Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy

ABSTRACT Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis. Clinically relevant linezolid regim...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Ashley N. Brown, George L. Drusano, Jonathan R. Adams, Jaime L. Rodriquez, Kalyani Jambunathan, Dodge L. Baluya, David L. Brown, Awewura Kwara, Jon C. Mirsalis, Richard Hafner, Arnold Louie
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0a8207688af7408c9f377cb7543d327b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:0a8207688af7408c9f377cb7543d327b
record_format	dspace
spelling	oai:doaj.org-article:0a8207688af7408c9f377cb7543d327b2021-11-15T15:41:24ZPreclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy10.1128/mBio.01741-152150-7511https://doaj.org/article/0a8207688af7408c9f377cb7543d327b2015-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01741-15https://doaj.org/toc/2150-7511ABSTRACT Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis. Clinically relevant linezolid regimens were simulated in the in vitro hollow-fiber infection model (HFIM) system to identify the linezolid therapies that minimize toxicity, maximize antibacterial activity, and prevent drug resistance. Linezolid inhibited mitochondrial proteins in an exposure-dependent manner, with toxicity being driven by trough concentrations. Once-daily linezolid killed M. tuberculosis in an exposure-dependent manner. Further, 300 mg linezolid given every 12 hours generated more bacterial kill but more toxicity than 600 mg linezolid given once daily. None of the regimens prevented linezolid resistance. These findings show that with linezolid monotherapy, a clear tradeoff exists between antibacterial activity and toxicity. By identifying the pharmacokinetic parameters linked with toxicity and antibacterial activity, these data can provide guidance for clinical trials evaluating linezolid in multidrug antituberculosis regimens. IMPORTANCE The emergence and spread of multidrug-resistant M. tuberculosis are a major threat to global public health. Linezolid is an oxazolidinone that is licensed for human use and has demonstrated potent activity against multidrug-resistant M. tuberculosis. However, long-term use of linezolid has shown to be toxic in patients, often resulting in thrombocytopenia. We examined therapeutic linezolid regimens in an in vitro model to characterize the exposure-toxicity relationship. The antibacterial activity against M. tuberculosis was also assessed for these regimens, including the amplification or suppression of resistant mutant subpopulations by the chosen regimen. Higher exposures of linezolid resulted in greater antibacterial activity, but with more toxicity and, for some regimens, increased resistant mutant subpopulation amplification, illustrating the trade-off between activity and toxicity. These findings can provide valuable insight for designing optimal dosage regimens for linezolid that are part of the long combination courses used to treat multidrug-resistant M. tuberculosis.Ashley N. BrownGeorge L. DrusanoJonathan R. AdamsJaime L. RodriquezKalyani JambunathanDodge L. BaluyaDavid L. BrownAwewura KwaraJon C. MirsalisRichard HafnerArnold LouieAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 6 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Ashley N. Brown George L. Drusano Jonathan R. Adams Jaime L. Rodriquez Kalyani Jambunathan Dodge L. Baluya David L. Brown Awewura Kwara Jon C. Mirsalis Richard Hafner Arnold Louie Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy
description	ABSTRACT Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis. Clinically relevant linezolid regimens were simulated in the in vitro hollow-fiber infection model (HFIM) system to identify the linezolid therapies that minimize toxicity, maximize antibacterial activity, and prevent drug resistance. Linezolid inhibited mitochondrial proteins in an exposure-dependent manner, with toxicity being driven by trough concentrations. Once-daily linezolid killed M. tuberculosis in an exposure-dependent manner. Further, 300 mg linezolid given every 12 hours generated more bacterial kill but more toxicity than 600 mg linezolid given once daily. None of the regimens prevented linezolid resistance. These findings show that with linezolid monotherapy, a clear tradeoff exists between antibacterial activity and toxicity. By identifying the pharmacokinetic parameters linked with toxicity and antibacterial activity, these data can provide guidance for clinical trials evaluating linezolid in multidrug antituberculosis regimens. IMPORTANCE The emergence and spread of multidrug-resistant M. tuberculosis are a major threat to global public health. Linezolid is an oxazolidinone that is licensed for human use and has demonstrated potent activity against multidrug-resistant M. tuberculosis. However, long-term use of linezolid has shown to be toxic in patients, often resulting in thrombocytopenia. We examined therapeutic linezolid regimens in an in vitro model to characterize the exposure-toxicity relationship. The antibacterial activity against M. tuberculosis was also assessed for these regimens, including the amplification or suppression of resistant mutant subpopulations by the chosen regimen. Higher exposures of linezolid resulted in greater antibacterial activity, but with more toxicity and, for some regimens, increased resistant mutant subpopulation amplification, illustrating the trade-off between activity and toxicity. These findings can provide valuable insight for designing optimal dosage regimens for linezolid that are part of the long combination courses used to treat multidrug-resistant M. tuberculosis.
format	article
author	Ashley N. Brown George L. Drusano Jonathan R. Adams Jaime L. Rodriquez Kalyani Jambunathan Dodge L. Baluya David L. Brown Awewura Kwara Jon C. Mirsalis Richard Hafner Arnold Louie
author_facet	Ashley N. Brown George L. Drusano Jonathan R. Adams Jaime L. Rodriquez Kalyani Jambunathan Dodge L. Baluya David L. Brown Awewura Kwara Jon C. Mirsalis Richard Hafner Arnold Louie
author_sort	Ashley N. Brown
title	Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy
title_short	Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy
title_full	Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy
title_fullStr	Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy
title_full_unstemmed	Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy
title_sort	preclinical evaluations to identify optimal linezolid regimens for tuberculosis therapy
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/0a8207688af7408c9f377cb7543d327b
work_keys_str_mv	AT ashleynbrown preclinicalevaluationstoidentifyoptimallinezolidregimensfortuberculosistherapy AT georgeldrusano preclinicalevaluationstoidentifyoptimallinezolidregimensfortuberculosistherapy AT jonathanradams preclinicalevaluationstoidentifyoptimallinezolidregimensfortuberculosistherapy AT jaimelrodriquez preclinicalevaluationstoidentifyoptimallinezolidregimensfortuberculosistherapy AT kalyanijambunathan preclinicalevaluationstoidentifyoptimallinezolidregimensfortuberculosistherapy AT dodgelbaluya preclinicalevaluationstoidentifyoptimallinezolidregimensfortuberculosistherapy AT davidlbrown preclinicalevaluationstoidentifyoptimallinezolidregimensfortuberculosistherapy AT awewurakwara preclinicalevaluationstoidentifyoptimallinezolidregimensfortuberculosistherapy AT joncmirsalis preclinicalevaluationstoidentifyoptimallinezolidregimensfortuberculosistherapy AT richardhafner preclinicalevaluationstoidentifyoptimallinezolidregimensfortuberculosistherapy AT arnoldlouie preclinicalevaluationstoidentifyoptimallinezolidregimensfortuberculosistherapy
_version_	1718427686545653760

Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy

Ejemplares similares