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

Antimicrob Agents Chemother. 2019 Jun 24;63(7):e00279-19. doi: 10.1128/AAC.00279-19. Print 2019 Jul.

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.

Keywords: Monte Carlo simulation; fluoroquinolones; multidrug resistance; pharmacodynamics; population pharmacokinetics; tuberculosis.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antitubercular Agents / administration & dosage*
  • Antitubercular Agents / pharmacokinetics*
  • Ciprofloxacin / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Female
  • Fluoroquinolones / administration & dosage
  • Fluoroquinolones / pharmacokinetics*
  • Humans
  • Levofloxacin / administration & dosage
  • Levofloxacin / pharmacokinetics
  • Male
  • Microbial Sensitivity Tests
  • Middle Aged
  • Models, Biological
  • Moxifloxacin / administration & dosage
  • Moxifloxacin / pharmacokinetics
  • Ofloxacin / pharmacokinetics
  • Retrospective Studies
  • Tuberculosis, Multidrug-Resistant / drug therapy*
  • Tuberculosis, Multidrug-Resistant / microbiology
  • Tuberculosis, Pulmonary / drug therapy
  • Tuberculosis, Pulmonary / microbiology
  • Young Adult

Substances

  • Antitubercular Agents
  • Fluoroquinolones
  • Ciprofloxacin
  • Levofloxacin
  • Ofloxacin
  • Moxifloxacin