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

Fluoroquinolones are central to TB treatment.

氟喹诺酮类药物在结核病治疗中占据核心地位。

Objective: To determine the dose of levofloxacin needed to achieve maximal efficacy and acceptable safety and tolerability as part of a multidrug TB regimen.

目的：确定利福平所需的剂量，以在多药物结核病方案中达到最大的疗效和可接受的安全性及耐受性。

Methods: Opti-Q was an international, multicenter, randomized, placebo-controlledphase 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).

方法：Opti-Q是一项国际多中心、随机、安慰剂对照的II期试验。符合条件的参与者患有对异烟肼和利福平耐药但对氟喹诺酮类药物敏感的结核病，被随机分配接受四种体重调整的每日一次利福平剂量之一，为期24周（共168剂），同时接受多药物方案：11 mg/kg（750 mg），14 mg/kg（750 mg/1,000 mg），17 mg/kg（1,000 mg/1,250 mg）或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).

主要疗效结果是痰培养转阴时间，主要安全结果是3级或以上不良事件（AEs）的发生。

Measurements and Main Results: A total of 111 participants were randomized from three sites in South Africa and Peru.

测量和主要结果：共有111名参与者在南非和秘鲁的三个地点进行了随机分组。

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.

83名（75%）患者胸部X光片显示有空洞，55名（50%）患者的痰涂片分级为3+，中位体重指数为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.

四个治疗组中，左氧氟沙星的曲线下面积（AUC）与最小抑菌浓度（MIC）的中位数分别为573、633、918和1,343。

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.

治疗组之间在固体或液体培养基上培养转阴时间上没有差异（分层对数秩检验P = 0.282），按最小抑菌浓度（AUC/MIC）的三分位数（P = 0.350）或按接受的剂量（P = 0.723）分层后也无差异；分别在固体培养基上，治疗组中有69.3%，74.8%，70.6%，和78.3%的患者在8周后表现出培养转阴；液体培养中则为64.6%，69.5%，52.6%，和69.6%。

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).

在较高剂量组中，更多参与者经历了3-5级不良事件（AE）（最高剂量组和最低剂量组分别为37.0%和16.0%；P = 0.042，Cochran-Armitage趋势检验），以及AUC的较高三分位数（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.

结论：作为多药物方案的一部分，每日剂量超过1000 mg的左氧氟沙星会导致更高的药物暴露和不良事件（AEs）发生频率增加，但并未导致痰培养转阴时间的加快。

A dose of 1,000 mg/d can achieve the target exposure in nearly all adults and was well tolerated.

每日1000 mg的剂量几乎可以在所有成人中达到目标暴露量，并且耐受性良好。

Clinical trial registered with www.clinicaltrials.gov (NCT01918397).

该临床试验已在www.clinicaltrials.gov注册（NCT01918397）。