Moxifloxacin increased the proportion of tuberculosis cultures converting to negative at 8 weeks by nearly 20% when added to the usual first-line triple-drug treatment regimen in a single-center, phase II trial in Brazil.

Compared with control patients who received ethambutol, more patients who received moxifloxacin were culture negative after just 1 week of treatment. While the findings don’t prove that moxifloxacin can shorten overall TB treatment times, “our data add to a growing body of evidence that suggests that moxifloxacin could shorten tuberculosis treatment by initially eradicating a greater number of organisms and improving the sterilizing activity of combination drug regimens,” Dr. Marcus B. Conde and his associates wrote in the April 4 issue of the Lancet (2009;373:1183-9).

At baseline, the study’s 146 patients were all sputum smear–positive for Mycobacterium tuberculosis that was not resistant to isoniazid, rifampicin, or ethambutol. They received recommended doses of isoniazid, rifampicin, and pyrazinamide by directly observed treatment and were randomized to receive also either 400 mg moxifloxacin with an ethambutol placebo or 15-20 mg/kg ethambutol plus moxifloxacin placebo.

Negative sputum cultures were achieved at week 8 by 59 of the 74 patients in the moxifloxacin group (79.7%), compared with 45 of 72 with ethambutol (62.5%), a difference of 17.2%. Among only the subjects who had sputum culture data at 8 weeks, those proportions were 59 of 64 with moxifloxacin (92.1%), versus 45 of 61 controls (73.7%), for a difference of 18.4%. (All missing data were deemed as treatment failures in the intent-to-treat analysis.)

After 1 week, 9 of 69 in the moxifloxacin group (13%) had negative sputum cultures, compared with 2 of the 68 ethambutol subjects (3%). At every week after enrollment, patients assigned to moxifloxacin had a higher rate of culture conversion than did those assigned to ethambutol, and the differences were significant at every time point except for weeks 6 and 7.

The median time to consistently negative cultures was 35.0 days in the treatment group, compared with 48.5 days for the control group, said Dr. Conde of Federal University of Rio de Janeiro and his associates, who included researchers from his own institution and from the Johns Hopkins University, Baltimore.

Adverse events did not differ by treatment group. There were eight serious events in each group, in a total of 12 patients. Only one event, a grade 3 cutaneous reaction, was deemed to be related to the study drug – and that was to ethambutol, not moxifloxacin. Only five patients discontinued treatment because of toxic effects, and no clinically or statistically significant changes in the QTc interval were recorded in patients in either group.

Seven patients had recurrence of TB – three in the moxifloxacin group at 11, 16, and 27 months after completing treatment, and four in the ethambutol group at 6, 7, 22, and 32 months. Six of the seven isolates were tested for drug resistance, and all remained susceptible to isoniazid and rifampicin, Dr. Conde and his associates wrote.

No drug previously has been shown to substantially enhance the activity of the isoniazid/rifampicin/pyrazinamide combination, noted Dr. Hans L. Rieder in an accompanying editorial. “The trial’s finding that culture conversion to negative occurred in 80% of patients in the moxifloxacin group, compared with 63% in the control group is, therefore, surprisingly large,” said Dr. Rieder of the tuberculosis department, International Union Against Tuberculosis and Lung Disease, Kirchlindach, Switzerland.

Fourth-generation fluoroquinolones appear to have similar bactericidal activity to isoniazid – and possibly better sterilizing capability. Thus, moxifloxacin might even improve the efficacy of triple therapy for TB that is multiresistant (resistant to isoniazid plus rifampicin), Dr. Rieder added, as long as it isn’t extensively drug resistant (additionally resistant to the fluoroquinolones and injectable drugs other than streptomycin).

“Perhaps one lesson from this new trial is that there is great potential for treating uncomplicated multidrug resistant tuberculosis with a simple standardized regimen containing a fourth-generation quinolone,” he wrote.

The study was funded by the U.S. Food and Drug Administration Office of Orphan Product Development, with additional support from the U.S. National Institutes of Health. All authors declared that they have no conflicts of interest.

 

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

巴西进行的一项单中心II期试验中发现，将莫西沙星加入常规一线三联治疗方案中8周后，结核培养转阴率的增加接近20%。

与使用乙胺丁醇的对照组病人相比，在使用莫西沙星后仅一周，很多病人的结核杆菌培养已呈阴性。虽然这个发现没有证明莫西沙星能缩短结核总治疗时间，但Marcus B. Conde博士和他的同事在《柳叶刀》杂志上发表文章说，“我们发现莫西沙星从一开始就可以根除大量病菌，改善联合用药方案的灭菌率。我们的资料为此类研究增添了新的证据。”（2009;373:1183-9）

研究中的146名病人均为痰涂片检查结核分枝杆菌阳性，对异烟肼、利福平及异烟酰胺无耐药性。他们接受推荐剂量的异烟肼、利福平及异烟酰胺直接监督疗法，随机分为两组，一组加用400mg莫西沙星+乙胺丁醇安慰剂，另一组则加用15~20mg/kg乙胺丁醇+莫西沙星安慰剂。

莫西沙星组治疗8周后，74个病人中有59例痰涂片呈阴性（79.9%），乙胺丁醇组72个病人中有45例痰涂片阴性（62.5%），相差17.2%。治疗8周后有痰培养资料的病例，莫西沙星组64人中阴性结果为59例（占92.1%），对照组61人中为45例（占73.7%），相差18.4%。（在意向处理分析中，认为所有失访的病例均为治疗失败。）

治疗1周后，莫西沙星组69例中有9例（13%）痰培养呈阴性，而乙胺丁醇组68例中有2例（3%）。纳入研究后每周莫西沙星组病人痰培养转阴率均比乙胺丁醇组高，除了在第6、7周之外其他每次检查结果两组均表现出显著差异。

里约热内卢联邦大学Conde博士和他的同事（包括Conde博士研究所和巴尔地摩约翰霍普金斯大学的研究人员）说，莫西沙星治疗组痰培养持续阴性中位时间为35.0天，而乙胺丁醇对照组为48.5天。

治疗组与对照组之间的不良反应没有差别。每组均有8种严重事件，共出现于12名患者。其中只出现一次3级皮肤反应，被认为与本研究中的药物有关，并且发生于乙胺丁醇组而非莫西沙星组。只有5例病人因为毒性反应中断治疗，两组病人QTc间期均没有发生临床上或统计学显著改变。

Conde博士及其同事在文中提到，7例病人出现复发，其中莫西沙星组3例，分别在完整治疗疗程后第11、16和27个月复发；乙胺丁醇组4例，分别在6、7、22和32个月复发。这7例中的6例进行了药物抵抗性检测，结果显示对异烟肼和利福平仍敏感。

Hans L. Rieder博士在同时发表的编者按中提到，在这之前没有哪种药物可以使异烟肼-利福平-异烟酰胺三联用药的活性有实质性的提高。来自瑞士Kirchlindach国际抗结核病和肺部疾病联合会结核病部的Rieder博士说，“这项研究发现，莫西沙星治疗组80%的病人痰培养转阴，而对照组中转阴率仅为63%，因此，很令人惊讶。”

Rieder博士还说，第四代氟喹诺酮类药物似乎有与异烟肼类似的杀菌活性，也许其灭菌活性更高。因此，只要不是广谱耐药（还对氟喹诺酮类及除链霉素外的注射剂耐药），莫西沙星可以改善对多药耐药（对异烟肼+利福平耐药）结核病三联治疗的疗效。

他还写道，“我们从这项试验中可以学到的一点是，对单纯性多药耐药性结核病可以使用简单的包含第四代喹诺酮类药物的标准化方案进行治疗。”

该研究由美国FDA罕见病治疗药物开发办公室资助，另外还获得美国国立卫生研究院的赞助。所有作者均声明没有利益冲突。

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