Efficacy and Safety of Higher Doses of Levofloxacin for Multidrug-resistant Tuberculosis: A Randomized, Placebo-controlled Phase II Clinical Trial

Abstract

Rationale: Evaluation of optimal dosing has generally been inadequate during tuberculosis (TB) drug development. Fluoroquinolones are central to TB treatment. Objective: To determine the dose of levofloxacin needed to achieve maximal efficacy and acceptable safety and tolerability as part of a multidrug TB regimen. Methods: Opti-Q was an international, multicenter, randomized, placebo-controlled phase II trial. Eligible participants with TB resistant to isoniazid and rifampicin but susceptible to fluoroquinolones were randomized to receive one of four weight-adjusted once-daily doses of levofloxacin for 24 weeks (168 doses) alongside a multidrug regimen: 11 mg/kg (750 mg), 14 mg/kg (750 mg/1,000 mg), 17 mg/kg (1,000 mg/1,250 mg) or 20 mg/kg (1,250 mg/1,500 mg). The primary efficacy outcome was time to sputum culture conversion, and the primary safety outcome was grade ≥3 adverse events (AEs). Measurements and Main Results: A total of 111 participants were randomized from three sites in South Africa and Peru. Eighty-three (75%) had cavities on chest X-ray, 55 (50%) had a smear grading of 3+, and the median body mass index was 20.4 kg/m². Median levofloxacin areas under the curve (AUCs)/minimum inhibitory concentrations were 573, 633, 918, and 1,343 across the four treatment arms. There was no difference in time to culture conversion on solid or liquid media by treatment arm (stratified log-rank P = 0.282), by tertile of AUC/minimum inhibitory concentration (P = 0.350), or by dose received (P = 0.723); 69.3%, 74.8%, 70.6%, and 78.3% exhibited culture conversion after 8 weeks on solid media, respectively, across the treatment arms; along with 64.6%, 69.5%, 52.6%, and 69.6% on liquid culture. More participants experienced a grade 3-5 AE at higher doses (37.0% and 16.0% in the highest and lowest dose groups, respectively; P = 0.042, Cochran-Armitage test for trend) and higher tertiles of AUC (P = 0.011). Conclusions: As part of a multidrug regimen, doses of levofloxacin >1,000 mg/d resulted in greater exposures and increased frequency of AEs but did not result in faster time to sputum culture conversion. A dose of 1,000 mg/d can achieve the target exposure in nearly all adults and was well tolerated. Clinical trial registered with www.clinicaltrials.gov (NCT01918397).

Keywords: MDR-TB; TB; double-blind randomized controlled trial; levofloxacin.

Figure 1.

Consolidated Standards of Reporting Trials participant flow chart. *Other reasons for exclusion were: reason unavailable (n = 4), concurrent use of known QT-prolonging drugs (n = 3), quinolone use for 7 days within the past 30 days (n = 3), hemoglobin concentration <9.0 g/dL (n = 3), estimated serum creatine clearance <50 mg/dl (n = 2), no negative pregnancy test for woman of childbearing potential (n = 1), and patient not expected to survive for ≥6 months (n = 1). AUC = area under the curve; DST = drug susceptibility testing; ITT = intention to treat; MIC = minimum inhibitory concentration; mITT = modified intention to treat; PK = pharmacokinetic; TB = tuberculosis.

Figure 2.

Summary of levofloxacin minimum inhibitory concentration (MIC) (A and B) and AUC/MIC (C and D) done on agar plate (A and C, primary method) and broth microdilution (B and D). The diamond indicates the median, and error bars show the 25th and 75th percentiles. AUC = area under the curve.

Figure 3.

Plot of AUC against maximum Fridericia-corrected QT interval (QTcF) from visits at or after randomization. The horizontal dashed line shows the 500-ms threshold. The black square shows a single participant with a QTcF of >500 ms (grade 3 adverse event); QT prolongation was considered likely attributable to concomitant use of azithromycin, a protocol-prohibited drug with known QT prolongation potential. The adverse event resolved after discontinuation of azithromycin; levofloxacin was not discontinued. The line of best fit is shown (excluding the participant who received azithromycin) as a solid black line with 95% confidence region (gray shaded area). AUC = area under the curve.

Figure 4.

Kaplan-Meier of time to culture conversion in 7H11S (upper) and MGIT (lower) by allocated dose (left) and by tertile of AUC/MIC (right). AP = agar plate; AUC = area under the curve; MGIT = Mycobacteria Growth Indicator Tube; MIC = minimum inhibitory concentration.