Efficacy and Safety of Higher Doses of Levofloxacin for MDR-TB: A Randomized Placebo-controlled Phase 2 Trial

Patrick Pj Phillips, University of California, San Francisco, UCSF Center for Tuberculosis, San Francisco, United States; Patrick.Phillips@ucsf.edu.
Charles A. Peloquin, University of Florida, College of Pharmacy and Emerging Pathogens Institute, Gainesville, Florida, United States.
Timothy R. Sterling, Vanderbilt University Medical Center, Nashville, Tennessee, United States.
Pawandeep Kaur, Boston University School of Public Health, Department of Global Health, Boston, Massachusetts, United States.
Andreas H. Diacon, TASK, Science Office, Bellville, South Africa.
Eduardo Gotuzzo, Universidad Peruana Cayetano Heredia Instituto de Medicina Tropical Alexander von Humboldt, Lima, Peru.
Debra Benator, Washington DC VA Medical Center and the George Washington University, Washington DC, United States.
Robin M. Warren, MRC Centre for Molecular and Cellular Biology, Medical Biochemistry, Tygerberg, South Africa.
David Sikes, Centers for Disease Control and Prevention, Laboratory Branch, Division of Tuberculosis Elimination, Atlanta, Georgia, United States.
Leonid Lecca, Socios En Salud, Lima, Peru.
Neel R. Gandhi, Emory University, Atlanta, Georgia, United States.
Elizabeth M. Streicher, Stellenbosch University, Biomedical Science, Tygerberg, Western Cape, South Africa.
Nancy Dianis, Westat Inc, Rockville, Maryland, United States.
Kathleen Eisenach, TB or NOT TB Consulting, Little Rock, Alabama, United States.
Carole D. Mitnick, Harvard Medical School, Global Health and Social Medicine, Boston, Massachusetts, United States.
C Robert Horsburgh, Boston University School of Public Health, Department of Epidemiology, Boston, Massachusetts, United States.

Document Type

Journal Article

Publication Date

3-13-2025

Journal

American journal of respiratory and critical care medicine

DOI

10.1164/rccm.202407-1354OC

Keywords

MDR-TB TB; double-blind randomized controlled trial; levofloxacin

Abstract

BACKGROUND: Evaluation of optimal dosing has generally been inadequate during TB drug development. Fluoroquinolones are central to TB treatment. We aimed 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, multi-center, randomized, placebo-controlled, phase II trial. Eligible participants with TB resistant to isoniazid and rifampicin but susceptible to fluoroquinolones (MDR-TB) were randomized to receive one of four weight-adjusted once-daily doses of levofloxacin given for 24 weeks(168 doses): 11mg/kg(750mg), 14mg/kg(750mg/1000mg), 17 mg/kg(1000mg/1250mg) or 20mg/kg(1250mg/1500mg) alongside a multidrug regimen. The primary efficacy outcome was time to sputum culture conversion and the primary safety outcome was grade 3 or higher adverse events. FINDINGS: 111 participants were randomized from three sites in South Africa and Peru. 83(75%) had cavities on chest x-ray, 55(50%) had a smear grading of 3+, median BMI was 20.4 kg/m. Median levofloxacin AUC/MIC was 573, 633, 918 and 1343 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/MIC (p=0.350), or by dose received (p=0.723); 69.3%, 74.8%, 70.6% and 78.3% achieved culture conversion after 8 weeks on solid media respectively across the treatment arms; 64.6%, 69.5%, 52.6% and 69.6% in liquid culture. More participants experienced a grade 3-5 adverse event by dose (37.0% and 16.0% in the highest and lowest dose groups respectively, p=0.042, Cochran-Armitage test for trend) and by tertile of AUC (p=0.011). INTERPRETATION: As part of a multidrug regimen, doses of levofloxacin above 1000mg resulted in greater exposures and increased frequency of adverse events but did not result in faster time to sputum culture conversion. A dose of 1000mg daily can achieve the target exposure in nearly all adults and was well tolerated. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT0191839.

Department

Medicine

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