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

Antimicrobial Agents and Chemotherapy
Jansy SarathyVéronique Dartois

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 ...Continue Reading

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Citations

Apr 3, 2020·Clinical Microbiology Reviews·Jansy P Sarathy, Véronique Dartois
Aug 3, 2019·The European Respiratory Journal·Helen R StaggUNKNOWN London INH-R TB study group
Aug 19, 2020·Annual Review of Pharmacology and Toxicology·Jacqueline P ErnestRada M Savic
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Jun 23, 2020·Current Drug Targets·Priyanka P Majalekar, Pramodkumar J Shirote
Apr 3, 2021·Frontiers in Cellular and Infection Microbiology·Hee-Jeong YangLaura E Via
Feb 10, 2021·Antimicrobial Agents and Chemotherapy·Shashikant SrivastavaTawanda Gumbo
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Jul 7, 2021·Antimicrobial Agents and Chemotherapy·Oluwaseun EgbelowoVéronique Dartois
Jul 22, 2021·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Kendra K RadtkeAnthony J Garcia-Prats
Jul 13, 2021·Antimicrobial Agents and Chemotherapy·Jacqueline P ErnestVéronique Dartois

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Methods Mentioned

BETA
laser capture microdissection
biopsy
sedation
PCR

Clinical Trials Mentioned

NCT02193776

Software Mentioned

Analyst
GraphPad Prism
GraphPad
GranSim

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