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embB 306 Mutations as Molecular Indicators to Predict Ethambutol Susceptibility in Mycobacterium tuberculosis


Sirgel, Frederick A; Warren, Robin M; Streicher, Elizabeth M; Victor, Thomas C; van Helden, Paul D; Böttger, Erik C (2012). embB 306 Mutations as Molecular Indicators to Predict Ethambutol Susceptibility in Mycobacterium tuberculosis. Chemotherapy, 58(5):358-363.

Abstract

Background: Discordant results in conventional susceptibility testing of ethambutol against Mycobacterium tuberculosis may lead to underreporting of drug resistance. Methods: A 240-bp region of the embB gene in 111 clinical isolates of M. tuberculosis was sequenced and examined for mutations linked to ethambutol resistance. The phenotypic susceptibility levels of the isolates were quantified by the BACTEC™ MGIT 960™ TB System and correlated with the genotypic test results. These data were analyzed to find information that could be used to clarify discordant ethambutol susceptibility test results. Results: Mutations M306I (n = 56), M306V (n = 18) and M306L (n = 3) in M. tuberculosis showed decreased susceptibility to ethambutol. The minimum inhibitory concentrations (MICs) in 73% (56/77) of embB306 mutants were at or just above the critical concentration (MICs, 5.0 to ≤12.5 µg/ml) of ethambutol reflecting borderline (or intermediate) resistance. Eight ethambutol-resistant isolates lacked embB mutations, probably due to mutational alterations elsewhere in the genome. Conclusion: Our findings suggest that clinical isolates containing embB306 mutations with MICs overlapping the critical concentration are associated with discordant ethambutol susceptibility test results. The clinical significance of borderline resistance in combination treatment of tuberculosis remains to be determined before alternative ethambutol breakpoints are considered.

Abstract

Background: Discordant results in conventional susceptibility testing of ethambutol against Mycobacterium tuberculosis may lead to underreporting of drug resistance. Methods: A 240-bp region of the embB gene in 111 clinical isolates of M. tuberculosis was sequenced and examined for mutations linked to ethambutol resistance. The phenotypic susceptibility levels of the isolates were quantified by the BACTEC™ MGIT 960™ TB System and correlated with the genotypic test results. These data were analyzed to find information that could be used to clarify discordant ethambutol susceptibility test results. Results: Mutations M306I (n = 56), M306V (n = 18) and M306L (n = 3) in M. tuberculosis showed decreased susceptibility to ethambutol. The minimum inhibitory concentrations (MICs) in 73% (56/77) of embB306 mutants were at or just above the critical concentration (MICs, 5.0 to ≤12.5 µg/ml) of ethambutol reflecting borderline (or intermediate) resistance. Eight ethambutol-resistant isolates lacked embB mutations, probably due to mutational alterations elsewhere in the genome. Conclusion: Our findings suggest that clinical isolates containing embB306 mutations with MICs overlapping the critical concentration are associated with discordant ethambutol susceptibility test results. The clinical significance of borderline resistance in combination treatment of tuberculosis remains to be determined before alternative ethambutol breakpoints are considered.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2012
Deposited On:12 Dec 2012 16:09
Last Modified:22 Jun 2016 13:54
Publisher:Karger
Series Name:Chemotherapy
ISSN:0009-3157
Publisher DOI:https://doi.org/10.1159/000343474
PubMed ID:23171739

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