve clinical diagnosis, population-level surveillance, and molecular diagnostic test development.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:78 |
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| Enthalten in: |
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America - 78(2024), 2 vom: 17. Feb., Seite 269-276 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Brown, Tyler S [VerfasserIn] |
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| Links: |
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| Themen: |
78846I289Y |
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| Anmerkungen: |
Date Completed 19.02.2024 Date Revised 27.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/cid/ciad596 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM363671978 |
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| 245 | 1 | 0 | |a Genotype-Phenotype Characterization of Serial Mycobacterium tuberculosis Isolates in Bedaquiline-Resistant Tuberculosis |
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| 500 | |a Date Revised 27.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com. | ||
| 520 | |a BACKGROUND: Emerging resistance to bedaquiline (BDQ) threatens to undermine advances in the treatment of drug-resistant tuberculosis (DRTB). Characterizing serial Mycobacterium tuberculosis (Mtb) isolates collected during BDQ-based treatment can provide insights into the etiologies of BDQ resistance in this important group of DRTB patients | ||
| 520 | |a METHODS: We measured mycobacteria growth indicator tube (MGIT)-based BDQ minimum inhibitory concentrations (MICs) of Mtb isolates collected from 195 individuals with no prior BDQ exposure who were receiving BDQ-based treatment for DRTB. We conducted whole-genome sequencing on serial Mtb isolates from all participants who had any isolate with a BDQ MIC >1 collected before or after starting treatment (95 total Mtb isolates from 24 participants) | ||
| 520 | |a RESULTS: Sixteen of 24 participants had BDQ-resistant TB (MGIT MIC ≥4 µg/mL) and 8 had BDQ-intermediate infections (MGIT MIC = 2 µg/mL). Participants with pre-existing resistance outnumbered those with resistance acquired during treatment, and 8 of 24 participants had polyclonal infections. BDQ resistance was observed across multiple Mtb strain types and involved a diverse catalog of mmpR5 (Rv0678) mutations, but no mutations in atpE or pepQ. Nine pairs of participants shared genetically similar isolates separated by <5 single nucleotide polymorphisms, concerning for potential transmitted BDQ resistance | ||
| 520 | |a CONCLUSIONS: BDQ-resistant TB can arise via multiple, overlapping processes, including transmission of strains with pre-existing resistance. Capturing the within-host diversity of these infections could potentially improve clinical diagnosis, population-level surveillance, and molecular diagnostic test development | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a bedaquiline | |
| 650 | 4 | |a drug resistance | |
| 650 | 4 | |a tuberculosis | |
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| 650 | 7 | |a 78846I289Y |2 NLM | |
| 650 | 7 | |a Antitubercular Agents |2 NLM | |
| 650 | 7 | |a Diarylquinolines |2 NLM | |
| 700 | 1 | |a Tang, Linrui |e verfasserin |4 aut | |
| 700 | 1 | |a Omar, Shaheed Vally |e verfasserin |4 aut | |
| 700 | 1 | |a Joseph, Lavania |e verfasserin |4 aut | |
| 700 | 1 | |a Meintjes, Graeme |e verfasserin |4 aut | |
| 700 | 1 | |a Maartens, Gary |e verfasserin |4 aut | |
| 700 | 1 | |a Wasserman, Sean |e verfasserin |4 aut | |
| 700 | 1 | |a Shah, N Sarita |e verfasserin |4 aut | |
| 700 | 1 | |a Farhat, Maha R |e verfasserin |4 aut | |
| 700 | 1 | |a Gandhi, Neel R |e verfasserin |4 aut | |
| 700 | 1 | |a Ismail, Nazir |e verfasserin |4 aut | |
| 700 | 1 | |a Brust, James C M |e verfasserin |4 aut | |
| 700 | 1 | |a Mathema, Barun |e verfasserin |4 aut | |
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