Dataset Information

Effect of Linezolid plus Bedaquiline against Mycobacterium tuberculosis in Log Phase, Acid Phase, and Nonreplicating-Persister Phase in an In Vitro Assay.

ABSTRACT: Tuberculosis is the ninth-leading cause of death worldwide. Treatment success is approximately 80% for susceptible strains and decreases to 30% for extensively resistant strains. Shortening the therapy duration for Mycobacterium tuberculosis is a major goal, which can be attained with the use of combination therapy. However, the identification of the most promising combination is a challenge given the quantity of older and newer agents available. Our objective was to identify promising 2-drug combinations using an in vitro strategy to ultimately be tested in an in vitro hollow fiber infection model (HFIM) and in animal models. We studied the effect of the combination of linezolid (LZD) and bedaquiline (BDQ) on M. tuberculosis strain H37Rv in log- and acid-phase growth and M. tuberculosis strain 18b in log- and nonreplicating-persister-phase growth in a plate system containing a 9-by-8 matrix of concentrations of both drugs alone and in combinations. A characterization of the interaction as antagonistic, additive, or synergistic was performed using the Greco universal response surface approach (URSA) model. Our results indicate that the interaction between LZD and BDQ is additive for bacterial killing in both strains for both of the metabolic states tested. This prescreen strategy was suitable to identify LZD and BDQ as a promising combination to be further tested in the HFIM. The presence of nonoverlapping mechanisms of drug action suggests each drug in the combination will likely be effective in suppressing the emergence of resistance by M. tuberculosis to the companion drug, which holds promise in improving treatment outcomes for tuberculosis.

SUBMITTER: de Miranda Silva C

PROVIDER: S-EPMC6105798 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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Effect of Linezolid plus Bedaquiline against Mycobacterium tuberculosis in Log Phase, Acid Phase, and Nonreplicating-Persister Phase in an <i>In Vitro</i> Assay.

de Miranda Silva Carolina C Hajihosseini Amirhossein A Myrick Jenny J Nole Jocelyn J Louie Arnold A Schmidt Stephan S Drusano George L GL

Antimicrobial agents and chemotherapy 20180727 8

Tuberculosis is the ninth-leading cause of death worldwide. Treatment success is approximately 80% for susceptible strains and decreases to 30% for extensively resistant strains. Shortening the therapy duration for <i>Mycobacterium tuberculosis</i> is a major goal, which can be attained with the use of combination therapy. However, the identification of the most promising combination is a challenge given the quantity of older and newer agents available. Our objective was to identify promising 2- ...[more]

PMID: 29866874

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Project description:BackgroundThe bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear.MethodsWe enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated.ResultsA total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups.ConclusionsA total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).

Dataset Information

Effect of Linezolid plus Bedaquiline against Mycobacterium tuberculosis in Log Phase, Acid Phase, and Nonreplicating-Persister Phase in an In Vitro Assay.

Publications

Effect of Linezolid plus Bedaquiline against Mycobacterium tuberculosis in Log Phase, Acid Phase, and Nonreplicating-Persister Phase in an <i>In Vitro</i> Assay.

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