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http://hdl.handle.net/10362/136627
Título: | Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid |
Autor: | Bateson, Anna Canseco, Julio Ortiz McHugh, Timothy D. Witney, Adam A. Feuerriegel, Silke Merker, Matthias Kohl, Thomas A. Utpatel, Christian Niemann, Stefan Andres, Sonke Kranzer, Katharina Maurer, Florian P. Ghodousi, Arash Borroni, Emanuele Cirillo, Daniela Maria Wijkander, Maria Toro, Juan C. Groenheit, Ramona Werngren, Jim Machado, Diana Viveiros, Miguel Warren, Robin M. Sirgel, Frederick Dippenaar, Anzaan Koeser, Claudio U. Sun, Eugene Timm, Juliano |
Palavras-chave: | SDG 3 - Good Health and Well-being |
Data: | 9-Mar-2022 |
Resumo: | 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. |
Peer review: | yes |
URI: | http://hdl.handle.net/10362/136627 |
DOI: | https://doi.org/10.1093/jac/dkac070 |
ISSN: | 0305-7453 |
Aparece nas colecções: | IHMT: MM - Artigos em revista internacional com arbitragem científica |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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Ancient_and_recent_differences_in_the_intrinsic_susceptibility.pdf | 623,87 kB | Adobe PDF | Ver/Abrir |
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