Phillips Patrick P J, Peloquin Charles A, Sterling Timothy R, Kaur Pawandeep, Diacon Andreas H, Gotuzzo Eduardo, Benator Debra, Warren Robin M, Sikes David, Lecca Leonid, Gandhi Neel R, Streicher Elizabeth M, Dianis Nancy, Eisenach Kathleen, Mitnick Carole D, Horsburgh C Robert
UCSF Center for Tuberculosis and.
Department of Medicine, University of California, San Francisco, San Francisco, California.
Am J Respir Crit Care Med. 2025 Jul;211(7):1277-1287. doi: 10.1164/rccm.202407-1354OC.
Evaluation of optimal dosing has generally been inadequate during tuberculosis (TB) drug development. Fluoroquinolones are central to TB treatment. To determine the dose of levofloxacin needed to achieve maximal efficacy and acceptable safety and tolerability as part of a multidrug TB regimen. 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). 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/m. 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 = 0.282), by tertile of AUC/minimum inhibitory concentration ( = 0.350), or by dose received ( = 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; = 0.042, Cochran-Armitage test for trend) and higher tertiles of AUC ( = 0.011). 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).
在结核病（TB）药物研发过程中，对最佳给药剂量的评估通常并不充分。氟喹诺酮类药物是结核病治疗的核心药物。为确定作为多药联合抗结核治疗方案一部分的左氧氟沙星剂量，以实现最大疗效以及可接受的安全性和耐受性。Opti-Q是一项国际多中心、随机、安慰剂对照的II期试验。符合条件的对异烟肼和利福平耐药但对氟喹诺酮类敏感的结核病患者被随机分配接受四种根据体重调整的每日一次剂量的左氧氟沙星之一，持续24周（168剂），同时接受多药治疗方案：11mg/kg（750mg）、14mg/kg（750mg/1000mg）、17mg/kg（1000mg/1250mg）或20mg/kg（1250mg/1500mg）。主要疗效指标是痰培养转阴时间，主要安全性指标是≥3级不良事件（AE）。共有111名参与者从南非和秘鲁的三个地点随机分组。83名（75%）胸部X线检查有空洞，55名（50%）涂片分级为3+，体重指数中位数为20.4kg/m²。四个治疗组的左氧氟沙星曲线下面积（AUC）/最低抑菌浓度中位数分别为573、633、918和1343。各治疗组在固体或液体培养基上培养转阴时间无差异（分层对数秩检验=0.282），按AUC/最低抑菌浓度三分位数分组无差异（=0.
