Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations
| Autor: | Hsin-Pin Ho Liang, Padmini Salgame, Brendan Prideaux, Firat Kaya, Jansy Sarathy, Marizel Mina, Jillian Dietzold, Denise E. Kirschner, Nadine Alvarez-Cabrera, Véronique Dartois, Landry Blanc, Paul O'Brien, Radojka M. Savic, Elsje Pienaar, Isabela Dias-Freedman, Matthew D. Zimmerman, Jennifer J. Linderman |
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| Rok vydání: | 2019 |
| Předmět: |
Moxifloxacin
Antitubercular Agents Levofloxacin Pharmacology Efficacy Tandem Mass Spectrometry Tuberculosis Multidrug-Resistant Medicine heterocyclic compounds Pharmacology (medical) 0303 health sciences Pharmacology and Pharmaceutical Sciences Multidrug-Resistant lesion-centric pharmacology 3. Good health Infectious Diseases tuberculosis Medical Microbiology Rabbits Infection medicine.drug Fluoroquinolones Tuberculosis Clinical Trials and Supportive Activities MDR-TB Microbial Sensitivity Tests fluoroquinolone Microbiology Vaccine Related 03 medical and health sciences Rare Diseases Pharmacokinetics Clinical Research Biodefense Potency Animals 030304 developmental biology 030306 microbiology business.industry Prevention bacterial infections and mycoses Editor's Pick medicine.disease Gatifloxacin Good Health and Well Being Emerging Infectious Diseases Orphan Drug Pharmacodynamics Antimicrobial Resistance business |
| Zdroj: | Antimicrobial agents and chemotherapy, vol 63, iss 5 Antimicrobial Agents and Chemotherapy |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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