Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid
© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy..
OBJECTIVES: To develop a robust phenotypic antimicrobial susceptibility testing (AST) method with a correctly set breakpoint for pretomanid (Pa), the most recently approved anti-tuberculosis drug.
METHODS: The Becton Dickinson Mycobacterial Growth Indicator Tube™ (MGIT) system was used at six laboratories to determine the MICs of a phylogenetically diverse collection of 356 Mycobacterium tuberculosis complex (MTBC) strains to establish the epidemiological cut-off value for pretomanid. MICs were correlated with WGS data to study the genetic basis of differences in the susceptibility to pretomanid.
RESULTS: We observed ancient differences in the susceptibility to pretomanid among various members of MTBC. Most notably, lineage 1 of M. tuberculosis, which is estimated to account for 28% of tuberculosis cases globally, was less susceptible than lineages 2, 3, 4 and 7 of M. tuberculosis, resulting in a 99th percentile of 2 mg/L for lineage 1 compared with 0.5 mg/L for the remaining M. tuberculosis lineages. Moreover, we observed that higher MICs (≥8 mg/L), which probably confer resistance, had recently evolved independently in six different M. tuberculosis strains. Unlike the aforementioned ancient differences in susceptibility, these recent differences were likely caused by mutations in the known pretomanid resistance genes.
CONCLUSIONS: In light of these findings, the provisional critical concentration of 1 mg/L for MGIT set by EMA must be re-evaluated. More broadly, these findings underline the importance of considering the global diversity of MTBC during clinical development of drugs and when defining breakpoints for AST.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:77 |
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| Enthalten in: |
The Journal of antimicrobial chemotherapy - 77(2022), 6 vom: 29. Mai, Seite 1685-1693 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bateson, Anna [VerfasserIn] |
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| Links: |
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| Themen: |
Antitubercular Agents |
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| Anmerkungen: |
Date Completed 02.06.2022 Date Revised 16.07.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/jac/dkac070 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM337917981 |
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| 100 | 1 | |a Bateson, Anna |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 02.06.2022 | ||
| 500 | |a Date Revised 16.07.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. | ||
| 520 | |a OBJECTIVES: To develop a robust phenotypic antimicrobial susceptibility testing (AST) method with a correctly set breakpoint for pretomanid (Pa), the most recently approved anti-tuberculosis drug | ||
| 520 | |a METHODS: The Becton Dickinson Mycobacterial Growth Indicator Tube™ (MGIT) system was used at six laboratories to determine the MICs of a phylogenetically diverse collection of 356 Mycobacterium tuberculosis complex (MTBC) strains to establish the epidemiological cut-off value for pretomanid. MICs were correlated with WGS data to study the genetic basis of differences in the susceptibility to pretomanid | ||
| 520 | |a RESULTS: We observed ancient differences in the susceptibility to pretomanid among various members of MTBC. Most notably, lineage 1 of M. tuberculosis, which is estimated to account for 28% of tuberculosis cases globally, was less susceptible than lineages 2, 3, 4 and 7 of M. tuberculosis, resulting in a 99th percentile of 2 mg/L for lineage 1 compared with 0.5 mg/L for the remaining M. tuberculosis lineages. Moreover, we observed that higher MICs (≥8 mg/L), which probably confer resistance, had recently evolved independently in six different M. tuberculosis strains. Unlike the aforementioned ancient differences in susceptibility, these recent differences were likely caused by mutations in the known pretomanid resistance genes | ||
| 520 | |a CONCLUSIONS: In light of these findings, the provisional critical concentration of 1 mg/L for MGIT set by EMA must be re-evaluated. More broadly, these findings underline the importance of considering the global diversity of MTBC during clinical development of drugs and when defining breakpoints for AST | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antitubercular Agents |2 NLM | |
| 650 | 7 | |a Nitroimidazoles |2 NLM | |
| 650 | 7 | |a pretomanid |2 NLM | |
| 700 | 1 | |a Ortiz Canseco, Julio |e verfasserin |4 aut | |
| 700 | 1 | |a McHugh, Timothy D |e verfasserin |4 aut | |
| 700 | 1 | |a Witney, Adam A |e verfasserin |4 aut | |
| 700 | 1 | |a Feuerriegel, Silke |e verfasserin |4 aut | |
| 700 | 1 | |a Merker, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Kohl, Thomas A |e verfasserin |4 aut | |
| 700 | 1 | |a Utpatel, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Niemann, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Andres, Sönke |e verfasserin |4 aut | |
| 700 | 1 | |a Kranzer, Katharina |e verfasserin |4 aut | |
| 700 | 1 | |a Maurer, Florian P |e verfasserin |4 aut | |
| 700 | 1 | |a Ghodousi, Arash |e verfasserin |4 aut | |
| 700 | 1 | |a Borroni, Emanuele |e verfasserin |4 aut | |
| 700 | 1 | |a Cirillo, Daniela Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Wijkander, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Toro, Juan C |e verfasserin |4 aut | |
| 700 | 1 | |a Groenheit, Ramona |e verfasserin |4 aut | |
| 700 | 1 | |a Werngren, Jim |e verfasserin |4 aut | |
| 700 | 1 | |a Machado, Diana |e verfasserin |4 aut | |
| 700 | 1 | |a Viveiros, Miguel |e verfasserin |4 aut | |
| 700 | 1 | |a Warren, Robin M |e verfasserin |4 aut | |
| 700 | 1 | |a Sirgel, Frederick |e verfasserin |4 aut | |
| 700 | 1 | |a Dippenaar, Anzaan |e verfasserin |4 aut | |
| 700 | 1 | |a Köser, Claudio U |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Eugene |e verfasserin |4 aut | |
| 700 | 1 | |a Timm, Juliano |e verfasserin |4 aut | |
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