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

IF 19.3 1区医学 Q1 CRITICAL CARE MEDICINE American journal of respiratory and critical care medicine Pub Date : 2025-03-13 DOI:10.1164/rccm.202407-1354OC

Patrick Pj Phillips, Charles A Peloquin, Timothy R Sterling, Pawandeep Kaur, Andreas H Diacon, Eduardo Gotuzzo, Debra Benator, Robin M Warren, David Sikes, Leonid Lecca, Neel R Gandhi, Elizabeth M Streicher, Nancy Dianis, Kathleen Eisenach, Carole D Mitnick, C Robert Horsburgh

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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/m². 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. Clinical trial registration available at www.

Clinicaltrials: gov, ID: NCT01918397.

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来源期刊

American journal of respiratory and critical care medicine 医学-呼吸系统

CiteScore

27.30

自引率

4.50%

发文量

1313

审稿时长

3-6 weeks

期刊介绍： The American Journal of Respiratory and Critical Care Medicine focuses on human biology and disease, as well as animal studies that contribute to the understanding of pathophysiology and treatment of diseases that affect the respiratory system and critically ill patients. Papers that are solely or predominantly based in cell and molecular biology are published in the companion journal, the American Journal of Respiratory Cell and Molecular Biology. The Journal also seeks to publish clinical trials and outstanding review articles on areas of interest in several forms. The State-of-the-Art review is a treatise usually covering a broad field that brings bench research to the bedside. Shorter reviews are published as Critical Care Perspectives or Pulmonary Perspectives. These are generally focused on a more limited area and advance a concerted opinion about care for a specific process. Concise Clinical Reviews provide an evidence-based synthesis of the literature pertaining to topics of fundamental importance to the practice of pulmonary, critical care, and sleep medicine. Images providing advances or unusual contributions to the field are published as Images in Pulmonary, Critical Care, Sleep Medicine and the Sciences. A recent trend and future direction of the Journal has been to include debates of a topical nature on issues of importance in pulmonary and critical care medicine and to the membership of the American Thoracic Society. Other recent changes have included encompassing works from the field of critical care medicine and the extension of the editorial governing of journal policy to colleagues outside of the United States of America. The focus and direction of the Journal is to establish an international forum for state-of-the-art respiratory and critical care medicine.