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Author Notes:

E-mail address: peloquin@cop.ufl.edu

We thank people who provided assistance in data collection, entry, cleaning, and provided feedback on our analysis, including Jürgen Bulitta, Carolina De Miranda Silva, George Drusano, Adam M. Dzedzy, Eric Egelund, Amirhossein Hajihosseini, Farzaneh Maleki, Toni Tablante, and Yang Zhao from the University of Florida; Kelli Christian, Nia Deese, Sammy Huddleston, Lobsang Tsering, and Brandon VanDeman from University of Texas at Tyler; Maria E. Gomez and Jerry Jean Stambaugh from the Florida Department of Health; Lacie J. McKamey from Novant Health Presbyterian Medical Center; Robert Bruce and Jessica Moro from the University of Georgia at Athens; and Amelia Blumberg, Amber Choquette-Deutschle, Su Jin Joo, Jennifer Kim, Taylor Osborne, Sarah E. Smith, and Tanushree Soni from Emory University.

We also thank the clinicians, staff, and patients from the participating TB centers.

There are no conflicts of interest to disclose.

Subjects:

Research Funding:

This study was supported in part by the National Institutes of Health (D43TW007124, U01 AI115594, and T32 AI007046), the National Institute of Allergy and Infectious Diseases (K23 AI103044, R21 AI122001, NO1 AI95383, and NO1 AI70022), and the International Science and Technology Center (G-2200).

Funding was also provided in part by the Bill and Melinda Gates Foundation via a subaward of grant OPP1031105, awarded to the Critical Path to TB Regimens (CPTR) Initiative at the Critical Path Institute (C-Path).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Microbiology
  • Pharmacology & Pharmacy
  • Monte Carlo simulation
  • fluoroquinolones
  • multidrug resistance
  • pharmacodynamics
  • population pharmacokinetics
  • tuberculosis
  • POPULATION PHARMACOKINETICS
  • MYCOBACTERIUM-TUBERCULOSIS
  • COMPARATIVE ROLES
  • LEVOFLOXACIN
  • MOXIFLOXACIN
  • OFLOXACIN
  • MODEL

Fluoroquinolones in Drug-Resistant Tuberculosis: Culture Conversion and Pharmacokinetic/Pharmacodynamic Target Attainment To Guide Dose Selection

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Journal Title:

Antimicrobial Agents and Chemotherapy

Volume:

Volume 63, Number 7

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Type of Work:

Article | Final Publisher PDF

Abstract:

Fluoroquinolones are group A drugs in tuberculosis guidelines. We aim to compare the culture conversion between new-generation (levofloxacin and moxifloxacin) and old-generation (ciprofloxacin and ofloxacin) fluoroquinolones, develop pharmacokinetic models, and calculate target attainment for levofloxacin and moxifloxacin. We included three U.S. tuberculosis centers. Patients admitted between 1984 and 2015, infected with drug-resistant tuberculosis, and who had received fluoroquinolones for 28 days were included. Demographics, sputum cultures and susceptibility, treatment regimens, and serum concentrations were collected. A time-to-event analysis was conducted, and Cox proportional hazards model was used to compare the time to culture conversion. Using additional data from ongoing studies, pharmacokinetic modelling and Monte Carlo simulations were performed to assess target attainment for different doses. Overall, 124 patients received fluoroquinolones. The median age was 40 years, and the median weight was 60 kg. Fifty-six patients (45%) received old-generation fluoroquinolones. New-generation fluoroquinolones showed a faster time to culture conversion (median 16 versus 40 weeks, P 0.012). After adjusting for isoniazid and clofazimine treatment, patients treated with new-generation fluoroquinolones were more likely to have culture conversion (adjusted hazards ratio, 2.16 [95% confidence interval, 1.28 to 3.64]). We included 178 patients in the pharmacokinetic models. Levofloxacin and moxifloxacin were best described by a one-compartment model with first-order absorption and elimination. At least 1,500 to 1,750 mg levofloxacin and 800 mg moxifloxacin may be needed for maximum kill at the current epidemiologic cutoff values. In summary, new-generation fluoroquinolones showed faster time to culture conversion compared to the old generation. For optimal target attainment at the current MIC values, higher doses of levofloxacin and moxifloxacin may be needed.

Copyright information:

Copyright © 2019 Al-Shaer et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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