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Editor's Pick Pharmacology

Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations

Jansy Sarathy, Landry Blanc, Nadine Alvarez-Cabrera, Paul O’Brien, Isabela Dias-Freedman, Marizel Mina, Matthew Zimmerman, Firat Kaya, Hsin-Pin Ho Liang, Brendan Prideaux, Jillian Dietzold, Padmini Salgame, Radojka M. Savic, Jennifer Linderman, Denise Kirschner, Elsje Pienaar, Véronique Dartois
Jansy Sarathy
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Landry Blanc
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Nadine Alvarez-Cabrera
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Paul O’Brien
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Isabela Dias-Freedman
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Marizel Mina
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Matthew Zimmerman
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Firat Kaya
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Hsin-Pin Ho Liang
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Brendan Prideaux
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Jillian Dietzold
bDepartment of Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Padmini Salgame
bDepartment of Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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Radojka M. Savic
cDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
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Jennifer Linderman
dDepartment of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA
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Denise Kirschner
eDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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Elsje Pienaar
dDepartment of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA
eDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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Véronique Dartois
aPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
bDepartment of Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
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DOI: 10.1128/AAC.02516-18
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ABSTRACT

Fluoroquinolones represent the pillar of multidrug-resistant tuberculosis (MDR-TB) treatment, with moxifloxacin, levofloxacin, or gatifloxacin being prescribed to MDR-TB patients. Recently, several clinical trials of “universal” drug regimens, aiming to treat drug-susceptible and drug-resistant TB, have included a fluoroquinolone. In the absence of clinical data comparing their side-by-side efficacies in controlled MDR-TB trials, a pharmacological rationale is needed to guide the selection of the most efficacious fluoroquinolone. The present studies were designed to test the hypothesis that fluoroquinolone concentrations (pharmacokinetics) and activity (pharmacodynamics) at the site of infection are better predictors of efficacy than the plasma concentrations and potency measured in standard growth inhibition assays and are better suited to determinations of whether one of the fluoroquinolones outperforms the others in rabbits with active TB. We first measured the penetration of these fluoroquinolones in lung lesion compartments, and their potency against bacterial populations that reside in each compartment, to compute lesion-centric pharmacokinetic-pharmacodynamic (PK/PD) parameters. PK modeling methods were used to quantify drug penetration from plasma to tissues at human-equivalent doses. On the basis of these metrics, moxifloxacin emerged with a clear advantage, whereas plasma-based PK/PD favored levofloxacin (the ranges of the plasma AUC/MIC ratio [i.e., the area under the concentration-time curve over 24 h in the steady state divided by the MIC] are 46 to 86 for moxifloxacin and 74 to 258 for levofloxacin). A comparative efficacy trial in the rabbit model of active TB demonstrated the superiority of moxifloxacin in reducing bacterial burden at the lesion level and in sterilizing cellular and necrotic lesions. Collectively, these results show that PK/PD data obtained at the site of infection represent an adequate predictor of drug efficacy against TB and constitute the baseline required to explore synergies, antagonism, and drug-drug interactions in fluoroquinolone-containing regimens.

FOOTNOTES

    • Received 30 November 2018.
    • Returned for modification 21 January 2019.
    • Accepted 17 February 2019.
    • Accepted manuscript posted online 25 February 2019.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.02516-18.

  • Copyright © 2019 Sarathy et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations
Jansy Sarathy, Landry Blanc, Nadine Alvarez-Cabrera, Paul O’Brien, Isabela Dias-Freedman, Marizel Mina, Matthew Zimmerman, Firat Kaya, Hsin-Pin Ho Liang, Brendan Prideaux, Jillian Dietzold, Padmini Salgame, Radojka M. Savic, Jennifer Linderman, Denise Kirschner, Elsje Pienaar, Véronique Dartois
Antimicrobial Agents and Chemotherapy Apr 2019, 63 (5) e02516-18; DOI: 10.1128/AAC.02516-18

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Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations
Jansy Sarathy, Landry Blanc, Nadine Alvarez-Cabrera, Paul O’Brien, Isabela Dias-Freedman, Marizel Mina, Matthew Zimmerman, Firat Kaya, Hsin-Pin Ho Liang, Brendan Prideaux, Jillian Dietzold, Padmini Salgame, Radojka M. Savic, Jennifer Linderman, Denise Kirschner, Elsje Pienaar, Véronique Dartois
Antimicrobial Agents and Chemotherapy Apr 2019, 63 (5) e02516-18; DOI: 10.1128/AAC.02516-18
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KEYWORDS

MDR-TB
fluoroquinolone
lesion-centric pharmacology
moxifloxacin
tuberculosis

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