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Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps
Background. Infants and toddlers often present with disseminated and lymph node tuberculosis, in which Mycobacterium tuberculosis (Mtb) is predominantly intracellular. Linezolid, used to treat tuberculosis in adults, has not been formally studied in infants. Infants clear linezolid 5 times faster th...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064157/ https://www.ncbi.nlm.nih.gov/pubmed/27742638 http://dx.doi.org/10.1093/cid/ciw482 |
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author | Deshpande, Devyani Srivastava, Shashikant Pasipanodya, Jotam G. Bush, Stephen J. Nuermberger, Eric Swaminathan, Soumya Gumbo, Tawanda |
author_facet | Deshpande, Devyani Srivastava, Shashikant Pasipanodya, Jotam G. Bush, Stephen J. Nuermberger, Eric Swaminathan, Soumya Gumbo, Tawanda |
author_sort | Deshpande, Devyani |
collection | PubMed |
description | Background. Infants and toddlers often present with disseminated and lymph node tuberculosis, in which Mycobacterium tuberculosis (Mtb) is predominantly intracellular. Linezolid, used to treat tuberculosis in adults, has not been formally studied in infants. Infants clear linezolid 5 times faster than adults and achieve lower 0- to 24-hour area under the concentration-time curves (AUC(0–24)). Methods. To mimic intracellular disease, we infected human-derived THP-1 macrophages with Mtb and inoculated hollow fiber systems. We performed dose-effect and dose-scheduling studies in which we recapitulated the linezolid half-life of 3 hours encountered in infants. Repetitive sampling for linezolid pharmacokinetics, Mtb intracellular burden, viable monocyte count, and RNA sequencing reads were performed up to 28 days. Results. The linezolid extracellular half-life was 2.64 ± 0.38 hours, whereas intracellular half-life was 8.93 ± 1.30 hours (r(2) = 0.89). Linezolid efficacy was linked to the AUC(0–24) to minimum inhibitory concentration (MIC) ratio (r(2) = 0.98). The exposure associated with maximal Mtb kill was an AUC(0–24)/MIC of 23.37 ± 1.16. We identified a 414-gene transcript on exposure to toxic linezolid doses. The largest number of genes mapped to ribosomal proteins, a signature hitherto not associated with linezolid toxicity. The second-largest number of differentially expressed genes mapped to mitochondrial enzyme inhibition. Linezolid AUC(0–24) best explained the mitochondrial gene inhibition, with 50% inhibition at 94 mg × hour/L (highest r(2) = 0.98). Conclusions. We identified the linezolid AUC(0–24)/MIC target for optimal efficacy against pediatric intracellular tuberculosis, and an AUC(0–24) threshold associated with mitochondrial inhibition. These constitute a therapeutic window to be targeted for optimal linezolid doses in children with tuberculosis. |
format | Online Article Text |
id | pubmed-5064157 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-50641572016-10-17 Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps Deshpande, Devyani Srivastava, Shashikant Pasipanodya, Jotam G. Bush, Stephen J. Nuermberger, Eric Swaminathan, Soumya Gumbo, Tawanda Clin Infect Dis A Development Paradigm for Novel Combination Regimens for Multidrug-Resistant and Drug-Susceptible Tuberculosis in Children: Flame for Work and Play Background. Infants and toddlers often present with disseminated and lymph node tuberculosis, in which Mycobacterium tuberculosis (Mtb) is predominantly intracellular. Linezolid, used to treat tuberculosis in adults, has not been formally studied in infants. Infants clear linezolid 5 times faster than adults and achieve lower 0- to 24-hour area under the concentration-time curves (AUC(0–24)). Methods. To mimic intracellular disease, we infected human-derived THP-1 macrophages with Mtb and inoculated hollow fiber systems. We performed dose-effect and dose-scheduling studies in which we recapitulated the linezolid half-life of 3 hours encountered in infants. Repetitive sampling for linezolid pharmacokinetics, Mtb intracellular burden, viable monocyte count, and RNA sequencing reads were performed up to 28 days. Results. The linezolid extracellular half-life was 2.64 ± 0.38 hours, whereas intracellular half-life was 8.93 ± 1.30 hours (r(2) = 0.89). Linezolid efficacy was linked to the AUC(0–24) to minimum inhibitory concentration (MIC) ratio (r(2) = 0.98). The exposure associated with maximal Mtb kill was an AUC(0–24)/MIC of 23.37 ± 1.16. We identified a 414-gene transcript on exposure to toxic linezolid doses. The largest number of genes mapped to ribosomal proteins, a signature hitherto not associated with linezolid toxicity. The second-largest number of differentially expressed genes mapped to mitochondrial enzyme inhibition. Linezolid AUC(0–24) best explained the mitochondrial gene inhibition, with 50% inhibition at 94 mg × hour/L (highest r(2) = 0.98). Conclusions. We identified the linezolid AUC(0–24)/MIC target for optimal efficacy against pediatric intracellular tuberculosis, and an AUC(0–24) threshold associated with mitochondrial inhibition. These constitute a therapeutic window to be targeted for optimal linezolid doses in children with tuberculosis. Oxford University Press 2016-11-01 2016-09-30 /pmc/articles/PMC5064157/ /pubmed/27742638 http://dx.doi.org/10.1093/cid/ciw482 Text en © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, contact journals.permissions@oup.com. |
spellingShingle | A Development Paradigm for Novel Combination Regimens for Multidrug-Resistant and Drug-Susceptible Tuberculosis in Children: Flame for Work and Play Deshpande, Devyani Srivastava, Shashikant Pasipanodya, Jotam G. Bush, Stephen J. Nuermberger, Eric Swaminathan, Soumya Gumbo, Tawanda Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps |
title | Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps |
title_full | Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps |
title_fullStr | Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps |
title_full_unstemmed | Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps |
title_short | Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps |
title_sort | linezolid for infants and toddlers with disseminated tuberculosis: first steps |
topic | A Development Paradigm for Novel Combination Regimens for Multidrug-Resistant and Drug-Susceptible Tuberculosis in Children: Flame for Work and Play |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064157/ https://www.ncbi.nlm.nih.gov/pubmed/27742638 http://dx.doi.org/10.1093/cid/ciw482 |
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