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

Abstract

BackgroundCurrent 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/designWe 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.DiscussionFluoroquinolones 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 registrationClinicalTrials.gov, NCT01918397. Registered on 5 August 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-2292-x) contains supplementary material, which is available to authorized users.

The present state of the tuberculosis drug development pipeline

“…The previously approved fluoroquinolones, levofloxacin and moxifloxacin, are now being evaluated in phase 2 trials designed at improving existing regimens for drug resistant disease. Three studies (MDR-END, OptiQ, and NEXT) containing levofloxacin (in combination with other drugs) in one or more of the treatment arms are active and recruiting patients with MDRTB [49]. All of these will be evaluating treatment success following 9–24 months of treatment with anticipated completion in 2019.…”

Increased Doses Lead to Higher Drug Exposures of Levofloxacin for Treatment of Tuberculosis

“…Other inclusion criteria included known HIV status (regardless of result and therapy), a weight of Ն40 kg, and a Karnofsky Performance Status score of Ͼ60. Full details of eligibility criteria and trial design are available in the published protocol (10). All study treatment doses were directly observed.…”

Towards individualised treatment of tuberculosis

“…Even if dysglycaemia has not been an issue for levofloxacin as for gatifloxacin, and there may be less problems than for moxifloxacin with regard to QT-prolongation and drug-drug interactions (192), less is known about tolerability and safety of higher than recommended doses of levofloxacin (70,193). A randomised ongoing dose-ranging study (OptiQ trial; NCT01918397) evaluating the contribution of levofloxacin to MDR-TB treatment, will present data on correlations of levofloxacin dose increments (11,14,17 and 20 mg/kg) and potential favourable treatment outcome without increased risk of toxicity (194). Until more evidence on safety and clinical outcome data is available, it may be wise to avoid using levofloxacin in case of low-level resistance mediated by mutations such as A90V, S91P or D94A, even if the MIC value is in the suggested ATU that technically is just below the current critical concentration (70,92).…”