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PLoS One. 2014 Jul 8;9(7):e101311. doi: 10.1371/journal.pone.0101311. eCollection 2014.

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

Author information

1
Institute for Therapeutic Innovation, College of Medicine, University of Florida, Lake Nona, Florida, United States of America.
2
Laboratory of Applied Pharmacokinetics, School of Medicine, University of Southern California, Los Angeles, California, United States of America.
3
Infectious Diseases PK Laboratory, College of Pharmacy, University of Florida, Gainesville, Florida, United States of America.

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.

PMID:
25003557
PMCID:
PMC4086932
DOI:
10.1371/journal.pone.0101311
[Indexed for MEDLINE]
Free PMC Article

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