An optimized background regimen design to evaluate the contribution of levofloxacin to multidrug-resistant tuberculosis treatment regimens: study protocol for a randomized controlled trial

• Type of Material: Article
• Authors: Tara C. Bouton, Brown University; Patrick P. J. Phillips, University College London; Carole D. Mitnick, Harvard Medical School; Charles A. Peloquin, University of Florida; Kathleen Eisenach, University of Arkansas for Medical Sciences; Ramonde F. Patientia, Stellenbosch University; Leonid Lecca, Socios en Salud Sucursal Peru; Eduardo Gotuzzo, Universidad Peruana Cayetano Heredia; Neel Gandhi, Emory University; Donna Butler, WESTAT Corp; Andreas H. Diacon, Stellenbosch University; Bruno Martel, Socios en Salud Sucursal Peru; Juan Santillan, Universidad Peruana Cayetano Heredia; Kathleen Robergeau Hunt, WESTAT Corp; Dante Vargas, Socios en Salud Sucursal Peru; Florian von Groote-Bidlingmaier, Stellenbosch University; Carlos Seas, Universidad Peruana Cayetano Heredia; Nancy Dianis, WESTAT Corp; Antonio Moreno-Martinez, TB Investigation Unit of Barcelona; C. Robert Horsburgh, Boston University
• Language: English
• Date: 2017-11-25
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13063-017-2292-x
• Title of Journal or Parent Work: Trials
• ISSN: 1745-6215
• Volume: 18
• Issue: 1
• Start Page: 563
• End Page: 563
• Grant/Funding Information: NIH Grant AI100805 and CDC contract 200750.
• Keywords: CULTURE CONVERSION; MOXIFLOXACIN; Life Sciences & Biomedicine; PULMONARY TUBERCULOSIS; Fluoroquinolones; Research & Experimental Medicine; PHARMACOKINETICS; Science & Technology; FLUOROQUINOLONES; RISK; Optimized background regimen; Levofloxacin; Multidrug resistant tuberculosis; Medicine, Research & Experimental
• Research Categories: Health Sciences, Epidemiology; Health Sciences, Public Health

Abstract

Background: Current guidelines for treatment of multidrug-resistant tuberculosis (MDR-TB) are largely based on expert opinion and observational data. Fluoroquinolones remain an essential part of MDR-TB treatment, but the optimal dose of fluoroquinolones as part of the regimen has not been defined. Methods/design: We designed a randomized, blinded, phase II trial in MDR-TB patients comparing across levofloxacin doses of 11, 14, 17 and 20 mg/kg/day, all within an optimized background regimen. We assess pharmacokinetics, efficacy, safety and tolerability of regimens containing each of these doses. The primary efficacy outcome is time to culture conversion over the first 6 months of treatment. The study aims to determine the area under the curve (AUC) of the levofloxacin serum concentration in the 24 hours after dosing divided by the minimal inhibitory concentration of the patient's Mycobacterium tuberculosis isolate that inhibits > 90% of organisms (AUC/MIC) that maximizes efficacy and the AUC that maximizes safety and tolerability in the context of an MDR-TB treatment regimen. Discussion: Fluoroquinolones are an integral part of recommended MDR-TB regimens. Little is known about how to optimize dosing for efficacy while maintaining acceptable toxicity. This study will provide evidence to support revised dosing guidelines for the use of levofloxacin as part of combination regimens for treatment of MDR-TB. The novel methodology can be adapted to elucidate the effect of other single agents in multidrug antibiotic treatment regimens. Trial registration: ClinicalTrials.gov, NCT01918397. Registered on 5 August 201 3.