两种老药新用的二联疗法对淋病有效

维也纳——一项纳入约400例患者的多中心研究显示，2种使用已获准抗生素的泌尿生殖器淋病感染根治方案，有效率几乎达到了100%。目前，淋病奈瑟菌的耐药性使得标准治疗的选项已经只剩下一种——头孢曲松，在此情况下，上述研究结果为这2种联合疗法作为淋病治疗备选方案提供了有力的证据。

美国疾病预防控制中心(CDC)性传播疾病(STD)预防办公室的Robert D. Kirkcaldy博士在国际性传播疾病研究学会(TSSTDR)与国际抗性传播感染联盟(IUASTI)联合会议上指出：“头孢菌素类耐药的出现已使淋病感染的经验性治疗变得更加复杂。”


Robert D. Kirkcaldy博士

他与同事检验的这2种新组合——庆大霉素+阿奇霉素(Zithromax)和吉米沙星(Factive)+阿奇霉素——“可能对头孢曲松治疗不成功的患者或头孢菌素类过敏的患者是有用的，但这2种新组合都算不上完美无缺，消化道副作用可能会限制其常规使用”。

这项研究从5家美国医院招募了年龄15~60岁、未经过治疗的单纯性泌尿生殖器淋病患者。完成该研究的401例患者的平均年龄为28岁。大约1/3的患者为男同性恋，略多于一半为男异性恋，大约10%为女性。近10%的患者为HIV阳性。这些患者接受240 mg庆大霉素2个部位肌内注射(体重≤45 kg者的用量酌减)，或者单次口服320 mg庆大霉素。所有患者还口服了2 g阿奇霉素。

这项研究的主要疗效终点是成功接受治疗并且返院接受随访微生物检查证实根除的患者所占比例。结果202例接受庆大霉素+阿奇霉素治疗的患者全部达到该终点，199例接受吉米沙星+阿奇霉素治疗的患者有198例(99.5%)达到该终点。少数患者除了泌尿生殖器感染之外还有直肠或咽部淋球菌感染。这2种治疗对这些部位的感染均达到了100%的根除率，但由于患者数量过少而无法证实对这些部位感染的疗效。

在接受庆大霉素+阿奇霉素和gemifloxicin+阿奇霉素治疗的患者中，分别有47%和55%发生了消化道不良反应。但是Kirkcaldy博士强调，所有这些不良反应均为轻至中度，没有发生1例严重不良反应，而且绝大多数患者在服药后至少能坚持1 h：在服用庆大霉素的患者和服用吉米沙星的患者中，分别有3%和8%在服药后1 h内发生呕吐，被排除在主要疗效分析之外。

CDC-STD预防办公室主任Gail Bolan博士在书面声明中写道：“这些试验结果是我们在对抗耐药淋病的战役中朝着正确方向迈出的重要一步，但是患者仍需要不良反应更少的更多口服治疗选择。”

2012年8月份，CDC的一个专家组发布了所有类型单纯性淋球菌感染(包括肛门直肠、咽部和泌尿生殖器感染)治疗的最新推荐意见。CDC推荐单次肌内注射头孢曲松(Rocephin)伴单次口服阿奇霉素，或者每日2次doxycycline治疗7天(MMWR 2012;61:590-4 )。

之所以提出这一推荐意见，是因为美国的头孢克肟(Suprax)耐药淋球菌感染日益增多，而该药是目前淋病治疗的支柱。CDC也在考虑从头孢克肟转向头孢曲松，声称患者可能很快就会面临头孢曲松耐药淋病的威胁。

“头孢曲松成为了唯一的一线治疗选择。抗菌药物的研发通道青黄不接，而淋病奈瑟菌的耐药性却在日渐增强。我们希望改变已获准药物的用法，将其用于头孢曲松治疗失败后的挽救治疗，以及用于头孢菌素类过敏的患者。”

庆大霉素是一种主要用于心内膜炎住院患者的药物，研究者之所以选择该药是因为它对淋病有一定疗效(大约91.5%)、单次用药对于其他方面健康的男女性的毒性风险较低，而且在美国容易获得。之所以选择吉米沙星，是因为它是一种已获准的口服药物，在体外对环丙沙星耐药性淋病奈瑟菌有活性。之所以添加阿奇霉素，是因为它对淋病有治疗作用，尽管近期的根除率达到97%~99%，但目前该药被认为不宜用于单药治疗。

Kirkcaldy博士指出，CDC将于明年制订新版STD治疗指南，届时将会参考上述新数据。

这项研究由美国国立过敏与感染性疾病研究所资助。Kirkcaldy博士声称无相关利益冲突。

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By: MITCHEL L. ZOLER, Ob.Gyn. News Digital Network

VIENNA – Two combination regimens using antibiotics already approved for U.S. use eradicated urogenital gonorrhea infections with virtually 100% efficacy in a multicenter U.S. study with about 400 patients, providing solid evidence for the potential of both combinations as backup treatments for Neisseria gonorrhoeae at a time when resistance in the pathogen has whittled standard treatment options down to one primary drug, ceftriaxone.

"The emergence of cephalosporin resistance complicates empiric treatment" of gonorrhea infections, Dr. Robert D. Kirkcaldy said at the joint meeting of the International Society for Sexually Transmitted Diseases Research and the International Union Against Sexually Transmitted Infections.
 
The two new combinations he and his associates tested – gentamicin plus azithromycin (Zithromax) and gemifloxicin (Factive) plus azithromycin – "may be useful for patients unsuccessfully treated with ceftriaxone or patients with a cephalosporin allergy, but neither [of the two new combinations] is a magic bullet," said Dr. Kirkcaldy, a medical epidemiologist in the division of STD prevention at the Centers for Disease Control and Prevention. "The gastrointestinal side effects [seen with both new regimens] may limit their routine use."

Gastrointestinal adverse effects occurred in 47% of the patients who received gentamicin plus azithromycin and in 55% of those who got gemifloxacin plus azithromycin. But Dr. Kirkcaldy highlighted that all of these effects were mild to moderate, none was serious, and the vast majority of patients were able to hold the oral drugs they received for more than an hour; 3% of the gentamicin recipients and 8% of the gemifloxacin recipients vomited within an hour of receiving treatment and were excluded from the primary efficacy analysis as a result.

"These trial results are an exciting step in the right direction in the fight against drug-resistant gonorrhea, but patients need more oral options with fewer side effects," Dr. Gail Bolan, director of the CDC’s division of STD prevention, commented in a written statement.

Less than a year ago, in August 2012, a panel of CDC staffers and outside experts released updated recommendations for treating all types of uncomplicated gonococcal infections, including anorectal, pharyngeal, and urogenital infections. The CDC recommended a single intramuscular injection of ceftriaxone (Rocephin) along with a single oral dose of azithromycin or a 7-day course of doxycycline given b.i.d. (MMWR 2012;61:590-4).

This recommendation came about because of an increasing U.S. incidence of gonococcal infections by strains resistant to cefixime (Suprax), the prior mainstay of treatment. The need to move from cefixime to ceftriaxone also concerned the CDC. The agency projects that patients may soon also face ceftriaxone-resistant gonorrhea.

"Ceftriaxone became the one remaining first-line option. The antimicrobial pipeline is running dry, and N. gonorrhoeae continues to acquire resistance. We wanted to repurpose approved drugs that could be used for salvage treatment on cetriaxone failures and for patients allergic to cephalosporins," Dr. Kirkcaldy said.

The study enrolled patients aged 15-60 years who presented at any one of five participating U.S. medical centers with uncomplicated, untreated urogenital gonorrhea. The 401 patients who completed the study averaged about 28 years of age. About a third were men who have sex with men, slightly more than half were men who have sex with women, and about 10% were women. Just under 10% were HIV positive. Patients received either 240 mg gentamicin as an intramuscular injection at two separate sites (with the dosage adjusted downward for patients weighing 45 kg or less) or a single, 320-mg oral dose of gemifloxacin. All patients also received a 2-g oral dose of azithromycin.

Gentamicin, a drug primarily used for hospitalized patients with endocarditis, was chosen because of its known, modest (about 91.5%) efficacy for gonorrhea, low risk of toxicity with a single dose in otherwise healthy men and women, and its U.S. availability, Dr. Kirkcaldy said. Gemifloxacin was selected because it’s an oral drug approved for sale in the United States that’s been shown to be active in vitro against ciprofloxacin-resistant strains of N. gonorrhoeae. Azithromycin was added because of its known activity against gonorrhea, although with recent eradication rates of 97%-99%, it is now deemed too unreliable for monotherapy.

The study's primary efficacy endpoint was the percentage of patients who successfully received treatment and returned for a follow-up microbiologic test of eradication. This happened in all 202 patients treated with gentamicin plus azithromycin, and in 198 of the 199 (99.5%) treated with gemifloxacin plus azithromycin. A small percentage of the patients enrolled also had rectal or pharyngeal gonococcal infections in addition to their urogenital infection. Both treatments were 100% effective at eradicating infections at those sites, but the numbers were too small to conclusively prove efficacy for these sites, he said.

These new data will be considered as the CDC develops its next revision of the U.S. STD treatment guidelines, due out next year, Dr. Kirkcaldy said.

The study was sponsored by the National Institute of Allergy and Infectious Diseases. Dr. Kirkcaldy said he had no relevant financial disclosures.