Fluoroquinolone efficacy against tuberculosis is driven by penetration into lesions and activity against resident bacterial populations [Pharmacology]

Fluoroquinolones are the pillar of multi-drug resistant tuberculosis (MDR-TB) treatment, with either moxifloxacin, levofloxacin or gatifloxacin being prescribed to MDR-TB patients. Recently, several clinical trials of 'universal' drug regimens, aiming to treat drug susceptible and resistant TB, have included a fluoroquinolone. In the absence of clinical data comparing their side-by-side efficacy 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 plasma concentrations and potency measured in standard growth inhibition assays, and to determine 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. Based on these metrics, moxifloxacin emerged with a clear advantage, whereas plasma-based PK/PD favored levofloxacin (plasma AUC/MIC range is 46-86 for moxifloxacin and 74-258 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 sterilizing cellular and necrotic lesions. Collectively, these results show that PK-PD at the site of infection is 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.

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