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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere02516-18
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number5
DOIs
StatePublished - May 1 2019
Externally publishedYes

Fingerprint

Fluoroquinolones
Tuberculosis
Multidrug-Resistant Tuberculosis
Levofloxacin
Population
Pharmacokinetics
Pharmaceutical Preparations
Drug Antagonism
Rabbits
Infection
Drug Interactions
Area Under Curve
Clinical Trials
Pharmacology
Lung
moxifloxacin
Growth

Keywords

  • Fluoroquinolone
  • Lesion-centric pharmacology
  • MDR-TB
  • Moxifloxacin
  • Tuberculosis

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Fluoroquinolone efficacy against tuberculosis is driven by penetration into lesions and activity against resident bacterial populations. / Sarathy, Jansy; Blanc, Landry; Alvarez-Cabrera, Nadine; O’Brien, Paul; Dias-Freedman, Isabela; Mina, Marizel; Zimmerman, Matthew; Kaya, Firat; Liang, Hsin Pin Ho; Prideaux, Brendan; Dietzold, Jillian; Salgame, Padmini; Savic, Radojka M.; Linderman, Jennifer; Kirschner, Denise; Pienaar, Elsje; Dartois, Véronique.

In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 5, e02516-18, 01.05.2019.

Research output: Contribution to journalArticle

Sarathy, J, Blanc, L, Alvarez-Cabrera, N, O’Brien, P, Dias-Freedman, I, Mina, M, Zimmerman, M, Kaya, F, Liang, HPH, Prideaux, B, Dietzold, J, Salgame, P, Savic, RM, Linderman, J, Kirschner, D, Pienaar, E & Dartois, V 2019, 'Fluoroquinolone efficacy against tuberculosis is driven by penetration into lesions and activity against resident bacterial populations', Antimicrobial Agents and Chemotherapy, vol. 63, no. 5, e02516-18. https://doi.org/10.1128/AAC.02516-18
Sarathy, Jansy ; Blanc, Landry ; Alvarez-Cabrera, Nadine ; O’Brien, Paul ; Dias-Freedman, Isabela ; Mina, Marizel ; Zimmerman, Matthew ; Kaya, Firat ; Liang, Hsin Pin Ho ; Prideaux, Brendan ; Dietzold, Jillian ; Salgame, Padmini ; Savic, Radojka M. ; Linderman, Jennifer ; Kirschner, Denise ; Pienaar, Elsje ; Dartois, Véronique. / Fluoroquinolone efficacy against tuberculosis is driven by penetration into lesions and activity against resident bacterial populations. In: Antimicrobial Agents and Chemotherapy. 2019 ; Vol. 63, No. 5.
@article{e3eb9d37bf804f33a0820c0067012fb3,
title = "Fluoroquinolone efficacy against tuberculosis is driven by penetration into lesions and activity against resident bacterial populations",
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.",
keywords = "Fluoroquinolone, Lesion-centric pharmacology, MDR-TB, Moxifloxacin, Tuberculosis",
author = "Jansy Sarathy and Landry Blanc and Nadine Alvarez-Cabrera and Paul O’Brien and Isabela Dias-Freedman and Marizel Mina and Matthew Zimmerman and Firat Kaya and Liang, {Hsin Pin Ho} and Brendan Prideaux and Jillian Dietzold and Padmini Salgame and Savic, {Radojka M.} and Jennifer Linderman and Denise Kirschner and Elsje Pienaar and V{\'e}ronique Dartois",
year = "2019",
month = "5",
day = "1",
doi = "10.1128/AAC.02516-18",
language = "English (US)",
volume = "63",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "5",

}

TY - JOUR

T1 - Fluoroquinolone efficacy against tuberculosis is driven by penetration into lesions and activity against resident bacterial populations

AU - Sarathy, Jansy

AU - Blanc, Landry

AU - Alvarez-Cabrera, Nadine

AU - O’Brien, Paul

AU - Dias-Freedman, Isabela

AU - Mina, Marizel

AU - Zimmerman, Matthew

AU - Kaya, Firat

AU - Liang, Hsin Pin Ho

AU - Prideaux, Brendan

AU - Dietzold, Jillian

AU - Salgame, Padmini

AU - Savic, Radojka M.

AU - Linderman, Jennifer

AU - Kirschner, Denise

AU - Pienaar, Elsje

AU - Dartois, Véronique

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

KW - Fluoroquinolone

KW - Lesion-centric pharmacology

KW - MDR-TB

KW - Moxifloxacin

KW - Tuberculosis

UR - http://www.scopus.com/inward/record.url?scp=85065315686&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065315686&partnerID=8YFLogxK

U2 - 10.1128/AAC.02516-18

DO - 10.1128/AAC.02516-18

M3 - Article

VL - 63

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 5

M1 - e02516-18

ER -