非淋球菌性尿道炎：阿奇霉素应退出一线？

布拉格——近期证据提示，有必要重新评估强力霉素和阿奇霉素在沙眼衣原体非淋球菌性尿道炎(NGU)治疗中的角色。

目前美国疾病预防控制中心(CDC)和其他主要医学组织推荐的NGU一线治疗的特点是：阿奇霉素单剂1 g或强力霉素100 mg bid治疗7天。单剂阿奇霉素因更方便而成为了一种流行的选择，可能具有更好的依从性。

沙眼衣原体

但巴黎圣约瑟夫医院皮肤科主任Janier博士在国际抗性传播感染联合会欧洲分会上指出，近期发表的2项重要的“头对头”对比试验在感染性疾病领域掀起了波澜。其中一项研究证明，强力霉素在消除衣原体NGU方面明显比阿奇霉素更有效，另一项研究则显示，强力霉素治疗后45天时沙眼衣原体持续率更低。

一项研究为Ⅱ期随机双盲试验，从美国4家性传播疾病医院招募了305例男性NGU患者，其中43%为沙眼衣原体NGU，31%为生殖支原体NGU。这些受试者被随机分组，接受指南推荐的阿奇霉素或强力霉素单药治疗，或加用替硝唑单剂2 g，以检验加用这种二线药物是否能提高治愈率。

在沙眼衣原体NGU患者中，强力霉素组的衣原体清除率为94.8%，而阿奇霉素组仅为77.4%。

但在生殖支原体NGU患者中，阿奇霉素的表现则明显优于强力霉素，支原体清除率分别为66.7%和30.8%(Clin. Infect. Dis. 2011;52:163-70)。

同一组研究者近期还分析了治疗后NGU持续率的数据，这些数据来自一项纳入293例异性恋NGU男性患者的研究。在129例沙眼衣原体NGU患者中，治疗后4周时通过核酸扩增检查发现，阿奇霉素组23%的患者仍有沙眼衣原体感染，而这一比例在强力霉素组仅为5%(J. Infect. Dis. 2012;206:357-65)。

阿奇霉素对衣原体NGU的治疗失败率之所以高于强力霉素，可能主要有两大原因：病原体对单剂抗菌药物的同型耐药性，来自在更大病原体负荷下生长率降低的细胞亚群的异位耐药性。

Janier博士还补充道，一方面虽然不必对同一组研究者开展的这两项研究反应过度，另一方面的确有不少感染病专家在考虑是否应当让阿奇霉素退出一线治疗。

这位皮肤病专家还引述了近期另一项关于不复杂沙眼衣原体NGU治疗的研究。这项随机双盲双对照的多中心试验招募了323例泌尿生殖衣原体感染的男性和非妊娠女性患者。这些受试者被随机分组，接受为期7天的缓释强力霉素(Doryx)200 mg每日1次治疗，或标准释放强力霉素(Vibramycin)100 mg bid治疗。

在主要终点方面，通过核酸扩增检测发现，缓释强力霉素组有95.5%的患者在第28天时达到微生物治愈，标准释放强力霉素组为95.2%。然而，缓释剂型的耐受性明显更佳，恶心率为仅13%，远低于标准释放剂型的21%，两组的呕吐率分别为8%和12%(Clin. Infect. Dis. 2012; 55: 82-8)。

Janier博士报告称无相关利益冲突。

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By: BRUCE JANCIN, Internal Medicine News Digital Network

PRAGUE – Recent evidence dictates the need to reassess the roles of doxycycline and azithromycin in treating Chlamydia trachomatis nongonococcal urethritis, according to Dr. Michel Janier.

Current first-line therapy for nongonococcal urethritis (NGU), as recommended by the Centers for Disease Control and Prevention and other major groups, features a choice: a single 1-g dose of azithromycin, or doxycycline at 100 mg b.i.d. for 7 days. Single-dose azithromycin is a popular option, given its convenience and likely better adherence.

But a couple of important head-to-head comparative trials published recently are making waves in the infectious disease world. Doxycycline proved significantly more effective than azithromycin in clearing chlamydial NGU in one study and had a markedly lower C. trachomatis persistence rate 45 days post treatment in the other, said Dr. Janier, head of dermatology at Saint Joseph Hospital in Paris and the French representative to the International Union Against Sexually Transmitted Infections–Europe.

One study was a phase IIb randomized, double-blind trial involving 305 men with NGU at sexually transmitted disease clinics in four U.S. cities. They were assigned to guideline-recommended treatment with either azithromycin or doxycycline alone or with a single 2-g dose of tinidazole, an antitrichomonal agent, in order to test the hypothesis that adding the second agent would boost cure rates. As it turned out, it did not.

Among the 43% of men with C. trachomatis NGU, the chlamydial clearance rate was 94.8% in the doxycycline arm compared with 77.4% with azithromycin.

While doxycycline outperformed azithromycin in men with C. trachomatis NGU, the converse was true among the 31% of participants with Mycoplasma genitalium NGU. The clearance rate was 30.8% in the doxycycline arm compared with 66.7% in the azithromycin arm (Clin. Infect. Dis. 2011;52:163-70).

The same group of investigators recently analyzed data on post-treatment persistence of NGU in a study involving 293 heterosexual men treated for NGU at STD clinics. Among the 129 men with C. trachomatis NGU, persistent C. trachomatis infection was detected via nucleic acid amplification testing 4 weeks post treatment in 23% of those who received azithromycin compared with just 5% treated with doxycycline (J. Infect. Dis. 2012;206:357-65).

The explanation for the observed higher failure rate with azithromycin compared with doxycycline in treating chlamydial NGU is probably twofold: homotypic resistance of the organism to a single dose of a bacteriostatic antibiotic, coupled with heterotopic resistance stemming from a persistent subpopulation of cells having a reduced growth rate within the larger pathogen load, Dr. Janier said.

He added that while it’s important not to overreact to a couple of studies carried out by a single group, there is intense interest on the part of many infectious disease experts in taking a closer look at the possibility that azithromycin may need to be dethroned as first-line therapy.

The dermatologist also highlighted another recent study that bears on the treatment of uncomplicated C. trachomatis NGU. The double-blind, randomized, double-dummy multicenter trial included 323 men and nonpregnant women with urogenital chlamydia. They were randomized to 7 days of once-daily delayed-release doxycycline (Doryx) at 200 mg or to 100 mg b.i.d. of standard-release doxycycline (Vibramycin).

The primary outcome, microbial cure by nucleic acid amplification testing on day 28, occurred in 95.5% of the delayed-release doxycycline group and a virtually identical 95.2% on Vibramycin. However, the delayed-release formulation was significantly better tolerated, with a 13% nausea rate compared with 21% in the Vibramycin group. Vomiting occurred in 8% of patients on delayed-release doxycycline, a significantly lower rate than the 12% with Vibramycin.

The investigators concluded that delayed-release doxycycline, with its once-daily dosing and better tolerability, could improve treatment adherence (Clin. Infect. Dis. 2012; 55: 82-8).

Dr. Janier reported having no relevant financial disclosures.