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Analysis of Combination Drug Therapy to Develop Regimens with Shortened Duration of Treatment for Tuberculosis

George L. Drusano mail, Michael Neely, Michael Van Guilder, Alan Schumitzky, David Brown, Steven Fikes, Charles Peloquin, Arnold Louie

Abstract

Rationale

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.

Objectives

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.

Methods

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.

Results

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.

Discussion

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.

Citation: Drusano GL, Neely M, Van Guilder M, Schumitzky A, Brown D, et al. (2014) Analysis of Combination Drug Therapy to Develop Regimens with Shortened Duration of Treatment for Tuberculosis. PLoS ONE 9(7): e101311. doi:10.1371/journal.pone.0101311
Editor: Andres R. Floto, Cambridge University, United Kingdom
Received: February 7, 2014; Accepted: June 5, 2014; Published: July 8, 2014


Copyright: © 2014 Drusano et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was funded by National Institute of Allergy and Infectious Diseases (R01 AI079578); Bill and Melinda Gates Foundation TB Accelerator Program; Pfizer, Inc for the Hollow Fiber System evaluation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have no competing interests with respect to Pfizer, Inc. and this applies to employment, consultancy, patents, products in development, marketed products, etc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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