Analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis.

<h4>Rationale</h4>Tuberculosis remains a worldwide problem, particularly with the advent of multi-drug resistance. Shortening therapy duration for Mycobacterium tuberculosis is a major goal, requiring generation of optimal kill rate and resistance-suppression. Combination therapy is requ...

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Autores principales:	George L Drusano, Michael Neely, Michael Van Guilder, Alan Schumitzky, David Brown, Steven Fikes, Charles Peloquin, Arnold Louie
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1256c6075bff4f35aa29eb4d2784a757
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spelling	oai:doaj.org-article:1256c6075bff4f35aa29eb4d2784a7572021-11-25T06:09:22ZAnalysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis.1932-620310.1371/journal.pone.0101311https://doaj.org/article/1256c6075bff4f35aa29eb4d2784a7572014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25003557/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Rationale</h4>Tuberculosis remains a worldwide problem, particularly with the advent of multi-drug resistance. Shortening therapy duration for Mycobacterium tuberculosis is a major goal, requiring generation of optimal kill rate and resistance-suppression. Combination therapy is required to attain the goal of shorter therapy.<h4>Objectives</h4>Our objective was to identify a method for identifying optimal combination chemotherapy. We developed a mathematical model for attaining this end. This is accomplished by identifying drug effect interaction (synergy, additivity, antagonism) for susceptible organisms and subpopulations resistant to each drug in the combination.<h4>Methods</h4>We studied the combination of linezolid plus rifampin in our hollow fiber infection model. We generated a fully parametric drug effect interaction mathematical model. The results were subjected to Monte Carlo simulation to extend the findings to a population of patients by accounting for between-patient variability in drug pharmacokinetics.<h4>Results</h4>All monotherapy allowed emergence of resistance over the first two weeks of the experiment. In combination, the interaction was additive for each population (susceptible and resistant). For a 600 mg/600 mg daily regimen of linezolid plus rifampin, we demonstrated that >50% of simulated subjects had eradicated the susceptible population by day 27 with the remaining organisms resistant to one or the other drug. Only 4% of patients had complete organism eradication by experiment end.<h4>Discussion</h4>These data strongly suggest that in order to achieve the goal of shortening therapy, the original regimen may need to be changed at one month to a regimen of two completely new agents with resistance mechanisms independent of the initial regimen. This hypothesis which arose from the analysis is immediately testable in a clinical trial.George L DrusanoMichael NeelyMichael Van GuilderAlan SchumitzkyDavid BrownSteven FikesCharles PeloquinArnold LouiePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e101311 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q George L Drusano Michael Neely Michael Van Guilder Alan Schumitzky David Brown Steven Fikes Charles Peloquin Arnold Louie Analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis.
description	<h4>Rationale</h4>Tuberculosis remains a worldwide problem, particularly with the advent of multi-drug resistance. Shortening therapy duration for Mycobacterium tuberculosis is a major goal, requiring generation of optimal kill rate and resistance-suppression. Combination therapy is required to attain the goal of shorter therapy.<h4>Objectives</h4>Our objective was to identify a method for identifying optimal combination chemotherapy. We developed a mathematical model for attaining this end. This is accomplished by identifying drug effect interaction (synergy, additivity, antagonism) for susceptible organisms and subpopulations resistant to each drug in the combination.<h4>Methods</h4>We studied the combination of linezolid plus rifampin in our hollow fiber infection model. We generated a fully parametric drug effect interaction mathematical model. The results were subjected to Monte Carlo simulation to extend the findings to a population of patients by accounting for between-patient variability in drug pharmacokinetics.<h4>Results</h4>All monotherapy allowed emergence of resistance over the first two weeks of the experiment. In combination, the interaction was additive for each population (susceptible and resistant). For a 600 mg/600 mg daily regimen of linezolid plus rifampin, we demonstrated that >50% of simulated subjects had eradicated the susceptible population by day 27 with the remaining organisms resistant to one or the other drug. Only 4% of patients had complete organism eradication by experiment end.<h4>Discussion</h4>These data strongly suggest that in order to achieve the goal of shortening therapy, the original regimen may need to be changed at one month to a regimen of two completely new agents with resistance mechanisms independent of the initial regimen. This hypothesis which arose from the analysis is immediately testable in a clinical trial.
format	article
author	George L Drusano Michael Neely Michael Van Guilder Alan Schumitzky David Brown Steven Fikes Charles Peloquin Arnold Louie
author_facet	George L Drusano Michael Neely Michael Van Guilder Alan Schumitzky David Brown Steven Fikes Charles Peloquin Arnold Louie
author_sort	George L Drusano
title	Analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis.
title_short	Analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis.
title_full	Analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis.
title_fullStr	Analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis.
title_full_unstemmed	Analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis.
title_sort	analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/1256c6075bff4f35aa29eb4d2784a757
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Analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis.

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